Drug Delivery: What The Future Holds - - BioPharm International


Drug Delivery: What The Future Holds

BioPharm International
Volume 20, Issue 8

The pulmonary route of administration offers a large surface area for absorption, and as a result, achieves rapid systemic levels.6 Figure 1 shows the pharmacokinetic profile of inhaled versus subcutaneously delivered regular insulin and insulin lispro (a rapidly absorbed lys-proinsulin analog). [Editors note: Figures for this article are not available online. To obtain a complete copy of the article with figures, please send your mailing address to
]. If Exubera is successful, it is likely that a number of other protein and peptide products delivered by this route will follow.


Controlled release (CR) oral formulations for small-molecule drugs have existed for decades and thus, may come as a surprise in a list looking to the future. However, the need for oral CR will remain strong in the future for two reasons. First, as new drug candidates are identified, many will not have the pharmacokinetic profiles needed for once-a-day dosing. Using drug delivery technology to enable once-a-day dosing is generally a much less expensive and more successful approach than an analog approach aimed at maintaining activity while modifying the pharmacokinetics.

This approach has been extremely successful in the past. Take Pfizer's CR nifedipine product Procardia XL, as an example. It should be noted that this was Pfizer's first billion-dollar product. The original, immediate-release Procardia product had only a one to two-hour plasma half-life leading to three-times-a-day dosing for angina.7 Sales in the US reached approximately $200 million annually at peak levels.8 Procardia XL was able to achieve $1.4 billion in US sales four years after launch, due to the convenience of once-a-day dosing and the addition of an indication for hypertension. The addition of this new indication was facilitated by the decreased plasma maximum concentration in the CR formulation relative to the immediate-release tablet.7 By leveraging Alza's OROS technology, Pfizer was able to prolong its Procardia franchise well beyond the end of the nifedipine patent, and at sales levels significantly higher than could have been achieved with an immediate-release tablet.

New technologies are likely to impact oral CR in the future. One shortcoming of systems like OROS is that the drug must be readily absorbed throughout the gastrointestinal (GI) tract. However, many drugs are poorly absorbed in the lower GI tract.9 One solution to this problem is to use gastroretentive systems which remain in the stomach for prolonged times, slowly delivering drug to the upper GI tract.10 Various approaches to gastroretentive formulations have been used, including dosage-form density, adhesion, swelling, and magnetic fields.

Pulsatile or chronotherapeutic delivery will provide improved treatment paradigms for various drugs. A delayed-release propranolol formulation, for example, intended to provide therapeutic morning blood levels following bedtime administration, has been shown to be effective in preventing acute cardiovascular events, which occur more commonly in the morning.11 Another recent example is Ambien CR for the treatment of insomnia. This formulation of zolpidem tartrate is a bilayered tablet, with one layer designed to dissolve immediately to induce sleep and the other layer dissolving slowly to help maintain sleep.


Poor oral bioavailability of most drugs can be attributed to low solubility, slow dissolution, low membrane permeability, or rapid metabolism prior to reaching the systemic circulation.12,13 Solubility and dissolution-limited absorption has long been a challenge to oral absorption, and has become more problematic in recent years due to the tendency of many high-throughput screens to select larger and more lipophilic drugs.14 Technologies that can solubilize drugs such as lipid-based formulations are one approach to this issue.15 Alternatively, one can eliminate the energy barrier related to melting the crystal lattice by producing and keeping the active in an amorphous state in the dosage form.16

For many drugs, metabolism and efflux by p-glycoprotein may be important factors in bioavailability.17 Metabolism may be the most significant factor in the absorption fate of small peptides.13 Competitive enzyme inhibitors may be administered along with the drug in order to minimize efflux and metabolism in order to improve bioavailability.

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