Introduction

The development of gastric retentive formulations (GRFs) has been actively pursued by researchers for more than 30 years [1-3]. The primary motivation behind this effort has been to enable sustained delivery of drugs to the stomach and/or proximal small intestine. This would enable once daily dosing of drugs with short half-lives, and whose site of action or absorption is in the upper gastrointestinal tract. In addition, a GRF may increase the extent and/or duration of absorption for drugs that have saturable or site-specific transport, very low solubility at intestinal pH values, or are chemically unstable in the small or large intestine.

GlaxoSmithKline R&D, Harlow, Essex, UK e-mail: [email protected]

C.G. Wilson and P.J. Crowley (eds.), Controlled Release in Oral Drug Delivery, Advances in Delivery Science and Technology, DOI 10.1007/978-1-4614-1004-1_17, © Controlled Release Society 2011

-Commercial

-Commercial

Idea

Clinical Proof of Concept Marketed Product Stage of Development

Fig. 17.1 Illustration of when gastric retentive formulations fail in development

Idea

Clinical Proof of Concept Marketed Product Stage of Development

Fig. 17.1 Illustration of when gastric retentive formulations fail in development

Lastly, GRFs may be useful in reducing the intra- and intersubject variability of the absorption of the aforementioned drugs by normalizing gastrointestinal transit time.

A wealth of information is available on past attempts, common strategies, and challenges; however, a true gastric retentive dosage form has yet to emerge from the plethora of attempts. We define a true gastric retentive dosage form as one whose performance is not explicitly dependent upon consumption of a large meal, regular snacks, or intake of liquids. Some dosage forms are claimed to be gastric retentive, but appear to offer no advantage over a large, nondisintegrating tablet taken with a meal. We concur with Waterman's comment in his review article on gastric retention [4]: "Although the goal remains valuable, the promise of gastric retentive systems remains unfulfilled at this time."

As gastric retentive dosage forms enter into the key clinical proof of concept stage, resource requirements begin to shift. When they transition from preclinical evaluation, to clinical and commercial feasibility, the highest rate of failure is observed. This has been referred to as the "Valley of Death" (Fig. 17.1).

To our knowledge, no truly gastric retentive dosage form has survived the "valley of death." In this chapter, we will focus on the key challenges during the clinical proof of concept stage to assist drug delivery scientists to propel their dosage forms past this stage to be deemed worthy of the title "gastric retentive dosage form." Specifically, in this chapter we will:

• Offer recommendations on how to assess if a GRF will improve the performance of a drug

• Review physiologic challenges and strategies to achieve gastric retention

• Provide guidance on how to develop and evaluate a GRF

• Present a case study using previously unpublished results of original research on a proposed GRF

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