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Self-nanoemulsifying drug delivery systems (SNEDDS) for solubility enhancement - new approaches for determining appropriate formulations for liquid SNEDDS and their conversion to solid SNEDDS

  • The poor aqueous solubility of many drug substances has been addressed using different solubility enhancement approaches in the pharmaceutical technology field over the last decades. In this context, advanced drug delivery systems based on lipids referred to as SNEDDS were used to overcome solubility limitations of drugs, that are often associated with a low bioavailability after oral administration. There are numerous examples in the literature for the development of L-SNEDDS, which have led to some pharmaceutical products available on the market. As L-SNEDDS development using conventional methods requires a lot of time and experimental effort, a streamlining of this procedure was aimed in the first part of the presented work. Starting with the development of L-SNEDDS formulations for solubility enhancement of poorly-water soluble drugs, extensive solubility studies with different BCS Class II drugs were performed in various excipients to determine drugs with high solubilities in these excipients as well as to evaluate multiple excipients for their suitability to be used in L-SNEDDS formulations. Celecoxib, efavirenz and fenofibrate were selected as model drugs and a pre-selection of excipients for further development was made. In a next step, a novel screening approach for L-SNEDDS formulation development based on a customized mapping method in a special triangular mixture design was established. This customized tool for L-SNEDDS development comprised the systematic analysis of results obtained with different in vitro characterization methods such as droplet size analysis and distribution, transmittance measurement and emulsification performance assessment. Furthermore, the novel approach streamlined the procedure for L-SNEDDS development as a reduction of experimental effort and time compared to conventional methods was achieved. The most promising L-SNEDDS formulations determined via the customized screening tool approach showed high drug release of celecoxib, efavirenz as well as fenofibrate, and clearly indicated that this method was suitable for efficiently designing stable and rapidly releasing L-SNEDDS formulations incorporating poorly water-soluble drugs. After the successful development of L-SNEDDS formulations with different drug substances using the novel screening approach, a further aspect of this work dealt with conversion of L-SNEDDS into S-SNEDDS, since a limited storage stability has been reported for many L-SNEDDS formulations. The conversion into S-SNEDDS required the determination of appropriate solid carriers with different material properties depending on the manufacturing process. As a first technological approach, adsorption to a solid carrier was investigated by adding a carrier to drug-loaded L-SNEDDS applying a defined mixing ratio resulting in a solid, particulate formulation. When performing drug release studies, S-SNEDDS based on different commercial carrier materials revealed major limitations due to incomplete drug release. Thus, a tailor-made microparticulate carrier material based on cellulose was developed for the purpose of adsorbing L-SNEDDS and presented with superior performance compared to conventional adsorbents based on cellulose or silica. Based on the obtained results, this novel cellulose-based microparticle prepared with gum arabic as a binder was determined to be the most promising material amongst all adsorptive carriers that were investigated. In addition to the technology approach of adsorption, another manufacturing process was considered in the course of the present work, which focused on the preparation of S-SNEDDS by means of HME. As a successful conversion of L-SNEDDS into S-SNEDDS using HME processing requires at least one additional polymeric component, a selection of marketed (co-)polymers that were frequently used in the field of solubility enhancement were evaluated for their suitability in this context. Critical process parameters and target properties of the (co-)polymers were determined, ultimately leading to the idea of developing a novel, customized polymer in order to perform the conversion step via HME in a more suitable and effective manner. In this context, a new copolymer referred to as ModE, as it disclosed a structural association with the commercially available copolymer EUDRAGIT® E PO, was developed. The novel copolymer ModE was evaluated for its suitability for different formulation technologies and showed promising results when used for S-SNEDDS and ASD formulations prepared by the HME process. Different variants of ModE in terms of Mw, Tg and PDI were synthesized via radical polymerization and it was found that the modification of Mw, Tg and PDI of the novel aminomethacrylate-based copolymer had significant effects on drug release as well as storage stability of S-SNEDDS and ASDs. The ModE copolymer type with a Mw of 173 kDa turned out to be the most suitable candidate for S-SNEDDS development using HME technology. In addition, drug-loaded S-SNEDDS based on the ModE variant 173 kDa were storage stable and presented with the highest drug release among all S-SNEDDS formulations tested. In conclusion, a novel screening tool approach for efficient L-SNEDDS development was established in order to streamline the process for obtaining stable and rapidly releasing L-SNEDDS formulations which improved the solubility of poorly water-soluble drugs. Apart from the L-SNEDDS development process, the conversion from L-SNEDDS into S-SNEDDS was successfully performed using the technology approaches of adsorption to a solid carrier and HME processing. An improved storage stability compared to L-SNEDDS as well as high drug release were achieved for several S-SNEDDS formulations, especially for those prepared with tailor-made materials. Based on the results obtained for S-SNEDDS formulations produced via adsorption, especially in terms of drug release performance, the new cellulose-based microparticle carriers (M-GA and M-MC) turned out to be the most suitable materials. S-SNEDDS that were manufactured via HME presented with a superior performance regardless of the incorporated drug when comparing the results of S-SNEDDS with those of the corresponding ASDs regarding drug release performance, amorphicity/crystallinity and storage stability. In this context, among all S-SNEDDS formulations prepared via HME, S-SNEDDS based on the ModE variant 173 kDa showed the best results, especially when using the drug substances celecoxib and efavirenz. Although the S-SNEDDS formulation approach is still largely unexplored, based on the research results generated in the present work, it represents a promising technology platform that should definitely be further developed in future experiments.

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Author:Dr. Fabian-Pascal Schmied
Title Additional (German):Selbstnanoemulgierende Wirkstoffabgabesysteme (SNEDDS) zur Verbesserung der Löslichkeit - neue Ansätze zur Bestimmung geeigneter Formulierungen für flüssige SNEDDS und deren Umwandlung in feste SNEDDS
Referee:Prof. Dr. Sandra Klein, Prof. Dr. Thomas Rades
Document Type:Doctoral Thesis
Year of Completion:2022
Date of first Publication:2023/05/22
Granting Institution:Universität Greifswald, Mathematisch-Naturwissenschaftliche Fakultät
Date of final exam:2023/05/09
Release Date:2023/05/22
Tag:solubility enhancement, drug delivery, oral administration, SNEDDS, nanoemulsions, polymer, adsorption, celecoxib, efavirenz, fenofibrate
GND Keyword:Wirkstofffreisetzung , Wirkstoff , Löslichkeit , Pharmazie , Forschung , Entwicklung , Formulierung
Page Number:137
Faculties:Mathematisch-Naturwissenschaftliche Fakultät / Institut für Pharmazie
DDC class:500 Naturwissenschaften und Mathematik / 500 Naturwissenschaften