British Journal of Clinical Pharmacology

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1 et al. DOI: /j x British Journal of Clinical Pharmacology Comparison of the pharmacokinetics of miconazole after administration via a bioadhesive slow release tablet and an oral gel to healthy male and female subjects J.-M. Cardot, 1,3 C. Chaumont, 2 C. Dubray, 3 D. Costantini 2 & J.-M. Aiache 1 1 Laboratoire de Biopharmacie, Faculté de Pharmacie, 28 Place Henri Dunant, BP 38, F Clermont-Ferrand, 2 Laboratoires BIOALLIANCE PHARMA, 59 Bd du G al Martial Valin, F Paris and 3 Centre de Pharmacologie Clinique, Bâtiment «3C», CHRU, 58 rue Montalembert, BP 69 F63003 Clermont-Ferrand, France Correspondence Dr J.-M. Cardot, Laboratoire de Biopharmacie, Faculté de Pharmacie, 28 Place Henri Dunant, BP 38, F Clermont-Ferrand, France. j-michel.cardot@u-clermont1.fr Keywords bioadhesive tablet, miconazole, pharmacokinetics Received 19 November 2003 Accepted 24 March 2004 Aims The aim of this study was to compare salivary miconazole pharmacokinetics following once daily application of bioadhesive tablets (50 or 100 mg), vs the current treatment with a gel (3 times a day, 375 mg day -1 ). Methods A three way cross over study was carried out in 18 healthy subjects (nine males, nine females) with a 1 week washout period between each treatment. Plasma and salivary pharmacokinetics of miconazole were assessed over a 24-h period. Results In all subjects the tablets gave higher and more prolonged salivary miconazole concentrations than the gel. Thus salivary miconazole AUC(0,24 h) was 37.2 times greater for the 100 mg tablet (90% confidence interval [CI] 22.9, 60.5) and 18.9 times greater for the 50 mg tablet (CI 11.7, 30.6) compared with the gel. Similarly, C max was 17.2 times greater (CI 11.8, 25.2) and 7.8 times greater (CI 5.3, 11.4) for the 100 mg tablet and 50 mg tablet, respectively. Comparison of the 100 mg and 50 mg tablets gave ratios of 2.2 and 2.0 for C max and AUC(0,24 h), respectively (CI 1.5, 3.2 and 1.2, 3.2). The mean time that salivary miconazole concentrations were above 0.4 mg ml -1 (the concentration reached 3 h after application of the oral gel according to published data) or above 1.0 mg ml -1 (the MIC of some Candida species) was greater for both bioadhesive tablets than for the oral gel (10 14 h vs 1.5 h and 7 h vs 0.6 h). Only 19 plasma samples from eight subjects had concentrations of miconazole above 0.4 mg ml -1. Ten of these were taken from five subjects after administration of the gel and nine from three subjects after administration of the tablets. Conclusions These data strongly support the further development of miconazole bioadhesive tablets as a sustained release formulation leading to improved antifungal exposure in the buccal cavity. A single daily application should improve compliance, whereas the low systemic absorption of miconazole will alleviate concerns regarding drug interactions and adverse effects Blackwell Publishing Ltd Br J Clin Pharmacol 58:

2 J.-M. Cardot et al. Introduction Candida organisms can live commensally on the skin and mucous without causing harm but can mutate to an aggressive form and invade tissue causing both acute and chronic disease in the host [1]. Usually the oral cavity is the first infection site from where candidiasis can spread to the oesophagus and the gastro-intestinal tract. The main predisposing factor involved in the conversion of oral commensal Candida to a parasitic form is an alteration of the immune status of the host. This may be associated with age, malnutrition, chemotherapy, immunosuppressive agents or severe disease (HIV, cancer and bone marrow transplantation) [2 4]. Symptoms of oral candidiasis are extremely variable and range from none to a sore, painful mouth, burning tongue, and dysphagia with involvement of the hypopharynx. Oral candidiasis impairs quality of life and may result in a decrease in fluid or food intake. Although the severity of symptoms may vary, the treatment of initial oropharyngeal candidiasis is considered obligatory [4, 5]. If left untreated, progressive colonization can lead to increased discomfort and, perhaps of greater concern, may predispose patients to more invasive disease, including oesophageal candidiasis. Treatments used against oral candidiasis include both topical and systemic drugs. Topical antifungals are usually the drugs of choice for uncomplicated, localized candidiasis [3, 5]. Topical agents may be administered in a suspension formulation, (nystatin or amphotericin B), in an oral gel (miconazole), or in lozenge form (clotrimazole troches). Systemic azole therapies include ketoconazole, itraconazole and fluconazole, and are generally administered once daily in tablet, capsule or elixir form [5, 6]. Owing to concerns over the development of resistance, systemic oral azoles are not recommended for the treatment of initial oropharyngeal candidiasis unless there are extenuating circumstances, such as oesophageal involvement. In the event that systemic azole therapy is necessary, the duration of acute treatment should be at least 2 weeks [3, 5]. Furthermore, these azoles, in particular ketoconazole and itraconazole, are potent inhibitors of the hepatic cytochrome P- 450 enzyme system and can dramatically affect the metabolic profile and half-life of a variety of other drugs, including antiretrovirals used in HIV treatment, immunosuppressive agents (cyclosporin, tacrolimus), oral hypoglycaemics and oral anticoagulants [7, 8]. Topical agents are efficient in the treatment of buccal candidiasis and are preferred as the potential for drug drug interactions is greatly diminished, as is the likelihood of the development of resistance. The main cause of therapeutic failure with topical agents is poor compliance [3]. Since they do not remain for long in the oral cavity, topical agents have to be applied several times a day (five times for clotrimazole troches, four times for miconazole oral gel). This problem is so common in patients with HIV that systemic azole treatment is recommended when compliance is difficult to achieve [9]. Other drawbacks that limit topical agent usage are inconvenient formulations (mouth wash, gel and troches), bad taste, and the risk of caries because of a high concentration of sugar to help hide the unpleasant taste [10]. Thus the need is great for a potent and convenient topical formulation for the treatment of candidiasis. Accordingly, we have developed a once a day topical formulation of miconazole, an antifungal of the azole family that acts by inhibiting ergosterol synthesis. This drug is marketed worldwide and is indicated for buccal or oesophageal candidiasis infections. It has well established tolerance (partly because of limited absorption) and efficacy profiles [11], and has a broad spectrum of activity against different species of Candida. Candida species more often encountered in buccal candidiasis show high or medium sensitivity to miconazole with minimal inhibitory concentrations (MIC) of between 1 and 10 mg ml -1 for C. albicans and 1 mg ml -1 for C. tropicalis and C. krusei [13]. The use of 125 mg of miconazole formulated as an oral gel (5 ml of Daktarin oral gel) results in salivary concentrations of miconazole that vary from 5.0 to 0.4 mg ml -1, from 30 min to 3 h after application [13, 14]. Our slow release formulation was developed as a bioadhesive tablet (Lauriad ), which can adhere to the buccal mucosa and release the antifungal. A natural polymer, extensively used in the food industry, with good tolerance and appropriate adhesive properties was used to formulate the drug. The tablet adheres to the buccal mucosa, and then absorbs water which triggers sustained and constant miconazole release and tablet erosion [12]. The tablet is designed for application inside the upper lip. Miconazole concentration in the oral cavity must be sustained at sufficient concentrations to eradicate effectively the Candida. The present study compared administration of two single doses of the bioadhesive tablet with administration of miconazole oral gel applied three times a day. The primary aim of the study was to determine the salivary pharmacokinetic parameters of miconazole. The secondary aims were the determination of plasma concentrations of miconazole, and the acceptability, safety and adhesion properties of the bioadhesive tablets in comparison with the oral gel. The evaluation of acceptability, safety and adhesion are published elsewhere [15]. This report presents the pharmacokinetic results of the study :4 Br J Clin Pharmacol

3 Pharmacokinetics of bioadhesive tablets of miconazole Methods Study design This phase I study followed a randomized, single centre, open label, three-way cross-over design with a washout period of 1 week between each sequential treatment period. Eligible subjects were healthy males or females (who had practised effective contraception for more than 3 months), years old, who agreed to be hospitalized during the study. The number of subjects was set to 18 due to the exploratory nature of the study. Conditions or circumstances that excluded subjects from the study included milk hypersensitivity, liver failure, abnormality of buccal mucosa or any salivation disorder. Informed consent was obtained before the start of the study. All subjects were questioned about any significant medical history at their first visit. Each subject received the three different miconazole formulations in random order. Subjects were given either one 50 mg bioadhesive tablet (treatment A), one 100 mg bioadhesive tablet (treatment B) or three applications of 125 mg of Daktarin oral gel at 0, 3.5 h and 8.5 h (treatment C). The dosing schedule for the gel was selected to be close to the therapeutic regimen (four applications per day) and to allow a minimum of salivary and blood samples during the night. The bioadhesive tablets were applied to the cuspid fossa and stayed in the oral cavity until erosion or detachment. Each drug administration was witnessed by staff at the study centre. Subjects were allowed to drink ad libitum, using a straw, from 1 h after drug administration except during the 10 min preceding salivary sampling. A standardized meal was provided between 4 and 4.5 h after drug administration. The study was carried out in the Clinical Pharmacology Centre of the Clermont-Ferrand University Hospital following Good Clinical Practice (ICH recommendations) and the French law (loi Huriet). The study protocol, informed consent forms and Investigator s Brochure were approved by an independent ethics committee (CCPPRB d Auvergne). Sample collection Salivary samples were taken immediately before administration of miconazole and at times centered on 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 24 h post-dose. 2 ml of saliva were collected into plain plastic tubes over 2 min, without any stimulation of the salivary glands, and the tubes were vortexed and centrifuged for 5 min at 4000 r.p.m. Supernatants were aliquoted and frozen at -20 C until assay. To prevent artificially high concentrations of miconazole being present in the saliva, the tongue remained out of contact with the tablet during the 10 min preceding sampling. In addition, the lips of the subjects were washed before the 30 min and subsequent samples. Venous blood (5 ml) was collected into heparin lithium tubes immediately before drug administration and at 0.5, 1, 2, 3, 4, 8, 12 and 24 h post-dose. Tubes were vortexed and centrifuged for min at 4000 r.p.m. Plasma was aliquoted and frozen at -20 C. Analytical procedure Miconazole was analyzed by an HPLC method derived from that published by Bouckaert et al. [16]. This method used a Merck RP18, 5 mm licrospher column mm, a mobile phase of 82 : 12 water : methanol containing 0.1% ammonium carbonate, and UV detection at 220 nm. After extraction with a mixture of acetonitrile and methanol, 70 ml of the supernatant was injected. The HPLC run lasted for 18 min. The internal standard was econazole nitrate The lower limit of determination of the assay was 0.4 mg ml -1. The interassay coefficients of variation (imprecision) at miconazole concentrations of 1 mg ml -1, 10 mg ml -1 and 20 mg ml -1 were 10%, 2.5% and 2.6%, respectively. Inaccuracy was -1%, -3.6% and +3.4% at the same three concentrations, respectively. Pharmacokinetic analysis The following miconazole pharmacokinetic parameters were determined using model independent methods [17] and SAS software (version 8.02, SAS Institute Inc., Cary, NC USA) [18]: C max (the highest observed concentration, mg ml -1 ), t max (the time at which C max occurred, h), AUC(0,12 h) and AUC(0,24 h) (the area under the concentration-time curve, mg ml -1 h). AUCs were calculated by the trapezoidal rule including all data points up to 12 h or 24 h (last sampling point). In addition to the above pharmacokinetic parameters, the duration of buccal miconazole exposure above 0.4 and 1.0 mg ml -1 was calculated. The 0.4 mg ml -1 is the lower limit of determination of miconazole in saliva and plasma and is cited in the Vidal French medicinal dictionary [14] as the concentration reached 3 h after application of the oral gel. The upper limit of 1 mg ml -1 was based on the minimal inhibitory concentrations (MIC) for C. albicans (1 10 mg ml -1 ) and C. tropicalis and C. krusei ( 1 mg ml -1 ) [13]. Statistical analysis Simple descriptive statistics (SAS 8.02 Proc means) were calculated. The time above 0.4 and 1.0 mg ml -1 as well as the main pharmacokinetic parameters were log transformed and compared by ANOVA (SAS 8.02, Proc GLM) with sequence, subject treatment and period as Br J Clin Pharmacol 58:4 347

4 J.-M. Cardot et al. factors. The least squares means were calculated for all parameters. The ESTIMATE statement of GLM provided the elements for the calculation of 90% confidence intervals (CI). CIs of the ratio of test treatments to the reference treatment, with a significance level of 0.1, were calculated for AUC and C max. Results Eighteen subjects (nine males and nine females) were studied. All subjects received all three formulations of miconazole. Their mean age was 23 years (range years), mean body weight was 66.9 kg (range kg) and mean height was 174 cm (range cm). None of the subjects was suffering from any known disease at entry to the study nor were they receiving regular medication/non-drug therapies (except oral contraceptives). No medication/non-drug therapies were prescribed during the study other than those prescribed by the investigator. None of these medications was contraindicated during treatment with miconozole. The salivary pharmacokinetic data are shown in Table 1 and Figure 1. Salivary miconazole was still detected after the removal of the tablets in 6 and 9 subjects given the 50 and 100 mg tablet, respectively. The maximum duration of detectable salivary drug concentrations after tablet removal was 14 h (observed in two subjects receiving the 100 mg dose). After gel administration, peak concentrations were observed at 30 min (median) after each application (0.5, 4 and 9 h), reaching a mean (± SD) of 0.9 mg ml -1 (± 1.0), 0.8 mg ml -1 (± 0.8) and 1.1 mg ml -1 (± 1.7), respectively. The tablets gave a single peak concentration peak at 6 or 7 h after application reaching means (± SD) of 15.1 mg ml -1 (± 16.2) and 39.1 mg ml -1 (± 49.3) for the 50 and 100 mg doses, respectively. Interindividual variability was high, with one subject having extremely low miconazole salivary concentrations at both tablets doses and one subject with detectable miconazole concentrations only 12 h after the 50 mg dose. The lowest interindividual variability was observed after the 50 mg tablet. A coefficient of variation of 110% for AUC(0,24 h) was obtained after the 100 mg dose compared with 64% after 50 mg. Geometric LS means and 90% CI are presented in Table 2. The wide range of the latter reflected the high intraindividual variability observed, which was confirmed by a power (1-b) of about 20% for all parameters. The salivary AUCs and C max values obtained after administration of the bioadhesive tablets were significantly higher (P < ) than those obtained after administration of the gel. Significant differences were also observed (P = 0.01) between the two dosages of bioadhesive tablet for both C max and AUC(0,24 h). The ratios of the pharmacokinetic parameters observed for the two doses are presented in Table 2 and were about two for all the parameters except for AUC(0,12 h) (1.52). The length of time that the salivary concentration stayed above 0.4 mg ml -1 and 1.0 mg ml -1 and was much greater after the tablets than after administration of the oral gel (P < for both doses). There was no significant difference between the two tablet doses. Plasma miconazole concentrations achieved from the three formulations were generally below the limit of determination (0.4 mg ml -1 ), confirming low absorption through the buccal mucosa or the gastrointestinal tract after swallowing saliva. A total of 19 plasma samples, out of 360 analyzed, from eight subjects had concentrations of miconazole above 0.4 mg ml -1 and none had concentrations greater than 1.0 mg ml -1. The gel, which gave lower salivary concentrations, led to measureable plasma concentrations more frequently than the tablets, probably due to swallowing of the gel and the higher dosage. Ten of the 19 miconazole positive plasma samples were taken after gel administration in five subjects compared with nine samples from three subjects after tablet administration. Plasma AUC, C max and t max were not calculated due to insufficient data above LOQ. The overall duration of tablet adhesion was good (except for three cases where the 100 mg tablets exhibited an adhesion time below 6 h) and the mean duration of adhesion was similar for the two formulations (15.1 ± 6.7 and 15.2 ± 4.4 h for 100 and 50 mg tablets, respectively). The minimum duration of adhesion was 4.8 h for the 100 mg tablet vs 9.6 h for the 50 mg tablet. No statistical differences between tablets were noted for the reasons for termination of adhesion (P = 0.12). Erosion, the natural process of tablet degradation, was the main cause of termination of adhesion. Detachment was reported in seven cases for the 100 mg tablet and in two cases for the 50 mg tablet. Overall the tablets, especially the 50 mg tablet, demonstrated better tolerance and acceptability than the gel, without any significant local side-effects. One subject noted a bad taste for the 50 mg tablet compared with 13 for the gel. Discomfort with the 100 mg tablet was essentially due to its size. No adverse event was recorded for the 50 mg tablet and this was the preferred formulation in 16 of 18 subjects. Discussion We have developed a once a day topical formulation of miconazole in the form of a slow release bioadhesive tablet. The present study has evaluated the salivary pharmacokinetics of miconazole after administration of two :4 Br J Clin Pharmacol

5 Pharmacokinetics of bioadhesive tablets of miconazole Table 1 Salivary pharmacokinetic parameters for miconazole 50 mg bioadhesive tablet 100 mg bioadhesive tablet Oral gel C max (mg ml -1 ) Mean * SD Range CV (%) P values vs gel P < P < P value vs 100 mg P = t max (h) Median 7 6 4# Range AUC(0,12 h) (mg ml -1 h) Mean SD Range CV (%) P values vs gel P < P < P value vs 100 mg NS (P = 0.06) AUC (0,24 h) (mg ml -1 h) Mean SD Range CV (%) P values vs gel P < P < P value vs 100 mg P = Mean duration of exposure above 0.4 mg ml -1 (h) Mean SD Global difference < Differences location NS vs 50 mg S vs tablets Mean duration of exposure above 1 mg ml -1 (h) Mean SD Global difference < Differences location NS vs 50 mg S vs tablets CV, coefficient of variation, NS, not statistically significant difference, S statistically significant difference (a = 0.05). # corresponding to 0.5 h after the second application. * corresponding to the mean of the highest concentrations observed over 24 h, means after each administrations were of 0.9 ± 1.0, 0.8 ± 0.8 and 1.1 ± 1.7 mg ml -1. Global difference: P value obtained after ANOVA comparing the three treatments. sizes of this bioadhesive tablet, containing 50 mg or 100 mg of drug, in comparison with Daktarin oral gel. The choice of 100 mg for the higher bioadhesive tablet dosage was based on a compromise between the maximizing dose and acceptable tablet size. The lower dose of 50 mg was chosen on the basis of a more convenient tablet size. For the oral gel, three applications of 125 mg drug were administered over 8.5 h instead of the manufacturer s guidelines of 500 mg day -1 in four applications. The main reason for this was improved convenience and avoidance of night time blood samples. The missing fourth dose was not considered to have a significant influence on the conclusions of the study, as it would only alter the AUC(0,24 h) and not the AUC(0,12 h) or C max values. Since salivary pharmacokinetic data reported by Bouckaert et al. [16] showed that miconazole concentrations after oral gel administration were below the limit of quantification (0.4 mg ml -1 ) by 60 min post application, the influence of the fourth application on AUC(0,24 h) could be deduced using the Br J Clin Pharmacol 58:4 349

6 J.-M. Cardot et al. data from the three previous applications. The gel AUC(0,24 h) would be increased by a mean of 33% (that is 1.4 mg ml -1 h) yielding an adjusted mean AUC(0,24 h) of approximately 5.6 mg ml -1 h for a 500 mg administration. This value is still approximately 10 times lower than the mean AUC(0,24 h) for the 50 mg tablet. Expressing the corrected AUC(0,24 h) as a function of dose emphasises the difference between the tablets and the gel ( mg ml h mg -1 for the gel compared with 1.1 and 1.4 mg ml -1 h mg -1 for the 50 and 100 mg dose tablets, respectively). The mean AUC(0,24 h) corrected for dose of the gel is then 73 or 93 times lower than the mean AUC(0,24 h) corrected for dose for the 50 and 100 mg tablets, respectively. Mean Conc (mcg/ml) Time (h) Figure 1 Mean salivary concentration vs time profiles. Administration ( ) of tablets at time = 0 h and gel at time = 0, 3.5 and 8.5 h. Miconazole 100 mg ( ); miconazole 50 mg ( ); miconazole gel ( ) All the salivary pharmacokinetic parameters (C max, AUC(0,12 h), AUC(0,24 h)) for the bioadhesive tablets were significantly greater than those for the oral gel. The AUC achieved with the 50 mg tablets was approximately half that achieved with the 100 mg tablets and at least 10 times greater than that achieved with the oral gel. The lower AUC(0,12 h) ratio between 100 and 50 mg tablets was mainly due to the fact that release of drug from the 100 mg tablet was not complete after 12 h. All three formulations showed high interindividual variability in their pharmacokinetics, which has been described previously by others [15]. This was mainly due to the variability in the secretion of saliva. However, the differences in the pharmacokinetic parameters between the 50 and 100 mg tablets were statistically significant except for the AUC(0,12 h). The median t max, was similar after the 50 mg and 100 mg tablet. The salivary pharmacokinetic profile of miconazole in the oral gel showed peak concentrations 30 min after each gel application. The mean maximum salivary miconazole concentration over the 12-h period occurred 30 min after the second application of the gel. The mean times that the concentration of miconazole was above 0.4 mg ml -1 and 1.0 mg ml -1 was greater than 10 h and 7 h, respectively for both tablets compared with 1.5 h for the oral gel. Although four gel applications rather than the three would have increased the duration of exposure to the drug, this increment would have been negligible in comparison with exposure to the drug from the tablets. These findings indicate that the tablets can provide prolonged exposure to miconazole which may lead to a better antifungal efficacy and, through a single application per day, to improved Table 2 Least squares mean values and ratios of the main pharmacokinetic parameters for miconazole Treatment C max (mg ml 1 ) AUC(0,24 h) (mg ml 1 h) AUC(0,12 h) (mg ml 1 h) 100 mg tablet mg tablet LS Means Gel vs (1.5, 3.2) (1.2, 3.2) (1.2, 3.2) 100 vs gel Ratio* (90% CI*) (11.8, 25.2) (22.9, 60.5) (22.9, 60.5) 50 vs gel (5.3, 11.4) (11.7, 30.5) (11.7, 30.5) *Obtained from Estimate statement of Proc GLM :4 Br J Clin Pharmacol

7 Pharmacokinetics of bioadhesive tablets of miconazole compliance. Furthermore, the drug detected after the removal of the tablets in a few of the subjects could be explained by a reservoir effect of the mucosa. As previously reported [15], secondary evaluation criteria in this Phase I study included tablet adhesion and tolerance. The mean adhesion time was the same for the two dosages (15 h). The tablets were tolerated better than the gel formulation. No adverse events were observed with the 50 mg tablet. The absence of unpleasant taste, in addition to the convenient application site on the cuspid fossa, convinced the majority of subjects to select bioadhesive tablets as the preferred formulation [15]. In summary, both bioadhesive tablet doses resulted in higher miconazole salivary concentrations, delayed t max, and longer exposure above the threshold concentrations in comparison with the oral gel, in spite of a lower dose of drug. These data strongly support the further development of bioadhesive tablets as a sustained release formulation leading to improved antifungal exposure in the buccal cavity with a single application per day. Sustained salivary miconazole concentrations, as observed in this study, are crucial to achieve optimal efficacy and to limit the emergence of resistance [4]. In conclusion, the present study in healthy subjects has demonstrated that a miconazole bioadhesive tablet administered once a day to the buccal mucosa allows a sustained release of drug and achieves significant local buccal concentrations that are greater than the gel formulation and with a lower dose. The authors are grateful to BioAlliance Pharma and CRITT Chimie (Centres Régionaux d Innovation et de Transferts de Technologie, Région Ile-de-France) for their financial support. The authors are grateful to M. Esther Race for her English reviewing. SAS is a trade mark of SAS institute Cary NC USA. Daktarin is a trade mark of Janssen Cilag Laboratories References 1 Appleton SS. Candidiasis: pathogenesis, clinical characteristics and treatment. J Calif Dent Assoc 2000; 28: Epstein AN, Stevenson Moore P. Periodontal disease and periodontal management in patients with cancer. Oral Oncol 2001; 37: Powderly WG, Gallant JE, Ghannoum MA, Mayer KH, Navarro EE, Perfect JR. Oropharyngeal candidiasis in patients with HIV: suggested guidelines for therapy. AIDS Res Hum Retroviruses 1999; 15: Vaszquez JA. Options for management of muccosal candidiasis in patients with AIDS and HIV infection. Pharmacotherapy 1999; 18: Rex JH, Walsh TJ, Sobel JD, Filler SG, Pappas PG, Dismukes WE. Practice guidelines for the treatment of candisosis. Clin Infect Dis 2000; 30: Ellopola AN, Samaranayake LP, Lee MT. Miconazole agent in oral candidosis: an overview. Dent Update 2000; 27: Lesse AJ. Antifungal agents. In Essentials of Pharmacology, eds Smith CM, Reynard A. Philadelphia, W.B. Saunders 1995; Hoesley C, Dismukes WE. Overview of oral azole drugs as systemic anti-fungal therapy. Semin Resp Crit Care Medl 1997; 18: Meis JF, Verweij PE. Current management of fungal infections. Drugs 2001; 61: Samaranayake LP, Holmstrup P. Oral candidiasis and human immunodeficiency virus infection. J Oral Pathol Med 1989; 18: Sawyer PR, Brogden RN, Pinder RM, Speight TM, Avery GS. Miconazole: a review of its antifungal activity and therapeutic efficacy. Drugs 1975; 9: Aïache J-M, Costantini D, Chaumont C Patent WO 03/ , Sustained release therapeutic bioadhesive system. 13 Compendium Suisse (Swiss Medicinal Compendium). Switzerland, Documed AG, Vidal, le dictionnaire (French Medicinal Dictionary). Issy les Moulineaux, France, Vidal Chaumont C, Cardot J-M, Dubray C, Costantini D, Aiache J-M. Safety, acceptability and adhesion of novel bioadhesive slow release tablet of miconazole in a phase I study. J Mycol Med 2003; 13: Bouckaert S, Schautteet H, Lefebvre R, Remon J, Van Clooster R. Comparison of salivary miconazole concentrations after administration of a bioadhesive slow-release buccal tablet and an oral gel. Eur J Clin Pharmacol 1992; 43: Wagner JG. Fundamentals of Clinical Pharmacokinetics, first edition Washington DC, USA, American Pharmaceutical Association, 1987; Cardot J-M, Jaouen A, Godbillon J. PKC, a new pharmacokinetic software using SAS. Eur J Pharm Biopharm 1997; 43: Br J Clin Pharmacol 58:4 351