Medical sponges are one of the most common tools used in various fields of medicine and are used to close wound surfaces in burns and trophic ulcers, showing absorbent and antiseptic properties, and stimulate tissue regeneration. The aim of this study was to optimize the composition of medical sponges with chlorhexidine digluconate based on a material of natural origin -xenoderma. The central composite design was used to establish the relationship between independent variables such as quantities of medical gelatin, propyleneglycol, and formaldehyde and dependent variables such as pH, the percentage of water absorption, the degree of in vitro degradation, thickness, and the time of complete dissolution, in order to obtain the optimal formulation using Response Surface Methodology. Using the concept of Quality by Design, the desired quality target product profile, critical quality attributes, risk assessment by Failure Mode Effects Analysis was determined that the number of excipients affects the pharmaco-technological parameters. It was found that sponges that contain 2% medical gelatin, 1% propyleneglycol, and 0.75% formaldehyde, are the best in composition, in terms of pH, the percentage of water absorption, the degree of in vitro degradation, thickness, the time of complete dissolution, in comparison with all other compositions.