Oral drug-delivery systems are the most acceptable form of controlled-release system to patients. Scientists have shown growing
interest in modified-release oral dosage forms in recent years. Current technologies, such as oral multiparticulate drug-delivery
systems (MDDS), have gained immensely in importance, not only because of their ability to control drug release, but also for
the modified drug-release profiles they facilitate.
These systems release the drug with constant or variable release rates, thus maintaining drug concentration within the therapeutic
window for a prolonged period of time. The desired release profile facilitates controlled absorption through the target site
in the body, ensures good therapeutic activity, and reduces side effects (1). MDDS comprises a large number of small discrete
particles (i.e., active ingredient and excipients), each demonstrating desirable features. They are prepared by methods including
extrusion–spheronization, pelletization, granulation, spray drying, and spray congealing.
Multiunit particulate systems
Multiunit particulate systems (MUPS) are a novel MDDS technique for controlled and modified drug delivery. MUPS offer various
advantages over other systems, including reduced risk of local irritation and toxicity, predictable bioavailability, reduced
likelihood of dose dumping, minimized fluctuations in plasma concentration of drug, and high dose-strength administration
(1). Multiparticulate systems show more reproducible pharmacokinetic behavior and lower intra- and intersubject variability
than conventional (i.e., monolithic) formulations (2). Tableting of pellets reduces the esophageal residence time, compared
with capsules, and improves physicochemical stability, compared with suspensions (2, 3).
The applications for which MUPS formulations are developed include taste masking (i.e., orodispersible MUPS tablets), enteric-release
(e.g., of acid-labile drugs), and modified- or controlled-release orodispersible drugs for geriatric or pediatric patients.
The technology of preparing compacted MUPS ensures that the desired objectives (e.g., taste masking coupled with orodispersibility
as well as modified-release characteristics) are effectively achieved.
A good example of a MUPS is AstraZeneca's Losec, an antiulcer drug, the second-highest-selling pharmaceutical product in Sweden
in 2002 (3). The product consists of microencapsulated drug granules tableted with excipients (4). Other marketed MUPS formulations
include Galanil PR (Galantamine HBr) for Alzheimer's disease, antiobesity drug Lipidown (Orilistat), and Esomezol (Esomeprazole
Sr) for erosive reflux esophagitis, which are all manufactured by Hanmi Pharmaceutical.
Challenges in the formulation of multiunit particulate systems
Each discrete particle in a MUPS product incorporates its own release characteristics and further contributes to the product's
therapeutic activity. Compressing these subunits without affecting their individual release profiles is a major challenge
of MUPS technology because compacting subunits may lead to structural changes in the coating and consequently alter drug-release
Other challenges for manufacturing pellets in tablets (i.e., MUPS) are weight variation, poor hardness, and friability. To
prevent subunits from being altered, formulators include a cushioning agent (i.e., an excipient with protective properties)
in the tablet formulation.
The compression-induced changes in the structure of the subunits may depend on numerous formulation factors, such as the type
and amount of coating, the properties and structure of the substrate pellets, and the incorporation of excipient particles.
During MUPS formulation, scientists must consider process variables such as the nature of the polymer; the shape, porosity,
and density of pellets; compression force and content of coated pellets in the tableting blend; the wall thickness of coating;
and the nature of the excipients.
Figure 1: Pelletization process. (FIGURE IS COURTESY OF THE AUTHOR)
Pelletization and multiunit particulate systems
Pellets are manufactured by both wet and dry granulation techniques or by layering. Extrusion–spheronization is a wet-granulation
technique that helps in the preparation of pellets or spherical agglomerates. The process involves a blending stage, in which
active ingredients are blended with excipients and mixed with suitable binding solutions to form a heavy plastic mass. This
mass is subjected to extrusion to form extrudates of equal length. After extrusion, the materials undergo a spheronizing stage
that rounds extrudates by cutting them and rolling them into spheres (see Figure 1).
Figure 2: Pelletized tablet with drug embedded polymer matrix system. (FIGURE IS COURTESY OF THE AUTHOR)
Manufacturers create modified-release systems in two main ways. They either coat spherical, uncoated pellets or embed a drug
in a polymer matrix system (6). The uncoated drug–polymer pellets prepared by extrusion–spheronization are subjected to compression
into tablets (see Figure 2). In another technique, the polymer or release-controlling material is coated along with the drug
onto the uncoated pellet to form a nonpareil seed (see Figure 3). These drug–polymer coated pellets are compressed into tablets
to obtain MUPS.
Figure 3: Pelletized tablet with polymer coated pellets. (FIGURE IS COURTESY OF THE AUTHOR)