Oral, ultra–long-lasting drug delivery: Application toward malaria elimination goals

November 16, 2016

Abstract: 

Efforts at elimination of scourges, such as malaria, are limited by the logistic challenges of reaching large rural populations and ensuring patient adherence to adequate pharmacologic treatment. We have developed an oral, ultra–long-acting capsule that dissolves in the stomach and deploys a star-shaped dosage form that releases drug while assuming a geometry that prevents passage through the pylorus yet allows passage of food, enabling prolonged gastric residence. This gastric-resident, drug delivery dosage form releases small-molecule drugs for days to weeks and potentially longer. Upon dissolution of the macrostructure, the components can safely pass through the gastrointestinal tract.

Introduction
Development of oral, long-acting therapies is fundamentally limited by the rapid gastrointestinal (GI) transit time. To counter this, attempts have been made to prolong the GI transit time by delaying gastric emptying of the drug through flotation or swelling in the gastric cavity (1–3) or by sedimentation in gastric folds or adhesion to mucosal surfaces. In addition, oral dosage forms that adopt a different conformation in the gastric cavity to prolong gastric residence time have been described over the last 30 years. These attempts have been limited, however, by lack of safety mechanisms incorporated into the dosage forms that ensure ultimate safe passage through the GI tract or limited (hours) duration of the gastric residence, or both. Recently, we developed new materials that can potentially improve safety and have the ability to fit into ingestible forms

Results
An oral sustained delivery dosage form that has prolonged gastric residence should (i) have a shape and size that can be ingested by a subject (such as a capsule), (ii) have the ability to adopt an alternative conformation in the gastric cavity that delays or prevents passage through the pylorus, (iii) be able to carry large loads of the therapeutic agent, (iv) provide controlled release of the agent for long time periods (weeks or months) with little or no potential for burst release, (v) maintain stability of the therapeutic agent in a low-pH gastric environment for an extended duration, (vi) degrade/dissolve or dissociate into forms in a predictable manner that can exit the stomach and pass through the GI lumen with no potential for obstruction or perforation, and (vii) have safety mechanisms that enable dissociation of the macrostructure in the event of inadvertent passage through the pylorus to avoid downstream intestinal obstruction (particularly at the ileocecal valve) (Fig. 1A).

Figure 1 Design of a modular gastric residence vehicle.
(A) Schematic of deployment of gastric residence drug delivery dosage form via ingestible capsule. (B) Two families of geometric arrangements of flexible and rigid elements able to fit into a capsule and method of dissolution via fracture at designed failure points in presence of intestinal pH. Schematic enteric linkers, such as those evaluated in vitro (see fig. S3), are represented by black lines. (C) Stress distribution of the flexible element when it is folded into the capsule, generated with the finite element method. (D) Representative dosage form after assembly and loading into a 00el gelatin capsule. Linkers, such as those evaluated in vitro in fig. S3, are yellow and black.