European Journal of Pharmaceutics and Biopharmaceutics
Research paperHot-melts in buccoadhesive patches: An approach for bioavailability enhancement of highly-metabolized drugs with short elimination half-life
Graphical abstract
Introduction
Formulation of highly-metabolized drugs into a bioavailable dosage form is considered as a major concern in modern pharmaceutics. One of the approaches to overcome this problem is to formulate such drugs into buccoadhesive patches that will help to avoid the extensive first pass effect of the drug in the liver and thus enhance its bioavailability [1]. If these drugs are also characterized by short elimination half-life that necessitates frequent administration, drug extended release is required. Formulating these drugs into hot-melts prior to its incorporation into buccal patches will achieve a dual control required to accomplish extended drug release. This could be considered as a novel approach in the field of buccal delivery.
Hot-melts are prepared by melting a physical mixture of the drug and a carrier, followed by sudden cooling of the molten mass, pulverization and sieving [2], [3]. Hot-melts can be used as a maneuver to control drug release if prepared with a water insoluble carrier, such as Compritol 888 ATO. Compritol has waxy lipophilic properties that make it an ideal retardant carrier for sustained release of water soluble drugs [4].
Buccoadhesive patches have high patient compliance owing to their small thickness and size, compared to lozenges and tablets [5], and they provide longer residence time and more accurate drug dosing if compared to gels and ointments [6]. Application of an impermeable backing layer to the patch provides a unidirectional release to prevent drug loss, and it minimizes disintegration and deformation of the patch throughout the application period [7]. The solvent casting technique is the most widely used method in the preparation of patches [5].
Tizanidine HCl (TIZ) is a short-acting skeletal muscle relaxant. TIZ undergoes extensive and rapid metabolism during the first pass in the liver which results in poor bioavailability (34–40%) after oral administration. The elimination half-life of TIZ ranges from 2.1 to 4.2 h [8]. Frequent administration of TIZ is necessary owing to its short half-life, and this probably results in poor patient compliance. Accordingly, TIZ was selected as a model drug in our study.
The aim of this study was to formulate TIZ into a buccoadhesive patch, in order to enhance its bioavailability. In an attempt to control TIZ release, we prepared Compritol-based TIZ hot-melts that were then incorporated into the patch. A Central Composite Face-centered Design (CCFD) was employed to study the effect of formulation variables and to reach an optimized formula, because it is a systematic and efficient method for this purpose [9]. In-vivo pharmacokinetic study in healthy human volunteers was carried out to compare the optimized formula with the market product.
Section snippets
Materials
The following materials were used: TIZ was kindly gifted by HiPharm for Manufacturing Drugs and Chemicals, Cairo, Egypt. Compritol 888 ATO (glyceryl behenate); was purchased from Gattefosse Co, St-Priest, France. Polyvinyl alcohol (PVA), Mwt 146,000–186,000; ethyl cellulose (EC), viscosity 100 cps; dibutyl phthalate (DBP) and Mucin from porcine stomach were purchased from Sigma–Aldrich Co., St. Louis, USA. Hydroxypropyl methyl cellulose K4M (HPMC); was purchased from Colorcon, Midland, USA.
Patches characterization
As shown in Table 3, drug content of the patches ranged from 96.25% to 104.1%. This ensures the efficiency of casting into individual molds technique [21]. Thickness of the patches ranged from 0.37 to 0.89 mm, with small SD for all formulae indicating thickness uniformity. All patches formulae had surface pH around 6.8, so they were expected to be nonirritant to buccal mucosa.
Statistical analysis of the CCFD and interpretation
ANOVA test was performed for results of Y1: mucoadhesion strength, Y2: Q0.5h, Y3: Q2h and Y4: T85% and it showed that the
Conclusion
TIZ hot-melts in buccoadhesive patches were successfully prepared. A pharmacokinetic study in human volunteers was conducted and it showed that the optimized hot-melt patch was able to control TIZ release in vivo with a median Tmax of 6 h and it enhanced bioavailability of TIZ 2.57 folds when compared to the immediate release Sirdalud®. These results introduce ‘hot-melts in buccoadhesive patches’ as promising patient-friendly systems for controlled delivery of highly metabolized drugs with short
Conflict of Interest
The authors have no conflict of interest to declare.
Acknowledgment
The authors would like to thank PharmaSolutions Research Center, Cairo, Egypt for performing the in-vivo study part.
References (23)
- et al.
Theophylline-loaded compritol microspheres prepared by ultrasound-assisted atomization
J. Pharm. Sci.
(2011) - et al.
A novel and alternative approach to controlled release drug delivery system based on solid dispersion technique
- et al.
Manufacture and characterization of mucoadhesive buccal films
Eur. J. Pharm. Biopharm.
(2011) - et al.
Mucoadhesive multiparticulate patch for the intrabuccal controlled delivery of lidocaine
Eur. J. Pharm. Biopharm.
(2013) - et al.
The use of mucoadhesive polymers in buccal drug delivery
Adv. Drug Deliv. Rev.
(2005) - et al.
Formulation of monolayered films with drug and polymers of opposing solubilities
Int. J. Pharm.
(2008) - et al.
Drug delivery from the oral cavity: a focus on mucoadhesive buccal drug delivery systems
PDA J. Pharm. Sci. Technol.
(2012) - et al.
Optimization and in vivo pharmacokinetic study of a novel controlled release venlafaxine hydrochloride three-layer tablet
AAPS PharmSciTech
(2010) - Clarke’s Analysis of Drugs and Poisons, fourth ed. Pharmaceutical Press,...
- et al.
Evaluation of chitosan/alginate beads using experimental design: formulation and in vitro characterization
AAPS PharmSciTech
(2010)