Osmotic drug delivery using swellable-core technology.

Swellable-core technology (SCT) formulations that used osmotic pressure and polymer swelling to deliver drugs to the GI tract in a reliable and reproducible manner were studied. The SCT formulations consisted of a core tablet containing the drug and a water-swellable component, and one or more delivery ports. The in vitro and in vivo performance of two model drugs, tenidap and sildenafil, formulated in four different SCT core configurations: homogeneous-core (single layer), tablet-in-tablet (TNT), bilayer, and trilayer core, were evaluated. In vitro dissolution studies showed that the drug-release rate was relatively independent of the core configuration but the extent of release was somewhat lower for the homogeneous-core formulation, particularly under non-sink conditions. The drug-release rate was slower with increasing coating thickness and decreasing coating permeability, and was relatively independent of the drug loading and the number and size of the delivery ports. The drug-release rates were similar for the two model drugs despite significant differences in their physicochemical properties. Tablet-recovery and pharmacokinetic studies conducted in beagle dogs showed that the in vivo release of drug from SCT formulations was comparable to the in vitro drug release.

Delivery of glipizide from asymmetric membrane capsules using encapsulated excipients.

The aim of this study was to demonstrate that the asymmetric membrane capsule can be used to deliver a poorly water soluble drug with a pH sensitive solubility such as glipizide. In order to obtain the desired delivery duration, the drug was solubilized with the use of a pH-controlling excipient. In osmotic systems, the release rate of an excipient relative to the release rate of the drug is an important factor that determines the duration of drug release. Thus, highly water-soluble excipients are released much faster than the drug, which can limit their usefulness. In the case of the asymmetric membrane capsule, it was shown that this limitation could be overcome by encapsulating the pH-controlling excipient in a membrane and including the coated excipient in the asymmetric membrane capsule core to prolong its availability within the core. Thus, prolonged release of glipizide could be obtained with the asymmetric membrane capsule.

Asymmetric membrane capsules for osmotic drug delivery. I. Development of a manufacturing process.

This paper describes a novel non-disintegrating polymeric capsule and a manual and a semi-automatic process developed for its manufacture. The capsule wall was made by a phase inversion process in which the membrane structure was precipitated on stainless steel mold pins by dipping the mold pins into a coating solution containing a polymer-solvent-nonsolvent system followed by dipping into a quench solution. The resulting asymmetric membrane wall was composed of a thin dense region supported on a thicker porous region. The asymmetric membrane capsules can be filled with a blend of the active agent and excipients for use in osmotically modulated controlled drug delivery applications.

Asymmetric membrane capsules for osmotic drug delivery II. In vitro and in vivo drug release performance.

In a previous paper, we described asymmetric membrane capsules and a phase inversion process for manufacturing them. In this paper, we describe the in vitro and in vivo drug release characteristics from these capsules. The capsule formulations were developed with model drugs to understand the variables that influenced drug release. Studies were also conducted to understand the drug release mechanism and it was shown that osmotic drug delivery was possible with asymmetric membrane capsules.

The kinetics of timolol in the rabbit lens: implications for ocular drug delivery.

This study examines the uptake and distribution of timolol in the rabbit lens following topical instillation using a heuristic approach. The implications of anisotropic drug diffusion through the lens are presented here and discussed in the context of actual in vivo data. The dynamics of timolol in the lens involve an initial, rapid uptake of the drug by the capsule and epithelium followed by slower, anisotropic diffusion through the cortex body. Kinetically, the capsule and epithelium can be treated as a separate compartment which is distinct from the cortex and which serves to provide a concentration gradient for subsequent diffusion of timolol into the dense interior structures of the lens. Model simulations support the hypothesis that the preferred route of penetration of timolol into the vitreous humor via the lens is the diffusion of drug around the capsule/epithelium and peripheral cortical layers. It is also shown that due to the high and increasing diffusional resistance toward the center of the lens, as well as the diminishing drug concentrations in the capsule and epithelium, steady-state levels in the lens may be extremely difficult to achieve in some therapeutic situations. This phenomenon could have a significant impact on the success or failure of a drug treatment involving the lens and ocular tissues.

Modelling of drug release kinetics from a laminated device having an erodible drug reservoir.

The purpose of this communication is to present a preliminary analysis to demonstrate the effect of laminating a drug-containing erodible polymer matrix with a second barrier membrane. A mathematical model for the diffusive release of the drug from an erodible polymer device undergoing surface erosion has been extended to similar devices with a secondary membrane to allow a comparison of the results. The results indicate that the constant rate of release characteristic of erodible devices is not sacrificed with the addition of the secondary membrane; moreover, the membrane provides additional controllable parameters at the disposal of the device designer.

Quantitative evaluation of topically applied pilocarpine in the precorneal area.

The bioavailability of topically applied pilocarpine is poor due to various loss mechanisms that serve to lessen delivery of the drug to the aqueous humor. Precorneal drainage and other routes of loss have been investigated qualitatively as well as quantitatively. The mechanistic models proposed to date suffer from the drawback of being dependent on our understanding of the mechanism of drug transport through the corneal membrane. This report quantifies the initial disposition of topically applied drugs and their availability for systemic and local absorption. The rate constant for the conjunctival absorption is determined and is independent of the mechanism of transcorneal transport.