Therapeutic proteins and peptides are currently administered parenterally. To avoid intravenous or intramuscular injections, increasing efforts have been put into the development of oral dosage forms. To further improve patient compliance, tablets would be the dosage forms of choice; however, such drugs might be denatured upon the volume reduction and release of frictional heat inherent in tablet compression. With this limitation in mind, tablet triturates (T.T.s) which are a molded solid dosage form could be used as an alternative. However, T.T.s made with traditional formulas generally are fast dissolving, and the commonly used hydro-alcoholic moistening agents might denature protein and peptide drugs.
The main focus of this study was therefore to develop a novel formulation for tablet triturates containing protein and peptide drugs. With this newly developed formulation, protein and peptide drugs could be released at steady rates without denaturation. Bovine serum albumin (BSA) was used as the model protein drug and Avicel® RC591 as the protein carrier, with microcrystalline cellulose (MCC) as the diluent. Concentrated sucrose syrup was the moistening agent to produce a mass suitable for molding the tablet triturates.
Before its incorporation into tablet triturates, BSA was loaded onto Avicel RC591 particles and freeze-dried into a powder to ensure accurate dose and uniform mixing with MCC. The maximum loading efficiency and minimum release rate were both achieved at pH 4.5. As observed with optical microscopy, a polymer rich phase formed upon the binding of BSA onto Avicel RC591 in water. Scanning electron microscopy (SEM) indicated the freeze-dried product of Avicel RC591-BSA complex was in the form of small porous particles with irregular shapes.
Homogeneously mixed freeze-dried Avicel RC591-BSA complex and MCC were wetted with 30% sucrose syrup at pH 4.5 and molded into tablet triturates. BSA was released steadily in vitro in a USP Apparatus 2. The release of BSA from such T.T.s best fitted the Hixson-Crowell release model. The drug release mechanism was Non-Fickian diffusion at low agitation speeds and Super Case II transport at high agitation speeds. The initial rate of release of BSA from the tablet triturates decreased with increasing concentration of sucrose syrup, and increased linearly with the weight ratio of MCC to the freeze-dried Avicel RC591-BSA complex. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) demonstrated no protein degradation. Circular dichroism (CD) and gel filtration indicated that BSA was released in an unchanged conformation.
To protect protein and peptide drugs from acidic gastric fluid, beeswax was used as the sub-coating material and Opadry® Enteric was used as the enteric coating material. With an enteric coating of 7 mg per tablet triturate, 1.73% of BSA was released in Modified Simulated Gastric Fluid (pH 1.2, USP) within 2 h. When the enteric coated tablet triturates were transferred to Modified Simulated Intestinal Fluid (pH 6.8, USP), BSA was released steadily.