Els Mehuys, Ph.D.

Contact info

dr. Els Mehuys

Laboratory of Pharmaceutical Technology
Harelbekestraat 72, 9000 Gent (Belgium)
Tel: +32 (0)9 2648082
E-mail Els.Mehuys@UGent.be

Ph.D. work

Title: Development of a matrix-in-cylinder system for sustained zero-order drug release

Electronic version

Summary:

Matrix systems are commonly used as an oral sustained release dosage form, however their drug release profile is generally characterised by a burst release effect. Since constant rate delivery is the primary goal of sustained release systems, considerable efforts have been made in the development of new drug delivery concepts in order to avoid the burst effect and to obtain zero-order drug release. Chapter 1 describes the different strategies proposed to limit burst release from matrix systems. Of the suggestions made, partial 'coating' of a matrix appeared to be the most successful method however the production process is complicated and time-consuming. The objective of this thesis was to develop a partially 'coated' matrix by means of a simple, flexible and economically feasible manufacturing method. Therefore, the properties of a 'matrix-in-cylinder system', based on a drug-containing matrix inserted into an impermeable hollow cylinder, were evaluated. Chapter 2 gives an overview of other pharmaceutical dosage forms using the principle of hollow cylinders as a method to control drug release.

Chapter 3 describes the formulation study of the matrix-in-cylinder system. The first part of this study focused on the production of the hollow cylinders using ethylcellulose as the hollow fiber forming material and hot-melt extrusion as the manufacturing method. The influence of formulation and process parameters on the quality of the extruded cylinders was evaluated. Another objective was to identify a core material for the matrix-in-cylinder system, which released the drug in a sustained and zero-order manner. Therefore, the ethylcellulose cylinders (l = 18 mm, d = 5 mm) were filled with triglyceride-bases (Witepsol®, Ovucire®) and saturated polyglycolised glycerides (Gelucire®) with different melting ranges (containing theophylline monohydrate as the model drug), and were evaluated by dissolution testing. From these experiments it could be concluded that a matrix-in-cylinder system with a Gelucire® 44/14 core met the proposed sustained zero-order drug release criterion, however at high drug loading only (60 % theophylline monohydrate). Decreasing the drug load resulted in an acceleration of drug release. Neither the incorporation of the more hydrophobic Gelucire® 50/02 nor the incorporation of inert fillers into the Gelucire® 44/14 core were able to provide a sustained and constant drug release from the matrix-in-cylinder system.

In Chapter 4 it was proposed to use a mixture of hydroxypropyl methylcellulose (HPMC) and Gelucire® 44/14 as the core material for the matrix-in-cylinder system, because the gel forming capacities of HMPC could be advantageous to the sustained release properties of the dosage form. In vitro drug release from matrix-in-cylinders containing 5 % theophylline monohydrate, 30 % HPMC (varying substitution type and viscosity grade) and 65 % Gelucire® 44/14 proceeded according to zero-order kinetics, but was too slow (in most cases < 50 % of the drug was released within 24 h). To achieve complete release of the drug, the composition of the inner core as well as the dimensions of the hollow pipe were modified in order to increase the erosion rate of the gelled polymer matrix. Reducing the HPMC concentrations suspended in Gelucire® nor replacing part of the HPMC by methylcellulose resulted in the targeted drug release profile. The influence of the dimensions of the hollow pipe on drug release was determined by subjecting matrix-in-cylinders with varying length (12, 15, 18 mm) and varying diameter (3, 5, 7 mm) to dissolution testing. Shortening the matrix-in-cylinder resulted in a quicker drug release, while changing the diameter did not affect drug release. Thus, the drug release rate from the matrix-in-cylinder dosage form could be tailored by modifying the length of the hollow pipes. The effect of drug solubility and drug loading on the matrix effect of the HPMC-Gelucire® system was also investigated. Drug solubility had a limited influence on drug release rates, while an increase of the drug loading induced a significant acceleration of the drug release. The formulations were stable for at least 12 months during storage at room temperature/60 % relative humidity (RH) and at 30°C/75 % RH.

Chapter 4 demonstrated that a matrix-in-cylinder system consisting of a hot-melt extruded non-erodible ethylcellulose pipe surrounding a drug-containing HPMC-Gelucire® matrix core could be used to formulate a once-a-day formulation characterized by a zero-order drug release profile. In an aqueous medium, the HPMC-Gelucire® core forms a gel plug, which releases the drug - through the open ends of the ethylcellulose pipe - by means of erosion. Erosion of the gel core is the most critical parameter in order to obtain the desired drug release rate and consequently the desired plasma concentration profiles in vivo. In vivo, the varying conditions along the gastrointestinal (GI)-tract (mechanical and hydrodynamic stress, presence of digestive enzymes and bile salts) can potentially affect the erosion of the gel core of the matrix-in-cylinder system and thereby alter the drug release rate. Therefore, the influence of hydrodynamics (dissolution at varying paddle speed) and mechanical forces (paddle-beads method) and the effect of different 'physiologically relevant' dissolution media on the in vitro drug release of the matrix-in-cylinder system, using propranolol hydrochloride as the model drug, were evaluated in Chapter 5. These experiments showed that the ethylcellulose pipe had a protective effect on the drug-containing HPMC-Gelucireâ core as it largely protected the core against hydrodynamics and mechanical stress. Furthermore, drug release from the matrix-in-cylinder system was only slightly affected by the composition of the dissolution medium. These observations suggested that drug release from the matrix-in-cylinder is probably independent of the GI-tract conditions.

The bioavailability from the matrix-in-cylinder systems, using propranolol hydrochloride as the model drug, was also described in Chapter 5. During the in vivo evaluation an oral dose of 80 mg propranolol HCl was administered to 6 male mixed-breed dogs in a randomized cross-over study. The matrix-in-cylinders consisted of 27 % propranolol HCl (equivalent with 80 mg), 23 % HPMC and 50 % Gelucireâ 44/14 and the bioavailability of the experimental formulation was compared to the in vivo behaviour of a hard gelatine capsule filled with an amount (equivalent with 80 mg propranolol HCl) of the core material of the matrix-in-cylinder system (core-in-capsule formulation) and to a commercial sustained release formulation (Inderalâ retard mitis, 80 mg propranolol HCl). Propranolol plasma concentrations were determined with a validated HPLC-fluorescence method.

Administration of the matrix-in-cylinder system resulted in plasma concentrations maintained at a level of 8-10 ng/ml during the first 6 h, then dropping slightly to a plateau at 5-6 ng/ml. Cmax of the core-in-capsule formulation was not significantly different from Cmax of the matrix-in-cylinder system, however the core-in-capsule formulation was not able to sustain drug release confirming that the surrounding ethylcellulose pipe is essential to obtain the in vivo sustained release profile. The plasma levels of Inderal® were much lower than with the matrix-in-cylinder system. The mean AUC0-24h of the matrix-in-cylinder system and of Inderal® were 146.0 and 35.8 ng ml-1 h-1, respectively; hence the relative bioavailability of the matrix-in-cylinder system to Inderal® is about 400 %. The bioavailability of the core-in-capsule is similar to that of Inderal®. The results of this in vivo study demonstrated that the matrix-in-cylinder system increased the bioavailability of propranolol in dogs when compared with a commercial sustained release formulation (Inderalâ). Since propranolol is a drug with extensive hepatic first pass elimination after oral administration, the improved bioavailability of the matrix-in-cylinder was ascribed to a partial bypass of the hepatic clearance through rectal absorption of propranolol: either via the haemorrhoidal veins or via the lymphatics, both having direct access to the systemic circulation.

Chapter 6 describes the human bioavailability of propranolol from the matrix-in-cylinder system. During the in vivo evaluation an oral dose of 80 mg propranolol HCl was administered to healthy volunteers (n = 10) in a randomized cross-over study. The matrix-in-cylinders consisted of 27 % propranolol HCl (equivalent with 80 mg), 23 % HPMC and 50 % Gelucireâ 44/14 and were administered under fasted as well as under fed conditions (concomitant intake of a high-fat, high-calorie breakfast). Inderalâ retard mitis was administered as reference product. Administration of the matrix-in-cylinder system resulted in similar plasma levels as the reference formulation Inderal®, during the initial 10 h after administration. 10 h after administration of the matrix-in-cylinder system, an increase of the propranolol plasma levels was noticed. This increase was most pronounced for the experimental dosage form co-administered with food. The matrix-in-cylinder system had a relative bioavailability of 156.0 % (fasted conditions) and 222.0 % (fed conditions) compared to the marketed reference product. In order to explain this increased bioavailability observed for the matrix-in-cylinder system, different hypotheses were checked. However none of them was able to provide a conclusive answer. To find out the exact mechanism by which the propranolol bioavailability was increased, further studies should be performed (for example: the incorporation of other drugs than propranolol in the matrix-in-cylinder system).

Keywords : Hot stage extrusion, matrix, hollow fibre, controlled release

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