Optimización de la formulación y procesado de emulsiones aceite/agua de interés nutricional estabilizadas con fosfolípidos de distintos orígenes

Abstract

Developing a new pharmaceutical product in the form of a parenteral emulsion, that being the target of this research work, involves not only characteristic properties of the product formulation scientifically justified but also abiding by the regulations from the conforming authorities, apart. Parenteral formulations, as the manufacturing scope of this thesis, are used not only as pharmaceutical products but also have nutritional values too, whereby using intravenously, these emulsion formulations are integral part of total parenteral nutrition (TPN). Constituents and characteristic properties of these formulations, in this way, follows far more restrict protocol of conformance in their production and clinical usage than other nutritional products. The use of lecithin, as a food based product, in the form of emulsifier in parenteral emulsions has long been recognized and many commercial parenteral formulations consume lecithin of egg and soy origin in their parenteral products. The adverse events related to autopsy findings that majorly include intravascular fat accumulation were the cause for finding sources of fats other than soy oil and emulsifiers other than commercially used lecithin with egg origin (Intralipid®). In this thesis, commercially available lecithin with different origin was used as an emulsifier to qualify emulsions as a parenteral product initially utilizing different oil types in the formulations. Olive oil, soy oil and fish oils were used as fat source in these formulations at pH values ranging from 2 to pH 9. Different pH controlled emulsions were produced with lecithin from soy, sunflower and rapeseed origin and a stability profile was generated on the basis of creaming evaluation, PSD and zeta potential characterization. Results indicated that the parenteral formulations with pH values higher than 7 were the most stable in this scenario with different oil types and lecithin origin. Collectively, concentrated fish oil emulsions (omegaven) have the least stability profile even at higher pH values. Soy oil emulsions gave maximum stability duration at pH 8 and 9 with different lecithin origin at commercial concentrations as an emulsifier i.e. 1.2%. The knowledge of these stability profiles at different pH values for different oil types and emulsifier concentration was utilized in order to develop novel emulsifier systems for parenteral emulsions. In this research work, formulations containing new emulsifier systems with marine origin, FKK042 and FKHEO30, were developed at only higher pH values with different emulsifier concentrations (i.e. 0.6 to 2.4%). These new emulsifiers have duel properties fulfilling not only nutritional demands but having emulsification characteristics as well in a parenteral product. The PSD and zeta potential profile of FKK042, containing sufficiently high phospholipids, equal to 42%, at a concentration of 1.8 and 2.4 gave stable and repeatable emulsions within pharmacopeia tolerance limitation (PSD < 0.5 pm and C, > ± 30 mV). The shelf life of FKK042 was sufficiently long enough with respect to initial studies and even at higher temperatures (40 °C) for accelerated stability studies, the particle size did not change and emulsions were stable throughout their stability period. The results of 1.8 and 2.4% FKK042 were almost similar for all oil types used (soy, fish, omegaven) while for another fat source used in this study comprised of a mixture of oils collectively known as SMOF (soy, medium chain triglycerides (MCT), olive and fish oil) with 20% oil loadings, due to higher oil contents of the emulsions, a 2.4% emulsifier quantity was preferable in order to keep the emulsions stable at accelerated stability study. Emulsions with 0.6% FKK042 emulsifier were marked unstable as free oil drops were found at the top after formulation processing. Lab preparations of these emulsions containing FKK042 produced a characteristic top emulsifier layer containing no naked oil drops at the said pH (8-9) and were confirmed through microscopic studies as well. The pilot plant production of the same overcame that characteristic layer during processing with no significant alteration in overall physical properties of the formulations containing FKK042. Similarly, formulations with FKHEO30 emulsifier in concentrations with 1.2, 1.8 and 2.4% were extremely unstable and their water/oil interphase separated out after preparations. The emulsifier concentration was reduced down to 0.6 and 0.9% to study FKHEO30 emulsifier formulations stability. It was observed that at least formulations were possible with lower concentration of FKHEO30 emulsifier; however, there was clear evidence of free oil drops at the top of each formulation and confirmed through microscopic studies too. The stability study was continued though; no satisfactory results were predicted by using FKHEO30 emulsifier in the parenteral emulsions except for soy and fish oil formulations contianing 0.6% FKHEO30 emulsifier oil. FKK042 emulsifier with 1.2 to 2.4% concentrations in the formulations at pH values between 8 and 9 is potentially a new emulsifier for the development of new parenteral emulsions comprising duel properties of marine nutrition in the form of omega-3 fatty acids, as well as processing aid in emulsification. Consequently, commercially available lecithin emulsifiers could be replaced entirely with all their complications based on long term dosage for any parenteral intravenous (IV) product with this novel emulsifier. Characteristically, FKK042 emulsions seemed appropriate candidate for the future of parenteral emulsions abiding by regulations from USP (United States Pharmacopeia) and Eur-Pharmacopeia (European Pharmacopeia).