In the past decade, the number of comparative clinical trials has increased considerably. Overencapsulation, (i.e., encapsulating
tablets in hard-gelatin capsules) is used as a quick and low-cost technique to blind investigators and volunteers in a clinical
study and to meet the challenging timelines for providing clinical material. Overencapsulation eliminates the need to outsource
a matching placebo and complex double-dummy study design. Although standard hard-gelatin capsules (HGCs) are widely used for
overencapsulation of materials in double-blind clinical trials, they might not always provide the features required for the
clinical-trial design and comparator products.
DBcaps, two-piece hard-gelatin capsules designed for double-blind clinical trials, were developed to overcome these limitations
for certain trials. Each capsule body is completely covered by the elongated design of the cap. This design makes it virtually
impossible to open the capsule without causing visible damage, thereby alerting investigators of blind breaking and bias.
The wide diameter of DBcaps capsules contains several shapes and sizes of tablets relatively easily while the short length
facilitates ease of swallowing. Whole tablets can be filled directly into DBcaps capsules without needing to be broken or
ground, thus eliminating concerns about inaccurate dosage or modification of the drug's intended performance. Standard two-piece,
HGCs also can be used for blinding tablets for clinical trials, but their smaller diameter (compared with that of DBcaps capsules)
limits the size of tablet that can be filled into the capsule.
It is legitimate to ask whether overencapsulation can affect dissolution, absorption, or bioavailability in clinical trials.
In comparative pharmacokinetic trials, overencapsulating an esomeprazole multiple-unit-pellet-system with HGCs did not influence
the rate (C
max) or extent of absorption in a study involving 49 volunteers (1). Other in vivo studies have shown the equivalence of in vivo disintegration time using gamma scintigraphy and therapeutic-effect onset time between encapsulated and nonencapsulated sumatriptan
tablets (2). Although some studies have shown that overencapsulation may not affect in vitro dissolution studies, it could delay the absorption and in vivo efficacy of drugs that are intended to have a fast onset of action. This delay was demonstrated in an open-trial design in
which patients scored a migraine drug's response to headache pain (3). Dissolution could also be affected by low capsule-fill
weight, type of filler, and drug solubility (4, 5). Using the right capsule size and excipients (or backfill) similar to those
in the tablet formulation could reduce the effect on dissolution. The solubility of the drug should be factored into the blinding
trials. This article focuses on overencapsulation's effect on disintegration and dissolution.
Propranolol, a highly soluble, highly permeable, Biopharmaceutics Classification System (BCS) Class I chiral drug marketed
as a racemic mixture, exists in two polymorphs. Crystallization solvents, grinding, and compression can cause change in the
crystalline state and, thus, differences in dissolution performance (6, 7). Although propranolol is not hygroscopic, the presence
of moisture in the backfill could cause interparticle surface interaction that could affect the performance of the encapsulated
tablet. Rofecoxib, a low-solubility and high-permeability BCS Class II drug, is susceptible to oxidation and photolysis (8).
The influence of moisture on the disintegration and dissolution of the encapsulated tablets has not been studied for either
class of drugs.
The model-independent similarity factor (f
2) may be used to compare the dissolution profiles of two drug products (see Equation 1). This equation measures the similarity
in the percent dissolution between the two curves. An f
2 greater than 50 implies that two dissolution profiles are similar (9). The US Food and Drug Administration recommends using
only one sample beyond 85% dissolution because the value of f
2 is sensitive to the number of sampling points used in the following equation (10, 11):
in which R
t and T
t are dissolution values of the reference and test batches, respectively, at time t, and n is the number of points. The dissolution profiles can be determined using the traditional approach of high-performance liquid
chromatography (HPLC) or the data can be acquired in real time using a fiber-optic diode-array probe or system (FOPS). Bijlani
and Adeyeye used the latter method to monitor the dissolution of a multiparticulate ibuprofen system. They found that it was
much faster and more accurate than the HPLC method (12).
The objective of the current study was to investigate the effect of overencapsulating on the in vitro disintegration and dissolution of tablets of a BCS Class I drug (i.e., propranolol) or Class II drug (i.e., rofecoxib). The
authors compared DBcaps capsules with HGCs in the presence and absence of backfill. The authors performed dissolution using
the Delphian FOPS method and examined the long-term stability of the overencapsulated products.