Evaluation of Pulsincap™ to provide regional delivery of dofetilide to the human GI tract

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Abstract

Pulsincap™ formulations designed to deliver a dose of drug following a 5-h delay were prepared to evaluate the capability of the formulation to deliver dofetilide to the lower gastrointestinal (GI) tract. By the expected 5-h release time, the preparations were well dispersed throughout the GI tract, from stomach to colon. Plasma analysis permitted drug absorption to be determined as a function of GI tract site of release. Dofetilide is a well-absorbed drug, but showed a reduction in observed bioavailability when delivered from the Pulsincap™ formulations, particularly at more distal GI tract sites. Dispersion of the drug from the soluble excipient used in this prototype formulation relies on a passive diffusion mechanism and the relevance of this factor to the reduced extent and consistency of absorption from the colon is discussed. In these studies the effects of the degree of dispersion versus the site of dispersion could not be ascertained; nevertheless the scintigraphic analysis demonstrated good in vitro–in vivo correlation for time of release from Pulsincap™ preparations. The combination of scintigraphic and pharmacokinetic analysis permits identification of the site of drug release from the dosage form and pharmacokinetic parameters to be studied in man in a non-invasive manner.

Introduction

For most immediate release drug formulations, absorption is complete by the time the swallowed dose has reached the colon and the extent of absorption in the distal gut is of little consequence. The situation is markedly different when oral sustained or delayed release formulations are employed, where the extent of absorption is more susceptible to regional differences in drug absorption and gut transit times. Using scintigraphic techniques, many studies have demonstrated quantitative differences in the extent and rate of absorption as the formulation arrives in the distal small intestine and proximal colon (Wilson et al., 1991, Olsson et al., 1995).

It follows from these observations that a prerequisite for the development of sustained release dosage form for a specific drug, is a knowledge of the extent of absorption of that drug throughout the length of the gastrointestinal (GI) tract. In the past, various experimental methods have been employed to investigate drug absorption in man which have often involved invasive intubation techniques (Barr et al., 1994, Chan et al., 1994, Vidon et al., 1989) or complex formulation assemblies (Gardner et al., 1997).

It has been appreciated for a long time that the intubation process itself can disturb the normal physiological function of the GI tract and cause any resulting drug absorption data to be questioned (Read et al., 1983). The formulation approaches employed to date can be loosely categorised as being either engineering-based or adaptations of classical formulation technology. The engineering-based systems, which generally rely on an external stimulus to trigger release from the device, include the HF capsule (Antonin, 1993), the telemetric capsule (Lambert et al., 1991) and the Intellisite® capsule (Gardner et al., 1997, Parr et al., 1999).

The HF capsule has been widely used to study drug absorption (Fuhr et al., 1994, Harder et al., 1990, Staib et al., 1989) but suffers from the disadvantages that it is only suitable for liquid drug formulations and requires the use of X-ray to follow GI transit. The Lambert telemetric capsule appears to be too complex to have gained acceptance, however Intellisite® has been widely employed and has the advantage that it can be tracked through the GI tract using non-invasive gamma scintigraphy. It is reported to be suitable for carrying both liquid and solid formulations, although its consistency in releasing solid drug formulations in the low-fluid environment of the distal GI tract has been questioned (personal communication, M.J. Humphrey) and Intellisite is now being superseded by an improved design, the Enterion Capsule (Connor et al., 2001).

The most commonly employed formulation systems rely on time-dependent mechanisms to provoke drug release from capsule devices using gamma scintigraphic techniques to visualise the site of release. An early prototype capsule device comprised a water permeable hydrogel capsule in which the internal cavity contained a mixture of drug with an expanding material; the contents being sealed inside the capsule by a hydrogel plug (Rashid, 1990). Water diffused through the hydrogel wall inducing swelling of the contents and expulsion of the plug, causing drug to be released predictably in the colon after a 5-h mouth to colon transit period (Wilding et al., 1992).

The Pulsincap™ device (McNeil et al., 1994) (P-CAP) comprises an impermeable capsule body containing a drug formulation sealed in the capsule with a hydrogel polymer plug. The plug expands in water or GI tract fluid and slowly exits the capsule body, releasing the capsule contents after a defined time-delay determined by the length of the hydrogel plug (Binns et al., 1993). It has been employed in human studies for colon targeting (Bakhshaee et al., 1992, Binns et al., 1996, Wilson et al., 1997, Hebden et al., 1999a, Hebden et al., 1999b) in timed-release modes as well as gastroresistant configurations. An alternative version of P-CAP, in which the hydrogel plug is replaced by an eroding tablet, has been described (Stevens et al., 1995, Krögel and Bodmeier, 1998, Ross et al., 2000).

In contrast to the inherent variability associated with the gastric emptying of single unit dosage forms, transit through the small intestine is reproducible at about 3–4 h (Wilson and Washington, 1988). With a dosage form releasing purely on a time-basis, it would be expected to be variably distributed within the GI tract, and thereby permit assessment of regional absorption from a range of sites. In this study we have used a 5-h delay P-CAP to deliver dofetilide to different sites in the GI tract, employing scintigraphy and pharmacokinetic analysis to evaluate its performance in providing regional drug delivery. Dofetilide was used as the experimental drug, being a weak base (pKa 7.0) with moderate lipophilicity (log D 0.96 at pH 7.4) and exhibiting linear pharmacokinetics and complete bioavailability after conventional oral administration (Smith et al., 1992). Dofetilide is a potent cardiovascular drug and its regional absorption had not previously been explored and was of interest in the context of future formulation strategies. Three doses were investigated in the study in order to investigate whether the kinetics of absorption from distal sites were linearly related to dose.

Section snippets

Preparation of radiolabelled Pulsincap™ dosage forms

All P-CAP components were supplied by Scherer DDS Ltd and consisted of size 0 gelatin capsule bodies coated with ethylcellulose (95%) and diethylphthalate (5%). The hydrogel polymer plug was prepared as rods by cross-linking polyethylene glycol (PEG molecular weight 8000) using 1,2,6-hexanetriol and dicyclohexylmethane-4,4-diisocyanate. The cross-linking reaction was catalysed by ferric chloride and the polymer washed in butylated hydroxyanisole solution (0.025%) before being cut into plugs of

In vivo study

Eight subjects completed the study receiving all four treatments. One subject received the 1.0 mg solution dose only, and one subject the solution and 0.25 mg P-CAP doses only. One subject received just the 0.25 and 0.5 mg P-CAP doses.

GI transit rate data are summarised in Fig. 2. Gastric emptying of the P-CAP formulations was generally rapid, although one capsule remained in the stomach for the duration of the study. Small intestinal transit, arrival at the ileocaecal junction, and entry into

Discussion

Low and prolonged levels of dofetilide following P-CAP administrations imply that either release of drug from the preparations was not instantaneous following capsule opening, or that absorption of dofetilide from the distal regions of the intestinal tract is less efficient than from the stomach and proximal small intestine. In part this may be due to sluggish agitation in the distal gut which compounds the loss of bioavailability due to a reduced surface area and decreased paracellular

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