United States Patent (19) [11] Patent Number: 4,863,970 Patel et al. 45 Date of Patent: Sep. 5, 1989

(54 PENETRATION ENHANCEMENT WITH 2153223 8/1985 United Kingdom. BINARY SYSTEM OF OLEICACID, OLEINS, AND OLEYL ALCOHOL WITH LOWER OTHER PUBLICATIONS ALCOHOLS Drug Delivery Systems, R. L. Juliano, "Characteristics and Biomedical Applications”, 1980, p. 159. 75) Inventors: Dinesh C. Patel, Murray, Utah; Jane Stotts and W. Jeanne Ely, “Induction of Human Yunik Chang, Lakewood, N.J. Skin Sensitization to Ethanol', 1977, pp. 69:219–222. 73 Assignee: Theratech, Inc., Salt Lake City, Utah William Brown et al., "Comparative Ultrastructure & 21 Appl. No.: 218,702 Cytochemistry of Epidermal Responses to Tape Strip ping, Ethanol & Vitamin A Acid in Hairless Mice", 22 Filed: Jul. 13, 1988 1979, 73:203-206. Primary Examiner-John F. Terapane Related U.S. Application Data Assistant Examiner-Catherine S. K. Scalzo 63 Continuation-in-part of Ser. No. 930,764, Nov. 14, Attorney, Agent, or Firm-Thorpe, North & Western 1986, abandoned. (57) ABSTRACT 51 Int. Cl...... A01N 61/00; A61K 31/00 52 U.S. Cl...... 514/784; 514/947; Penetration-enhancing pharmaceutical compositions 514/772; 514/785; 514/786 for topical transepidermal and percutaneous application 58 Field of Search ...... 424/59; 514/946, 947, are disclosed which are non-irritating to the skin. These 514/69, 784, 785, 786, 772 compositions are made up of a safe and effective amount of an active pharmaceutical permeant, including hydro 56) References Cited philic salt forms, contained in a novel penetration U.S. PATENT DOCUMENTS enhancing vehicle comprising, (i) 1-95% w. of a cell 4,379,454 4/1983 Campbell ...... 424/448 envelope disordering compound selected from the 4,381,307 4/1983 Sloan ...... 514/192 group consisting of oleic acid, oleyl alcohol, glycerol 4,460,372 7/1984 Campbell et al. . ... 424/449 monoleate, glycerol dioieate, glycerol trioleate and 4,537,776 8/1985 Cooper ...... 54/424 mixtures thereof, (ii) 5-7.5% w., and preferably 5-49% 4,552,872 11/1985 Cooper et al. 514/174 w., of a lower alkanol selected from the group consist 4,557,934 12/1985 Cooper ...... 514/159 X ing of ethanol, propanol and isopropanol and mixtures 4,588,580 5/1986 Gale et al...... 424/449 thereof and (iii) 0-45% w, and preferably 1-4.5% w, of 4,593,048 6/1986 Sato et al...... 514/778 an inert diluent which, according to properties of the 4,764,379 8/1988 Sanders ...... 424/449 permeant used, may range from hydrophilic to hydro FOREIGN PATENT DOCUMENTS phobic. Water, polyethylene or polypropylene glycols 0043738-1/1982 European Pat. Off. . and mineral oil are exemplary diluents. 0095813 12/1983 European Pat. Off. . 01 17080 3/1984 European Pat. Off. . 40 Claims, No Drawings 4,863,970 2 U.S. Pat. No. 4,537,776, Cooper, issued Aug. 27, PENETRATION ENHANCEMENT WITH BINARY 1985, contains an excellent summary of prior art and SYSTEM OF OLEICACID, OLEINS, AND OLEYL background information detailing the use of certain ALCOHOL WITH LOWER ALCOHOLS binary systems for permeant enhancement. Because of the completeness of that disclosure, the information and BACKGROUND OF THE INVENTION terminology utilized therein are incorporated herein by reference. That patent teaches using a binary system This invention is a continuation-in-part of Ser. No. wherein N-(2-hydroxyethyl) pyrrolidone is used as the 06/930,764, filed Nov. 14, 1986 now abandoned. solvent and the cell-envelope disordering compounds This invention relates to compositions which enhance 10 are selected from the group consisting of methyl lau the penetration of pharmaceutically-active agents rate, oleic acid, oleyl alcohol, moloolein, myristy alco through the integument. More particularly, this inven hol and mixtures thereof. tion relates to binary combinations of certain penetra Similarly, European Patent Application No. 43,738, tion enhancers which facilitate percutaneous and trans published Jan. 13, 1982, teaches using selected diols as epidermal delivery of a broad range of pharmaceutical 15 solvents along with a broad category of cell-envelope ly-active agents. disordering compounds for delivery of lipophilic phar The resistance of the skin to being penetrated by macologically-active compounds. This reference also pharmaceutically-active agents is well documented. As teaches that cosmetically acceptable solvents may also compared to mucosal tissues, the stratum corneum is be combined with permeant and the diol and cell compact and highly keratinized. The lipids and proteins 20 envelope disordering compounds provided the solvent of the stratum corneum, although relatively thin, is evaporates rapidly and completely to leave only the compact and quite impermeable. Such impermeability active components of the composition at the site of of the skin is highly essential to the well being of a living application. The acceptable solvents are stated to be organism in that it serves as a barrier to the ingress of ethanol or isopropanol. Because of the detail in disclos pathogens and toxic materials, and the egress of physio 25 ing the cell-envelope disordering compounds and the logic fluids. diols, the disclosure of European Patent Application The impermeability of pharmaceutical agents No. 43,738 is also incorporated herein by reference. through the skin is due to the nature of the very thin Most of the cell-envelope disordering compounds stratum corneum layer which is only 10-15 cells, i.e. mentioned in these publications are unsaturated lipid about 10 microns thick. This layer is formed naturally 30 components having polar head groups. by cells migrating toward the skin surface from the A binary system for enhancing metoclopramide pene basal layer. Cells slowly move from the basal layer to tration is disclosed in UK Patent Application No. GB the surface where they are sloughed off. As they 2,153,223 A, published Aug. 21, 1985 and consists of a progress toward the surface they become progressively monovalent alcohol ester of a C8-32 aliphatic monocar more dehydrated and keratinized. 35 boxylic acid (unsaturated and/or branched if C18-32) Because of the advantages of dermal application of or a C6-24 aliphatic monoalcohol (unsaturated and/or pharmaceutically-active agents, various penetration branched if C14-24) and an N-cyclic compound such as enhancers have been sought. A penetration enhancer is 2-pyrrollidone, N-methylpyrrolidone and the like. It is one or more compounds which alter the skin as a barrier postulated that the N-cyclic compound serves a solvent to increase the flux of a desired pharmaceutical perme 40 function which carries the active agent whereas the ant across the skin. esters or alcohols serve as adjuvants to open up the Penetration enhancers have been primarily catego stratum corneum, i.e. as cell-envelope disordering com rized according to their ability to enhance permeant pounds. flux via three pathways. The first is the continuous In referring to the epidermal permeability of lower polar or aqueous pathway composed of proteins. It is 45 alkanols, Drug Delivery Systems, Characteristics and thought that solvent swelling or protein conformational Biomedical Applications, Oxford University Press, NY, changes provide the key to altering the penetration of 1981, edited by R. L. Juliano, teaches at page 159 that the polar pathway. Surfactants alter the transport of simple alcohols through n-butanol have epidermal per polar permeant molecules to a much greater extent than meabilities no different than that of water. However, the transport of nonpolar permeants. Solvents such as SO U.S. Pat. Nos. 4,379,454 to Campbell et al.; Campbell et DMSO, 2-pyrrolidone and dimethylformamide can al, 4,460,372 and Gale et al, 4,588,580 refer to the use of swell the stratum corneum to also enhance the polar gelled ethanol as an enhancer in specialized transdermal pathway. or percutaneous drug delivery devices. The second pathway is a continuous non-polar path U.S. Pat. No. 4,593,048, Sato, issued June 3, 1986, way consisting of lipids. The key to altering this path 55 shows skin permeation of drugs using a system consist way appears to be fluidizing the lipids which, in the ing of a major amount of a lower alcohol having 1 to 4 stratum corneum, appear to be crystalline. Solvents carbon atoms and a minor amount of an adjuvant con such as DMSO, 2-pyrrolidone, and dimethylformamide, sisting of (1) a saturated straight chained, branched previously mentioned also appear able to solubilize or chained or cyclic aliphatic hydrocarbon containing 5 to fluidize lipids. Other solvents include diols such as glyc 60 20 carbon atoms which may be optionally halogen sub erol and propylene glycol. stituted, (2) a carboxylic acid ester containing 13 to 24 The third pathway is a heterogeneous polar-nonpolar carbon atoms wherein the acid moiety contributes 12 to multilaminate of lipids and proteins. Binary vehicles 18 carbon atoms and the alcohol moiety is from 1 to 6 appear best suited to act as enhancers on this multilami and preferably from 3 to 6 carbon atoms and (3) an ether nate pathway. Prior art binary systems consist of a par 65 containing 8 to 16 carbon atoms. The adjuvant is incor ticular category of a polar solvent combined with a porated in amounts ranging from 1 to 50 percent by variety of compounds generally referred to as "cell weight, and preferably 5 to 30 percent by weight, based envelope disordering compounds'. on the lower alcohol. 4,863,970 3 4. From the above cited art and incorporated disclo The invention is therefore not limited to any specific sures, it is apparent that some binary enhancers favor category or categories of permeants but is inclusive of lipophilic permeants. There appears to be no recogni all therapeutically active compounds and their use tion of an enhancer system that favors the penetration of which are responsive by being incorporated into the salts and other hydrophilic permeants. Moreover, those binary mixture as more fully set forth herein. binary systems containing diols and N-cyclic solvents Also, the invention is drawn to treatment methods by may cause considerable skin irritation even at low con means of which an effective amount of a permeant, centrations. However, diols or N-cyclic solvents are combined with the binary mixture, is topically applied taught to be necessary components of a binary system. to a human or animal subject. In general, simple alcohols are taught to be solvents or 10 cosolvents to help bring various mixtures into solution DETAILED DESCRIPTION OF THE but are to be evaporated rapidly from the skin surface INVENTION and do not function as penetration enhancers any better The following definitions, when used and as they than water. apply to the present invention, are consistent with those A problem associated with use of high amounts of 15 contained in U.S. Pat. No. 4,537,776. lower alcohols, i.e. above about 50%, is that they are By "topical administration' or "topical application' known to induce human skin sensitization and have is meant directly laying or spreading upon epidermal been stated to be unsuitable as solvents for compounds tissue, especially outer skin or membrane, including the applied to the skin. See, for example, Stotts, et al, Induc skin or membrane of the oral or vaginal cavities. tion of Human Skin Sensitization to Ethanol, J. of In 20 By "safe and effective', is meant a sufficient amount vestigative Dermatology, 69:219–222 (1977) and Brown of the permeant composition to provide the desired et al, Comparative Ultrastructure and Cytochemistry of systemic effect and performance, or local activity, or Epidermal Responses to Tape Stripping, Ethanol and both at a reasonable benefit/risk ratio attendant any Vitamin A Acid in Hairless Mice, J. of Investigative medical treatment Within the scope of sound medical 25 judgment, the amount of permeant used will vary with Dermatology 73:203-206 (1979). the particular condition being treated, the severity of Other patents or publications relating to transdermal the condition, the duration of the treatment, the specific administration of active permeants are Cooper, Euro permeant compound employed, its concentration, the pean Patent Application No. 95,813, A2, published July condition of the patient, concurrent therapies being 12, 1983, entitled Penetrating Topical Pharmaceutical 30 administered and other factors within the knowledge Compositions Containing 9-(2-Hydroxyethoxymethyl)- and expertise of the patient or the attending physician Guanine; Durrant et al, European Patent Application or other practitioner. No. 117,080, published Aug. 29, 1984, entitled Skin By “toxicologically- or pharmaceutically-accepta Treatment Composition. ble' is meant the pharmaceutical actives (or permeants), SUMMARY OF THE INVENTION 35 as well as the other compatible drugs, medications or inert ingredients which the term describes, are suitable The present invention relates to improved composi for use in contact with the tissues of humans and animals tions and methods for improving the penetration of a without undue toxicity, irritation, allergic response, and broad category... of pharmaceutically-active agents the like commensurate with a reasonable benefit/risk which are lipophilic or hydrophilic including salts and ratio. which produce little or no skin irritation to human or By the terms "comprising” is meant that various animal tissue systems. The invention provides penetrat other compatible drugs and medicaments, as well as ing topical compositions based on the use of a phar inert ingredients, occlusive agents, and cosmetic vehi maceutically-active agent dissolved in, or admixed cles, can be conjointly employed in the compositions with, a penetration-enhancing binary mixture of (a) 45 and methods of this invention, as long as the critical about 1 to 95% by weight of one or more cell-envelope binary penetration enhancement vehicle and pharma disordering compounds selected from the group con ceutically active permeant are used. sisting of oleic acid, oleyl alcohol, glycerol monooleate, By "afflicted situs' is meant a localized area of pa glycerol dioleate and glycerol trioleate and mixtures thology, discomfort, infection, inflammation or lesion, thereof and (b) 5-75%, and preferably 5-49%, by 50 and the immediately surrounding area. weight of a C2 or C3 lower alcohol. In addition, the By "application situs' is meant a site suitable for formulation can optionally contain 0 to 45% by weight topical application with or without he means of a me of inert ingredients which are soluble within the en chanical sustained release device, patch or dressing, e.g. hancer composition. Such ingredients can vary from behind the ear, on the arm, back, chest, stomach, leg, hydrophilic to hydrophobic depending upon the de 55 top of foot, etc. sired combination. Representative inert ingredients in By "penetration-enhancing' is meant that the binary clude water, polypropylene glycol, polyethylene gly penetration enhancing carriers or vehicles of this inven col, polyvinyl alcohols, polyvinylpyrrollidone, mineral tion with or without optional inert ingredients provide oil, silicone oil, ethylene-vinyl acetate polymers or marked transepidermal or percutaneous delivery of an other low molecular weight polymers soluble in water, incorporated active permeant, when compared to other lower alcohols or suitable oils. compositions at equal chemical potential. Equal chemi By employing this binary mixture with or without cal potential is important since varying solubilities of optional inert ingredients, it has been found that signifi drugs in different carrier vehicles will affect their trans cant penetration of salts and other hydrophilic perme port across skin. As stated in U.S. Pat. No. 4,537,776, if ants as well as lipophilic permeants is obtained and that 65 a drug is soluble in vehicle A to the extent of 24%, and skin irritation often associated with cell-envelope disor in vehicle B to the extent of 4%, were the compositions dering compounds and/or solvents is essentially nonex to be compared at equal percentage concentration, istent. rather than equal chemical potential, the lower solubil 4,863,970. 5 6 ity carrier would show a misleading six-fold difference Since all of the above are derivatives of oleic acid in in transport over the more soluble vehicle. Therefore, that they are either oleic acid perse, esters of oleic acid the simplest way of assuring equal chemical potential or the alcohol resulting from the reduction of oleic acid, for evaluating penetration enhancement is to use satu they will collectively be referred to as the “oleic rated solutions or solutions of equal percentage of satu group'. It is realized that there are many other oleic ration of active permeants in the various enhancer com acid derivatives, i.e. methyl oleate and other esters, binations, e.g. 50% saturated. In the examples used oleamide and other amides, olealdehyde, etc. which herein, unless stated otherwise, the enhancer combina could be classified as being of the oleic group. How tions are saturated with the active permeant compo ever, for purposes of description of the present inven rents. O tion the terms "oleic group' is believed to be suffi As used herein, all percentages and ratios are by ciently limited to oleic acid, glycerol esters of oleic acid weight of the total composition unless otherwise speci and oleyl alcohol and all combinations thereof. fied. The members of the oleic group may be present in The terms "permeant”, “active”, “pharmaceutical concentrations that vary widely in the penetration en active", "pharmacological active", "pharmaceutical 15 hancer combination. They may range between about 1 agent”, “pharmacological agent', 'pharmaceutically-, to 95% by weight of the overall binary penetration or pharmacologically-active agent", "chemical agent', enhancer combination. "therapeutic agent', and "drug', are used interchange The concentration of the lower alcohols has been ably herein. found to be more limited and generally ranges between 20 about 5 and 75% by weight of the penetration enhancer The compositions of this invention require, at a mini combination. At concentrations above about 50% by mum, a permeant capable of producing systemic effects, weight, as noted above, lower alcohols can cause skin or producing or possessing local activity, in a binary irritation and one may also become sensitized to the vehicle or carrier comprising a cell-envelope disorder alcohols. However, when used in the present combina ing compound selected from the group consisting of 5 tion with oleic group compounds, skin irritation is sig oleic acid, oley alcohol, glycerol monoleate, glycerol nificantly reduced. In most cases, it is preferred to main dioleate, glycerol trioleate and mixtures thereof, and a tain the alcohol concentration in the enhancer combina lower alcohol selected from the group consisting of tion between about 5 and 49% by weight and most ethyl alcohol, propyl alcohol or isopropyl alcohol with preferably between about 20 and 49% by weight. or without optional inert ingredients within the stated 30 Although the enhancer combination is referred to as concentration ranges. “binary', it is often preferable to add an optional third The composition may also contain other optional inert component when it is desired to maximize the components which enhance their cosmetic appeal or effectiveness of the binary oleic group and lower alco acceptability, i.e., thickeners, pigments, fragrances, per hol components with any given active permeant and fumes, and the like. The binary penetration combina 35 retain the lower alcohol within the desired range of tions are essentially free of skin irritation characteristics. 75%, and preferably 49%, and below. Thus, it is often However, a perimeant combined with the penetration desirable to incorporate an inert ingredient to make up enhancers may cause some irritation. Therefore, if de from about 0 to 45% by weight of the overall penetra sired, other components which tend to reduce skin tion enhancer and preferably between about 1 and 45% irritation may be incorporated into the compositions. 40 by weight. Such third component can be any compati BINARY PENETRATION ENHANCEMENT ble inert ingredient which is soluble in the oleic group lower alcohol enhancer combination. Such ingredient VEHICLES may be hydrophilic or hydrophobic depending upon The binary penetration enhancement combinations of the enhancer combination and the active permeant to be the present invention significantly enhance the penetra 45 used. The invention is not limited to any particular inert tion of a host of pharmaceutically-active permeants ingredient as such will be readily ascertainable by one including salts. These permeants may be lipophilic or skilled in the art. Typical of such inert ingredients are hydrophilic or partially lipophilic or hydrophilic. water, polypropylene glycol, polyethlene glycol, poly The binary combinations comprise one or more of the vinyl alcohols, polyvinylpyrrollidone, mineral oil, sili stated cell-envelope disordering compounds and a 50 cone oil, ethylene-vinyl acteate polymers or other low lower alkanol selected from the group consisting of molecular weight polymers soluble in water, lower ethanol, propanol and isopropanol with or without the alcohols or suitable oils. optional inert ingredients. The compositions of the invention typically contain While certain cell envelope disordering compounds from about 50 to 99.99%, and preferably about 70 to are known in the art previously cited, it has been found 55 99.99%, by weight of the overall enhancer composition that oleic acid, oley alcohol and glycerol esters of oleic mixture comprising the oleic group, the lower C2 or C3 acid used separately or in combination provide for ex alcohol and inert ingredients within the ranges defined cellent skin penetration of active permeants when com herein. The exact amount of active permeant, and the bined with lower alcohols within the stated concentra range of each ingredient used in the enhancer combina tion ranges. Preferred combinations are (a) oleic acid or tion may be readily determined by one having ordinary oleyl alcohol in combination with lower alcohols; (b) skill in the art. All that is required is that an effective glycerol esters of oleic acid mixed with oleic acid or amount of the active permeant be incorporated into the oleyl alcohol in combination with lower alcohols; (c) penetration enhancing composition as described, with glycerol esters of oleic acid in combination with lower or without the present of other optional ingredients. alcohols; (d) mixtures of oleic acid and oleyl alcohol in 65 combination with lower alcohols and (e) mixtures of PHARMACEUTICALLY-ACTIVE PERMEANTS oleic acid and oleyl alcohol mixed with glycerol esters The binary penetration enhancers of the present in of oleic acid. vention may be formulated to incorporate a broad range 4,863,970 7 8 of pharmaceutically-active permeants. One of the dis effective amount. Dosages will obviously be a function tinct advantages of these enhancer combinations is that of various variables, such as how active the agent is, they function to enhance penetration of both lipophilic how soluble it is in the penetration enhancing composi and hydrophilic permeants including salts and are virtu tion, how often it is to be applied, whether the use is to ally free from skin irritation effects. The compositions be topical (applied to the "afflicted situs') or systemic of this invention may be utilized in delivering active (applied to the "application situs'), whether two or permeants to the "target” areas as mentioned in U.S. more active permeants are to be combined, the particu Pat. No. 4,537,776, i.e. (1) at the surface of the skin; (2) lar patient being treated, and the like. In any event, the in the stratum corneum itself; (3) in the viable epidermis dosage will be the smallest that will achieve the desired and upper dermis, just below the stratum corneum; (4) 10 result and the period of administration will be as short in the various glands and structures in and beneath the as possible to attain this result. dermis (e.g., subcutaneous adipose, dermal vasculature); In general, dosages and means of application as and/or (5) the general system (i.e. systemic effects). taught in U.S. Pat. No. 4,537,776 are appropriate to the In view of this, the invention is not limited to any present invention Levels of active permeants may vary specific type or class of active permeants. Based on the 15 from about 0.01% to about 50% by weight of the total parameters contained herein it is within the ability of composition with levels of from about 0.01 to 30% one having ordinary skill in the art to determine which being preferred. Levels from about 0.05 to 15% being permeants can be utilized. Some routine experimenta especially preferred and levels of from about 0.1 to 10% tion or testing may be required to determine optimum being most especially preferred for some active perme conditions such as exact concentrations of permeants, 20 ants. However, for some active permeants, it may be ratios of oleic group cell-envelope disordering com required to use more or less than stated above to attain pounds to alcohols, and the like. Also, some permeants the desired results. Hence, the invention is not directed may work best with one particular class of oleic group to any particular amount of active ingredient as long as cell-envelope disordering compounds and/or alcohols. it is safe and effective. The screening of all possible combinations and ratios of 25 A compendium of active permeants is contained in permeants, oleic group cell-envelope disordering com U.S. Pat. No. 4,537,776 and published European Patent pounds and C2 and C3 alcohols has not been attempted. Application No. 43,738 and incorporated herein by However, based on the formulation of a representa reference. However, for purposes of illustration, a con tive sampling of diverse active permeants, it is apparent cise listing of active agents follows. that the binary combination of an oleic group cell 30 Typical antihypertensive agents which may be uti envelope disordering compound and a C2 or C3 alcohol lized include, without limitation, minoxidil, nadolol, will function to enhance the penetration of a broad pargyline, pindolol, propranolol, reserpine, timolol, spectrum of, pharmaceutically-active permeants. Such trimethaphan, metoprolol, hydrochlorothiazide, hy agents include, without limitation, those mentioned in dralazine, furosemide, clonidine, and chlorthalidone. U.S. Pat. 4,537,776 such as antimicrobials, antibacteri 35 Diuretics include, without limitation, benzthiazide, als, antibiotics, antimyobacterials, antimalarials, antia buthiazide, cyclopenthiazide, cyclothiazide, metola mebics, anthelmintics, antifungals, antivirals, neoplastic zone, triamterelene, chlorazanil, clazolimme, and hy agents, agents affecting the immune response, blood droflumethiazide. calcium regulators, peptide and protein hormones, male Exemplary of anorexigenics are, without limitation, sex hormones, female sex hormones, agents useful in amphetamine, methamphetamine, chlorphentermine, glucose regulation, anticoagulants, antithrombotics and chlortermine, phentermine, phendimetrazine, mazindol, hemostatics, antihyperlipidemic agents, cardiac drugs, oxazoline, and phenoxyalbyleneamine. thyromimetic and antithyroid drugs, adrenergics, anti Fungistatic and fungicidal agents encompass, without hypertensive agents, cholinergics, anticholinergics, an limitation, thiabendazole, chloroxine, fungimycin, gris tispasmodics, antiulcer agents, skeletal and smooth mus 45 eofulvin, chlordantoin, salicylic acid, nystatin, clo cle relaxants, histamine H2-receptor agonists and antag trimazole, fezatione, sodium pyrithione, amphotericin onists, dopamine receptor agonists and antagonists, B, 5-fluorocytosine, haloprogin, vifampin, and pimari prostaglandins, general inhibitors of the allergic re C. sponse, antihistamines, local anesthetics, analgesics, A broad range of analgesics may be utilized includ narcotic antagonists, antitussives, sedative-hypnotic 50 ing, without limitation, morphine, codeine, heroine, agents, anticonvulsants, antipsychotics, anti-anxiety methadone, thebaine, orpiarine, buprenorphine, mor agents, antidepressant agents, anorexigenics, non-steroi phinans, benzomorphans, acetaminophen, butorphanol, dal anti-inflammatory agents, steroidal anti-inflamma diflunisal, fenoprofen, fentanyl, fentanyl citrate, hydro tory agents, bone-active agents, antiarthritics, vitamins, codone, aspirin, sodium salicylate, ibuprofen, oxymor diagnostic agents and sunscreens. These agents can be 55 phone, pentaxicine, naproxen, nalbuphine, mefenamic used for systemic effect, local activity, or both, as ap acid, meperidine and dihydroergotamine. propriate. Examples of pharmaceutically-active perme A typical narcotic antagonist is haloxone. Exemplary ants are well-known in the art and can be found listed in antitussive agents include, without limitation, diphen sources identified in U.S. Pat. No. 4,537,776 as well as hydramine, guaifenesin, hydromorphone, ephedrine, others. For example, active agents, in approved com phenylpropanolamine, theophylline, codeine, nosca mercially available formulations, their recommended pine, levopropoxyphene, carbetapentane, chlorpehn dosages, adverse reactions, side effects and the like are dianol and benzonatate. listed in the annual publication of the Physicians' Desk Among the sedatives which may be utilized are, with Reference, published by Medical Economics Company, out limitation, chloral hydrate, butabarbital, al a division of Litton Industries, Inc. 65 prazolam, amobarbital, chlordiazepoxide, diazepam, The pharmaceutically-active permeants may be used mephobarbital, secobarbital, diphenhydramine, ethin in the compositions and methods of the present inven amate, flurazepam, halazepam, haloperidol, prochlor tion at any safe and effective level, or in any safe and perazine, oxazepam, and talbutal. 4,863,970 9 10 Examples of cardiac drugs are, with limitation, quini ingredients will be sufficient in most instances to obtain dine, propranolol, nifedipine, procaine, dobutamine, the desired results. However, in preparing formulations digitoxin, phenytoin, sodium nitroprusside, nitroglyc for actual use, it may be desirable, in addition to inert erin, verapamil HCl, digoxin, nicardipine HCl, and diluents, to add other components such as excipients, isosorbide dinitrate. dyes, perfumes fragrances, pacifiers, thickening agents, Antimicrobial agents are inclusive of, without limita preservatives, anti-oxidants, gelling agents, surfactants tion, erythromycin, sulfonamide, lincomycin, clindamy and stabilizers. For example, when forming gels or cin, tetracycline, chlortetracycline, demeclocycline, cremes, it may be desirable to add significant amounts of doxycycline, and methacycline. water, i.e. up to 45% in some cases for gels. Such mate Examples of useful antibacterial agents are, without O rials, when added, should not unduly interfere with the limitation, phenols, hydroxy benzoic acid, hydroxy penetration enhancement of these compositions. Such quinoline, nitrofuran, nitroimidazoles, oxolinic acid, formula modifications to improve cosmetic acceptabil actinomycetin, bacitracin, tyrothricin, kanamycin, neo ity are well within the skill of workers in the art and do mycin and chloramphenicol. not form part of the present invention. A typical antiviral agent is Ara-A. Steroidal anti-in 15 flammatory agents are illustrated by, without limitation, METHOD OF USE triamcinolone acetonide, beclomethasone dipropionate, In any form of medical practice, there are many vari hydrocortisone acetate, fluocinolone acetonide, ables which affect the particular treatment regimen. In betamethasone valerate, prednisolone, prednisone, that regard, the final diagnosis and treatment is left to methyl prednisolone and paramethasone. 20 the expertise of the practitioner and patient. As previ Inclusive of non-steroidal anti-inflammatory agents are acetyl salicylic acid, fenoprofen calcium, ibuprofen, ously stated, in clinical practice, it is the goal that the ketoprofen, indomethacin, meclofenamate sodium, dosage of any active permeant be as small as possible to mefenamic acid, naproxen sodium, phenylbutazone, and achieve the result desired and that the administration of oxyphenbutazone. 25 the permeant be as short as possible. To attain these Anti-emetics are illustrated by, without limitation, conditions, it is imperative that the amount of active thiethylperazine, metoclopramide, cyclizine, meclizine, ingredient utilized is a safe and effective amount prochlorperazine, doxylamine succinate, promethazine, whether applied to an afflicted situs or an application triflupromazine, and hydroxyzine. situs. When local treatment is desired, the compositions A typical dopamine receptor agonist is bromocriptine 30 are applied to the afflicted situs. When systemic treat mesylate. Exemplary amino acid, peptide and protein ment is desired, the compositions are applied to an ap hormones include, without limitation, thyroxine, plication situs, preferably from a sustained release de growth hormone (GH), interstitial cell stimulating hor vice such as a patch, bandage, web, film or the like. mone (ICSH), follicle-stimulating hormone (FSH), thy When both local and systemic treatments are indicated, rotropic hormone (TSH), adrenocorticotropic hormone 35 the compositions can be applied at both the afflicted (ACTH), gonadotropin releasing hormone (GnRH) situs and application situs, or both. The selection of such as leuprolide acetate, vasopressin and their active active permeant or combination of permeants, particu degradation products Some products may have suffi lar penetration enhancement combination and the like ciently high melecular weights that absorption through are necessarily left to the skill of the practitioner pro the stratum corneum or mucous membranes may be 40 vided the parameters outlined herein are followed. difficult. Therefore, the invention is applicable only to The dosage, rate of application, place of application, those hormones which have molecular weights and and other treatment parameters are generally outlined stereo configurations which will allow passage through in U.S. Pat. 4,537,776 and are incorporated herein by the skin. reference rather than being repeated. What is a safe and Female sex hormones which can be used include, 45 effective amount of any ingredient will obviously de without limitations, estradiol, diethylstilbestrol, conju pend upon the active ingredient being used, the site of gated estrogens, estrone, norethindrone, medroxypro application, the effectiveness of the penetration en gesterone, progesterone, and norgestrel. hancer and other parameters outlined herein. Typical male sex hormones which may be utilized A practitioner being skilled in the art will be able to may be represented by, without limitation, testosterone, 50 determine the application parameters of each specific methyltestosterone, and fluoxymesterone. formulation based on the needs of each patient. The above listed active permeants may, along with others not specifically disclosed, be used separately or EXAMPLES in combination according to the treatment regimen The following examples demonstrate the penetration desired. 55 enhancement which is obtained by the binary oleic Preferred categories of active permeants include anti group cell envelope disordering compounds-lower al hypertensive agents, cardiac drugs, analgesics, sedative kanol compositions. In making these tests, human skin hypnotic agents, anti-anxiety agents, steroidal anti-in consisting of heat-separated abdominal epidermis, taken flammatory agents, non-steroidal anti-inflammatory at autopsy, was placed in a standard Franz diffusion agents, male sex hormones, and female sex hormones. 60 apparatus in a horizontal position between a lower, Those active permeants specifically listed above under capped diffusion cell and an upper open cell. A normal each category are particularly preferred. saline solution was added to the lower diffusion cell in The components of this invention are inclusive of the contact with the subcutaneous side of the skin, and the active permeants combined with the binary penetration test composition, consisting of a saturated (unless other enhancing mixture of oleic group cell-envelope disor 65 wise indicated) solution of an active drug being moni dering compounds and C2 and C3 alcohols with or with tored formulated in the binary penetration enhancer, out the addition of inert ingredients or diluents. It is was added to the diffusion cell in contact with the upper contemplated that compositions containing only these or epidermal side of the skin. 4,863,970 11 12 The cell assembly was kept at a constant temperature greater than additive enhancement effects which one of 37 C. At predetermined intervals, the diffusate from would expect when combining these ingredients. the cell on the subcutaneous side of the skin was with drawn and the amount of drug in the diffusate was EXAMPLE III measured using standard analytical techniques. Each 5 Following the procedure and penetration enhance test was run using a separate skin sample. Unless stated ment systems of Example II, the relative flux of halo differently, the amount of active drug used was that peridol as active agent was determined. The results are required to form a saturated solution. The results are as follows: reported in terms of flux mcg/cm2/day (hour) or relative flux. O ENHANCEMENT RELATIVE FLUX EXAMPLE I Test No. SYSTEM (%w/w) Haloperidol III-A 40% OA 19.1 To show the penetration enhancement effects of the 40% GDO binary oleic group cell envelope disordering com 20% EtOH pound-lower alkanol compositions are applicable to 15 80% OA active agents inclusive of hydrophilic, salts and hydro III-B 20% EtOH 10.8 80% GDO phobic agents the following compositions were tested. III-C 20% EtOH 21.7 95% PG 2 III-D 5% OA 22.4 Flux (mcg/cm2/dayl 20 III-E 100% OA S.2 Glycerol III-F 100% EtOH 5.1 Active Propylene Dioleate GDO/Ethanol III-G 100% PG 1.0 Test No. Ingredient Glycol (GDO) (80:20 w/w) II-H 100% GDO 12.2 EtOH = Ethanol Estradiol 14.9 14.3 20.9 PG = Propylene Glycol Na-Salicylate 38.6 6,626.0 13,696.4 GDO = Glycerol Dioleate Ara-A 0.44 0.48 3.98 25 OA = Oleic Acid

The combination of 20% ethanol and 80% GDO It is evident from the above that the combinations of shows substantial penetration enhancement effects as 80% glycerol dioleate and/or oleic acid with 20% etha compared to a diol (propylene glycol) or GDO alone nol provide penetration enhancement similar to that for all three active agents. 30 obtained with propylene glycol and oleic acid and, as will subsequently be demonstrated, does not possess the EXAMPLE II skin irritation properties of propylene glycol-oleic acid A series of tests similar to Example I were conducted combinations. The enhancement obtained by combining utilizing a greater variety of active agents with various GDO and oleic acid cell-envelope disordering agents component combinations forming penetration enhance 35 with ethanol was far greater than that obtained utilizing ment systems which were directly compared with indi the individual components alone. vidual components making up the systems as follows: EXAMPLE IV

FLKUX mcg/cm2/day) ENHANCEMENT Propranolol Minoxidil Sodium Test No. SYSTEM (% W/W) Estradiol Prednisolone HC HCl Salicylate I-A 40% OA 75.6 915.7 1,216.0 383.6 12,838.0 40% GDO 20% EtOH II-B 80% OA 21.2 462.0 889.0 303.0 22,905.0 20% EtOH I-C 80% GDO 48.6 57.0 767.0 1970 12,541.0 20% EtOH II-D 95% PG 120.1 1640 2,259.0 1,155.0 834.0 5% OA I-E 100% OA 31.8 291.0 258.0 22.5 8,349.0 II-F 100% EtOH 18.7 81.0 45.0 23.4 1,094.0 I-G 100% PG 2.6 5.0 25.0 14.6 231.8 II-H 100% GDO 12.1 92.0 257.0 62.1 - EtOH = Ethanol PG = Propylene Glycol GDO = Glycerol Dioleate OA se Oleic Acid The penetration enhancer composition utilized in Test II-D is taught in the prior art and shown in Exam ple XIV of European Patent Application No. 43,738 and generally provides for excellent skin penetration enhancement. However, this combination of oleic acid Again, following the procedure of the preceding and propylene glycol causes severe skin irritation. The examples, a series of tests utilizing glycerol dioleate penetration enhancement systems of Tests II-A, II-B 65 and/or oleic acid as cell-envelope disordering compo and II-C, with minor exceptions, showed across the nents combined with isopropyl alcohol as penetration board improvement in penetration enhancement over enhancers, were performed using propranolol HCl and the individual components used alone and generally testosterone as active agents. Results are as follows: 4,863,970 13 14 Each of these formulations were gelled with 1% w/v. Carbopol 1342, (an emulsifying and gelling agent con Test ENHANCEMENT FLUX ACTIVE sisting of a copolymer of acrylic acid and long chain No. SYSTEM (% w/w) mcg/cm2/day) AGENT alkyl methacrylates). Each sample was evaluated in six Skin Sample #1 V-A 100% GDO 448.8 Propranolol HC (6) albino rabbits. The skin was shaved from the backs IV-B 100% PrOH 67.2 Propranolol HCl of the rabbits 24 hours prior to test sample application. 80% GDO The gelled test samples were applied to the back of the IV-C 20% i-ProH 1,000.8 Propranolol HCl rabbits using 1 cm2. Finn TM Chambers containing 0.1 Skin Sample #2 cc of test sample. The entire abdomen of the rabbit was IV-D 100% GDO 1200 Testosterone 10 then wrapped with surgical tape to prevent the animal IVE 100% OA 1440 Testosterone 80% OA from removing the Finn Chambers. After 24 hours of V-F 20% -ProH 456.0 Testosterone exposure, the Finn Chambers were removed from the 80% OA backs of the rabbits and any residual test sample adher IV.G 10% i-ProH 912.0 Testosterone ing to the skin was gently removed with surgical gauze 10% GDO 15 Skin Sample i3 and distilled water. Test sites were scored for erythema IV-H 100% OA 76.8 Testosterone and edema one hour and 48 hours following removal 80% OA according to the scales listed in Table 2. V- 20% i-ProH 374.4 Testosterone TABLE II 80% GDO IV- 20% i-ProH 384.0 Testosterone Evaluation of Skin Reactions i-ProH as Isopropanol Value GDO = Glycerol Dioleate OA = Oleic Acid Erythema and escar formation: No erythema O Very slight erythema (barely perceptible) 1 The above show that enhancers consisting of oleic Well-defined erythema 2 group cell-envelope disordering compounds and isopro 25 Moderate to severe erythema 3. panol are clearly superior to the individual components Severe erythema (beet redness) to slight eschar formation (injuries in depth) 4 used separately. Edena formation: EXAMPLE V No edema O Very slight edema (barely perceptible) In copending application Ser. No. 06/930,764, a test 30 Slight edema (edges of area well defined by definite raising) 2 was reported showing results of eight different compo Moderate edema (raised approximately sitions on skin irritation and sensitization. This test, 1 millimeter) 3. commonly referred to as a "patch insult test' is de Severe edema (raised more than signed to study both irritation and sensitization. It 1 millimeter and extending beyond screens out compositions which are flagrant irritants or 35 the area of exposure) 4. sensitizers. However, because the protocol allows a recovery time between applications, it is not a stringent Using the above scores, an irritation index (II) was test for irritation since the skin is given a chance to then calculated for each test sample as the sum of all recover between tests. Furthermore, due to the low edema and erythema scores in all test animals divided number of subjects and the relatively short induction by the number of animals evaluated in each test sample phase, this test is not capable of screening out mild (6) and the number of parameters scored (2; sensitizing agents. edema-erythema). The scores are reported in Table 3 A more standard and acceptable model for skin irrita as follows: tion is found in a Primary Skin Irritation (PSI) test utilizing albino rabbits as test subjects. This test, using 45 TABLE III rabbits, is typically a more sensitive indicator of skin Primary Skin Irritation Index Summary irritation than might be obtained using human subjects. Formulation Irritation Index 1 8 This test was directed only to a binary enhancer sys 2 .9 tem and no active permeant was involved. The purpose 50 3 .8 of the test was to get an indication as to at what concen 4. 1. trations ethanol would begin to show significant irrita 5 1.7 tion. The enhancer system, expressed as v/v%, con sisted of a constant 10% GMO (glycerol monooleate or These data indicate that ethanol concentrations of 70 monoolein) as the cell envelope disordering compound, 55 and 75 v/v% produced significant skin irritation and concentrations of ethanol at 25%, 45%, 55% and whereas ethanol concentrations of 55 v/v% and below 75% with the remainder being water. An additional test produced only about one-half the irritation. Based on using 70% ethanol and 30% methyl laurate was also these data it is deemed preferable to limit the ethanol included in the test and is also reported. The composi concentration in any enhancer system to less than 50%. tions tested are listed in Table 1: 60 TABLE 1 EXAMPLE VI Formula Composition The ability to enhance the penetration of peptide 25/10/65 (Ethanol/GMO/H2O) permeants by using enhancers consisting of a mixture of 45/10/45 (Ethanol/GMO/H2O) a glycerol oleate ester and ethanol, as compared to a 55/10/35 (Ethanol/GMO/H2O) 65 water and ethanol mixture, are shown in this example. 75/10/15 (Ethanol/GMO/H2O) A procedure similar to that outlined in Example I was 70/30 (Ethanol/Methyl Laurate) followed except that the flux is reported on an hourly instead of a daily basis The active permeants used were 4,863,970 15 16 a saturated enhancer solution of bromocriptine mesylate and leuprolide acetate at a loading of 5 mg/ml in the -continued enhancer. The results are as follows: PEG 400 45 FORMULATION VII-H Metoclopramide 10-15% 5 Enhancer 85-90% - Flux incs/cm/hi Glycerol Dioleate 30 Active 60% EtOH 50%. EtOH 70% EtOH Ethanol 25 Test No. Ingredient 40% GMO 50% GDO 30% H2O 8 PPG 2000 45 VI-A Brono- 1.63 - 0.08 - FORMULATION VII-I criptine Propranolol HCl 5% Mesylate 10 Enhancer 95% VI-B Leuprolide - 1.33- 0.48 sk Glycerol Dioleate 60 Acetate Ethanol 20 GMO = glycerol monooleate PEG 400 20 GDO = glycerol dioleate FORMULATION VII-J * = Below detection imit Propranolol 20% 15 Enhancer 80% These results show that penetration of peptide perme Glycerol Dioleate 70 Ethanol 20 ants are clearly enhanced by the use of a combination of PPG 2000 10 either monooleate and dioleate esters of glycerol and FORMULATION VII-K ethanol as compared to the use of an aqueous ethanol 20 Propranolol HCl 5% solution. Enhancer 95% Glycerol Monooleate 6 EXAMPLE VII Ethanol 49 H2O 45 The following are exemplary of other compositions FORMULATION VII-L which can be formulated within the scope of this inven 25 Propranolol 15% tion. However, they are illustrative only and are not Enhancer 85% Glycerol Trioleate 20 intended to define the scope of the invention. The com Isopropanol 40 positions can be conveniently formulated simply by Mineral Oil 40 mixing all components thoroughly. In some formula FORMULATION VII-M tions, exact percentages are given whereas others are 30 Fentanyl Citrate 2% expressed by ranges. All compositions are in present by Enhancer 98% weight. Glycerol Monooleate 6 Ethanol 49 H2O 45 w FORMULATION VII-A FORMULATION VII-N Testosterone 5-5% 35 Fentanyl 1% Enhancer 99% Enhancer - 85-95% Glycerol Dioieate 5-90% Glycerol Trioleate 5 Ethanol 5-49% Isopropanol 45 *PEG 400 0-45% Mineral Oil 40 T FORMULATION VII-B FORMULATION VII-O Methadone 10-30% Nicardipine 5% Enhancer 70-90% Enhancer 95% Glycerol Dioleate 20 Oleyl Alcohol 10 Ethanol 49 Isopropanol 45 *PEG 400 31 **PPG 2000 45 FORMULATION VII-C FORMULATION VII-P 45 Nicardipine HCl 10% Estradiol 0.1-1.0% Enhancer 90% Enhancer 99-99.9% Oleic Acid 2 Glycerol Dioleate 10 Glycerol Dioleate 10 Ethanol 49 Ethanol 45 *PEG 400 41 *PEG 400 43 FORMULATION VII-D 50 FORMULATION VII-Q Ketoprofen 10-20% Naloxone HCl 10% Enhancer 80-90% Enhancer 90% Glycerol Dioleate 40 Glycerol Monooleate 5 Ethanol 40 Oleic Acid 2 tippG 2000 20 Ethanol 49 FORMULATION VII-E 55 H2O 44 Dihydroergotamine 1-10% FORMULATION VII-R Enhancer 90-99% Naloxone 5% Glycerol Dioleate 40 Enhancer 95% Ethanol 40 Glycerol Trioleate 75 PEG 400 20 Propanol 5 FORMULATION VII-F Mineral Oil 20 Nifedapine 2-0% FORMULATION VII-S Enhancer 90-98% Griseofulvin 5% Glycerol Dioleate 45 Enhancer 95% Ethanol O Glycerol Trioleate 50 Mineral Oil 45 Isopropanol 15 FORMULATION VII-G 65 PPG 2000 35 Thiethylperazine 1-5% FORMULATION VII-T Enhancer 95-99% Fluocinolone Actonide 1% Glycerol Dioleate 0 Enhancer 99% Ethanol 45 Glycerol Trioleate 80 4,863,970 17 18 -continued -continued Isopropanol 10 Enhancer 95% Mineral Oil 10 Oleyl Alcohol 25 FORMULATION VII-U Isopropanol 30 Clindamycin 2.5% 5 PEG 400 45 Enhancer 97.5% FORMULATION VII-HH Oleyl Alcohol 40 Methyl Testosterone 5% Isopropanol 30 Enhancer 95% ME Oil 30 Glycerol Trioleate 40 FORMULATION VII-V Isopropanol 40 Neomycin Sulfate 5% O *PPG 2000 20 Enhancer 95% *PEG 400 = polyethylene glycol of average molecular weight 400 Glycerol Monooleate 6 "PPG 2000 = polypropylene glycol of average molecular weight 2000 Ethanol 49 H2O FORMULAtid, V-W While the above examples illustrate numerous em clidi Hc 19, 15 bodiments of the invention, the scope is limited only by Enhancer 99% the operability exhibited by improved enhancement of Glycerol Dioleate 10 permeants attributable to the enhancer combination of Eo oleic group components and lower alkanols, with or FORMULATION VI-X without added inert diluents. It is to active permeants Hydroflumethiazide 10% 20 contained in that enhancer composition that this inven Enhancer 90% tion is drawn. It is, therefore, limited in scope only by Glycerol Dioleate O the appended claims and their functional equivalents. Oleic Acid 5 We claim: legal 1. A pharmaceutical composition for topical applica FORMULATION VII.Y 25 to having penetration-enhancing properties consisting pe T 5% essentially of: Enhancer 95% (a) a safe and effective amount of an active pharma Glycerol Trioleate 60 ceutical agent contained in, Ron . (b) a penetration-enhancing vehicle exclusive of diols FORMULATION VI-Z. 30 and N-cyclic solvents consisting essentially of: phetermine Hc T 10% (i) 1-95% by weight of one or more cell-envelope Enhancer 90% disordering compounds selected from the group Glycerol Monooleate 6 consisting of oleic acid, oleyl alcohol, glycerol Ethanol 49 esters of oleic acid and mixtures thereof; H2O FORMULATIovii-AA 35 (ii) 5-75% by weight of a lower alkanol selected - - 5% from the group consisting of ethanol, propanol Enhancer 95% and isopropanol and mixtures thereof; and Glycerol Trioleate 40 (iii) 0-45% by weight of an inert diluent. g: - - 3. 2. A composition according to claim 1 wherein the FORMULATION VII-BB 40 lower alkanol is present in amounts of between 5 and Morphine sulfate T 5% 49% by weight. Enhancer 95% 3. A compositionpo accordingg to claim 2 wherein the Glycerol Monooleate 6 active pharmaceutical agent is present in amount rang Oleic Acid 4. ing from about 0.01 to 50% by weight and the penetra Eoo 45 tion enhancing vehicle is present in amounts ranging FORMULATION VII-CC from about 50.99.99% by weight. - - 5% 4. A composition according to claim 3 wherein the Enhancer 95% cell-envelope disordering compounds are members se Glycerol Trioleate lected from the following groupings: Ribn 2. 50 (1) oleic acid and oley alcohol or mixtures thereof; FORMULATION VII-DD (2) one or more glycerol esters of oleic acid; Ibuprofen - - (3) oleic acid and one or more glycerol esters of oleic Enhancer 90% acid; Glycerol Trioleate 20 (4) oleyl alcohol and one or more glycerols ester of Isopropanol 49 55 oleic acid; and PPG 2000 FORMULATION31 VII-EE (5) mixtures sof oleic acid and oleyl alcohol and one or Naproxen sodium 10% more glycerol esters of oleic acid. Enhancer 90% 5. A composition according to claim 4 wherein the Glycerol Dioleate 40 active pharmaceutical agent is present in amounts rang glycohol 60 ing from about 0.01 to 30% by weight and the penetra PEG 400 30 tion enhancing vehicle is present in amounts ranging FORMULATION VL-FF from about 70 to 99.99% by weight. Naproxen Sodium 0% 6. A composition according to claim 5 wherein the Enhancer 90% cell-envelope disordering compound is a member se Syers Monooleate s 65 lected from the group consisting of oleic acid and oleyl H2O 45 alcohol and mixtures thereof. FORMULATION VII-GG 7. A composition according to claim 5 wherein the Progesterone 5% cell-envelope disordering compound is oleic acid. 4,863,970 19 20 8. A composition according to claim 6 wherein the lected from the group consisting of oleic acid and oleyl cell-envelope disordering compound is oleyl alcohol. alcohol and mixtures thereof. 9. A composition according to claim 5 wherein the 25. A composition according to claim 24 wherein the cell-envelope disordering compound is a member se cell-envelope disordering compound is oleic acid. lected from the group consisting of a one or more glyc 26. A composition according to claim 24 wherein the erol esters of oleic acid. cell-envelope disordering compound is oleyl alcohol. 10. A composition according to claim 9 wherein the 27. A method according to claim 23 wherein the cell-envelope disordering compound is glycerol mono cell-envelope disordering compound is a member se oleate. lected from the group consisting of a one or more glyc 11. A composition according to claim 8 wherein the O erol esters of oleic acid. cell-envelope disordering compound is glycerol diole 28. A composition according to claim 27 wherein the ate. cell-envelope disordering compound is glycerol mono oleate. 12. A composition according to claim 7 wherein the 29. A composition according to claim 27 wherein the cell-envelope disordering compound is glycerol triole 15 ate. cell-envelope disordering compound is glycerol diole ate. 13. A composition according to claim 5 wherein the 30. A composition according to claim 27 wherein the cell-envelope disordering compound is oleic acid ad cell-envelope disordering compound is glycerol triole mixed with a member selected from the group consist ate. ing of a one or more glycerol esters of oleic acid. 31. A composition according to claim 23 wherein the 14. A composition according to claim 13 wherein the cell-envelope disordering compound is oleic acid ad cell-envelope disordering compound is glycerol mono mixed with a member selected from the group consist oleate. ing of a one or more glycerol esters of oleic acid. 15. A composition according to claim 13 wherein the 32. A composition according to claim 31 wherein the cell-envelope disordering compound is glycerol diole 25 cell-envelope disordering compound is glycerol mono ate. oleate. 16. A composition according to claim 13 wherein the 33. A composition according to claim 31 wherein the cell-envelope disordering compound is glycerol triole cell-envelope disordering compound is glycerol diole ate. ate. 17. A composition according to claim 5 wherein the 30 34. A composition according to claim 31 wherein the cell-envelope disordering compound is oleyl alcohol cell-envelope disordering compound is glycerol triole admixed with a member selected from the group con ate. sisting of a one or more glycerol esters of oleic acid. 35. A composition according to claim 23 wherein the 18. A composition according to claim 17 wherein the cell-envelope disordering compound is oleyl alcohol cell-envelope disordering compound is glycerol mono 35 admixed with a member selected from the group con oleate. sisting of a one or more glycerol esters of oleic acid. 36. A composition according to claim 35 wherein the 19. A composition according to claim 17 wherein the cell-envelope disordering compound is glycerol mono cell-envelope disordering compound is glycerol diole oleate. ate. 37. A composition according to claim 35 wherein the 20. A composition according to claim 17 wherein the cell-envelope disordering compound is glycerol diole cell-envelope disordering compound is glycerol triole ate. ate. 38. A composition according to claim 35 wherein the 21. A composition according to claim 5 wherein the cell-envelope disordering compound is glycerol triole alcohol is present in the penetration enhancer vehicle in 45 ate. amounts of between about 20 and 49% by weight. 39. A composition according to claim 23 wherein the 22. A composition according to claim 4 wherein the inert diluent is a member selected from the group con inert diluent is present in the penetration enhancer vehi sisting of water, polypropylene glycol, polyethylene cle in amounts ranging from 1 to 45% by weight. glycol, polyvinyl alcohols, polyvinylpyrrolidone, min 23. A composition according to claim 22 wherein the 50 eral oil, silicone oil, ethylene-vinyl acteate polymers or active pharmaceutical agent is present in amounts rang other suitable water or oil soluble low molecular weight ing from about 0.01 to 30% by weight and the penetra polymers. tion enhancing is present in amounts ranging from about 40. A composition according to claim 23 wherein the 70 to 99.99% by weight. alcohol is present in the penetration enhancer combina 24. A composition according to claim 23 wherein the 55 tion in amounts between about 20 and 49% by weight. cell-envelope disordering compound is a member se is k

65 w UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. : 4, 863,970 DATED ; September 5, 1989 INVENTOR(S) : Dinesh C. Patel, Yunik Chang it is certified that error appears in the above-identified patent and that said Letters Patent is hereby Corrected as shown below:

Column 9, line 1, reading "with" should read - -Without

Signed and Sealed this Eleventh Day of January, 1994

BRUCELEHMAN Attesting Officer Commissioner of Patents and Trademarks