sublingual tablet

European Journal of Pharmaceutical Sciences 20 (2003) 327–334

In vitro and in vivo evaluation of a new sublingual tablet system for rapidoromucosal absorption using fentanyl citrate as the active substance

Susanne Bredenberga, Margareta Dubergb, Bo Lennernäsc, Hans Lennernäsa,Anders Petterssond, Marie Westerbergb, Christer Nyströma,∗

a Department of Pharmacy, Uppsala University, Box 580, SE-751 23 Uppsala, Swedenb Orexo AB, Uppsala, Sweden

c Department of Oncology, Sahlgrenska Academy, Gothenburg, Swedend 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 substancebefore it has been released and absorbed locally into the systemic circulation. This paper introduces a new tablet system for sublingualadministration and rapid drug absorption. The tablet is based on interactive mixtures of components, consisting of carrier particles partiallycovered 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 absorptionin the oral cavity, a bioadhesive component was also added to the carrier particles. Tablets containing 100, 200 and 400�g of fentanyl weretested both in vitro and in vivo. The tablets disintegrated rapidly and dissolution tests revealed that fentanyl citrate was dissolved from theformulation almost instantly. Plasma concentrations of fentanyl were obtained within 10 min, with no second peak. These results indicatedthat the bioadhesive component prevented the fentanyl from being swallowed (the fraction swallowed was considered smaller compared toother mucosal delivery systems), without hindering its release and absorption. This new sublingual tablet formulation may also hold potentialfor 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

1.1. Background

A rapid onset of pharmacological effect is often desiredfrom drugs, especially in the treatment of acute disorders.This can effectively be achieved by parenteral administra-tion, but this method may not always be convenient for thepatient. Therefore, there is growing interest in developingnew, non-parenteral, reliable and convenient dosage formsusing administration routes where a rapidly dissolved drugis immediately absorbed into the systemic circulation. Tabletformulations are generally the first choice for drug admin-istration because of the relative ease of both production and

∗ Corresponding author. Tel.:+46-18-471-44-72;fax: +46-18-471-42-23.

E-mail address: [email protected] (C. Nyström).

usage. However, for acute disorders, the time to onset ofaction for a conventional oral tablet is generally not accept-able; this is usually attributable to gastric emptying causinga highly variable lag time between drug administration andonset of intestinal absorption.

Oromucosal delivery, especially that utilising the buccaland sublingual mucosa as absorption site, is a promisingdrug delivery route which promotes rapid absorption andhigh bioavailability, with subsequent almost immediate on-set of pharmacological effect. These advantages are the re-sult of the highly vascularised oral mucosa through whichdrugs enter the systemic circulation directly, bypassing thegastrointestinal tract and the first pass effect in the liver(Moffat, 1971). Among the most important characteristicsof tablet formulations used for oromucosal delivery are ashort disintegration and dissolution time. However, in orderto achieve optimal oromucosal delivery, properties of the ac-tive compound and other properties of the formulation have

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328 S. Bredenberg et al. / European Journal of Pharmaceutical Sciences 20 (2003) 327–334

also to be considered. The parent compound has to be sol-uble, stable and able to easily permeate the mucosal barrierat the administration site. Further, the dosage form has tobe rapidly dissolved while retaining a sufficiently long con-tact time at the administration site. If dissolution of the drugis incomplete, contact time is short, and/or permeation toolow, part of the dose will not be absorbed through the oralmucosa and will be swallowed, with subsequent effects onbioavailability.

The main prerequisites for rapid dissolution of drugs in-clude a large surface area of the drug exposed to the dis-solving liquid and the lack of thick, stagnant hydrodynamicboundary layers around the drug particles that hinder drugdissolution by slowing diffusional transport (e.g.Noyes andWhitney, 1897; Nyström et al., 1985; Bisrat et al., 1992).While the drug surface area effectively in contact with thedissolving fluid can be enlarged by using very finely dividedgrades of drug, the added excipients should not hinder dis-solution by separating the dissolving liquid from the drugparticles. The use of water-soluble excipients is the mostcommon approach in this context. Freeze–drying the dosageform is an expensive but effective way of obtaining highlyporous tablets, which promote rapid exposure of the drugphase and thus rapid drug dissolution (e.g.Corveleyn andRemon, 1998). Another, more simple, method of improv-ing drug exposure is to use so-called ordered or interactivemixtures (Westerberg, 1992). These are achieved by mix-ing coarse carrier particles with a fine drug component fora relatively long time so that the fine drug particles adhereto the surface of the carrier particle by adhesion forces, andare optimally exposed to the dissolving fluid (Nyström andWesterberg, 1986).

1.2. The new sublingual tablet concept

This paper outlines a new formulating system for rapidlyabsorbed sublingual tablets. The new concept is based onthe use of ordered mixtures of fine drug particles attachedto coarser excipient carrier particles. These ordered units(each unit comprises a well defined carrier particle coatedwith drug particles) offer several formulation advantages:(a) they potentially facilitate the design of rapidly disinte-grating tablets, (b) they provide optimal drug exposure and(c) they have the potential to provide immediate drug disso-lution. Certain factors are required to achieve an interactivemixture containing a low proportion of drug and high ho-mogeneity of dose. Obviously, the drug should be able toform strong adhesive interactions with the carrier particles.Previous studies have indicated that the drug particle sizeshould not exceed 5�m in diameter and should preferablyhave a narrow size distribution (Nyström and Malmqvist,1980; Sundell-Bredenberg and Nyström, 2001). It is also ap-parent that high dose homogeneity can be obtained by drymixing micronised drugs in proportions as low as 0.015%(w/w) (Sundell-Bredenberg and Nyström, 2001). Westerbergand Nyström (1993)found that the use of ordered mix-

tures with a low surface area coverage of the carrier parti-cle resulted in drug dissolution rates even faster than thosefrom well-dispersed suspensions. These studies thus sug-gest that a finely divided potent drug mixed with a coarsewater-soluble material ought to result in both a high unifor-mity of drug content and rapid drug dissolution. Further, theuse of this dry mixing technique allows direct compressionof the tablets, with associated economical advantages overthe classic wet granulation technique.

One problem associated with sublingual tablet formula-tions is the potential for the patient to swallow parts of thedose before the active substance has been released and ab-sorbed locally into the systemic circulation. Addition of abioadhesive component to the formulation is a well-knownapproach of increasing the probability of a more site-specificdrug release. However, because this concept is normally ap-plied to non-disintegrating tablets or discs in order to extendthe release of the active substance, such a system may notbe suitable for an immediate-release formulation. A new ap-proach to the problem has been suggested byBredenbergand Nyström (2003), who found that by dry mixing, carrierparticles could be partially covered with fine dry particlesof a bioadhesive material to form an interactive mixture.These small, bioadhesive units could then replace the large,bioadhesive, single unit (tablet or disc). It is then theoreti-cally possible to add the active substance to the surface ofthese carrier particles, resulting in ordered units comprisingcoarse particles carrying both bioadhesive component anddrug. After compression, tablets composed of these unitswould have the potential to rapidly disintegrate and releasethe units to adhere to the sublingual mucosa. Provided thedrug is instantly dissolved and able to permeate the mucousmembranes easily, it will be rapidly absorbed at the admin-istration site before there is a chance of it being swallowed.

Patients with cancer often suffer from chronic pain andrequire round the clock opioid therapy. However, break-through pain frequently appears despite this analgesic ther-apy, and supplemental opioid doses are required (Portenoyand Hagen, 1990). Then, administering oral morphine, theonset of action is often delayed up to 60 min (Hanks et al.,1998). Parenteral therapy would provide instant relief fromthis pain, but this route is not particularly convenient for thepatient. In this context, a specially designed tablet formu-lation would have the potential to be both therapeuticallyeffective and easy for the patient to use.

Fentanyl is a potent synthetic opioid, which is used inthe treatment of breakthrough pain (Portenoy and Lesage,1999). As the citrate salt, fentanyl is sparingly soluble inwater and highly lipophilic, and is expected to be rapidlyabsorbed after complete dissolution because of its ease ofpermeation through mucous membranes (McClain and Hug,1980; Dollery et al., 1991). An existing product in the formof a lollipop containing fentanyl citrate was designed to al-low rapid absorption of the drug from the oral cavity (Mocket al., 1986; Ashburn et al., 1989). The active compoundwas incorporated into a dissolvable candy matrix and placed

S. Bredenberg et al. / European Journal of Pharmaceutical Sciences 20 (2003) 327–334 329

on a stick. The patient holds the lollipop against the buccalmucosa and licks it. However, it is documented that a largeproportion of the active substance is swallowed using thisdelivery system (Zhang et al., 2002). This results in highlyvariable bioavailability, since fentanyl citrate undergoes ex-tensive cytochrome P450 (CYP)-3A4-mediated metabolismin both the intestine and the liver (Streisand et al., 1991;Labroo et al., 1997). The absorption (Weinberg et al., 1988)and efficacy (Zeppetella, 2001) of fentanyl delivered as a so-lution to the sublingual mucosa has also been investigated.In a study byZeppetella (2001), a solution of fentanyl citrate(maximum 3 ml, corresponding to 150�g fentanyl base) wasplaced under the patient’s tongue; for most patients (82%),an analgesic effect was obtained after 10–15 min. However,some patients found it difficult to retain the solution underthe tongue and swallowed it.Weinberg et al. (1988)useda solution of fentanyl with a pH of 6.5, which is the natu-ral pH of saliva. The solution (1 ml corresponding to 50�gfentanyl base) was held under the tongue for 10 min withoutswallowing, at which point the solution was expectoratedand analysed. The mean amount absorbed was calculated tobe 51% of the fentanyl dose, higher than the 22% calculatedfor morphine.

Considering the shortcomings of the approaches currentlyavailable for administration of fentanyl to patients sufferingbreakthrough pain, it was felt that a new sublingual soliddosage form that provided a rapid and reproducible onset ofaction and was also convenient for the patient was a desirableaim. This dosage form should also encourage retention ofthe active substance under the tongue, so as to increase con-tact time at the absorption site and avoid the potential intra-and interindividual variability resulting from swallowing it.The studies described in this paper were designed to evalu-ate a new sublingual tablet system using low doses of fen-tanyl citrate (Rapinyl®). In this system, water-soluble carrierparticles are covered with fentanyl citrate and a bioadhesivematerial during dry mixing. In principle, the tablet quicklydisintegrates into the ordered units consisting of carrier, fen-tanyl citrate and bioadhesive component (Fig. 1). These unitsinitially adhere to the mucosa. The water-soluble carrier par-ticles gradually dissolve and fentanyl citrate dissolves alongwith them. With this approach, optimal exposure of activesubstance to the dissolving fluids is combined with bioad-hesive retention of the drug in the oral cavity.

The main objective of this report is to investigate whetherrapid disintegration and dissolution in vitro could result in

Fig. 1. Schematic model of the disintegration, bioadhesion and drug dissolution of the new sublingual tablet system.

improved systemic exposure of the parent drug, especiallyregarding absorption rate. Another objective was to studythe bioadhesion of the particles and avoidance of swallowingthe active ingredient in a clinical trial.

2. Materials and methods

2.1. Materials

Fentanyl citrate (Diosynth, The Netherlands) was milledby hand in a mortar. Fentanyl citrate is sparingly solublein water (1:40), has a pKa of 8.43, a partition coefficientin octanol/water of 955 and a dose-dependent plasma halflife of 1–6 h (Dollery et al., 1991). Granulated mannitol(Roquette, France) was used as carrier material, cross-linkedpolyvinylpyrrolidone (Kollidon CL, BASF, Germany) wasused as the disintegrant and bioadhesive component, silici-fied microcrystalline cellulose (ProSolv SMCC® 90, Pen-west Pharmaceuticals Co., USA; referred to hereafter asSMCC) was used as the binder and magnesium stearate (Pe-ter Greven, Fett-Chemie GmbH & Co., KG, Germany) wasused as the lubricant; all were used as supplied.

2.2. Methods

2.2.1. Primary characterisation of test materialsThe apparent particle density (B.S. 2955, 1958) of the

materials (n = 3) was measured using a helium pycnome-ter (AccuPyc 1330 Pycnometer, Micromeritics, USA). Theexternal specific surface area of mannitol was determinedusing Friedrich permeametry (Eriksson et al., 1990). Blainepermeametry (Kaye, 1967) was used to determine the exter-nal specific surface area of all other powders (except magne-sium stearate); the surface areas were corrected for slip flowbecause of the small particle size (Alderborn et al., 1985).

2.2.2. Preparation of mixturesCoarse mannitol particles were covered with fentanyl

citrate by dry mixing (Fig. 2). The materials were mixedin a Teflonized metal jar in a tumbling mixer (Turbulamixer T2F, W.A. Bachofen AG, Switzerland) at 90 rpmfor 48 h. However, for the lowest drug proportion (100�gbase drug per tablet), the mixing time was increased to 72 h(Sundell-Bredenberg and Nyström, 2001). Kollidon CL andSMCC were added to the interactive mixture and mixed at30 rpm for an additional 30 min (Fig. 2).


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

2.2.3. Compaction of tabletsPrior to compaction, all tablet masses were mixed with

magnesium stearate (0.5% (w/w)) in the tumbling mixerat 30 rpm for 2 min. Tablets were made in a single punchpress (Korsch EK0, Germany) using 6 mm flat bevel edgedpunches; the powder was filled into the die with a feedshoe. The tablets contained fentanyl citrate correspondingto 100�g, 200�g or 400�g of fentanyl base. Each batchcomprised 1000 tablets.

2.2.4. Characterisation of tablets

2.2.4.1. Porosity. The tablet porosity was calculated fromthe dimensions and weight of the tablet and the apparent par-ticle density of the mixture, which was calculated accordingto Jerwanska et al. (1995).

2.2.4.2. Tensile strength. A diametral compression test(Kraemer HC97, Kraemer Elektronik GmbH, Germany) wasperformed according toEuropean Pharmacopoeia (1997)method 2.9.8 (resistance to crushing of tablets) (n = 35).

2.2.4.3. Friability. The friability of the tablets was mea-sured according toEuropean Pharmacopoeia (1997)method2.9.7 (friability of uncoated tablets), i.e. using the Roche fri-ability apparatus for 4 min with the drum rotating at a speedof 25 rpm. Twenty tablets were weighed before and after themeasurement and the weight loss was calculated (n = 1).

2.2.4.4. Disintegration time. The disintegration time ofthe tablets was measured in water according toEuropeanPharmacopoeia (1997)method 2.9.1 (disintegration oftablets and capsules, test A) (Kraemer DES-1, KraemerElektronik GmbH, Germany). In this study, the disintegra-tion time was recorded both with and without the use ofdiscs.

2.2.4.5. Assay of fentanyl. The content of fentanyl in tentablets was analysed using reversed-phase high-performance

liquid chromatography (RP-HPLC) with UV detection. Themobile phase consisted of phosphate buffer (pH 2.8) with35% acetonitrile. The analyses were performed accord-ing to the European Pharmacopoeia and by Quintiles AB,Sweden.

2.2.4.6. Drug dissolution. Dissolution tests were per-formed according to a modified European Pharmacopoeiapaddle method (Prolabo dissolutest, Germany). The pad-dle rotation rate was 50 rpm and the dissolution mediumwas water (volume: 300 ml; temperature 37◦C). Sampleswere collected after 1, 3, 5, 7 and 10 min. The amountof fentanyl was determined using liquid chromatography(LC) with Shimadzu SPD-10A vp detector. The mobilephase consisted of 65% phosphate buffer (pH 2.8) and 35%acetonitrile. The LC system was equipped with a AquasilC18 column (250 mm× 4.6 mm, 5�m). The analysis wasperformed by Mikro Kemi AB, Sweden. The percentage ofdissolved drug was calculated in relation to the maximumamount detected (=100%) and the data were presented inthe dissolution rate profiles as a function of time.

2.3. Clinical study

2.3.1. Study designAfter giving written informed consent to participate in the

study, one patient (62 years male) with cancer (myeloma)received fentanyl doses of 100, 200 and 400�g, respec-tively, as a single dose in the form of a sublingual tablet.The doses were given in random order and were separatedby wash-out periods of at least 3 days. Blood samples(n = 16, 7 ml each) for determination of fentanyl in plasmawere collected at 0–600 min. Tolerability parameters suchas blood pressure, heart rate and oxygen saturation werefollowed during the complete study day. Adverse eventswere continuously monitored throughout the study. A safetyfollow-up, including physical examination, routine haema-tology and clinical chemistry was performed 2–5 days afterthe last dose. This paper presents results from one patient,


which was included in a study with eight patients withcancer (Lennernäs et al., submitted for publication). Thestudy was approved by the ethics committee of GothenburgUniversity.

2.3.2. Sample analysisFentanyl was separated from plasma samples by liq-

uid/liquid extraction, using n-heptan containing 3%2-butanol at pH >12. After evaporation, the residue wasdissolved in 5 mM formic acid solution. The amount offentanyl was determined using RP-HPLC with LC–MS/MSdetection. The mobile phase consisted of acetonitrile:water(18:82) containing 5 mM formic acid. The analysis wasperformed by Quintiles AB, Sweden.

3. Results and discussion

3.1. The formulation of the fentanyl tablets

The materials used and composition of the tablets in thisstudy are presented inTable 1 and Fig. 2. In interactivemixtures consisting of close to identical ordered units, thedrug dissolution rate is affected by the particle size of boththe drug and the carrier as well as by the physicochemicalproperties of the carrier (Westerberg, 1992). Westerberget al. (1986)found that the carrier particle is required tobe highly soluble for rapid drug dissolution. In this study,the carrier material was mannitol, which has been shownpreviously to have good carrier properties, such as highwater solubility (Wade and Weller, 1994). High dissolutionrates were also maintained after tableting mixtures con-taining mannitol (Westerberg and Nyström, 1991). Drugdissolution is also affected by the surface area coverage ofthe carrier, calculated in this study according toNyströmet al. (1982). Low surface area coverage (<20%) results

Table 1Primary characteristics of test materials and composition of the fentanyl tablets

Material Apparent particledensitya (g/cm3)

External specificsurface areab (m2/g)

Test materials corresponding to Placebo (mg)

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 59.6SMCC 1.578 (±0.003) 0.35 (±0.00) 7.00 7.00 7.00 7.00Kollidon CL 1.224 (±0.001) 0.42 (±0.025) 3.00 3.00 3.00 3.00Magnesium stearate 1.071 (±0.004) g 0.400 0.400 0.400 0.400Tablet 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.

in complete deagglomeration of drug particles and rapiddissolution; an intermediate degree of surface area cover-age (20–100%) also results in rapid drug dissolution eventhough some of the drug particles will be released in theform of small agglomerates rather than as discrete particles(Westerberg, 1992). However, as mentioned in the introduc-tion, these values are also dependent on the characteristicsof the drug (e.g. agglomeration tendency and particle size).In this study, the surface area coverage of mannitol withfentanyl citrate particles was 7% (100�g), 14% (200�g)and 27% (400�g).

Bredenberg and Nyström (2003)have shown that highlywater-soluble carrier materials are less bioadhesive than in-soluble carriers, probably because the tensile fracture goesthrough the partly dissolved carrier particles rather thanthrough the mucosa or between the mucosa and the bioad-hesive material. However, it is not always desirable to con-centrate only on optimal bioadhesion and the choice ofcarrier for these fentanyl tablets involved consideration ofboth a high dissolution rate to optimise absorption of fen-tanyl over the sublingual mucosa and adequate bioadhe-sive properties to minimise swallowing of the substance.Since mannitol fulfils both these criteria (Westerberg, 1992;Bredenberg and Nyström, 2003) it was chosen as the car-rier material. Kollidon CL also has bioadhesive properties(Bredenberg and Nyström, 2003) and was therefore expectedto prolong the residence time of the ordered units at thesublingual mucosa. Kollidon CL also has the advantageof being a very effective disintegrant (e.g.Kornblum andStoopak, 1973; Shangraw et al., 1980). Addition of a highlydeformable binder during compaction could, by forming adeformable microstructure around the particles, counteractthe effect of a disintegrant (Mattsson et al., 2001). SMCCis a moderately deformable binder (Mattson and Nyström,2001) and is unlikely to significantly impair the disintegra-tion process.


Table 2Technical properties and drug content of fentanyl tablets

Tablets(�g fentanyl)

Weighta (mg) Friabilityb (%) Crushingstrengthc (N)

Averagecontentd (%)

Uniformity of content(minimum–maximum) (%)

Disintegration time

Withdiscse (s)

Withoutdiscsf (s)

100 70.2 (±0.78) 0.44 12.1 (±1.38) 95 91.0–101.4 50 <10200 70.0 (±0.59) 0.74 11.3 (±1.69) 95 87.7–105 33 <10400 69.3 (±0.73) 0.64 11.7 (±2.27) 96 88.2–94.4 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

3.2.1. Tablet strength, weight, friability and porosityThe tablets were characterised regarding weight, tablet

strength and friability (Table 2). The weight and friabil-ity results were within the limits specified in theEuropeanPharmacopoeia (1997). Both tablet strength and disintegra-tion time are affected by tablet porosity. The porosity of thetablet may affect the efficacy of the disintegrant. A relativelylow porosity was most effective for the action of a disinte-grant in some studies (Shangraw et al., 1980; Ferrari et al.,1995). However, no general relationship between porosityand disintegration time was seen in the study byMattssonet al. (2001)and it was concluded that the material proper-ties of the tablet components, such as solubility and bond-ing ability, would also affect disintegration time. The aimof this study was to achieve high tablet tensile strength andfast tablet disintegration. The tablet porosity was approxi-mately 25% for all three batches, which appears adequateconsidering the results for tablet strength (Table 2).

3.2.2. Average drug content and content uniformitySince the amount of active substance in the tablets was

relatively low and dry mixing was applied to obtain theordered units, it was essential to document the average drugcontent and uniformity of the tablets. With a mean tabletweight of approximately 70 mg (Table 2), the correspond-ing content of fentanyl citrate was 0.22% (w/w) (100�g),0.45% (w/w) (200�g) and 0.90% (w/w) (400�g). Sincea small amount of drug is mixed with a large amount ofa coarse excipient, it is important to have an adequatenumber of drug particles present (Sundell-Bredenberg andNyström, 2001). This was achieved by using a small par-ticle size (≤5�m in diameter) (Nyström and Malmqvist,1980; Sundell-Bredenberg and Nyström, 2001). Thereby,the possibility of the statistical probability to find a suffi-cient number of drug particles on each carrier particle isincreased. In this study, the particle size of fentanyl citratewas not determined directly; however, the specific surfacearea was used as a surrogate measure. The surface area,at 2.3 m2/g, was considered to indicate sufficiently small

particles. This was confirmed by the tests of average drugcontent and content uniformity, which showed that onlyminor segregation had occurred during tablet processing(i.e. mixing and tableting) (Table 2).

3.2.3. Tablet disintegrationIn principle, the tablets should disintegrate rapidly, to in-

stantly generate many ordered units consisting of mannitol,fentanyl citrate and Kollidon CL (Fig. 1). The disintegra-tion time of the three batches of tablets containing fentanylcitrate corresponding to 100, 200 and 400�g fentanyl basewas 33–50 s using discs and less than 10 s without discs(Table 2). The higher value with discs was probably causedby adhesion of the tablets to the discs (because of the ad-dition of bioadhesive), which fudged the endpoint. It seemsreasonable from these results that the tablet will adhere tothe mucosa in the mouth. The in vitro data obtained withdiscs probably better reflects the disintegration time in vivointo ordered units. However, the peristaltic movements thatoccur in the mouth may contribute to the disintegration ofthe tablets.

3.2.4. Drug dissolutionThe dissolution tests revealed that fentanyl was dissolved

almost instantly from the tablets. Data for the amount ofdissolved fentanyl as a function of time are presented inFig. 3. For tablets of 100 and 200�g fentanyl, roughly 75%of the substance was dissolved from the tablet within 1 min,and more than 95% within 3 min. Drug dissolution fromtablets containing 400�g was slightly slower: 75% within2 min and 95% within 5 min. The dissolution profiles for alltablets are comparable with those obtained for ordered mix-tures byWesterberg and Nyström (1991), i.e. compactionof the ordered units did not negatively influence the disso-lution rate. After initially rapid disintegration, ordered unitsare quickly exposed to the solvent and drug dissolution startsmore or less instantly. The somewhat lower dissolution ratefor tablets containing 400�g fentanyl was thus not due toretardation by the disintegration process, but was probablydue to the higher surface area coverage of the hydrophobicdrug (Westerberg and Nyström, 1993).


0

20

40

60

80

100

120

0 1 2 3 4 5 6 7 8 9 10

Time (min)

Fen

tan

yl

cit

rate

rele

ase

d (

%)

Fig. 3. Amount of fentanyl (%) dissolved from the tablets containingfentanyl citrate corresponding to 100�g (�), 200�g (�) and 400�g (�)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-solution medium was used (300 ml, pH 7.3). However, thevolume of fluid used in vivo was much smaller. Since thesolubility of fentanyl citrate is 25 mg/ml in water (Dolleryet al., 1991), approximately 0.025 ml fluid would theoreti-cally be required to dissolve a dose of fentanyl citrate corre-sponding to 400�g base. The fentanyl base has a solubilityof 0.74 mg/ml in buffered aqueous media at pH 7.04 (Royand Flynn, 1989), and the corresponding volume requiredfor complete dissolution using this measurement is 0.54 ml.

3.3. Pharmacokinetic study

After single dose administration, plasma concentrationsof fentanyl were obtained within 10 min, with no secondpeak corresponding to possible gastrointestinal absorption(Fig. 4). It therefore appears that the bioadhesive compo-nent (Kollidon CL) promoted the retention of the orderedunits under the tongue without hindering the release andlocal absorption of fentanyl. It appears that the fraction ofthe fentanyl dose that was swallowed was smaller comparedto other mucosal delivery systems (Streisand et al., 1998).This was further supported by calculating the area underthe plasma concentration–time curves (AUC) and compar-ing them with pharmacokinetic data from intravenous ad-ministration (data from the literature:Mather et al., 1998).Based on this comparison, at least 70% of the doses admin-istered, reached the systemic circulation (Lennernäs et al.,submitted for publication).

The fast-acting sublingual tablet described in this paperhas potential to be a valuable addition to the arsenal ofdrugs for breakthrough pain. The technique could also beuseful for substances other than fentanyl where a rapid on-set of effect is desirable. However, the new sublingual tabletsystem would probably be less useful for hydrophilic drugmolecules, since this group of drugs will not undergo suf-ficiently rapid absorption across the sublingual mucosa to

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

0 50 100 150 200 250 300 350 400 450 500 550 600

Time (min)

Pla

sma c

on

cen

trati

on

of

fen

tan

yl

(ng

/ml)

Fig. 4. Plasma concentration–time profiles of fentanyl in one cancer patientfollowing a sublingual dose of 100�g (�), 200�g (�) and 400�g (�)fentanyl base.

effectively utilise the advantages of rapid disintegration anddrug dissolution that are built into this system.

4. Conclusions

With this new sublingual tablet system, an optimal expo-sure of active substance to the dissolving fluids in the mouthis combined with bioadhesive retention of the drug in theoral cavity, resulting in rapid sublingual absorption whereintestinal absorption is thus essentially avoided. The possi-bility to attain a rapid absorption into the systemic circula-tion give promises of a new approach to treat breakthroughpain.

The new sublingual tablet system could also be useful forsubstances other than fentanyl where a rapid onset of effectis desirable.

Acknowledgements

Orexo AB (Sweden) is gratefully acknowledged for finan-cial support. Two of the authors, Bredenberg and Nyström,would also like to acknowledge AstraZeneca (Sweden),Pharmacia Corporation (Sweden) and the Knut and AliceWallenberg Foundation for financial support.

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