Research paper
Hot-melts in buccoadhesive patches: An approach for bioavailability enhancement of highly-metabolized drugs with short elimination half-life

https://doi.org/10.1016/j.ejpb.2014.09.015Get rights and content

Highlights

  • TIZ hot-melts in buccoadhesive patches were successfully prepared.

  • The hot-melt patch controlled TIZ release in vivo with a median Tmax of 6 h.

  • It enhanced bioavailability of TIZ 2.57 folds compared to immediate-release tablet.

  • Dose reduction and minimizing frequency of administration could be achieved.

  • Suitable for delivering highly metabolized drugs with short elimination half-lives.

Abstract

The present study deals with the inclusion or incorporation of hot-melts into buccoadhesive patches. Our aim is to develop a patient-friendly dosage form that is capable of extending release of short elimination half-life drugs so to decrease dosing frequency and to increase the bioavailability of highly-metabolized drugs with the ultimate aim of dose reduction. Tizanidine hydrochloride (TIZ) was used as a model drug. TIZ was incorporated into Compritol-based hot-melts, and then further formulated into buccal patches prepared using HPMC, PVA and Polyox. A Central Composite Face-centered Design was employed to statistically optimize the formulation variables; HPMC solution/PVA solution weight ratio, Compritol/TIZ ratio in the hot-melts and percentage Polyox. The optimized formula suggested by the software was successful in controlling drug release, where 85% of TIZ was released after 4 h and the patch showed acceptable mucoadhesion properties. Pharmacokinetic parameters of TIZ from the optimized formula were compared to those of the immediate release tablet, Sirdalud®, as reference in human volunteers using a randomized crossover design. Significant increase was observed for Cmax, Tmax, AUC(0–12) and AUC(0–∞). The increase in relative bioavailability of TIZ from the optimized formula was 2.57 folds.

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)

  • A.N.S. Alqadi et al.

    Uses of central composite design and surface response to evaluate the influence of constituent materials on fresh and hardened properties of self-compacting concrete

    KSCE J. Civ. Eng.

    (2012)
  • Cited by (0)

    View full text