CA1216522A - Penetrating topical pharmaceutical compositions containing corticosteroids - Google Patents

Abstract

IMPROVED PENETRATING TOPICAL
PHARMACEUTICAL COMPOSITIONS
CONTAINING CORTICOSTEROIDS
ABSTRACT

Topical pharmaceutical compositions containing a cortico-steroid component and a penetration-enhancing vehicle are dis-closed. The vehicle comprises a binary combination of a C3-C4 diol and a "cell-envelope disordering compound". The vehicle provides marked transepidermal and percutaneous delivery of corticosteroids. A method of treating certain rheumatic and inflammatory conditions, systemically or locally, is also disclosed.

Description

IMPRC)VED PENETRATING TOPICAL
PHARMACEUTICAL COMPOSITIONS
CONTAlNiNG C:ORTICOSTEROIl)S
Eugene R. Cooper Maurice E. Loomans Mahdi B. Fawzi T ECH N I CA L Fl ELD
The present invention relates to topical compositions effective in delivering high levels of certain pharmaceu~;cally--active cor-ticosteroid agents through the integument.
BACKGROUND OF THE INVENTION
Because of the ease of access, dynamics of applieation, large surface area, vast exposure to the circulatory and iymphatic networks, anci non-invasive nature of the treatment, the delivery of pharmaceutically-active agents through the skin has long been a promising concept. This is true whether the bioavailability desired is systemic or dermal, regional or local.
The advantages of this form of delivery includa, but are not limited to: avoidance of the risks associated with parenteral treatment; elimination of the inconveniences of parenteral treat-ment; avoidance of the variable rates of absorption and metabolism inherent in oral treatment; increasing the continuity of drug administration by permitting delivery of agents with short biologi~
cal half-lives; and elimination of gastrointestinal irritation re-sulting from exposing the gastrointestinal tract to pharmaceutical actives~ preservatives, tabieting agents, and the like. Most importantly, topica! deiivery possesses the potential ~or effectively treating conditions which are local in nature (or which exhibit local manifestations), systemically as well as locally with the same treatment regimen~ Thus, effective compositions to deiiver pharmaceutical agents are highly sought after.
However, because it must serve as a barrier to the ingress of pathogens and toxic materials, and the egress of physioiogic fluids, the skin is highly impermeable. It must be impermeable to preserve its own integrity while 3t the same time maintaining the delicate dynamic electrolyte balance of the body. The skin must _~ r~

~ ~g~9 serve a containment function; it must also function as a microbial, chemical, radiation and thermal barrier.
A good deal of this impermeability of the skin results from the nature of one very thin layer crea~ed by normal developmental 5 and physiological changes in the skin. After ce!is are formed in the basal layer, they begin to migrate toward the skin surface, until they are eventually sloughed off. As they undergo this migration, they become progressively rnore dehydrated and keratinized. When they reach the surface, just prior to being 10 discarded, they form a thin layer of dense, metabolically inactive cells approximately ten microns (10-15 cells) thick. This layer is cailed the stratum corneum or the cornified layer . As a result of the high degree of keratinization of the cells which comprise the stratum corneum, a formidable barrier is created. Therefore, 15 penetration via the nonpolar route, i . e., across the membrane of these celis, remains most difficult.
Other possible penetration routes are available. First, any mechanism which allows the egress of materials, e.g. the sebaceous apparatus, can be manipula~ed to allow the ingress of 20 materials. Second, the straturn corneum, though keratinized to a great degree, is composed of about 15% lipid-based intercellular material. This may offer a less formidable route despite the close packing of the cells.
It is known that certain binary skin penetration systems can 25 increase the disorder of these lipids. By so increasing the disorder of the lipid portion of the cell-envelope in the stratum corneum, the lipid packing of the cells can be disrupted. This disruption allows certain pharmaceutically active agents to pass through the stratum corneum. This discovery has been confirmed 30 by differential scanning calorimetery, indicating that certain binary skin penetration enhancement systems eliminate the Tm-2 peak associated with melting of cell-envelope lipids.
Adrenal corticosteroids, and the synthetic analogues thereof, are some of the most usefui pharmaceutical actives known in the 35 art. These compounds have the capacity to prevent the develop-ment of, or suppress existing, localized heat, redness, tenderness and sweiling which characterizes any inflammation of skin or mucous membrane. The utility of these compounds is magnified in a clinical setting by the fact that corticosteroids inhibit this inflammatory response whether the inciting cause or S agent is radiant, mechanical, chemical, infectious or immunologi-cal. Since the first recognition of the potent anti-inflammatory properties of these compounds in 1949, thei r therapeutic uses have increased dramatically. The unique biochernical, pharmaco-logic and physiologic properties of corticosteroids make them 10 almost universally useful in the topical treatment of inflammatory conditions .
Corticosteroids are also useful in treating many conditions when used by systemic application. For example, their potent, anti-inflammatory and immunosuppressive effects make them useful 15 in the treatment of most rheumatic conditions and diseases.
While corticosteroids are highly effective in the treatment of the above systemie and local conditions, they suffer from one significant disadvantage. The size and shape of corticosteroids makes them exceedingly difficuit to deliver percutaneously.
20 Conventional and commercial topical steroid preparations are only marginally effective in delivering sufficient steroid for immediate treatment of local conditions; systemic steroid treatment by percu-taneows delivery from known vehicles is virtually impossible.
Accordingly, a vehicle system which increases both the level and 25 speed of penetration of the steroid through the skin would be more efficient in the treatment of localized conditions and, more importantly, would greatly increase the chances of making systemic treatment by topical application viable. Effective systemic delivery of steroids by the topical mocle of treatment is 30 highly desirable since the topical treatment would result in 3 lower level of side effects than those associated with conventional ~oral or parenteral) methods of administrtation when systemic steroid therapies are indicated.
It has now been discovered that steroids can be effectively 35 dellvered percutaneously by incorporating them into a specific vehicle which provides an exceptlonal increase in penetration over ~ 0~, l ~
~ ~ D~

conventional steroid vehicies, and, more surprisingly, at a rate which now makes the systemic method of administering steroids percutaneously a practical alternative. Specifically, it has been discovered that a select number of combinations of a binary 5 penetration system comprising a cell-envelope disordering compound and a diol compound, heretofore thought only to be useful in delivering nonsteroidal varieties of anti-inflammatory actives and select substituted adenosine- and guanine-derived antivirals, can consistently and dramatically improve the topical 10 delivery of certain corticosteroids, such as triamcinolone aceto-nide, when used in a vehicle or formulation which is free of certain common solvents, cosvlvents, excipients and lipids other than the selected cell-envelope disordering compound.
U.S. Patent 4,343,798, Faw~i, issued August 10, 1982, 15 describes topical antimicrobial/anti-inflammatory compositions containing C5-C12 fatty acids in combination with corticosteroids.
U . S . Patent 3, 934, 013, Poulsen, issued January 20, 1976, describes topical pharmaceutical compositions containing at least two corticosteroids, propylene glycol, a fatty alcohol and water.
20 The patentee describes the "fatty alcohol ingredient" as any fatty alcohol having from 16-24 carbon atoms and, pre~rably, as a saturated, monohydric primary alcohol such as cetyl alcohol, stearyl alcohol or behenal alcohol.
U.S. Patent 4,289,764, Yarrow, et al., issued September 15, 25 1981, describes topical pharmaceutical compositions with increased shelf stability. These compositions comprise a steroid, 15-50% by weight propylene glycol and are buffereci to a pH of 2.7-3.3.
The specification describes the desirability of thickening the propylene glycol ldue to its low viscosity) with a compound 30 selected from long-chain paraffins, fatty aicohols, and waxes, including cetyl stearyl alcohol, white soft paraffin and liquid paraffin .
U.S. Patent 4,070,462, Ecker, issued February 24, 1978, discloses a topical vehicle which includes (i~ 5-15%
1,2-propanediol, 2,3-butanediol or 2-methyi-2,4, propanediol; lii) %

1-3% propylene glycol monostearate; and (iii~ petrolatums and waxes to 100%.
European Patent Application 13,459, published July 23, 1980~ describes compositions useful in the treatment of acne. These compositions contain benzoyl peroxide, C6-C14 primary alcohols7 and a diol selected from 1,2-propane-diol, 1,2-butanediol, 1,3-butanediol, and 2,3-butanediol.
A foreign equivalent of this application was made avail~
able to the public July 23, 1980. See European Patent Application 13,459.
Canadian Patent No. 1,165,240, issued April 10, 1984, describes compositions for topical application. These compositions described are suitable for effective deli-very of lipophilic, pharmacologically active compounds using primary alcohols or various carboxylate compounds in combination with selected diols. See European Patent Application 43,738.
Canadian Patent Application Serial Number 429,252, Cooper, filed May 31, 1983, discloses and claims a binary penetration system utilizing a diol and a cell-envelope disordering compound to aid in the penetration of 9-hydroxyethoxymethyl (and related) derivatives of 6- and

2,6~substituted purines. These purine compounds are reported to be effective in the treatment of viral in-f~ctions, especially herpes, and can be administeredparenterally, orally or topically. 9-~2-hydroxyethoxy-methyl)guanine is disclosed as being particularly active.
1,2-propanediol ("propylene glycoll') and the C10-C14 alcohols have been used, separately, in cosmetic and phar-maceutical formulations. In particular, propylene glycolhas been described in several articles in the literature as enhancing the penetration of certain pharmacologically active agentsl such as the corticosteroids. See Rosuold, J., et al., "Effect of Formulation On In Vitro Release and In Vivo Absorption of Corticosteroids from Ointments", ~edd. Novsk Favm Selsk, 44, 21~45 (1982); see also, Anjo, D.M., et al., "Methods for Predicting Percutaneous .~' Penetration in Man", Percutaneous Absorption of Steroids. pp 31-51, Academic Press, New York, New York (1980).
U.S. Patent 3,535,422, Cox, et al., October 20, 1970, relates to stable benzoyl peroxide compositions containing organic emollients. The compositions include emollients selected from the C -C aliphatic alcohols, C2-C3 glycols ~ C12 C20 y their esters, and mixtures thereof.
U.S. Patent 4,070,462, Ecker, issued January 24, 1978, describes topical steroid compositions containing 6% propylene glycol and 1~6 propylene glycol monostearate.
Canadian Patent 1,072,009, Sipos, issued February 19, 1980, describes topical antimicrobial compositions con~aininy C5-C1 0 straight chain alcohols or C17 branched chain alcohols in which, the longest chain is C5-C1 0.
CA 92:153,181j; describes an indomethacin ointment contain ing 10~ propylene glycol and 1.19~ diisopropanolamine.
U.S. Patent 2,990,331, Neumann, et al., issued June 27, 1961, ciescribes tetracycline compositions containing carboxylic acid alkylolamides.
H. Barnes, et al., Br J. Derm. 93, 459 (1975), describe testing of fluocinonide and fluocinolone acetonide in a vehicle described as fatty alcohol propylene glycol ~FAPG).
P,J.W. Ayres, et al., Br. J. Derm., 99, 307 (1978), report comparative skin penetration of cortisol from commercially available cortisol ointments, Schaaf and Gross, Dermatolog--a, 106, 357 11953), note that unsaturated fatty acids and C6-C1 4 saturated fatty acids are particularly active in provoking epidermal thickening~
J. ~atz, et al., J. Pharm. Sci., 67, 789 (1978), describe the effect of formulation factors on penetration of hydrocortisone through mouse skin.
S. K. Chandrasekaran, et al., J. Pharrn. Sci., 67, 1370 [1978~, discuss the pharmacokinetics of drug permeation through human skin.
B. Idson, Cosmetics ~ Toiletries, 95, 59 (1980), states that the factors affecting drug penetration and, consequently, in most ~65;~

cases, effectiveness, are complex. He observes that the vehicle that provides ideal conditions for one drug may prove unsatisfactory for another. The author concludes that prediction is not simple and product suitability must be assessed by human trials. The same article indicates that Synalar Cream, a topical corticosteroid preparation, contains sorbitan monooleate and propylene glycol.
M.M. Rieger, Cosmetics & Toiletries, 94, 32-37 (1979) ._________,_ __________ .__ and 95, 26-38 (1980), provides a review of current litera-ture in the area of skin penetration.
U.S. Patent 4,299,826, Luedders, issued November 10, 1981, describes a composition for the treatment of acne by using diisopropyl sebacate as a penetration enhancer for an erythromycin derivative in combination with an alcohol.
U.S. Patent 2,990,331, Neumann, et al., issued June 27, 1961, describes the parenteral administration of tetracycline salts from a stable aqueous solution.
CA 79: 122,308, describes an electromagnetic study of n-alkyl ionic surfactants as aiding in human epidermis penetration.
SUMMARY OF THE INVENTION
The present invention relates to improved compositions and methods for the percutaneous delivery of corticoste-roids to human and animal tissue and systems. The inven-tion provides penetrating corticosteroid compositions andtherapies, and is based on the use of a corticosteroid together with a binary mixture of a cell-envelope dis-ordering compound and a diol compound formulated (and applied) in compositions which are substantially free 3Q of any polar lipids or cosolvents which interfere with steroid penetration.
The composition of this inventions comprises: (a) a safe and effective amount of a pharmaceutically-active corticosteroid; (b) 0% to about 80% by weight of a sol-vent selected from the group consisting of water~ ethanolor 2-propanol; and (c) about 10% to about 99.9% by weight of a penetration-enhancing carrier consisting essentially of: (i) a diol selected from the group consisting of 1,2-propanediol, 1,2-butanediol, 1,3-butanediol, 2,3-butane~

,, %~%~
- 7a -diol, or mixtures thereof, and lii) a cell-envelope dis-ordering compound selected from the group consisting of methyl laurate, oleic acid, myristyl alcohol, or mix-tures thereof; wherein said diol and said cell-envelope disordering compound are present in a ratio of diol:cell-envelope disordering compound of from about 1~1 to about 500:1 by weight; and wherein said penetration-enhancing composition is substan~ially free from any single member of the C16-C20 straight chain, saturated normal fatty alcoholsl and C~-C20 straight chain, saturated mono or dicarboxylic acids.

. ~ . i %~

The compositions act to provicle effective topical treatment of corticosteroid-indicated conditions by effectively delivering high levels of the steroid through the skin. These compositions can be formulated to deliver steroids at levels and rates useful in local or systemic treatment. The effectiveness of this binary mixture, designed for lipophilic anti~ flammatory actives of the nonsteroidal variety, as well as selected antivirals, is surprising in light of the dissimilar nature of the steroid active.
The inven~ion also encompasses treatment regimens for inflammatory or other steroid-indicated conditions comprising topically administering to a human or lower animal in need of such treatment a safe and effective amount of the composition. The composition is applied at the afflicted sitis when the condition being treated is responsive to local treatment regirnens.
DETAILED DESCRIPTION OF THE INVENTION
By "topical administration", as used herein, is meant directly iaying on or spreading on epidermal tissue, especially outer skin or membrane, including the skin or membrane of the oral or vagTnai cavi~ies.
By "safe and effective amount", as used herein, is meant a sufficient amount of the composition to provide the desired immunosuppresive or anti-inflammatory effect and performance at a reasonable benefit/risk ratio attendant any medical treatment.
Within the scope of sound meciical judgment, the amount of phar-maceutical active used will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the specific compound employed, its concentration, the condition of the patient, concurrent therapies being administered, and like factors within the specific knowledge and expertise of the patient or the attending physiclan.
By "toxicologically- or pharmaceutically- acceptable", as used hereln, is meant the steroid compounds, as weli as the other compatable drugs, medicaments or inert ingredients which the term describe~ are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/ risk ratio.
By the term "comprisin~", as used herein, is meant that various other compatible drugs and medicaments, as well as inert 5 ingredients, occlusive agents, and cosmetic vehicles, çan be con-jointly employed in the compositions and processes of this in-vention, as long as the critical binary penetration enhancement vehicle and pharmaceutical active are used and the penetration-interfering lipids are limited in the manner disclosed 10 herein. The term "comprising" thus encompasses and includes the more restrictive terms ~'consisting of" and "consisting essentially of" which characterize the use of the essential in-gredients in the manner disclosed herein.
By "afflicted situs", as used herein, is meant a localized 15 area of inflammation or lesion, and the immediately surrounding area .
~ y "application situs", as used hereint is meant a site suitable for application via a mechanical sustained release device or dressing, e . g ., behind the ear, on the back, leg, arm, top of 20 the ~oot, etc.
By "penetration-enhancing", as used herein, is meant that the binary penetration enhancing carriers of this composition provide marked transepidermal or percutaneous delivery of an incorporated steroid, when compared to other compositions at 25 equal chemical potential. This latter aspect is important, since varying solubilities of drugs in different vehicles will necessarily affact their transport across skin. Thus, for example, if a drug is soluble in vehicle A to the extent of 24~, and in vehicle B to the extent of 4%, if the compositions were to be compared at equal 30 percentage concentration, rather than equal chemical potential, the lower solubility carrier will show a misleading six-fold di~-ference in transport over the more soluble vehicle. The simplest way of assuring equal chemical potential for evaluating penetration enhancen~ent is to use saturated solutions or solutions of equal 35 percentage of saturation of pharmacological active in the various vehicles, ~%~6S;~

By "substantially free", as used herein, is meant that the penetration-enhancing compositions and carriers of the present invention contains less than about 3. 5%, preferably less than about 1~, and most preferably less than about 0 . 5%, of any single or specific compound, or member of the group of compounds, described by this term.
As used herein, all percentages are by weight unless other-wise specifi7~d.
The compositions of this invention require, at a minimum, a corticosterold active useful as an Immunosuppresive or anti-inflam-matory agent, a diol compound, and a cell-envelope disordering compound. The compositions of this invention may additionally contain other optional components which reduce skin irritation, or, enhance their cosmetic appeal and acceptability, i.e., thickeners, pigments, and the like. The composi~ions must be substantially free from penetration-interfering polar lipids or polar cosolvents, particularly straight chain C16-C~0 saturated primary alcohols, and C4-C20 mono- or dicarboxylic acids, STE RO I DS
The steroid components useful in the present invention are well-known in the pharmaceutical art. While many types of ster-oids may be used, including contraceptive-type steroids, cortico-steroids are preferred. These are described in detail in Miller and Munro, Dru~s, 19, 119-134 (1980): and Wolfe, Burger's Medicinal Chemistry, 3, 4th Ed., John Wiley and Sons, New York, New York, pp. 1273-1316, 917-1309 (1981). The essen-tial s-teroid structure consists of 17 carbon atoms, arranged in 4 rings, 3 six-n~mbered rings and one 5-membered ring,(See Base steroid structure, below~. Since this is a rigid structure, small changes in the subst~tuents can lead to significant changes in biological acti-vity. This is presumably the result of a change in the interaction with specific site receptors involved in protein metab~lism.

,.

`~j ~, ~BASE STEROID STRUCTURE~
Many valuable anti-inflammatory steroids have been developed by various modifica~ions of the basic steroid structure. For lO example, the introduction of a double ~ond at the 1,2 position into hydrocortisone increases glucocorticoid activity by approxi-mately 4 orders of magnitude while at the same time reducing mineralo corticoid effects. Prednisone and prednisolone are examples of such a modification.
Exampies of corticosteroids useful in the present invention include, without limitation are hydroxyltriamcinolone, alpha methyl dexamethasone, beta methyl betamethasone, beclomethasone dipro-pionate, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, clobetasol valerate, desonide, desoxy-20 methasone, dexamethasone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butyl-ester, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcir:onide, hydrocortisone acetate, hydrocor-25 tisone butyrate, methylprednisolone, triamcinolone acetonide,cortisone, cortodoxone, flucetonide, fludrocoreisone, difluorosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcina-fide, betamethasone and the balance of its esters, chioropredni-sone, clocortelone, clescinolone, dichlorisone, difluprednate, 30 flucloronide, flunisolide, fluoromethalone, fluperolone, flupred-nisolone, hydrocortisone, meprednisone, paramethasone, predniso-Ione, prednisone, beclomethasone dipropionate.
Mixtures of corticosteroids, particularly any of the above eorticosteroids, are also useful in the present invention.

Examples of specific corticosteroids and their customary dosage levels useful in the present invention when local treatment is desirable can be broken down into four classes:
(1 ) Very potent Beclomethasone dipropionate 0.596 Clobetasol propionate 0 . 05%
Diflucortolone valera~e 0 . 3%
Fluocinolone acetonide û. 2%
( 2 ) Potent Beclomethasone dipropionate 0, 025%
Betamethasone benzoate 0. 025~
IBetamethasone dipropionate 0 . 05%
Betamethasone valerate 0.1 Desonide 0. 05%
Desoxymethasone 0 . 2596 Diflorasone diacetate 0. 05 Diflucortolone valerate 0.1~
Fluclorolone acetonide 0, 025%
Fluosinolone acetonide 0.02596 Fluocinonide 0. 05 Fluocortolone 0 . 5%
Fluprednidene (fluprednylidene) acetate 0.1%
Flurandrenolone 0. 05%
Halcinonide 0.1%
Hydrocortisone butyrate 0.1%
Triamcinolone acetonide~0.196

(3) Moderately Potent Clobetasone l~utyrate 0 . 05~
Flumethasone pivalate 0.02%
Fluocinolone acetonide 0.019g Flucortin butylester 0. 75%
Flucortolone 3 . 2~6 Flurandrenalone 0 . 01259~-0 . û2596 Hydrocorti one with urea 196 ~4) Mild Dexamethasone 0 . 01%

Hydrocortisone (alcohol or acetate) 0.1~6-1%
Methylprednisolone 0 . 25%
Mix~ures of corticosteroids are also useful in the present invention. Particularly preferred corticosteroids ~or use in the present invention when topical treatment is desired include triam-cinolone acetonide, hydrocortisone acetate, betamethasone valer-ate, fluocinolone acetonide, flupamesone, and mixtures of these compounds .
Examples of specific corticosteroids useful in the present invention when systemic treatment is desired include deso)cycorti-costerone, fludrocortisone, hydrocortisone, betamethasone, corti-sone, ~examethasone, prednisolone, prednisone, methyl predniso-lone, paramethasone, triamcinoione, and mixtures of these com-pounds .
Cornpositions of the present invention contain a safe and effective amount of the corticosteroid component; preferably the compositions contain from about 0 . 01% to about 10%, more preferably from about 0.02g~ to about 596, of corticosteroid. The compositions most preferably contain about 0 . 0596 to about 5~ of corticosteroid. Of course, the levei of steroid will vary with the condition being treated, whether topical or systemic effects are desired, the surface area avaiiable for application, and the par-ticular vehicle selected, and the method of appl3cation. Higher ievels are usually required when systemic effects are desired.
VEH I C LE
~ .
The vehicles of the present invention significantly enhance the penetration of the corticosteroid. They comprise, at a mini-mum, a diol and a cell-envelope elisordering compound.
The diol compounds useful in the compositions and methods of the instant invention include 1,2 propanediol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, or mixtures of these diol compounds. 1 ,2-propanediol and 1 ,2-butanediol are preferred diol compounds. 1,2-propanediol is an especially preferred diol compound.
The "cell envelope" disordering compounds usefui in the compositions and methods of the present invention include m~thyl laurate, oleic acid, oleyl alcohol, monoolein, and myristyl alcohol.
Mixtures of ~hese "cell-enve!ope" disordering compounds may also be employed. Preferred cell-envelope disordering compounds for use in the present invention include methyl laurate, oleic acid and myristyl alcohol. Methyl laurate is a particulariy preferred celi-envelope disordering compound.
Binary mixtures of any of the ~oregoing diol compounds and cell-envelope disordering compounds, in a weight ratio of diol compound:cell-envelope disordering compound of from about 1:1 to about 500 :1, provide significant enhancement of penetration for the corticosteroids described herein. A ratio of diol compound:
cell-envelope disordering compound of from about 5 :1 to about 100:1 is preferred, and the penetrating components are most preferably present in a ra7io of about 10:1 to about 100:1. In a highly preferred embodiment, the penetrating components are present in a ratio of about 10:1 to about 50:1.
The compositions of this invention typically contain from about 10% to about 99 . 9~, and preferably about 15~ to about 99. 9%, by weight, of the penetration enhancing binary mixture of the diol compounds and cell-envelope disordering compounds, employing the ratios described above. In a highly preferred embodiment the binary mixture is present in the composition of the present invention at a level of about 50~6 to about 99. 9% by weight .
~he preferences expressed above are predicated solely upon maximizing penetration. In certain topical formulations, however, aesthetic and cosmetic qualitites may be of equal or even para-mount importance. Accordingly, ranges other than those de-scribed above may be preferred. In general, a composition employing a weight:weight ratio of about 1:1 to about 10:1 will not demonstrate the sarne degree of penetration enhancement as a system emloying the same components at a weight ratio of about 10:1 to about 50:1. However, such ratios (1:1-10:1) may be preferred for certain vehicles or systems because they frequently produce better aesthetic qua1ities. It should be noted that while not generally providing maximum penetration, such aesthetically pleasing compositions nonetheless demonstrate a dramatic enhance-ment of penetration when compared to conventional or art-dis-closed vehicles or systems. Compositions comprising a binary mixture at a ievel of about 25~ to about 45% of the overall com-S position and employing weigh~: weight ratios of about 4:1 to about6:1 provide an excellent compromise or balance of cosmetic ac-ceptability and enhanced penetration and are accordingly preferred OPTIONAL COMPONENTS
In addition to the components described abs)ve, the composi-tions of this invention may optionally contain a cosmetically ac-ceptable solvent. The solvent, if used, should not significantly interfere with the penetration action of the binary combination, and should preferably evaporate rapidly and completely to leave 15 only the active components of the composition at the site of appli-cation. Preferred solvents include ethanol and isopropanol.
Water may be used as a solvent or component in the composi-tions of the present invention. However, simple addition of water to these compositions may cause some or all of the penetration-20 enhancing compounds to preçipitate out. Such action in theformulation of the compositions of the present invention may significantly reduce the overall effectiveness of the system. In order to prevent this, if water is used, it is preferred that an emulsion or gel be formed. Since these compounds themselves, 25 used alone, do not form an emulsion or gel stable enough for the intended use of the compositions, emulgents or gelling agents should therefore be employed.
Such solvents , i . e., water , ethanol or 2-propanol ~ isopro-panol; isopropyl alcohol), may comprise frorn 096 to about 80~ of 30 the total composition by weight. Ethanol and 2-propanol are preferably present at a level of 09~ to about 709~.
However, certain solvents, cosolv~nts, excipients, tipid materials and other generally acceptable components conventionally found in topical pharmaceutical compositions ~other ~han the 35 cell-envelope disordering compounds) should be avoided in the practice of the present invention. It is thought that such ~2~2~

compounds compete in some fashion for the role the cel l-envelope disordering compounds play, or the cite ~hese compounds occupy, in the stratum corneum. This competition prevents the disruption or disorderin~3 of the lipids of the stratum corneum by the cell-5 envelope disordering compounds. Some of these compounds mayalso compete with the lipids of the stra~um corneum ~or the cell-envelope disordering compound and the cell-envelope disordering compound will preferentially partition into such lipid-like com-pounds in the vehicle rather than the lipids of the stratum cor-10 neum~ Such selective competition wi!l also prevent lipid disorder-ing or disruption by the cell-envelope disordering cornpound and, accordingly, the steroid cannot be aided in penetrating. Thus, such compounds should be avoided when formulating the composi~
tions of the present invention. If used, such compounds should 15 generally be used as sparingly as possible, far below art-estab-lished leveis.
For example, hydrocarbons such as liquid petrolatum ~mineral oil, liquid paraffin, paraffin oil), white petrolatum, yellow petrolatum, paraffin, microcrystalline wax, and ceresin are 20 all known to be useful as hydrophobic vehicles or structural matrix formers in topical pharmaceutical formulations. However, all of these excipients are capable of significantly interfering with the penetration enhancing abilities of the present invention. It is thought that these compounds inhibit the ability of the 25 cell-envelope disordering compound to effectively disrupt the intercellular lipid structure of stratum corneum by preventing the cell-envelope disorderin~ compound from effectively reaching the lipids of the stratum corneum, possibly by selective competition for the cell-envelnpe disordering compound. Whiie a certain level 30 of such ingredients can be tolerated in a system which is otherwise particularly effective, in a preferred embodiment of the present invention such inyredients are limited to less than about 10%, and preferably less than about 5~6.
Certain straight chain, saturated Cl 6-C2~ normal fatty 35 alcohols should also be avoided. Cetyl alcohoi and stearyl alcohol are extremely comrnon, ubiquitous ingredients in topical s~

formulations. Both of these aicohols are capabie of significant interference with the penetration enhancement of the present vehicle. These alcohols, as well as the C18 saturated normal alcohol, are likely to retard the penetration enhancing abilities of the systems of the present invention. Accordingly, in a pre~rred embodiment, the compositions of the present invention are substantially free of such compounds, i.e., any particular compound should be present at a level of less than 3.5%, and more preferably at a level less than 1% by weight of the entire composition. In a highly preferred embodiment the compositions of the present invention contain less than 0. 596 of any specific member of said alcohol group.
Certain fatty acids are also capable of gross interference' with steroid penetration. These acids include the straight chain C4-C20 saturated monocarboxyiic and dicarboxylic acids. Octanoic and decanoic acid are particularly harmful to the vehicles of the present system. In a preferred embodiment, the compositions of the present invention are substantially free of these acids, i.e., contain less than about 3 . 59~ of any particular member of C4-C20 saturated monocarboxylic and dicarboxylic acids, and more prefer-ably less than about 196 of said acids by weight of the entire composition. In a highly preferred embodiment the compositions of the present invention contain less than 0 . 5~ of any specific member of said acid group.
The compositions of the present invention may additional Iy contain other adjunct components conventionally found in pharma-ceutical compostions, not recited above, at thair art-established usage levals. Thus, for exampie, the compositions may contain additional compatible phramaceutically-active materials for combi-nation therapy (such as antimicrobials, antipruritics, astringents, local anesthetics, or non-steroidal anti-inflammatory agents), or may contain materials useful in physical1y formulating various dosage ~orms of the present invention, such as excipients, dyes, perfumes, fragrances, preservatives, anti-oxidants, opacifiers, thickening agents and stabilizers. Such materials, when added, shouid not unduly interfere with the penetration enhancement of ~2~ 2 these compositions~ Such formula modifications to improve cosmetic acceptability are well within ~he skill of work-ers in the cosmetic and dermatological arts and, by them-selves, constitute no part of the present invention.
All optional components should be selected to prevent substantial interference with the penetration ability of the composition.
It can be seen from the foregoing that the compositions of the present invention admit of considerable variation, so long as the critical components of corticosteroid, diol compound, and cell-envelope disordering compound is present within the ranges indicated above and the stated penetra-tion interfering components are minimized.
METHOD OF USE
__.___ _ ______ It will be appreciated that this invention provides a method for treating and preventing conditions which respond to either local or systemic activity of corticosteroids.
Such conditions may be responsive to either the immunosup-pressive or anti-inflammatory action of such steroids.
When local treatment is desired, the compositions of the present invention are applied to the afflicted situs.
When systemic treatment is desired, the compositions of the present invention are applied to an application situs, pre~erably from a sustained release film, web, bandage or device. Such devices are well-known in the art r and exam-ples of such films, webs, bandages, devices, and the like can be found in Johnson, J.C., et al., Sustalned Release MedicationsL Chemlcal Technolo~ Review No. 177, Noyes Data Corporation, Park Ridge, New Jersey, pp, 82-113, (1980). When both local and systemic treatments are indi-cated or desired, the compositions of the present inven-tion can be applied at the afflicted situs, an application situs, or both. Accordingly, this invention provides a method for treating and preventing nonendocrine immuno-logic or rheumatic diseases such as rheumatoid arthri-tis, rheumatic fever, disseminated lupus erythematosus, hypersensitivity reactions such as bronchial asthma, serum sickness, anaphylaxis, bee stings, angioneurotic 2~

edema and hay fever, hemolytic enemia, drug reactions and agranulcytosis. The present invention aiso provides a method for treating diseases of the liver such as chronic active hepatitis.
Certain neurological conditions such as cerebral edema, or an 5 increase in intracranial pressure, may also be treated. The present invention further provides a method for treating and preventing inflammatory conditions such as ulcerative colitis, dermatitis ~atopic, eczematoid, exfoliative, stasis, nummular, contact, or seborrheic), pemfhigus, gout and other inflammations 10 of skin or mucous memhranes caused by chemical, thermal, mechanical or radiant agents. In addition, the present invention may be formulated and used in a veterinary context, for example in the treatment of dermatoiogical disorders characterized by inflammation and dry or exudative dermatitis, eczematous 15 dermatitis, contact dermatitis, seborrheic dermatitis, and as an adjunct in the treatment of dermatitis due to parasitic infestation.
It will be appreciated that the number and severity of side effects produced by systemic corticosteroid therapy are signifi-cantly increased when compared with localized therapy. Thus, 20 the decision to use corticosteroids for systemic treatment requires a clear definition of the benefits to be gained by such treatment, an identification of the risks the subject may encounter, so that informed overall assessment may be made. The risks attendant the systemic use of corticosteroids include abnormal sodium reab-25 sorption and potassium excretion. This interference with the twoimportant monovalent ions may result in hypokalemic alkalosis, edema, hypertension and other abnormalities associated with electrolyte imbalances. Corticosteroids, when delivered systemic-ally, may also suppress the natural healing process of injuries, 30 especially those that cause a break in the integument. The immunosuppresive properties of corticosteroids, the very property which makes them valuable in the treatment of immunologically mediated disease, can result in a compromise of the subject's ability to fight infection. They can also mask the symptoms of 35 some infections, thus preventing or delaying diagnosis and treat-ment. Further side effects include abnormal function within the gastrointestinal, cardiovascular, endocrine and central nervous systems. These may occur in any subject receiving a supra-physiologic concentration of corticosteroid hormones or their synthetic equivaients. In general, the frequency and severity of 5 such slde effects are proportional to the dose given, and the duration of treatment. When either the amount per dose, or the period of time over which therapy is given is increased, an increase in side effects can aiso be anticipated.
Accordingly, in actual clinical practice, two rules become 10 paramownt when systemic corticosteroid therapy is to be administered in the treatment of any condition or episode:
(1 ) the period of administration must be as short as possi-bie; and (2) the delivered dosage must be the smallest one that will i5 achieve the desired effect.
When the therapy which calls for single administration is indicated, the sin~le administration can be viewed as inocuous in character. Short courses of systemic steroid therapy of substan-tial doses may be proper in conditions which are not life-20 threatening assuming the absence of specific contraindications.However, it is generaily accepted that courses of long-term therapy at a high dosage should be reserved only for llfe-threat-ening disease. This rule is occassionaiiy vioiated justifiably when the patient is threatened with significant and permanent dlsabii-25 ity. See Goodman and Ciiman, The Pharmacoio~icai Basis ofTherapeutics, Macmillan Publishing Company, Inc., pp. 1497-1500 (1975), In summary, the individual dosage must be particularly suited to the individual condition being treated when using the 30 compositions of the present invention for systemic treatment as well as localized treatment when systemic effects are possible side-effects of such iocalized treatment.
The compositions of this invention are typicaily applied one to six times dally to the afflicted situs when topical treatment is 35 desired. When systemic effects are aiso desired, or when it is deslred to reduce the c ance rf the SpreDù of infectlon, the . .

, compositions of this invention are applied to larger areas, more frequently, or from a meshanical sustained release device or dressing .
Topical treatment regimens according to the practice of this 5 invention comprise applying the compositions herein directly to the skin, i . e O, at the affl icted situs or the appl ication situs .
The compositions may aiso be formula~ed for use in the oral or vaginal cavities. The rate of application and duration of treat-ment will, of course, depend on many factors. A typical safe and 10 effective usage rate for topical treatment is about 1 mg of the total topical composition per square centimeter of skin to about 10 mg of total topical composition per square centimeter of skin per application and about 1 mg of the total topical composition to, about 100 mg of the total topical composition per square centi-15 meter of skin when systemic, or locai and systemic, effects ortreatment are desired. The skilled artisan will appreciate that this application rate will vary with the desired effect (systemic, local, or systemic and local), the condition being treated, its progress and response, the area involved, the severity and 20 nature of the condition being treated, the nature of the actives or carriers, the presence or absence of penetration-interfering solvents, cosolvents, excipients and lipids, the physical condition of the patient, concurrent therapies being administeredt the concentration of the actives or carriers being used, as well as 25 other factors within the particular knowledge of the patient and/or physician within the scope of sound medical judgment.
However, usage rates of up to 500 rng of total composition per square centimeter of skin may be used when the composition is used as an occlusive dressin~. Even larger rates may be 30 employed when a mechanical sustained delivery device or dressing is used.
The compositions can be applied once every twenty-four hours to about twenty-four times every twenty-~our hours.
Application intervals of every 4 hours to every 12 hours are 35 preferred. A treatment regimen of application ~very 6 hours is particularly preferred because it minimizes the amount of steroid which is applied at one time while reducing the incon-venience of frequent applications. However, any treat-ment regimen which allows a safe and effective amount of steroid to reach the afflicted situs or the bloodstream can be employed while using the compositions of this invention. For possibly compatible and related topical compositions and treatment regimens, see UOS. Patent

4,557,934, issued ~ecember 10, 1985 and U S. Patent 4,537,776, issued August 27, 1985O
The following are nonlimiting examples of the compo-sition of the present invention. They are conventionally formulated by mixing all components thoroughly.
EXAMPLE 1 = PART A
Co~osition I
15 Triamcinolone acetonide (Triamcinolone hereafter) 1.0%
Propylene Glycol (1,2-propanediol) 95.0~
Methyl laurate 4.0%

Com~osition II
20 Eydrocortisone acetate 1.0%
Propylene Glycol (1,2-propanediol) 94.0%
Oleic Acid 5.0%

Com~osition III
25 Betamethasone valerate 0.5 Propylene Glycol (1,2-propanediol) 93.5 Oleyl alcohol 6.0 Com~Qosition IV
30 Fluocinolone acetonide 0.5%
Propylene Glycol (1,2-propanediol) 94.5%
Monoolein 5.0 Com~osition V
Flupamesone 0.5%
Propylene Glycol (1,2-propanediol) 97.5%
Myristyl alcoho] 2.0%

Composition Vl Triamcinolone 0. 5 1,2 butanediol 95-5~
Methyl laurate 1~. 0%
Composition Vl i _ . , .
Triamcinolone 0 . 5%
1, 3-butanediol 97 . 5%
Mel:hyl laurate 2 . 0%
Composition Vl l l Hydrocortisone acetate 0. 25 1, 2-butanediol 97 . 75 Oleic acid 2,0%
Composi~ion I X
Hydrocortisone acetate 2.0%
1,3-butanediol 93.0 Oleic acid 5 . 0%
Composition X
Betamethasone valerate 2 . 0%
1, 2-butanediol 93 . 0%
Oleyl alcohol 5.0%
Composition X I
_.
Fluocinolone acetonide 5 . 096 1, 2-butanediol 92, 0 Monoolein 3 . %
Composition X l l Flupamesone 1 . 0%
Hydrocortisone Acetate 1.0g~
Propylene glycol ~1, 2-propanediol )93 . 0~6 Myristyl alcohol 5 . 0 Composition X l l l .
Desoxycor~icosterone 5 . 0%
Propylene Glycol (1,2 propanediol) 90.096 Oleic acid 5.09 Compos tion X I V
Prednisolone 5 %
Propylene Glycol (1,2-propanediol) 91.096 Myristyl alcohol 4 . 0 Composition XV
~ .
Prednisone ~ %
1,2-butanediol 54.0%

5 Oleic acid 4. 0%
ethanol 4û . 096 Composition XVI
~ .
Methyl prednisolone 4 . 0%
1,3-butanediol 55.0%
10 Oleyl alcohol 1 . 0~6 isopropanol 40 . 0~
The ~ollowing are nonlimiting examples of the methods of the present invention.

. .
Composition I is applied to a human afflicted with dermatitis at the afflicted situs at a rate of 5 mg of composition per square centimeter of skin three times daily for a period of 5 days.
Complete elimination of inflammation is noted after 48 hours.
Substantially similar results are obtained when the composition is 20 replaced by compositions ll, Ill, IV or V of Example 1.
PENETRATION STUDIES
EXAMPLES ?-3' The following Penetration Studies demonstrate the penetration-enhancing capabilities of the cormpositions and methods 25 of the present invention. These nonlimiting Examples demonstrate the ability of the compositions of the present invention to enhance penetration of triamcinolone or hydrocortisone when compared to a propylene glycol or a propylene glycol-containiny vehicle formu-lated without the presence of the critical cell envelope disordering 30 compound.
The ~ollowing Penetration Studies were carried out in the following manner. Human skin (heat-separated or dermatomed abdominal epidermis, taken at autopsy, or excised, full thickness hairless mouse skin) is placed in a standard Franz diffusion 35 apparatus (Crown Glass Company, Somervilla, NJ) in a horizontal position between a lower, capped diffusion cel I and an upper, open cell. A normal saline solution is addecl to the iower diffusion cell, abutting the subcutaneous side of the skin. The test composition (comprising a solution of active or actives added to the carrier at the indicated formulation in 3 conventional 5 manner by thoroughly mixing) is added to the diffusion cell abutting the epidermal side of the skin at the !evels indicated.
This cell assembly is kept at a constant temperature of about 31 C. At appropriate or desired in~ervals ~these are the time designations given in the following examples) each diffusion cell 10 assembly i5 opened and the diffusate from the cell abutting the subcutaneous side of the skin is withdrawn. Drug actives in a diffusate is measured using standard analytical techniques. Each trial is run on a separate sample of skin.
In the following examples, (*) indicates that human skin was 15 selected for this trial, and (**) indicate that hairless mouse skin was selected. All ratiss represented by AtB, or A/B/C, and all percentages, are by weight. The compounds described as C12 1 80H are the straight chain, saturated, normal alcohols .
EtOH is ethanol. The term mcg = microgram.

Vehicle mcg/cm2 (0-24 hrs. ?*
.5% Triamcinolone in a vehicle of 0.4 Propylene Glycol .5% Triamcinolone in a vehicle of 11 98% Propylene Glycol + 296 Cl 40H
,5~ Triamcinolone in a vehicle of , 172 95% Propylene Glycol + 5% Oleic Acid Vehicle mcg/cm~ (0-8 hrs. )**
~
30.5% Triamcinolone in a vehicle of 0.35 Propylene Glycol .5% Triamcinolone in a vehicle of 45 95% Propylene Glycol + 5% Oleic Acid Vehlcle mcg/cm2 ~0-8 hrs. )**
.5% Triamcinolone in a vehicle of 0.21 Propylene Glycol 5.1% Triamcinolone in a vehicle of 1.8 Oleic Acid .596 Triamcinolone in a vehicle of 23 99~ Propylene Glycol ~ 1 ~ Oleic Acid .5~ Triamcinolone in a vehicle of 46 1095~ Propylene Glycol ~ 5~ Oleic Acid .4~ l riamcinolone in a vehicle of 39 75% Propylene Glycol + 25% Oleic Acid Vehicle mcg/cm2 (0-6 hrs.~**
15.196 Triamcinolone in a vehicie of 0.17 20180 Propyiene Glycol/EtOH
.1%, riamcinolone in a vehicle of 2.55 15/5/80 Propylene Glycol/Oleic Acid/
EtOH
20ol96 Triamcinolone in a vehicle of 2.73 15/5/80 Propylene GlycollMethyl laurate/
EtOH
.1~ Triamcinoione in a vehicle of 1.40 1515/R0 Propylene GlycollC14OH/EtOH
25.1 % Triamcinolone in a vehicle of 0.49 15/5180 Propylene Glycol/Monoolein/EtOH
.1 % Triamcinolone in a vehicle of 1.87 1515180 Propylene GlycollAzone/EtOH
EXAMPLE_6 30Vehicle mcglcm2 (0 4 hrs. ~**
.1% Triamcinolone in a vehicle of 0.94 20180 Propylene Glycol/EtOH
.196 Triamcinolone in a vehicle of 5.4 15/5180 Propylene Glycol/Oleic Acidl 35EtOH
.196 Triamcinolone in a vehicle of 5.4 15/S/30 Propylene Cilycol/Linoleic Acid/
EtOH
.1% Triamcinolone in a vehicie of 3.1 15/5/80 Propylene (;Iycol/Oleyl Alcohol/
EtOH
.1g6 Triamcinolone in a vehicle of 5.3 15/5180 Propylene (:;lycol/Linoleyl Alcohol/
EtOH

10Vehicle mcg/cm2 ~0-70 hrs. )*
.1% Triamcinolone in a vehicle of . 29 20/80 Propylene Glycol/EtOH
.196 Triamcinolone in a vehicle of 1 . 6 15/5180 Propylene Glycol/Methyl Laurate/
1 5EtOH
196 Hydrocortisone in a vehicle of 20/80 2.8 Propylene G Iycol / EtO H
1% Hydrocortisone in a vehicle of 15/5180 5.4 Propylene Glycol/Methyl Laurate/EtOH
2019~ Hydrocortisone in a vehicle of 15/S/80 13.0 Propylene G!ycol/Oleic Acid/EtOH
1% Hydrocortisone in a vehicle of 15/5/80 8.8 Propylene C;lycol/C140H/Ett)H

The following Example demonstrates the dramatic reduction in penetration that takes place when the penetration-inhibiting compound described herein are added to compositions of the present invention.
Vehicle mcg/cm2 ~0-72 hrs. )*
196 Triamcinolone in a vehicle of o1 Propylene Glycol 1% Triamcinolone in a vehicle of 30 9896 Propylene Glycol + 2% Cl 40H
1~6 Triamcinolone in a vehicle of 1 94% Propylene Glycol ~ 296 Cl 4C)H ~ 4 Octanoic Acid As can be seen from this example, the addition of a pro-scribed compound such as straight chain, normal C8 monocarboxylic acid (octanoic acid), reduces penetration by 50%.
Substantially similar results occur with addition of decanoic acid, cetyl alcohol or stearyl alcohol.

Vehicle mcg/cm (24 hrs. )*
.1~ Triamcinolone in Propylene Glycol 23 vehicle 10 .1% Triamcinolone in a vehicle of Propylene Glycol + 3% Oleic Acid 72 ,1% Triamcinolone in a vehicle of Propylene Glycol + 3~6 Cl 20H 56 ,1% Triamcinolone in a vehicle of Propylene Glycol + 3~ C1 40H 36 ,1~ Triamcinolone in a vehicle of Propylene Glycol -~ 3% Cl 6OH 14 ,1% Triamcinolone in a vehicle of Propylene Clycol + 3% Cl 8OH 20 20 ,1~ Triamcinolone in a vehicle of Propylene Glycol ~ 3~ Oleyl Alcohol 56 .1% Trlamcinolone In a vehicle of Propylene Glycol/PEG 400 6 mC~/cm2 mC~/c~,~2*
~ e~ @2 4 h rs . @48 h rs .
. .
Trlamcinolone 0 .1~ 11 . 2 20, 8 Methyl Laurate 5 . 0~
Propylene Glycol 25, 0%
30 EtOH 30 . 0%
Carbopol 934 1 . 0%
TEA (triethanol amine~ 0. 3 Tween 80 0, 2 Water qs 38, 4~
35 1 - Carbopol 934 is the trademark for a polyacrylic acid polymer available from B.F. G301rich .~

~2~

2 - Tween 80 is the trademark for a nonionic, liquid sorbitan monooleate available from ICI Americas . EXAMPLE 11 mc~!cm~ mcg/cm2*
Component @24 hrs. @48 hrs ._ . . O
Triamcinolone0 ,1~ 12, 5 37, 0 Oleic Acid 2.0%
Propylene Glycol25.0 EtOH 30. 0~
Carbopol 934 1 . 0%
TEA 0. 3%
Tween 80 0, 2%
Water qs 41.4~

1 5 mc~ / c m 2 mc~ /_m 2 *
Component @24 hrs. @48 hrs . _ .: . _ . _ _ .. __ _ . _ .... ___ Triamcinolone 0,1~ 20 . 7 50, 9 Olelc Acid 4.0 Propylene Glycol25.0 EtOH 30.0%
Carbopol 934 1.0 TEA 0. 3%
Tween 80 0. 2 Water qs 39.4~

~--2 mcg / cm2 ~ .
.
Component @24 hrs. @48 hrs.
Hydrocortisone1 . 0% 56.3 104. 7 Methyl Laurate5 . 05~
Propylene Glycol25 . 0%
EtOH 30.0~
Carbopol 934 1.0%
TEA 0, 3%
Tween 80 0,2%
Water qs 37.5~

~2~

~ 30 --mcg /cm2 mcg !cm2*
~24 hrs. @48 hrs.
Hydrocortisone 1 . 0~6 42 . 591 . 6 S Oleic Acid 2 . 0~
Propylene Glycol 257 0g6 EtOH 30 . 0%
Carbopol 934 1 . 0~6 TEA 0 . 3%
Tween 8û 0. 2 Water qs 40. 5~

~ mcg /cm2*
Component_ @?4 hrs. @48 hrs.
Hydrocortisone 1 . 0~ 51 . 8129. 6 Oleic Acid 4. 0~
Propylene Glycol 25 . 096 EtOH 30. 0%
Carbopol 934 1. 0%
TEA 0. 3~
Tween 80 0 . 2%
Water qs 38.5~6 mcg!cm2 mcg/cm~*
_ Component _ @24 hrs. @48 hrs.
Hydrocortisone 1 . 096 53 . 9136 . 7 Methyl Laurate 5 . 0%
1-~2-hyclroxyethyl)-aza-20.0%
cyclopentan-2-one EtOH 30. 0%
Carbopol 934 1. 096 TEA 0 . 3g~
Tween 80 0 . 2%
Water qs 4~.596 mC9lcm2 mcg/cm2*
Component ~24 hrs. @48 hrs.
Triamcinolone 0.1~ 1 . 694. 31 Propylene Clycoi 25.096 EtOH 30, 0%
Carbopol 934 1 . 0~6 TEA O . 3%
Tween 80 0 . 2 Water qs 43 . 49~

mcg / cm2 ~*
Component _ @24 hrs. @48 hrs.
Hydrocortisone 1.0% 5.96 12.7 Propylene Glycol 25.0%
EtOH 30 . Og6 Carbopol 934 1 . 0%
TEA O . 3~6 Tween 80 0. 2%
Water qs 42.5%

mcg/cm2 mcg/cm *
C:omponent @24 hrs. @48 hrs.
Hydrocortisone 1.0% 5.71 18.8 1-(2-hydroxyethyl)aza-20,096 cyclopentan-2-one EtO H 30 . 0~
Carbopol 934 1 . 096 TEA 0.3 Tween 80 0. 2~
Water qs 47.5%

mc~ / cm2 mc~/ cm2 *
Component _ @24 hrs. @48 hrs.
Triam~inolone 0.19~ 1 . 44 5 ~ 75 Propylene Glycol 25 . 09~

5~2 EtOH 74 . 996 mcg / crn mcg / cm2 *
Component __ @24 hrs. ~48 hrs.
S Hydrocortisone 1 . 0% 6 . 48 18 . 3 Propylene Glycol 24 . 5%
EtOH 74. 5%

Vehicle mcg/cm2~0-48 hrs. )*
l O. 5~ Triamcinolone in a vehicle . 056 of Propylene Glycol .1% Triamcinolone in a vehicle .92 of Oleic Acid 4 . 5% Triamcinolone in a vehicle . 92 15of Azone .696 Triamcinolone in a vehicle of 50/50 .45 C)leic Acid/Azone .59~ Triamcinolone in a vehicle of 63.0 Propylene Glycol ~ 5% Oleic Acid 20.5% Triamcinolone in a vehicle of 8.4 Propylene Glycol ~ 5~ Azone Vehicle mcg/cm2 (0-4 hrs. )**
196 Triamcinolone in a vehicle of ,14 25Propylene Glycol 7.8% Triamcinolone in a vehicle of Azone a.5 .05% Triamcinolone in a vehicle of Oleic .81 Acid .7% Triamcinolone in a vehicle of 50/50 1.5 30Azone/Oleic Acid 1% Triamcinolone in a vehicle of Propylene 8.2 Glycol + 496 Azone 196 Triamcinolone in a vehcile of Propylene 123.0 Glycol + 496 Oleic Acid

6~

Vehicle ~ mcg/cm2(0-22 hrs)**
1~ Triamcinolone in a vehicle of 2045 Propylene Giycol

7.8% Triamcinolone in a vehicle of Azone 77 .05% Triamcinolone in a vehicle of Oleic 11 Acid . 7% Triamcinolone in a vehicle of 50J50 14, 8 Azone/Oleic Acid 1~ Triamcinolone in a vehicle of Propylene 147 Glycol + 4~ Azone 1% Triamcinolone in a vehcile of Propylene 254 Glycol ~ 4% Oleic Acid Vehicle mcg/cm2(0-68 hrs.)*
1% Triamcinolone in a vehicle of .082 Propylene Glycol 7.û% Triamcinolone in a vehicle of .S
Azone .0596 Triamcinolone in a vehicle of Oleic .089 Acid .7% Triamcinolone in a vehicle of 50/50 .22 Oleic Acid/Azone 1~ Triamcinolone in a vehicle of Propylene 10.5 Clycol ~ 4% Oieic Acid 196 Triamcinolone in a vehicle of Propylene 2.1 G Iycol ~ 4~6 Azone The follosving Skin Penetration Study demonstrates the 30 dramatic increase in penetration of a pharmaceutically-active agent (here Triamcinolone) when the binary combination of diol ~ Azone is employed, when compared to a vehicle containing just Azone, or JUst the diol, and a compatable volatile solvent. The following penetration study further demonstrates the criticality of the levels 35 required by the present invention.

Vehicle mcg/cm2 (24 hrs. ~*
0.1% Triamcinolone in a vehicle of .85 95/5 Ethanol/Azone 0.1~ Triamcinolone in a vehicle of . 85 585110/5 E~hanol/Propylene Glycol/
Azone 0 .1% Triamcinolone in a vehicle of1 . S
75/2015 Ethanol/Propylene Glyçol/
Azone 100.1% Triarncinolone in a vehicle of 3.0 55140/5 Ethanol/Propylene C;lycol/
Azone 0.196 Triamcinolone in a vehicle of 5.2 75/2015 Ethanol/Propylene Glycol/
lSOleic Acid 0.1~ Triamcinolone in a vehicle of 0.37 80/20 Ethanol/Propylene Glycol Vehicle mcg /cm 2( 0-48 hrs . ~ *
20.1g6 Triamcinolone in a vehicle of.12 20/80 Propylene Glycol/EtOH
.1~ Triamcinolone in a vehicle of 3.5 20/80 Pyrrolidone/EtOH
.1% Triamcinolone in a vehicle of 5.4 2515/5/80 Propylene Glycol/Oleic Acidl EtOH
.196 Triamcinolone in a vehicle of 9.9 15/5/80 PyrrolidonelOleic Acid/EtOH

30Vehicle mcg/cm2 (0-50 hrs. ~*
.
1% Triamcinolone in a vehicle of .8 20/80 Propylene Glycol/EtOH
1% Triamcinolone in a vehicle of 1.1 20/80 Hydroxyethylpyrrolidone/
35EtOH

196 Triamcinolone in a vehicle of 3.4 20/80 Pyrroiidone/EtOH
1% Triamcinolone in a vehicle of 3.3 1515/80 Propylene Glycol/Oleic Acid/
EtOH
1% Triamcinolone in a vehicle of 5.9 15/5180 Pyrrolidone/Oleic Acid/EtOH
1% Triamcinolone in a vehicle of 11 . 6 15/5/80 Hydroxyethylpyrrolidone/Oleic Acid/EtOH

Vehicle mcg/cm2l0-Ç5 hrs.)*, .1% Triamcinolone in a vehicle of .27 20/80 Propylene C;lycol/EtOH
.1% Triamcinolone in a vehicle of 1.5 15/5/80 Propylene Glycoi/Methyl laurate/
EtOH
.1% Triamcinolone in a vehicle of . 29 20/80 Hydroxyethylpyrrolidone/EtOH
.196 Triamcinolone in a vehicle of 3.6 15/5/80 Hydroxyethylpyrrolidone/Methyl lau rate/ EtOH
,19g Triamcinolone in a vehicle of .10 20/80 Hydroxypropyipyrrolidone/EtOH
.1~ Triamcinolone in a vehicle of .81 15/5/80 HydroxypropylpyrrolidonetMethyl lauratel EtOH
,1% Triamcinolone in a vehicle of 1 . 3 20/80 Methyl Pyrrolidone/FtOH
.1% Triamcinolone in a vehicle of 3.4 15/5180 Methyl Pyrrolidone/Methyi laurate/
EtOH

Vehicle mc~/cm2(0-48 hrs.?*
1% Hydrocortisone in a vehicle vf 7.5 20/80 Propylene Glycol/EtOH

~2~

1~ Hydrocortisone in a vehicle of17.0 15/5/80 Propylene Glycol/Methyl laurate/
EtOH
1 % Hydrocortisone in a vehicle of19.0 15/S/80 Propylene Glycol/Oleic Acid/
EtOH
1~ 11ydrocortisone in a vehicle of14.0 20/80 Hydroxyethylpyrrolidone/FtOH
1 g6 Hydrocortisone in a vehicle of120.0 15/5/80 i-iydroxyethylpyrrolidone/Oleic Acid/EtOIl Vehicle mcg/cm2 (0-48 hrs )*
196 Hydrocortisone in a vehicle of7.6 20/80 Propylene Glycol/EtOH
1 % Hydrocortisone in a vehicle of33.0 1515/80 Propylene Glycol/Methyl iaurate/
EtOH
1% Hydrocortisone in a vehic1e of~.3 20/80 Hydroxyethylpyrrolidone/EtOH
1 % Hydrocortisone in a vehicle of124.0 15/5/80 Hydroxyethyipyrrolidone/Oleic Acid/EtOH

The ~ollowing composition is ~ormulated by conventional means .
Component 9g w/w Hydrocortisone 0.5 Methyi laura~e 5.0 Propylene glycol 25,0 Polysorbate 80 0.2 C:arbopol 934P 1.5 Disodium EDTA 0.1 Titanium Dioxide 0.1 2.596 aqueous NaOH 1.5 Sorbic acid 0.1 D isti I led water 66 . 0 ~00.00 The above composition is applied at the afflicted situs of a 5 human afflicted with dermatitis at a rate of 5 mg of composi-tion/cm2 of skin three times dai!y for a period of five days. A
significant reduction of inflammation is noted afte1o 48 hours.
Substantially similar results are obtained when the hydro-cortisone in the above composition is replaced, in whole or in 10 part, with triamcinolone, betamethasone valerate, fluocinolone, acetonide, flupamesone, and mixtures thereof.
Likewise, substantially similar results are obtained if the methyl laurate is replaced, in whole or in part, by oleic acid,~
oleyl alcohol, monoolein, myristyl alcohol, or mixtures thereof.

Claims (16)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A penetration-enhancing pharmaceutical composition for topical application, comprising:
(a) a safe and effective amount of a pharmaceuti-cally-active corticosteroid;
(b) 0% to about 80% by weight of a solvent selected from the group consisting of water, ethanol or 2-propanol;
and (c) about 10% to about 99.9% by weight of a penetration-enhancing carrier consisting essentially of:
(i) a diol selected from the group consisting of 1,2-propanediol, 1,2-butanediol, 1,3-butanediol, 2,3-butanediol, or mixtures thereof, and (ii) a cell-envelope disordering compound selected from the group consisting of methyl laurate, oleic acid, myristyl al-cohol, or mixtures thereof; wherein said diol and said cell-envelope disordering compound are present in a ratio of diol:
cell-envelope disordering compound of from about 1:1 to about 500:1 by weight;
and wherein said penetration-enhancing composition is substantially free from any single member of the C16-C20 straight chain, saturated normal fatty alcohols, and C4-C20 straight chain, saturated mono- or dicar-boxylic acids.

2. A composition according to claim 1 wherein the cell-envelope disordering compound is methyl laurate.

3. A composition according to claim 1 wherein the cell-envelope disordering compound is oleic acid.

4. A composition according to claim 1 wherein the cell-envelope disordering compound is myristyl alcohol.

5. A composition according to claim 1 wherein the level of any specific member of the C16-C20 straight chain, saturated normal fatty alcohols, and C4-C20 straight chain, saturated mono- or dicarboxylic acids is less than about 3.5% by weight.

6. A composition according to claim 5 wherein the level of any specific member of the C16-C20 straight chain, saturated normal fatty alcohols, and C4-C20 straight chain, saturated mono- or dicarboxylic acids is less than about 1% by weight.

7. A composition according to claim 1, which is sub-stantially free from octanoic acid, decanoic acid, cetyl alcohol and stearyl alcohol.

8. A penetration-enhancing pharmaceutical composition for topical application, comprising:
(a) about 0.05% to about 5%, by weight of a corti-costeroid selected from the group consisting of triam-cinolone acetonide, hydrocortisone acetate, betamethasone valerate, fluocinolone acetonide, flupamesone, or mixtures thereof;
(b) 0% to about 80% by weight of a solvent selected from the group consisting of water, ethanol or 2-propanol;
and (c) about 10% to about 99.9% by weight of a penetration-enhancing carrier consisting essentially of:
(i) a diol selected from the group consisting of 1,2-propanediol, 1,2-butanediol, or mixtures thereof, (ii) a cell-envelope disordering compound selected from the group consisting of methyl laurate, oleic acid, myristyl alcohol, or mixtures thereof;
wherein said diol and said cell-envelope disordering com-pound are present in a ratio of diol:cell-envelope dis-ordering compound of from about 10:1 to about 100:1 by weight; and wherein said penetration-enhancing composi-tion is substantially free from any specific member of the C16-C20 straight chain, saturated normal fatty al-cohols, and C4-C20 straight chain, saturated mono- or dicarboxylic acids.

9. A composition according to claim 8 wherein the diol compound is 1,2-propanediol.

10. A composition according to claim 8 wherein the diol compound is 1,2-butanediol.

11. A composition according to claim 8 wherein the cell-envelope disordering compound is oleic acid.

12, A composition according to claim 8 wherein the cell-envelope disordering compound is myristyl alcohol.

13. A composition according to claim 8 wherein the level of any specific member of the C16-C20 straight chain, saturated normal fatty alcohols, and C4-C20 straight chain, saturated mono- or dicarboxylic acids is less than about 3.5% by weight.

14. A composition according to claim 13 wherein the level of any specific member of the C16-C20 straight chain, saturated normal fatty alcohols, and C4-C20 straight chain, saturated mono- or dicarboxylic acids is less than about 1% by weight.

15. A composition according to claim 8 which is sub-stantially free from octanoic acid, decanoic acid, cetyl alcohol and stearyl alcohol.

16. A penetration-enhancing pharmaceutical composition for topical application, comprising:
(a) a safe and effective amount of a pharmaceuti-cally-active corticosteroid;
(b) 0% to about 80% by weight of a solvent selected from the group consisting of water, ethanol or 2-propanol;
and (c) about 10% to about 99.9% by weight of a penetration-enhancing carrier consisting essentially of:
(i) 1,2-butanediol, and (ii) a cell-envelope disordering compound selected from the group consisting of methyl laurate, oleic acid, oleyl al-cohol, monoolein, myristyl alcohol, or mixtures thereof;
wherein said 1,2-butanediol and said cell-envelope dis-ordering compound are present in a ratio of diol:cell-envelope disordering compound of from about 1:1 to about 500:1 by weight; and wherein said penetration-enhancing composition is substantially free from any single member of the C16-C20 straight chain, saturated normal fatty alcohols, and C4-C20 straight chain, saturated mono- or dicarboxylic acids.