STEREOSPECIFIC DELIVERY OF A DRUG USING ELECTROTRANSPORT

Abstract: Drug delivery devices suitable for preferential delivery, via electrotransport, of a preferred isomeric form of a pharmaceutically active chiral compound from a mixture of the isomeric forms of said compound is provided. The device is characterised by one of the following features: the size of the donor electrode, the concentration of drug in the formulation, the current provided by the source of electrical power or the amount of the formulation applied, are less than those necessary to provide therapeutically effective levels of the drug, if the preferred and less preferred isomers are delivered transdermally at the same rate.

Description: Stereospecific Delivery of a Drug Using Electrotransport TECHNICAL FIELD This invention relates generally to drug delivery. More particularly, the invention relates to the use of electrotransport to effect stereospecific drug delivery, i.e., preferential delivery of a single preferred enantiomer of a chiral drug from a pharmaceutical formulation containing the drug as a mixture of isomers. BACKGROUND ART A number of drugs contain chiral centers and thus can exist in two or more isomeric forms. A drug with a single chiral center can be formed as two "mirror-image" isomers, known as "enantiomers." In many instances, the enantiomers exhibit differences in pharmacokinetic properties, e.g., metabolism, protein binding, or the like, and/or pharmacological properties, e.g., the type of activity displayed, the degree of activity, toxicity, or the like. Isolation of a single enantiomer from a mixture, i.e., "resolution" of the mixture, is typically carried out by reaction with a standard asymmetric substance, followed by separation of the different products using conventional means. Fractional crystallization is another technique which may be employed to isolate a single enantiomer. Frequently, however, isolation of a single enantiomer from a mixture is difficult, as the two enantiomers within the mixture are by definition identical in terms of molecular composition and thus, in many instances, are substantially similar in reactivity. Altematively, a single enantiomer of a drug or other compound may be prepared using a stereospecific synthesis which gives rise to the product in enantiomerically pure form. Such syntheses are typically somewhat difficult to implement ana often do not provide the desired product in high yield. ι Recent reports detail the lengths undertaken in order to obtain 2 purified isomers of useful drugs. For example, U.S. Patent No. 5,545,745 to 3 Gao et al. claims a multistep process for preparing optically pure albuterol, 4 employing reaction of a mixture of albuterol isomers with a chiral acid and 5 selective crystallization of one of the products, followed by debenzylation to 6 yield optically pure albuterol. U.S. Patent No. 5,442,118 to Gao et al. claims 7 a method of asymmetric synthesis of (R) and (S) arylethanolamines from β aminoketones, useful for the preparation of pharmaceutical agents such as 9 albuterol, terbutaline, isoproterenol and sotalol, using a borane reducing o agent in the presence of a chiral 1 ,3,2-oxazaborolidine catalyst, wherein the i reagents must be added in a specific order. U.S. Patent No. 5,516,943 to 2 Gao et al. describes the stereoselective conversion of a rrans-1-amino-2- 3 hydroxycycloalkane to the cis isomer by acylating the amine group and then treating with a strong acid; also disclosed is the direct formation of particular s isomers of aminoindanol from indene using exotic chiral catalysts. U.S. 6 Patent No. 5,498,625 to Evans et al. describes the enzymatic production of 7 one enantiomer of a lactam by reacting a racemic y lactam with a 8 stereospecific lactamase. U.S. Patent No. 4,800,162 to Matson claims a 9 method of resolving a racemic mixture by passing a solution containing the 0 mixture through a filtering device having a stereoselective enzyme attached to 1 the filter matrix on a first side: the enzyme selectively reacts with one isomer, 2 creating a product which is then more soluble in an immiscible solvent flowing 3 in the opposite direction on the opposite side of the matrix; the product then diffuses across the matrix, yielding a pure solution of enantiomeric product on 5 the opposite side and producing a pure solution of the unreacted enantiomer 6 on the first side. 7 As can be seen, elaborate efforts have been made in order to 8 produce purified isomers of pharmacologically active agents. 9 With chiral drugs, if one enantiomer is pharmacologically more 0 active, less toxic, or has a preferred disposition in the body as compared with 1 the other enantiomer, it would be therapeutically more beneficial to administer that enantiomer preferentially. In this way, the patient undergoing treatment would be exposed to a lower total dose of the drug, or to a lower amount of a toxic isomer. Costly and complicated stereospecific synthesis or purification schemes would then be unnecessary. Accordingly, there is a need in the art for a means of drug administration which enables preferential delivery of a single enantiomer of a chiral drug. International Patent Publication No. WO 94/10985 describes the benefits provided by transdermal delivery of the active enantiomer of ketorolac compared to delivery of the racemic mixture. The active enantiomer was found to have a more rapid clearance than the other enantiomer, so that the continuous delivery provided by a transdermal system allowed for even lower dosages to be used than expected. That is, whereas one might expect that half of the total amount of the pure enantiomer would be as effective as the full dose of the racemic mixture, even less than half the amount of the pure enantiomer was found to be effective. This was attributed to the more rapid clearance and shorter half-life of the active enantiomer. Continuous delivery using the passive transdermal system provided a more steady level of the minimum therapeutic amount of the active enantiomer as compared with periodic dosing of the racemic mixture by immediate release oral or parenteral administration. Passive transdermal delivery was claimed to be beneficial for all enantiomers with high clearance values and short half-lives. Problems with passive transdermal drug delivery systems were also discussed, including the limits on the doses capable of being provided because of the limited permeability of the stratum corneum layer of the skin and the unacceptability of large patches to patients because of contact- related side effects, aesthetics, comfort and wearability. The melting temperature of a drug is believed to be one factor limiting the ability of that drug to permeate the skin. Lawter and Pawelchak (U.S. Patent No. 5,114,946) claimed that, for a chiral drug that is a solid at or above skin temperature, purified enantiomers or nonracemic mixtures of the drug display faster passive transdermal delivery rates when the purified enantiomers or the nonracemic mixtures have melting temperatures 5° to 10° C below that of the racemic mixture. However, no increase in the flux rate of one isomer relative to the other isomer in a mixture was noted. Sanderson (U.S. Patent No. 4,818,541) similarly reported that the purified individual isomers of phenylpropanolamine gave rise to faster transdermal penetration rates compared to the racemic mixture. The mechanism by which this occurred was not stated with certainty, but the increased solubility of the individual isomers compared to the mixture was suggested as one possibility. Each of the four individual purified isomers exhibited nearly identical flux rates. The inventors herein have now found that passive transdermal drug delivery of a composition containing a drug (ketorolac) in the form of a racemic mixture does not provide for any significant difference in flux between the two isomers. This is consistent with previous reports that (-) ketorolac and racemic ketorolac have similar flux characteristics when used in several different types of passive transdermal systems (U.S. Patent No. 5,589,498 to Mohr et al.). (-) Ketorolac is the active enantiomer of ketorolac, a non- steroidal anti-inflammatory analgesic which can produce gastrointestinal side effects when delivered orally. Transdermal patches of the adhesive matrix type, reservoir type, and monolithic matrix type were all reported to deliver similar flux rates of (-) ketorolac and racemic ketorolac. Unexpectedly, electrotransport drug delivery has been discovered to give rise to a substantial differential in the rate of transport of two enantiomers contained in a mixture. Prior to applicants' invention, it was believed that the capability of administering a drug using electrotransport was solely a function of the drug's physico-chemical properties; now, it is clear that electrotransport drug delivery can be stereospecific as well. In contrast to passive transdermal or transmucosal systems, electrotransport has been found to provide for the preferential delivery of one isomer from a mixture while providing a faster overall flux rate than passive ι delivery systems, and requires no special synthetic or purification schemes. 2 Additionally, preferential isomer delivery via electrotransport is not limited to 3 particular mixtures of drug isomers that have a lower melting temperature 4 than the racemic mixture, or to enantiomers with high clearance values and 5 low half-lives. As a result of the increased transfer rate, electrotransport can 6 permit a shorter time of delivery or the use of a smaller, more acceptable coverage area in order to deliver the desired amount of compound than such 8 passive delivery systems. Generally, it is preferred that at least a 20% 9 increase in the rate of in vivo delivery of the preferred isomer is achieved. o However, a smaller increase in rate of delivery, of about 5 or 10%, may prove i acceptable in some cases, for example where the drug is particularly 2 expensive. 3 By eliminating the need for stereospecific synthesis or complicated purification procedures, selective delivery of one isomer via electrotransport s can lead to improvements in therapeutic costs and treatment regimens. 6 Costs of synthesis can be decreased by eliminating the need for 7 stereospecific synthesis or purification of one isomer from a mixture. A s simpler scheme for synthesis and purification can result in a lowered 9 generation of hazardous materials and a lessened exposure of personnel to 0 those materials. Additionally, stereoselective electrotransport can be used to i preferentially deliver one isomer where stereospecific synthesis or purification 2 of that isomer has not yet been achieved. By receiving an increased amount 3 of the preferred isomer, patients can thus be exposed to a lesser total amount of compound or be treated for a shorter time or over a smaller region of their 5 body. 6 Furthermore, even if passive drug delivery could give rise to 7 differences in flux rates of desired isomers, electrotransport can increase this 8 differential while providing higher overall flux rates than passive systems, 9 allowing for smaller, more acceptable delivery devices. Similarly, where 0 chemical synthesis or purification schemes provide a greater proportion of the ι desired enantiomer in a mixture, electrotransport delivery of the mixture can 2 further increase the proportion of desired enantiomer which is delivered. 3 Herein the term "electrotransport drug delivery" is used to refer to 4 the delivery of pharmaceutically active agents through an area of the body 5 surface by means of an electromotive force to a drug-containing reservoir. 6 The drug may be delivered by electromigration, electroporation, 7 electroosmosis or any combination thereof. Electroosmosis has also been 8 referred to as electrohydrokinesis, electro-convection, and electrically induced 9 osmosis. In general, electroosmosis of a species into a tissue results from o the migration of solvent in which the species is contained, as a result of the i application of electromotive force to the therapeutic species reservoir, i.e., 2 solvent flow induced by electromigration of other ionic species. During the 3 electrotransport process, certain modifications or alterations of the skin may 4 occur such as the formation of transiently existing pores in the skin, also s referred to as "electroporation." Any electrically assisted transport of species 6 enhanced by modifications or alterations to the body surface (e.g., formation 7 of pores in the skin) are also included in the term "electrotransport" as used s herein. Thus, as used herein, the term "electrotransport" refers to (1) the 9 delivery of charged drugs or agents by electromigration, (2) the delivery of 0 uncharged drugs or agents by the process of electroosmosis, (3) the delivery i of charged or uncharged drugs by electroporation, (4) the delivery of charged 2 drugs or agents by the combined processes of electromigration and 3 electroosmosis, and/or (5) the delivery of a mixture of charged and uncharged 4 drugs or agents by the combined processes of electromigration and 5 electroosmosis. 6 DISCLOSURE OF THE INVENTION 8 9 The invention thus provides an electrotransport drug delivery device 0 and a method of making the device, which preferentially delivers a preferred 1 isomer from a pharmaceutical formulation containing the drug as a mixture cf ι preferred and less preferred isomers. The device includes a source of 2 electrical power which is electrically connected to a pair of body surface- 3 contacting electrode assemblies. At least one of the electrode assemblies 4 includes a drug-containing donor reservoir containing the drug formulation as 5 a mixture of isomers. The device operates in such a manner as to deliver the 6 formulation by electrotransport through the same body surface so that the 7 transport of a preferred isomer is enhanced relative to the transport of a less β preferred isomer. Generally, the device is operated by placing an 9 electrotransport drug reservoir containing the aforementioned formulation in o drug-transmitting relation to the selected area of the body surface; electrically i connecting the drug reservoir to a source of electrical power; and then 2 delivering the drug through the body surface by electrotransport. As 3 explained above, the device is operated in a manner such that the preferred enantiomer is delivered at a rate sufficient to induce a therapeutic effect, while s the corresponding, second enantiomer is delivered at a substantially lower 6 rate. Methods of making such drug delivery devices are also provided. 7 s BRIEF DESCRIPTION OF THE DRAWINGS 9 0 Fig. 1 is a perspective view of an electrotransport drug delivery 1 device which may be used in conjunction with the present invention. 2 Figs. 2 and 3 are graphs illustrating the mean plasma R- and S- 3 ketorolac concentrations, respectively, in subjects undergoing ketorolac 4 treatment administered via either electrotransport, passive transdermal or 5 intravenous injection. 6 7 MODES FOR CARRYING OUT THE INVENTION 8 9 It is to be understood that this invention is not limited to specific 0 pharmaceutical compositions, carriers, drug delivery device structures, or the 1 like, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, reference to "a drug" includes mixtures of drugs, reference to "an enhancer" includes mixtures of enhancers, reference to "a carrier" includes mixtures of carriers, and the like. In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set out below. The terms "drug," "active agent" or "pharmacologically active agent" are used interchangeably herein to mean any chemical material or compound which induces a desired local or systemic effect in an individual subject (human or animal), and is capable of being delivered to the subject by electrotransport. By the term "dosage" is meant the amount of drug delivered from an electrotransport delivery device. The term is intended to encompass the amount of drug delivered per unit time, the total amount of drug delivered over a period of time, the duration of time over which the drug is to be delivered, and the like. The term "optional" as used herein, as in the recitation that the presence of a particular component in a pharmaceutical composition is "optional," means that the component may or may not be present, and includes instances where the component is present and instances where the component is not present. Drugs, therapeutics or otherwise active agents useful in connection with the present invention include any pharmaceutical compound that is capable of being delivered by electrotransport, wherein the compound exists in the form of an isomeric mixture, and further wherein it is desired to preferentially deliver a preferred isomer from those in the mixture, or wherein it is desired to preferentially not deliver a less preferred isomer. This includes drugs with one, two, or more chiral centers, having two, four, or more isomers, wherein one, two, or more of the isomers are preferred, and/or one, two, or more of the isomers are less preferred. The active agents which may be administered using the methodology of the invention includes agents in all of the major therapeutic areas. For example, suitable active agents include, but are not limited to, anti-infectives such as antibiotics and antiviral agents, analgesics and analgesic combinations, anesthetics, anorexics, antiarthritics, antiasthmatic agents, anticonvulsants, antidepressants, antidiabetic agents, antidiarrheals, antihistamines, anti-inflammatory agents, antimigraine preparations, antimotion sickness preparations, antinauseants, antineoplastics, antiparkinsonism drugs, antipruritics, antipsychotics, antipyretics, antispasmodics, including gastrointestinal and urinary anticholinergics, sympathomimetics, xanthine derivatives, calcium channel blockers, beta-blockers, beta-agonists, antiarrhythmics, antihypertensives, ACE inhibitors, diuretics, vasodilators, central nervous system stimulants, cough and cold preparations, decongestants, diagnostics, hormones such as parathyroid hormone, bisphosphoriates, hypnotics, immunosuppressives, muscle relaxants, parasympatholytics, parasympathomimetics, prostaglandins, psychostimulants, sedatives and tranquilizers. The invention is also useful in conjunction with the electrotransport delivery of proteins, peptides and fragments thereof. A particularly preferred drug which can be administered using the methodology of the invention is the anti-inflammatory, analgesic agent ketorolac ((±)-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid)), as the S- isomer of the drug has been found to be significantly more active than the R- isomer. It has been established that the S:R ratios of anti-inflammatory and analgesic activities are 57 and 230, respectively (Mroszczak et al. (1994) Clin. Pharm Ther. 49: 126; Hayball et al. (1993) Chirality 5:31-35). Therefore, it is advantageous to deliver the single S-isomer preferentially. Other enantiomeric drugs where preferential isomeric delivery is desirable include ibuprofen (the S-isomer is the active ingredient), terfenadine (the S-isomer is active), nicotine (the S (-) isomer has been found less irritating in transdermal patch formulations), nebivolol (the (+) isomer is a β- blocker, while the (-) isomer is a vasodilating agent), zacopride (one isomer is a 5-HT 3 blocker, the other is an agonist), atenolol (the S-isomer is a β- blocker), zopiclone (the S-isomer is a sedative), flurbiprofen (the S-isomer is a nonsteroidal antiinflammatory drug, or "NSAID"), and ketoprofen (the S- isomer is an NSAID). Further nonlimiting examples of drugs which are available as racemates but wherein one isomer would be preferred for delivery include acebutolol, acenocoumarol, albuterol/salbutamol, alprenolol, amosulolol, amoxicillin, ampicillin, astemizole, atenolol, baclofen, benazepril, benzyl glutamate, betaxolol, bethanecol, bisprolol, bopindolol, bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butaclamol, butoconazole, butofilolol, calcitonin, camazepam, captopril, captopril, caraxolol, carvedilol, cefadroxil, cicloprofen, ciprofloxacin, corticosteroids, cromakalim, curteolol, cytrabine, deprenyl, dexfenfiuramine, dihydroxythebaine, diltiazem, disopyramide, dobutamine, enalapril, ephedrine, estradiol, ethambutol, fenbuphen, fenfluramine, fenoprofen, fluorogesterone, fluoxetine, flurbiprofen, gonadorelin, hexobarbital, ibuprofen, indenolol, indoprofen, ketamine, ketodesogestrel/estrogen, ketoprofen, lisinopril, lorazepam, lovastatin, meclizine, mepindolol, metaproteranol, methadone, methyldopa, metipranolol, metoprolol, minoxiprofen, 3-hydroxy-N-methyl morphinan, nadolol, naproxen, nicardipine, nilvadipine, nitanol, norfloxacin, norgestrel, ofloxacin, oxaprotiline, oxpranolol, oxybutynin, perindopril, phenprocoumon, phenylpropanolamine, pindolol, pirprofen, polycloram-phetamine, prilocaine, progestinpropanolol, propoxyphene, sertraline, sotalol, steroids, suprofen, terbutaline, terfenadine, testosterone, thioridazine, timolol, tocainide, toliprolol, toloxaton, tomoxetine. triamcinolone, verapamil, viloxazin, warfarin, xibenolol, and 1 ,4- dihydropyridine chiral compounds. The compounds may be in the form of pharmaceutically acceptable salts, esters, amides or prodrugs, or may be modified by appending one or more appropriate functionalities to enhance selected biological properties ι Such modifications are known in the art and include those which increase 2 biological penetration into a given biological system, increase bioavailability, 3 increase solubility to allow administration by a particular mode, and the like. 4 Compounds may be converted into pharmaceutically acceptable 5 salts, and the salts may be converted into the free compound using standard 6 procedures known to those skilled in the art of synthetic organic chemistry 7 and described, for example, by J. March, Advanced Organic Chemistry: β Reactions, Mechanisms and Structure. 4th Ed. (New York: Wiley- 9 Interscience, 1992). o Acid addition salts are prepared from the free base (e.g., i compounds having a neutral -NH 2 or cyclic amine group) using conventional 2 means, involving reaction with a suitable acid. Typically, the base form of the 3 compound is dissolved in a polar organic solvent such as methanol or ethanol 4 and the acid is added at a temperature of about 0°C to about 100°C, s preferably at ambient temperature. The resulting salt either precipitates or 6 may be brought out of solution by addition of a less polar solvent. Suitable 7 acids for preparing acid addition salts include both organic acids, e.g., acetic s acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, 9 malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 0 benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, 1 ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well 2 as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, 3 nitric acid, phosphoric acid, and the like. An acid addition salt may be 4 reconverted to the free base by treatment with a suitable base. Preferred 5 acid addition salts of the present compounds are the citrate, fumarate, 6 succinate, benzoate and malonate salts. 7 Basic salts of acid moieties which may be present (e.g., carboxyhc 8 acid groups) can be prepared in a similar manner using pharmaceutically 9 acceptable inorganic or organic bases. Examples of inorganic bases include 0 ammonia and carbonates, hydroxides and hydrogen carbonates of group I 1 and group II metals such as sodium, potassium, magnesium and calcium ι Examples of organic bases include aliphatic and aromatic amines such as 2 methylamine, trimethylamine, triethylamine, benzylamine, dibenzylamine or α- 3 or β-phenylethyiamine, and heterocyclic bases such as piperidine, 1- 4 methylpiperidine and morpholine. 5 Compounds may also be converted into pharmaceutically e acceptable esters. Suitable esters include branched or unbranched, 7 saturated or unsaturated C, to C 6 alkyl esters, for example, methyl, ethyl and 8 vinyl esters. 9 Preparation of esters involves functionalization of hydroxyl and/or o carboxyl groups which may be present. Esters are typically acyl-substituted i derivatives of free alcohol groups, i.e., moieties which are derived from 2 carboxylic acids of the formula RCOOH where R is alkyl, and preferably is 3 lower alkyl. Pharmaceutically acceptable esters may be prepared using 4 methods known to those skilled in the art and/or described in the pertinent s literature. Esters can be reconverted to the free acids, if desired, by using 6 conventional hydrogenolysis or hydrolysis procedures. Preparation of amides 7 and prodrugs can be performed in an analogous manner. s Electrotransport devices which can be employed in the method of 9 the present invention typically comprise at least two electrodes. Each of 0 these electrodes is placed in intimate electrical contact with some portion of 1 the skin of the body. One electrode, called the active or donor electrode, is 2 the electrode from which the drug is delivered into the body. The other 3 electrode, called the counter or return electrode, serves to close the electrical 4 circuit through the body. In conjunction with the patient's skin, the circuit is 5 completed by connection of the electrodes to a source of electrical energy, 6 e.g., a battery, and usually to circuitry capable of controlling current passing 7 through the device. If the drug to be driven into the body is positively 8 charged, then the positive electrode (the anode) will be the active electrode 9 and the negative electrode (the cathode) will serve as the counter electrode, 0 completing the circuit. If the drug to be delivered is negatively charged, then the cathodic electrode will be the active electrode and the anodic electrode will be the counter electrode. Electrotransport devices additionally require a drug reservoir or source of the pharmaceutically active agent which is to be delivered or introduced into the body. Such drug reservoirs are connected to the anode or the cathode of the electrotransport device to provide a fixed or renewable source of one or more desired species or agents. The drug reservoirs are usually polymeric hydrogels. Suitable polymers useful for forming hydrogel drug reservoirs include: polyvinyl alcohols; polyvinyl-pyrrolidone; cellulosic polymers, e.g., hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, and the like; polyurethanes; polyethylene oxides; polyanhydrides; polyvinyl pyrrolidone/vinyl acetate copolymers, and the like; and mixtures and copolymers thereof. One material suitable for electrotransport drug reservoirs is polyvinyl alcohol, which has been found to have good skin biocompatibility. The drug reservoirs may contain a number of components, such as preservatives, solubilizing agents, pH modifiers, antimicrobials, antifungais, anti-inflammatory agents, stabilizers, surfactants, and the like. The drug delivery systems may in addition contain a skin permeation enhancer. That is, because the inherent permeability of the skin to some drugs may be too low to allow therapeutic levels of the drug to pass through a reasonably sized area of unbroken skin, it is necessary to coadminister a skin permeation enhancer with such drugs. Suitable enhancers are well known in the art and include, for example, dimethylsulfoxide (DMSO), dimethyl formamide (DMF), N,N-dimethylacetamide (DMA), decylmethylsulfoxide (C 10 MSO), C 2 -C 6 alkanediols, and the 1 -substituted azacycloheptan-2-ones, particularly 1-n- dodecylcyclazacycloheptan-2-one (available under the trademark Azone® from Whitby Research Incorporated, Richmond, VA), alcohols, and the like. ι It will be appreciated by those working in the field that the present 2 method can be used in conjunction with a wide variety of electrotransport 3 drug delivery systems, as the method is not limited in any way in this regard. 4 For examples of electrotransport drug delivery systems, reference may be 5 had to U.S. Patent Nos. 5,147,296 to Theeuwes et al., 5,080,646 to e Theeuwes et al., 5,169,382 to Theeuwes et al., and 5,169,383 to Gyory et al. 7 Figure 1 illustrates a representative electrotransport delivery device 8 that may be used in conjunction with the present invention. Device 10 9 comprises an upper housing 16, a circuit board assembly 18, a lower housing o 20, anode electrode 22, cathode electrode 24, anode reservoir 26, cathode i reservoir 28 and skin-compatible adhesive 30. Upper housing 16 has lateral 2 wings 15 which assist in holding device 10 on a patient's skin. Upper housing 3 16 is preferably composed of an injection moldable elastomer (e.g., ethylene 4 vinyl acetate). Printed circuit board assembly 18 comprises an integrated s circuit 19 coupled to discrete components 40 and battery 32. Circuit board 6 assembly 18 is attached to housing 16 by posts (not shown in FIG. 1) passing 7 through openings 13a and 13b, the ends of the posts being heated/melted in s order to heat stake the circuit board assembly 18 to the housing 16. Lower 9 housing 20 is attached to the upper housing 16 by means of adhesive 30, the 0 upper surface 34 of adhesive 30 being adhered to both lower housing 20 and 1 upper housing 16 including the bottom surfaces of wings 15. 2 Shown (partially) on the underside of circuit board assembly 18 is a 3 button cell battery 32. Other types of batteries may also be employed to 4 power device 10. 5 The device 10 is generally comprised of battery 32, electronic 6 circuitry 19,40, electrodes 22,24, and drug/chemical reservoirs 26,28, all of 7 which are integrated into a self-contained unit. The outputs (not shown in 8 FIG. 1 ) of the circuit board assembly 18 make electrical contact with the 9 electrodes 24 and 22 through openings 23,23' in the depressions 25,25' formed in lower housing 20, by means of electrically conductive adhesive strips 42,42'. Electrodes 22 and 24, in turn, are in direct mechanical and electrical contact with the top sides 44',44 of drug reservoirs 26 and 28. The bottom sides 46',46 of drug reservoirs 26,28 contact the patient's skin through the openings 29',29 in adhesive 30. Device 10 optionally has a feature which allows the patient to self-administer a dose of drug by electrotransport. Upon depression of push button switch 12, the electronic circuitry on circuit board assembly 18 delivers a predetermined DC current to the electrode/reservoirs 22,26 and 24,28 for a delivery interval of predetermined length. The push button switch 12 is conveniently located on the top side of device 10 and is easily actuated through clothing. A double press of the push button switch 12 within a short time period, e.g., three seconds, is preferably used to activate the device for delivery of drug, thereby minimizing the likelihood of inadvertent actuation of the device 10. Preferably, the device transmits to the user a visual and/or audible confirmation of the onset of the drug delivery interval by means of LED 14 becoming lit and/or an audible sound signal from, e.g., a "beeper". Drug is delivered through the patient's skin by electrotransport, e.g., on the arm, over the predetermined delivery interval. Anodic electrode 22 is preferably comprised of silver and cathodic electrode 24 is preferably comprised of silver chloride. Both reservoirs 26 and 28 are preferably comprised of polymer hydrogel materials. Electrodes 22,24 and reservoirs 26,28 are retained by lower housing 20. The push button switch 12, the electronic circuitry on circuit board assembly 18 and the battery 32 are adhesively "sealed" between upper housing 16 and lower housing 20. Upper housing 16 is preferably composed of rubber or other elastomeric material. Lower housing 20 is preferably composed of a plastic or elastomeric sheet material (e.g., polyethylene) which can be easily molded to form depressions 25,25' and cut to form openings ι 23,23'. The assembled device 10 is preferably water resistant (i.e., splash 2 proof) and is most preferably waterproof. The system has a low profile that 3 easily conforms to the body, thereby allowing freedom of movement at, and 4 around, the wearing site. The reservoirs 26 and 28 are located on the skin- 5 contacting side of the device 10 and are sufficiently separated to prevent 6 accidental electrical shorting during normal handling and use. 7 The device 10 adheres to the patient's body surface (e.g., skin) by β means of a peripheral adhesive 30 which has upper side 34 and body- 9 contacting side 36. The adhesive side 36 has adhesive properties which o assures that the device 10 remains in place on the body during normal user i activity, and yet permits reasonable removal after the predetermined (e.g., 24- 2 hour) wear period. Upper adhesive side 34 adheres to lower housing 20 and 3 retains the electrodes and drug reservoirs within housing depression 25, 25' 4 as well as retains lower housing 20 attached to upper housing 16. s The reservoirs 26 and 28 comprise a gel matrix, with at least one of 6 the reservoirs comprised of the hydrogel formulation of the invention. Drug 7 concentrations in the range of approximately 1 x 10 " M to 1.0 M or more can s be used, with drug concentrations in the lower portion of the range being 9 preferred. Concentrations lower than about 1 x 10"* M may also be effective, 0 particularly with peptide or protein drugs. Generally it is preferred that the 1 drug concentration not become so low during drug delivery that flux becomes 2 dependent on drug concentration, but remains dependent on current. For an 3 expensive drug, however, this may not be possible. Factors which affect the 4 ultimate device formulation include device size, drug solubility, drug cost, and 5 dosing regimen. 6 While the invention has been described in conjunction with the 7 preferred specific embodiments thereof, it is to be understood that the 8 foregoing description as well as the examples which follow are intended to 9 illustrate and not limit the scope of the invention. Other aspects, advantages ι and modifications within the scope of the invention will be apparent to those 2 skilled in the art to which the invention pertains. 3 4 EXAMPLE 1 5 The transport of the R- and S- isomers of ketorolac was evaluated e using passive transdermal delivery and electrotransport, in a study conducted in healthy volunteers. Intravenous (IV) bolus administration of 24 mg racemic 8 ketorolac served as the reference treatment. The relative amounts of R- and 9 S- ketorolac absorbed following passive transdermal (TTS) and o electrotransport transdermal (ETS) administration were determined relative to i intravenous R- and S- ketorolac clearance (assuming that the racemic 2 ketorolac contained equal amounts of the R- and S- isomers). The mean 3 amounts of R- and S- ketorolac absorbed following passive transdermal 4 administration were 5.0 mg and 4.8 mg (mean total = 9.8 mg) respectively, s and, following electrotransport administration, were 7.9 and 11.7 mg (mean 6 total = 19.6 mg) respectively. Following passive transdermal administration, 7 the amount of R-ketorolac absorbed was similar to that of S-ketorolac (p > s 0.5). However, following electrotransport administration the mean amount of 9 R-ketorolac absorbed was found to be lower than that of S-ketorolac 0 absorbed. The S/R ratio of amount absorbed ranged from 0.8 to 1.43 (mean, 1 1.15; median, 1.18). 2 3 EXAMPLE 2 4 Drugs comprising mixtures of enantiomers are evaluated to 5 determine a preferred isomer. Purified isomers as well as mixtures of isomers 6 are delivered to test subjects and the efficacy, pharmacokinetics and 7 pharmacodynamic profile of the isomers are determined. Preferred isomers 8 are identified as those that are effective and exhibit some beneficial feature 9 as compared to a mixture of isomers, for example improved therapeutic index, improved activity, improved half-life, lower effective dosage, lower toxicity, fewer or lessened side effects, or the ability to be delivered via electrotransport to an effective therapeutic level in an acceptable patch size, and the like. EXAMPLE 3 A mixture of isomeric forms of a drug is incorporated into an electrotransport device. The device is applied to test subjects, and blood samples are subsequently taken from the subjects at various time intervals before, during and after treatment. Plasma concentrations of the preferred isomer and the other isomers are determined. Drugs for which electrotransport provides increased uptake of the preferred isomer are identified. Generally, it is preferred that at least a 20% increase in the rate of in vivo delivery of the preferred isomer is achieved. However, a smaller increase in rate of delivery, of about 5 or 10%, may prove acceptable in some cases, for example where the drug is particularly expensive. EXAMPLE 4 A study was performed in order to compare the pharmacokinetic parameters of R- and S-ketorolac following intravenous, passive transdermal and electrotransport administration of a racemic mixture of ketorolac. SCREENING PROCEDURES Twelve healthy male volunteers were enrolled in a pilot feasibility study. Subjects were required to undergo a pre-study screening to evaluate whether they met study inclusion or exclusion criteria. Screening procedures included a medical history, physical exam, electrocardiogram and clinical laboratory tests. MATERIALS AND METHODS Study Design: The study was an open-label, randomized, three-treatment crossover pharmacokinetics study designed to compare plasma ketorolac concentrations during 24-hour treatment regimens with an electrotransport system ("ETS"), a (passive) therapeutic transdermal system ("TTS") and intravenous ("IV") ketorolac bolus injection. Treatment Overview and Randomization: The ketorolac treatments are listed below; there was a washout period of at least 6 days between treatments. ETS (ketorolac): Ketorolac delivered with electrotransport from a total cathode area of 18 cm 2 , at a current density of 100 μA/cm 2 , for 24 hours TTS (ketorolac): Ketorolac delivered passively through the skin from three systems, total area 75 cm 2 , for 24 hours Intravenous ketorolac: Intravenous bolus injection of ketorolac, 12 mg of free acid (18 mg of ketorolac tromethamine salt), at Hour 0 and Hour 12 (a total of 24 mg). Subjects were assigned randomly to receive the three ketorolac treatments in one of the following randomization schemes: Sequence Subject Number ETS, TTS, Bolus 103, 106, 107, 110 TTS, Bolus, ETS 101 , 104, 108, 112 Bolus, ETS, TTS 102, 105, 109, 111 ETS Treatment: During the ETS (ketorolac) treatment, each subject was expected to receive an estimated 26 mg of ketorolac free acid over a 24-hour period, delivered by electrotransport from a total cathode area of 18 cm 2 , based on an estimated in vitro flux rate of 60 μg/cm 2 /h. ETS System Description: The ALZA Model 6443 Electrical Current Source ("ECS"), in combination with the Electrotransport Delivery Platform containing the active drug gel at the cathode and the pharmacologically inactive gel at the anode, makes up the electrotransport drug delivery system. The Model 6443 ECS is a reusable electrical current regulator (controller). The controller was set in the direct current ("DC") mode to provide continuous electrical current for the delivery of ketorolac during ETS treatment. The electrotransport delivery platform consisted of a housing containing the anode and cathode electrodes and two gel reservoirs. The cathode reservoir was designed to hold the active gel imbibed with ketorolac and was 6 cm 2 . The anode reservoir comprised a pharmacologically inactive gel and was 6 cm 2 . The inactive anode gels were placed against the anode electrode during manufacture and assembly of the housing. The drug- imbibed cathode gels were inserted into the platform just prior to use. A pressure sensitive adhesive permitted application of the system to the skin The delivery platform was connected to the ECS by a cable. ι Three electrotransport systems, with a total cathode gel area of 18 2 cm 2 , were applied to the upper arms of each subject in this study. Each of 3 the three controllers was set to provide a total direct current of 0.6 mA, which maintained a current density of 100 μA/cm 2 . 5 A current and voltage check of the controller were performed using a 6 voltmeter at hours 0, 2, 4, 8, 12 and 24 of the ETS application If the voltage exceeded 15 volts or the current was not within ± 20% β of target value, the controller was adjusted. If adjustment did not correct the 9 problem, the controller was replaced and the subject continued in the study 0 1 TTS Treatment: 2 During TTS treatment, each subject was expected to receive an 3 estimated 50 mg of ketorolac free acid over a 24-hour period, delivered 4 passively through the skin from a total application area of 75 cm 2 based on an 5 estimated in vitro flux rate of 25 to 30 μg/cm 2 /h. 6 7 TTS System Description: s The TTS systems were produced with a backing and protective liner 9 in a 25 cm 2 size. The system formulation contained drug (free acid), ethylene 0 vinyl acetate (40% vinyl acetate), glycerol monolaurate, and Ceraphyl ® 31 1 Three TTS monoliths, with a total surface area of 75 cm 2 , were used to deliver 2 the drug. The combined systems contained 135 mg of ketorolac free acid 3 Because the systems were not self-adhesive, an adhesive overlay was required to ensure good skin contact. 5 6 Intravenous Ketorolac Bolus Injection Treatment: 7 During the intravenous bolus treatment, each subject received a 8 total of 24 mg of ketorolac free acid (36 mg of ketorolac tromethamine salt) 9 Drug was delivered by IV bolus injections of 12 mg of ketorolac free acid (18 mg of ketorolac tromethamine salt) which were administered at Hour 0 and at Hour 12. A 1 mL aliquot of each ketorolac solution was retained directly after syringe preparation and prior to injection. Treatment Schedule: Initially either the ETS or the TTS was applied, or the first intravenous injection was administered. ETS and TTS treatments continued for 24 hours, and the bolus treatment was completed after the second dose at 12 hours. Blood and urine samples were collected at intervals during a 48- hour period after initiation of each ketorolac treatment regimen. After completion of all three drug treatments and blood and urine collection phases, a post-study physical examination, electrocardiogram, and clinical laboratory tests were performed. Blood Sampling for Pharmacokinetics Assessment: Blood samples, 7 mL each, were collected from each subject at intervals during the 48 hour period after initiation of treatment. Plasma levels of ketorolac were determined by HPLC assay, performed at the Clinical Pharmacology Division of the School of Medicine at Indiana University, Wishard Memorial Hospital, Indianapolis, Indiana. Topical Evaluations: Skin site assessments were conducted at intervals at both the anode and the cathode sites of the electrotransport system and at the sites to which the TTS (ketorolac) systems were applied. Pharmacokinetics Methods: Actual blood sample collection times were used for all calculations and data were summarized by nominal sampling times. Plasma ketorolac ι concentrations below the assay quantification limit of 20 ng/mL were assigned 2 a value of zero. 3 The maximal observed plasma concentrations (C max ) of R- and S- 4 ketorolac and the corresponding sampling times (T max ), expressed in hours, 5 were determined over the entire sampling interval following TTS and ETS 6 treatment. 7 The apparent elimination rate constants (k) for both R- and S- β ketorolac were estimated by linear regression of log-transformed plasma 9 concentrations during the terminal log-linear decline phase following o intravenous administration. Apparent half-life (t 1/2 ) values were calculated as i 0.693/k. 2 The area under the plasma R- and S-ketorolac concentration time 3 profiles, from Hour 0 to the last detectable concentration at time t (AUC t ), 4 were determined by the linear trapezoidal method. The AUC value s extrapolated to infinity (AUC ιnf ) was determined as the sum of AUC, and the 6 area extrapolated to infinity, and was calculated by the concentration at time t 7 (C t ) divided by k. The average steady-state drug concentrations (C avg ) were s calculated as AUC, nf /24. 9 The R- and S- ketorolac AUC, nf ratio was determined for all three 0 treatments. The amounts of R- and S-ketorolac absorbed following the ETS 1 (ketorolac) and TTS (ketorolac) treatments were calculated using the 2 estimated intravenous clearance (Dose/AUC ιnf ) as given in Equation 1 , which 3 assumed no interconversion between the enantiomers: 4 5 Amount absorbed = AUC ιnf (TTS/ETS) * CL, V (Equation 1) 6 7 The disposition of R- and S-ketorolac following intravenous 8 administration could be best described by a two-compartment open model. 9 The pharmacokinetics parameters following intravenous administration of R- and S-ketorolac were estimated by non-linear regression of the plasma concentration-time profile (Equation 2). The rate of drug input and the absorption rate constant following both ETS (ketorolac) and TTS (ketorolac) administration were then estimated by fitting the respective plasma concentration-time profile to Equation 3. The pharmacokinetics parameters such as V, K1 , K2, and K21 estimated from intravenous data were used as constants. D (K21 - Kl) * (1 - exp (dι * K1 * τ) (exp (-Kl * t) ') C(t) = [ V * (K1- K2) (1 - exp** 1 * r) ) + (K21 - K2) * (I - exp (dl*K2* τ) ) * (exp (~κ2 ' °) j (l-exp^ 2* ^) (Equation 2) c(t)= R * Ka r (1 - exp(K1* θ) * (exp(~ κl*(t~ T))) * (K21 - K1) V Kl* (K1-K2)* (Ka-Kl) (1 - exp^ 2* θ) ) * (exp ( - * (t~ T)) ) * (K21 - K2) K2* (Kl- K2)* (Ka- K2) (1 - exp** 0* θ) ) * (exp (~ Ka* (t~ T)) ) * (K21 - Ka) , Ka* (Kl- Ka)* (K2- Ka) (Equation 3) Where: D = intravenous dose di - dose number (i = dose 1 , 2) R = rate of input for duration -c t = time since initiation of the input Kl = distribution rate constant K2 = elimination rate constant K21 = rate constant for transfer from peripheral compartment to central compartment V = volume of distribution of central compartment Ka = transdermal absorption rate constant T = T lag , lag time Θ = t when t < τ or T when t > T All statistical comparisons were done using analysis of variance (ANOVA). The treatment comparisons contained the following effects: subject within sequence, sequence, treatment, and period. RESULTS Disposition of Enrolled Subjects: Twelve subjects enrolled in the study and eleven completed the study. Subject Demographics: All subjects were found to be healthy according to medical history and physical examination and clinical laboratory and electrocardiogram results. Ketorolac Pharmacokinetics: The individual plasma concentration-time profiles following R- and S- ketorolac intravenous bolus injection and administration from ETS and TTS are presented in Tables 3 and 4. The mean (SD) plasma concentration-time profiles are shown in Figures 2 and 3. Following intravenous administration of ketorolac, mean C max values of 872 and 404 ng/mL were observed at 0.5 hours post dose for R- and S- ketorolac, respectively. The R-ketorolac plasma concentrations during ETS and TTS administrations were not detectable until 1 hour and 4 to 8 hours post administration, respectively. The R-ketorolac plasma concentrations observed during TTS administration were lower than those observed during ETS administration. The R-ketorolac C max values during ETS and TTS were ι 195 and 132 ng/mL and the T max values were 22 and 23 hours, respectively. 2 The S-ketorolac C max values during ETS and TTS administrations were 82 3 and 60 ng/mL and the T max values were 22 and 23 hours, respectively (Tables A, B, 3, and 4). 5 The mean terminal half-lives for R- and S-ketorolac were 5.0 and 2.0 e hours, respectively, and the terminal rate constants were 0.14 h '1 and 7 0.41 h 1 , respectively (Tables A, B, 5 and 6) following IV treatment. 8 Mean R-ketorolac AUC iπf values following intravenous, ETS and TTS 9 administrations were 6171 , 4298 and 2408 ng-h/mL, respectively, and mean o S-ketorolac AUC iπf values following intravenous, ETS and TTS were 1566, i 1608 and 602 ng-h/mL, respectively (Tables A, B, 7 and 8). 2 Following intravenous administration, R- and S-ketorolac clearance 3 differed. The amounts of R- and S-ketorolac absorbed following ETS and 4 TTS administrations were determined using Equation 1. Following TTS s administration, the mean amounts of R- and S-ketorolac absorbed were 4.96 6 mg and 4.76 mg (mean total = 9.72 mg), respectively (Tables A, B, 10 and 7 11), and were not significantly different from each other (p<0.1). Following s ETS administration, the mean amounts of R- and S-ketorolac absorbed were 9 7.9 mg and 11.65 mg (mean total = 19.55 mg), respectively (Tables A, B, 10, 0 and 11), and were significantly different from each other (p=0.057). In this i study, the target amount of total delivered R-, S-ketorolac over a 24-hour 2 period was 24 mg. The amount absorbed following ETS treatment was close 3 to the target value (19.59 mg), but it was considerably less than 24 mg 4 following TTS treatment (9.72 mg). 5 The estimated pharmacokinetic parameters following intravenous 6 administration of ketorolac are listed in Table 12. The mean distribution and 7 elimination rate constants were 1.54 and 0.15 h "1 , respectively, for R-ketorolac 8 and 2.10 and 0.35 h "1 , respectively, for S-ketorolac (Table 12). The mean 9 volume of distributions were 5.4 and 10.33 L for R- and S-ketorolac, respectively (Table 12). These estimated parameters were used as constants in Equation 3 and the absorption rate, K a , and T lag were estimated following TTS administration (Table 13). The mean K a and absoφtion rate values were 0.61 rr 1 and 334 μg/h for R-ketorolac, and 1.7 h "1 and 470 μg/h for S- ketorolac, respectively (Table 13). In the case of ETS, the plasma concentration could be best fitted to a model without T, ag . The R-ketorolac mean K a and rate of absorption following ETS were 1.57 h "1 and 392 μg/h, respectively (Table 14). For S- ketorolac, the parameters could be estimated for only 9 of 12 subjects; the K a and rate of absorption values were 0.83 h '1 and 570 μg/h, respectively (Table 14). iΛVW nvotn oooooo • • • u u TABLE 1B Plasma R-Ketorolac Concentrations (ng/mL) TTS (ketorolac), 24 h (n=11) Subject Study Hour Number 0 0 1 0 2 0 3 0 4 0 6 0 8 0 12 0 16 0 20 0 24 0 24 S 25 0 26 0 28 0 32 0 48 0 t il l 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 26 0 34 0 38 0 31 0 29 0 27 0 0 0 0 0 H).> 0 0 0 0 0 0 0 0 28 0 66 0 90 0 174 0 185 0 239 0 247 0 227 0 196 0 164 0 82 0 47 0 0 0 10) 00 00 00 00 00 00 00 400 420 53 0 760 75 0 690 700 490 250 00 MM 00 00 00 00 00 00 00 0 0 00 57 0 990 47 0 400 57 0 250 00 00 10b 00 00 00 00 00 00 00 260 530 870 860 1440 1170 1020 800 990 350 107 00 00 00 00 00 00 00 670 520 64 0 500 550 430 380 360 440 00 108 00 00 00 00 00 00 240 560 71 0 1200 1660 1640 1530 1290 790 1010 200 109 00 00 00 00 00 00 260 67 0 115 0 1900 2030 1930 1700 1600 1230 690 31 0 110 00 00 00 00 00 00 00 690 760 81 0 1260 1050 1250 830 620 51 0 00 111 00 00 00 00 00 550 320 620 81 0 1090 1480 1680 1440 121 0 950 640 330 112 00 00 00 00 00 00 00 00 85 0 1190 1000 980 750 1060 760 590 00 MfAN 000 000 000 000 255 1009 1564 51 00 6909 104 09 121 36 11945 105 73 9627 66 73 5082 1082 SO 000 000 000 000 B 44 2245 27 72 4966 51 79 6280 6493 6372 57 11 4559 3035 3362 1545 SE 000 000 000 000 255 6 77 β 36 1497 1561 1894 1958 1921 1722 13 75 9 15 10 14 466 TABLE 1C Plasma R-Ketorolac Concentrations (ng/mL) IV Injection, 2 Doses q12h (n=12) Subject Study Hour Number 00 05 1 0 20 4 0 60 80 120 125 130 14 0 160 180 200 240 101 00 11620 8500 8440 477 0 224 0 1260 820 14220 817 0 451 0 2680 2150 1710 990 102 00 7320 497 0 2780 1490 670 480 540 10400 717 0 4030 2800 111 0 880 380 103 00 7540 521 0 3170 1900 114 0 73 0 31 0 6350 4460 3180 161 0 920 740 500 104 00 6190 4550 3260 1950 141 0 920 500 6960 5300 3670 2420 1740 1270 81 0 105 00 8180 517 0 341 0 1960 1330 1350 890 8230 6260 4390 2900 2330 1330 850 106 00 6780 5200 3860 2660 1720 1030 750 7530 5720 3860 2700 1780 1370 960 107 00 6290 4190 2670 1020 580 34 0 00 6850 4990 344 0 1830 1120 780 44 0 108 00 861 0 6000 3690 1860 1160 540 920 8980 6470 3860 2030 1390 1030 510 109 00 9670 7060 4940 331 0 194 0 234 0 1230 11440 974 0 8070 5820 3860 2940 1600 110 00 6500 4730 2900 1710 1260 660 430 6260 5000 3920 2920 2500 1930 1360 111 00 8220 6570 464 0 2960 1660 1130 71 0 9130 651 0 4920 2740 1880 1620 930 112 00 627 0 485 0 3000 161 0 1000 71 0 340 691 0 487 0 3260 1790 1260 930 490 MIAN 000 77658 56833 38967 22667 13425 96 75 6200 86050 622 17 42592 26867 18367 137 75 8183 SD 000 163 19 124 11 15968 101 73 4901 53 75 3325 24072 15451 13041 10927 8149 6224 3822 SE 000 47 11 3583 4609 2937 14 15 1552 960 6949 44 60 3765 3154 2352 1797 11 03 OOOOOOOOOOOO oooooooooooo 0000000000* 0 oo ooooooooo ooo ooo o ooo oooooooooooo oooooooooooo ooooooooooo o ooooo oooo oooooo o oooooooooooo oooooo oooooooooooo 3 Z ^o oooooo-— ~ — TABLE 2B Plasma S-Ketorolac Concentrations (ng/mL) TTS (ketorolac), 24 h (n=11) Subjec Study Hour Number 00 1 0 20 3 0 4 0 60 B 0 120 160 200 24 0 245 250 260 280 320 480 101 00 00 00 00 00 00 0 0 00 0 0 00 0 0 00 00 00 00 00 00 102 00 00 00 00 00 270 41 0 630 62 0 97 0 830 700 550 400 00 00 00 103 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 104 00 00 00 00 00 00 00 00 00 41 0 650 00 00 00 00 00 00 106 00 00 00 00 00 00 00 00 00 250 21 0 21 0 21 0 00 00 00 00 107 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 108 00 00 00 00 00 00 00 00 380 31 0 680 250 630 460 00 00 00 109 00 00 00 00 00 00 00 350 450 730 680 580 450 360 210 00 00 110 00 00 00 00 00 00 00 00 00 00 330 31 0 620 270 00 280 00 111 00 00 00 00 00 00 00 00 260 450 600 680 520 360 21 0 00 00 112 00 00 00 00 00 00 00 00 00 00 300 00 00 280 00 00 00 MEAN 000 000 000 000 000 245 3 73 891 1555 2B 36 3800 2482 2709 1936 382 255 000 SO 000 000 000 000 000 8 14 1236 2079 2309 3344 3051 2853 2817 1923 849 844 000 SE 000 000 000 000 000 245 3 73 627 696 1008 920 860 849 580 256 255 000 vn vo oooooooooooo rs-^ro o o o o en o o o *r o o enoco oooooooooooo voenc oooooooooooo αscc-q- en tr» σ^^^r I •v σ> — —• o o r co co en r- oooooooooooo βHf ooooooooooo ooooooooooo TABLE 3A TABLE 3B C max and T max Values C m „ and T max Values r R-Ketoroiac Concentration for R-Ketorolac Concentration ETS (ketorolac), 24 h TTS (ketorolac), 24 h (n=12) (n-11) Subject c.„ τ.„ Subject Number (ng/mL) (h) Number (ng/ml) (h) 101 326.0 245 161.0 240 101 38.0 245 102 103 340 12.0 102 2470 24 0 104 219 0 16.0 103 760 240 105 267 0 240 104 990 24 0 106 35.0 240 106 1440 245 107 65 0 240 107 670 12 0 2620 245 108 108 1660 240 109 3860 25 0 109 2030 240 110 79 0 240 110 1260 24 0 2970 240 111 111 1680 24 5 205.0 160 112 112 1190 20 0 Mean 13209 Mean 19467 21.83 22 69 119.63 444 SD 6193 3 76 SD CV 4688 CV 61.45 20.35 1658 Gmean 14855 21.32 117.2C 22 30 Gean 306 Mean(ln) 476 ' < 10 MeantIn) 500 87 024 SD(ln) 0 54 0 -1 SD(ln) 0 TABLE 3C C max and T m „ Values for R-Ketoroiac Concentration IV injection, 2 Doses q12h (π-12) Subject Number (cn.g/mL) M (h) 101 14220 125 102 10400 125 103 7540 0.5 104 696.0 12.5 105 823.0 12.5 106 7530 125 107 685 0 125 108 898.0 12.5 109 11440 12.5 110 6500 05 111 9130 12.5 112 691 0 125 Mean 87242 10.50 SD 230 72 467 CV 2645 4449 Gmean 34826 731 Mean(ln) 6 74 1 99 SD(ln) 024 1.25 TABLE 4A C max and T max Values TABLE 4B or S-Ketorolac Concentration C ma * and T max Values ETS (ketorolac), 24 h for S-Ketorolac Concentration (n-9) TTS (ketorolac), 24 h (n- β ) Subject r Number (ng/mL) (h) Subject „ τ«, Number (ng/mL) ( ) 101 1120 245 102 53 0 245 104 830 120 102 970 20 0 105 890 240 104 55 0 240 108 850 20 0 106 25 0 20 0 109 1220 240 108 680 240 110 310 240 109 73 0 20 0 111 1000 240 110 620 25 0 112 610 200 111 680 245 112 30 0 24 0 Mean 8178 2189 SD 2908 4 13 Mean 59 75 2269 CV 35 56 1887 SD 2336 2 25 CV 3909 992 Gmean 76 14 2144 Mean(ln) 433 3 07 Gmean 55 00 22 59 SD(ln) 043 023 Meant In) 401 3 12 SD(ln) 046 0 10 NOTE Concentrations for subjects 103106 107 were zero TABLE 4C C ma χ and T max Values for S-Ketorolac Concentration IV Injection, 2 Doses q12h (n=12) Subject „ T Number (ng/mL) (h) 101 7810 125 102 ■4440 125 103 3240 05 104 3270 125 105 3650 05 106 3170 125 107 2910 125 108 4160 125 109 5040 125 110 325 0 125 111 4550 125 112 2940 125 Mean 403 58 1050 SD 13784 467 CV 34 15 4449 Gmean 38697 731 Mean π 596 199 SD(ln) 029 1 25 TABLE 5 Apparent Elimination Rate Constant (k) and Half-Life (t^) Values for R-Ketoroiac Concentration IV Injection, 2 Doses q12h (n-12) Subject t„ 2 Number (h) (h 1 ) Time Points n r 1 101 5.5 0.125 16.00- 24.00 4 1.00 102 3.8 0.183 18.00- 24.00 3 0.98 103 6.9 0.101 18.00- 24.00 3 1.00 104 5.1 0.136 16.00- 24.00 4 0.99 105 4.3 0.160 18.00- 24.00 3 0.94 106 5.6 0.125 16.00- 24.00 4 0.96 107 40 0.174 16.00- 24.00 4 0.98 108 4.1 0171 16.00- 24.00 4 1.00 109 44 0.158 16.00- 24.00 4 0.99 110 7.1 0.098 16.00- 24.00 4 0.99 111 5.3 0.130 16.00- 24.00 4 0.99 112 43 0.161 16.00- 24.00 4 1.00 Mean 5.02 0 1435 SD 1.10 0.0285 CV 21.90 19.8270 Gmean 4.92 0.1408 Mean(ln) 1.59 1.9604 SD(ln) 0.21 0.2091 TABLE 6 Apparent Elimination Rate Constant (k) and Half-Life (t, a ) Values for S-Ketorolac Concentration IV Injection, 2 Doses q12h (n=12) Subject t.,-. k Number ( ) ( 1 ) Time 1 'oints n r ; 101 1.8 0.382 14.00- 18.00 102 3 0.98 1.2 • 0.561 13.00- 16.00 103 3 0.98 1.2 0.560 13.00- 16.00 104 3 0.99 2.0 0.345 14.00- 18.00 3 105 1.00 2.6 0.264 14.00- 18.00 3 106 0.99 2.8 0.250 16.00- 20.00 107 3 1.00 12 0.563 13.00- 16.00 3 108 0.99 1.1 0.653 13.00- 16.00 3 109 0.99 2.0 0.349 13.00- 20.00 110 5 1.00 3 6 0.190 16.00- 24.00 4 111 1.00 3.2 0.220 13.00- 24.00 6 112 0.81 1.1 0.625 13.00- 16.00 3 0.99 Mean 1.99 04135 SD 0.88 0 1690 V 4415 40.8757 Gmean 1.82 03803 Mean( lr.) 0 60 •09667 SD(ln) 044 04372 TABLE 7A AUC and C avg Values for R-Ketorolac Concentration ETS (ketorolac), 24 h (π-12) Subject AUC . AUC ,„.„ Number AUC ,., (ng- h/mL) (ng- h/mL) (ng-h/mL) (n- /V) 101 7451.63 7451.63 102 8243.53 155.24 3177.39 3177.39 103 3297.53 586.50 66.20 586.50 104 833.75 4484.50 12.22 4484.50 105 4822.49 93.43 5430.25 5430.25 106 5798.90 381.25 113.13 381.25 107 605.63 7.94 607.75 607.75 108 791.24 5160.69 12.66 5160.69 5324.37 109 8456.77 107.51 no 8456.77 9076.31 1166.00 176.18 1166.00 111 1483.95 24.29 6994.62 6994.62 112 7224.87 145.72 3813.66 3813.66 4074.72 79.45 Mean 3975.917 3975.917 SD 4298.107 2850.239 82.832 2850.239 CV 2976.405 59.380 71.688 71.688 69.249 71.688 Gmean 2623.602 2623.602 Meant I n) 3047.308 54.658 7.872 7.872 SD( l n) 8.022 4.001 1.113 1.113 0.981 1.113 Max 8456.767 8456.767 Mi n 9076.311 176.183 381.250 381.250 605.630 7.943 TABLE 7B AUC and C avg Values for R-Ketorolac Concentration TTS (ketorolac), 24 h (n=11) Subject AUC AUC 0!4 AUC ,„, Number (ng h/ml) (ng h/mL) (ng h/mL) (πg/°mL) 101 29330 172 00 50927 717 102 421825 331000 447490 13792 103 110225 69200 134950 2883 104 61475 42600 79844 1775 106 2679 78 83744 296025 3489 107 115725 832 00 140955 3467 108 323198 139200 334889 5800 109 3793 53 1971 78 398951 8216 110 1745 62 115537 226869 4814 111 310950 151000 3362 78 6292 112 164993 1014 76 201667 4228 Mean 2145 103 1210305 2408 042 50429 SD 1328602 860 038 1317 606 35835 CV 61936 71 060 54 717 71060 Gmean 1671989 949910 2005 097 39580 Meant In) 7422 6856 7603 3678 SD(ln) 0831 0 787 0 694 0787 Max 4218250 3310 000 4474904 137917 Min 293 300 172 000 509273 7 167 TABLE 7C AUC and C avg Values for R-Ketorolac Concentration IV Injection, 2 Doses q12h (n=12) Subject AUC . AUC ro 24) AUC ,„, Number (ng- h/mL) (ng- h/mL) (ng- h/mL) (ng/mL) 101 8126.25 8126.25 8918.15 338.59 102 4637.50 4637.50 •4845.01 193.23 103 4097.00 4097.00 4591.51 170.71 104 4869.52 4869.52 5464.67 202.90 105 5726.00 5726.00 6257.10 238.58 106 5545.25 5545.25 6314.55 231.05 107 3596.00 3596.00 3848.30 149.83 108 5008.22 5008.22 5306.35 208.68 109 9436.25 9436.25 10447.75 393.18 110 5214.50 5214.50 6609.36 217.27 HI 6305.32 6305.32 7019.11 262.72 112 4125.50 4125.50 4430.08 171.90 Mean 5557.275 5557.275 6170.994 231.553 SD 1705.638 1705.638 1923.591 71.068 CV 30.692 30.692 31.171 30.692 Gmean 5350.361 5350.361 5926.687 222.932 Mean( l n) 8.585 8.585 8.687 5.407 SD(ln) 0.280 0.280 0.291 0.280 Max 9436.250 9436.250 10447.75 393. 177 Mm 3596.000 3596.000 3848.304 149.833 TABLE 8A AUC and C avg Values for S-Ketorolac Concentration ETS (ketorolac), 24 h (n-9) Subject AUC , AUC (o tt) AUC ,-, Number (ng- h/mL) (ng- h/mL) (ng- h/mL) (ng/mL) 101 2377.28 2377.28 2.445.36 49.53 102 912.84 912.84 950.25 19.02 104 1542.50 1542.50 1644.06 32.14 105 1544. 75 1544.75 1669.74 32.18 108 1431.26 1431.26 1478.71 29.82 109 2632.40 2632.40 2755.45 54.84 110 201.75 201.75 327.86 4.20 111 1890.73 1890. 73 2004.50 39.39 112 1157.67 1157.67 1196.09 24. 12 Mean 1521.243 1521.243 1608.003 31.693 SD 737.945 737.945 744.809 15.374 CV 48.509 48.509 46.319 48.509 Gmean 1270. 138 1270. 138 1398.258 26.461 Mean( l n) 7.147 7. 147 7.243 3.276 SD(l n) 0.764 0.764 0.636 0.764 Max 2632.400 2632.400 2755.452 54.842 Min 201. 750 201. 750 327.864 4.203 TABLE 8B AUC and C avg Values for S-Ketorolac Concentration TTS (ketorolac), 24 h (n-8) Subject AUC t AUC .„. r Number (ng - h/mL) (ng- h/mL) (ng- h/mL) (ng/mL) 102 13.48.00 1231.00 1419.25 51.29 104 274.00 274.00 433.60 11.42 106 163.03 142.38 247. 16 5.93 108 511.83 412.00 582.24 17.17 109 902.75 748.00 962.84 31.17 110 232.75 66.00 379.88 2.75 111 567.00 404.00 662.56 16.83 112 81.00 59.50 125.82 2.48 Mean 510.046 417. 110 601.669 17.380 SD 430.405 399.861 419.610 16.661 CV 84.386 95.865 69.741 95.865 Gmean 362.386 263. 839 477.449 10.993 Mean( l π) 5.893 5.575 6.168 2.397 SD( l π) 0.929 1.093 0.765 1.093 Max 1348.000 1231.000 1419.245 51.292 Mi n 81.000 59.500 125.822 2.479 TABLE 8C AUC and C avg Values for S-Ketoroiac Concentration IV Injection, 2 Doses q12h (n-12) Subject AUC AUC , 0 ,,, AUC ,„, C „, Number (ng h/mL) (ng h/mL) (ng h/mL) (ng/mL) 101 2654 50 265450 272782 11060 102 1103 00 110300 1181 37 45 96 103 990 25 99025 1049 15 4126 104 1305 50 130550 139836 5440 105 1271 25 127125 1422 76 5297 106 1427 75 142775 152790 5949 107 826 50 82650 89045 3444 108 1295 03 129503 134860 5396 109 2121 51 212151 221880 88.40 110 1697 75 169775 1823.86 70 74 111 2192 78 219278 2283.80 91.37 112 880 75 88075 92397 3670 Mean 1480 548 1480548 1566403 61689 SD 574 106 574106 582992 23921 CV 38 777 38777 37219 38 777 Gmean 1388 048 1388048 1474236 57835 Mean(ln) 7 236 7236 7296 4058 SD(ln) 0 370 0370 0361 0370 Max 2654 500 2654500 2727 817 110604 Min 826 500 826500 890453 34438 TABLE 9A R-Ketoroiac and S-Ketorolac AUC Ratios (n-12) Subject ETS (ketorol ac) TTS (ketorol ac) IV Injection Number /S Ratio R/S Ratio R/S Ratio 101 3.37 3.27 102 3.47 3.15 4.10 103 4.38 104 2.93 1.84 3.91 105 3.47 4.40 106 11.98 4.13 107 4.32 108 3.60 5.75 3.93 109 3.29 4.14 4.71 110 4.53 5.97 3.62 111 3.60 5.08 3.07 112 3.41 16.03 4.79 Mean 3.520 6.743 4.054 SD 0.427 4.805 0.529 CV 12.140 71.266 13.048 SE 0. 142 1.699 0.153 Min 2.93 1.84 3.07 Max 4.53 16.03 4.79 TABLE 9B R-Ketorolac and S-Ketorolac AUC Ratios (n> =6) Subject ETS (ketorolac) TTS (ketorolac) IV Injection Number R/S Ratio R/S Ratio R/S Ratio 102 3.47 3.15 4.10 104 2.93 1.84 3.91 108 3.60 5.75 3.93 109 3.29 4.14 4.71 111 3.60 5.08 3.07 112 3.41 16.03 4.79 Mean 3.385 5.999 4.087 SD 0.251 5.105 0.628 CV 7.412 85.105 15.359 SE 0.102 2.084 0.256 Mm 2.93 1.84 3.07 Max 3.60 16.03 4.79 NOTE: Table is computed for subjects with AUC,., for both enantiomers in all three treatments TABLE 10A AUC and Amount Delivered (AD) Values for R-Ketoroiac Concentration (n-12) ETS (ketorol ac 1 TTS (ketorolac) IV Injection Subject AUC .. AUC „ AUC ,„, ETS/IV ' TTS/IV" Number (ng h/mL) (ng h/mL) (ng h/mL) AD (mg) AD (mg) 101 8243 5 5093 89182 1109 069 102 32975 44749 48450 817 1108 103 8338 13495 4591 5 2 18 3 53 104 48225 7984 54647 1059 1 75 105 57989 6257 1 11 12 106 6056 29602 63146 1 15 5 53 107 7912 14096 38483 247 440 108 53244 33489 5306 3 1204 757 109 90763 39895 104478 1042 458 110 14839 2268 7 66094 269 4 12 111 72249 33628 7019 1 1235 5 75 112 4074 7 2016 7 4430 1 1104 546 Mean 4298 11 240804 617099 7943 4960 SD 297641 131761 192359 4431 2 782 CV 6925 54 72 31 17 55 779 56 102 SE 85921 3972 7 555 29 1279 0839 Gmean 304731 2005 10 592669 6 170 4 080 Mean(ln) 802 760 8 69 1820 1 406 SO(ln) 098 069 029 0855 0 750 Mm 6056 5093 38483 1 15 069 Max 90763 44749 104478 1235 11 08 ' ETS/IV - AUC „, for E T S (ketorolac) vs AUC ., for IV injection s TTS/IV - AUC „, for TTS (ketorolac) vs AUC ., for IV injection TABLE 10B AUC and Amount Delivered (AD) Values for R-Ketorolac Concentration ETS (ketorolac) TTS (ketorolac) IV Injection Subject AUC ,., AUC ., AUC .„, ETS/IV • TTS/IV Number (ng h/mL) (ng h/mL) (ng h/mL) AD (mg) AD (mg) 102 32975 •44749 48450 8.17 11 08 104 4822 5 7984 54647 10.59 1 75 108 53244 3348 9 5306.3 12.04 757 109 9076 3 39895 104478 10.42 458 111 72249 3362 8 7019 1 12.35 5 75 112 4074 7 2016 7 4430 1 11.04 546 Mean 5636 72 2998 53 6252.16 10.769 6 034 SD 2145 94 1353 06 223634 1491 3 121 CV 38 07 45 29 3577 13845 51 724 SE 87607 55443 912.98 0 609 1274 Gmean 5318 15 2620 37 5978.08 10.675 5 260 Meant In) 8.58 787 8.70 2.368 1660 SD(ln) 037 0 64 031 0 148 0 620 Mm 32975 7984 4430 1 8.17 1 75 Max 9076.3 4474 9 104478 12.35 11 OS ' ETS/IV - AUC ,, for ETS (ketorolac) vs AUC ,. for IV injection ' πs/ιv - AUC ., for TTS (ketorolac) vs AUC ., for IV injection TABLE 11A AUC and Amount Delivered (AD) Values for S-Ketorolac Concentration (n-12) ETS (ketorol ac) TTS (ketorol ac) IV Injection Subject AUC „, AUC ,., AUC .., ETS/IV ' TTS/IV 5 Number (πg' h/mL) (ng h/mL) (ng- h/mL) AD (mg) AD (mg) 101 2445 4 2727.8 10.76 102 950 2 1419 2 1181.4 9.65 14 42 103 1049. 1 104 1644 1 433 6 1398 4 14.11 3 72 105 1669 7 1422.8 14.08 106 247 2 1527.9 1 94 107 890.5 108 1478 7 582 2 1348.6 13. 16 5 18 109 2755 5 962 8 2218.8 14 90 5 21 110 327.9 379 9 1823 9 2.16 2 50 111 2004 5 662.6 2283.8 10.53 3 48 112 1196.1 125.8 924.0 15.53 1 63 Mean 1608 00 601.67 1566.40 11.654 4 760 SD 744 81 419 61 582 99 4 124 4 126 CV 46.32 69 74 37.22 35.386 86 676 SE 248.27 148.35 168.30 1.375 1 459 Gmean 1398 26 477 45 1474 24 10 404 3 760 Meaπ( l n) 7 24 6 17 7 30 2.342 i 324 SD(l π) 0 64 0 77 0.36 0.614 0 689 Min 327 9 125 8 890 5 2 16 1 63 Max 2755.5 1419 2 2727 8 15.53 14 42 ' AUC eal cul abl e ' ETS/IV ■ - AUC „, for ETS (ketorol ac > vs AUC ., for IV injection = TTS/ IV - AUC ,-, for TTS (ketorol ac) vs AU .. for IV injection TABLE 11B AUC and Amount Delivered (AD) Values for S-Ketorolac Concentration (n-β) ETS (ketorolac) TTS (ketorolac) IV Injection Subject AUC .„, AUC ,„, AUC,., ETS/IV ' TTS/IV Number (ng-h/mL) (ng-h/mL) (ng-h/mL) AD (mg) AD ( g) 102 950.2 1419.2 1181.4 9.65 14.42 104 1644.1 433.6 1398.4 14.11 3.72 108 1478.7 582.2 1348.6 13.16 5.18 109 2755.5 962.8 2218.8 14.90 5.21 111 2004.5 662.6 2283.8 10.53 3.48 112 1196.1 125.8 924.0 15.53 1.63 Mean 1671.51 697.72 1559.15 12.981 5.607 SD 643.43 447.73 561.54 2.391 4.512 CV 38.49 64.17 36.02 18.420 80.479 SE 262.68 182.78 229.25 0.976 1.842 Gmean 1574.95 553.52 1478.16 12.786 4.494 Meaπ(ln) 7.36 6.32 7.30 2.548 1.503 SD(ln) 0.38 0.83 0.36 0.194 0.711 Min 950.2 125.8 924.0 9.65 1.63 Max 2755.5 1419.2 2283.8 15.53 14.42 ' ETS/IV • • AUC ... for ETS (ketorolac) vs AUC .„, for IV injection. s TTS/ IV > - AUC ... for TTS (ketorolac) vs AUC ,., for IV injection. TABLE 12 Pharmacokinetic Parameters Following Administration of IV injection Compartmental Analysis (n-12) R-Ketorolac S-Ketorolac Subject Volume Kl K2 K21 Volume Kl K2 K21 Number (L) (h 1 ) (h--) (h 1 ) (L) (h 1 ) (h l ) (h 1 ) 101 0.970 5.814 0.297 1.336 1.235 5.889 0.420 1.062 102 4.788 0.907 0.063 0.164 9.586 1.072 0.049 0.076 103 4.829 2.372 0.287 1.208 12.454 1.947 0.603 1.483 104 6.923 1.051 0.135 0.477 13.240 1.494 0.404 1.034 105 4.971 1.313 0.131. 0.493 9.379 1.655 0.388 0.803 106 5.850 1.627 0.177 0.879 14.862 0.847 0.159 0.284 107 7.116 0.676 0.049 0.108 7.172 5.415 0.769 2.769 108 4.775 1.043 0.182 0.424 7.083 2.734 0.671 1.688 109 5.156 0.570 0.067 0.225 10.448 0.678 0.043 0.096 110 7.943 0.673 0.045 0.179 14.778 0.785 0.025 0.098 111 4.995 1.468 0.202 0.856 10.623 0.713 0.067 0.123 112 6.729 0.950 0.161 0.408 13.162 1.996 0.643 1.535 Mean 5.4204 1.5386 0.1497 0.5630 10.3353 2.1020 0.3534 0.9210 SD 1.7791 1.4364 0.0860 0.4137 3.8860 1.7747 0.2771 0.8450 CV 32.8229 93.3557 57.4578 73.4884 37.5995 84.4298 78.4052 91.7490 SE 0.5136 0.4146 0.0248 0.1194 1.1218 0.5123 0.0800 0.2439 Max 7.943 5.814 0.297 1.336 14.862 5.889 0.769 2 . " 69 Min 0.970 0.570 0.045 9.108 1.235 0.678 0.025 , ι " " TABLE 13 Rate of Absorption Following Administration of ETS (ketorolac) Compartmental Analysis (n-12) R-Ketorolac S-Ketorolac Subject Ka Rate Ka Rate Number" (h l ) (μg/h) (h>) 0-g/h) 101 2.864 745.87 1.626 876.62 102 0.892 337.91 0.537 358.79 103 0.722 66.62 104 0.843 455.22 0.901 568.18 105 2.691 534.76 1.313 568.72 106 0.243 57.17 107 0.835 76.68 108 0.695 489.14 0.351 559.18 109 0.837 856.01 1.008 963.00 no 2.093 126.00 0.174 126.01 111 0.877 600.20 0.856 695.26 112 5.292 359.57 0.655 407.17 Mean 1.5737 392.096 0.8245 569.214 SD 1.4413 271.333 0.4583 258.002 CV 91.5881 69.201 55.5873 45.326 SE 0.4161 78.327 0.1528 86.001 Max 5.292 856.01 1.626 963.00 M 0.243 57.17 0.174 126.01 Subjects 103. 106 and 107: Ka not estimable for S-ketorolac. TABLE 14 Rate of Absorption Following Administration of TTS (ketorolac) Compartmental Analysis (n-9) R Ketorolac S Ketoroi ac Subject t (a τ lag Rate Ka τ ι.α Rate Number* (h ) (h) (yg/h) (h l ) (h) (μg/h) 101 0 842 156 11189 102 2 309 4 9 545 78 1865 5 0 637 72 103 0 361 7 2 17757 106 0 087 7 1 394 18 3 912 15 8 211 16 108 0 182 6 3 38833 0688 11 9 433 09 109 0 541 9 1 49071 1289 98 54109 110 0 570 7 3 27222 111 0 169 2 7 338 16 0 743 13 9 52890 112 0 449 10 2 28708 Mean 0 6122 7 83 333991 16995 1131 470 391 SD 0 6789 3 64 139561 13257 4 19 162 029 CV 110 8859 46 50 41 786 780049 37 06 34446 SE 0 2263 1 21 46520 05929 187 72461 Max 2 309 15 6 545 78 3 912 15 8 637 72 Min 0 087 2 7 HI 89 0688 5 0 211 16 a Subjects 101 103 and 112 Ka not estimable for S ketorolac Subjects 104 and 107 Ka not estimable for both R and S-ketorolac Subject 105 discontinued study before TTS treatment Subject 110 Concentrations of S ketorolac were observed only after patch removal

Claims: ι CLAIMS 2 3 1. A device for administering a drug via electrotransport to an individual, including a donor electrode suitable for application to the skin of 5 said individual, said donor electrode comprising a formulation of a drug as a 6 mixture of a preferred isomer and a less preferred isomer, a counter electrode suitable for application to the skin of said individual, and a source of electrical 8 power adapted to be electrically connected to the donor electrode and the 9 counter electrode, the device being characterized by at least one of: o a) the size of said donor electrode being less than that necessary to i provide therapeutically effective levels of the drug if the preferred and less 2 preferred isomers were delivered transdermally via electrotransport at the 3 same rate; 4 . b) the concentration of drug in the formulation being less than that s necessary to provide therapeutically effective levels of the drug if the 6 preferred and less preferred isomers were delivered transdermally via 7 electrotranport at the same rate; 8 c) current provided by the source of electrical power being less than 9 that necessary to provide therapeutically effective levels of the drug if the 0 preferred and less preferred isomers were delivered transdermally via 1 electrotransport at the same rate; and/or 2 d) the amount of the formulation applied is less than that necessary 3 to provide therapeutically effective levels of the drug if the preferred and less 4 preferred isomers were delivered transdermally via electrotransport at the 5 same rate. 6 7 2. The device of claim 1 , wherein the body surface is intact skin. 8 3. The device of claim 2, wherein the source of electrical power and the electrodes apply a current density of about 50 to 625 A/cm 2 . 4. The device of claim 3, wherein the source of electrical power and the electrodes apply a current density of about 100 A/cm 2 . 5. The device of claim 1 , wherein the formulation further comprises a permeation enhancer present in an amount effective to decrease the electrical resistance of the body surface to the drug and thereby enhance the rate of penetration of the drug therethrough during electrotransport drug delivery. 6. The device of claim 1 , wherein the drug is selected from the group consisting of acebutolol, acenocoumarol, albuterol/salbutamol, alprenolol, amosulolol, amoxicillin, ampicillin, Ansaid, astemizole, atenolol, baclofen, benazepril, benzyl glutamate, betaxolol, bethanecol, bisprolol, bopindolol, bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butaclamol, butoconazoie, butofilolol, calcitonin, camazepam, captopril, captopril, caraxolol, carvedilol, cefadroxil, cicloprofen, ciprofloxacin, corticosteroids, cromakalim, curteolol, cytrabine, deprenyl, dexfenfluramine, dihydroxythebaine, diltiazem, disopyramide, dobutamine, enalapril, ephedrine, estradiol, ethambutol, fenbuphen, fenfluramine, fenoprofen, fluorogesterone, fluoxetine, flurbiprofen, gonadorelin, hexobarbital, ibuprofen, imovane, indenolol, indoprofen, ketamine, ketodesogestrel/estrogen, ketoprofen, ketorolac, lisinopril, lorazepam, lovastatin, meclizine, mepindolol. metaproteranol, methadone, methyldopa, metipranolol, metoprolol, minoxiprofen, 3-hydroxy-N-methyl morphinan, nadolol, naproxen, nebivolol. nicardipine, nicotine, nilvadipine, nitanol, norfloxacin, norgestrel, ofloxacin, Orudis, oxaprotiline, oxpranolol, oxybutynin, perindopril, phenprocoumon, ι phenylpropanolamine, pindolol, pirprofen, polycloranphetamine, prilocaine, 2 progestinpropanolol, propoxyphene, sertraline, sotalol, steroids, suprofen, 3 tenormin, terbutaline, terfenadine, testosterone, thioridazine, timolol, 4 tocainide, toliprolol, toloxaton, tomoxetine, triamcinolone, verapamil, viloxazin, 5 warfarin, xibenolol, zacopride, and 1 ,4-dihydropyridine chiral compounds, and 6 pharmaceutically acceptable salts and esters thereof. 7 8 7. The device of claim 1 , wherein the drug is an antiinflammatory. 9 o 8. The device of claim 7, wherein the antiinflammatory is an NSAID. 1 2 9. The device of claim 8, wherein the drug is ketorolac or a 3 pharmacologically acceptable salt or ester thereof. 4 s 10. The device of claim 9, wherein the preferred enantiomer is the 6 S-isomer. 7 s 11. The device of claim 10, wherein the drug is ketorolac 9 tromethamine. 0 1 12. The device of claim 1 , wherein said less preferred isomer is 2 toxic. 3 4 3. The device of claim 1 , wherein said less preferred isomer is a 5 mutagen. 6 7 14. A method of making an electrotransport system, comprising: 8 (a) determining the relative fluxes of the isomers of a mixture of a 9 drug through a body surface; (b) determining the relative bioactivities of the isomers of the mixture of said drug; (c) selecting a preferred isomer based on the determined flux and relative bioactivity; and (d) constructing an electrotransport system wherein the size of a drug delivery electrode, the concentration of drug in a formulation contained in the drug delivery electrode, and the current to be used are calculated based on the determined flux and relative bioactivity of the preferred isomer. 15. Use of a drug as a mixture of a preferred isomer and a less preferred isomer in the manufacture of a composition useful for delivering the drug by electrotransport through a body surface, wherein said drug is present in said composition in a manner effective to enhance the transport of said preferred isomer relative to the transport of said less preferred isomer. 16. The use of claim 15, wherein the body surface is skin. 17. The use of claim 16, wherein the electrotransport is at a current density of about 50 to 625 A/cm 2 . 18. The use of claim 17, wherein the electrotransport is at a current density of about 100 μA/cm 2 . 19. The use of claim 15, wherein the formulation further comprises a permeation enhancer present in an amount effective to decrease the electrical resistance of the body surface to the drug and thereby enhance the rate of penetration of the drug therethrough during electrotransport drug delivery. ι 20. The use of claim 15, wherein the drug is selected from the 2 group consisting of acebutolol, acenocoumarol, albuterol/salbutamol, 3 alprenolol, amosulolol, amoxicillin, ampicillin, Ansaid, astemizole, atenolol, 4 baclofen, benazepril, benzyl glutamate, betaxolol, bethanecol, bisprolol, 5 bopindolol, bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butaclamol, e butoconazole, butofilolol, calcitonin, camazepam, captopril, captopril, 7 caraxolol, carvedilol, cefadroxil, cicloprofen, ciprofloxacin, corticosteroids, 8 cromakalim, curteolol, cytrabine, deprenyl, dexfenfluramine, 9 dihydroxythebaine, diltiazem, disopyramide, dobutamine, enalapril, o ephedrine, estradiol, ethambutol, fenbuphen, fenfluramine, fenoprofen, i fluorogesterone, fluoxetine, flurbiprofen, gonadorelin, hexobarbital, ibuprofen, 2 imovane, indenolol, indoprofen, ketamine, ketodesogestrel/estrogen, 3 ketoprofen, ketorolac, lisinopril, lorazepam, lovastatin, meclizine, mepindolol, 4 metaproteranol, methadone, methyldopa, metipranolol, metoprolol, s minoxiprofen, 3-hydroxy-N-methyl morphinan, nadolol, naproxen, nebivolol, 6 nicardipine, nicotine, nilvadipine, nitanol, norfloxacin, norgestrel, ofloxacin, 7 Orudis, oxaprotiline, oxpranolol, oxybutynin, perindopril, phenprocoumon, s phenylpropanolamine, pindolol, pirprofen, polycloranphetamine, prilocaine, 9 progestinpropanolol, propoxyphene, sertraiine, sotalol, steroids, suprofen, 0 tenormin, terbutaline, terfenadine, testosterone, thioridazine, timolol, 1 tocainide, toliprolol, toloxaton, tomoxetine, triamcinolone, verapamil, viloxazin, 2 warfarin, xibenolol, zacopride, and 1 ,4-dihydropyridine chiral compounds, and 3 pharmaceutically acceptable salts and esters thereof. 4 5 21. The use of claim 15, wherein the drug is an antiinflammatory. 6 7 22. The use of claim 21 , wherein the antiinflammatory is an NSAID. 8 23. The use of claim 22, wherein the drug is ketorolac or a pharmacologically acceptable salt or ester thereof. 24. The use of claim 23, wherein the preferred enantiomer is the S- isomer. 25. The use of claim 24, wherein the drug is ketorolac tromethamine. 26. The use of claim 15, wherein the current used during electrotransport is less than that necessary to provide therapeutically effective levels of the drug if the preferred and less preferred isomers were deliverable via electrotransport at the same rate. 27. The use of claim 15, wherein the amount of the formulation applied is less than that necessary to provide therapeutically effective levels of the drug if the preferred and less preferred isomers were deliverable via electrotransport at the same rate. 28. The use of claim 15, wherein the concentration of drug used in the formulation is less than that necessary to provide therapeutically effective levels of the drug if the preferred and less preferred isomers were deliverable via electrotransport at the same rate. 29. The use of claim 15, wherein the formulation is provided in the form of a patch of a size less than that necessary to provide therapeutically effective levels of the drug if the preferred and less preferred isomers were deliverable via electrotransport at the same rate.

Inventors: GUPTA SUNEEL K, PADMANABHAN RAMA, SATHYAN GAYATRI, GUPTA, SUNEEL, K., PADMANABHAN, RAMA, SATHYAN, GAYATRI
Applicants: ALZA CORP, ALZA CORPORATION
Application year: 1998
Main classification: A61N1
IPC codes: A61K9, A61N1