Drug Candidates

Not all drugs are suitable for development in modified release form, nor is modification necessary in many cases. Drivers for such modification concern the various "biological" properties of the drug, the characteristics of the clinical condition, and the properties of the drug. Considerations may include:

• Pharmacokinetic target: The requisite plasma concentration, duration, and time of onset considerations (target plasma profile). This usually needs to be defined and validated by clinical experience. Lack of such information increases the risk of program failure.

• Elimination (excretion) half life: Drugs with half lives in the region 1-10 h are most suited to release modification, provided that plasma presence is directly related to therapeutic effect.

• Therapeutic dose(s): If the aim of modifying release concerns prolonging duration of action this usually requires that a dose contain higher levels of drug. This can present unit size challenges where dose is high. It may be possible in such cases to utilize the active as the base particle for coating.

• Dose response (therapeutic index): If dose response is steep, the target plasma concentration limits may be narrow. Performance standards are more stringent as a consequence. Multiparticulate formulations may be potentially advantageous in this context due to more consistent gastrointestinal transit and lower risk of "dose dumping" because of coat failure.

• Location for drug absorption in GI tract: The ideal drug for sustaining absorption is well and consistently absorbed throughout most of the GI tract, particularly the small intestine. In practice, pH-solubility effects, absorption windows, and susceptibility to metabolizing enzymes in the intestinal wall can affect absorption efficiency in the small intestine, regardless of technology used to modify release.

• Physicochemical characteristics of the drug: Absorption of drug and release from the dosage form requires that it be in solution. Solubility, however, can be affected by pH and possibly other environmental conditions in the GI tract. Multiparticulates may be advantageous with respect to release as their ready dispersion provides a larger surface area for dissolution than does a monolithic unit.

Multiparticulate systems offer an efficient platform for the development and manufacturing of products combining different drugs or one drug with different release profiles. For example, dual release can be achieved by the combination of a coated and uncoated fraction of the same multiparticulate composition. Dexlansoprazole, the R-enantiomer of the proton pump inhibitor lansoprazole, was developed using dual release to achieve a once-daily dosing regimen. The product combines enteric coated pellets releasing drug in the proximal duodenum and pellets that release drug in the distal small intestine [28]. Particles can also be "sprinkled" or otherwise dispersed in food or beverages to make for easier swallowing [29].

The same strategy has been adopted for treating Parkinson's disease patients. Dual release of a combination of two drugs (carbidopa and l-DOPA or benserazide-l-DOPA) was shown to prolong the therapeutic effect [30, 31].

Chronotherapy consists of aligning drug presence in the biosystem with circa-dian rhythm. Conditions that may be amenable to such therapy are hypertension, CNS disorders, cardiovascular disease, asthma, and cancer [32]. Multiparticulates have the potential, in certain cases to deliver drug(s) that provide such therapeutic advantage, being capable of providing appropriate release profiles [33]. Figure 13.9 shows a hypothetical design of a pulsatile releasing pellet.

Timed Pulsatile Release Drug Layer

First Pulsed Drug Layer

Protective or Entric Coating

Timed Pulsatile Release Drug Layer

First Pulsed Drug Layer

Core Granules Release Control Polymer a

Drug Release from No Drug Drug Release

Outer layer as Release from Core

Entric coating dissolves

Drug Release from No Drug Drug Release

Outer layer as Release from Core

Entric coating dissolves



Pulse Release Pulse Release

Pulsatile Release

(TPR) Pulse


Acid Phase

Lag Time Lag Time


d . / . \

. 1 . / .

Time (hours)

Fig. 13.9 Hypothetical design and plasma drug profile of a multiparticulate system. (a) Design of a pellet with multiple layers and b. (b) Subsequent bimodal plasma concentration profile [33]

Multiparticulate units can be advantageous for modified release formulations in early drug development programs where the therapeutic dose remains to be determined. Dose adjustment for dose-response studies can be readily made by filling different amounts of microparticles into capsules without any additional processing or formulation that could alter the release pattern.

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