Geomatrix Partially Coated Swellable Matrices

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There have been many attempts to control release kinetics in hydrophilic matrices by manipulating and balancing diffusion and relaxation mechanisms. Zero-order release from a matrix was obtained by designing an appropriate matrix shape [1] or nonuniform drug distribution [2], by using ionic-exchange resins, hydrophobic porous materials [3, 4], hydrophilic soluble polymers capable of modifying the effective diffusivity of drug [5], or by surface cross-linking of the matrix [6] and others. Geometric design of zero-order release in swellable matrices resides in maintaining a constant release area during matrix swelling and drug diffusion. This releasing area is the area of the swollen matrix surface in contact with the dissolution medium. A partially coated matrix, providing a constant releasing area takes the form of a "core-in-cup" system, i.e., a "disk" of drug and swellable/soluble polymer coated with an impermeable film on the lateral surface and on one base (Fig. 11.2).

The coating film is impermeable to water and drug diffusion. On contact with aqueous media, the uncoated base undergoes swelling and erosion. If erosion/dissolution is sufficiently fast, core thickness inside the impermeable polymer cup is reduced maintaining a constant releasing area. Zero-order release kinetics are obtained if fronts are synchronized. Varying the type or amount of swellable/soluble

Fig. 11.2 Picture of different sizes of core-in-cup matrices obtained by coating one base and the size surface of the disk

polymer in the core enables the rate of release to be modulated, as does the area for release. In vitro release rate and in vivo absorption were directly related to releasing area [7].

Mechanisms governing drug release in such a system were explored using swellable polymers (PVA, HPMC, and NaCMC) that interact differently with water (swelling and dissolution). Diclofenac sodium was used as the model drug [8]. The unidirectional swelling induced by the core coating enabled the monitoring of the movement of the erosion and swelling fronts over time. When a soluble polymer such as polyvinylalcohol (PVA) was used, the synchronization of the movement of swelling and erosion fronts provided linear release kinetics of drug from such swelling-activated delivery systems. Such findings indicated that polymer swelling and dissolution in the matrix core governed front movement. Front synchronization was not attained with hydroxypropyl methylcellulose (HPMC) polymer; with sodium carboxymethylcellulose (NaCMC) front synchronization took place, but later than with PVA. Moreover, using drugs with different aqueous solubilities (diclofenac sodium, dyprofilline, and cimetidine) and PVA as polymer, the thickness of gel layer at synchronization increased with drug solubility [8]. Nevertheless, at front synchronization the release rates were the same since the concentration gradients of the differently soluble drugs in the gel were the same.

Hydrogel matrices may not always encounter environments that readily attain synchronization of the fronts, particularly when less soluble polymers are used. In this situation, during drug release, matrix swelling predominates over erosion/ dissolution [9].

Geometric control of release rates during swelling can be obtained by applying impermeable coatings to different surfaces/areas of a disk matrix. This is illustrated in the sketch of Fig. 11.3. Case 0 matrices were not coated. Other cases are as follows [10]:

• Case 3: lateral surface was coated

• Case 4: lateral surface and one base were coated

Applications of impermeable coatings on different surfaces of a matrix containing a water-soluble drug and HPMC as polymer do not alter the basic diffusion characteristics of drug within the matrix. This enables the design of dimensionality driven release systems in which the preferred dimension for release can be changed.

Hence, the matrix composition can remain unchanged, but release rate is altered by partial coating, thereby changing the dimensionality of swelling of the matrix. Swollen matrices present different shapes as a function of the location of the impermeable coating, as illustrated in Fig. 1 of Ref. [11]. This leads to the following observations:

• The uncoated cylindrical matrix (Case 0) exhibited isometric swelling with a propensity for thickness increase on hydration. This is typical of compressed swellable disk matrices.

Fig. 11.3 Schematic representation of partially coated matrices. From the top: case 0; case 1; case 2; case 3; case 4

• The matrix with one face coated (Case 1) showed a less intense radial swelling with respect to the coated face compared to the uncoated face.

• The matrix with both faces coated (Case 2) exhibited the lowest axial increase in thickness and the largest diameter increase, indicating that swelling was mainly radially orientated.

• Increase in thickness was greatest in the matrix where the cylindrical sides of the compact were coated (Case 3), reflecting axial swelling.

• The matrix with the side and one face coated (Case 4) exhibited a one-direction axial swelling.

The findings indicated that coating applied to the disk faces changed matrix relaxation in axial or radial directions. The association between matrix swelling behavior and drug release was studied by changing the release areas for each of the partially coated matrices as shown in Fig. 11.3. The coating extension decreased in the order Case 4 > Case 2 > Case 1 > Case 3 > Case 0. Release rate decreased as the coat coverage increased. Plots of amount of drug released versus releasing area were linear in all cases (Fig. 11.4).

Surprisingly it was found that, as coating coverage was increased, a greater amount of drug was released per unit releasing area of swollen matrix. This indicated that swelling enhanced drug release by increasing the contribution of the relaxation mechanism to drug transport.

The Amount Drug
Fig. 11.4 Releasing area plotted versus the amount of drug released for the uncoated and partially coated matrices

Release rate profiles from the five systems were typical of swellable matrices. Release rate profiles over time were consistent for each system, being greatest with compacts where no coat was applied and least where all but one base surface were coated (Fig. 11.5).

The linear relationship between the swollen releasing area and the amount of drug released suggested that matrix swelling rates dictated release kinetics. Normalizing instantaneous release rates with the time-corresponding releasing area values revealed that swelling kinetics determined release kinetics. In fact, fluxes (amounts of drug released per unit area and time) for the five systems were practically the same (Fig. 11.6), despite the differing release rates from the complete units shown in Fig. 11.5. In conclusion, changes in releasing area due to matrix swelling determine rates and kinetics of delivery from swellable matrices.

Dimensionless numbers are frequent in drug transport analysis. A commonly used number is the Swelling Interface Number (Sw), defining anomalous release behaviors of swellable systems. The Sw, in analogy with the Peclet number, compares a pseudoconvective process with a diffusion-based process. The Sw value relates the contributions of penetrant transport (water) with the solute transport (drug) according to the expression:

where n is the penetrant front velocity, S the swollen layer thickness, and D the drug diffusivity.

Fig. 11.5 Variation of release rate versus time for the uncoated and partially coated matrices
Fig. 11.6 Flux of the uncoated and partially coated matrices plotted versus time

A similar dimensionless number can be defined, based on the increase of matrix release area consequent to three-dimensional expansion due to swelling. This is relevant to release from matrices because the Sw value is inherently related to one-dimensional transport (as in thin disks or films). The new dimensionless number, in contrast, describes the behavior of three-dimensional systems such as matrices. The dimensional analogy between the releasing area rate and diffusion coefficient allows an improved Swelling Area Number, Sa, to be defined viz.:

where dA/dt is the rate of increase of the releasing area of the matrix.

Sa values greater than 1 indicate Fickian diffusion; values lower than 1 indicate a relaxation-controlled (Case II) transport. When the expansion rate of the matrix drops to values similar to the drug diffusion coefficient, the release rate approaches a constant value.

The Sa numbers calculated for the five cases discussed here ranged from 30 to 10 as the coating extension increased, since the rate of development of releasing area decreased.

Matrix coating can also utilize permeable and semipermeable films, particularly for systems coated on the side and on one base, i.e., a core-in-cup system [13]. Permeable coating films can increase the delivery from partially coated matrices by adding other contributions to their swelling-dependent delivery mechanism. Semipermeable and permeable cups increase release rate, compared to an impermeable cup. However, the systems described so far require the application by casting of an impermeable film on a portion of the matrix. As an alternative, the application by compression of a polymeric barrier layer to both bases of the core disk was developed [12, 14].

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