Bringing Together the Benefits of Lipid-Based Formulations and Modified-Release Drug Delivery

Lipid-based systems with modified-release profiles present exciting opportunities for drug developers. “On the one hand, lipid-based formulations provide benefits such as solubility and permeability enhancement, modulation of transporter, elimination of food effects, reduction of inter-patient and intra-patient variability, greater API loading, and the avoidance of dose dumping,” observes Julien Meissonnier, vice-president of Science & Technology at Catalent. “On the other, with extended or sustained drug release, dosing frequency can be reduced; peaks and troughs of drug levels in the blood are dampened, which consequently optimizes therapeutic effectiveness while minimizing concentration-dependent adverse effects.”  

Meissonnier explains that in some cases, conventional approaches for modified-release drug delivery may prove difficult because of physicochemical and pharmacokinetic challenges posed by the drug compounds. “For example, most APIs in today’s development pipeline are poorly soluble or poorly permeable, and some have low melting points. When these physico-chemical challenges are not addressed properly by the formulation technology, it often results in extensive positive food effects, which when combined with a narrow therapeutic window, can trigger a potential risk to the patient, with the potential risk of dose dumping,” he says. “Modified-release lipid-based formulations in softgel capsules can address these challenges. For poorly soluble compounds, lipid-based formulations promote solubilization along the gastrointestinal tract; whereas for poorly permeable compounds, lipid-based systems facilitate transcellular or paracellular transport by exploiting the lipid assimilation pathway as well as potential uptake through the lymphatic pathways. Lipid excipients can be used to modulate transporter and pre-systemic metabolism. All these mechanisms result in increased drug exposure, reduction of inter-patient and intra-patient variability, and elimination of food effects,” he explains. “In addition, dose dumping can be eliminated with lipid-based matrix systems.”

The dosage form of choice for a modified-release lipid-based formulation is a soft capsule. “Soft capsules are the proven dosage form for lipid-based formulations,” says Meissonnier. “They have good developability and manufacturability. They are compatible with the wider range of lipid liquid and semi-solid excipients and formulations. Moreover, soft capsules do not compromise the performance of the lipid-based fill.”

According to Meissonnier, there are various ways of modifying the release of actives through the lipid-based fill or the soft capsule shell. “Whereas monolithic softgels can be designed, the preference would be to leverage multi-particulate soft-gelatin capsules to further reduce variability. These softgels can be designed to have a solid lipid matrix core that will extend release rate through an erosion diffusion process. The other option is a film-coated soft-gelatin capsule with a liquid fill where the drug release profile is facilitated using coated beadlets, and controlled by the nature of the coating polymer.”

Meissonnier cites a case study where an extended-release lipid-based formulation was developed using Catalent’s OptiShell soft capsule technology. The formulation was approved by the United States Food and Drug Administration in 2016. 

“This is the first FDA-approved treatment using OptiShell soft capsule technology to deliver an extended-release semisolid formulation in a softgel format,” says Meissonnier. “The active ingredients are used to increase vitamin D levels, but peak concentrations or ‘surges’ in 25-hydroxyvitamin D3 levels induce the expression of the metabolizing enzyme Cytochrome P450 subfamily 24, resulting in lesser activity attenuating the inhibition of parathyroid hormone,” he explains. “Controlling the drug release maintains 25-hydroxyvitamin D3 levels in the blood above the 30 ng/mL concentration, avoiding peaks that result in lesser activity. In addition, gradual repletion of 25-hydroxyvitamin D3 could provide more predictable maintenance of serum levels below the poorly defined safe upper limit of approximately 100 ng/mL, allowing for more consistent dosage.”

The product’s controlled-release system is a semisolid lipid-based matrix and, according to Meissonnier, “lipid-based matrices, in which the drug is homogeneously dispersed/dissolved, are the system of choice for low-dose potent compounds. Catalent’s OptiShell soft capsule technology uses a precisely controlled hot-filling process for encapsulation of the lipid-based matrix, providing content uniformity performance above standard oral solid forms.” He adds that the patented shell composition can handle encapsulation of high-temperature fill formulations for semisolid and highly viscous fill formulations. It can also handle higher pH fill formulations.

Article Details

Pharmaceutical Technology
Vol. 41, No. 12
December 2017
Page: 26

Citation

When referring to this article, please cite it as A. Siew, “Bringing Together the Benefits of Lipid-Based Formulations and Modified-Release Drug Delivery,” Pharmaceutical Technology 41 (12) 26 (2017).