This article is part of a special issue on Drug Delivery.
Liquid-filled hard-capsule technology is well-established for formulation and manufacture (1). In addition to being a convenient
product format, it is well recognized as offering a wide range of applications, including for use in compounds with low bioavailability
or with low-dose uniformity issues. Liquid-filled hard capsules can provide products with various release profiles and may
be used to overcome stability concerns such as moisture uptake. Capsule-in-capsule formats represent a significant further
development in the product type. In this format, a formulated capsule (i.e., liquid-filled or dry-filled) is nested in an
outer liquid-filled capsule. Each capsule achieves a particular formulation aim (e.g., prompt or controlled release). This
article will describe formulation approaches and provide examples of in vitro investigations of a capsule-in-capsule system that enables the presentation of multiphase or multidrug formulations in a
single dosage unit.
Formulation aims and carrier selection
Figure 1 suggests a range of possible formulation aims that capsule-in-capsule technology may achieve. This drug-delivery
system has beneficial flexibility. The formulation aims for each component capsule may be achieved by selecting the carrier
suited to the particular delivery goal (e.g., a prompt or slow-release profile). Available carriers include the following
- Nonaqueous fluid, possibly thickened with a thixotropic agent (e.g., colloidal silicone dioxide)
- Thermosoftening excipients with various solution characteristics that can be matched to in vivo release requirements
- Self-emulsifying carriers.
The resulting formulations may be nonaqueous solutions, suspensions, semisolid matrices, or microemulsions, all of which are
suited to liquid-filled hard capsule formats.
Figure 1: Target areas for the capsule-in-capsule platform. CPD is compound. (FIGURE IS COURTESY OF THE AUTHOR)
Common suitable nonaqueous fluids include pharmaceutical or nutraceutical oils (e.g., medium-chain triglycerides or soya oil),
which are selected according to technical or market needs. Individual materials may require the inclusion of antioxidants
or filling under nitrogen to minimize oxidation. Thermosoftening carriers are commonly fully synthetic [e.g., the high-molecular-weight
polyethylene glycols (PEGs) or poloxamers], selected according to melting point and viscosity. Thermosoftening carriers also
may be semisynthetics such as the macrogolglycerides (e.g., lauroyl, linoleoyl, and caprylocaproyl), selected according to
melting point and hydrophilic–lipophilic balance (HLB). Varying carrier HLB values (i.e., 2–14) enable the solubility profile
of the active ingredient to be matched to the required release profile. For example, a soluble compound may be formulated
with a low-HLB carrier to give a slow-release profile, and a high-HLB material may improve the dissolution rate of a poorly