Pore Diameter and Controlled Release of Poorly Soluble Drugs

A major advantage of OMS concerns flexibility of synthesis. Judicious selection of the template and conditions can provide an end product that is engineered to meet user requirements. Although other porous silicates have been used for drug delivery, such materials possess irregularly shaped pores of broad size distribution. OMS pores, in contrast, are more uniform in shape with very narrow size distribution. The capability to "tailor" pore diameter during manufacture thereby allows close control of drug release rate. Decreased pore size leads to decreased drug release rate and vice versa [5, 9, 24]. Figure 10.1 exemplifies this effect. Depending on the pore size, drug release can occur in minutes, hours, or days.

Particle size/morphology may also significantly affect drug release rate [25], and several protocols have been published on how to modify OMS particle size/ morphology [26, 27]. However, capability to control pore diameter may offer a better way of "designing" release rate. Drugs contained in OMS pores, being non-crystalline, can exhibit dissolution rates, and concentrations for absorption, not achievable by dissolution of low-energy crystalline forms. Stated otherwise, the release of poorly soluble drugs from OMS is associated with supersaturation. From a dosage form design perspective, this poses an interesting challenge based on the following possibilities:

• Increased concentrations at the site of absorption may - by virtue of Fick's First Law - enhance the flux of drug across the gastrointestinal epithelium or

• Supersaturation inherently poses the risk of the drug precipitating as an energetically more favorable but less soluble form, thereby reducing availability for absorption [28].

Fig. 10.1 Release profiles of itraconazole from SBA-15 in simulated gastric fluid supplemented with 1% of sodium lauryl sulfate. The release rate increases with increasing pore size. The subscripts denote the average pore diameter in nanometers

Fig. 10.1 Release profiles of itraconazole from SBA-15 in simulated gastric fluid supplemented with 1% of sodium lauryl sulfate. The release rate increases with increasing pore size. The subscripts denote the average pore diameter in nanometers

O FFB:SBA-15 A

O FFB:SBA-15 A

Fig. 10.2 In vitro release profiles of fenofibrate formulated with OMS materials with different pore diameter recorded under supersaturating conditions (left panel ) and plasma concentration-time profiles of fenofibric acid (the active metabolite of fenofibrate) (right panel). The pore diameter of the materials amounts to: 7.3 nm for SBA-15 A, 4.4 nm for SBA-15 B, and 2.7 nm for MCM-41. The results are discussed in the text

Fig. 10.2 In vitro release profiles of fenofibrate formulated with OMS materials with different pore diameter recorded under supersaturating conditions (left panel ) and plasma concentration-time profiles of fenofibric acid (the active metabolite of fenofibrate) (right panel). The pore diameter of the materials amounts to: 7.3 nm for SBA-15 A, 4.4 nm for SBA-15 B, and 2.7 nm for MCM-41. The results are discussed in the text

OMS offers specific advantages over other supersaturating drug delivery systems in that the rate at which supersaturation occurs can be controlled. This is illustrated in a study on the effect of release rate from OMS on rate and extent of dissolution and absorption of the poorly soluble drug fenofibrate (Fig. 10.2) [23]. In vitro studies employing materials with the largest pore size showed an immediate, burst-like release, followed by rapid supersaturation of the dissolution medium. However, drug levels in solution then fell rapidly to equilibrium solubility levels. In contrast, materials with smaller pore diameter released fenofibrate more gradually and exhibited sustained supersaturation. This trend was reflected in vivo (rats, fasted state): the formulation with the smallest pore size (and thus, slowest release rate) exhibited the highest extent of absorption. Furthermore, the extent of absorption of the slow-releasing OMS-based formulations was higher than that of a commercially available product incorporating micronized drug (Lipanthyl®). OMS thus offers the potential to control the degree of supersaturation to maximize availability for absorption. For other supersaturating drug delivery systems, exerting such tight control over the drug release process may be much more complicated (solid dispersions, high-energy salt forms) or even impossible (lipid-based systems).

Capability to precisely design drug release rate has led many authors to conclude that OMS constitutes a valuable controlled release technology. At this time, there are no studies demonstrating that controlled release from OMS provides sustained blood levels in humans. Furthermore, various drug delivery systems exist that enable zero-order drug release. By contrast, drug release from OMS more closely resembles first-order kinetics. Although some authors have altered in vitro release kinetics by functionalizing the silica surface of an OMS material [29, 30], an in vivo proof of concept for such systems is still lacking.

However, zero-order release in vivo may not always be most appropriate. More rapid release after dosage (as could be obtained with a first order-type release profile) may be more suitable for drugs that are rapidly eliminated. It may be necessary to provide an effective therapeutic plasma concentration at the outset that is then maintained by the slower, later release (as would be provided by first-order kinetics). A modified release system has to take account of the pharmacokinetics of the drug and its therapeutic plasma window. What OMS-based systems may offer is very consistent release behavior that may translate to less intersubject variation, as would be important for medications with narrow therapeutic windows or rapid metabolism and clearance.

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