Capsules for Modified Release 1441 Single Release

Multiparticulates in capsules received substantial attention in the mid-1980s as a way of controlling drug release, when the first proton pump inhibitor (PPI) omeprazole was developed. Omeprazole is extremely pH-sensitive, with a degradation half-life of less than 10 min below pH 4.0. Conventional immediate-release dosage forms were not appropriate so an enteric-coated multiparticulate pellet formulation was developed [21]. The pellet contained an alkaline-reacting component, a basic salt of omeprazole together with high pH-buffering materials in a subcoat and an enteric film top coat [US4786505, Nov 22, 1988 and US4853230, Aug 1, 1989]. Pellets were contained in

0.4 fim two-piece hard gelatin capsules. The formulation protected the omeprazole from acid degradation in the stomach and released drug rapidly in the small intestine (Losec®). This technology has subsequently been applied to other acid labile compounds.

Roxithromycin is an oral macrolide antibiotic with half-life in simulated gastric fluid of about 14 min. Enteric-coated roxithromycin pellets were developed and compared in an in-vivo human study with a dispersible tablet formulation. Bioavailability was enhanced by 143% with the pellet formulation. of the pellet formulation was delayed slightly consequent to the delayed release provided by the coat (2.83 h vs. 1.43 h) [22].

Multiparticulates, from which drug release is controlled have also been effective in treating chronic pain, with potent analgesic compounds having short biological half-lives and consequently limited duration of action. Tramadol, a drug for treating chronic pain has an elimination half-life of 5-6 h and requires 4-6 times a day dosing for pain control. A sustained-release pellet formulation was compared to the marketed SR tablet formulation in a bioequivalence study in 24 subjects. Findings were:

• Both formulations had similar AUC values.

• Elimination half-life was significantly longer with pellets (13.4 vs. 10.4 h).

Moreover, the inter- and intrasubject variability in terms of rate and extent of absorption was much less for the pellet formulation. Hence, pellets provided a less variable and more prolonged plasma profile [23].

Morphine sulfate is also used for chronic pain, particularly in terminal illness. Elimination half-life is short (2.2 h) as is its duration of action (about 4 h). An extended-release capsule formulation comprising coated pellets provided plasma levels that sustained the analgesic effect for at least 12 h with dose proportionality over the dose range of 30-100 mg for Cmax and AUC. Thus, the pellet formulation in capsules had equivalent performance to the twice-a-day SR tablet formulation [24].

Hydromorphone hydrochloride is an opioid analgesic with a short elimination half-life (2.3 h). Immediate-release formulations need to be dosed every 3-6 h to sustain analgesia. An ER pellet formulation was compared with an IR tablet for food effect, dose proportionality, and steady-state behavior. The pellet formulation demonstrated dose proportionality and provided more constant steady-state plasma levels with lower C and higher C plasma concentrations (Fig. 14.9). Adverse max ° min r \ c /

drug reactions were fewer in the pellet cohort, possibly ascribable to the smoother plasma profile [25].

Formulation of diclofenac as multiparticulates reduced in vivo disintegration lag time compared to coated monoliths. This lead to faster release, more rapid drug absorption, and increased bioavailability [26, 27].

Valproate is used to treat epilepsy. A relatively constant plasma concentration is necessary for optimal efficacy and safety, but its rapid absorption and fast elimination rate causes plasma concentrations to fluctuate. Wangemann et al. compared the pharmacokinetic profile of a multiparticulate capsule formulation with an enteric-coated tablet formulation, both containing 300 mg sodium valproate. Under a twice-daily

Time (hours)

Fig. 14.9 Mean steady-state plasma concentration of hydromorphone hydrochloride following the administration of 12 mg ER pellet capsules once daily (closed circle) compared to every 6 h 3 mg IR tablets (open circles) [25]

Time (hours)

Fig. 14.9 Mean steady-state plasma concentration of hydromorphone hydrochloride following the administration of 12 mg ER pellet capsules once daily (closed circle) compared to every 6 h 3 mg IR tablets (open circles) [25]

regimen, both formulations showed comparable extent of absorption at steady state. However, the plasma fluctuations on dosage of the multiparticulate capsule formulation were only one-third of those seen on dosage of the enteric-coated tablet formulation [28].

Pulsatile delivery may enable the design of chronotherapeutic delivery systems [29]. Single-unit approaches using coated capsules have been described and discussed earlier [16-19]. Multiparticulate pulsatile drug delivery systems in capsules might reduce the unpredictability of gastric transit that is evident with monolithic units. They also offer the possibility of combining multiparticulate populations with distinct time-release profiles in a single capsule [30].

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