Drug Delivery

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Development and Evaluation of Nasal

Formulations of Ketorolac

Muhammad Quadir, Hossein Zia, Thomas E. Needham

To cite this article: Muhammad Quadir, Hossein Zia, Thomas E. Needham (2000) Development
and Evaluation of Nasal Formulations of Ketorolac, Drug Delivery, 7:4, 223-229, DOI:
10.1080/107175400455155

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Drug Delivery, 7:223 – 229, 2000
Copyright ° c 2000 Taylor & Francis
1071-7544 /00 $12.00 + .00
Development and Evaluation of Nasal Formulations
of Ketorolac
Muhammad Quadir, Hossein Zia, and Thomas E. Needham
Department of Pharmaceutics, College of Pharmacy, University of Rhode Island, Kingston,
Rhode Island, USA
Ketorolac tromethamine is a potent non-narcotic analgesic with
moderate anti-in ammatory activity. Clinical studies indicate that
ketorolac has a single dose efŽ cacy greater than morphine for post-
operative pain and has excellent applicability in the emergency
treatment of pain. Due to incomplete oral absorption of ketoro-
lac, several approaches have been tried to develop a nonoral for-
mulation in addition to injections, especially for the treatment of
migraine headache. The aim of our study was to develop a nasal
formulation of ketorolac with a dose equivalent to the oral formu-
lation. A series of spray and lyophilized powder formulations of
ketorolac were administered into the nasal cavity of rabbits, and
their pharmacokinetics proŽ les were assessed. The spray and pow-
der formulations were compared through their pharmacokinetics
parameters and absolute bioavailability. Drug plasma concentra-
tion was determined using solid phase extraction, followed by an
HPLC analysis. Nasal spray formulations were signiŽ cantly better
absorbed than powder formulations. A nasal spray formulation
of ketorolac tromethamine showed the highest absorption with an
absolute bioavailability of 91%. Within 30 min of administration,
the plasma concentration was comparable to that resulting from
an intravenous injection. The absolute bioavailability of a solution
of ketorolac acid was 70%. Apparently, the dissolution of ketoro-
lac acid into the mucous layer limits its absorption. There were
no signiŽ cant differences in absorption between different powder
formulations. Even the reduction of particle size from 123 µ m to
63 µ m did not indicate better absorption of ketorolac tromethamine
from powder formulations. Interestingly, the absolute bioavailabil-
ity of ketorolac tromethamine from a powder formulation is only
38%, indicating that the drug may not be totally released from
the polymer matrix before it is removed from nasal epithelium by
mucociliary clearance.
Keywords Bioadhesive Polymer, Ketorolac Acid, Ketorolac Tro-
methamine, Microcrystalline Cellulose, Nasal Powder,
Nasal Spray
Received 7 February 2000; accepted 11 March 2000.
Address correspondence to Hossein Zia, Department of Pharma-
ceutics, College of Pharmacy, University of Rhode Island, Kingston,
RI 02881, USA.
223
Nasal drug formulations for local application are widely used
as over-the-counter products for such frequently occurring dis-
eases as the common cold and hayfever. However, over the past
two decades, using the nasal route as an alternative to parenteral
injections has been explored. In fact, there is an increased
number of nasally administered dosage forms for systemic ap-
plication currently in market. The nasal route is advantageous
because of the rapid absorption of drug molecules across the
nasal membrane and the relative ease of administration. Many
small molecules like dihydroergotamine, metoclopramide, bu-
torphanol tartrate, and sumatriptan succinate, as well as larger
molecules such as vitamin B12 , vasopressin, and calcitonin, have
been successfully delivered intranasally.
Limitations of the nasal drug delivery include possible local
tissue irritation, rapid removal of the therapeutic agent from the
site of absorption, and pathologic conditions such as cold or al-
lergies that may alter signiŽ cantly the nasal bioavailability of
drugs. To overcome the rapid removal of the drugs from site of
absorption, the addition of bioadhesive materials has been in-
vestigated. By adding these materials to the drug in solution or
powder preparations, drug absorption has been increased by ex-
tending the residence time in the nasal cavity (Harris et al. 1989;
Nagai et al. 1984). Increased intranasal absorption of insulin was
reported when insulin was mixed with a microcrystalline cellu-
lose (MCC) (Dondeti et al. 1995), and even greater absorption
was achieved when freeze-dried insulin was mixed with car-
bopol 934P powder (Nagai et al. 1984). It has been postulated
that mucoadhesive polymers provide a relatively short-term ad-
hesion between the drug and mucus and/or the epithelial cell
surface (Peppas and Buri 1985; Park and Robinson 1984).
In developing a new nasal formulation, using a proper ani-
mal model, a suitable dosage form, an effective delivery device,
and mode of application are important factors in evaluation of
drug absorption and efŽ cacy. Spray formulations are preferred
for nasal delivery and successfully deliver numerous therapeutic
agents. Solutions administered using spray pumps or pressurized
meter-dose inhalers that deposit mainly in the anterior portion of
224 M. QUADIR ET AL.
the nasal cavity. Since this region is largely nonciliated, clear-
ance is relatively slow when compared with the formulations
deposited in the ciliated region (Aoki and Crawley 1976; Bond
et al. 1984; Hardy et al. 1985; Newman et al. 1987). Further-
more, a spray device can deposit precisely measured doses into
the nostrils and allow delivery to the required site in the desired
volume and concentration. Nasal powder formulations may pro-
vide several advantages over liquid formulation. For example,
the chemical stability of a drug is increased in powders; the mi-
crobiologic stability of powders is higher; preservatives may not
be required; and larger amounts of the drug and excipients can be
administered with a nasal powder formulation (Lee et al. 1991).
Our project involves the development of a nasal formula-
tion of ketorolac for the treatment of postoperative pain and mi-
graine headache. Several recent studies have examined the use of
ketorolac in the emergency treatment of migraine headache
(Buckley and Brogden 1990; Larkin and Prescott 1992; Davis
et al. 1993; DeAndrade and Maslanka 1994). Migraine treatment
by administering drugs via the oral route is, at best, incomplete,
abortive, and somewhat ineffective. This is mainly due to the
dysfunction and atony of the gastrointestinal tract, the dilation
of the stomach, and the closure of the pyloric sphincter during a
migraine attack. However, the need for repeated injections due
to the rapid metabolism of ketorolac (half-life 4 – 5 hr) makes
this mode of delivery inconvenient in many situations. Thus,
a strong need exists for alternative modes of ketorolac deliv-
ery that do not have gastrointestinal side effects and may be
more convenient than injection. The principal objective of our
study was to develop an effective nasal formulation of ketoro-
lac tromethamine that exhibited enhanced bioavailability. Since
lipophilicity is one of the rate-determining factors for improved
transport through the nasal epithelium (McMartin et al. 1987),
nasal formulations of ketorolac acid also were investigated. The
liquid and powder formulations were compared by determining
their pharmacokinetic parameters and absolute bioavailability
after administration into the nasal cavity of rabbits.
MATERIALS
Ketorolac tromethamine was obtained as a gift from Lem-
mon Pharmaceuticals, PA. Polysorbate 80 was obtained from
Ruger (Irvington, NJ). Phenylethlyl alcohol, butylated hydroxy
anisole, dextrose and tolmetin sodium were purchased from
Sigma Chemical (St. Louis, MO). FMC Corp. (Newark, DE)
supplied microcrystalline cellulose as a sample. Ketamine HCl
and Xylazine HCl were purchased from Fort Dodge Laborato-
ries (Fort Dodge, Iowa); acepromazine maleate was obtained
from Aveco Co. (New York, NY); heparin was purchased from
Elkins-Sinn (Cherry Hill, NJ); Sep-Pak Light C18 cartridges
were purchased from Waters (Milford, MA); plasma separa-
tors were obtained from Becton Dickinson (Rutherford, NJ);
and normal saline, syringes, and needles were purchased from
Central Pharmacy (Cranston, RI). All other regents were of
analytical grade.
Valois of America (Greenwich, CT) generously supplied the
nasal spray pumps. Nasal insuf ators were kindly provided by
Miat (Milan, Italy); gelatin capsules No. 3 were supplied by Eli
Lilly (Indianapolis, IN).
METHODS
Intravenous Injection
For intravenous injection, a solution of 10 mg/ml ketorolac
tromethamine in normal saline was prepared. The administered
dose was 2 mg/kg body weight of rabbit.
Spray Formulations
For the spray formulation, 5 gm of ketorolac tromethamine
was dissolved in a 1.5% microcrystalline cellulose solution. The
tonicity was adjusted with dextrose. Phenylethyl alcohol, at a
concentration of 0.25% (v/v), was used as a preservative and
anticaking agent. The pH of the formulation was 5.95. For the
ketorolac acid spray, the amount of drug used was equivalent
to 5 gm of tromethamine salt. As ketorolace acid has very lim-
ited solubility in water, this formulation was designed to remain
suspended after being shaken. The ketorolac acid was sieved
to 45 l m before incorporation into the polymer solution. The
initial pH of this formulation was 3.2. As the pH of the nasal
mucosa was 5.5 to 6.0, the pH of the ketorolac acid formulation
was adjusted to 6.0. Using the MCC polymer in the formulation
increased the residence time of the dosage. The aqueous spray of
both ketorolac tromethamine and ketorolace acid formulations
were prepared in a similar manner but without microcystalline
cellulose and were used as controls. The pH of the aqueous spray
of ketorolac tromethamine was 6.1 and of the ketorolac acid was
adjusted to pH 6.0.
Lyophilized Powder of Ketorolac with Microcrystalline
Cellulose
For the powder formulation, 1.5 gm of ketorolac trometha-
mine was dissolved in water and added to a hydrated suspension
of an equal amount of microcrystalline cellulose. The volume
was adjusted to 50 ml, and the contents were lyophilized for
48 hr. The Ž nal weight of the formulation was 2.85 gm indi-
cating a yield of approximately 95%. A powder formulation
of ketorolac acid was also prepared in a similar manner. The
amount of free acid used in the formulation was equivalent to
1.5 gm of ketorolac tromethamine. The Ž nal weight of ketorolac
acid formulation was 2.32 gm with a yield of » 92%. The for-
mulations were then sieved through 45-, 63-, and 123-l m mesh
sieves. The content uniformity results showed that the experi-
mental drug loading agreed with the theoretical drug loading,
indicating that the polymer was homogeneously mixed with the
ketorolac (Quadir 1999). Free form of ketorolac tromethamine
or ketorolac acid powders with a particle size of 45 l m was
used as a control.
 DEVELOPMENT AND EVALUATION OF NASAL FORMULATIONS OF KETOROLAC
Animal Model
New Zealand white male rabbits weighing 3 – 5 kg were pur-
chased from Charles River Labs (Amherst, MA). The study pro-
tocol was reviewed and approved by the Institutional Animal
Care and Use Committee, University of Rhode Island – Kingston.
Bioavailability Study of Ketorolac Formulation
New Zealand white male rabbits weighing 3 – 5 kg were used
as the animal model to evaluate the bioavailability of the drug.
Rabbits were fasted for 12 hr prior to the experiment with free
access to water. The rabbits were initially sedated with an intra-
muscular (IM) dose of 5.0 mg/kg of acepromazine maleate and
then anesthetized with an IM injection of 50 mg/kg of ketamine
hydrochloride and 8.9 mg/kg of xylazine hydrochloride. An ad-
ditional dose of 50 mg of ketamine was injected if necessary
after 3 hr to prolong anesthesia. The rabbits were kept lying on
thermal rugs during the experiment. A catheter was placed in the
rabbit’s median ear artery to allow withdrawal of multiple blood
samples throughout the experiment. The ketorolac formulations
were administered either by the intravenous or intranasal route.
Blood samples (0.8– 1.0 ml) were collected at 5, 10, 30, 60, 90,
120, 180, 240, and 300 min after administration. All blood sam-
ples were placed into plasma separator tubes and centrifuged
at 3000 rpm for 12 min. The supernatant was transferred into
tubes, sealed, and stored at ¡ 70°C until assayed.
Administration of Nasal Formulations
The concentration of the developed nasal spray formulation
was 50 mg/ml and 200 l l of formulation was required to deliver
10 mg of ketorolac tromethamine. A nasal spray-pump (Valois
of America) with an ability to deliver 100 l l of nasal formulation
for each spray was used in this study. The precision and repro-
ducibility of the spray pump were determined gravimetrically
by spraying the different formulations 10 times after priming the
pump (Quadir 1999). A total volume of 200 l l of formulation
was sprayed into both nostrils (100 l l each) of the rabbit. As the
ratio of ketorolac tromethamine and polymer in the powder for-
mulations is 1:1, a total of 20 mg of the powder formulation was
administered using the powder insuf ator into both nostrils (10
mg each) of the rabbit. Thus, the powder formulation delivered
a dose of ketorolac tromethamine equivalent to that in the spray
formulation. The ketorolac acid powder formulation also con-
tained a dose equivalent to that of the ketorolac tromethamine
and was administered into both nostrils.
The Miat nasal insuf ator was tested for repoducibility of
dose delivered by weighing the predetermined amount of
ketorolac tromethamine powder formulation (particle size
63 l m) into a No. 3 capsule. The capsule was placed in the insuf-
 ator and pierced with a needle. Then the powder was sprayed
by squeezing the rubber bulb (pufŽ ng). The amount of powder
delivered after each puff was measured using weight difference.
The measurements were taken after each puff for a total of 5
puffs. The insuf ator was characterized for different doses of
225
powder (5, 10, and 20 mg).The same device was used through-
out the entire study for all the formulations. We determined that
after the third pufŽ ng for a 20-mg formulation, 97.8% of the
contents was delivered. After 5 puffs, the entire amount of pow-
der was delivered for all the powders (Quadir 1999).
Study Design
The ketorolac formulations were administered to the rabbits
as per a randomized crossover design. A washout period of at
least 1 week was held between the treatments.
Analytical Method
Equipment
A Waters HPLC (Waters Associates, Milford, MA), equipped
with automated gradient controllers, Model 717 plus autosam-
pler, Model 515 HPLC pumps, Model 480 LC spectrophotome-
ter, and Model 746 data module integrator was used. For chro-
matography, a l Bondapak C-18 column (3.9 mm id £ 30 cm,
10 l m, Waters Associates) was used. A Waters HLPC precol-
umn inserts (l Bondapak C-18) was used throughout the experi-
ment. An IEC Micro-MB centrifuge (USA) was used to separate
plasma from the blood sample.
Extraction of Ketorolac from Blood Samples
The extraction of ketorolac from the plasma was carried out
by solid-phase extraction using a Sep-Pak Light C-18 cartridge
rather than a traditional extraction procedure. This approach has
high efŽ ciency and time-saving advantages. The procedure used
for ketorolac extraction (Berninger and Darsh 1986) was mod-
iŽ ed as follows: Initially, the cartridge was conditioned with 2
ml of methanol followed by 3 ml of water and then 2 ml of a 1.3-
mM phosphoric acid solution at pH 3.0. Then 200 l l of plasma
sample, 100 l l of internal standard (Tolmetin sodium 5 l g/ml
in water), and 400 l l of water were loaded in each cartridge.
The cartridges were successively eluted by 1 ml of the above-
mentioned 1.3 mM phosphoric acid solution and 2 ml of water to
remove unwanted components. Finally, 2 ml of methanol  ushed
the ketorolac out of the cartridges. The methanolic extract was
evaporated under a stream of nitrogen and the residue was re-
dissolved in 200 l l of mobile phase.
Chromatographic Conditions
The mobile phase was made up of CH3 CN/phosphori c acid
solution (1.3 mM) with a ratio of 34 : 66 (v/v) at pH 3.0 § 0.1.
The mobile phase was Ž ltered through a 0.45-m Millipore mem-
brane Ž lter before use and was delivered at 2 ml/min. The ab-
sorption wavelength was set at 320 nm and an injection volume
of 20 l l was used (Mrosczak and Lee 1987). The column
was operated at ambient temperature. For standard curve, the
peak area ratio of ketorolac/tolmetin were plotted versus known
concentrations of ketorolac. Triplicate sets of extraction stan-
dard curves of ketorolac tromethamine in plasma sample were
prepared on three different days for interassay validation. This
226 M. QUADIR ET AL.

method was shown to be linear over the range of 0.5 – 10 g/ml,

with an obtained correlation coefŽ cient (r 2 ) of 0.997 to 1.000
(Quadir 1999).

Data Analysis
A noncompartmental model analysis was used to estimate the
pharmacokinetic variables and area under the curve of ketorolac
in plasma. After a single dose, maximum plasma concentration
(Cmax ) and time to maximum concentration (Tmax ) were deter-
mined. Areas under the plasma concentration time curve (AUC)
were calculated using the trapezoidal rule. The plasma concen-
tration was then normalized for both the dose and weight of the
rabbit. The absolute bioavailability of the nasal formulation was
Ž nally calculated using the following equation:

AUCin DOSEiv
F = £ 100
AUCiv DOSEin
where F is percent absolute bioavailability and AUCin, AUCiv,
DOSEin, and DOSEiv are the area under the curve and corre-
sponding dose for intranasal and intravenous.
Statistics
Data, expressed as a mean with standard deviation, were di-
vided into two groups for statistical testing: spray formulations
and powder formulations. To test for signiŽ cant differences be-
tween spray and powder formulations, a single factor analysis of
variance (ANOVA) was performed with the aid of a Microsoft
Excel software package. The multiple comparisons within the
formulations were determined using Duncan’s multiple range
test (Montgomery 1997). Differences between the treatments
were assumed to be signiŽ cant at p < 0.05.
RESULTS
Intravenous Administration
Plasma concentrations of ketorolac following intravenous ad-
ministration to rabbits are shown in Figure 2. The average Cmax
FIG. 1. Structure of kelorolac tromethamine and ketorolac acid.
achieved was 1.343 § 0.387 l g/ml at a Tmax of 0.08 hr. The
normalized area under the curve, by both dose and weight, was
an average of 0.998 § 0.159 (hr l g/ml)/kg (Table 1).
Nasal Absorption of Ketorolac Spray Formulations
The pharmacokinetic data for the various ketorolac spray for-
mulations investigated are summarized in Table 1. The aqueous
spray formulation of ketorolac tromethamine, dissolved only in
water, was used as a control formulation. The plasma proŽ le
of this control formulation indicated there was a rapid absorp-
tion with an average maximum concentration of 0.28 § 0.134
l g/ml occurring 0.23 § 0.185 hr after application (Figure 2).
The normalized area under the curve was found to be 0.549 §
0.106 (hr l g/ml)/kg. However, with the ketorolac tromethamine
spray formulation containing the bioadhesive polymer, the Cmax
increased to 0.428 § 0.122 l g/ml at a Tmax of 0.5 hr. The nor-
malized area under the curve was 0.906 § 0.223 (hr l g/ml)/kg
indicating an absolute bioavailability of 91%. The increase in

TABLE 1
Pharmacokinetic parameters of nasal spray formulations of ketorolac in rabbits (N = 4)

Formulation Tmax in hour Cmax in (l g/ml) AUC in (hr l g/ml)/kg Percent bioavailability
Intravenous injection 0.08 § 0 1.345 § 0.316 0.998 § 0.159 100
KT aqueous pH 6.1 0.23 § 0.185 0.280 § 0.134 0.549 § 0.106 55.03
KT-MCC pH 5.95 0.50 § 0 0.428 § 0.122 0.906 § 0.223 90.77
KA-MCC pH 3.2 0.34 § 0.191 0.31 § 0.045 0.637 § 0.288 63.89
KA-MCC pH 6.0 0.229 § 0.185 0.203 § 0.086 0.706 § 0.214 70.6
KA aqueous pH 6.0 0.250 § 0.167 0.128 § 0.051 0.468 § 0.167 46.8
KT = ketorolac tromethamine.
KA = ketorolac acid.
MCC = microcrystalline cellulose.
 DEVELOPMENT AND EVALUATION OF NASAL FORMULATIONS OF KETOROLAC 227

FIG. 2. Plasma level of ketorolac after dosing of different spray

formulations.
both Cmax and Tmax from this formulation shows that the pres-
ence of the bioadhesive polymer in the formulation increased
bioavailability and may have increased the residence time.
The nasal dose of ketorolac acid used was equivalent to
that used in the ketorolac tromethamine formulations. The con-
trol formulation, where ketorolac acid was suspended only in
water with an adjusted pH of 6.0, provided a Cmax of 0.128 §
0.051 l g/ml occurring 0.25 § 0.167 hr after application
(Figure 2 and Table 1). The normalized area under the curve
was found to be 0.468 § 0.167 (hr l g/ml)/kg. However, in case
of spray formulation with microcrystalline cellulose, both Cmax
and AUC increased signiŽ cantly as compared with the control
formulation. The Cmax obtained from the pH 3.2 ketorolac acid
formulation was 0.310 § 0.045 l g/ml with a Tmax of 0.34 §
0.191 hr. The normalized area under the curve was 0.637 §
0.228 (hr l g/ml)/kg. When this formulation was adjusted to pH
6.0, even though the solubility of ketorolac acid was increased,
there was no signiŽ cant change in bioavailability. The normal-
ized area under the curve was 0.706 § 0.214 (hr l g/ml)/kg with
a Cmax of 0.203 § 0.086 at Tmax of 0.229 § 0.185 hr. Lowering
the pH to 3.2 indicated a slight local irritation that was visually
observed during the administration of the formulation.
The spray formulation of ketorolac tromethamine has better
bioavailability compared with ketorolac acid. Apparently, the
FIG. 3. Plasma level of ketorolac after dosing of different powder
formulations.
limited solubility of the ketorolac acid in nasal mucosa may be
the reason. The single-factor ANOVA performed on the bioavail-
ability data for the above spray formulations, and the intra-
venous injection, indicated signiŽ cant difference in bioavailabil-
ity among formulations at a = 0.05. Duncan’s multiple range
test showed there was a signiŽ cant difference in bioavailability
between intravenous and spray formulations with the exception
of ketorolac tromethamine spray (Quadir 1999).
Nasal Absorption of Ketorolac Powder Formulations
The pharmacokinetics of ketorolac powder formulations
studied are summarized in Table 2. In these experiments, simple
powder of ketorolac tromethamine and ketorolac acid were used
as controls. The free form of ketorolac tromethamine showed
(Figure 3) an average maximum plasma concentration of 0.09 §
0.06 l g/ml occurring approximately 0.17 hr after administra-
tion. The normalized area under the curve was 0.289 § 0.142
(hr l g/ml)/kg. However, when an equivalent dose of ketorolac
acid powder was administered, there was an increase in Cmax of
0.183 § 0.11 l g/ml at a Tmax of 0.2 hr. The normalized area
under the curve was increased to 0.568 § 0.042 (hr l g/ml)/kg.
Drug absorption from the nasal cavity seems to depend on the

TABLE 2
Pharmacokinetic parameters of nasal powder formulations of ketorolac in rabbits (N = 4)

Formulation Tmax in hour Cmax in (l g/ml) AUC in (hr l g/ml)/kg Percent bioavailability
Intravenous injection 0.080 § 0 1.345 § 0.316 0.998 § 0.159 100
KT free powder (45 l ) 0.170 § 0 0.09 § 0.065 0.289 § 0.142 29
KA free powder (45 l ) 0.208 § 0.20 0.183 § 0.111 0.568 § 0.042 57
KT-MCC powder (123 l ) 0.104 § 0.025 0.130 § 0.099 0.359 § 0.264 36
KT-MCC powder (63 l ) 0.148 § 0.045 0.170 § 0.131 0.382 § 0.147 38
KA-MCC powder (45 l ) 0.103 § 0.045 0.095 § 0.010 0.454 § 0.104 45
KT = ketorolac tromethamine.
KA = ketorolac acid.
MCC = microcrystalline cellulose.
228 M. QUADIR ET AL.
time available for the drug to pass through the nasal mucosa.
Ketorolac acid, due to its lipophilic character, may have bet-
ter absorption in nasal epithelium; however, ketorolac trometh-
amine, from higher solubility in nasal mucosa, may be easily
cleared by mucocilliary clearance.
The powder formulation of ketorolac tromethamine-MCC
with a particle size of 123 l m did not show any signiŽ cant
improvement in absorption as compared with the control. The
Cmax was of 0.13 § 0.099 l g/ml occurring approximately 0.1
hr after administration. The normalized area under the curve
was 0.358 § 0.264 (hr l g/ml)/kg. When the particle size of this
formulation was reduced to 63 l m, no signiŽ cant change in
absorption was observed. Although the Cmax was increased to
0.17 § 0.131 l g/ml with a Tmax of 0.15 hr, the normalized area
under the curve was essentially the same (Table 2). Therefore, the
inclusion of polymer in powder formulation did not in uence
nasal bioavailability. This was also true for the powder formu-
lation of ketorolac acid-MCC. The Cmax obtained for this for-
mulation was 0.095 § 0.01 l g/ml at a Tmax of 0.103 § 0.045 hr
with an absolute bioavilability of only 45%. Ketorolac may not
be releasing totally from the polymer matrix before it is removed
by mucocilliary clearance.
The single-factor ANOVA performed on the bioavailability
data of the different powder formulations indicated no signiŽ cant
variation in bioavailability among formulations at a = 0.05.
Duncan’s multiple range test also showed that there was no sig-
niŽ cant difference in bioavailability between powder formula-
tions with an exception between free ketorolac acid and free
ketorolac tromethamine powder (Quadir 1999).
DISCUSSION
Compared with all the formulations investigated in this study,
the ketorolac tromethamine nasal spray formulation contain-
ing microcrystalline cellulose showed the highest absorption
with an absolute bioavailability of 91%, indicating no signiŽ -
cant difference from intravenous injection ( p < 0.05; ANOVA,
n = 4; §SD). The plasma concentration after 0.5 hr is almost
equivalent to intravenous and is slightly higher after 3 hr. This
spray formulation showed rapid absorption and higher bioavail-
ability than the nasal drops developed by Santus et al. (1993),
which contained sodium glycocolate as an absorption enhancer.
Ketorolac acid showed slower absorption than ketorolac tro-
methamine nasal spray and had an absolute bioavailability of
70%. As ketorolac acid has very limited solubility in water, ap-
parently the dissolution of ketorolac acid into the mucus layer
is a limiting factor in intranasal ketorolac acid absorption. Al-
though the bioadhesive polymer may somewhat increase the
residence time, mucociliary clearance ultimately removes the
ketorolac acid before its complete absorption from its limited
solubility.
The absorption of ketorolac acid in a spray formulation can
be improved by incorporating a hydroalcoholic solution in the
formulation to increase the solubility of the ketorolac acid (Roy
and Manoukian 1994). However, a hydroalcoholic solution of
ketorolac acid at a low pH has a tendency to form a ketorolac
acid ester with long-term storage. As a result, the potency of
formulation would signiŽ cantly decrease during storage even at
room temperature (Roy and Manoukian 1994). The maximum
plasma concentration of ketorolac acid formulation at pH 3.2 was
higher than at pH 6.0, although there were no signiŽ cant changes
in absolute bioavailabilities. Also, there were structural changes
of the epithelial cells in the nasal mucosa when treated with an
isotonic buffer at pH 2.94 (Ohwaki et al. 1987). Therefore, at pH
3.2, there was a possibility of local tissue irritation that caused
an increase in plasma concentration.
For migraine therapy, rapid absorption and convenient ad-
ministration are required. Several approaches have been taken
to develop a nonoral formulation and offset the incomplete ab-
sorption of ketorolac. Transdermal application of ketorolac acid
and ketorolac tromethamine in rhesus monkeys showed abso-
lute bioavailability of 35% (Yu et al. 1988). The results also
indicated that the skin permeation of ketorolac free acid and
ketorolac tromethamine salt were somewhat similar when the
drug was delivered through a hydroalcoholic vehicle contain-
ing potential skin penetration enhancers. In the case of rectal
administration, the absolute bioavailability of a suppository for-
mulation made with ketorolac tromethamine was found to be
61% in rabbits (Zia et al. 1998). When given orally, the rabbit
exhibited a larger degree of presystemic metabolism with an ab-
solute bioavailability of only 52% (Mroszczak and Lee 1987).
Therefore, the developed nasal spray formulation of ketorolac
tromethamine seems to be a suitable alternative dosage form for
migraine therapy.
Multiple factors may contribute to the higher bioavailability
of ketorolac tromethamine from a nasal spray formulation. The
rheologic studies indicated that the inclusion of a bioadhesive
polymer resulted in an increase in viscosity of the spray formula-
tion as compared with the control. Furthermore, the thixotropic
behavior of the formulation caused a convenient means of ad-
ministration, which subsequently regains its consistency rapidly
enough to increase the residence time (Quadir 1999).
Previous studies showed that increasing viscosity of a formu-
lation resulted in a larger globule size and thus affected the de-
position pattern in the nasal cavity (Morimoto et al. 1985, 1991;
Harris et al. 1988, 1989; Pennington et al. 1988; Lin et al. 1993).
The large globules tend to give a more localized deposition in the
anterior portion of the vestibule than the smaller globules that de-
posit in the posterior portion of the nose. This, in turn, reduces the
overall clearance of the dosage form from the nose. The polysor-
bate 80 present in the spray formulation may open the junctions
between the cells of nasal epithelium or increase the number
of hydrophilic channels and therefore enhance the absorption
of a hydrophilic drug such as ketorolac tromethamine (Gordon
et al. 1985; McMartin et al. 1987). Thus, the combination of
bioadhesive polymer and a safe surfactant such as polysorbate
80 in the formulation may have a synergistic effect that provides
rapid absorption and higher bioavailability.
 DEVELOPMENT AND EVALUATION OF NASAL FORMULATIONS OF KETOROLAC
CONCLUSIONS
Our study demonstrates that an intranasal spray formulation
of ketorolac tromethamine is an attractive alternative to intra-
venous administration as indicated by rapid, reliable absorption
and adequate bioavailability. The spray formulation of ketorolac
acid also indicated a higher bioavailability through the intranasal
route, though it has a signiŽ cant difference from the intravenous
formulation. The bioavailability of ketorolac acid can be im-
proved by incorporating solubilizing agent in the formulation,
which promotes faster dissolution in the mucus layer. However,
the powder formulations of ketorolac were not as effective as
the spray formulations. The superiority of the polymer spray
formulation of ketorolac tromethamine indicates strongly that
this nasal spray formulation is preferable. By removing the oxy-
gen level from the formulation, it is possible to develop a stable
nasal spray formulation. Furthermore, the pH and the tonicity
of this formulation is compatible with the nasal environment.
Since the acceptability of a nasal formulation depends on lo-
cal tissue tolerance, it is very important to evaluate the effect of
this formulation on the nasal epithelium. A gross morphologic
study of the nasal epithelium through endoscope and the release
of marker compounds after repeated administrations of this for-
mulation did not show any signiŽ cant change in nasal mucosa
compared with control (Quadir et al. 1999).
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