Self-Emulsifying Granules and Pellets: Composition and Formation Mechanisms for Instant or Controlled Release

Abstract

Many articles have been published in the last two decades demonstrating improvement in the dissolution and absorption of low solubility drugs when formulated into self-emulsifying drug delivery systems (SEDDS). Several such pharmaceutical products have appeared in the market for medium dose (Neoral® for Cyclsoprin A, Kaletra® for Lopinavir and Ritonavir), or low dose medications (Rocaltrol® for Calcitriol and Avodart® for Dutasteride). However, these are in the form of viscous liquids or semisolid presentations, characterized by the disadvantages of high production cost, stability problems and the requirement of large quantities of surfactants. Solid SEDDS (S-SEDDS), as coarse powders, granules or pellets, besides solubility improvement, can be filled easily into capsules or processed into tablets providing a handy dosage form with instant release, which can be further developed into controlled release by mixing with suitable polymers or coating with polymeric films. In this review, the materials used for the preparation of S-SEDDS, their properties and role in the formulations are detailed. Factors affecting the physical characteristics, mechanical properties of S-SEDDS as well as their in vitro release and in vivo absorption are discussed. The mechanisms involved in the formation of instant and sustained release self-emulsifying granules or pellets are elucidated. Relationships are demonstrated between the characteristics of S-SEDDS units (size, shape, mechanical properties, re-emulsification ability, drug migration and drug release) and the properties of the submicron emulsions used as massing liquids, with the aim to further elucidate the formation mechanisms. The influence of the composition of the powdered ingredients forming the granule or pellet on the properties of S-SEDDS is also examined. Examples of formulations of S-SEDDS that have been reported in the literature in the last thirteen years (2004–2017) are presented.

Current Status of Supersaturable Self-Emulsifying Drug Delivery Systems

“…The appropriate solid excipients for the solidification of su-SEDDSs should be selected carefully because of their critical implications for not only the physicochemical properties of the su-SEDDS formulation but also in vivo drug absorption from the formulation [14]. The water-insoluble mesoporous silica and Microcrystalline cellulose (MCC), water-soluble polysaccharide, or polymeror protein-based solid carriers are generally used as solidification excipients [131].…”

“…Mesoporous Silica Different grades of mesoporous silica, colloidal silicon dioxide (CSD), and magnesium aluminosilicate, which are pharmaceutically acceptable excipients with high lipid loading capacities, have been used commonly as adsorbents in the preparation of SEDDS solid dosage forms [14,200]. Several cases of solidification of su-SEDDS were reported for celecoxib using silicon dioxide (Sylysia 350 fcp) [108], fenofibrate using mesoporous silica [26], glipizide using calcium carbonate and talc, and valsartan using calcium silicate (Florite ® ) [127].…”

“…Many granulations and pellet formulations that are produced industrially by extrusion/spheronization contain some amount of MCC as an excipient, to ensure successful processing [14]. This is owing to the ability of this material to restrain water in its own structure, restricting the separation of water from the solid material during the granulation and extrusion processes, yielding a wet mass.…”

“…In addition, drugs can be maintained in a solubilized state during formulation dispersion and digestion [13]. SEDDSs easily form stable submicron-sized emulsions in the aqueous environments of the GIT with mild agitation provided by gastric mobility [14,15]. The particle size of the dispersion formed in the GIT has been regarded as a very important factor for the development of formulations that spontaneously emulsify to form oil in water emulsions with nanometer particle sizes and narrow distribution to provide improved in vivo performance.…”

Untitled

“…Orit can be formulated as granules using a wet granulation technique, where the SES will be used as a binder or granulating media. [34] Dough masses consisting of SES can be converted to pellets by extrusion and spheronization. Even though self-emulsifying tablets and pellets have been extensively investigated and published in literature, no commercial products were available in these forms.…”