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development of lipid-based formulations. The mechanism by which lipid-based formulations enhance bioavailability has been thoroughly reviewed in literature.8-9

Application of a parallel screening approach

during development is used to accelerate and choose the best types and combinations of excipients. The expert formulator can begin to incorporate Quality-by-Design (QbD) principles at the pre-formulation stages. Some of the critical parameters of interest would include: screening for solubility in excipients, biorelevant media, and lipid digestion products; excipient compatibility; risk of precipitation upon dispersion and digestion; and API degradation. A key consideration for delivering a LBDDS is that most formulations are liquids or semi-solids having low melting points.

Soſt Capsules Are Excellent Delivery Vehicles For Lipid-Based Formulations

There are many papers and articles that not only discuss the scientific merits of the LBDDS, but also their positive outcomes during development, formulation, manufacturing, and clinical phases of de- velopment. The clinical and commercial success of a LBDDS is in large part due to the use of soft capsules for their delivery. Soft capsules are excellent delivery vehicles because of the compatibility and versatility they offer. Soft capsules are compatible with a wide range of lipid excipients ranging from highly lipophilic to amphiphilic to hydrophilic properties. The soft capsule shell can be tailored to meet both the needs of the API and fill containing the API (liquid and semi-solid). For example, during encapsulation of soft capsules, the lipid-formulation is filled into the capsule shell with no headspace and hermetically sealed, which protects oxygen sensitive APIs. Importantly, soft capsules do not compromise or alter the performance properties of the lipid fill material in-vivo. Properly formulated soft capsule shells rapidly rupture and dissolve upon administration thus allowing the LBDDS to perform as designed. For a faster onset of action, improved absorption, or reduced variability in absorption, lipid-based formulations in soft capsules are often designed to spontaneously disperse forming very fine, thermodynamically stable emulsions for Immediate Release (IR) of the API. Lipid semi-solids filled into softgels can also be used for IR application as a means of increasing drug loading (i.e., solid solutions/ dispersions) as well as improving stability of unstable APIs (i.e., APIs prone to hydrolysis) by reducing potential for migration of the API or excipients between the fill and the shell. More recently, the use of semi- solid fills in soft capsules to achieve Controlled Release (CR) of APIs has been demonstrated.10

By using plant polysaccharide-based soft

capsule shells, higher melting point semisolid fills and highly viscous liquids can now be encapsulated at elevated temperatures expanding the range of lipid-based fills available to the formulator. In addition to CR applications, Delayed Release (DR) can be achieved using film coated soft capsule shells. Because soft capsules do not compromise a LBDDS’s performance, whether it is for IR, CR or DR applications, the formulator has the confidence that extrapolation of pre-formulation and formulation study results will apply in the fully developed soft capsule dosage form for commercial marketing.

Another important advantage of using soft capsules for LBDDS is that quantities are readily increased to commercial scale numbers, given that the process parameters obtained during lab-scale and pilot-scale are translatable to larger scale manufacturing. The time for critical process parameter assessment can be much shorter for soft capsules compared to other formulation approaches. This is particularly true for highly potent compounds where doses can be less than 100 mcg and dose uniformity is extremely challenging. By starting with an API in solution, the manufacturing process for soft capsules ensures a highly accurate and reproducible API filling solution during encapsulation. In addition, the history of New Drug Approvals (NDAs) with soft capsule products and lipid-based formulations provides an excellent precedent for US FDA and foreign regulatory agencies’ approval.

Patient acceptance is critical to any commercially successful technology. Soft capsules incorporate many patient-centric factors such as easier swallowability when compared to tablets, they are fast acting, and can incorporate odor and taste masking. There are numerous clinical examples that illustrate how soft gelatin capsules have enabled the commercially viable development of APIs that could not be developed as conventional dose forms. One well known example is the use of purified omega-3 fatty acid esters for the treatment of patients with high triglyceride levels. These are challenging molecules because of their liquid state at ambient temperatures, oxygen instability, and strong odor and taste. It would be very difficult to formulate an API with these characteristics into an acceptable dosage form other than soft capsules.

The case of abiraterone acetate and enzalutamide helps illustrate certain benefits of using a LBDDS compared to traditional formulation techniques. Both drugs are approved for the treatment of metastatic castration-resistant prostate cancer.11-12

Abiraterone acetate inhibits

the synthesis of ligands that bind to androgen receptors, while enzalutamide inhibits androgen receptors directly. Both agents appear to be equally effective for patients pre- and post-chemotherapy and are well tolerated.13

Abiraterone acetate and enzalutamide are

administered orally, once daily. Because of their similarities, a clinician is likely to choose one agent over the other based on patient factors. Since enzalutamide is known to induce several drug metabolism enzymes (Table 1), patients taking multiple medications may have a higher likelihood of drug-drug interactions. Although abiraterone acetate has relatively minimal drug-drug interaction concerns, it dis- plays pharmacokinetic challenges. It is possible to address these challenges using bioavailability enhancing technologies such as lipid- based formulation.

Abiraterone acetate is a BCS Class IV compound (low solubility, low permeability). It has poor absorption, high pharmacokinetic variability, and significant food effect. The combination of these characteristics may raise safety concerns for patients. Abiraterone acetate is commercially available as a conventional tablet formulation. Studies have shown that high-fat meals and formulation in olive oil can increase exposure.11

It is possible that a lipid formulation of

abiraterone acetate could improve bioavailability and consequently decrease inter- and intra-subject variability. Enzalutamide is a BCS Class II compound. As mentioned before, lipid-based formulations are favorable options for this class. The lipid formulation of enzalutamide | | 11


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