United States Patent (19) [11] Patent Number: 4,970,206 Alexander et al. 45 Date of Patent: Nov. 13, 1990

(54) PYROGLUTAMIC ACDESTERS USED AS 51) Int. Cl...... A61K 31/56; A61K 31/58 DERMAL PENETRATION ENHANCERS 52 U.S. C...... 514/174; 514/179; FOR DRUGS 514/180 58 Field of Search ...... 514/174, 179, 180 75 Inventors: Jose Alexander; Takeru Higuchi, both of Lawrence, Kans. Primary Examiner-Stanley J. Friedman Attorney, Agent, or Firm-Joseph F. DiPrima; Manfred 73 Assignee: Merck & Co., Inc., Rahway, N.J. Polk 21 Appl. No.: 348,914 57 ABSTRACT 22 Filed: May 8, 1989 The invention relates to pyroglutamic acid esters used Related U.S. Application Data as dermal penetration enhancers for therapeutic agents having poor skin permeation. 60 Division of Ser. No. 220,853, Jul. 18, 1988, Pat. No. 4,847,250, which is a continuation-in-part of Ser. No. 802,907, Nov. 29, 1985, Pat. No. 4,762,851. 20 Claims, No Drawings 4,970,206 1. 2 Effective delivery of such drugs through the skin would PYROGLUTAMIC ACD ESTERS USED AS require much lower doses because the so called "first DERMAL PENETRATION ENHANCERS FOR pass' metabolism would be avoided. Additionally, the DRUGS topical application of the drug has the advantage that their pharmacological action is exhibited gradually over CROSS REFERENCE TO RELATED an extended period of time avoiding the possibility of APPLICATIONS inducing undesirable physiological action by abrupt This is a division application of U.S. Ser. No. 220,853 increase in concentration in vivo. filed July 18, 1988, now U.S. Pat. No. 4,847,250, which But most drugs are not absorbed in sufficient concen in turn, is a continuation-in-part of U.S. application Ser. 10 tration through the skin to exhibit pharmacological No. 802,907 filed Nov. 29, 1985, now U.S. Pat. No. effect. This is because skin is an effective barrier to 4,762,851. penetration. The outer layer of the epidermis, called the stratum corneum, offers the maximum resistance to BACKGROUND OF THE INVENTION penetration, whereas the lower-layers are relatively The invention relates to novel compositions and 15 permeable. For proper treatment of dermal conditions, methods for enhancing permeation of topically adminis it is important that the active agent penetrate the stra tered drugs by incorporating therein pyroglutamic acid tum corneum where it is retained. From this reservoir in esters as dermal penetration enhancing agents. the outer layer, the therapeutic agent could be slowly Transdermal drug delivery to achieve systemic effect released and penetrates the underlying areas where it is an area of much current interest and activity. While 20 could exhibit its therapeutic or cosmetic effect. When the cutaneous route of input is advantageous in many dermatological agents such as sunscreens, which pro respects such as ease of use, better patient compliance, tect the underlying tissue from external factors (ultravi decreased first pass metabolism etc., the excellent bar olet rays) are used, maximum retention in the stratum rier nature of the skin has so far limited the drugs con corneum is essential. On the other hand, the relative sidered suitable for transdermal delivery to very few. 25 permeability of the layers of the epidermis below the The use of adjunctive chemicals known as skin penetra stratum corneum can also allow access to the systemic tion enhancers widens the scope of transdermal drug circulation; indeed, it is necessary for the therapeutic delivery. Such use involves controlled impairment of agent to penetrate the stratum corneum in order to the skin's protective layer, the stratum corneum. Ide provide systemic therapeutic effect from the trans ally, no elements of the skin other than this horny layer 30 should be involved in such a drug delivery approach, dermal route. because participation of any living tissue could result in DESCRIPTION OF THE PRIOR ART cellular insult and lead to an irritant or allergic re sporise. So an ideal penetration enhancer is one which Many investigators have turned to various enhancing speeds the permeation of the drug through the stratum 35 agents such as dimethylsulfoxide, dimethylformamide corneuin, without itself crossing this barrier, or if it and various other aliphatic and aromatic amides, cyclic crosses, undergoes fast metabolic destruction and/or amides (Akerman et al., Pharmacol. et Toxicol. 1979, detoxification in the viable area of the skin. This inven 45, 58), methyldecylsulfoxide (U.S. Pat. No. 527,864), tion deals with an analagous series of penetration en dimethyl acetamide (U.S. Pat. No. 3,472,931) and the hancers of the latter type. 40 like to deliver topically active agents more efficiently It is well known that a number of therapeutically through the skin, as well as to enhance the absorption of active agents, such as g-blockers, antihypertensives, systemically active therapeutic agents through the skin antiarrhythmics, antiangingl agents, vasodilators, antie into general circulation. U.S. Pat. No. 3,989,816 dis metics, antibacterials, antifungals, corticosteroids, an closes that 1-substituted azacyclopetane-2-one deriva tiinflammatories and the like when administered to 45 tives enhance penetration of a physiologically active warm-blooded animals by a number of various routes agent through the skin. U.S. Pat. No. 3,920,814 discloses such as by intravenous infusion, intramuscular injection, that the antibacterial activity of antibiotics such as peni oral, rectal or buccal routes, enter the general circula cillins and cephelosporins is potentiated by coadminin tion and produce the appropriate systemic therapeutic stration with pyrrolidone carboxylic acid or a salt deriv effect. It is also known that the aforementioned methods 50 ative thereof. The reference directs itself to oral and of administration have certain disadvantages. For exam intravenous forms of administration. U.S. Pat. No. ple, the intravenous and intramuscular routes are not 3,836,665 discloses a topical dermatological composi only painful for the patient, but also must be performed tion for cosmetic sebacious gland excretion-inhibiting by a trained individual. Buccal and rectal administration treatment or therapeutic antiphlogistic treatment of the often produce discomfort and annoyances for the pa 55 skin consisting of an inert dermatological carrier and tient. Oral administration, although generally accept alkyl esters of 5-pyrolidone-2-carboxylic acid. Finally, able for the patient, often does not deliver much of the European Patent Application No. 0123948Al (1984) therapeutic agent to systemic circulation. This dimin claims glycerol pyroglutamates wherein one or both of ished drug delivery is usually attributed to poor absorp the glycerol hydroxyls etherified with alkyl or alkenyl tion from the gastrointestinal tract and/or to degrada 60 groups as shown below a penetration enhancers: tion of the agent by the acidic medium of the stomach, by the enzymes in the gastrointestinal tract and sur rounding tissue, or by the rapid metabolism by enzymes of the liver through which the drug must pass before it enters the systemic circulation. For example, drugs such 65 CO2CH2CH-CH2OR2 as anti bacterials, narcotic analgesics, g-blockers and OR others require relatively high doses when given orally due to the remarkable liver metabolism encountered. 4,970,206 3 4. The similarity of the side chain in the above mentioned agent for said drugs. The dermal penetration enhancing application to nonionic surfactants and the use of such agents are described according to the general structural agents in enhancing the penetration of medication formula below: through mucous membranes of warm blooded animals has been studied heretofore. In fact, Japanese Patent Application No. 2961/1984 teaches that pyroglutamic acid monoglycerides have surface active action and are effective emulsifiers, penetrants, detergents, spreaders and antistatic agents and are considered to have skin protecting acion. However, our discovery that simple 10 alkyl and alkenyl esters of pyroglutamic acid which do not have the non-ionic-surfactant-like side chain are wherein R is a straight or branched chain alkyl (C5-C20) skin penetration enhancers is unanticipated and unobvi such as pentyl, heptyl, octyl, decyl, dodecyl, tetradecyl, ous. In fact, our compounds have certain advantages hexadecyl, octadecyl, stearyl, eicosyl and the like; alke over the others: (1) the alkyl and alkenyl esters do not 15 nyl (C5-C20) with 1-6 double bonds such as pentenyl, show skin irritation on occlusive application for 24 octenyl, decenyl, dodecenyl, farnesyl, oleyl and the hours, whereas the glyceride esters show erythema on like; hydroxylalkyl (C5-C20) with 1 to 3 hydroxy application for 24 hours; (2) the alcohols derived from groups such as hydroxypentyl, hydroxydecyl, hydrox hydrolysis of our compounds are non-toxic and are yhexadecyl, dihydroxyoctadecyl and the like; ketoalkyl endogenous substances or metabolic precursors of fatty 20 (C5-C20) such as 2-ketapentyl, ketododecyl, ketohex acids whereas some glycerol ethers are known to be adecyl and the like; unsaturated hydroxyalkyl (C5-C20) potent mutagens (J. Am. Chem. Soc 1982, 104, 6149). such as hydroxyoctenyl, hyroxydodecenyl, hydrox SUMMARY OF INVENTION yhexadecenyl and the like; carboxyalkyl (C5-C20) such This invention relates to pyroglutamic acid ester used 25 as co-carboxyoctyl, co-carboxyhexadecyl and the like or as dermal penetration enhancers for thereapeutic agents alkoxycarbonylalkyl (C5-C20) such as ethoxycarbonyl having poor skin permeation. hexyl, ethoxycaronyldodecyl and the like. Accordingly, it is an object of the invention to pro The pyroglutamic esters of the invention are known vide a novel concept in skin penetration enhanced drug compounds and processes for their preparation are delivery, namely, the use of penetration enhancers that 30 known in the art. undergo metabolic destruction when they cross the In accord with the foregoing objects, the invention stratum corneum into the viable area of the skin tissue. provides a novel composition of matter for topical ap A further object of the invention is to provide a novel plication comprising at least one drug or therapeutic class of skin penetration enhancers which after achiev agent and an ester of pyro-glutamic acid and further ing their function of promoting the permeation of a 35 comprises, if desired, a non-toxic topical pharmaceuti drug or medicament through the stratum corneum, cally acceptable carrier. The therapeutic agent is pres: undergo fast metabolic breakdown into nontoxic meta ent in a biologically effective amount, i.e., in an amount bolic products as soon as they reach the live area of the sufficient to produce the desired biological effect. Thus, skin. when the therapeutic agent is a dermatological agent, it Another object of the present invention is to provide is utilized in a dermally effective amount, i.e., in an a novel class of penetration enhancers, which will en amount sufficient to evoke the desired dermal effect hance the dermal absorption of therapeutic or cosmetic (which may be cosmetic or therapeutic in nature). On agents, such enhancers being capable of improving de the other hand, when the therapeutic agent is systemi livery through the skin and into the general circulation cally active and introduction of the agent into the gen of systemically active drugs. t 45 eral circulation is desired then the amount is employed Another object is to provide penetration enhancing in a systemically effective amount, i.e., in an amount agents devoid of toxic side effects by virtue of fast meta sufficient to produce the desired systemic response. bolic breakdown as they come into contact with living Pyroglutamate ester is employed in such compositions tissue. in an amount sufficient to enhance skin permeation of Still another object of this invention is to provide a 50 class of penetration enhancing agents whose breakdown the therapeutic agent. products are endogenous, or precursors of endogenous Various active agents provide beneficial effects when substances which can be metabolized through normal administered to patients. Such agents which can be pathways available in the body. made more useful by enhancing its absorption in accor Yet another object of the invention is to provide 55 dance with this invention, are exemplified by, but not novel compositions utilizing the aforementioned en limited to, the following classes of agents: hancing agents for topical application and novel meth (A) Antiarrythmic: Bucainide, diisopyramide, encai ods of enhancing the skin penetration of therapeutic nide, tocainide, verapamil, and the like; agents. (B) Antihypertensive such as clonidine, enalapril, hy These and other objects and advantages of the inven dralazine, prazosin, a-methyldopa and the like; tion will become apparent from the following descrip (C) Antivirals such as acyclovir, cytarabine, envirox tion. ine, floxuridine, ribavarin, vidarabine, idoxuridine, trifluriding and the like; DESCRIPTION OF THE INVENTION (D) (3-Blockers such as propranolol, bupranolol. meto The invention is concerned with novel compositions 65 prolol, atenolol, pindolol, betaxalol, timolol, sotalol, and methods for enhancing the permeation of topically alprenolol, nadolol, oxprenolol and the like; administered drugs by incorporating therein a pyro (E) Diuretics such as aldactone, hydrochlorothiazide, glutamic acid ester as a dermal penetration enhancing ticrynafer and the like; 4,970,206 5 6 (F) Non-steroidal antiinflammatory agents, such as in ing agent in the total combination of drug plus agent is domethacin, naproxen, fenoprofen, ibuprofen, alcol 5-99% with a preferred ratio of enhancing agent in the fenac, phenylbutazone, mefenamic acid, diflunisal, total combination of agent plus drug being 10-40%. sulindac, desoxysulindac, aspirin, salicylamide, sali The following examples illustrate preparation of vari cylic acid, oxyphenbutazone, apazone, cintazone, ous compositions of the invention. The examples should flufenamic acid, meclofenamic acid, flunixin, dimefa be construed as illustrations rather than limitations dane, indoxole, intrazole, nimbane hydrochloride, thereof. paranylene hydrochloride, tetrydamine, benzindopy rine hydrochloride, fluprofen, ibufenac, ketoprofen, EXAMPLE 1. naproxol, fenburan, cinchophen, diflumidon sodium, 10 Decyl Pyroglutamate fenamole, flutiazin, metazamide, letimide hydrochlo ride, nexeridine hydrochloride, octazamide, molina To an ice cold suspension of pyroglutamic acid (1.3 g) zole neocinchophen, nimazole, proxazole citrate, and n-decanol (1.6 g) in dichloromethane (50 ml), dicy tesicam, tesimide, tolmetin, tramadol, triflunidate clohexylcarbodiimide (2.1 g) and 4-dimethylaminopyri and the like; 15 dine (0.1 g) were added. After stirring at ice bath tem (G) Steroidal antiinflammatory agents, i.e., corticoster perature for 2 hours, the cooling bath was removed and oids, such as hydrocortisone, hydrocortisone 17-val the mixture was stirred at room temperature overnight. erate, hydrocortisone 17-butyrate, hydrocortisone The michloromethane was evaporated off. The residue 21-acetate, betamethasone valerate, triamcinolone 20 was taken in ether and filtered. The filtrate was washed acetonide, fluocinonide, desonide, fluocinolone with 1N HCl, water, aqueous bicarbonate and water. It acetonide, dexamethasone, prednisolone, halopred was then dried over Na2SO4 and evaporated. The resi none, cortisone acetate, cortisone cyclopentylpropio due weighed 2.75g. It was chromatographed over silica nate, cortodoxone, flucetonide, fludrocortisone ace gel. The pure decyl ester was eluted with ethylacetate tate. flurandrenolone acetonide, medrysone, ancina 25 chloroform (1:4), 2.3 g m.p. 34-35. fal, amcinafide, betamethasone, betamethasone ben n-Dodecyl, farnesyl an oleyl pyroglutamates were zoate, chloroprednisone acetate, clocortolone ace prepared similarly and purified by chromatography. tate, descinolone acetonide, desoximetasone, dichlor isone acetate, diflupredinate, flucloronide, flumetha EXAMPLE 2 sone, flunisolide acetate, fluocortolone, fluorometho 30 Rat plasma hydrolysis of decyl pyroglutamate lone, fluperolone acetate, fluprednisolone, fluprednis olone valerate, meprednisone, methyl prednisolone, Freshly prepared rat plasma (2 ml) was mixed with paramethasone acetate, prednisolamate, prednisone, decyl pyroglutamate (0.6 mg) and was maintained at 37 prednival, triancinolone, triamcinolone hexaceto C. Aliquots were removed at different time intervals mide, cortivazol, formocortal, nivazol and the like; 35 and vortexed with heptane (1 ml) containing dodecanol (H) Muscle relaxants such as theophylline, cyclobenza as an internal standard. The decanol produced by enzy prine, aminophylline, diphylline, oxtriphylline, ambu matic hydrolysis was assayed by gas chromatography tyline, fenethylline, guathylline, pentoxyfylline, xan on a 6'X2 mm (id) column packed with OV-101 (me thinol niacinate, theophylline glycinate, glucopylline thylsilicone) on gas chrom Q (100-120 mesh), pro and the like; grammed from 125 to 175' C. Decyl pyroglutamate (I) Polypeptides such as cyclo-(N-Me-Ala-Tyr-D-Trp generated decanol with a t of 1.7 min. by enzymatic Lys-Val-Phe)actetate, somatostatin, insulin, gastrin, hydrolysis. caerulein, cholecystokinin and the like; (J) Coronary Vasodilators such as, diltiazem, dipyrida EXAMPLE 3 mole, erythritol tetranitrate, nifedipine and the like: 45 Skin Irritation Study of Pyroglumate Esters (K) Prostanoids such as rioprostil, viprostil, doxaprost, Fuzzy rats (Temple University) 150 to 200 g were enisoprost, enprostil and the like; and (L.) Dual lipoxygenase-cycloxygenase inhibitors such as used to study the dermal irritancy as the neat com 2,3-dihydro-5-hydroxy-6-(o-hydroxymethylcin pounds. Test preparations (50mg) were applied to cir namyl)benzofuran and the like. 50 cular gauze pads 1 mm thick and 16 mm in diameter, The enhancement of drug absorption in accordance and affixed to the animals' dorsal surface with occlusive with this invention is not by any means limited to the adhesive film (Adhesive Plaster for Patch Test, above drugs, but are in general applicable to other Kanebo, Ltd., Osaka, Japan). The occlusive dressings classes of drugs such as analgesics, anabolics, andro were removed after 3 or 7 days. Treated skin areas were gens, anorexics, adrenermics, antiadrenergics, antialler 55 then evaluated according to a modified Draize scoring gics, antibacterials, anticholinermics, antidepressants, method, and the irritation index was evaluated for each antidiabetics, antifungal agents, antihypertensives, anti test site. The first or "primary irritation index” (PII) neoplastics, antipsychotics, sedatives, cardiovascular was an average value reflecting irritation both immedi agents, antiulcer agents, anticoagulants, anthelmintics ately after dressing removal, and 72 hours later. The and the like. "secondary irritation index' (SII) was determined 7 The amount of drug varies over a wide range but in days after dressing removal. The maximum possible PII general the therapeutically effective unit dosage or SII was 8 with a total possible score of 4 erythema, amount of the selected drug depends on that amount and a total possible score of 4 for edema. A PII or SII known in the art to obtain the desired results. less than or equal to 2 indicated a mild irritant, a PII or Generally, the amount of enhancing agent employed SII greater than 2 but less than or equal to 6 indicated a in the practice of this invention ranges from 0.75 mg to moderate irritant, and a PII greater than 6 indicated a 1 g in each unit dose. The weight percentage of enhanc severe irritant as shown in Table 1 below: 4,970,206 7 8 TABLE 1. Irritation data for pyroglutamate esters Secondary Primary Irritation Index Irritation Index Sample (50 mg applied To-T72hrs at 7 days over 2 cm surface) 3 DAY occlusion 3 DAY occlusion Decyl pyroglutamate 0.9 - 1.1 (4) O Oleyl pyroglutamate 0.1 - 0.3 (4) O Dodecyl pyroglutamate 0 (2) 0 Farnesyl pyroglutamate 0 (2) O Azone 4.0 - 1.9 (5) O To is time at which occlusive application is removed. Irritation index -t. SD (n).

EXAMPLE 4 15 TABLE II-continued Permeation enhancement using pyroglutamate esters Penetration Enhancement of Indonethacin - weight ratio of flux of In the examples given below, the permeation en- enhancer/ indomethacin hancement was determined using an in vitro diffusion skin penetration enhancer indomethacin plg/cm/hr cell procedure. The molts of adult Elaphae obsolete 20 oley pyroglutamate 15.0 0.450 (black rat snake) was used as the model for stratum None non-detectable corneum membrane (R. Ibuki, Ph.D. Thesis, University of Kansas, 1985). The shed snake skin has great similari ties to human skin in terms of thickness, composition of TABLE III constituents and structure and has been proposed as the 25 Penetration Enhancement. Using most suitable model for human stratum corneum for - Dodecyl pyroglutamate - permeability studies. weight ratio of flux of g Glass diffusion cells consisting of a donor and recep- Drug enhancer/drug g/cm/hr tor cells separated by the shed snake skin membrane Hydrocortisone 0 Not detectable were assembled using circular O-ring joints held to- 30 Propranolol 15O 0.3383,680 gether by spring clamps. The exposed membrane sur- FF 15 7.410 face area of the diffusion cell measured 1.8 cm2. Before being mounted in the diffusion cell approximately 25 mg of an ointment containing the therapeutic agent and EXAMPLE 5 the penetration enhancer was carefully applied to the 35 membrane and was spread over the desired area. The Percutaneous Delivery of receptor side was filled with approximately 8.5 ml of 2,3-dihydro-5-hydroxy-6-(o-hydroxymethylcinnamyl)- buffer solution consisting of 1.5x10-1 M NaCl, benzofuran 5X10-4 NaH2PO4 and 2.0x10-4MNa2HPO4 adjusted The transport of 2,3-dihydro-5-hydroxy-6-(o-hydrox to pH 7.2 with NaOH. The diffusion cell was immersed 40 ymethylcinnamyl)benzofuran, through shed snake skin, vertically in a water bath maintained at 32"-1" C. The which has been reported to be a good model for human receptor cell was stirred constantly with a magnetic stratum corneaum in terms of thickness, compositional stirrer. To determine the amount of compound pene- features, structure and permeability, was measured in trated through the snake skin membrane from the upper the presence of decyl, dodecyl and oleyl esters of L chamber, 0.2 ml samples were withdrawn at varying 45 pyroglutamic acid used as penetration enhancers. intervals from the receptor chamber using a syringe. An Because of the poor aqueous solubility of 2,3-dihydro equal amount of fresh buffer was replenished during 5-hydroxy-6-(o-hydroxymethylcinnamyl)benzofuran sampling. The concentration of drug penetrated in each (<0.0002 mg/ml at 32), 20% propyleneglycol in iso diffusion cell was measured using high pressure liquid tonic pH 7.2 phosphate buffer was used as the receptor chromatography. The results reported for each experi- 50 medium. Control experiments showed that the presence ment are the average values from 5 replicate diffusion of 20% propylene glycol did not affect the barrier prop cells. erties of snake skin. A weighed amount of a petrolatum The ointments used for the experiments contained ointment (30-35 mg) containing 1% (w/w) of 2,3-dihy varying concentrations of the drug and penetration dro-5-hydroxy-6-(o-hydroxymethylcinnamyl)benzofu enhancing agent. The drug was dispersed in the en- 55 ran with or without 15% (w/w) of the permeation en hancer and this was then mixed with white petrolatum hancer was applied to 1.76 cm2 area of shed skin of adult USP using a vortex mixer around 55 C. The ointments Elaphae obsolata (black rat snake), and held between the were kept in a water bath at 32"-1" C. for 1 day before donor and receptor compartments of a diffusion cell by use in in vitro studies. See Tables II and III below for O-rings. The receptor compartment had a capacity of the results of penetration enhancement effects. 60 8-9 ml. The diffusion cells were maintained at 32-1 TABLE II C. The amount of drug diffused into the receptor cham ber was measured by HPLC using acetonitrile-water Penetration Enhancement of Indomethacin (2:3) at a flow rate of 1 ml/min as mobile phase, a C18 weight ratio of flux of column and a UV detector set at 260 mm. The results skin penetration enhancer indomethacinenhancer/ indomethacinug/cm/hr 65 (Table IV below) are averages offive diffusion4. cells for n-Decyl pyroglutamate 15.0 0.477 each experiment. n-Dodecyl pyroglutamate 15.0 0.630 The L-pyroglutamate esters were designed to act as Farnesyl pyroglutamate 15.0 0.317 "soft permeation enhancers,' which after exercising 4,970,206 10 their action at the stratum corneum barrier where the wherein R is a straight or branched chain alkyl effect is desired, would undergo enzymatic breakdown (C5-C20), alkenyl (C5-C20) with 1-6 double bonds, hy into non-toxic metabolites in the viable tissue. Decyl droxyalkyl (C5-C20) with 1-3 hydroxy groups, ketoal L-pyroglutamate, for example, breaks down in rat kyl (C5-C20), unsaturated hydroxyalkyl (C5-C20), car plasma with t of 1.7 minutes. These esters produced 5 boxyalkyl (C5-C20) or alkoxycarbonylalkyl (C5-C20). zero irritation in a modified Draize test involving three 2. The method of claim 1, wherein said drug is se day occlusive dermal application on fuzzy rats. lected from the group consisting of hydrocortisone, hydrocortisone 17-valerate, hydrocortisone 17-buty TABLE IV rate, hydrocortisone 21-acetate, betamethasone valler Effects of Permeation Enhancers on the Delivery of O 2,3-dihydro-5-hydroxy-6-O-hydroxymethylcinnamyl)- ate, triancinolone acetonide, fluocinonide, desonide, benzofuran Through Snake Skin fluocinolone acetonide, dexamethasone, prednisolone, Fluxug/cm/ % delivered in haloprednone, cortisone acetate, cortisone cyclopentyl Permeation Enhancer hir SD 48 hrs - SD propionate, cortodoxone, flucetonide, fludrocortisone None 0.19 4.24 - 0.53 acetate, flurandrenolone acetonide, medrysone, amcina Decyl L-pyroglutamate 0.70 : 0.06 16.1 3.0 15 fall, ancinafide, betamethasone, betanethasone benzo Dodecyl L-pyroglutamate 0.61 - 0.04 3.4 - 1.5 ate, chloroprednisone acetate, clocortolone acetate, Oleyl L-pyroglutamate 0.95 0.09 2.7 - 1.1 descinolone acetonide, desoximetasone, dichlorisone in s 5 acetate, diflupredinate, flucloronide, flumethasone, flunisolide acetate, fluocortolone, fluorometholone, Tables V-VI below, show permeation enhancement 20 fluperolone acetate, fluprednisolone, fluprednisolone ofenalapril, clonidine and acyclovir using various pyro valerate, meprednisone, methyl prednisolone, para glutamic esters. methasone acetate, prednisolamate, prednisone, predni TABLE V val, triamcinolone, triamcinolone hexacetonide, cor Permeation Enhancement of Enalapril tivazol, formocortal and nivazol and said enhancing Using Pyroglutamate Esters 25 agent is represented when R is selected from the group Flux (ug/cm/ % delivered in consisting of alkyl, alkenyl hydroxyalkyl, ketoalkyl and Enhancer hr) - SD 48 hrs - SD alkoxycarbonylalkyl. None (n = 13) -- 0.9 -- 0.5 3. The method of claim 2, wherein said drug is hydro Decyl pyroglutamate (n = 4) 0.15 0.01 4.3 - 0.9 Dodecyl pyroglutamate 0.51 0.09 9.9 - 2.7 30 cortisone, prednisolone, methyl prednisolone, betame (n = 4) thasone, betamethasone benzoate or triamcinolone Oleyl pyroglutamate (n = 5) 0.92 - 0.22 18.7 - 5.4 acetonide and said enhancing agent is represented when R is alkyl, alkenyl, hydroxyalkyl, ketoalkyl or alkoxy carbonylalkyl. TABLE VI 35 4. The method of claim 3, wherein said enhancing Perneation Enhancement of Clonidine agent is represented when R is alkyl or alkenyl. Using Pyroglutanate Esters 5. The method of claim 4, wherein R is alkyl. Flux (ug/cm/ % delivered in 6. The method of claim 4, wherein R is alkenyl. Enhancer hr) - SD 48 hrs - SD 7. A pharmaceutical composition for enhancing der None (n = 12) - 1.1 - 0.3 Decyl pyroglutamate (n = 4) 0.31 - 0.13 8.1 - 2.1 40 mal absorption of a topically administered steroidal Dodecyl pyroglutamate 0.63 - 0.21 13.2 : 0.6 anti-inflammatory drug comprising a therapeutically (n = 4) effective dosage amount of said drug and a pyro Oleyl pyroglutamate (n = 4) 0.26 - 0.15 4.4 - 1.4 glutamic acid ester enhancing agent of the formula:

9 TABLE VII 45 Permeation Enhancement of Acyclovir Using Pyroglutamate Esters' Flux (ug/cm/ % delivered in O N CO2R Enhancer hr) - SD 48 hrs - SD H None not detectable 50 Decyl pyroglutamate 0.063 - 0,0. 0.25 - 0.03 Dodecyl pyroglutamate 0.072 - 0.04 0.26; 0.15 wherein R is a straight or branched chain alkyl (C5-C20), alkenyl (C5-C20) with 1-6 double bonds, hy n = 4 droxyalkyl (C5-C20) with 1-3 hydroxy groups, ketoal What is claimed is: 55 kyl (C5-C20), unsaturated hydroxyalkyl (C5-C20), car 1. A method of enhancing the rate of dermal absorp boxyalkyl (C5-C20) or alkoxycarbonylalkyl (C5-C20). tion of a topically administered composition comprising 8. The composition of claim 7, wherein said drug is a therapeutically effective dosage amount of a steroidal selected from the group consisting of hydrocortisone, anti-inflammatory drug and a pyroglutamic acid ester hydrocortisone 17-valerate, hydrocortisone 17-buty absorption enhancing agent of the formula: 60 rate, hydrocortisone 21-acetate, betamethasone valler ate, triamcinolone acetonide, fluocinonide, desonide, fluocinolone acetonide, dexamethasone, prednisolone, haloprednone, cortisone acetate, cortisone cyclopentyl propionate, cortodoxone, flucetonide, fludrocortisone O CO2R 65 acetate, flurandrenolone acetonide, medrysone, amcina N fall, ancinafide, betamethasone, betamethasone benzo H ate, chloroprednisone acetate, clocortolone acetate, descinolone acetonide, desoximetasone, dichlorisone 4,970,206 11 12 acetate, difluprednate, flucloronide, flumethasone, 12. The composition of claim 11, wherein said alkyl is selected from the group consisting of octyl, decyl, do flunisolide acetate, fluocortolone, flurometholone, decyl, tetradecyl, hexadecyl or eicosyl. fluperolone acetate, fluprednisolone, fluprednisolone 13. The composition of claim 12, wherein said alkyl is valerate, meprednisone, methyl prednisolone, para octyl. methasone acetate, prednisolamate, prednisone, predni 14. The composition of claim 12, wherein said alkyl is val, triamcinolone, triamcinolone hexacetonide, cor decyl. tivazol, formocortal and nivazol and said enhancing 15. The composition of claim 12, wherein said alkyl is agent is represented when R is selected from the group dodecyl. consisting of alkyl, alkenyl, hydroxyalkyl, ketoalkyl and O 16. The composition of claim 10, where R is alkenyl. alkoxycarbonylalkyl. 17. The composition of claim 16, wherein said alkenyl is selected from the group consisting of decenyl, 9. The composition of claim 8, wherein said drug is dodecenyl, farnesyl, hexodecenyl, oleyl and octadeca hydrocortisone, prednisolone, methyl prednisolone, dienyl. betamethasone, bridesonide, betamethasone benzoate or 15 18. The composition of claim 17, wherein said alkenyl triamcinolone acetonide and said enhancing agent is is farnesyl. represented when R is alkyl, alkenyl or hydroxyalkyl. 19. The composition of claim 17, wherein said alkenyl 10. The composition of claim 9, wherein said drug is is oleyl. hydrocortisone, and said enhancing agent is represented 20. The composition of claim 7 further comprising when R is alkyl or alkenyl. 20 pharmaceutically acceptable excipients. 11. The composition of claim 10, wherein R is alkyl. is

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