Absorption of clonazepam after intranasal and buccal administration.
ABSTRACT Serum concentrations of clonazepam after intranasal, buccal and intravenous administration were compared in a cross-over study in seven healthy male volunteers. Each subject received a 1.0 mg dose of clonazepam intranasally and buccally and 0.5 mg intravenously. A Cmax of 6.3 +/- 1.0 ng ml-1 (mean; +/- s.d.) was measured 17.5 min (median) (range 15-20 min) after intranasal administration. A second peak (4.6 +/- 1.3 ng ml-1) caused by oral absorption was seen after 1.7 h (range 0.7-3.0 h). After buccal administration a Cmax of 6.0 +/- 3.0 ng ml-1 was measured after 50 min (range 30-90 min) with a second peak of 6.5 +/- 2.5 ng ml-1 after 3.0 h (range 2.0-4.0 h). Two minutes after i.v. injection of 0.5 mg clonazepam the serum concentration was 27 +/- 18 ng ml-1. It is concluded that intranasal clonazepam is an alternative to buccal administration. However, the Cmax of clonazepam after intranasal administration is not high enough to recommend the intranasal route as an alternative to intravenous injection.
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ABSTRACT: In order to obtain an alternative to the intravenous (i.v.) dosage form of clonazepam (CZ), an oral droplet formulation of CZ was developed previously; however, the droplet was physically unstable. Therefore, in the present study, it was attempted to develop an easily-handled dosage form, which was more physically stable and allowed rapid drug absorption from oral mucosa. A semi-solid dosage form, composed of polyethylene glycol 1500 (PEG), CZ, and oleic acid (OA) at 37/1/2 (w/w) and named PEG/CZ/OA, and a semi-solid dosage form containing PEG and CZ at 39/1 (w/w), called PEG/CZ, were prepared. Their physical stability in air at room temperature and oral mucosal absorption in rats were investigated. The semi-solid dosage forms were much more stable physically than the droplet, that is, no recrystallization of CZ was observed for at least 8 days. The effective concentration for humans and rats (20 ng/mL or more) was achieved within 30 min after buccal administration for both PEG/CZ/OA and PEG/CZ. The plasma concentration increased gradually and less varied at each time point for PEG/CZ/OA. PEG/CZ/OA was found to show more rapid and higher absorption of CZ in buccal administration than in sublingual administration. Buccal administration with the semi-solid dosage PEG/CZ with or without OA was suggested to be a possibly useful novel dosage form as an alternative to i.v. injection.Drug Development and Industrial Pharmacy 01/2011; 37(7):809-14. · 1.54 Impact Factor
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ABSTRACT: Ritodrine hydrochloride (RD-HCl) tablets containing alginate (AL) and lactose (LC) with or without microcrystalline (MC) as excipients were produced as a buccal dosage form. The RD-HCl (2mg) tablets with AL/LC but no MC swelled and dissolved gradually in the in vitro dissolution test. The tablet showing the fastest dissolution and highest drug release rate, called Tablet A1, was selected as a tablet to show rapid and prolonged absorption. However, in the in vivo buccal absorption test using rats, it could not give a plasma concentration over the human minimal effective level (15ng/ml). The modified tablet containing AL, LC, MC and RD-HCl (4mg), named Tablet B/MC, showed better hardness and faster drug release. Tablet B/MC gave a plasma concentration over the human effective level within 15min, and the plasma concentration was maintained at >15ng/ml over 4h. Moreover, the deconvolution analyses demonstrated that a prolonged high plasma levels could be achieved in vivo best with Tablet B/MC. Tablet B/MC improved the pharmacokinetic profile in comparison with Tablet A1 and the solution dosage form. The RD-HCl buccal tablets with AL, LC and MC as excipients are suggested to be possibly useful for the treatment of premature labor.International Journal of Pharmaceutics 04/2014; · 3.99 Impact Factor
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ABSTRACT: A semisolid dosage form of clonazepam (CZP), administered to the oral cavity between the lower gum and bottom lip with small volume of saline, was developed to obtain the stable dosage which can replace the injection dosage form. Semisolid dosage forms were prepared using a mixture of CZP/(polyethylene glycol 1500 (PEG))/(oleic acid (OA)) at the ratios of 1/39/0, 1/37/2 and 2/36/2 (w/w), named CZP1-PEG, CZP1-PEG-OA and CZP2-PEG-OA, respectively, and were evaluated in vitro and in vivo. No crystal of CZP was observed in CZP1-PEG-OA for at least 8 days, while CZP crystal appeared before administration for CZP2-PEG-OA. When a small volume of saline was added to CZP1-PEG-OA just before the oral cavity administration, more than 80% (w/w) was found to exist in the soluble form. Each semisolid dosage form (40 mg) was administered to the oral cavity in rats, and CZP 1 mg suspension in 0.5% (w/v) sodium carboxymethylcellulose aqueous solution was administered into rat stomach as a control. CZP1-PEG-OA gave the plasma concentrations of more than 5 ng/ml and 12 ng/ml at 30 min and 1 h after administration, respectively, which might be near the plasma levels effective for the suppression of epileptic seizures in human, while the plasma concentration was less than 5 ng/ml at 30 min or did not reach 10 ng/ml at 1 h for the other formulations. It is proposed that the semisolid dosage form CZP1-PEG-OA should be a possibly useful preparation for the antiepileptic or sedative medication.Yakugaku zasshi journal of the Pharmaceutical Society of Japan 01/2010; 130(1):119-25. · 0.46 Impact Factor
Br J clin Pharmac 1995; 39: 449-451
Absorption of clonazepam afterintranasal and buccal
M. W. G. SCHOLS-HENDRIKS', J. J. H. M. LOHMAN', R. JANKNEGT1, J. J. KORTEN2, F. W. H. M. MERKUS3
& P. M. HOOYMANS1
'Department of Clinical Pharmacy and Toxicology, 2Department of Neurology, Maasland Hospital, Sittard and
3the Center for Bio-Pharmaceutical Sciences, University of Leiden, Leiden, The Netherlands
Serum concentrations of clonazepam after intranasal, buccal and intravenous admini-
stration were compared in a cross-over study in seven healthy male volunteers. Each
subject received a 1.0 mg dose of clonazepam intranasally and buccally and 0.5 mg
intravenously. A Cmax of 6.3 ± 1.0 ng ml-' (mean; ± s.d.) was measured 17.5 min
(median) (range 15-20 min) after intranasal administration. A second peak (4.6 ± 1.3
ng ml-') caused by oral absorption was seen after 1.7 h (range 0.7-3.0 h). After
buccal administration a Cmax of 6.0 ± 3.0 ng ml-' was measured after 50 min (range
30-90 min) with a second peak of 6.5 ± 2.5 ng ml-' after 3.0 h (range 2.0-4.0 h).
Two minutes after i.v. injection of 0.5 mg clonazepam the serum concentration was
27 ± 18 ng ml-'. It is concluded that intranasal clonazepam is an alternative to buccal
administration. However, the Cmax of clonazepam after intranasal administration is
not high enough to recommend the intranasal route as an alternative to intravenous
For adequate treatment of status epilepticus or serial
of effective concentrations
sequently, intravenous injection is generally the route
In several institutions in The Netherlands buccal
administration of clonazepam is used in mentally
retarded children with serial seizures . However,
accurate buccal clonazepam dosing
In these situations intranasal administration may be
an alternative. Intranasal administration is also more
administration. The nasal formulation for clonazepam
solubilizer and absorption enhancer. Cyclodextrins
are biocompatible polymers, able to form inclusion
complexes with drugs. Clonazepam is virtually water
insoluble. However, stable aqueous solutions can be
prepared with DMiCD . The aim of this study was
to compare serum concentrations of clonazepam after
intranasal, buccal and intravenous administration.
is necessary and, con-
is difficult in
Subjects and protocol
The study involved seven healthy male volunteers
aged 26 to 58 years, weighing from 69 to 82 kg. All
were healthy and took no other medication. The
protocol was approved by the local Ethics Committee
and all volunteers gave written informed consent.
Intranasal clonazepam (5 mg ml-) was prepared
by dissolving clonazepam (Bufa, The Netherlands)
together with dimethyl-,3-cyclodextrin (Avebe, The
Netherlands) in a molar ratio of 1:8 in 96% v/v
ethanol. The solvent was evaporated and the residue
redissolved in 0.9% w/v saline. The pH was adjusted
to 3.0. The intranasal spray device was a unit-dose
pump (Pfeiffer GmbH, Germany).
The subjects participated in three test sessions at
2 week intervals. During the sessions they received a
1.0 mg dose of intranasal or buccal clonazepam or
0.5 mg clonazepam intravenously. Each intranasal
dose was administered in one spray of 0.1 ml in both
nostrils. Clonazepam was administered buccally b
rubbing 0.4 ml of a 2.5 mg ml-' solution (Rivotril
solution, Roche, The Netherlands)
Correspondence: Dr M. W. G. Schols-Hendriks, Department of Clinical Pharmacy, Maasland Hospital, P.O. Box 5500, 6130 MB
Sittard, The Netherlands
M. W G. Schols-Hendriks et al.
buccal mucous membrane. After administration the
volunteer was instructed not to swallow the solution
for as long as possible and not to speak for
Clonazepam (Rivotril® injection, Roche, The Nether-
lands) was injected into a forearm vein at a dose of
0.5 mg over 2 min. The medication was given after
an overnight fast. Two hours after administration a
normal diet was resumed.
Venous blood samples were taken at 0, 2, 5, 10, 15,
20, 30, 40, 60, 90 min, 2, 3, 4, 6, 8 and 24 h after
dosing. The serum samples were stored at -20°C
To 0.5 ml serum were added 100glwater, 50
desmethyldiazepam in ethanol 96% (2.5 gg ml-',
internal standard) and 200
0.04 mol 1-l (pH 9.0), and the mixture was extracted
with dichloromethane. The organic phase was sepa-
rated and evaporated to dryness. The residue was
in mobile phase and injected onto the
The h.p.l.c. system consisted of a Waters-Millipore
486 tunable absorbance detector,
U6K pump and a Spectra Physics Data jet integrator
for determination of peak heights. The column (30
cm x 3.9 mm i.d.) was packed with ,u-Bondapak C18
phase (pH 3.6) consisted of a mixture of acetonitrile,
methanol and phosphate buffer solution 6 mmol 1-l
(180 + 200 + 500). The flow rate was 2.0 ml min-'.
U.v. detection was
were linear (r > 0.999) up to 50 ng ml-'. The limit of
determination was 2 ng ml-' at which concentration
the intra-run coefficient of variation was 16%. The
inter-run coefficient of variation was 10% for a 4 ng
pl borax buffer solution
a 510 injector, a
at 210 nm. Calibration
Values of AUC(0,2 h) were calculated using a com-
bination of the linear- and log-trapezoidal methods.
The highest observed concentration and the corre-
sponding sampling time were defined as Cmax and
examined using the Student's t-test for paired data.
Data are reported as mean ± s.d. To assess the stati-
stical significance of the
administration routes the 95% CI for the mean differ-
ence was calculated.
Mean serum concentrations of clonazepam after intra-
intranasal and buccal
shown in Figure 1. After intravenous administration
the concentrations declined over the first 10-15 min
such that after 20 to 40 min they were similar to the
peak values after buccal and intranasal administra-
tion. After 2 h no significant differences in serum
different routes of administration. All participants
completed the study. Intravenous data for one subject
were excluded from analysis because of extravasation
during the injection. Serum drug concentrations after
buccal administration to another subject could not be
measured because of chromatographic interference.
Values of Cmax and tmax
are shown in Table1.
after intravenous (0.5 mg, A), buccal (1.0 mg, V) and
intranasal (1.0 mg, *) administration of clonazepam.
Mean (+ s.d.) serum clonazepam concentrations
intranasally to seven healthy male volunteers
Cmax and tmax values following the administration of 0.5 mg clonazepam intravenously and 1.0 mg bucally and
*No data because of extravasation.
tNo data because of analytical interference.
significantly faster after intranasal compared with
buccal administration (P < 0.05; 95% CI for the mean
difference: 1.3 to 66.7 min). The differences in these
concentrations after intranasal (6.3 ± 1.0
ng ml-) and buccal (6.0 ± 3.0 ng ml-') admini-
stration did not reach statistical significance (P > 0.5;
95% CI for the mean difference
After intravenous administration of 0.5 mg drug
the mean AUC(0,2 h) was
Relative, dose-normalised AUC(0,2 h) values after
buccal and intranasal administration were 0.41 and
: -4.4 to +4.6
11 ± 3 ng ml-'
After both intranasal and buccal administration of
clonazepam two peak serum drug concentrations were
obtained in six of seven and three of six subjects,
respectively. The first peak was presumed to reflect
initial rapid mucosal absorption and the second was a
consequence of oral absorption.
The usual intravenous administered dose of clon-
azepam is at least 1.0 mg. However, a dose of 0.5 mg
was used in this study for safety reasons. In studies in
patients with status epilepticus therapeutic benefit
was associated with serum clonazepam concentra-
tions ranging from 13 to 90 ng ml-' . A thera-
peutic concentration threshold of 18 ng ml-' has been
suggested . However, after buccal and intranasal
administration of 1.0 mg clonazepam, concentrations
above 18 ng ml-' were not observed in this study.
Therefore we conclude that, although intranasal
clonazepam (1.0 mg)
administration in patients with serial seizures, initial
serum drug concentrations are too low to recommend
its use as an alternative to intravenous injection in
patients with status epilepticus.
is an alternative
1 Overweg J, Binnie CD. Benzodiazepines in neurlogical
benzodiazepines: From molecular
biology to clinical practice, ed Costa E. New York:
Raven Press, 1983: 339-347.
2 Hermens WA, Deurloo MJ, Romeijn SG, Verhoef J,
Merkus FW. Nasal absorption enhancement of
estradiol by dimethyl-p-cyclodextrin in rabbits and rats.
Pharm Res 1990; 7: 500-503.
3 Pinder RM, Brogden RN,
Speight TM, Avery GS.
Clonazepam: A review of its pharmacological properties
and therapeutic efficacy in epilepsy. Drugs 1976; 12:
4 Rylance GW, Poulton J, Cherry RC, Cullen RE. Plasma
concentrations of clonazepam after single rectal admini-
stration. Arch Disease Childh 1986; 61: 186-188.
(Received 2 August 1994,
accepted 24 November 1994)