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. 2016 Dec 14:10:4031-4045.
doi: 10.2147/DDDT.S120613. eCollection 2016.

Transbuccal delivery of betahistine dihydrochloride from mucoadhesive tablets with a unidirectional drug flow: in vitro, ex vivo and in vivo evaluation

Mohamed A El-Nabarawi  1 , Adel A Ali  2 , Heba M Aboud  2 , Amira H Hassan  2 , Amany H Godah  2
Affiliations

Transbuccal delivery of betahistine dihydrochloride from mucoadhesive tablets with a unidirectional drug flow: in vitro, ex vivo and in vivo evaluation

Mohamed A El-Nabarawi et al. Drug Des Devel Ther. .

Abstract

Objective: Betahistine dihydrochloride (BH.2HCl), an anti-vertigo histamine analog used in the treatment of Ménière's disease, undergoes extensive first-pass metabolism and suffers from short biological half-life. The aim of the present work was to develop and estimate controlled release mucoadhesive buccal tablets of BH.2HCl with a unidirectional drug flow to overcome this encumbrance.

Methods: A direct compression method was adopted for preparation of the tablets using mucoadhesive polymers like guar gum, hydroxypropyl methyl cellulose K4M, sodium carboxymethyl cellulose and their combinations. The tablets were coated from all surfaces except one surface with a solution of 5% (w/v) cellulose acetate and 1% (w/v) dibutyl phthalate. Different permeation enhancers like 2% sodium deoxycholate, 2% sodium cholate hydrate (SCH) and 5% menthol were tested. Swelling index, ex vivo residence time, mucoadhesion strength, in vivo testing of mucoadhesion time, in vitro dissolution and ex vivo permeation were carried out. Furthermore, compatibility and accelerated stability studies were performed for the drug excipients. Finally, drug bioavailability of the BH.2HCl-optimized buccal mucoadhesive formulation was compared with that of the orally administered Betaserc® 24 mg tablet in six healthy male volunteers.

Results: Formulation F10, which contained a combination of 35% guar gum and 5% sodium carboxymethyl cellulose, exhibited long adhesion time, high adhesion strength and diminished irritation to volunteers and showed zero-order release kinetics. SCH produced a significant enhancement in permeation of BH.2HCl across buccal mucosa. BH.2HCl-optimized buccal mucoadhesive formulation showed percentage relative bioavailability of 177%.

Conclusion: The developed mucoadhesive tablets represent a promising alternative for the buccal delivery of BH.2HCl.

Keywords: betahistine dihydrochloride; permeation enhancer; relative bioavailability; transbuccal delivery; unidirectional drug flow.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Diagrammatic sketch of mucoadhesive buccal tablet with a unidirectional drug flow.
Figure 2
Figure 2
Plot of % swelling vs time for BH.2HCl mucoadhesive buccal formulations (A) F1–F6 and (B) F7–F12. Abbreviation: BH.2HCl, betahistine dihydrochloride.
Figure 3
Figure 3
Release profile of BH.2HCl from different mucoadhesive buccal formulations: (A) F1–F6 and (B) F7–F12. Abbreviation: BH.2HCl, betahistine dihydrochloride.
Figure 4
Figure 4
Permeation profile of BH.2HCl from different mucoadhesive buccal formulations. Abbreviations: BH.2HCl, betahistine dihydrochloride; SCH, sodium cholate hydrate; SDC, sodium deoxycholate.
Figure 5
Figure 5
DSC thermograms of (A) pure BH.2HCl, (B) guar gum, (C) Na CMC, (D) HPMC K4M, (E) mannitol, (F) Aerosil 200, (G) magnesium stearate (H) SCH and (I) formulation F10 in addition to SCH. Abbreviations: BH.2HCl, betahistine dihydrochloride; DSC, differential scanning calorimetry; HPMC K4M, hydroxypropyl methyl cellulose grade K4M; Na CMC, sodium carboxymethyl cellulose; SCH, sodium cholate hydrate.
Figure 6
Figure 6
FTIR spectra of (A) pure BH.2HCl, (B) guar gum, (C) Na CMC, (D) HPMC K4M, (E) mannitol, (F) Aerosil 200, (G) magnesium stearate (H) SCH and (I) formulation F10 in addition to SCH. Abbreviations: BH.2HCl, betahistine dihydrochloride; FTIR, fourier-transform infrared spectroscopy; HPMC K4M, hydroxypropyl methyl cellulose grade K4M; Na CMC, sodium carboxymethyl cellulose; SCH, sodium cholate hydrate.
Figure 7
Figure 7
Chromatogram of BH.2HCl in the mobile phase at λmax 260 nm. Abbreviations: BH.2HCl, betahistine dihydrochloride; min, minutes.
Figure 8
Figure 8
Plot of log % BH.2HCl remained vs time after storage of the optimized buccal formulation for 12 weeks at 40°C and 60°C according to first-order kinetics. Abbreviation: BH.2HCl, betahistine dihydrochloride.
Figure 9
Figure 9
BH.2HCl plasma concentrations following the administration of the optimized buccal formulation and oral tablets Betaserc® 24 mg. Abbreviation: BH.2HCl, betahistine dihydrochloride.
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