JP2906146B2 - Transdermal composition - Google Patents

Description

The present invention relates to a composition for transdermal administration of a drug. For more information, see the equation Wherein R represents an unsubstituted unsaturated aliphatic hydrocarbon group. The present invention relates to a transdermal composition containing an N-substituted morpholine represented by the formula:

An object of the present invention is to provide a transdermal composition containing an excellent transdermal absorption enhancer.

[Prior Art] Generally, systemic administration of a drug is performed orally or by injection. On the other hand, for example, drugs such as non-steroidal anti-inflammatory drugs have side effects such as gastrointestinal disorders, and it is therefore desirable to switch to local therapy as the symptoms alleviate.

In addition, topical therapy is considered to be appropriate for patients with mild or limited affected areas, and studies on percutaneous absorption enhancers of drugs have been conducted.

Conventionally, N-alkylmorpholines described in JP-A-62-87528 and JP-A-62-230710 are known as transdermal absorption enhancers.

[Problems to be Solved by the Invention] However, N-alkylmorpholine as a percutaneous absorption enhancer described in these publications has not yet had a sufficient percutaneous absorption promotion effect, and is more excellent in percutaneous absorption. There was a need for the development of accelerators.

[Means for Solving the Problems] Under such circumstances, the present inventors have conducted intensive studies and as a result, have found that the N-substituted morpholine represented by the formula [I] achieves the above object, and completed the present invention. I came to.

Hereinafter, the formula [I] used in the transdermal composition of the present invention will be described.
Will be described in detail.

Examples of the unsaturated aliphatic hydrocarbon group for R include alkenyl, alkadienyl, and alkatrienyl groups. Specifically, these groups include a palmitoleyl group, an oleyl group, a linoleyl group, a linolenyl group,
A ricinoleyl group;

Next, a method for producing the compound of the formula [I] used in the transdermal composition of the present invention will be described.

The N-substituted morpholine represented by the formula [I] can be produced according to a known method or a method analogous thereto, and for example, can be produced by the following production steps.

(In the formula, X represents a halogen atom such as chlorine, bromine or iodine, and R has the same meaning as described above.) This reaction is carried out by the usual substitution reaction between a halogenated unsaturated aliphatic hydrocarbon and an amine. The same can be done.

(In the formula, R ¹ is an unsubstituted unsaturated aliphatic hydrocarbon group; R has the same meaning as described above.) This reaction is performed, for example, by using lithium aluminum hydride, sodium borohydride, or the like. The reaction can be carried out by subjecting it to a usual reduction reaction of carbonyl used.

The N-substituted morpholine represented by the formula [I] can be used as a transdermal absorption enhancer, and these transdermal absorption enhancers may be used alone or in combination of two or more. May be used.

Of the unsubstituted unsaturated aliphatic hydrocarbon groups for R, preferred are unsubstituted unsaturated aliphatic hydrocarbon groups having 16 to 20 carbon atoms, and particularly preferred are substituted And an unsaturated aliphatic hydrocarbon group having 18 carbon atoms, especially an oleyl group.

The amount of the N-substituted morpholine used may be an amount having substantially no local irritation or allergic effect, and is generally 0.1 to 80% by weight based on the total weight of the preparation, preferably 0.5 to 50% by weight.

As the drug used in the transdermal administration composition of the present invention,
For example, nonsteroidal anti-inflammatory agents such as piroxicam, ketoprofen, indomethacin, ibuprofen, ibufenac, alclofenac, diclofenac, mefenamic acid, flurbiprofen and flufenamic acid; benzodiazepines such as diazepam, nitrazepam, lorazepam, fludiazepam and clonazepam.
Thiazides such as bendroflumethiazide, polythiazide, methyclothiazide, trichlormethiazide, cyclopentiazide, benzylhydrochlorothiazide, hydrochlorothiazide and diuretics such as bumetanide; antihypertensives such as clonidine; diphenhydramine, carbinoxamine and Ethanolamines such as diphenylpyralin, ethylenediamines such as fenbenzamine and monoamine antihistamines such as chlorpheniramine; antitumor agents such as 5-fluorouracil, tegafur, cytarabine and fluoxuridine; cortisone, hydrocortisone, prednisolone, prezonisone, Steroid anti-inflammatory drugs such as triamcinolone, dexamethasone and betamethasone; anti-inflammatory drugs such as ethosuximide Antiarrhythmic agents such as azimarin, brazimarin, pindolol, propranolol and quinidine; antipsychotics such as clofluverol, trifluberidol, haloperidol and moperone; scopolamines such as methylscopolamine and butylscopolamine; metoclopramide; chlorpromazine; methylatropine Atropine such as bromide and methyl anisotropine bromide; vasodilators such as isosorbide dinitrate, nitroglycerin, pentaerythritol tetranitrate, propanyl nitrate and dipyridamole; tetracyclines such as tetracycline, oxytetracycline, metacycline, doxycycline and minocycline; Antibiotics such as chloramphenicol and erythromycin ; And LH-RH
And peptides such as insulin.
In addition, these drugs may form a pharmaceutically acceptable salt, if necessary.

The amount of the drug used can be appropriately selected depending on the type of the drug, the patient's age, weight, symptoms, and the like, and is sufficient as long as the desired effective pharmacological effect can be achieved. It is 0.01 to 50% by weight, preferably 0.05 to 10% by weight, based on the total amount of the base composition containing the substituted morpholine.

The dose and frequency of administration of the transdermal administration composition of the present invention are as follows:
It can be appropriately selected according to the patient's age, body weight and symptoms, and the amount of the drug, 0.001 mg to 500 mg, may be applied to the affected part once to several times a day.

As the pharmaceutical preparation of the composition for transdermal administration of the present invention, a liquid preparation;
Ointments such as paste-containing creams and gels; lotions, plasters and cataplasms, which are administered as a pharmaceutical preparation to the outer skin. Further, known pharmaceutically acceptable components may be added to these pharmaceutical preparations.

Next, a method for producing a pharmaceutical preparation of the transdermal composition of the present invention will be described.

The pharmaceutical preparation of the composition for transdermal administration of the present invention can be prepared by adding a new preparation development system comprehensive technical base additive (R & D planning: 198).
5 years) and the development of transdermal and transmucosal absorption preparations and the practice of new tests, experiments, and evaluation methods-Comprehensive technical materials-(published by Techno Eye Publishing Division: 1986).

A liquid preparation can be produced by dissolving the transdermal composition of the present invention in a conventional solvent such as ethanol, propylene glycol or glycerin, and further preparing the obtained liquid preparation, for example, by using gauze or a porous membrane. Absorbent may be impregnated.

Ointments, gels or creams can be prepared by adding the usual ingredients such as carboxyvinyl polymer, polyethylene glycol and hydroxypropylcellulose to the transdermal composition of the present invention.

Further, the plaster or cataplasm is a transdermal composition of the present invention and a conventional adhesive such as a combination of an elastic body and a tackifier, an acrylate copolymer or a crosslinked product of polyacrylic acid. It can be manufactured using a base, applied to paper such as release paper, dried, spread on a double-stretched nylon film or the like, and used for use.

Next, the transdermal absorption effect of the pharmaceutical preparation of the representative composition of the present invention will be described.

1. Percutaneous absorption test Animal test method: One day before administration of the drug, rats whose backs were depilated with a hair clipper and a depilatory cream (trade name: Evaclaim S: manufactured by Tokyo Tanabe Seiyaku) (Wistar strain; male, 200 to 220 g; 1 group) A preparation containing various N-substituted morpholines and a control preparation containing no N-substituted morpholine were applied or applied to 10 cm ² (3.16 cm × 3.16 cm) of the back of 3 animals. After administration, 2
Blood was collected every hour and serum was separated. The blood concentration of the drug was measured using high performance liquid chromatography (HPLC), and the area under the blood concentration-time curve (AUC ₆ ) and the maximum blood concentration (C _max ) up to 6 hours after administration were determined.

 The results are shown in Tables 1 to 5.

The liquid was 0.1 g (0.15 mg as piroxicam or 0.3 mg as ketoprofen); the ointment was 0.1 g (0.4 mg as piroxicam); and the plaster was 1.0 mg of piroxicam.

The percentages used in Tables 1 to 5 are weight percentages unless otherwise specified.

In addition, the following abbreviations used in the tables have the following meanings:

PXM: piroxicam KP: ketoprofen Also, in Tables 1 to 5, (AUC ₆ ratio and C
_max ratio) was calculated based on the following equation.

As is clear from Tables 1 to 5, the transdermal composition of the present invention has an excellent transdermal absorption effect.

[Effect of the Invention] The transdermal administration composition of the present invention can be used as a transdermal absorption enhancer for drugs.

[Example] Next, a method for producing the N-substituted morpholine of the formula [I] will be specifically described with reference to a reference example.

Unless otherwise specified, silica gel [Kieselgen 60, art.7734 (Kieselgel 60, Art.7734)] manufactured by Merck was used as the carrier in the column chromatography.

The mixing ratio in the elution solvent is a volume ratio unless otherwise specified.

Reference Example 1 Synthesis of N-oleylmorpholine 6.59 g of oleyl chloride was converted to N, N-dimethylformamide
After dissolving in 30 ml, morpholine 2.00 g, potassium carbonate
3.17 g and 3.44 g of sodium iodide are added and stirred at room temperature for 7 days. Then, 150 ml of ethyl acetate and 100 ml of water are added to the reaction solution, the upper layer is separated, washed with water and saturated saline in this order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (elution solvent: benzene: ethyl acetate =
Purification by 1: 0 to 2: 1) gives 4.24 g (54.7%) of N-oleylmorpholine as a colorless oil.

^{IR (KBr) cm -1; 2980} (sh), 2910,2840,2780, 1640,1450,1345,1290,1260,1135 (sh), 1110, 1060,905,860,710 NMR (CDCl 3) δ value: 0.68 to 2.64 (37H, m), 3.64 to 3.94 (4H, m), 5.47 (2H, t, J = 4.5 Hz) Reference Example 2 N-palmitrail morpholine 1.34 g of lithium aluminum hydride was added to 120 ml of anhydrous tetrahydrofuran under ice cooling. Add slowly. Then, a solution of N-palmitoleoyl morpholine (5.70 g) in anhydrous tetrahydrofuran (10 ml) was added dropwise thereto over 10 minutes.
This is refluxed for 1 hour. Then, the reaction mixture is cooled, 5 ml of a saturated aqueous solution of sodium sulfate are added dropwise at 10 to 20 ° C., and the insoluble matter is removed. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (elution solvent;
Purification with toluene: ethyl acetate = 1: 0 to 2: 1) gives 3.97 g (61.6%) of colorless oily N-palmitrail morpholine
Get.

^{IR (KBr) cm -1; 2980,2920,2850,2780,1450} , 1350,1290,1260,1135 (sh), 1115,1065,1000, 905,860,720 NMR (CDCl 3) δ value; 0.68~2.64 (33H, m), 3.60-3.86 (4H, m), 5.46 (2H, t, J = 4.5 Hz) Similarly, the following compound is obtained.

N-linoleylmorpholine colorless oil IR (KBr) cm ^-1 ; 2980,2920,2850,2780,1445,1390,1350,1290,1260,1130 (sh), 1115,1065,1000,910,860,710 NMR (CDCl ₃ ) δ value: 0.62 to 2.64 (31H, m), 2.64 to 3.00 (2H, m), 3.62 to 3.92 (4H, m), 5.26 to 5.68 (4H, m) N-linolenylmorpholine Colorless oil ^{IR (KBr) cm -1; 3000,2920,2850,2790,1440} , 1390,1350,1270,1140 (sh), 1120,1060,1000, 910,865,710 NMR (CDCl 3) δ value; 0.66~2.64 (25H, m), 2.64 to 3.08 (4H, m), 3.64 to 3.94 (4H, m), 5.26 to 5.68 (6H, m) ◎ N-ricinoleylmorpholine colorless oil IR (KBr) cm ^-1 ; 3400,2980 (sh), 2920,2850, 2790,1450,1350,1290,1265,1110,1060,1030, 1000,910,860,720 NMR (CDCl 3) δ value; 0.68~2.64 (35H, m), 1.94 (1H, s) , 3.56 to 3.92 (5H, m), 5.22 to 5.96 (2H, m) Next, the present invention will be specifically described with reference to formulation examples, but the present invention is not limited to only the following formulation examples. Absent.

Formulation Example 1 Piroxicam 167 mg was dissolved in ethanol: propylene glycol mixed solution (1: 1) 99.83 g, and the content of piroxicam was
A 0.167% solution is obtained.

N-Oleylmorpholine (100 mg) was dissolved in this piroxicam solution (900 mg) to give a piroxicam content of 0.15% and N
Obtaining a solution with an oleylmorpholine content of 10%.

Formulation Examples 2 to 3 The liquid preparations were prepared in the same manner as in Formulation Example 1 except that N-oleylmorpholine in Formulation Example 1 was replaced with N-linoleylmorpholine and N-linolenylmorpholine.
~ 3.

Formulation Example 4 Piroxicam 158 mg was dissolved in 99.84 g of a mixture of ethanol and propylene glycol (1: 1), and the content of piroxicam was determined.
A 0.158% solution is obtained.

50 mg of N-oleyl morpholine was dissolved in 950 mg of this piroxicam solution to give a piroxicam content of 0.15% and N-
A solution with an oleyl morpholine content of 5% is obtained.

Formulation Example 5 188 mg of piroxicam was dissolved in 99.81 g of a mixture of ethanol and propylene glycol (1: 1), and the content of piroxicam was determined.
A 0.188% solution is obtained.

200 mg of N-oleyl morpholine was dissolved in 800 mg of this piroxicam solution to give a piroxicam content of 0.15% and N
Obtaining a solution with a oleyl morpholine content of 20%.

Formulation Example 6 piroxicam 15 mg, N-oleylmorpholine 300 mg,
Styrene-isoprene-styrene block copolymer (trade name; Calflex TR1107: manufactured by Ciel Chemical Co., Ltd.) 592.5 mg
And 592.5 mg of a terpene resin (trade name: YS Resin Px800: manufactured by Yasuhara Yushi Kogyo KK) is stirred and dissolved in 8 ml of toluene to obtain a piroxicam solution.

An amount of 14 mg of the piroxicam solution corresponding to piroxicam is applied to 140 cm ² of release paper, dried, and spread on a biaxially stretched nylon film to obtain a plaster having a piroxicam content of 1 mg / 10 cm ² .

Formulation Example 7 N-oleylmorpholine (22.2 mg), propylene glycol (50 mg) and ethanol (125 mg) were added to 1 g of piroxicam ointment (trade name: Baxo ointment; manufactured by Toyama Chemical Co., Ltd.), and the mixture was uniformly mixed to give a piroxicam content of 0.4% and N-oleyl. A piroxicam ointment with a morpholine content of 1.85% is obtained.

Formulation Example 8 33 mg of ketoprofen is dissolved in 9.967 g of propylene glycol to obtain a solution having a ketoprofen content of 0.33%.

100 mg of N-oleylmorpholine is dissolved in 900 mg of this solution to obtain a liquid preparation having a ketoprofen content of 0.3% and an N-oleylmorpholine content of 10%.

 The control test preparation is produced as follows.

Control PXM solution To 900 mg of the piroxicam content of 0.167% in Formulation Example 1 was added 100 mg of a mixture of ethanol and propylene glycol (1: 1) and uniformly dissolved to obtain a solution having a piroxicam content of 0.15%.

Control PXM Plaster Agent A piroxicam plaster agent containing no N-oleylmorpholine is obtained in the same manner as in Preparation Example 6.

Control PXM ointment piroxicam ointment (trade name; baxo ointment: Toyama Chemical Co., Ltd.) (1 g) was added with propylene glycol (50 mg) and ethanol (125 mg), mixed uniformly, and piroxicam content was 0.4.
% Ointment.

Control KP solution 100 mg of propylene glycol was added to 900 mg of the solution of Formulation Example 8 having a ketoprofen content of 0.33%, and uniformly dissolved.
A solution with a ketoprofen content of 0.3% is obtained.

Continuation of the front page (56) References JP-A-62-287528 (JP, A) JP-A-1-268648 (JP, A) JP-A-3-504861 (JP, A) JP-A-3-500287 (JP) , A) (58) Field surveyed (Int. Cl. ⁶ , DB name) A61K 47/22, 9/00

Claims (6)

(57) [Claims] (1) Expression A transdermal administration composition comprising an N-substituted morpholine represented by the formula: wherein R represents an unsubstituted unsaturated aliphatic hydrocarbon group. 2. The composition for transdermal administration according to claim 1, wherein R is an unsubstituted unsaturated aliphatic hydrocarbon group having 16 to 20 carbon atoms. 3. The composition for transdermal administration according to claim 1, wherein R is an unsubstituted unsaturated aliphatic hydrocarbon group having 18 carbon atoms. 4. The method according to claim 3, wherein the unsubstituted unsaturated aliphatic hydrocarbon group having 18 carbon atoms is an oleyl group.
The composition for transdermal administration according to Item. 5. The transdermal composition according to claim 1, wherein the drug is a non-steroidal anti-inflammatory drug. 6. The composition for transdermal administration according to claim 5, wherein the nonsteroidal anti-inflammatory agent is piroxicam.