JPS6287528A - N-alkylmorpholine-containing composition for exodermis administration - Google Patents

Abstract

PURPOSE:The titled composition useful as a base for exodermis administration preparation, raising synergistically permeability of physiological activator and endermic absorption, containing an N-alkylmorpholine and a polar compound. CONSTITUTION:A composition for exodermis administration containing an N-alkylmorpholine shown by the formula I (R is 7-14C alkyl) and a polar compound. Thioglycerol, lactic acid, its ester and a cyclic urea shown by the formula II (R1 and R2 are H or 1-4C lower alkyl) are preferable as the polar compound. The amount of the compound shown by the formula I blended is preferably 0.5-50wt% based on total amounts of the compound shown by the formula I and the polar compound. The compound shown by the formula I attains adjuvant function and the polar compound acts as a solvent to raise solvation of adjuvant and promotes synergistically endermic absorption of activator. Blend of the titled composition with an activator gives an external preparation having improved absorption properties of the activator.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a method for promoting transdermal absorption of a physiologically active agent (hereinafter sometimes abbreviated as "active agent").

[Conventional technology]

Active agents are typically administered to the skin or mucosal tissues to treat localized areas, and systemic administration of active agents is generally carried out orally or by injection.

On the other hand, attempts have recently been made to achieve systemic administration of active agents by local application to the skin or mucosal IJ1 tissues. Such localized means of systemic administration has the advantage that desired blood concentrations can be easily achieved and the intercostal area of treatment can be easily controlled and maintained. That is, side effects caused by excessive administration of the active agent can be prevented. Also, avoidance of primary metabolism in the liver, which is characteristic of certain drugs when administered orally, and gastrointestinal disturbances, such as those seen with oral administration of indomethacin, can also be eliminated.

However, for most therapeutic agents, normal skin is relatively impermeable and the desired blood levels of therapeutic agents cannot be achieved by transdermal absorption; therefore, transdermal absorption of therapeutic agents is limited to adjuvant or osmotic It has been devised to increase this by using accelerators.

One of the best known such osmotic adjuvants is dimethyl sulfoxide, whose use is described in U.S. Pat.
, 551.554 [Hersc.
hlor et al.].

This patent cites the use of dimethyl sulfoxide as a systemic adjuvant for psychopharmacological agents such as henzodiazepine derivatives.

British Patent No. 1.504,302 [Blue Car (
Brooker et al.] deal with sedation methods and compositions, and apply aromatic hydrocarbons, paraffins, halogenated aliphatic hydrocarbons, ketones, esters, ethers, 2-8 carbons, etc. to the skin of non-human animals. Discloses the administration of sedatives by applying sedative compounds of the world that exhibit their effect on a base consisting of one or more of the following osmotic adjuvants, such as alcohols, amides, dimethylacetamide or sulfones having atoms. ing. Bruker et al. indicate that one or more of the above liquid agents can be used in combination, but they only exemplify carbon tetrachloride as the halogenated aliphatic hydrocarbon and dimethylformamide as the amide.

JP-A-52-148614 discloses that sulfone, a by-product of petroleum refining, is used as a solvent or drug penetration enhancer to enhance the efficacy of drugs for skin diseases, although there are no explanations of the substance or experimental results showing its effects. ing.

U.S. Patent No. 4,202,888 [Enocart (
Eekert et al.] disclose absorbable pharmaceutical compositions consisting of at least one cardiotonic glycoside distributed in a vehicle consisting of at least some glyceride fatty acids of medium chain length that promote absorption.

U.S. Patent No. 3,472.931 (Stoughton (
Regarding transdermal absorption using lower alkyl amides, Stoughton) exemplifies two-component systems consisting of dimethylacetamide and ethanol, dimethylacetamide and isopropyl alcohol, and dimethylacetamide and isopropyl palmitate. Stoughton does not illustrate or disclose the combination of high molecular weight alcohols and dimethylacetamide. Stoughton suggests in column 5 that emollients, which generally include lanolin alcohols and fatty alcohols, increase transdermal absorption and retention and improve softening and moisturizing effects. The principal transdermal components used in Stoughton's system are amides, including N,N-dimethylacetamide.

U.S. Patent No. 3,969,516 (Stoughton)
discloses compositions and methods for treating acne comprising about 0.1 to 10% lincomycin class of antibiotics. Stoughton lists substantial numbers of additional ingredients that can be used in such formulations, including stearyl alcohol.
For example, preferred ingredients include ingredients that enhance percutaneous absorption, such as alcohol, 2-pyrrolidone, and 2-g-N-lower alkylpyrrolidone. In Example 2, a formulation is prepared including, inter alia, N-methyl-2-pyrrolidone and stearyl alcohol. Stearyl alcohol is solid at about 37°C as Cl1
1 alcohol.

U.S. Pat. No. 3,989,816 [Rajadhyaksha] +j Consists of an effective, non-toxic star of certain 1-substituted-azacyclohebutan-2-ones, which protects body membranes such as the skin. Discloses a method of delivering a physiologically active agent through the molecule. Rajad Hyakusoya's formulation is broad enough to include, for example, methylcaprolactam (not exemplified).

An inert carrier can be used in the composition of rajadhyam. In Example 3, isopropyl myristate was used, in Example 5 stearyl alcohol (a C1 alcohol with a melting point of 59°C), and in Examples 8 and 11, cetyl alcohol (and a melting point of 49°C) was used. C 17 alcohol) is used.

U.S. Pat. No. 4,017,641 (DiGiulic) has about 10 to 20 carbon atoms.
2-pyrrolidone-containing skin moisturizing compositions are disclosed in which a suitable oil or wax containing three aliphatic linear fatty acids and their alcohols may be used. However, this patent does not disclose transdermal administration of physiologically active agents.

European Patent Application No. 0043738 describes alcohol,
Ingredients such as esters, amides, monoglycerides,
A two-component transdermal preparation containing a diol or diol ether is disclosed.

[Problem that the invention seeks to solve]

The present invention encompasses multicomponent carrier systems for transdermal administration of physiologically active agents that are different from the systems disclosed in the prior art.

In accordance with the present invention, it has been discovered that certain multicomponent carrier systems provide enhanced transdermal absorption of physiologically active agents.

The first object of the present invention is to provide a base composition for external pharmaceutical preparations that increases the permeability of active agents through the skin and percutaneous absorption of active agents, or formulations that promote percutaneous absorption (hereinafter referred to as "base compositions"). (abbreviated)).

A second object of the invention is to provide a pharmaceutical composition for external use which provides good penetration of the active agent through the skin and transdermal absorption of the active agent according to the invention.

A third object of the present invention is to provide a method of increasing the permeability of active agents through the skin and transdermal absorption of active agents using the base compositions of the present invention.

A fourth object of the invention is to provide a base composition that ensures rapid transdermal administration of physiologically active agents in humans or other animals.

A fifth object of the present invention is to provide therapeutic agents for the treatment of humans and other animals in the bloodstream. ;An object of the present invention is to provide such a rapid transdermal administration method.

The sixth object of the present invention is to achieve the following by transdermal administration of a physiologically active agent:
The aim is to provide, at a suitably adjusted rate, a blood concentration with a relatively constant therapeutic effect, which avoids side effects and reduced therapeutic efficacy resulting from drastic fluctuations in blood concentration over time.

[Means for solving the problem] The present invention provides at least one compound selected from N-alkylmorpholines (1) represented by the general formula R (wherein R represents an alkyl group having 7 to 14 carbon atoms). (hereinafter also referred to as component A) and at least one polar compound (hereinafter also referred to as component B).

-a In formula (1), alkyl having 7 to 14 carbon atoms is
Either straight chain or branched chain (such as Lfn-heptyl, n-octyl, n-nonyl, 2-ethylhexyl,
Examples include tetradecyl.

Specific examples of N-alkylmorpholine (1) include N-octylmorpholine, N-decylmorpholine,
Examples include 11-1'decylmorpholine, N-tetradecylmorpholine, and 2-ethylhexylmorpholine.

One or more types of N-alkylmorpholine (1) are used.

A polar compound is further blended into the composition of the present invention. Such polar compounds (component B) are preferably exemplified by the following; fil thioglycerol Any mono-, di-, or trithioglycerol can be used; Examples include thioglycerol.

(2) Lactic acid and its esters Among the esters, lower alkyl esters having 1 to 4 carbon atoms are particularly preferred, and specific examples include lactic acid, methyl lactate,
Examples include ethyl lactate, butyl lactate, and others.

(3) Cyclic urea (n) represented by the general formula (wherein R+ and R2 each represent a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms), preferably a 5- or 6-membered ring, and special examples thereof Examples include ethylene urea, N,N-dimethylethylene urea and the corresponding propylene urea, among others.

(4) General formula [In the formula, R3-Rh is each a hydrogen atom, and (having 1 to 4 carbon atoms)
Compounds (I[
[) Specific examples thereof include urea, N-methylurea, N-ethylurea, N-butylurea, 1,1-dimethylurea, 1.
3-dimethylurea, 1,1,3.3-tetramethylurea, 1.1-diethylurea, 1,3-diethylurea, N-
Examples include acetyl-No-methylurea, nitrourea, and others.

(5) General formula [wherein R1 represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms (methyl, ethyl, n-propyl, iso-propyl, etc.), and n represents an integer of 3 to 5] Specific examples of the represented pyrrolidone compound (rV) include 2-pyrrolidone, N-methylpyrrolidone, N-methylpiperidone, caprolactam, N-methylcaprolactam, and others.

(6) General formula [wherein R8, R9 and R16 are each a hydrogen atom or a lower alkyl having 1 to 3 carbon atoms 2! i (e.g. methyl,
ethyl, n-propyl, etc.), R3, R4 and R
IG has at least 3 carbon atoms in total] Amide compounds (V) Specific examples thereof include N,N-diethylformamide,
N, N-dimethylacetamide, N, N~diethylacetamide, N, N-dimethylpropionamide, N
, N-diethylpropionamide, and others.

(7) Lactone having 4 to 6 carbon atoms Specific examples thereof include T-butyl lactone, δ-valerolactone, and others.

(8) Lower-hydric alcohol having 1 to 4 carbon atoms Specific examples of this include methyl alcohol, ethyl alcohol, n-propyl alcohol, iso-propyl alcohol, n-butyl alcohol, iso-butyl alcohol, 5ee-butyl alcohol, Examples include t-butyl alcohol.

(9) Glycol having 3 to 4 carbon atoms propylene glycol, 1,2-phthylene gelylcol,
Examples include 2,3-butylene glycol and 1,4-butylene gelcol.

In addition to M, there are certain I- also preferred bottle compositions of the present invention, which are discussed below.

The present inventors have discovered that N-alkylmorpholine (1) basically plays an adjuvant function, and that polar compounds such as pyrrolyne-type compounds act as solvents etc. that enhance the solvation of the adjuvant. It is believed to synergistically promote skin absorption. We further believe that the polar compound carries the active agent while the adjuvant spreads over the stratum corneum. However, we do not wish to be bound by these theories, and we do not wish to be bound by these theories, and we do not wish to be bound by these theories;
It is only used to distinguish between different types of components.

The most preferred adjuvant as component A of the present invention is an N-alkylmorpholine (1 ).

The most preferred compounds as component B include the above-mentioned pyrrolidone compound (Iv) and Ryomide (V).

The base composition of the present invention can be prepared by dissolving component A in component B. The amount of component A to be used is generally 0.1 to 8, based on the total weight of components A and B.
0 weight percent, preferably 0.5 to 50 weight percent. Of course, pharmaceutically acceptable additives such as water, etc. can also be added to the base composition.

Pharmaceutical compositions for topical application according to the invention can be prepared by incorporating the active agent into the base composition. In addition, the active agent is not blended into the base composition in advance,
The active agent may be administered cutaneously in the presence of the base composition at the time of use. There are no particular restrictions on the active agent as long as it can be used transdermally.

Examples of active agents include henzodiazebins (e.g. diazepam, nitrazepam, flunitrazebam, lorazepam, fludiazepam, clonazebam), diuretics [e.g. chloromethylidezide, noclopenthiazide, hentylhydrochlorothiazide, hydrochlorothiazide, bumetanide)], antihypertensive agents (e.g., clonidine), antihistamines [e.g., aminoethers (e.g., diphenhydramine, carbinoxamine, diphenylbilarin),
Ethylenediamines (e.g. fenhenzamine), monoamines (e.g. chlorofurnylamine)], non-steroidal anti-inflammatory agents (e.g. indomethanone, ibuprofen, ibufenac, alclofenac, diclofenac, mefenamic acid, flurbiprofen, flufenamic acid) , ketoprofen), antitumor agents [e.g., 5-
Fluorouranol, 1-(2-tetrahy10furyl)-
5-Fluorouranol5. /tarabine, fluofthralizin], etc. Also, steroid anti-inflammatory agents (e.g., cortisone, cortisone, prednisolone, prednisone, triamunolone, dexamethacin, butamethacin), antiepileptic agents (e.g., succinimide), antiarrhythmic agents (e.g., ajmarin, brashimin, pindolol) , propranolol, quinidine), antipsychotics (e.g., clofluperol, E. rifulberidol, heloberidol, mopelon), scopolamine (e.g., methylscopolamine, butylscopolamine), methyclobramide, chlorpromazine, ryotropin (e.g., methylato (robinpromide, methylanisotropinpromide), vasodilators (e.g. isosorbide dinitrate, nitroglycerin, pentaerythritol tetranitrate, propanyl nitrate, dipyridamole), antibiotics [e.g. tetracycline, methacycline, doxycycline, methacycline), chloramphenicol, erythromycin], peptides (
For example, LH-RH, insulin), etc. can also be used. Of course, hydrogen chloride, sodium, potassium, hydropromide, and pharmaceutically acceptable salts thereof can be used.

The amount of active agent to be mixed is sufficient depending on the species of active agent, patient's weight, symptoms, etc., as long as the desired effective pharmaceutical effect can be achieved.

Therefore, the amount is preferably 1! under these conditions. I can see it. -C is preferably used in an amount of 0.01 to 50 weight percent, preferably 0.05 to 10 weight percent, based on the weight of the base composition consisting of component A and component 1B.

The dose of active agent administered can be controlled by increasing or decreasing the area of skin to which the pharmaceutical composition is applied. Therefore, the activator stars are not necessarily limited to those mentioned above.

As will be clear to those skilled in the art, by increasing the amount of active agent 7.
More active agent is absorbed by the main body.

This is also tied to the total area of skin application since the amount of active agent absorbed in the area of administration increases substantially linearly with area.

1 of the active agent in the blood at any given time, for a given area of administration and a given absolute amount of adjuvant.
The concentration is also a function of the concentration of active agent in the composition. That is,
The increased 28 degrees of active agent in the formulation results in more rapid active agent penetration and higher blood levels.

Another factor that must be considered is that the amount of active agent absorbed depends on the location of application, such as the scalp, abdominal forearms, behind the ears, chest, etc.

Typically, a region with many blood vessels is selected.

For most applications, the intensity of the active agent in the base composition consisting of Component A and Component B is between 0.01 and 5.
0% and the applied base composition is about 0.1 to 100 mg per Ca, and the total area of application is in the range of about 0.5 to 2, QOcj, which is the desired Provides a therapeutically effective blood V intensity for the active agent.

However, these ranges should not be considered limiting.

In general, the rate of transdermal active agent absorption depends on the factors previously discussed (the nature and amount of the base composition, the amount of active agent in the formulation, etc.).
4 degrees and the surface area of skin stone application) approaches the rate of oral absorption. Thus, the peak blood intensity of the active agent is reached more rapidly or at about the same rate than when administered orally;
, almost the same as that obtained by oral administration? ; reach a degree. Alternatively, the level of active agent in the blood obtained by multiple transdermal administrations can be maintained for an extended period of time by subsequent transdermal administration of the active agent. In the latter case, the initial oral dose is much lower than the normal therapeutic oral dose, so that the amount of t-in-dose is higher than the minimum therapeutically effective dose achieved by the reduced oral dose. ;The side effects associated with
This can be avoided by following transdermal administration at an appropriate rate.

A therapeutic L-4j dose of diazepam in humans produces a blood intensity of approximately 1100 n/+a7 plasma [Journal of the Pharmaceutical Society (J, R'harm, Sci.), 62
．． 1789-1796 (1973)), such blood 1
The therapeutic efficacy can be easily achieved by transdermal administration according to the present invention and produces pharmacological (agonistic) signs of therapeutic efficacy in suitable animal models for humans, such as rhesus monkeys.

The base composition of the present invention can be applied to the udder in general, especially humans and domestic animals such as cattle, rods, horses, dogs, cats, etc.

The pharmaceutical composition of the invention can be used as an m-mixture or as a solution,
It is administered to the skin as a pharmaceutical formulation by adding a known pharmaceutically acceptable third component in the form of ointments (paste-containing creams and gels), lotions, adhesive tapes, salves, and other forms.

For example, the solution may simply consist of the active agent dissolved in a base composition, along with optional ingredients such as glycerin (and the solution may also be incorporated into an absorbent material, such as gauze, porous membrane, etc.). good.

Ointments, gels or creams contain conventional ingredients to form them (e.g. polyethylene glycol and hydroxypropyl cellulose, etc.) and can be spread on banking materials such as plastic film. can.

Similarly, snoring agents or adhesive tapes can include an active agent and a base composition in an adhesive agent, such as acrylic copolymer:E or other synthetic gum.

The component labeled π1 should be essentially inert in the system and should not increase or decrease the effectiveness of the base composition.

The base composition may optionally have a varying Y, generally from 10 to 9
It can be added to the composition by weight at 9%.

[Action/Effect]

The composition comprising component A and component B according to the present invention is
It has the ability to promote transdermal absorption of active agents and can also be used as a base for dermal preparations. Therefore,
By incorporating an active agent into the composition, an external preparation with excellent absorption of the active agent can be obtained. Furthermore, by administering the active agent to the skin in the presence of the composition, the active agent can be absorbed transdermally very easily.

〔Example〕

The present invention will be described below with reference to Examples and Experimental Examples, but these are not intended to limit the present invention.

In addition, in the following examples, the liquid composition first contains component A.
is prepared by mixing with component B and then incorporating the active agent into the mixture. The inventors obtained a qualitative evaluation of the effect of the active agent/base composition on transdermal absorption using the diffusion cell method.

In vitro skin immersion by diffusion cell i - 250~3
The skin was scraped from the open abdomen of a 00 g male Alpino rat, and the subcutaneous fat was carefully removed with scissors, washed with physiological saline, and the skin was mounted horizontally in a glass diffusion cell.

An active agent/base composition solution of known concentration was added to the epithelial side of the skin, in the upper compartment of the exposed cell, and saline/8 solution was placed in the lower compartment.

8 Speed was investigated using a lotus which was stable at 30°C. At appropriate intervals, samples were collected from the lower compartment and then analyzed for active agent concentration by standard analytical methods.

Examples 1 to 10 Basic combination fil drug 1% by weight (2) Component 8
89% by weight (3) Component A
Using the liquid composition shown in Table 1 as 10% i11, (2) and (3), first mix (3) with (2), and then dissolve txt. By doing so, 4) 1 was made.

Control formulation (11 drugs 1% by weight (2) Ingredients 8
Using the components listed in Table 1 as 99% by weight M% (2), +11 was dissolved in (2) to obtain a composition in which component (3) was removed from each Example.

Comparative Example 1.2 (1) Drug l% (2) Ingredient 8
89 Chonghui% (3) Morpholine compound 1
0i111! As the it% morpholine compound, N-pentyl mole;1 phosphorus or N-octadenlemo'morpholine was used.

Experimental Example 1 The skin excess of drug in the compositions of Examples 1 to 10, Control Example, and Comparative Example 1.2 was measured by the diffusion cell method, and the results are shown in Tables 1 and 2.

Note that the Q values in Tables 1 and 2 mean the following.

Q=C/D C: Skin i3 overdose D of drug in Examples or Comparative Examples:
Skin i3 super star of drug in control formulation (below margin)

Claims (4)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) At least one type selected from N-alkylmorpholine (I) represented by (in the formula, R represents an alkyl group having 7 to 14 carbon atoms) 1. A composition for dermal administration, comprising at least one solvent selected from compounds of the above and polar compounds. (2) The polar compound is thioglycerol, lactic acid or its ester, general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (II) (In the formula, R_1 and R_2 are each a hydrogen atom or a lower alkyl having 1 to 4 carbon atoms. Cyclic urea (II) represented by the general formula (III) ▲ formula,
There are chemical formulas, tables, etc. ▼ (III) (In the formula, R_3 to R_6 are each a hydrogen atom, and the number of carbon atoms is 1 to 4.
lower alkyl group, nitro or acyl group having 1 to 2 carbon atoms) Compound (III), general formula (IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) (In the formula, R_7 is A compound represented by a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, where n is an integer of 3 to 5), general formula (V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) (in the formula , R_8, R_9 and R_1_0 each represent a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, and R_8
, R_9 and R_1_0 have at least 3 carbon atoms in total) Amide compound (V) represented by ~
4. The composition for dermal administration according to claim 1, which is at least one selected from the group consisting of 4 glycols. (3) The polar compound is at least one selected from the group consisting of a compound represented by the general formula (IV) and an amide compound represented by the general formula (V).
2) The composition described in item 2). (4) The composition according to any one of claims (1) to (3), further containing a physiologically active substance.