Patents on many popular medicines will soon expire, and makers of generic drugs threaten to reduce Big Pharma's profits by
marketing low-cost versions of these therapies. Because the industry's pipelines remain anemic, many companies have sought
to extend the patents on their products by developing new controlled-release formulations. Multiparticulate dosage forms could
extend patent protection, offer great control over release rates, and expand drugmakers' formulation options.
The particulars of multiparticulates
Multiparticulates is a general term for roughly spherical pellets that have diameters of approximately 0.25 to 3 mm. These pellets may contain
one or more active pharmaceutical ingredients (APIs), or they may consist of inert cores coated with APIs. Multiparticulates
release their drug loads independently. They can be compressed into tablets, filled into hard gelatin capsules or sachets,
or mixed into liquid oral suspensions.
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Minitabs, one type of multiparticulate, are tablets with diameters of between 2 and 3 mm. They can be filled into hard capsules, administered
as single units, or compacted into bigger tablets that release their subunits as multiple dosage forms upon disintegration.
Multiplying the means of control
Multiparticulates can control a drug's release rate by mechanisms similar to those used in conventional controlled-release
tablets. For example, a multiparticulate can release its drug load as it erodes in the gastrointestinal (GI) tract. This technique
is appropriate for low-dose or low-solubility drugs. "The formulation of the particulate core can become rather sophisticated
to provide a customizable release profile," says David Oakley, director of technical sales for oral dosage forms at AAIPharma
(Wilmington, NC). Formulators can include permeation enhancers, buffers, or solubilizers in the pellets, for example.
Elan Drug Technologies's SODAS multiparticulate contains an active-pharmaceutical-ingredient core coated with layers of functional
polymers that control the drug's release rate. (IMAGE IS COURTESY OF ELAN)
But the most common approach to controlling multiparticulates' release profiles is to apply functional coatings to the pellets,
says Oakley. Coatings often are selected to provide sustained or delayed release. The coating formulation can be modified
to form pores through which the drug can diffuse. Manufacturers can achieve sophisticated release profiles by applying multiple
Enteric polymers such as methacrylic acid copolymer and hydroxypropyl methylcellulose phthalate protect pellets as they travel
through the stomach, but dissolve in the near-neutral pH environment of the upper small intestine. Aqueous media can permeate
ethyl cellulose and ammonio methacrylate copolymer coatings, thus allowing the drug to be transported from the multiparticulate,
says Joe Cobb, senior formulation scientist at Metrics (Greenville, NC). Manufacturers can also coat pellets with an insoluble
barrier membrane through which the drug diffuses from inside the core into the surrounding medium. Changing the coating levels
or the combination of polymers that coat the multiparticulate allows the creation of complex release profiles.
The Micropump system is Flamel Technologies's (Venissieux, France) method of creating multiparticulate dosage forms. The company
surrounds an inert core with an API and coats the multiparticulate with various polymers to achieve the desired controlled-release
properties. The system produces multiparticulates that can be used in liquid oral suspensions. The coating that the company
applies to multiparticulates withstands long-term storage in liquid suspension without any change in its permeability, says
Catherine Castan, Flamel's director of research and development of oral dosage forms. Coreg CR, GlaxoSmithKline's (London)
controlled-release formulation of carvedilol, uses Flamel's Micropump technology, she adds.
An operator at Flamel Technologies empties Micropump coated multiparticulates from a fluid bed onto a tray. (IMAGE IS COURTESY
OF FLAMEL TECHNOLOGIES)
Although multiparticulates and tablets share similar methods for controlling drug release, multiparticulate systems offer
a higher degree of flexibility in dosage-form design and development than tablets do. "Each subunit in a multiparticulate
system contains part of the drug, and the sum of the drug in all subunits makes the total dose, but the functionality of the
overall dose is directly correlated to the functionality of individual subunits," says Ali Rajabi-Siahboomi, senior director
of scientific affairs at Colorcon (Harleysville, PA). By filling capsules with multiparticulates that release the same drug
at various rates, drugmakers have the flexibility to create an array of dosage forms—from simple to complex, tailored release