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European Journal of Pharmaceutical Sciences 20 (2003) 327334

In vitro and in vivo evaluation of a new sublingual tablet system for rapid
oromucosal absorption using fentanyl citrate as the active substance
Susanne Bredenberg a , Margareta Duberg b , Bo Lennerns c , Hans Lennerns a ,
Anders Pettersson d , Marie Westerberg b , Christer Nystrm a,
a Department of Pharmacy, Uppsala University, Box 580, SE-751 23 Uppsala, Sweden
b Orexo AB, Uppsala, Sweden
c Department of Oncology, Sahlgrenska Academy, Gothenburg, Sweden
d Department of Gastro Research, Sahlgrenska Academy, Gothenburg, Sweden

Received 16 April 2003; received in revised form 29 July 2003; accepted 30 July 2003

Abstract

Oromucosal delivery of drugs promotes rapid absorption and high bioavailability, with subsequent almost immediate onset of pharmaco-
logical effect. However, many oromucosal delivery systems are compromised by the possibility of the patient swallowing the active substance
before it has been released and absorbed locally into the systemic circulation. This paper introduces a new tablet system for sublingual
administration and rapid drug absorption. The tablet is based on interactive mixtures of components, consisting of carrier particles partially
covered by fine dry particles of the drug, in this case fentanyl citrate. In the interests of increasing retention of the drug at the site of absorption
in the oral cavity, a bioadhesive component was also added to the carrier particles. Tablets containing 100, 200 and 400 g of fentanyl were
tested both in vitro and in vivo. The tablets disintegrated rapidly and dissolution tests revealed that fentanyl citrate was dissolved from the
formulation almost instantly. Plasma concentrations of fentanyl were obtained within 10 min, with no second peak. These results indicated
that the bioadhesive component prevented the fentanyl from being swallowed (the fraction swallowed was considered smaller compared to
other mucosal delivery systems), without hindering its release and absorption. This new sublingual tablet formulation may also hold potential
for other substances where a rapid onset of effect is desirable.
2003 Elsevier B.V. All rights reserved.

Keywords: Sublingual tablet; Fentanyl; Oromucosal delivery; Interactive mixture; Ordered mixture; Bioadhesion

1. Introduction usage. However, for acute disorders, the time to onset of


action for a conventional oral tablet is generally not accept-
1.1. Background able; this is usually attributable to gastric emptying causing
a highly variable lag time between drug administration and
A rapid onset of pharmacological effect is often desired onset of intestinal absorption.
from drugs, especially in the treatment of acute disorders. Oromucosal delivery, especially that utilising the buccal
This can effectively be achieved by parenteral administra- and sublingual mucosa as absorption site, is a promising
tion, but this method may not always be convenient for the drug delivery route which promotes rapid absorption and
patient. Therefore, there is growing interest in developing high bioavailability, with subsequent almost immediate on-
new, non-parenteral, reliable and convenient dosage forms set of pharmacological effect. These advantages are the re-
using administration routes where a rapidly dissolved drug sult of the highly vascularised oral mucosa through which
is immediately absorbed into the systemic circulation. Tablet drugs enter the systemic circulation directly, bypassing the
formulations are generally the first choice for drug admin- gastrointestinal tract and the first pass effect in the liver
istration because of the relative ease of both production and (Moffat, 1971). Among the most important characteristics
of tablet formulations used for oromucosal delivery are a
Corresponding author. Tel.: +46-18-471-44-72; short disintegration and dissolution time. However, in order
fax: +46-18-471-42-23. to achieve optimal oromucosal delivery, properties of the ac-
E-mail address: christer.nystrom@farmaci.uu.se (C. Nystrm). tive compound and other properties of the formulation have

0928-0987/$ see front matter 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.ejps.2003.07.002
328 S. Bredenberg et al. / European Journal of Pharmaceutical Sciences 20 (2003) 327334

also to be considered. The parent compound has to be sol- tures with a low surface area coverage of the carrier parti-
uble, stable and able to easily permeate the mucosal barrier cle resulted in drug dissolution rates even faster than those
at the administration site. Further, the dosage form has to from well-dispersed suspensions. These studies thus sug-
be rapidly dissolved while retaining a sufficiently long con- gest that a finely divided potent drug mixed with a coarse
tact time at the administration site. If dissolution of the drug water-soluble material ought to result in both a high unifor-
is incomplete, contact time is short, and/or permeation too mity of drug content and rapid drug dissolution. Further, the
low, part of the dose will not be absorbed through the oral use of this dry mixing technique allows direct compression
mucosa and will be swallowed, with subsequent effects on of the tablets, with associated economical advantages over
bioavailability. the classic wet granulation technique.
The main prerequisites for rapid dissolution of drugs in- One problem associated with sublingual tablet formula-
clude a large surface area of the drug exposed to the dis- tions is the potential for the patient to swallow parts of the
solving liquid and the lack of thick, stagnant hydrodynamic dose before the active substance has been released and ab-
boundary layers around the drug particles that hinder drug sorbed locally into the systemic circulation. Addition of a
dissolution by slowing diffusional transport (e.g. Noyes and bioadhesive component to the formulation is a well-known
Whitney, 1897; Nystrm et al., 1985; Bisrat et al., 1992). approach of increasing the probability of a more site-specific
While the drug surface area effectively in contact with the drug release. However, because this concept is normally ap-
dissolving fluid can be enlarged by using very finely divided plied to non-disintegrating tablets or discs in order to extend
grades of drug, the added excipients should not hinder dis- the release of the active substance, such a system may not
solution by separating the dissolving liquid from the drug be suitable for an immediate-release formulation. A new ap-
particles. The use of water-soluble excipients is the most proach to the problem has been suggested by Bredenberg
common approach in this context. Freezedrying the dosage and Nystrm (2003), who found that by dry mixing, carrier
form is an expensive but effective way of obtaining highly particles could be partially covered with fine dry particles
porous tablets, which promote rapid exposure of the drug of a bioadhesive material to form an interactive mixture.
phase and thus rapid drug dissolution (e.g. Corveleyn and These small, bioadhesive units could then replace the large,
Remon, 1998). Another, more simple, method of improv- bioadhesive, single unit (tablet or disc). It is then theoreti-
ing drug exposure is to use so-called ordered or interactive cally possible to add the active substance to the surface of
mixtures (Westerberg, 1992). These are achieved by mix- these carrier particles, resulting in ordered units comprising
ing coarse carrier particles with a fine drug component for coarse particles carrying both bioadhesive component and
a relatively long time so that the fine drug particles adhere drug. After compression, tablets composed of these units
to the surface of the carrier particle by adhesion forces, and would have the potential to rapidly disintegrate and release
are optimally exposed to the dissolving fluid (Nystrm and the units to adhere to the sublingual mucosa. Provided the
Westerberg, 1986). drug is instantly dissolved and able to permeate the mucous
membranes easily, it will be rapidly absorbed at the admin-
1.2. The new sublingual tablet concept istration site before there is a chance of it being swallowed.
Patients with cancer often suffer from chronic pain and
This paper outlines a new formulating system for rapidly require round the clock opioid therapy. However, break-
absorbed sublingual tablets. The new concept is based on through pain frequently appears despite this analgesic ther-
the use of ordered mixtures of fine drug particles attached apy, and supplemental opioid doses are required (Portenoy
to coarser excipient carrier particles. These ordered units and Hagen, 1990). Then, administering oral morphine, the
(each unit comprises a well defined carrier particle coated onset of action is often delayed up to 60 min (Hanks et al.,
with drug particles) offer several formulation advantages: 1998). Parenteral therapy would provide instant relief from
(a) they potentially facilitate the design of rapidly disinte- this pain, but this route is not particularly convenient for the
grating tablets, (b) they provide optimal drug exposure and patient. In this context, a specially designed tablet formu-
(c) they have the potential to provide immediate drug disso- lation would have the potential to be both therapeutically
lution. Certain factors are required to achieve an interactive effective and easy for the patient to use.
mixture containing a low proportion of drug and high ho- Fentanyl is a potent synthetic opioid, which is used in
mogeneity of dose. Obviously, the drug should be able to the treatment of breakthrough pain (Portenoy and Lesage,
form strong adhesive interactions with the carrier particles. 1999). As the citrate salt, fentanyl is sparingly soluble in
Previous studies have indicated that the drug particle size water and highly lipophilic, and is expected to be rapidly
should not exceed 5 m in diameter and should preferably absorbed after complete dissolution because of its ease of
have a narrow size distribution (Nystrm and Malmqvist, permeation through mucous membranes (McClain and Hug,
1980; Sundell-Bredenberg and Nystrm, 2001). It is also ap- 1980; Dollery et al., 1991). An existing product in the form
parent that high dose homogeneity can be obtained by dry of a lollipop containing fentanyl citrate was designed to al-
mixing micronised drugs in proportions as low as 0.015% low rapid absorption of the drug from the oral cavity (Mock
(w/w) (Sundell-Bredenberg and Nystrm, 2001). Westerberg et al., 1986; Ashburn et al., 1989). The active compound
and Nystrm (1993) found that the use of ordered mix- was incorporated into a dissolvable candy matrix and placed
S. Bredenberg et al. / European Journal of Pharmaceutical Sciences 20 (2003) 327334 329

on a stick. The patient holds the lollipop against the buccal improved systemic exposure of the parent drug, especially
mucosa and licks it. However, it is documented that a large regarding absorption rate. Another objective was to study
proportion of the active substance is swallowed using this the bioadhesion of the particles and avoidance of swallowing
delivery system (Zhang et al., 2002). This results in highly the active ingredient in a clinical trial.
variable bioavailability, since fentanyl citrate undergoes ex-
tensive cytochrome P450 (CYP)-3A4-mediated metabolism
in both the intestine and the liver (Streisand et al., 1991; 2. Materials and methods
Labroo et al., 1997). The absorption (Weinberg et al., 1988)
and efficacy (Zeppetella, 2001) of fentanyl delivered as a so- 2.1. Materials
lution to the sublingual mucosa has also been investigated.
Fentanyl citrate (Diosynth, The Netherlands) was milled
In a study by Zeppetella (2001), a solution of fentanyl citrate
by hand in a mortar. Fentanyl citrate is sparingly soluble
(maximum 3 ml, corresponding to 150 g fentanyl base) was
in water (1:40), has a pKa of 8.43, a partition coefficient
placed under the patients tongue; for most patients (82%),
in octanol/water of 955 and a dose-dependent plasma half
an analgesic effect was obtained after 1015 min. However,
life of 16 h (Dollery et al., 1991). Granulated mannitol
some patients found it difficult to retain the solution under
(Roquette, France) was used as carrier material, cross-linked
the tongue and swallowed it. Weinberg et al. (1988) used
polyvinylpyrrolidone (Kollidon CL, BASF, Germany) was
a solution of fentanyl with a pH of 6.5, which is the natu-
used as the disintegrant and bioadhesive component, silici-
ral pH of saliva. The solution (1 ml corresponding to 50 g
fied microcrystalline cellulose (ProSolv SMCC 90, Pen-
fentanyl base) was held under the tongue for 10 min without
west Pharmaceuticals Co., USA; referred to hereafter as
swallowing, at which point the solution was expectorated
SMCC) was used as the binder and magnesium stearate (Pe-
and analysed. The mean amount absorbed was calculated to
ter Greven, Fett-Chemie GmbH & Co., KG, Germany) was
be 51% of the fentanyl dose, higher than the 22% calculated
used as the lubricant; all were used as supplied.
for morphine.
Considering the shortcomings of the approaches currently 2.2. Methods
available for administration of fentanyl to patients suffering
breakthrough pain, it was felt that a new sublingual solid 2.2.1. Primary characterisation of test materials
dosage form that provided a rapid and reproducible onset of The apparent particle density (B.S. 2955, 1958) of the
action and was also convenient for the patient was a desirable materials (n = 3) was measured using a helium pycnome-
aim. This dosage form should also encourage retention of ter (AccuPyc 1330 Pycnometer, Micromeritics, USA). The
the active substance under the tongue, so as to increase con- external specific surface area of mannitol was determined
tact time at the absorption site and avoid the potential intra- using Friedrich permeametry (Eriksson et al., 1990). Blaine
and interindividual variability resulting from swallowing it. permeametry (Kaye, 1967) was used to determine the exter-
The studies described in this paper were designed to evalu- nal specific surface area of all other powders (except magne-
ate a new sublingual tablet system using low doses of fen- sium stearate); the surface areas were corrected for slip flow
tanyl citrate (Rapinyl ). In this system, water-soluble carrier because of the small particle size (Alderborn et al., 1985).
particles are covered with fentanyl citrate and a bioadhesive
material during dry mixing. In principle, the tablet quickly 2.2.2. Preparation of mixtures
disintegrates into the ordered units consisting of carrier, fen- Coarse mannitol particles were covered with fentanyl
tanyl citrate and bioadhesive component (Fig. 1). These units citrate by dry mixing (Fig. 2). The materials were mixed
initially adhere to the mucosa. The water-soluble carrier par- in a Teflonized metal jar in a tumbling mixer (Turbula
ticles gradually dissolve and fentanyl citrate dissolves along mixer T2F, W.A. Bachofen AG, Switzerland) at 90 rpm
with them. With this approach, optimal exposure of active for 48 h. However, for the lowest drug proportion (100 g
substance to the dissolving fluids is combined with bioad- base drug per tablet), the mixing time was increased to 72 h
hesive retention of the drug in the oral cavity. (Sundell-Bredenberg and Nystrm, 2001). Kollidon CL and
The main objective of this report is to investigate whether SMCC were added to the interactive mixture and mixed at
rapid disintegration and dissolution in vitro could result in 30 rpm for an additional 30 min (Fig. 2).

Fig. 1. Schematic model of the disintegration, bioadhesion and drug dissolution of the new sublingual tablet system.
330 S. Bredenberg et al. / European Journal of Pharmaceutical Sciences 20 (2003) 327334

Fig. 2. Schematic model of the mixing and tableting procedures for the sublingual fentanyl tablets and the tablet components.

2.2.3. Compaction of tablets liquid chromatography (RP-HPLC) with UV detection. The


Prior to compaction, all tablet masses were mixed with mobile phase consisted of phosphate buffer (pH 2.8) with
magnesium stearate (0.5% (w/w)) in the tumbling mixer 35% acetonitrile. The analyses were performed accord-
at 30 rpm for 2 min. Tablets were made in a single punch ing to the European Pharmacopoeia and by Quintiles AB,
press (Korsch EK0, Germany) using 6 mm flat bevel edged Sweden.
punches; the powder was filled into the die with a feed
shoe. The tablets contained fentanyl citrate corresponding 2.2.4.6. Drug dissolution. Dissolution tests were per-
to 100 g, 200 g or 400 g of fentanyl base. Each batch formed according to a modified European Pharmacopoeia
comprised 1000 tablets. paddle method (Prolabo dissolutest, Germany). The pad-
dle rotation rate was 50 rpm and the dissolution medium
2.2.4. Characterisation of tablets was water (volume: 300 ml; temperature 37 C). Samples
were collected after 1, 3, 5, 7 and 10 min. The amount
2.2.4.1. Porosity. The tablet porosity was calculated from of fentanyl was determined using liquid chromatography
the dimensions and weight of the tablet and the apparent par- (LC) with Shimadzu SPD-10A vp detector. The mobile
ticle density of the mixture, which was calculated according phase consisted of 65% phosphate buffer (pH 2.8) and 35%
to Jerwanska et al. (1995). acetonitrile. The LC system was equipped with a Aquasil
C18 column (250 mm 4.6 mm, 5 m). The analysis was
2.2.4.2. Tensile strength. A diametral compression test performed by Mikro Kemi AB, Sweden. The percentage of
(Kraemer HC97, Kraemer Elektronik GmbH, Germany) was dissolved drug was calculated in relation to the maximum
performed according to European Pharmacopoeia (1997) amount detected (=100%) and the data were presented in
method 2.9.8 (resistance to crushing of tablets) (n = 35). the dissolution rate profiles as a function of time.

2.2.4.3. Friability. The friability of the tablets was mea- 2.3. Clinical study
sured according to European Pharmacopoeia (1997) method
2.9.7 (friability of uncoated tablets), i.e. using the Roche fri- 2.3.1. Study design
ability apparatus for 4 min with the drum rotating at a speed After giving written informed consent to participate in the
of 25 rpm. Twenty tablets were weighed before and after the study, one patient (62 years male) with cancer (myeloma)
measurement and the weight loss was calculated (n = 1). received fentanyl doses of 100, 200 and 400 g, respec-
tively, as a single dose in the form of a sublingual tablet.
2.2.4.4. Disintegration time. The disintegration time of The doses were given in random order and were separated
the tablets was measured in water according to European by wash-out periods of at least 3 days. Blood samples
Pharmacopoeia (1997) method 2.9.1 (disintegration of (n = 16, 7 ml each) for determination of fentanyl in plasma
tablets and capsules, test A) (Kraemer DES-1, Kraemer were collected at 0600 min. Tolerability parameters such
Elektronik GmbH, Germany). In this study, the disintegra- as blood pressure, heart rate and oxygen saturation were
tion time was recorded both with and without the use of followed during the complete study day. Adverse events
discs. were continuously monitored throughout the study. A safety
follow-up, including physical examination, routine haema-
2.2.4.5. Assay of fentanyl. The content of fentanyl in ten tology and clinical chemistry was performed 25 days after
tablets was analysed using reversed-phase high-performance the last dose. This paper presents results from one patient,
S. Bredenberg et al. / European Journal of Pharmaceutical Sciences 20 (2003) 327334 331

which was included in a study with eight patients with in complete deagglomeration of drug particles and rapid
cancer (Lennerns et al., submitted for publication). The dissolution; an intermediate degree of surface area cover-
study was approved by the ethics committee of Gothenburg age (20100%) also results in rapid drug dissolution even
University. though some of the drug particles will be released in the
form of small agglomerates rather than as discrete particles
2.3.2. Sample analysis (Westerberg, 1992). However, as mentioned in the introduc-
Fentanyl was separated from plasma samples by liq- tion, these values are also dependent on the characteristics
uid/liquid extraction, using n-heptan containing 3% of the drug (e.g. agglomeration tendency and particle size).
2-butanol at pH >12. After evaporation, the residue was In this study, the surface area coverage of mannitol with
dissolved in 5 mM formic acid solution. The amount of fentanyl citrate particles was 7% (100 g), 14% (200 g)
fentanyl was determined using RP-HPLC with LCMS/MS and 27% (400 g).
detection. The mobile phase consisted of acetonitrile:water Bredenberg and Nystrm (2003) have shown that highly
(18:82) containing 5 mM formic acid. The analysis was water-soluble carrier materials are less bioadhesive than in-
performed by Quintiles AB, Sweden. soluble carriers, probably because the tensile fracture goes
through the partly dissolved carrier particles rather than
through the mucosa or between the mucosa and the bioad-
3. Results and discussion hesive material. However, it is not always desirable to con-
centrate only on optimal bioadhesion and the choice of
3.1. The formulation of the fentanyl tablets carrier for these fentanyl tablets involved consideration of
both a high dissolution rate to optimise absorption of fen-
The materials used and composition of the tablets in this tanyl over the sublingual mucosa and adequate bioadhe-
study are presented in Table 1 and Fig. 2. In interactive sive properties to minimise swallowing of the substance.
mixtures consisting of close to identical ordered units, the Since mannitol fulfils both these criteria (Westerberg, 1992;
drug dissolution rate is affected by the particle size of both Bredenberg and Nystrm, 2003) it was chosen as the car-
the drug and the carrier as well as by the physicochemical rier material. Kollidon CL also has bioadhesive properties
properties of the carrier (Westerberg, 1992). Westerberg (Bredenberg and Nystrm, 2003) and was therefore expected
et al. (1986) found that the carrier particle is required to to prolong the residence time of the ordered units at the
be highly soluble for rapid drug dissolution. In this study, sublingual mucosa. Kollidon CL also has the advantage
the carrier material was mannitol, which has been shown of being a very effective disintegrant (e.g. Kornblum and
previously to have good carrier properties, such as high Stoopak, 1973; Shangraw et al., 1980). Addition of a highly
water solubility (Wade and Weller, 1994). High dissolution deformable binder during compaction could, by forming a
rates were also maintained after tableting mixtures con- deformable microstructure around the particles, counteract
taining mannitol (Westerberg and Nystrm, 1991). Drug the effect of a disintegrant (Mattsson et al., 2001). SMCC
dissolution is also affected by the surface area coverage of is a moderately deformable binder (Mattson and Nystrm,
the carrier, calculated in this study according to Nystrm 2001) and is unlikely to significantly impair the disintegra-
et al. (1982). Low surface area coverage (<20%) results tion process.

Table 1
Primary characteristics of test materials and composition of the fentanyl tablets
Material Apparent particle External specific Test materials corresponding to Placebo (mg)
densitya (g/cm3 ) surface areab (m2 /g)
100 g (mg) 200 g (mg) 400 g (mg)

Fentanyl citrate 1.282 (0.001) 2.3c 0.157d 0.314e 0.628f


Mannitol 1.486 (0.000) 0.024 (0.001) 59.4 59.3 59.0 59.6
SMCC 1.578 (0.003) 0.35 (0.00) 7.00 7.00 7.00 7.00
Kollidon CL 1.224 (0.001) 0.42 (0.025) 3.00 3.00 3.00 3.00
Magnesium stearate 1.071 (0.004) g 0.400 0.400 0.400 0.400
Tablet weighth 70.0 70.0 70.0 70.0
a Measured with a helium pycnometer (AccuPyc 1330 Pycnometer, Micromeritics, USA). Mean values (S.D.), n = 3.
b Measured with a Friedrich permeameter (Eriksson et al., 1990) or Blaine permeameter (Kaye, 1967; Alderborn et al., 1985). Mean values (S.D.),
n = 3.
c n = 1.
d Corresponding to 100 g fentanyl base.
e Corresponding to 200 g fentanyl base.
f Corresponding to 400 g fentanyl base.
g Not determined.
h Nominal value.
332 S. Bredenberg et al. / European Journal of Pharmaceutical Sciences 20 (2003) 327334

Table 2
Technical properties and drug content of fentanyl tablets
Tablets Weighta (mg) Friabilityb (%) Crushing Average Uniformity of content Disintegration time
(g fentanyl) strengthc (N) contentd (%) (minimummaximum) (%)
With Without
discse (s) discsf (s)
100 70.2 (0.78) 0.44 12.1 (1.38) 95 91.0101.4 50 <10
200 70.0 (0.59) 0.74 11.3 (1.69) 95 87.7105 33 <10
400 69.3 (0.73) 0.64 11.7 (2.27) 96 88.294.4 45 <10
a Mean values (S.D.), n = 20.
b n = 1.
c Mean values (S.D.), n = 35.
d Ten tablets were analysed. The mean content of fentanyl was calculated and related to the nominal content for the tablets (i.e. 100, 200 and 400 g).
e Maximum value from 12 tablets (2 6). The measurements were performed with discs.
f The measurements were performed without discs. Maximum value from six tablets.

3.2. Primary characteristics of the fentanyl tablets in vitro particles. This was confirmed by the tests of average drug
content and content uniformity, which showed that only
3.2.1. Tablet strength, weight, friability and porosity minor segregation had occurred during tablet processing
The tablets were characterised regarding weight, tablet (i.e. mixing and tableting) (Table 2).
strength and friability (Table 2). The weight and friabil-
ity results were within the limits specified in the European 3.2.3. Tablet disintegration
Pharmacopoeia (1997). Both tablet strength and disintegra- In principle, the tablets should disintegrate rapidly, to in-
tion time are affected by tablet porosity. The porosity of the stantly generate many ordered units consisting of mannitol,
tablet may affect the efficacy of the disintegrant. A relatively fentanyl citrate and Kollidon CL (Fig. 1). The disintegra-
low porosity was most effective for the action of a disinte- tion time of the three batches of tablets containing fentanyl
grant in some studies (Shangraw et al., 1980; Ferrari et al., citrate corresponding to 100, 200 and 400 g fentanyl base
1995). However, no general relationship between porosity was 3350 s using discs and less than 10 s without discs
and disintegration time was seen in the study by Mattsson (Table 2). The higher value with discs was probably caused
et al. (2001) and it was concluded that the material proper- by adhesion of the tablets to the discs (because of the ad-
ties of the tablet components, such as solubility and bond- dition of bioadhesive), which fudged the endpoint. It seems
ing ability, would also affect disintegration time. The aim reasonable from these results that the tablet will adhere to
of this study was to achieve high tablet tensile strength and the mucosa in the mouth. The in vitro data obtained with
fast tablet disintegration. The tablet porosity was approxi- discs probably better reflects the disintegration time in vivo
mately 25% for all three batches, which appears adequate into ordered units. However, the peristaltic movements that
considering the results for tablet strength (Table 2). occur in the mouth may contribute to the disintegration of
the tablets.
3.2.2. Average drug content and content uniformity
Since the amount of active substance in the tablets was 3.2.4. Drug dissolution
relatively low and dry mixing was applied to obtain the The dissolution tests revealed that fentanyl was dissolved
ordered units, it was essential to document the average drug almost instantly from the tablets. Data for the amount of
content and uniformity of the tablets. With a mean tablet dissolved fentanyl as a function of time are presented in
weight of approximately 70 mg (Table 2), the correspond- Fig. 3. For tablets of 100 and 200 g fentanyl, roughly 75%
ing content of fentanyl citrate was 0.22% (w/w) (100 g), of the substance was dissolved from the tablet within 1 min,
0.45% (w/w) (200 g) and 0.90% (w/w) (400 g). Since and more than 95% within 3 min. Drug dissolution from
a small amount of drug is mixed with a large amount of tablets containing 400 g was slightly slower: 75% within
a coarse excipient, it is important to have an adequate 2 min and 95% within 5 min. The dissolution profiles for all
number of drug particles present (Sundell-Bredenberg and tablets are comparable with those obtained for ordered mix-
Nystrm, 2001). This was achieved by using a small par- tures by Westerberg and Nystrm (1991), i.e. compaction
ticle size (5 m in diameter) (Nystrm and Malmqvist, of the ordered units did not negatively influence the disso-
1980; Sundell-Bredenberg and Nystrm, 2001). Thereby, lution rate. After initially rapid disintegration, ordered units
the possibility of the statistical probability to find a suffi- are quickly exposed to the solvent and drug dissolution starts
cient number of drug particles on each carrier particle is more or less instantly. The somewhat lower dissolution rate
increased. In this study, the particle size of fentanyl citrate for tablets containing 400 g fentanyl was thus not due to
was not determined directly; however, the specific surface retardation by the disintegration process, but was probably
area was used as a surrogate measure. The surface area, due to the higher surface area coverage of the hydrophobic
at 2.3 m2 /g, was considered to indicate sufficiently small drug (Westerberg and Nystrm, 1993).
S. Bredenberg et al. / European Journal of Pharmaceutical Sciences 20 (2003) 327334 333

120 1.00
Plasma concentration of fentanyl

0.90
Fentanyl citrate released (%)

100 0.80
0.70
80
(ng/ml)

0.60
60 0.50
0.40
40
0.30

20 0.20
0.10
0 0.00
0 1 2 3 4 5 6 7 8 9 10 0 50 100 150 200 250 300 350 400 450 500 550 600
Time (min) Time (min)

Fig. 4. Plasma concentrationtime profiles of fentanyl in one cancer patient


Fig. 3. Amount of fentanyl (%) dissolved from the tablets containing
following a sublingual dose of 100 g (), 200 g () and 400 g ()
fentanyl citrate corresponding to 100 g (), 200 g () and 400 g ()
fentanyl base.
fentanyl base, as a function of time (min). Mean values S.D. (n = 6).

In these in vitro dissolution studies, a large amount of dis- effectively utilise the advantages of rapid disintegration and
solution medium was used (300 ml, pH 7.3). However, the drug dissolution that are built into this system.
volume of fluid used in vivo was much smaller. Since the
solubility of fentanyl citrate is 25 mg/ml in water (Dollery
et al., 1991), approximately 0.025 ml fluid would theoreti- 4. Conclusions
cally be required to dissolve a dose of fentanyl citrate corre-
sponding to 400 g base. The fentanyl base has a solubility With this new sublingual tablet system, an optimal expo-
of 0.74 mg/ml in buffered aqueous media at pH 7.04 (Roy sure of active substance to the dissolving fluids in the mouth
and Flynn, 1989), and the corresponding volume required is combined with bioadhesive retention of the drug in the
for complete dissolution using this measurement is 0.54 ml. oral cavity, resulting in rapid sublingual absorption where
intestinal absorption is thus essentially avoided. The possi-
3.3. Pharmacokinetic study bility to attain a rapid absorption into the systemic circula-
tion give promises of a new approach to treat breakthrough
After single dose administration, plasma concentrations pain.
of fentanyl were obtained within 10 min, with no second The new sublingual tablet system could also be useful for
peak corresponding to possible gastrointestinal absorption substances other than fentanyl where a rapid onset of effect
(Fig. 4). It therefore appears that the bioadhesive compo- is desirable.
nent (Kollidon CL) promoted the retention of the ordered
units under the tongue without hindering the release and
local absorption of fentanyl. It appears that the fraction of Acknowledgements
the fentanyl dose that was swallowed was smaller compared
to other mucosal delivery systems (Streisand et al., 1998). Orexo AB (Sweden) is gratefully acknowledged for finan-
This was further supported by calculating the area under cial support. Two of the authors, Bredenberg and Nystrm,
the plasma concentrationtime curves (AUC) and compar- would also like to acknowledge AstraZeneca (Sweden),
ing them with pharmacokinetic data from intravenous ad- Pharmacia Corporation (Sweden) and the Knut and Alice
ministration (data from the literature: Mather et al., 1998). Wallenberg Foundation for financial support.
Based on this comparison, at least 70% of the doses admin-
istered, reached the systemic circulation (Lennerns et al.,
submitted for publication). References
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