JPH0119365B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to compositions that promote transdermal absorption of physiologically active agents (hereinafter often simply referred to as "active agents"). Active agents are typically administered to the skin or mucosal tissues to treat localized lesions, and systemic administration of active agents is typically via pill ingestion or injection. However, recently attempts have been made to achieve systemic administration of active agents by local application to the skin or mucosal tissues. Such local means of systemic administration has the advantage that desired blood concentrations can be easily achieved and the duration of treatment can be easily maintained in a controllable manner. That is, side effects due to excessive administration of the active agent can be prevented. Additionally, the first passage through the liver that is characteristic of certain drugs, such as indomethacin, when administered orally.
Passage-based metabolic and gastric disorders can also be eliminated. However, normal skin is relatively impermeable to most therapeutic agents since the desired blood levels of therapeutic agents cannot be achieved by transdermal absorption. Transdermal absorption of therapeutic agents, however, is enhanced by adjuvants or penetration enhancers. One of the best known such osmotic adjuvants is dimethyl sulfoxide, the use of which is described in detail in US Pat. No. 3,551,554 (Herschler et al.). This patent broadly suggests the use of dimethyl sulfoxide as an osmotic adjuvant for psychopharmacological agents such as benzodiazepine derivatives. British Patent No. 1504302 (Brooker et al.) deals with sedative methods and compositions and applies aromatic hydrocarbons or paraffin to the skin of non-human animals.
halogenated aliphatic hydrocarbons, ketones, esters,
The administration of sedation by applying sedative amounts of one or more sedative compounds in various osmotic adjuvants such as ethers, alcohols, amides or hydrocarbons such as sulfonates is disclosed. Bruker et al. broadly indicate that one or more of the above fluids can be used in combination, but halogenated aliphatic hydrocarbons are exemplified only by carbon tetrachloride, and amides are exemplified only by dimethylformamide. I'm just doing it. Patent Application No. 148614 (unexamined, Yonemushi)
discloses the use of sulfon, a by-product of petroleum refining, "as a solvent to enhance the efficacy of dermatological drugs" and "as a drug penetration enhancer" without supporting data or describing the substance. U.S. Pat. No. 4,202,888 (Eckert et al.) discloses an absorbable pharmaceutical composition comprising at least one cardiotonic glycoside distributed in a medium-chain-length vehicle comprising at least a portion of a glyceride in an amount that promotes the absorption of fatty acids. Disclosed. US Pat. No. 3,472,931 (Staughton) relates to transdermal absorption using lower alkyl amides and 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 or low molecular weight esters with dimethylacetamide. U.S. Patent No. 4017641 (DiGiulio) is approximately 10-20
Skin moisturizing compositions consisting of 2-pyrrolidone can be used with suitable oils and waxes containing aliphatic linear fatty acids of 5 carbon atoms and alcohols. However, this patent does not address transdermal administration of physiologically active agents. European Patent Application No. 0043738 discloses a two-component transdermal delivery system consisting of a monodaliseride, diol or diol ether in combination with a second component such as an alcohol, ester, amide, etc. 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 and controlled transdermal delivery of physiologically active agents. The carrier system of the invention comprises at least one adjuvant (component A), at least one solvent (component B).
and at least one diol moderator. The adjuvant of the present invention is selected from halogen-substituted aliphatic hydrocarbons, higher aliphatic monoalcohols or mixtures thereof. The adjuvant of the present invention has a melting point of 38°C or less. The solvent of the present invention has the following formula: It is expressed as selected from pyrrolidone type compounds, amides or mixtures thereof. According to the present invention, a physiologically active agent can be administered transdermally by mixing it with a formulation of component A, component B and a diol moderator and applying it to the skin. The composition can be used as a base for pharmaceutical formulations containing active agents that can be applied to epithelia. The first object of the present invention is to provide a base consisting of component A, component B and a diol moderator (hereinafter often abbreviated as PAEC) for a topical pharmaceutical formulation that increases the permeability of active agents through the skin and the transdermal absorption of active agents. The object of the present invention is to provide a composition or a composition that promotes transdermal absorption. A second object of the present invention is to provide a pharmaceutical composition comprising PAEC for topical use that provides good penetration of the active agent through the skin and transdermal absorption of the active agent. A third object of the present invention is to provide compositions that enhance the permeability of active agents through the skin and transdermal absorption of active agents using the PAEC according to the present invention. In preferred embodiments, the formulations of the present invention to enhance transdermal absorption include certain pyrrolidone-type compounds and one or more elements selected from the group consisting of amides and mixtures thereof, certain alkyl halides, higher aliphatic monoalcohols, and It consists of one or more elements selected from the group consisting of mixtures thereof and one or more diol moderators. A fourth object of the invention is to provide a PAEC that ensures rapid and controlled transdermal administration of physiologically active agents in humans or other animals. A fifth object of the present invention is to provide such a rapid and controlled transdermal administration that provides a therapeutic range of drug blood concentrations for the treatment of humans and other animals. A sixth object of the present invention is to have a relatively constant therapeutic power by transdermal administration, at a suitably regulated rate, avoiding side effects and reduced therapeutic efficacy resulting from wide fluctuations in blood concentration over time. It is to provide blood concentration. Examples of component A include the following compounds. (1) Straight chain, branched or cycloaliphatic hydrocarbons having 5 to 24 carbon atoms substituted with one or more halogens. Bromine and chlorine are preferred as halogen substitutes. Straight-chain or branched hydrocarbons having 5 to 24 (preferably 6 to 18) carbon atoms can be used. These may be saturated or unsaturated, preferably with 1 to 2 unsaturated bonds. In the case of cyclic hydrocarbons, 6- to 10-membered mono- or 10- to 12-membered di-cyclic hydrocarbons are preferred, such as saturated hydrocarbons having 1 to 4 carbon atoms such as methyl, butyl, isopropyl, etc. Alternatively, it may be substituted with unsaturated alkyl. Specific examples include n-pentane, n-hexane, n-
Heptane, n-octane, n-nonane, n-decane, n-undecane, n-dodecane, n-tetradecane, n-hexadecane, n-octadecane,
n-methylpentane, n-methylhexane, 2,
3-dimethylhexane, 2-methylnonane, 2,
6-dimethyloctane, 2,2,4,4,6,
8,8-heptamethylnonane, pristane, limonene, hydrogenated limonene dimer, cyclohexane,
Examples include halogen-substituted 1,3-dimethylcyclohexane, cyclooctane, isobutyl-cyclohexane, cyclododecane, methyldecalin, delicane, etc., octyl chloride, decyl chloride, dodecyl chloride, hexadecyl chloride, dodecyl bromide, dichlorododecane, and others. (2) Branched, linear, saturated, unsaturated or cyclic, and primary, secondary or tertiary, 10
Higher aliphatic monoalcohols with ~26 carbon atoms. Examples of component B include the following compounds. (1) General formula [In the formula, R ₅ is 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. ] A compound represented by Specific examples of this include 2-pyrrolidone, N-
Examples include methyl-pyrrolidone, N-methylpiperidone, caprolactam, N-methylcaprolactam, and others. (2) General formula [In the formula, R ₆ is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms (methyl, ethyl, n-
propyl, etc.) and R ₇ and R ₈
represents an alkyl group each having 1 to 3 carbon atoms; R ₆ , R ₇ and R ₈ in total represent at least 3 carbon atoms;
carbon atoms. ] A compound represented by Specific examples of this include N,N-diethylformamide, N,N-dimethylacetamide, N,
Examples include N-diethylacetamide, N,N-dimethylpropionamide, N,N-diethylpropionamide, and others. As previously indicated, diol moderators are used in combination with active agents and components A and B of the invention. The diol may be linear or branched, and the diol selected is preferably a diol of 3 to 8 carbon atoms, most preferably 3 to 6 carbon atoms, such as 1,2-propanediol. , 1,3-butanediol, 2,3-butanediol, 1,5-pentanediol or 1,6
-Hexanediol. The amount of diol moderator used is not unduly limited and typically ranges from about 10 to 400% by weight based on the weight of solvent component B, more preferably about
It ranges from 25 to 200% by weight. Of course, the resulting raw material formulation is in liquid form. Diol moderators are components A and B of the invention.
and provide a means to further control the rate of active agent absorption. A higher amount of diol moderator will decrease the rate of activator flux, while a lower amount of diol moderator will increase the rate of activator flux compared to a higher amount. It is understood that diol moderators do not enhance transdermal absorption according to the present invention, but rather ultimately reduce the rate of transdermal absorption, an effect that is beyond doubt in the art. Furthermore, certain most preferred embodiments according to the present invention
There are PAECs, which are described below. Although it is unclear why the most preferred PAEC formulations of the present invention provide enhanced transdermal absorption, the data obtained by the inventors indicate that by varying the amount of diol moderator as desired, It shows that there is a synergistic effect between components A and B that can be modified. The inventors have discovered that raw materials such as pyrrolidone-type compounds and amides essentially serve as solvents, and that raw materials such as alkyl halides, fatty acid esters, higher aliphatic monoalcohols, and aliphatic hydrocarbons act as solvents. It is believed that it acts as an adjuvant that enhances the solvation function. The inventors further believe that the solvent carries the active agent while the adjuvant spreads over the stratum corneum. We do not wish to be bound by these theories and we maintain the terms "solvent" and "adjuvant" to distinguish between two types of raw materials used as essential ingredients in a formulation. It is only used to do. Component A of the present invention includes one or more elements selected from the group consisting of alkyl halides, higher aliphatic monoalcohols, and mixtures thereof. For alkyl halides, those having 8 to 16 carbon atoms are most preferred with chloride being the preferred halogen. Although both alkyl bromides and iodides are potentially useful,
However, alkyl bromides and alkyl iodides tend to be unstable. Alkyl fluorides are also useful. The alkyl moiety can be straight or branched, cycloaliphatic or unsaturated, such as alkanes and alkenes being useful. The most preferred alkyl halide will be exemplified later. Preferred higher mono-alcohols include aliphatic mono-alcohols having 12 to 24 carbon atoms. Aliphatic monoalcohols can be branched, straight chain,
Can be saturated, unsaturated or cyclic. Component B includes pyrrolidone type compounds and amides. Pyrrolidone most preferably has the formula (wherein R ₁ is an alkyl group containing up to 4 carbon atoms and n is from 3 to 5). Amide is most preferably of the formula (wherein R ₂ is hydrogen or an alkyl group having up to 3 carbon atoms, and R ₃ and R ₄
can be an aliphatic group having up to 3 carbon atoms. ). The basic composition of the invention can be prepared by dissolving component A in component B and then mixing therein the diol moderator. The amount of component A to be used is generally from 0.1 to 80% by weight, preferably from 0.5 to 50% by weight, based on the total weight of components A and B. Preferred properties of diol moderators have been described above. 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 mixing the active agent with said composition. There are no particular restrictions on the active agent used as long as the active agent is systemically effective and can be applied transdermally. Particular examples of active agents include benzodiazepines (e.g. diazepam, nitrazepam, flunitrazepam, lorazepam, fludiazepam, clonazepam), diuretics [e.g. thiazides (e.g. bendroflumethiazide, polythiazide, methyclothiazide, trichloromethiazide, cyclopenthiazide, benzylhydrochlorothiazide, hydrochlorothiazide, bumetanide)], antihypertensive agents (e.g. clonidine), antihistamines [e.g. aminoethers (e.g. diphenhydramine, carbinoxamine, diphenylpyraline), ethylenediamine (e.g. phebenzamine) , monoamines (e.g., chlorophenylamine)], non-steroidal anti-inflammatory agents (e.g., indomethacin, ibuprofen, ibuquenac, alclofenac, diclofenac, mefenamic acid, flurbiprofen, flufenamic acid, ketoprofen), antitumor agents ( for example,
5-fluorouracil, 1-(2-tetrahydrofuryl)-5-fluorouracil, cytarabine,
Fluoxuridine is mentioned. Steroid anti-inflammatory agents (e.g., cortisone, hydrocortisone, prednisolone, prednisone, triamcinolone, dexamethasone, betamethasone), antiepileptic agents (e.g., ethosuximide), antiarrhythmic agents (e.g., ajmarin, pradimarine, pindolol, pupanolol, quinidine), psychotropic agents agents [e.g., clofluperol, trifluperidol, haloperidol, mopelone), scopolamine (e.g., methylscopolamine, butylscopolamine), metoclopramide, chlorpromazine, atropine (e.g., methylatropine bromide,
methylanisotropin bromide), vasodilators (e.g. isosorbide dinitrate, nitroglycerin, pentaerythritol tetranitrate, propanyl nitrate, dipyridamole),
Antibiotics, such as tetracyclines (eg, tetracycline, oxytetracycline, methacycline, doxycycline, minocycline), chloramphenicol, erythromycin], etc. The composition of the invention also includes LH-RH,
It can also be used for transdermally administered peptides such as insulin. Of course, hydrogen chloride, sodium, potassium, hydrobromide, and other pharmaceutically acceptable salts can be used. The present invention has particular applications with regard to benzodiazepine raw materials, and these will be discussed in more detail below. A particularly preferred benzodiazepine raw material is expressed by the following formula: [wherein X is Cl, Br or NO ₂ and Y is with varying degrees of unsaturation and substitution at the 1, 2, 3, 4 and 5 positions as shown in the formula below.

【formula】 【formula】

【formula】

[Formula] a 1,2 and 4,5 are unsaturated, R ₁ and R ₃ are H, and R ₂ is

[Formula] (wherein R is H or CH ₃ ) and N-Z
is N→O. b 1,2 is saturated and 4,5 is unsaturated: R ₃ is H or OH and -R ₂ is -H
or =O or =N*; R ₁ is

[Formula] (wherein R is H, CH ₃ or

[Formula]), or CH ₂ -CH ₂ -N(C ₂ H ₅ ) ₂ or R ₁ is C(R)
=N* (in the formula, R is H or CH ₃ ), and as follows It is bonded to R ₂ via “*” (single bond). c 1,2 and 4,5 are saturated, R ₁ is H, −R ₂ is =O, R ₃ is H,
And the positions of 4 and 5 are as follows: (wherein R and R ₁ are H and CH ₃ )
It constitutes a second ring system as shown in . ] It has a benzodiazepine skeleton as shown schematically. Specific examples of transdermally administrable benzodiazepines using the active ingredient/osmotic adjuvant formulations of the present invention include: a Chlordiazepoxide; 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide b Diazepam; 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H- 1,4-
Benzothiazepine-2-one c oyusazepam; 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,
4-benzodiazepine-2-one d temazepam; 7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-2H-1,
4-Benzodiazepine-2-one e Lorazepam; 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepine-2-one f Prazepam; 7-chloro- 1-cyclopropylmethyl-1,3-dihydro-5-phenyl-
2H-1,4-benzodiazepine-2-oneg fludiazepam; 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-1-methyl-2H-1,4-benzodiazepine-2-
Flurazepam; 7-chloro-1-(2-(dimethylamino)ethyl)-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4
-Benzodiazepine-2-one i Medazepam; 7-chloro-2,3-dihydro-1-methyl-5-phonyl-1H-5,4-
Benzodiazepine j Bromazepam; 7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepine-2
(1H)-onek Nitrazepam; 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-onel Nimetazepam; 1-methyl-7-nitro-5
-Phenyl-1,3-dihydro-2H-1,4
-benzodiazepine-2-one m clonazepam; 5-(o-chlorophenyl)
-7-nitro-1H-1,4-benzodiazepine-2(3H)-one flunitrazepam; 5-(o-fluorophenyl)-1,3-dihydro-1-methyl-7-
Nitro-2H-1,4-benzodiazepine-2
-On o estazolan; 8-chloro-1,6-phenyl-4H-s-triazolo(4,3-)(1,
4)-Benzodiazepine p triazolam; 8-chloro-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo(4,3-)(1,4)-benzodiazepine q alprazolam; 8-chloro-1- Methyl6-phenyl-4H-s-triazolo(4,3
-) (1,4)-benzodiazepine r oxazolam; 10-chloro-2,3,5,
6,7,11b-hexahydro-2-methyl-
11b-Phenylbenzo(6,7)-1,4-diazepino(5,4-b)-oxazol-6-ones Cloxazolam; 10-chloro-11b-(o-
Chlorophenyl)-2,3,5,6,7,11b
-hexahydrobenzo(6,7)-1,4-diazepino-(5,4-b)-oxazole-6-
Ont Haloxazolam; 10-bromo-11b-(o-
fluorophenyl)-2,3,7,11b-tetrahydro-oxazolo(3,2-d) (1,4)
Benzodiazepine-6(5H)-one Particularly preferred are benzodiazepine b),
e), i), k), l), n) and o). The amount of active agent mixed is sufficient if it is effective to achieve the desired pharmaceutical effect, which will vary depending on the type of active agent, patient weight, condition, etc. The amount can therefore be suitably selected depending on these conditions. Generally, it is preferred to use from 0.01 to 50% by weight, more preferably from 0.05 to 10% by weight, based on the total amount of component A and component B. 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 amount of active agent is not necessarily limited to those mentioned above. As will be apparent to those skilled in the art, by increasing the active agent concentration, increasing amounts of the active agent will be absorbed by the subject. The next consideration is given in terms of the blood concentration of drug (in ng/ml of plasma), which is important for skin applications since the amount of active agent absorbed in a region increases virtually linearly with area. Based on total area. For a given area of application and a given absolute amount of adjuvant, the blood concentration of active agent at any given time is also a function of the concentration of active agent in the composition. That is, the increased concentration 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 will depend 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 concentration of active agent in PAEC is generally between 0.01 and 50% based on components A and B.
range, and the amount of PAEC applied is approximately per ^cm2 .
0.1-100mg, and the total area of application is about 0.5
~100 ^cm2 , which provides therapeutically effective blood concentrations of the desired active agent. However, these ranges should not be considered limiting. In general, the rate of transdermal active absorption approaches the rate of oral absorption due to the factors previously discussed (nature and amount of PAEB, concentration of active agent in the formulation, and surface area of skin application). Thus, the peak blood concentration of the active agent is reached more slowly or at about the same rate, and about the same concentration as obtained with oral administration. Alternatively, blood levels of the active agent obtained by a single oral administration can be maintained for an extended period of time by subsequent transdermal administration of the active agent. In the latter case, because the initial oral dose is much lower than the normal therapeutic oral dose, side effects associated with higher than minimum therapeutically effective blood concentrations achieved by the reduced oral dose can be maintained at an appropriate rate by subsequent transdermal administration. Therapeutic oral doses of diazepam in humans produce blood concentrations of approximately 100 ng/ml plasma [SA Kaplan, ML Jack, K. Alexander and
REWeinfield, J.Phar Sci., 62 1789―1796
(1973)]. Such blood concentrations are easily achieved by transdermal administration according to the present invention and produce pharmacological (agonistic) signs of therapeutic efficacy in suitable animal models for humans, such as rhesus monkeys. The compositions of the present invention can be applied to mammals in general, especially humans and domestic animals such as cattle, sheep, horses, dogs, cats and the like. The pharmaceutical compositions of the present invention can be prepared by adding a known pharmaceutically acceptable third component, either as a single mixture or in the form of solutions, ointments (creams and gels containing pastes), lotions, adhesive tapes, salves, etc. Administered integumentally as a pharmaceutical preparation. For example, the solution may simply consist of the dissolved active agent of PAEC along with optional ingredients such as glycerin, and the solution may be incorporated into an absorbent material such as gauze, porous membrane, etc. Ointments, gels or creams contain conventional ingredients to form them, such as polyethylene glycol and hydroxypropyl cellulose, etc., and can be spread on a backing material, such as a plastic film. Similarly, plasters or adhesive tapes can contain the active agent and PAEC in an adhesive base, such as an acrylic copolymer or other synthetic gum. The components should be essentially inert in the system and do not increase or decrease the effectiveness of PAEC. PAEC is generally 10 to 99, with varying amounts as desired.
% by weight can be added to such compositions. In developing the invention, we used diffusion cells and animal models. A qualitative evaluation of the active agent/PAEC effect on transdermal absorption was obtained using the diffusion cell method. The animal model rhesus monkey study was also conducted by J.
Soc.Cosmct.Chem., 30, 297-307 provides an acceptable pharmacological model for humans. Experimental Example: In vitro skin penetration study using diffusion cell technology.The sufficient thickness of the rat skin allows Michael's diffusion cell method (AlchE Journal, 21 [5], 985-996,
1975). Rat skin was placed in the diffusion cell in a vertical position between the upstream and downstream compartments. The exposed area of skin was approximately 4.15 cm ² . The skin was scraped from the shaved abdomen of a male albino rat weighing 250-300 g, and the subcutaneous fat was carefully removed with scissors and washed with normal saline. Active agent/PAEC solution of known concentration was added to the upper compartment of the cell, exposed on the epithelial side of the skin, and normal saline solution was placed in the lower compartment. Penetration rates were investigated in a thermostable bath at 30°C. At appropriate intervals, samples were collected from the lower compartment and then analyzed for activator concentration by standard analytical methods. Alternatively, Franz's restricted dose technique [Curr.
Probl. Dermatol., Vol. 7, P. 58-68 (Karger.
Basel, 1978) also placed rat skin horizontally in a diffusion cell container, and the exposed area of the skin was approximately 0.7 mm.
It can be done in ^cm2 . Active agent/PAEC solution of known concentration was added to the upstream compartment to expose the epithelial side of the skin, and normal saline was added to the downstream compartment. In Vivo Rhesus Experiments If desired, in vivo rhesus experiments such as those described below can also be used to determine the effectiveness of the PAEC/diol moderator formulations of the present invention. Male rhesus monkeys weighing 10-14 kg can be used as subjects. A suitable area of the monkey's chest is shaved 24 hours before drug application. A drug regimen consisting of PAEC is applied to certain areas of the chest. Tie the monkey to a chair to prevent it from touching your breasts. After application, blood samples are taken at appropriate intervals. Heparinized blood is spun down to remove plasma and stored at -20°C until analysis. Diazepam in plasma
It can be analyzed according to the GLC method (J. Chromatog., 75 , 55-78, 1973). EXAMPLES The present invention will be explained in more detail with reference to Examples below, but the Examples are not intended to limit the present invention. An example of a formulation of components A and B according to the present invention is
METHOD FOR Counsel document A-4271 published on May 20, 1983 under the name of S. Sato et al.
PERCUTANEOUSLY ADMINISTRING
PHYSIOLOGICALLY ACTIVE AGENTS, in which no diol moderators are used, and in Counsel document A-4556, published under the name of K. Saito et al.
METHOD FOR PERCUTANEOUSLY
ADMINISTERING PHYSIOLOGICALLY
ACTIVE AGENTS USING ANALCOHOL
It is given the name ADJUVANT AND ASOLVENT. The composition was prepared by first dissolving component A with component B, then mixing the active agent in the mixture, and then mixing this with the diol. The order of mixing is not important. When component B was solid at room temperature or did not mix uniformly with component A, 20% by weight of ethylene glycol monobutyl ether, based on the weight of components A and B, was used as a solubilizing agent. Additionally, in the following examples, the following abbreviations are used: C ₁₂ OH-dodecanol C ₁₂ Cl-dodecyl chloride DMAc-dimethylacetamide MP-1-methyl-2-pyrrolidone Unless otherwise indicated, in the following examples the active agent is diazepam or metoclopramide hydrochloride. The flux of activator is μg/cm ² /
It is given for 8 hours. Component A and component B
25% by volume of component A, with or without diol, was used in the composition along with 2.5% by weight of active agent. For comparison, the results for an adjuvant with a diol in one example are given. Example 1 The figure shows 25% C ₁₂ Cl in DMAc, 25% C ₁₂ Cl in a 1:1 weight mixture of DMAc/2,3-butanediol and 1:2 of DMAc/2,3-butanediol.
Figure 2 is a plot of diazepam flux versus time (hours) illustrating the moderating effect of diols for a 25% C ₁₂ Cl system by weight. 25% C ₁₂ Cl in 2,3-butanediol is also shown for comparison. Example 2 This example shows 25% C ₁₂ OH in MP and MP/1,
25% in a 1:1 volume mixture of 2-propanediol
The moderating effect of diols on the C ₁₂ OH system is shown. Table 2 shows the 8 hour metoclopramide HCl flux with these systems. Table 2 Fluxes (μg/cm ² /8 hours) 25% C ₁₂ OH in MP 4382 25% C ₁₂ OH in a 1:1 volume mixture of MP/1,2-propanediol 1369 The present invention in detail and its special features Although specific embodiments have been described, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention.

[Brief explanation of drawings]

The figure is a graph of diazepam flux versus time for various compositions according to the invention and comparative compositions.

Claims (1)

[Scope of Claims] 1. At least one of the following components A: Component A: a straight chain having 5 to 24 carbon atoms substituted with one or more halogen atoms;
Branched or cycloaliphatic hydrocarbons, aliphatic monoalcohols having 10 to 26 carbon atoms and mixtures thereof; at least one of the following component B; component B: formula (In the formula, R ₅ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, and n represents 3 to 4 carbon atoms.
Represents an integer of 5. ) Compounds represented by the general formula (In the formula, R ₆ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R ₇ and R ₈
each represents an alkyl group having 1 to 3 carbon atoms, and R ₆ , R ₇ and R ₈ have a total of at least 3 carbon atoms. ); and at least one diol moderator,
Components A and B are present in amounts effective to enhance transdermal delivery of the active agent, and the diol moderator is present in an amount effective to modulate the rate of transdermal absorption within therapeutically effective rates. Absorption enhancers for physiologically active agents consisting of mixtures present. 2 Component A is a halogen-substituted alkyl halide having 8 to 18 carbon atoms, an aliphatic hydrocarbon group having 10 to 18 carbon atoms, an aliphatic monoalcohol having 12 to 24 carbon atoms, and these and component B is selected from the group consisting of a mixture of
is the formula (wherein n is 1 to 3 and R ₁ is an alkyl group containing 1 to 4 carbon atoms) or the general formula (wherein R ₂ is hydrogen or an alkyl group having up to 3 carbon atoms, and R ₃ and R ₄ are 3
an alkyl group having up to carbon atoms;
The total number of carbon atoms in _R2 - _R4 is at least three. 2. The absorption enhancer according to claim 1, wherein the absorption enhancer is selected from the group consisting of compounds represented by: 3. Process according to claim 1, characterized in that the diol has 3 to 8 carbon atoms. 4. The absorption enhancer according to claim 1, wherein the diol is an aliphatic diol having 3 to 6 carbon atoms.