Development of Novel Microsphere and Microballoon DDSs by Polymeric Spherical Crystallization

Abstract

In this chapter, polymeric spherical crystallization with an acrylic polymer, such as Eudragit (RS, S or L), which is used as a matrix agent, for dispersing the API in the system, is presented as a way to directly prepare polymeric microspheres in water or polyvinyl alcohol. In this system, quasi-emulsion droplets are instantaneously formed by introducing the ethanolic API solution and the polymer in an aqueous medium in which the API and the polymer are co-precipitated to form a spherical micro-sponge-like matrix containing the API. A controlled-drug-releasing polymeric-microsphere system is developed by this process, known as the ESD method. Physicochemical properties, such as surface topography, particle diameter, and drug-releasing behavior, are determined by the polymer-to-drug ratio in the formulation, the agitation speed of the system, and the diffusion rate of ethanol from the emulsion droplets, which depends on the hydrogen bonds formed between the API (ibuprofen) and ethanol and the pH of medium. The drug-releasing rate of the microspheres is designed as pH depended as solubility dependency of polymer, e.g., enteric property with Eudragit L. The pharmacokinetics of microspheres containing Eudragit RS, administered orally to a beagle dog, revealed that the absorption and elimination rate constants of microsponges are smaller than those of immediately released Brufen granules. Furthermore, the time to reach the peak plasma concentration of ibuprofen after administration is prolonged and the area under the plasma-concentration-versus-time curve of the microsponges is increased. Since drug release from the microsponges is prolonged, the absorption of drug is effectively continued in the gastrointestinal trac. It is considered that Eudragit RS microsponges significantly prolong the residence time in the stomach due to their strong adhesive interaction with muco-polysaccharides on the surface of the stomach wall. Hollow microspheres (microballoons) used for multiple floating-controlled drug-delivery systems have been developed by polymeric spherical crystallization. To quantitatively describe the floating behavior of the microballoons in the stomach, a novel radio-scintigraphical method with ^{99 m}Tc was developed. The enhanced bioavailability of the microballoons could be explained owing to their prolonged residence time in the stomach.