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.
- [Show abstract] [Hide abstract]
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
- [Show abstract] [Hide abstract]
ABSTRACT: Background: Although ritodrine (RD)-hydrochloride (HCl), named RD-HCl, is widely used in the treatment of premature labor by intravenous prolonged infusion or frequent oral dosing of tablets, those administrations often lower patients' quality of life (QOL) or cause undesirable side effects, such as tachycardia; therefore, in this study, the potential usefulness of buccal administration as a novel administration method was examined in vivo. Method: First, the HPLC method was assessed for the determination of plasma RD concentration. Then, after RD-HCl solution in saline was administered intravenously (1 mg/kg), intragastrically (10 mg/kg) or buccally (10 mg/kg) in rats, the plasma concentration-time profiles were investigated, and the absorption extent and rate compared. Results: The present modified determination method by HPLC with fluorescence detection (Ex. 278 nm, Em. 306 nm) was suitable to analyze the plasma level at 8-200 ng/mL. Buccal administration gave the best plasma concentration-time profile for maintenance of an effective plasma level and fewer side effects. Absorption rates calculated by deconvolution also supported better sustained absorption in buccal dosing. Conclusion: Buccal application of RD-HCl was demonstrated to be a potentially useful dosing method in the treatment of premature labor with RD-HCl.Drug Development and Industrial Pharmacy 07/2012; · 1.54 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Koelewijn M, Wanrooij BS. Als de patiënt niet meer kan slikken… Huisarts Wet 2006;49(10):519-24. In dit artikel bespreken we de problemen die kunnen ontstaan als een patiënt in de laatste fase van zijn leven niet meer kan slikken. Achtereenvolgens staan we stil bij vragen over uitdroging, het belang van goede mondverzorging en de mogelijkheden om noodzakelijke medicatie toe te dienen als het langs orale weg niet meer gaat. Van een aantal veelgebruikte medicijnen in deze fase komen vooral de subcutane, transdermale, rectale en transmucosale toedieningswijze aan de orde. Aan de hand van een casus laten we zien dat het de kwaliteit van leven van de patiënt kan bevorderen als de huisarts al in een eerder stadium in de palliatieve fase de medicatie herziet en alternatieve manieren van toediening overweegt. darmaandoening-farmacotherapie-mondaandoeningen-palliatieve zorg-terminale zorgHuisarts en wetenschap 01/2006; 49(10):728-735.
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)