Pharmaceutical Research, Vol. 5, No. 7, 1988
`
`Report
`
`Percutaneous Absorption of Nicardipine and Ketorolac in
`Rhesus Monkeys
`
`Diana Yu, 1·3 Lynda M. Sanders, 1 George W. R. Davidson 111, 1 Martha J. Marvin, 1 and
`Teck Ling2
`
`Received October 2, 1987; accepted February 10, 1988
`
`Vehicle effects on the percutaneous absorption of nicardipine base, nicardipine hydrochloride, keto(cid:173)
`rolac acid, and ketorolac tromethamine were determined using the rhesus monkey as an in vivo model
`for human skin penetration. Vehicles investigated included blends of propylene glycol, trimethylene
`glycol, ethanol, Azone, Tween 20, water, and long-chain fatty acids. Formulations were prepared such
`that the compound dose, application area, and percentage saturation of the compound in the vehicle
`were held constant. Variations in absorption of the compounds were therefore attributable to vehicle
`effects. Each formulation was applied to three monkeys for a period of 24 hr using 10 Hill Top
`Chambers. Plasma samples were taken at appropriate intervals for 36 to 48 hr. The results indicated
`that trimethylene glycol and Tween 20 did not enhance absorption of the test compounds despite
`claims by other investigators. Azone and ethanol provided moderate enhancement of both the rate
`and the extent of absorption, while long-chain fatty acids in combination with propylene glycol signifi(cid:173)
`cantly enhanced penetration. In general, higher fluxes were observed with the more lipophilic com(cid:173)
`pounds nicardipine base and ketorolac acid as compared to the hydrochloride and tromethamine salts.
`KEY WORDS: percutaneous absorption; nicardipine; ketorolac; penetration enhancers; vehicle ef(cid:173)
`fects.
`
`INTRODUCTION
`
`sumed that all solutions are ideal:
`
`An analogy has often been made between the percuta(cid:173)
`neous absorption of drug compounds and solute diffusion
`through a membrane (1-6). The complexities of human skin
`are generally ignored and the stratum corneum is considered
`to be the rate-limiting membrane through which the solute
`must penetrate. Based on irreversible thermodynamics, the
`steady-state flux, or diffusion rate per unit area, of a solute
`through a membrane may be generally expressed as
`
`J = -L !!:.._ (!!_) = -L RT !!:.._ (~)
`dxT
`adxT
`
`(l)
`
`where J is the flux, Lis the Onsager phenomenological coef(cid:173)
`ficient for diffusion, u is the chemical potential of the solute,
`Tis the temperature, a is the thermodynamic activity of the
`solute, and R is the ideal gas constant (7 ,8). At a constant
`temperature, therefore, the driving force behind the diffu(cid:173)
`sional process is the thermodynamic activity gradient across
`the membrane, da/dx. Equation (1) simplifies to the well(cid:173)
`known Fick's first law of diffusion only when it is also as-
`
`1 Institute of Pharmaceutical Sciences, Syntex Research, 3401 Hill(cid:173)
`view Avenue, Palo Alto, California 94304.
`2 Bioanalytical and Metabolic Research, Syntex Research, Palo
`Alto, California 94304.
`3 To whom correspondence should be addressed.
`
`LR da
`1= - (cid:173)
`a dx
`
`de
`-D(cid:173)
`dx
`
`(2)
`
`where c it the concentration of the solute and D is the diffu(cid:173)
`sion coefficient of the soiute. This assumption of ideality has
`often been ignored in discussions on membrane perme(cid:173)
`ability, resulting in undue importance being placed on the
`concentration gradient.
`The concept of activity gradient-driven diffusion be(cid:173)
`comes especially important when considering vehicle effects
`on percutaneous absorption. Since the thermodynamic ac(cid:173)
`tivity of a solute is maximized at the solubility limit, the ac(cid:173)
`tivity gradient and, therefore, the diffusional flux may be
`maximized by using a saturated donor phase. Absorption
`enhancement due to vehicle effects, therefore, becomes ap(cid:173)
`parent when nonidentical fluxes are obtained with different
`vehicles at a constant thermodynamic activity (not a con(cid:173)
`stant concentration) (9).
`In this study, vehicle effects on the percutaneous ab(cid:173)
`sorption of drug compounds were determined using the
`rhesus monkey as a model for human skin penetration.
`Studies have indicated that the rhesus monkey is a good an(cid:173)
`imal model for this purpose (10). Nicardipine (free base),
`nicardipine hydrochloride, ketotolac (free acid), and keto(cid:173)
`rolac tromethamine were selected as test drug compounds
`(see Fig. 1).
`Several vehicle solvents were selected based on poten-
`
`457
`
`0724-8741/8810700-0457$06.00/0 © 1988 Plenum Publishing Corporation
`
`CRTXCAR0007030
`
`EKR Therapeutics, LLC Exhibit 2018 Page 1
`
`

`

`458
`
`Yu, Sanders, Davidson, Marvin, and Ling
`
`SNO,
`~ CH, ©
`
`CH,OOC
`
`H,C
`
`,.....CH3
`COOCH,CH,N 'CH,
`
`@NO,
`
`•HCI
`
`CH,OOCOCOOCH,CH,N;::~~:
`
`H,C ~ CH, ©
`
`(A)
`
`(B)
`
`r61 n
`"V'rrr
`
`0
`
`COOH
`
`(C)
`
`(D)
`
`Fig. 1. Drug compounds used in this study: (A) nicardipine; (B)
`nicardipine hydrochloride; (C) ketorolac; (D) ketorolac trometh(cid:173)
`amine.
`
`tial absorption enhancement. In particular, propylene glycol
`has been reported to enhance percutaneous absorption in
`some cases (ll). Trimethylene glycol has been claimed as a
`skin penetration enhancer for nifedipine and nicardipine
`(12). Ethanol has been shown to increase the skin perme(cid:173)
`ation rate of estradiol (13). Cooper has published results in(cid:173)
`dicating that blends of polar solvents, such as propylene
`glycol, and long-chain fatty acids, such as linoleic and oleic
`acids, increase the permeability of lipophilic compounds
`(14). Azone (1-dodecylazacycloheptan-2-one) is claimed to
`be a penetration enhancer and several investigators have re(cid:173)
`ported skin penetration enhancement in the presence of sur(cid:173)
`factants (11,15-17). Vehicles composed of a combination of
`two or three of these solvents were chosen for use in this
`study.
`
`MATERIALS AND METHODS
`
`Materials. Nicardipine, nicardipine hydrochloride, ke(cid:173)
`torolac, and ketorolac tromethamine were provided by
`Syntex Corporation (Palo Alto, Calif.). Propylene glycol,
`USP (PG) (Syntex Corporation, Palo Alto, Calif.), trimethy(cid:173)
`lene glycol (TMG) (1,3-propanediol; Eastman Kodak Co.,
`Rochester, N.Y.), linoleic acid (LA) (Sigma Chemical Co.,
`St. Louis, Mo.), oleic acid, NF-FCC (OA) (J. T. Baker
`Chemical Co., Phillipsburg, N.J.), Azone (AZ) (Nelson Re(cid:173)
`search and Development, Irvine Calif.), Tween 20 (TW) (ICI
`Americas, Inc., Wilmington, Del.), and alcohol, USP (95%
`ethanol) (E) (190-proof alcohol, USP; U.S. Industrial Chem(cid:173)
`icals), were used as obtained. Twice deionized water (W)
`was used in some vehicles. Hill Top Chambers (HTCs) (18)
`were used as received from Hill Top Research.
`Solubility Studies. Although the skin temperature of
`rhesus monkeys is higher, solubility studies were carried out
`at 25°C. In assuming maximum thermodynamic activity,
`therefore, the temperature coefficient of solubility for each
`compound was also assumed to be identical in each of the
`vehicles. The solubilities of nicardipine and nicardipine hy(cid:173)
`drochloride in PG/W, TMG/W, PG/LA, PG/W/AZ, PG/LA/
`W, and E/W were determined in triplicate by placing excess
`compound with each vehicle blend in a screw-capped vial.
`The vials were then rotated for 3 days in a 25°C water bath.
`Upon removal, the suspensions were filtered through 0.45-
`
`1-1m membrane filters, diluted in mobile phase, and assayed
`for drug content by high-performance liquid chromatog(cid:173)
`raphy (HPLC). The solubilities of ketorolac and ketorolac
`tromethamine in PG/W, PG/LA, PG/OA, PG/W/TW, and
`E/W were also determined.
`Percutaneous Absorption Studies. Formulations were
`chosen based on the results of the solubility studies. A 10-ml
`solution of each formulation was prepared, the appropriate
`volume of which was then loaded into each HTC using a
`1000-fLl glass syringe fitted with an 18-gauge needle.
`For each formulation, three female rhesus monkeys
`(Macaca mulatta) weighing 6 to 9 kg were used. Chest hair
`was clipped closely rather than shaved in order to ensure
`that the stratum corneum remained intact. Prior to dosing,
`the animals were lightly anesthetized with 5 to 8 mg/kg keta(cid:173)
`mine. Each formulation was then applied over a total chest
`area of 27 cm2 using 10 HTCs per monkey held in place by a
`single strip of adhesive tape. Three-milliliter blood samples
`were taken from the saphenous vein prior to dosing and at
`appropriate intervals over a period of 36 to 48 hr. The
`monkeys were restrained in metabolism chairs during the 24
`hr application period. Following HTC removal, the applica(cid:173)
`tion site was washed with soap and water. Plasma levels of
`compound were determined by HPLC (ketorolac and keto(cid:173)
`rolac tromethamine) (19) or a capillary column gas chro(cid:173)
`matographic (GC) method with electron capture detection
`(nicardipine and nicardipine hydrochloride) (20).
`Compound Remaining Assay. Following removal of the
`HTCs from each monkey, the cotton swatches from 5 of the
`10 HTCs were removed, placed in a 50-ml beaker with 30 ml
`of acetonitrile, methanol, or alcohol, U.S.P., and sonicated
`for 15 min. The extract was then filtered through a 0.45-fLm
`membrane filter into a 100-ml volumetric flask. After two
`additional rinses, the extract solution was made to volume,
`diluted in mobile phase, and assayed for drug content by
`HPLC.
`HPLC Analytical Methods. For nicardipine and nicar(cid:173)
`dipine hydrochloride, the retention time was 7.8 min using
`50:50 CH,CN:0.05 M KH2P04 at 1.0 ml/min through a
`Whatman -Partisil 5 ODS-3 column. Detection was by UV
`absorption at 237 nm. For ketorolac and ketorolac trometh(cid:173)
`amine, the retention time was 6.4 min using 40:60:0.2
`CH3CH:H20:CH3 COOH at 1.3 ml/min through an ASI-C8
`(10 1-1m) column. Detection was by UV absorption at 254
`nm.
`
`RESULTS AND DISCUSSION
`Solubility Studies. Since the development of therapeuti(cid:173)
`cally effective formulations was the ultimate goal, an appro(cid:173)
`priate compound dose, d, was selected for each compound.
`Both the area of application and the allowable donor phase
`volume range, v, were fixed based on the use of 10 HTCs for
`formulation application. Therefore, in order to maintain a
`constant percentage saturation, f, in the vehicle, a solubility
`limit, s, falling within a specified range of values was re(cid:173)
`quired:
`
`(3)
`
`CRTXCAR0007031
`
`EKR Therapeutics, LLC Exhibit 2018 Page 2
`
`

`

`Percutaneous Absorption of Nicardipine and Ketorolac,
`
`459
`
`Table I. Doses and Target Solubility Ranges
`
`" A
`
`Compound
`
`Nicardipine
`Nicardipine
`hydrochloride
`Ketorolac
`Ketorolac
`tromethamine
`
`Dose
`(mg)
`
`Desired%
`saturation
`
`93
`
`100
`60
`
`85
`
`90
`
`90
`95
`
`95
`
`Solubility
`range
`(mg/ml)•
`
`29.5-207
`
`31.8-222
`18.0-126
`
`25.6-179
`
`Preferred
`solubility
`(mglml)b
`
`34.4
`
`37.0
`21.0
`
`29.8
`
`• Based on Eq. (3).
`b Based on Eq. (3); v = 3.0 ml is optimal based on HTC design.
`
`where v = 0.5 to 3.5 ml. For example, for nicardipine base,
`the desired dose, d, was 93 mg. With v = 0.5 to 3.5 ml and/
`= 0.90, solubilities ranging from 29.5 to 207 mg/ml were re(cid:173)
`quired. Doses and target solubility ranges for these com(cid:173)
`pounds are shown in Table I. Solutions rather than suspen(cid:173)
`sions were used in order to avoid the possibility of solid drug
`dissolution being the rate-limiting step in absorption of the
`compounds.
`
`A
`
`~ 400
`,£ 350
`
`J
`
`,._+-+-+-~~~~~~~~~~~~~~~~
`o
`s
`ss
`so
`ss
`eo
`es go
`gs
`too
`
`50
`
`10
`
`7'5
`
`10
`
`1~
`
`20
`
`i!S
`
`30
`
`35
`
`.o~o
`
`.o~s
`
`% Propylene Glycol
`or % Ethanol
`(E)
`
`(PG)
`
`8
`
`(PG)
`% Propylene Glycol
`or % Trimethylene Glycol
`(TMG)
`Fig. 2. (A) The solubility of nicardipine at 25°C in blends of
`(0) PG/W, (D) PO/LA, and (L) E/W. (B) The solubility of ni(cid:173)
`cardipine hydrochloride at 25oc in blends of (0) PG/W, (D)
`TMG/W, and (6) PO/LA.
`
`91: Propylene Glycol
`or % Ethane 1
`(E)
`
`(PG)
`
`B
`
`-
`
`5!50
`
`E ci, 500
`.§ 4!50
`
`';:! 350
`n
`
`E 400
`~ ::
`
`% Propylene Glycol
`(PG)
`Fig. 3. (A) The solubility of ketorolac at 25°C in blends of (0)
`PG/W, (D) PO/LA, (L) PG/OA, and (\7) E/W. (B) The solu(cid:173)
`bility ofketorolac tromethamine at 25oC in blends of(O) PG/W,
`(D) PO/LA, and (6) PG/OA.
`
`Table II. Vehicle Blends Chosen for Percutaneous Absorption
`Testing in Rhesus Monkeys
`
`Vehicle composition
`
`Compound
`
`Solvents
`
`% (w/w)
`
`Solubility (SD)
`(mg/ml)
`
`Nicardipine
`
`Nicardipine
`hydrochloride
`
`Ketorolac
`
`Ketorolac
`tromethamine
`
`PG/W
`PO/LA
`PG/LA/W
`PG/W/AZ
`E/W•
`
`PG/W
`TMG/W
`PG/W
`PO/LA
`PG/OA
`PG/W/TW
`E/W•
`
`PO/LA
`PGIOA
`
`97/3
`93/7
`9017/3
`8713/10
`56/44
`
`56144
`61/39
`77/23
`16/84
`32168
`7312215
`63137
`
`7193
`8/92
`
`29.0 (0.7)
`(1.6)
`113
`99.2 (4.3)
`87.3 (4.4)
`45.0 (0.7)
`
`33.0 (0.1)
`34.0 (0.2)
`2l.Oh
`2l.Oh
`2l.Oh
`18.4 (0.2)
`2l.Ob
`
`29.8h
`29.8b
`
`• Gelled with 1.5% hydroxypropyl cellulose (Klucel, HF; Hercules,
`Inc., Wilmington, Del.).
`b Interpolated solubility value.
`
`CRTXCAR0007032
`
`EKR Therapeutics, LLC Exhibit 2018 Page 3
`
`

`

`460
`
`201
`
`~ 16
`
`!:J
`
`~ 101
`+'u~o
`I 'T
`~
`
`I
`
`(L
`
`'
`
`11me
`(hours)
`Fig. 4. Plasma levels of nicardipine and nicardipine hydrochloride
`following transdermal administration of nicardipine in (0) PG/W,
`(D) PG/LA, (Li) PG/LA, (Li) PG/LA/W (N = 2), ('V) PG/W/AZ (N
`= 2), and (e) E/W and nicardipine hydrochloride in <•l PG/W, and
`(&) TMG/W.
`
`Figures 2 and 3 show solubility profiles for nicardipine
`in PG/W, PG/LA, and E/W blends, nicardipine hydrochlo(cid:173)
`ride in PG/W, TMG/W, and PG/LA blends, ketorolac in
`PG/W, PG/LA, PG/OA, and E/W blends, and ketorolac tro(cid:173)
`methamine in PG/W, PG/LA, and PG/OA blends. These data
`did not correlate well with various theories predicting solu(cid:173)
`bility in mixed solvent systems, including the regular solu(cid:173)
`tion theory and the extended Hildebrand solubility approach
`(21-23). Based on the results of the solubility studies, ve(cid:173)
`hicle blends for formulations were chosen for percutaneous
`absorption testing (see Table II).
`Nicardipine Absorption Studies. The percutaneous ab(cid:173)
`sorption of nicardipine and nicardipine hydrochloride for(cid:173)
`mulations at 90% saturation was tested in rhesus monkeys.
`The results are shown in Fig. 4.
`Both formulations of nicardipine hydrochloride gave
`much lower plasma levels than all of the formulations of ni(cid:173)
`cardipine, indicating that the more lipophilic free base pene(cid:173)
`trates the skin much more readily than the hydrochloride
`salt. Plasma levels obtained from the TMG/W formulation of
`
`Yu, Sanders, Davidson, Marvin, and Ling
`
`nicardipine hydrochloride were comparable to plasma levels
`obtained from the PG/W formulation, indicating that tri(cid:173)
`methylene glycol did not provide greater absorption en(cid:173)
`hancement compared with propylene glycol.
`Plasma levels obtained from the PG/W formulation of
`the more lipophilic free base were roughly five times higher
`than plasma levels obtained from the PG/W formulation of
`the hydrochloride salt. With the PG/W formulation con(cid:173)
`taining nicardipine, steady-state plasma levels had not been
`achieved by the time the HTCs were removed at 24 hr. In
`comparison, plasma concentrations obtained from the
`PG/LA, PG/W/AZ, and E/W formulations containing nicar(cid:173)
`dipine achieved steady state after 6 hr. Linoleic acid, Azone,
`and ethanol, therefore, enhanced the initial rate of nicardi(cid:173)
`pine absorption into the systemic circulation. In decreasing
`order of enhancement, LA > AZ > E. The PG/LA/W for(cid:173)
`mulation of nicardipine provided a plasma concentration
`profile with characteristics associated with both linoleic acid
`(initial absorption rate enhancement) and the PG/W combi(cid:173)
`nation (gradual increase in plasma levels for 24 hr).
`Assay results for the amount of compound remaining in
`the HTCs following percutaneous absorption studies are
`shown in Table III. The absolute bioavailability relative to
`an intravenous dose of nicardipine hydrochloride is also
`shown in Table III. The systemic availability of nicardipine
`and nicardipine hydrochloride from all of the formulations
`tested was low despite depletion of the HTCs of up to 57.5%
`of the loading dose. The highest absolute bioavailability ob(cid:173)
`tained was from the PG/LA/W formulation of nicardipine
`(0.77% bioavailability).
`Ketorolac Absorption Studies. The percutaneous ab(cid:173)
`sorption of ketorolac and ketorolac tromethamine in formu(cid:173)
`lations at 95% saturation was tested in rhesus monkeys. The
`results are shown in Fig. 5. The PG/W, PG/W/TW, and E/W
`formulations containing ketorolac gave low plasma levels.
`Therefore, Tween 20 and ethanol did not provide greater
`enhancement of ketorolac penetration through the stratum
`corneum as compared to propylene glycol. The plasma level
`profile obtained from the PG/W formulation of ketorolac
`parallelled the plasma level profile obtained from the PG/W
`formulation of nicardipine, with plasma levels rising gradu(cid:173)
`ally throughout the 24-h period.
`Plasma levels obtained from the PG/LA and PG/OA for(cid:173)
`mulations of both ketorolac and ketorolac tromethamine
`
`Table III. Absorption of 93 mg Nicardipine or 100 mg Nicardipine Hydrochloride Following 24-hr Transdermal Application in
`Rhesus Monkeys
`
`Compound
`
`Nicardipine
`
`Nicardipine
`hydrochloride
`
`Vehicle
`
`PG/W
`PG/LA
`PG/LNW
`PG/W/AZ
`E/W
`
`PG/W
`TMG/W
`
`Cmax (SD)
`(ng/ml)
`
`10.7 (0.40)
`9.33 (0.75)
`13.4 (0.42)
`6.55 (1.6)
`4.77 (2.6)
`
`1.90 (2.4)
`2.33 (0.23)
`
`AUC (SD)
`(ng-hr/m!)•
`
`(35)
`189
`(30)
`233
`(16)
`272
`(25)
`128
`90.8 (40)
`
`31.6 (46)
`44.2 (13)
`
`Bioavailability
`(SD)h
`
`%remaining
`(SD)
`
`NDC
`ND
`0.77 (0.05)
`0.37 (0.07)
`0.26 (0.11)
`
`ND
`ND
`
`42.5 (2.9)
`79.4 (7.7)
`50.4 (2.2)
`49.8 (3.0)
`94.6 (2.1)
`
`88.2 (4.4)
`(2.3)
`104
`
`a AVC values are approximate given the 14- to 18-hr interval between later time points.
`b Bioavailability determined relative to i.v. bolus dosing.
`c Not determined.
`
`CRTXCAR0007033
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`EKR Therapeutics, LLC Exhibit 2018 Page 4
`
`

`

`Percutaneous Absorption of Nicardipine and Ketorolac,
`
`461
`
`:;;;; 6500
`
`t 6000
`
`c
`;: 5000
`
`~ 4500 s 4000
`
`~ 3500
`u 3000
`ro
`~ 2500
`
`~ 2000
`()._
`
`~ 30
`
`~ "
`
`! ::
`
`Tcmt:
`
`(nour·s]
`
`Fig. 5. Plasma levels of ketorolac and ketorolac tromethamine fol(cid:173)
`lowing transdermal administration of ketorolac in (0) PG/W, (0)
`PG/LA, (L) PG/OA, ('v) PG/W/TW, and (e) E/W and ketorolac tro(cid:173)
`methamine in (.) PG/LA and (.&) PG/OA.
`
`were significantly higher. Both linoleic acid and oleic acid,
`in combination with propylene glycol, enhanced the pene(cid:173)
`tration of both the free acid and the more hydrophilic tro(cid:173)
`methamine salt. The results of this study were consistent
`with the results obtained by Cooper (14). Enhancement ob(cid:173)
`tained by using a blend of propylene glycol and a long-chain
`fatty acid was inversely proportional to the degree of satura(cid:173)
`tion of the fatty acid hydrocarbon chain.
`Assay results for the amount of compound remaining in
`the HTCs following percutaneous absorption studies are
`shown in Thble IV. The absolute bioavailabilities of keto(cid:173)
`rolac and ketorolac tromethamine relative to an intravenous
`dose of ketorolac tromethamine are also shown in Table IV.
`The highest absolute bioavailability was achieved with the
`PG/LA formulations of both ketorolac and ketorolac tro(cid:173)
`methamine (35% bioavailability). The assay results for com(cid:173)
`pound remaining in the HTCs correlated well with the bio(cid:173)
`availability results, with the bioavailability inversely pro(cid:173)
`portional to the percentage dose remaining (see Fig. 6).
`Enhancement Effect of Vehicle Components. In sum-
`
`% Dose RE!m~ining
`
`Fig. 6. Correlation between absolute bioavailability of keto(cid:173)
`rolac (0) and ketorolac tromethamine (D) administered using
`Hill Top Chambers and percentage dose remaining in the Hill
`Top Chambers after 24 hr.
`
`mary, the choice of vehicle significantly affected the percu(cid:173)
`taneous absorption of nicardipine, nicardipine hydrochlo(cid:173)
`ride, ketorolac, and ketorolac tromethamine in the rhesus
`monkey. Formulations of compound in PG/W and TMG/W
`blends gave plasma levels of compound characterized by a
`gradual rise in plasma concentrations over 24 hr. Both tri(cid:173)
`methylene glycol and the nonionic surfactant Tween 20 had
`no additional enhancement effect. Azone and ethanol were
`both found to enhance plasma levels of nicardipine as well
`as to increase the initial flux of compound into the systemic
`circulation. Ethanol, however, did not enhance percuta(cid:173)
`neous absorption of ketorolac, indicating that absorption en(cid:173)
`hancement provided by ethanol varies by compound. For(cid:173)
`mulations containing oleic or linoleic acids, in combination
`with propylene glycol, were found to enhance compound
`plasma levels, with an increase in the initial flux of com(cid:173)
`pound into the systemic circulation as well.
`In general, higher fluxes \1/ere observed with the more
`lipophilic compounds nicardipine and ketorolac. The PG/LA
`ketorolac formulation and the PG/LA/W nicardipine formu(cid:173)
`lation provided the highest absolute bioavailability for these
`compounds.
`
`Table IV. Absorption of 60 mg Ketorolac or 85 mg Ketorolac Tromethamine Following 24-hr Transdermal Application in Rhesus Monkeys
`
`Compound
`
`Ketorolac
`
`Ketorolac
`tromethamine
`
`Vehicle
`
`PG/W
`PG/LA
`PG/OA
`PG/W/TW
`E/W
`
`PGILA
`PG/OA
`
`Cmax (SD)
`(f.l-g/ml)
`
`0.270 (0.17)
`(1.0)
`7.94
`(1.2)
`4.24
`0.239 (0.14)
`0.0617 (0.032)
`
`5.42
`2.47
`
`(0.59)
`(0.46)
`
`AUC (SD)
`(f.l-g-hr/mJ)a
`
`4.57 (1.7)
`(23)
`126
`69.2 (6.7)
`3.87 (1.9)
`1.11 (0.28)
`
`(6.4)
`121
`62.9 (2.4)
`
`Bioavailability
`(SD)b
`
`%remaining
`(SD)
`
`1.2 (0.4)
`(5)
`35
`18
`(I)
`ND<
`0.3 (0.1)
`
`35
`16
`
`(I)
`(I)
`
`99.4 (3.0)
`14.9 (1.9)
`32.2 (4.6)
`94.5 (9.2)
`(3.2)
`114
`
`17.6 (6.3)
`56.7 (7.4)
`
`a AVC values are approximate given the 16-hr interval between later time points.
`b Bioavailability determined relative to i.v. bolus dosing.
`c Not determined.
`
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