Piperine as a Placebo: Stability of Gelatin Capsules without a Cross-Linker

Gelatin has been the biomaterial of choice for decades now. Its low cost, renewable, nontoxic, and biodegradable properties make it one of the most desirable materials for controlled release applications. However, the usage of gelatin is limited by its poor mechanical/thermal stability and high water solubility. Chemical cross-linkers and hydrophobic modifications of gelatin have solved this problem, but they lead to the problem of toxicity and/or a high processing cost. This research attempts to employ a nontoxic hydrophobic drug molecule to curb early degradation of gelatin in an aqueous environment. We report the design of non-cross-linked gelatin capsules with a high dissolution resistance in an aqueous medium. Piperine, a hydrophobic drug (solubility = 40 mg/L in water), was coated on the gelatin capsules to enhance its stability in an aqueous environment. The hydrophobic piperine molecules repelled the water molecules to intensify its dissolution resistance. This stabilization was used to control the release of naproxen sodium, encapsulated inside the gelatin matrix. Piperine, in this case, acts as a placebo; i.e., it has zero therapeutic effect, but its presence was necessary to control the early degradation of the gelatin matrix. The deposition of piperine was done using the solvent evaporation method where ethanol was used as the solvent. The wettability studies revealed the hydrophobic nature of the surface after the deposition of piperine, while SEM analysis showed the presence of long cylindrical (fiber-like) structures over the gelatin surface. Further investigation (FTIR/ATR and molecular dynamics) revealed that the long fiber structures were due to the crystallization of piperine over the surface of gelatin. This crystallization was triggered by the intermolecular association (hydrogen bond) of ethanol and piperine. These observations enabled us to optimize the piperine loading protocol over the gelatin capsules that helped in achieving a zero-order naproxen release for 32 h.