GB2141025A - Compositions for percutaneous administration - Google Patents

Abstract

A pharmaceutical composition for administration to the skin comprises a pharmaceutical agent, e.g. benzodiazepine, and a percutaneous carrier liquid comprising: A) a 5-24C aliphatic or cycloaliphatic hydrocarbon which may be halo-substituted, an ester of an alcohol and a 7-18C aliphatic carboxylic acid, a C10-18 mono- or di-ether, and/or a C11-15 ketone; and B) a thiogylercol, lactic acid or ester, cyclic urea, alkyl or acyl urea, alkyl amide and/or pyrrolidone or N-alkyl pyrrolidone.

Description

SPECIFICATION Pharmaceutical compositions for percutaneous admi nistration The present invention relates to pharmaceutical compositions which include a carrier composition for accelerating the percutaneous absorption of a physi cologically active or pharmaceutical agent (the latter is often merely described herein as an "active agent" for brevity) into the compositions.

Active agents are commonly administered to the skin or mucosal tissues to treat local problems, whilst systemic administration of active agents is commonly accomplished by ingesting pills or by injections.

However, recently attempts have been made to achieve systemic administration of active agents by topical applicationsto the skin or mucosal tissues.

Such topical means of achieving systemic administration has the advantage that desired blood levels can be readily achieved and maintained so thatthe duration of therapy can be readily controlled; thus, side effects due to an overdose of the active agent can be prevented. Also, metabolism due to a first pass through the liver or to gastric disturbances, which are characteristic of certain drugs such as indomethacin when administered orally, can also be eliminated.

However, normal skin is relatively impermeable to most therapeutic agents, so that desired blood levels ofthe therapeutic agent cannot be achieved by means of percutaneous absorption. The percutaneous absorption of therapeutic agents can, however, be enhanced by means of adjuvants or penetration enhancers.

One ofthe best known of such penetrating adjuvants is dimethyl sulfoxide, the use of which is described in detail in U.S. Patent3,551,S54Herschler et al, which patent broadly suggests the use of dimethyl sulfoxide as a penetrating adjuvant for psychopharmocological drugs such as benzodiazepine derivatives.

British Patent 1,504,302 Brookeretal deals with sedative methods and compositions and discloses the administration of sedatives by applying to the skin of a non-human animal a sedating amount of one or more sedative compounds in various penetrating adjuvants such as hydrocarbons such as aromatic hydrocarbons or paraffins, halogenated aliphatic hydrocarbons, ketones, esters, ethers, alcohols, amides orsulfones.

Brookeretal broadly indicates that oneor more of the above liquids can be used in combination, but exemplify the halogenated aliphatic hydrocarbons only with carbon tetrachloride and exemplify the amides only with dimethylformamide.

Japanese Patent Application 52-148,614 (unex mined) Yonemushi discloses, without supporting data or explanation of substance, the use of sulfones by-produced in the refining of petroleum "as solvents to enhance the efficacy of drugs for skin disease" and "as drug penetration enhancers".

U.S. Patent 4,202,888 Eckert et al discloses absorbable pharmaceutical compositions comprising at least one cardiac glycoside distributed in a vehicle comprising an absorption-enhancing amount of at least a partial glyceride of a fatty acid of medium chain length.

U.S. Patent 3,472,931 Stoughton relates to percutaneousabsorption using loweralkyl amides, and exemplifies binary systems which comprise dimethy lacetamide and ethanol, dimethylacetamide and isop ropyl alcohol and dimethylacetamide and isopropyl palmitate. Stoughton does not exemplify nor disclose the combination of dimethylacetamide with higher molecularweight alcohols or higher molecularweight esters.

U.S. Patent 4,017,641 DiGiulie discloses skin moisturizing compositions comprising 2-pyrrolidones which can be used with suitable oils and waxes including aliphatic straight chain fatty acids and alcohols of from about lotto about 20 carbon atoms.

This patent does not, however, deal with percutaneous administration of physiologically active agents.

European Patent Application 0043738 discloses binary percutaneous administration systems which comprise a monoglyceride, a diol or a diol ether in combination with a second component such as an alcohol, ester, amide or the like.

The present invention involves multicomponent carrier systems for the percutaneous administration of physiologically active agents which differ from the systems disclosed in the above prior art.

In the present invention, it has been discovered that certain multicomponent carrier systems provide enhanced percutaneous administration of physiologically active agents.

The carrier systems ofthe present invention comprise at least one adjuvant (Component A) and at least one solvent (Component B) as defined in Claim 1.

The adjuvants of the present invention are selected from aliphatic hydrocarbons or halogen substituted aliphatic hydrocarbons, alcohol esters of aliphatic carboxylic acids, mono- or di-ethers, ketones, or mixtures thereof.

The solvents of the present invention are selected from thioglycerols, lactic acid or esters thereof, cyclic ureas, compounds represented by the general formula R1 R2NCONR3R4, pyrrolidone-type compounds, amides, lactones or mixtures thereof.

In the present invention,a physiologically active agent can be percutaneously administered by blending the same with a combination ofComponentAand Component B and applying the same to theskin.

The above-described compositions can be used as bases four medical preparations comprising active agents applicable to the outer skin.

One object of the present invention isto provide base compositions or percutaneous absorption enhancing combinations (often abbreviated as PAEC or PAECs hereafter) for medical preparations for external use which enhance the permeability of active agents through the skin and the percutaneous absorption of active agents.

A second object of the present invention is to provide pharmaceutical compositions comprising a PAEC for external use which provides good per meabilityofactive agents through the skin and percutaneous absorption of active agents.

Athirdobjectofthepresentinvention is to provide a method for enhancing the permeabilityof active agentsthrough the skin and percutaneous absorption of active agents using a PAEC perthe present invention.

In a preferred embodiment, the combination ofthe present invention which enhances percutaneous absorption comprises one or more members selected from the group consisting of certain pyrrolidone-type compounds and amides and mixturesthereofand one or more members selected from the group consisting of certain alkyl halides, fatty acid esters, hydrocarbons and mixtures thereof.

Afourth objectofthe present invention isto provide PAECs which ensure rapid transepidermal delivery of physiologically active agents in man or other animals.

A fifth object ofthe present invention is to provide such rapid transepidermal delivery which provides drug blood levels in the therapeutic rangeforthe treatment of humans and otheranimals.

A sixth object ofthe present invention is to provide, through transepidermal delivery, at appropriately adjusted rates, relatively constant therapeutic blood levels so as to avoid the side effects and reduced therapeutic effects that may resultfromwidefluctuar tions in blood levels overtime.

In the accompanying drawing: The Figure showsthetransdermal penetration rate of an active agent with compositions having varying ratios of component A and component B (see Example 24).

Examples of componentA include thefollowing compounds.

(1) Straight, branched or cyclic aliphatic hydrocarbons having 5 to 24carbon atoms which may be substitutedwith one or more halogens.

As halogen substituents, bromine and chlorine are preferred.

Straight or branched hydrocarbons having 5 to 24 (preferably 6to 18) carbon atoms can be used which may be saturated or unsaturated with preferably 1 to 2 unsaturated bonds. In the case of cyclic hydrocarbons, 6to 10 membered mono- or lOto 12 membered di-cyclichydrocarbons are preferred and such may be substituted with saturated or unsaturated alkyl groups having 1 to 4 carbon atoms such as methyl, butyl, isopropenyl, etc.

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, 2-methylpentane, 2-methylhexane, 2,3- dimethylhexane,2-methylnonane, 2,6-dimethyloc- tane, 2,2,4,4,6,8,8 - heptamethylnonane, pristane, limonene, hydrogenated limonene dimer, cyclohex ane, 1,3 - dimethylcyclohexane, cyclooctane, isobutyl - cyclohexane, cyclodecane, methyldecaline, decaline, octyl chloride, decyl chloride, dodecyl chloride, hexadecyl chloride, dodecyl bromide, dichlorododecane, etc.

(2) Alcohol esters ofaliphatic carboxylic acids having atotal numberofcarbon atomsoffrom7to 18, preferably7to 17: Asthe alcohol moiety, monovalent alcohols having 1 to 6 carbon Eroms such as methyl alcohol, ethyl alcohol, n-propyl alcohol, iso-propyl alcohol, n-butyl alcohol, iso-butyl alcohol, sec-butyl alcohol, t-butyl alcohol, n-amyl alcohol, iso-amyl alcohol, n-hexyl alcohol, etc., are preferred. Further, as the carboxylic acid moiety, fatty acids having 6to 16 carbon atoms are preferred and saturated fatty acids having 8 to 14 carbon atoms are most preferred. Specific examples of such esters include methyl laurate, ethyl laurate, butyl laurate, isopropyl myristate, etc.

(3) Mono-ordi-ethershaving 10 to 18 carbon atoms: Specifically, there are alkyl monoetherssuch as dihexyl ether, dioctyl ether, methoxydodecane, ethoxydodecane, etc., ethers having an alicyclic group such as 1,8-cineole, etc., alkyl dietherssuch as ethylene glycol dibutyl ether, ethylene glycol dioctyl ether, etc.

(4) Ketones having 10 to 18 carbon atoms: Aliphatic ketones are preferred, examples of which include 2-undecanone, 3-undecanone, 4-undecanone, 5-undecanone,6-undecanone,2-dodecanone,4 dodecanone, 5-dodecanone, 2-tridecanone, 3-trideca- none, 7-tridecanone, 8-pentadecanone, etc.

ExamplesofcomponentB include the following compounds: (1) Thioglycerols: Any mono-, di- and trithioglycerols can be used, an example of which includes oc-monothioglycerol.

(2) Lactic acid and esters thereof: As the alcohol moiety in the esters, monovalent aliphatic alcohols having 1 to 4 carbon atoms are preferred, specific examples of which include lactic acid, methyl lactate, ethyl lactate, butyl lactate, etc.

(3) Cyclic ureas: 5-Membered or6-membered rings are preferred, specific examples ofwhich include N,N' dimethyleneurea, N.N' - diethyl ethylene urea and the corresponding propylene ureas, etc.

(4) Compounds represented by the general formula:

wherein R1, R2, R3 and R4 each represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms (methyl, ethyl, n-propyl, iso-propyl, n-butyl, etc.) or an acyl group having 1 or 2 carbon atoms: Specific examplesthereof include urea, N - methylurea, N - ethylurea, N-butylurea, 1,1 - dimethylurea, 1,3 - dimethylurea, 1,1,3,3 -tetramethylurea, N acetyl - N' - methylurea.

(5) Compounds represented bythe generalfor- mula:

wherein R5 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms (methyl, ethyl, n-propyl, iso-propyl, etc.) and n represents an integer of 3to5: Specific examples thereof include 2 - pyrrolidone, N - methyl - pyrrolidone, N - methylpiperidone, caprolactam, N - methylcaprolactam, etc.

(6) Compounds represented by the general formula:

wherein R6 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms (methyl, ethyl, n-propyl, etc.) and R7 and R8 each represents an alkyl group having 1 to 3 carbon atoms, with the proviso that R6, R7 and R8 have in total at least3 carbon atoms: Specific examples thereof include N,N - diethyl formamide, N,N - dimethylacetamide, N,N - diethylacetamide, N,N - dimethylpropionamide, N,N diethylpropionamide, etc.

(7) Lactones having 4to 6carbon atoms: Specific examples thereof include y - butyrolactone, 5-valerolactone, etc.

In addition to the above, there are certain most preferred PAECs in the present invention, and these are discussed below.

We are unsure why the most preferred combination of PAECs of the present invention offers enhanced percutaneous absorption; however, the data we have obtained indicate that there is a synergistic effect between the two groups of materials.

We considerthe Component B such as the pyrrolidone compounds and amides to act as solvents and the Component Asuch as the alkyl halides, fatty acid esters, and hydrocarbons to serve as an adjuvant which enhances solvating function of the solvent. We further believe that the solvents carrythe active agent whereas the adjuvants open up the stratum corneum.

We do not wish to be bound by these theories, and we merely use the terminology "solvent" and "adjuvant" to maintain a line of distinction between the two classes of materials which are mandatorily used in combination.

The most preferred adjuvants as componentAof the present invention include one or more members selected from the group consisting of alkyl halides, fatty acid esters, hydrocarbons and mixtures thereof.

Of the alkyl halides, those having from 8 to 16 carbon atoms are most preferred, with chloride being the preferred halogen. Both alkyl bromides and iodides are potentially useful, but alkyl bromides and alkyl iodidestend to be unstable. Alkyl fluorides are also useful.

The alkyl moiety may be straight or branched chain, may be aliphatic, cycloaliphatic or unsaturated, e.g., alkanes and alkenes are useful.

Most preferred alkyl halides are later exemplified.

The hydrocarbons most preferably have 1 Oto 18 carbon atoms. They may be straight or branched chain and may be aliphatic, cycloaliphatic or unsaturated, e.g., alkanes and alkenes are useful.

Thefattyacid esters are conveniently represented bytheformula R1COOR2, R1 representing the acid moiety and R2 representing the alcohol moiety. It is most preferred that the total number of carbon atoms in R1 and R2befrom 10to 17.

R1 and R2 may be linear, branched, saturated, unsaturated, or aromatic.

The most preferred solvents as component B include the pyrrolidone-type compounds and the amides.

The pyrrolidones are most Dreferablv alkvl Dvrroli- donesoftheformula:

where R1 is an alkyl group containing up to 4 carbon atoms and n is 3 to 5.

The amides are most preferably represented by the formula:

where R2 can be hydrogen or an alkyl group with up to 3 carbon atoms and R3 and R4 can be an aliphatic group with upto 3carbon atoms.

The base compositions of the present invention can be prepared by homogeneously dissolving component A in component B. The amount of componentA to be used is generally from 0.1 to 80% by weight based on the total weight of components A and B, preferably 0.5 to 50% by weight Of course, pharmaceutically acceptable additives such as water, etc., can also be added to the base compositions.

The pharmaceutical compositions fortopical application per the present invention can be prepared by blending active agents with the above-described base compositions. There is no particular limit on the active agents used so long as the active agents are systemically active and percutaneously applicable.

Specific examples of active agents include benzodiazepines (e.g., Diazepam, Nitrazepam, Flunitrazepam, Lorazepam, Fludiazepam, Clonazepam), diuretic agents [e.g.,thiazides (e.g., Bendroflumethiazide, Polythiazide, Methyclothiazide, Trichloromethiazide, Cyclopenthiazide, Bentyl hydroch lorothiazide, Hydrochlorothiazide, Bumetanide)], antihypertensive agents (e.g., Clonidine), antihistamic agents [e.g., aminoethers (e.g., diphenhydramine, Carbinoxamine, Diphenylpyraline), ethylenediamines (e.g., Fenbenzamine), monoamines (e.g., Chlorophenylamines)j, non-steroid antiinflammatory agents (e.g., Indomethacine, Ibuprofen, Ibufenac, Alclofenac, Diclofenac, Mefenamic acid, Flurbiprofen, Flufenamic acid, Ketoprofen), antitumor agents (e.g., 5 - fluorouracil, 1 - (2 -tetrahydro- furyl) - 5 -fluorouracil, Cytarabine, Floxuridine), steroid antiinflammatory agents (e.g., Cortisone, Hydrocortisone, Prednisolone, Predonisone, Triamcinolone, Dexamethasone, Betamethasone), antiepileptic agents (e.g., Ethosuximide), antiarrythmic agents (e.g., Ajmalin, Purajmalin.Pindolol, Propranolol, Quinidine), psychotropic agents [e.g., Clofluperol, Trifluperidol, Haloperidol, Moperone), scopolamines (e.g., methyl scopolamine, butyl scopolamine), Metoclopramide, Chlorpromazine, atropines (e.g., methyl atropine bromide, methylanisotropine bromide), vascular dilating agents (e.g., isosorbide dinitrate, nitroglycerine, pentaeryth ritol tetranitrate, propanyl nitrate, dipyridamole), antibiotics, e.g., tetracyclines (e.g., Tetracycline, Oxytetracycline, metacycline, doxycycline, Minocycline), chloramphenicols, erythrnmycinesj, etc. The method of the present invention can also be utilized to percutaneously administer peptides such as LH-RH, insulin and the like. Of course, pharmaceutically acceptable salts such as the hydrochloride, sodium chloride, potassium, or hydrogen bromide salts can be used.

Since the present invention is of particularapplica- tion with respect to the benzodiazepine materials, these are discussed in more detail below. Particularly preferred benzodiazepine materials are those which have the benzodiazepine skeleton as schematically illustrated

wherein Xis Cl, Br, or NO2 andY is

with varying degrees of unsaturation and substitution at positions 1,2,3,4 and 5 as follows: a) 1,2 and 4,5 are unsaturated: Ra and R3 are H; R2 is # (R is H or CH3) and N-Z is N# O.

b) 1,2 are saturated and 4,5 are unsaturated: R3 is H or -R2 is -H or=O or=N*; R1 is # (R is H,CH or CH2-}, or CH2-CH2-N(C2H5)2 or R1 is C(R)=N* (R is H or CH3) and is joined to R2 via "*" (a single bond) as

c) 1,2 and 4,5 are saturated: R1 is H; - R2 is =O; R3 is H and positions 4 and 5 constitute a second ring system as

where Rand R' are H and CH3.

Specific examples of benzodiazepines which can be percutaneously administered using the active ingrndient'penetration adjuvant combinations of the present invention include: a) Chlordiazepoxide; 7 - Chloro - 2 - methylamino 5- phenyl - 3H - 1,4- benzodiazepine - oxide.

b) Diazepam; 7 - Chloro - 1,3 - dihydro - 1 - methyl 5 - phenyl -2H - 1,4 - benzodiazepine - 2 - one.

c) Oxazepam; 7 - Chloro - 1,3 - dihydro -3 - hydroxy - 5 - phenyl - 2H - 1,4 - benzodiazepine - 2 one.

d) Temezepam; 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 - one g) Fludiazepam; 7-Chloro - 1,3-dihydro-5- (2fluorophenyl) - 1 - methyl - 2H - 1,4 - benzodiazepine 2-one.

h) 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 - phenyl - 1 H - 5,4 - benzodiazepine.

j) Bromazepam; 7 - Bromo - 5(2 - pyridyl) - 3H - 1,4 - benzodiazepine - 2(1 H) - one.

k) Nitrazepam; 1,3-Dihydro-7-nitro -5-phenyl 2H - 1,4- benzodiazepine-2-one.

I) Nimetazepam; 1-Methyl-7-nitro-5- phenyl 1,3 - dihydro - 2H - 1,4- benzodiazepine - 2 - one.

m) Clonazepam; 5-(o-Chlorophenyl)-7-nitro1H-1,4-benzodiazepine-2(3H)-one.

n) Flunitrazepam; 5 - (o - Fluorophenyl) - 1,3 dihydro-1 -methyl-7- nitro-2H-1,4- benzodiazepine - 2 - one.

o) Estazolam; 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 - a) (1,4) - benzodiazepine.

q) Alprazolam; 8- Chloro - 1 - methyl - 6 - phenyl 4H-s-triazolo (4,3-a) (1,4)-benzodiazepine.

r) Oxazolam; 10-Chloro-2,3,5,6,7,11b-hexahydro - 2 - methyl - 11 b - phenylbenzo(6,7) - 1,4 diazepino(5,4- b - oxazol - 6 - one.

s) Cloxazolam; 10-Chloro-llb-(o-chlorophenylJ - 2,3,5,6,7,11 b - hexahydrobenzo(6,7) 1,4-diazepino - (5,4 - b)oxazol - 6 - one.

t) Haloxazolam; 10-Bromo-11b-(ofluorophenyl) - 2,3,7,11 b - tetrahydro - oxazolo(3,2, d) (1,4)benzodiazepine-6(5H)-one.

Especially preferred are benzodiazepines b), e), i), k), l), n) and o).

The amount of active agent(s) blended is sufficient if it is effective for achieving the desired pharmaceutical effect, which varies depending upon the kind of active agents, body weight of the patient, symptoms, etc. The amount may thus be suitably chosen depending upon these conditions. In general, it is preferred that active agents be employed in an amount of 0.01 to 50% by weight, more preferably 0.05 to 10% by weight, based on the total amount of the PAEC comprising componentA and component B.

The dose ofthe active agents administered can be controlled by increasing or decreasing the area of skin to which the pharmaceutical compositions are applied. Accordingly, the amount ofthe active agent is not necessarily limited to the above-described ones.

As will be apparentto one skilled in the art, with increasing concentrations of active agent, increasing amounts of active agent will be absorbed by the subject The following discussion is given in terms of blood levels of drug (ng/ml of plasma), this being dependent upon thetotal area of dermal application, as there is a substantially linear increase in amount of active agent absorbed with area.

For a constant area of application and a constant absolute amount of adjuvant, the blood level of active agent at any given time is a function of the concentration of active agent in the composition. That is, increased concentrations of active agent in the formulation result in more rapid active agentpenetration and higher blood levels.

Afurtherfactorwhich must be considered is that the amount of active agent absorbed will depend on the site of application, for example, scalp, ventral forearm, behind the ear, chest, etc. Typically an area rich in blood vessels is selected.

For most applications, the concentration of active agent inthe PAEC will generally be ofthe order of 0.01 to 50%,the amount of PAEC applied will be about 0.1 mg to 100 mg per cm2 and the total area of application will be on the order ofabout 0.5 cm2to about 10cm2 which will provide therapeutic blood levels ofthe desired active agent.

These ranges are not, however, to be considered as limitative.

In general, the rate of transepidermal active agent absorption will approach the rate of oral absorption depending upon the factors previously discussed (nature and amount of PAEC, concentration of active agent in the formulation, and surface area of skin application). Thus, peak blood levels of the active agent may be reached more slowly or at about the same rate and will reach aboutthe same level as those obtained by oral administration. Alternatively, the blood level of active agent attained by single dose oral administration may be maintained for an extended period by subsequent percutaneous administration ofthe active agent.In the latter case, the initial oral dose may be smallerthan the normal therapeutic oral dose so that side effects associated with higher than - minimal therapeutic blood levels attained by a reduced oral dose may be maintained by the subsequenttransepidermal administration art a proper rate.

Therapeutic oral doses of diazepam in man pro duce blood levels of approximateiy 100 ng/ml plasma [S. A. Kaplan, ML. Jack, K. Alexander, and R. E.

Weinfield, J. Pharm. Sci., 62,1789-1796(1 973)1. Such a blood level is easily attainable by percutaneous administration by way of the present invention and produces pharmacological (behavioral) signs ofther apeuticeffectiveness in appropriate animal models for man, e.g.,the rhesus monkey.

The method ofthe present invention finds application with mammals in general, most particularly man and domestic animals such as cows, sheep, horses, dogs, cats and the like.

The pharmaceutical composition of the present invention is administered to the outer skin as a simple mixture or as a medical preparation by adding known pharmaceutically acceptable third components in the form of solutions, ointments (paste-including creams and gels), lotions, adhesive tapes, a plaster, etc.

For example,solutions may simply comprise the active agent dissolved in the PAEC with optional components, e.g., glycerin, and the solutions may be incorporated into absorbents, e.g., a gauze, porous membrane, etc.

Ointments, gels or creams may contain conventional ingredients (e.g., polyethylene glycol and hydroxy propyl - cellulose, etc.) toform the same, and the same may be spread onto backing materials, e.g., a plastic film.

Similarly, plasters or adhesives tapes may contain the active agent and PAEC in an adhesive base, e.g., acrylic copolymers or other synthetic gums.

The PAEC may be added to such a composition in varying amounts as desired, generally from lotto 99% by weight.

In developing the present invention, we have used both diffusion cells and an animal model. The diffusion cell methods provided a qualitative assessment ofthe active agent/PEAC effect on percutaneous absorption and the animal model (rhesus monkey) test provided the most acceptable pharmacokinetic model for man as indicated in J. Soc. Cosmet. Chem., 30,297-307. Sept/Oct. 1979 and Toxicol. Appl.

Pharmacol.,32,394-398, 1975.

EXPERIMENTAL In Vitro Skin Penetration Studies with Diffusion Cell Technique Rat full thickness skins were used in the following two types of diffusion cell methods.

The skin was excised from the shaved abdominal site of male albino rats weighing 250/300 g, and washed with normal saline solution afterthe subcutaneous fat was carefully removed with scissors.

In examples 1 to 34 and 37,the finite dose technique of Franz, Curr. Probl. Dermatol., Vol.7, p.

58/68 (Karger, Basel, 1978) was followed. The rat skin was mounted horizontally in a diffusion cell apparatus; the exposed area ofthe skin approximated 0.7 cm2.

The active agent/PEAC solution of known concentration was added to the upper compartment ofthe cell, which was exposed to the epithelial side ofthe skin and a normal saline solution was placed in the lower compartment.

The penetration rate was studied in a thermostated bath at 30"C. At appropriate intervals samples were withdrawn from the lower compartment and subsequently analyzed for active agent concentration by standard analytical methods.

In examples 35 and 36, transdermal penetration effects were analyzed following the method of Michaels, AIChE Journal, 21 [5], 985-996,1975. The rat skin was mounted in the diffusion cell in a vertical position between the upstream and the downstream compartments; the exposed area of the skin approximated 4.15 cm2.

The active agent/PEAC solution of known concentration was added to the upstream compartment to which the epithelial side of the skin was exposed, and a normal saline solution was added to the downstream compartment.

In Vivo Rhesus Monkey Test Male rhesus monkeys weighing 10-14 Kg each were used as the subject An appropriate area ofthe monkey's chest was shaved 24 hours before drug application.

Drug formulations comprising the PEAC were applied to a certain area ofthe chest as indicated in each example. The monkey was restrained in a chair to prevent it from touching its chest.

Blood samples were taken at appropriate intervals aftertheapplication.Theheparinized blood was centrifuged, and the plasma was removed and stored at -20 Cuntilanalyzed.

Diazepam in plasma was analyzed following the GLC method of Aingales, J. Chromatog., 75,55-78, 1973.

The results are set forth in the following Examples.

Hereafter the present invention will be illustrated with reference to the examples and experiments in more detail, but it is not to be deemed to be limited thereto.

Examples 1 to 23 [Basic Formulation] (1) Diazepam 3g (2) Component 72g (3) ComponentA 259 Liquid compositions having the above-described basic formulation were prepared using the compo nents shown in Table 1 as (2) and (3), respectively, by firstly mixing (3) with (2) and then dissolving (1) in the mixture. In the case that component B was a solid at ambient temperature orwas not homogeneously mixed with component A, 20 wt.% of ethylene glycol monobutyl ether based on the weight of components A and B was used as an agent for assisting dissolution (in this case, a * mark is attached in Table 1).

Control Formulation 1 (1) Diazepam ag (2) Component B 97g The 23 examples of Control Formulation 1 thus obtained were used to calculate the Q values later described.

Compositions were obtained using only component B described in Table 1, respectively, by dissolving (1) in (2) wherein ComponentAwas not present in the Examples.

Comparative Examples 1 and2 (1) Diazepam 3g (2) Polarcompound 729 (3) ComponentA 259 The compositions described above were prepared using componentA and a compound (see Table 2) outside the present invention, in accordance with the procedures of Examples 1 to 23.

Comparative Examples 3 and 4 (1) Diazepam 3g (2) Component B 72g (3) Non-polarcompound 259 The compositions described above were obtained using component B and a compound (see Table 3) outside the present invention, in accordance with the procedures of Examples 1 to 23.

The amount of transport ofthe active agent in the compositions obtained in Examples 1 to 23, Control Formulation 1 and Comparative Examples 1 to 4 through the rat skin was measured as earlierdescribed. The results are shown in Table 1, Table 2 and Table 3.

In Table 1, Table 2 and Table 3, the Qvalue has the following meaning: C/D=Q C: Transport of active agent through the skin in the Examples and the Comparative Examples.

D: Permeation amount of active agentthrough the skin in Control Formulation 1.

Table 1 Example No. Component B Component A Q Value 1* methyl lactate bexane 3.4 2* methyl lactate dodecane 4.0 3* methyl lactate dodecyl bromide 22.0 4 methyl lactate isopropyl myristate 4.8 S* methyl lactate dihexyl ether 12.4 6 methyl lactate 2-dodecanone 2.6 7* ethyl J actate dodecane 2.9 8 ethyl lactate isopropyl myristate 4.9 9 butyl lactate dodecane 2.2 10* e-thioglycerol isopropyl myristate 9.0 11 N,N-dimethyl ethylene urea dodecane 5.3 12 N,Ndimethyl ethylene urea isopropyl myristate 8.5 13* propylene urea isopropyl myristate 4.7 14* l,3-diaethyl Urea isopropyl myristate 4.2 15 1,1,3,3-tetramethyl isopropyl myristate 10.7 urea 16* 2-pyrrolidone isopropyl myristate 9.2 17 N-nethyl-2- pyrrolidone isopropyl myristate 14.2 18 N-methyl-2 piperidone isopropyl myristate 13.2 19 N-methyl #-caprolactam isopropyl myristate 11.5 20 N,N-di ethyl acetaide isopropyl tyristate 13.8 21 N,N-diethyl acetamide isopropyl myristate 12.2 22 N,N-disethyl propionaaide isopropyl myristate 12.9 23 -butyrolactone isopropyl myristate 4.9 Table 3 Comparative Component A Example No.Component B (false) Q Value 3 N-methyl-2- tetraethylene 0.9 pyrrolidone glycol 4 N-methyl-2- ethyl alcohol 1.1 pyrrolidone Table ' Comparative Component B Example No. (false) Component A O Value 1 glycerin isopropyl 0.6 triacetate myristate 2 N,N-diethyl isopropyl 1.4 toluamide myristate Example 24 (1) Diazepam 3% (2) Component B (3) ComponentA 100-09 Compositions were prepared by dissolving 3 g of diazepam in 100 g mixtures of component B and componentA prepared by varying the mixing ratio (weight ratio) from 100:0 to 0:100. With the respective compositions thus obtained, the skin permeation rateofdiazepamfor8 hours was measured and the results are shown in Fig. 1.In Fig. 1,they-axis indicates relative values ofthe permeation rates of each ofthe compositions to the permeation rate of the active agent with the composition comprising component B alone and the x-axis indicates the % by weightof component Btothetotal weight of componentA and component B. Component B was N,N,N',N'-tetramethyl urea and component A was isopropyl myristate.

Examples25-34 (Basic Composition A) (1) active agent 3y (2) 25 volume % isopropyl myristate in dimethyl propionamide (based on total volume 979 (Comparative Composition B) (1) active agent 39 (2) dimethyl propionamide 979 (Comparative Composition C) (1) active agent 39 (2) acetone 979 The above compositions of various active agents shown in Table 4were prepared andtheflux rate of the active agent was measured. The results are shown in Table 4.

Table 4 Composition Example A B C No. Active Agent Flux ( g/cm/24 hr@) 25 tetracycline 2157 355 0 26 chloramphenicol 272 182 8 27 scopolamine (free base) 3039 1596 685 28 haloperidol 327 357 22 29 bendroflumethiazide 92 26 - 30 chlorpheniramine maleate 1091 329 348 31 ibuprofen 1095 835 242 32 dichlorfenac sodium 829 588 @28 33 flufenamic acid- 598 311 26 34 indomethacine 394 150 30 NOTE: in the case of formulation C, the upper compartment ofthe diffusion cell was open to the air and the acetone was evaporated off.

Further, in the following examples, the abbreviations below are used: EtOH - ethanol C12C1 - dodecyl chloride iPrM - isopropyl myristate DMAc - di methyl acetamide MP - methyl pyrolidone Unless otherwise indicated, in all ofthefollowing examplesthe active agent is diazepam, diazepam flux is given in terms of g/cm/8 hours, 25 volume percent component B with respect to component A and component B volume was used in the composition and 2.5 weight percent diazepam was used. For purposes of comparison, in certain instancesthe resultsforsolvents alone and adjuvants alone are given.

Example 35 This example shows the use of an alkyl halide as componentAin combination with a pyrrolidone or an amide as component B.

All results are in termsofdiazepam flux ratefor8 hoursthrough the skin.

The flux values for 8 hours are shown in Table 5.

Table 5 Diazepam Flux Component B Component A ( g/cm/8 hrs) N-methyl-2-pyrrolidone - 94 N,N-dimethyl acetamide - 139 - 1-chlorododecane 40 N-methyl-2-pyrrolidone 1-chlorododecane 849 N,N-dimethyl acetamide 1-chlorododecane 887 Example 36 This exampleshowsthe use of pyrrolidones as component B and a fatty acid ester as componentA forthe present invention.

With isoproply myristate alone the diazepam flux was 29. With N-methyl pyrrolidone alone the flux was 94. For 25% iPrM in MP,thefluxwas 530.

Again, the synergistic effect of the PAEC of the present invention is easily seen.

Also, for nitrazepam, a type of benzodiazapine as is diazepam, a flux of 524 was obtained with 25% iPrM in MP.

Table 6 shows the relative diazepam fluxwith lower concentrations of Pr Min MP compared to the flux with 25% iPrM in MP. Also Table 9 shows substantial ly greaterfluxfor a higher N-alkyl derivative of a 2-pyrrolidone, N - ethyl -2 - pyrrolidone, as opposed to N-methyl-2-pyrrolidone.

Table 6 Relative Flux 2SX iPffl in BE am 1 10% iPrM in MP 1.0 5% iPrM in MP 1.0 1% iPrM in MP 0.5 25% iPrM in N-methyl-2-pyrrolidone 1.5 Example 37 This example shows the use of fatty acid esters as component A and amides as component B.

For 25% iPrM in DMAc, the diazepam flux was 749.

Table 10 shows the relative flux of 25% various fatty acid esters in various amidesto 25% iPrM in DMAc. Also, as a comparison, the relative flux of combinations, at least one of which was outside of this invention,to25% iPrM in DMAc is shown in Table 7.

Table 7 Formulations Relative Flux 25% methyl caprylate in DMAC 1.0 25% methyl laurate in DlFc 1.4 25T isopropyl myristate in DMAc as 1.0 2SX ethyl palpitate in DMAc 0.50 25% (isopropyl palmitate) in DMAc 0.35 2SX (ethyl stearate) in DMAC 0.15 25: isopropyl myristate in diethyl formide 1.1 25X isopropyl myristate in am as 1.0 2SX isopropyl myristate in diethyl acetaiide 0.90 25: isopropyl myristate in dimethyl propionalide 0.95 25 isopropyl myristate in (dimethyl) formamide) 0.60 25X isopropyl myristate in (methyl acetside) 0.10 Note: Compounds in ( ) are outside of this invention.

Example 38 This example shows in vivo plasma Diazepam levels with a topical diazepam formulation using a combination of componentA and component B of this invention.

150 g of diazepam was dissolved in 6 ml of 25% C12Cl in MP. To this solution was added 1.2 g of polyvinyl pyrrolidone (Aldrich Chemical Co; Cat. 85, 647-9; molecularweight approx. 36,000). Aviscose solution was obtained.

0.5 ml ofthe solution was placed in a polyester cup 4 cm2 in diameter, 2 mm in depth and having a volume of 0.5 ml. The solution in the cup was placed on the monkey's chest and fixed thereto with adhesive. As a comparison, a 10 mg Diazepam tablet (Valium; Roche) was given orallyto the same monkey. The results are shown in Table 8.

Table B Diazepam Plasma Level (rlv/ml of plasma) Foriulations 1 hr 3 hr 5 hi 7 hr Topical Foraulation 34 42 37 30 oral Adainistration 50 - 34 Example 39 This example shows in vivo plasma diazepam levels with a topical gel formulation.

150 mg of Diazepam was dissolved in 6 ml of 25% iPrM in N,N' - dimethyl ethylene urea. To this solution was added 120 mg of Klucel (cross-linked hydroxypropylcellulose type HF, Hercules Inc.) and the same stirred thoroughly to obtain a uniform gel.

1.0 ml ofthe gel was applied to 49 cm2 ofthe chest area ofthe monkey; the applied area was left open to the airforthe duration oftheexperiment.Theresultis shown in Table 9.

Table 8 Diazepam Plasma Level (ug/el of plasma) Formulations 1 hr 2 hr 3 hr 5 hr 7 hr Gel 215 181 147 132 128

Claims (17)

1. Pharmaceutical composition suitable for percutaneous administration which comprises a physiologically active agent dissolved in a mixture of at least one of the following components A and at least one of the following components B: ComponentA: straight, branched or cyclic aliphatic hydrocarbons having 5to 24carbon atoms, straight, branched orcyclicaliphatic hydrocarbons having 5to 24 carbon atoms substituted with one or more halogen atoms, an alcohol ester of an aliphatic carboxylicacid having a total number ofcarbon atoms of from 7 to 18, a mono or diether having 10 to 18 carbon atoms, a ketone having 11 to 15 carbon atoms, and mixturesthereof; Component B:: athioglycerol,a lactic acid oran esterthereof, a cyclic urea, alactone, a compound represented by the general formula:

where 1 to R4 each represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an acyl group having 1 or 2 carbon atoms, a compound represented by the general formula:

wherein R5 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms and n represents an integer of 3, 4 or 5, a compound represented by the general formula:

wherein Re represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms and R7 and R8 each represents an alkyl group having 1 to 3 carbon atoms, with the proviso that Re, R7 and R8 have in total at least 3 carbon atoms.

2. AcompositionasclaimedinClaim 1,wherein ComponentA is an alkylhalide, cycloalkyl halide, alkene halide or cycloalkene halide.

3. Acomposition as claimed in Claim 2, wherein said halide has 8 to 16 carbon atoms.

4. A composition as claimed in Claim 1, wherein componentAisa hydrocarbon.

5. Acomposition as claimed in Claim 4,wherein said hydrocarbon is saturated or unsaturated and may be cylicand has 10 to 18carbon atoms.

6. AcompositionasclaimedinClaim 1,wherein component A is a fatty acid ester.

7. A composition as claimed in Claim 6wherein the ester has from 11 to 18 carbon atoms.

8. Acomposition as claimed in any preceding claim, wherein component B is ofthe general formula:

where n is3to 5 and R1 is an alkyl group containing from 1 to4carbon atoms.

9. Acomposition as claimed in any one of claims 1 to 7, wherein component B is represented by the general formula:

where R2can be hydrogen oran alkyl group with upto 3 carbon atoms, with the proviso thatthetotal number of carbon atoms in R2, R3 and R4 is at least 3.

10. Acomposition as claimed in any preceding claim, wherein said active agent is a benzodiazepine.

11. A composition as claimed in Claim 10, wherein said benzodiazepine is ofthe general formulae (B) shown and defined hereinbefore.

12. A composition as claimed in any preceding claim, wherein componentA constitutes 0.1 to 80 weight percent of components A and B.

13. A composition as claimed in Claim 12, wherein componentA constitutes 0.5 to 50 wt. % of A and B.

14. Acomposition as claimed in any preceding claim, wherein the active agent constitutes 0.01 to 50 weight percent of component A and B.

15. A composition as claimed in any preceding claim, together with additional carrier components to form a solution, ointment, lotion, adhesive tape, or incorporated into an absorbent vehicle.

16. A pharmaceutical composition as claimed in Claim 1, substantially as hereinbefore described with reference to any of the foregoing Examples.

17. A method of pharmaceutical administration to a mammal which comprises applying to the skin thereof a composition as claimed in any preceding claim.