R

Fig. 11.9 Piled (right) and void configuration (left) of assembled modules

The convex base exhibited the highest increase in matrix surface area when exposed to dissolution medium (at the erosion front), the concave surface being lowest; the flat base area was intermediate. Observations of the shape of the swollen parts of the matrices suggested that the polymeric chains in the gel entangled differently in the extreme cases:

• The chains expanded along the outline of the curved surface of the convex base.

• For the concave base, the polymer chains were constrained to entanglement in the cavity.

Consequently, different release behaviors were evident from compacts with the three bases [15]. Although the two curved bases had the same initial area (in the dry state), the convex base released the water-soluble model drug buflomedil pyridoxal phosphate much faster than the concave surface. The release profile of the concave base was also lower than that of the flat base, which had the lowest initial area (Figure 6 in [15]). When drug release was expressed in flux units (amount released per unit surface area per unit time), flux values were practically identical in all cases. Such behavior again indicated that release rates were dictated by the swelling rates of the matrix bases.

Assembly of two swellable matrix modules can give delivery systems containing double amounts of drug but having a lower surface area/volume ratio relative to the two individual (nonassembled) modules. Type of assembly also plays a role. In void configuration, release rate was significantly slower compared to the nonassembled modules but was slightly higher than from modules assembled in "piled configuration" (Fig. 11.9) due to the different volume/area ratio.

Fig. 11.10 Void assemblage of male and female modules

Fig. 11.10 Void assemblage of male and female modules

Figure 11.10 shows two uniquely shaped Dome Matrix® "male" and "female" modules designed to facilitate assembly in void, stacked, or mixed configurations by friction interlocking.

The concave female module can also fit the convex bases of both female and male modules. Clicking the concave bases of both male and female modules provides a unit with an empty inner space.

Dome Matrix® technology was successfully used to accommodate the antima-larials artesunate and clindamycin in one unit. Male and female modules containing clindamycin and formulated as swellable matrices for prolonged release were studied with particular attention to shape effects on drug release. Release profiles of clindamycin from male and female modules were typical for swellable matrices. The male module released drug more slowly than the female module, reflecting differing surface areas exposed to the dissolution medium. Rate profiles showed a rapid rate decrease of the initial delivery (first 100 min), followed by more steady release rate. Such behavior can be attributed to "burst" release, typical of hydro-philic matrices occurring before the formation of the rate controlling gel layer. The female module released the clindamycin faster than the male counterpart over the first 90 min. Release from the female module then decreased unexpectedly, falling lower than for the male module. Thereafter, the male module maintained a quasi-constant release rate, delivering more than 80% of drug load in 300 min [17].

Swelling/erosion behaviors were considered to explain such release rates. Photographic area measurements of swollen modules were compared with clindamycin release. Although the releasing areas between the two modules differed, fluxes were practically super-imposable. This suggests that modules could be designed with specific geometries to control release profiles from swellable matrices.

The delivery system for malaria treatment was completed by incorporation of two additional female modules, viz. one providing immediate (rapid) release of a fraction

Fig. 11.11 Clindamycin/ artesunate combination delivery system obtained by assemblage of four modules of the clindamycin dose and a module for immediate release of artesunate. This four-module assembly (Fig. 11.11) allows the patient to receive the artesunate and one-third of the clindamycin dose, formulated for immediate release, followed by the remainder of the clindamycin, formulated for prolonged retention/release under gastro-retentive conditions (80% in 8 h in vitro). Either assembly configuration (void or stacked) allowed site-specific delivery and alignment with kinetics and dynamics of both drugs in one unit. The void configuration, to enable floating and gastric retention, was obtained by joining the two prolonged release modules, having "male and female" shapes. The complete unit included the two additional immediate release (IR) modules stacked on either side of the sustained release modules assembled in void configuration. The four-module system was nonbuoyant (sank in aqueous systems), but rapid disintegration of the two fast releasing modules led to the assembled prolonged release modules attaining the appropriate density and floatation.

A bioavailability study in dogs (without the artesunate module) showed that the system sustained significant clindamycin plasma levels for up to 8 h, increased absorption (bioavailability), and suggested that dose frequency could be reduced [17]. The system is being proposed for delivery in one dosage unit the daily therapeutic dose suggested in WHO Guidelines. Other modules could be fitted to the system for a second "burst" of artesunate, for its sustained release, or for other drugs.

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