The absorption and oral bioavailability of poorly water-soluble drugs is often limited by poor aqueous solubility and slow dissolution in the gastrointestinal (GI) tract. Lipid-based formulations are a popular formulation approach to enhance oral bioavailability for drugs where water solubility is the primary limitation to absorption. The research undertaken in this thesis examines the use of different types and masses of lipids to improve drug solubilisation and absorption, and investigates the contribution of gastric processing to the improvements in oral bioavailability typically seen after co-administration of poorly water-soluble drugs with lipids and lipid-based formulations. A simple in vitro lipid digestion model was used to assess the effect of lipid type and mass on the solubilisation of three model lipophilic drugs (danazol, cinnarizine and halofantrine). Digestion of medium chain triacylglyceride (MCT) formulations yielded improved drug solubilisation (and resulted in drug supersaturation) at high lipid mass (250 mg). In contrast, for long chain triacylglyceride (LCT) formulations, drug concentrations in the aqueous phase of the digests were higher after digestion of the smallest lipid masses, regardless of drug lipophilicity. In all cases, digestion of the LCT formulations was incomplete, resulting in a residual oil phase. At low masses of LCT lipid (50 mg), digestion was more complete, resulting in increased drug transfer into the aqueous phase. For the more lipophilic drugs, partitioning into the residual oil phase increased. Drug lipophilicity, the choice and quantity of lipid, and the need for complete digestion of the formulation were therefore important indicators of the performance of the in vitro lipid digestion assay. Cinnarizine (CZ) was subsequently chosen as a model poorly water-soluble drug to exemplify the effects of lipid load on drug exposure in in vivo studies and to compare in vitro and in vivo performance. In vivo bioavailability studies were undertaken at fixed and varied lipid:CZ ratios and after administration with LCT and MCT. In all cases, the bioavailability of CZ was higher after administration of LCT rather than MCT formulations, regardless of lipid mass. At a fixed lipid:CZ ratio, increasing the quantity of formulation did not affect oral bioavailability, and linear pharmacokinetics were observed. When the lipid:CZ ratio was increased, CZ absorption increased at lipid doses from 50 mg to 250 mg, but did not increase further beyond 250 mg. The data suggest that the type and mass of lipid co-administered are important, but that in most cases, LCT formulations outperform the equivalent MCT formulation.The same lipids were also given by intraduodenal administration as both a lipid solution and as a dispersed lipid formulation, to assess the contribution of gastric processing to oral bioavailability. CZ bioavailability was reduced when either formulation was administered intraduodenally and similar trends were evident for MCT and LCT. The data suggest that gastric and intestinal processing contribute to improved CZ absorption. Finally, aspiration of GI content after formulation administration revealed that the digestion of MCT was more prevalent in the stomach than LCT. Gastric processing may explain the improvements in bioavailability when MCT formulations (both solution and dispersion) were administered orally when compared to intraduodenally. Surprisingly, LCT formulations were seemingly less dependent on gastric processing. In summary, the research described in this thesis highlights the potential utility (and drawbacks) of in vitro lipid digestion models to predict in vivo absorption, and further shows that the mass and type of lipid, and processing in both the stomach and the intestine are important determinants of oral bioavailability from lipid-based formulations.
Oral lipid-based formulations are attracting considerable attention due to their capacity to facilitate gastrointestinal absorption and reduce or eliminate the effect of food on the absorption of poorly water-soluble, lipophilic drugs. Despite the obvious and demonstrated utility of these formulations for addressing a persistent and growing problem
This volume is intended to provide the reader with a breadth of understanding regarding the many challenges faced with the formulation of poorly water-soluble drugs as well as in-depth knowledge in the critical areas of development with these compounds. Further, this book is designed to provide practical guidance for overcoming formulation challenges toward the end goal of improving drug therapies with poorly water-soluble drugs. Enhancing solubility via formulation intervention is a unique opportunity in which formulation scientists can enable drug therapies by creating viable medicines from seemingly undeliverable molecules. With the ever increasing number of poorly water-soluble compounds entering development, the role of the formulation scientist is growing in importance. Also, knowledge of the advanced analytical, formulation, and process technologies as well as specific regulatory considerations related to the formulation of these compounds is increasing in value. Ideally, this book will serve as a useful tool in the education of current and future generations of scientists, and in this context contribute toward providing patients with new and better medicines.
The work presented in this thesis has provided additional information regarding the utilisation of lipid-based self-emulsifying formulations for lipophilic drugs, making use of fenofibrate as a model. Specifically the work focused on lipid-based formulation in the context of the emerging "Lipid Formulation Classification System" (LFCS) which has been previously proposed as a new means of classifying lipid-based formulations. This is the first study to address lipid formulations using a small group of related excipients to cover a wide range of lipid formulations. The roles of the lipid phase, the effect of the ratio of lipid to surfactant and the presence of cosolvent on the performance of formulations were investigated. A series of phase diagrams were constructed to examine the phase behaviour during dispersion of anhydrous formulations. Type II, IIIA, IIIB and IV (SEDDS & SMEDDS) were investigated using medium chain glycerides (MCGs), polysorbates and propylene glycol (PG) as excipients. Equilibrium solubilities of the drug were determined in mixtures equivalent to diluted formulations to examine the likelihood of precipitation on dispersion. These data were compared with drug precipitation data obtained in dynamic dispersion experiments. Precipitation was measured over time after 1 in 100 dilutions of formulations in aqueous media. Aqueous dispersion of Type II lipid formulations resulted in turbid emulsions, followed subsequently by very slow precipitation of fraction of the drug dose. Type IIIA formulations, which carried less drug in solution at equilibrium, nevertheless typically maintained drugs in a metastable state for several hours or even days. These studies suggested that Type II and Type IIIA formulations were the most appropriate for fenofibrate. Diluted formulations were also subjected to in vitro digestion to predict the fate of the drug in the gastrointestinal (GI) tract after exposure of the formulation to pancreataic enzymes and bile. In vitro digestion experiments were carried out using a pH-stat maintained pH 7.5 for 30 minutes using intestinal fluids simulating the fed and fasted states (FeSSIF and FaSSIF). The digestion rate was higher in Type II & IIIA systems. Formulations with higher content of hydrophillic materials (Type IIIB or Type IV) resulted in more rapid precipitation, and extensive precipitation of drug from Type IV formulations took place rapidly. The high concentration of surfactant and or cosolvent lowered the rate of digestion but considerable precipitation occurred due to lack of solvent capacity of diluted formulations. Digestion experiments suggested that drug was in a supersaturated state which could be maintained in the presence of mixed bile salt micelles. The fate of fenofibrate is dependent on the choice of lipid formulation as exemplified by the LFCS. In particular the current study suggests that Type IIIB or Type IV formulation may be unsuitable for highly lipophilic drugs, but in vitro tests suggested that after digestion there was a considerable risk of precipitation from all formulations.
This book is the first text to provide a comprehensive assessment of the application of fundamental principles of dissolution and drug release testing to poorly soluble compounds and formulations. Such drug products are, vis-à-vis their physical and chemical properties, inherently incompatible with aqueous dissolution. However, dissolution methods are required for product development and selection, as well as for the fulfillment of regulatory obligations with respect to biopharmaceutical assessment and product quality understanding. The percentage of poorly soluble drugs, defined in classes 2 and 4 of the Biopharmaceutics Classification System (BCS), has significantly increased in the modern pharmaceutical development pipeline. This book provides a thorough exposition of general method development strategies for such drugs, including instrumentation and media selection, the use of compendial and non-compendial techniques in product development, and phase-appropriate approaches to dissolution development. Emerging topics in the field of dissolution are also discussed, including biorelevant and biphasic dissolution, the use on enzymes in dissolution testing, dissolution of suspensions, and drug release of non-oral products. Of particular interest to the industrial pharmaceutical professional, a brief overview of the formulation and solubilization techniques employed in the development of BCS class 2 and 4 drugs to overcome solubility challenges is provided and is complemented by a collection of chapters that survey the approaches and considerations in developing dissolution methodologies for enabling drug delivery technologies, including nanosuspensions, lipid-based formulations, and stabilized amorphous drug formulations.
With the advance of combinational chemistry and high throughput screening, an increasing number of pharmacologically active compounds have been discovered and developed. A significant proportion of those drug candidates are poorly water-soluble, thereby exhibiting limited absorption profiles after oral administration. Therefore, advanced formulation and processing technologies are demanded in order to overcome the biopharmaceutical limits of poorly water-soluble drugs. A number of pharmaceutical technologies have been investigated to address the solubility issue, such as particle size reduction, salt formation, lipid-based formulation, and solubilization. Within the scope of this dissertation, two of the pharmaceutical technologies were investigated names thin film freezing and hot-melt extrusion. The overall goal of the research was to improve the oral bioavailability of poorly water-soluble drugs by producing amorphous solid dispersion systems with enhanced wetting, dissolution, and supersaturation properties. In Chapter 1, the pharmaceutical applications of hot-melt extrusion technology was reviewed. The formulation and process development of hot-melt extrusion was discussed. In Chapter 2, we investigated the use of thin film freezing technology combined with template emulsion system to improve the dissolution and wetting properties of itraconazole (ITZ). The effects of formulation variables (i.e., the selection of polymeric excipients and surfactants) and process variables (i.e., template emulsion system versus cosolvent system) were studied. The physic-chemical properties and dissolution properties of thin film freezing compositions were characterized extensively. In Chapter 3 and Chapter 4, we investigated hot-melt extrusion technology for producing amorphous solid dispersion systems and improving the dissolution and absorption of ITZ. Formulation variables (i.e., the selection of hydrophilic additives, the selection of polymeric carriers) and process variables (i.e., the screw configuration of hot-melt extrusion systems) were investigated in order to optimize the performance of ITZ amorphous solid dispersions. The effects of formulation and process variables on the properties of hot-melt extrusion compositions were investigated. In vivo studies revealed that the oral administration of advanced ITZ amorphous solid dispersion formulations rendered enhanced oral bioavailability of the drug in the rat model. Results indicated that novel formulation and processing technologies are viable approaches for enhancing the oral absorption of poorly water-soluble drugs.
Explore possible new approaches for overcoming poorly soluble drugs - a challenge to drug formulation work and an increasing problem. Many newly developed drugs are poorly soluble, very often simultaneously in aqueous and in organic media. Emulsions and Nanosuspensions for the Formulation of Poorly Soluble Drugs aims to: review the possibilities, limitations and future perspectives of emulsions as drug carriers considering technology from other than the phamaceutical industry (i.e food industry). show the production technology of nanosuspensions, explain the special dissolution properties (i.e. increased saturation solubility) and increased dissolution velocity (theory), and cover the possible applications. present the theory of high pressure homogenization and high pressure extrusion in dispersion techniques, including examples of applications and size measurements in concentrated dispersions.
In an effort to provide alternatives to trans and saturated fats, scientists have been busy modifying the physical properties of oils to resemble those of fats. In this fashion, many food products requiring a specific texture and rheology can be made with these novel oil-based materials without causing significant changes to final product quality. The major approach to form these materials is to incorporate specific molecules (polymers, amphiphiles, waxes) into the oil components that will alter the physical properties of the oil so that its fluidity will decrease and the rheological properties will be similar to those of fats. These new oilbased materials are referred to as oil gels, or “oleogels,“ and this emerging technology is the focus of many scientific investigations geared toward helping decrease the incidence of obesity and cardiovascular disease. Presents a novel strategy to eliminate trans fats from our diets and avoid excessive amounts of saturated fat by structuring oil to make it behave like crystalline fat Reviews recent advances in the structuring of edible oils to form new mesoscale and nanoscale structures, including nanofibers, mesophases, and functionalized crystals and crystalline particles Identifies evidence on how to develop trans fat free, low saturate functional shortenings for the food industry that could make a major impact on the health characteristics of the foods we consume
Summary Solid dispersions are a promising approach for controlled release drug delivery systems as both the bioavailability enhancement of poorly water-soluble drugs as well as the sustained release of water-soluble drugs are possible to optimize their in vivo performance. Different methods for the manufacture of solid dispersion systems have been introduced in literature. In the present work, two methods are compared: hot-melt extrusion and ultrasound-assisted compaction technique. Various carrier systems and drugs with different physicochemical properties are applied to investigate the feasibility of the technologies for pharmaceutical formulation. The formulations are compared to the corresponding untreated physical blends of the components regarding their solid state structure and dissolution behavior to assess the effect of the manufacturing technique. Ultrasound-assisted compaction technique improves the initial dissolution rate of fenofibrate, a poorly water-soluble model drug. The crystalline API is partially converted into its amorphous state. As equivalent results can be achieved if the polymers are added directly to the dissolution medium, the dissolution enhancement is attributed to an improved wettability of the drug. A statistical design of experiments is employed to investigate the effect of the process parameters on the results. Difficulties are encountered in the determination of process parameters which result in an optimal outcome. The process is very sensitive to the smallest changes of settings, for example of the position of the sonotrode. Additionally, the delivery of ultrasound energy is inhomogeneous. There is no or only insufficient user control of these parameters available. Furthermore, the duration of ultrasound energy delivery which is identified as a crucial parameter cannot be set by the user. The variable factors ultrasound energy, pressure of the lower piston and pressure of the upper piston affect the defined responses in the opposite direction. Hence, there are no settings which result in a satisfactory outcome. A strong influence of the material characteristics on the process is observed leading to a batch to batch variability. Due to an insufficient reproducibility of results, the application of the technology cannot be recommended in its current state in the pharmaceutical formulation development and/or production. Improvements in homogeneity of energy delivery, process monitoring, user control and amount of leakage are mandatory for an acceptable performance and a future application in the pharmaceutical sector. The polymers COP, HPMC and PVCL-PVAc-PEG are well suitable as carriers for hot-melt extruded formulations of fenofibrate. All three extrudates are amorphous one-phase systems with the drug molecularly dispersed in the polymer. The enhancement of the initial dissolution rate and the maximum concentration level achieved are dependent on the applied carrier system. Supersaturation levels of up to 12.1 times are reached which are not stable due to recrystallization processes. The application of blends of polymers as carriers reduces the decrease rate after cmax. Because of water absorption and polymer relaxation, the overall dissolution performance decreases with increasing storage times which can be avoided through an optimization of the packaging. If oxeglitazar is used as API, the initial dissolution rate of the extrudates is below that of the untreated drug, with the exception of the ternary blend of COP, HPMC and oxeglitazar which shows a substance-specific super-additive effect. In contrast to the other extrudates, the formulation of PVCL-PVAc-PEG and oxeglitazar does not form a molecularly dispersed solid solution of the drug in the carrier. Instead, an amorphous two-phase system is present. No changes are observed after storage, presumably due to higher glass transition temperatures of the hot-melt extruded systems which are considerably above those of the corresponding fenofibrate extrudates. With felodipine as API, the dissolution profile is enhanced with COP as single carrier. If HPMC or PVCL-PVAc-PEG is used as single or additional polymeric carriers, the dissolution is equivalent (HPMC) or lower (PVCL-PVAc-PEG) than that of the pure drug although molecularly disperse systems are present in all cases. Out of the two investigated methods only hot-melt extrusion is a suitable technology to manufacture solid dispersions with an improved dissolution behavior. The dissolution profile of the extrudates can be influenced by adding polymers with differing physicochemical characteristics. Predictions on the dissolution behavior of the extrudates with polymeric blends as carriers can be made if there is knowledge on the dissolution profiles of the corresponding single polymeric extrudates. Due to substance-specific effects, the results are not transferable from drug to drug. Even so, the data are promising as the release behavior of the manufactured extrudates can be easily modified and readily adapted to one's needs. Further research will have to be conducted to verify the concept and the relevance of the results in vivo. Zusammenfassung Feste Dispersionen sind ein vielversprechender Ansatz zur Herstellung von Drug Delivery-Systemen mit kontrollierter Wirkstofffreisetzung, da sie sowohl die Bioverfügbarkeit schlecht wasserlöslicher Arzneistoffe verbessern als auch die Freisetzung gut wasserlöslicher Arzneistoffe verzögern können und so deren in vivo Verhalten optimieren. Verschiedene Herstellungsmethoden wurden in der Literatur vorgestellt. In der vorliegenden Arbeit werden zwei Technologien miteinander verglichen: Schmelzextrusion und Ultraschall gestützte Verpressung (USAC). Verschiedene Trägersysteme und Arzneistoffe mit unterschiedlichen physikochemischen Eigenschaften werden untersucht, um die Einsatzmöglichkeit im pharmazeutischen Bereich zu überprüfen. Die Struktur der hergestellten Systeme und deren Freisetzungsverhalten werden mit den physikalischen Mischungen der Komponenten verglichen, um den Einfluss der Formulierung zu bestimmen. Durch USAC wird die initiale Freisetzungsrate von Fenofibrat, einem schlecht wasserlöslichen Modellarzneistoff, verbessert. Eine teilweise Umwandlung vom kristallinen in den amorphen Zustand tritt auf. Vergleichbare Ergebnisse werden bei einer Polymerzugabe zum Freisetzungsmedium erreicht; daher wird davon ausgegangen, dass vor allem eine verbesserte Benetzbarkeit des Arzneistoffs eine Rolle spielt. Mittels statistischer Versuchsplanung wird der Einfluss der verschiedenen Prozessparameter untersucht. Die Einstellung der Prozessparameter, um ein optimales Ergebnis zu erhalten, gestaltet sich schwierig. Der Prozess reagiert auf kleinste Veränderungen, zum Beispiel der Position der Sonotrode, überaus sensitiv. Außerdem wird die Ultraschallenergie nicht homogen übertragen. Die Kontrolle dieser Parameter durch den Anwender ist nicht oder nur unzureichend möglich. Ebenso kann die Dauer der Ultraschallapplizierung, die essentiell für den Prozess ist, nicht eingestellt werden. Die Prozessparameter Ultraschallenergie, Unterstempeldruck und Sonotrodendruck beeinflussen die Zielgrößen in entgegengesetzter Richtung. Daher gibt es keine Einstellung, die für alle Zielgrößen optimale Ergebnisse liefert. Zusätzlich ist der Prozess stark abhängig von den Eigenschaften des verwendeten Materials: Die Verwendung unterschiedlicher Polymerchargen macht eine Anpassung der Prozessparameter notwendig, um vergleichbare Ergebnisse zu erhalten. Eine ausreichende Reproduzierbarkeit der Ergebnisse für einen Einsatz dieser Technologie in Formulierungsentwicklung oder Produktion ist nicht gegeben. Eine homogene Ultraschallenergiezufuhr sowie Verbesserungen der Prozessüberwachung, der Benutzerkontrolle und eine Verminderung der austretenden Materialmenge sind für eine akzeptable Leistung und eine zukünftige Anwendung im pharmazeutischen Bereich zwingend erforderlich. Die Polymere COP, HPMC, PVCL-PVAc-PEG sind für eine Freisetzungsverbesserung von Fenofibrat mittels Schmelzextrusion geeignet. Es liegen einphasige, molekulardisperse feste Lösungen vor. Abhängig von der Trägersubstanz wird die initiale Freisetzungsrate unterschiedlich stark erhöht, ebenso die maximale Konzentration des Arzneistoffes in Lösung. Eine bis zu 12.1-fache Übersättigung wird erreicht, die aufgrund von Rekristallisationsprozessen nicht stabil ist. Der Einsatz von polymeren Mischungen reduziert die Geschwindigkeit des Konzentrationsabfalls. Die Absorption von Wasser und Relaxationseffekte vermindern die Freisetzungserhöhung mit zunehmender Lagerdauer; dieser Entwicklung kann durch eine Optimierung des Packmittels entgegengewirkt werden. Wird der ebenfalls schwer wasserlösliche Arzneistoff Oxeglitazar verwendet, so ist die initiale Freisetzungsrate der Extrudate der des reinen Arzneistoffs unterlegen, mit Ausnahme der ternären Mischung von COP, HPMC und Oxeglitazar, die einen substanzspezifischen überadditiven Effekt aufweist. PVCL-PVAc-PEG-Oxeglitazar-Extrudate bilden im Gegensatz zu den übrigen Formulierungen keine molekulardisperse feste Lösung, sondern ein amorphes Zwei-Phasen-System. Eine Veränderung während der Lagerzeit wird nicht beobachtet, vermutlich aufgrund der höheren Glasübergangstemperaturen dieser Systeme. Lediglich das Freisetzungsprofil von COP-Felodipin-Extrudaten ist verbessert. Gegenüber dem reinen Arzneistoff ist die Freisetzung der übrigen Extrudate vergleichbar (HPMC) oder verringert (PVCL-PVAc-PEG), obwohl auch hier molekulardisperse Systeme vorliegen. Von den beiden untersuchten Technologien ist lediglich die Schmelzextrusion geeignet, um feste Dispersionen mit einem verbesserten Freisetzungsverhalten herzustellen. Das Freisetzungsprofil der Extrudate kann durch den Zusatz von Polymeren mit unterschiedlichen Eigenschaften optimiert und vorhergesagt werden, wenn das Freisetzungsprofil der Einzelpolymer-Extrudate bekannt ist. Die Ergebnisse sind aufgrund von substanzspezifischen Effekten nicht von Arzneistoff auf Arzneistoff übertragbar. Nichtsdestotrotz sind die Erkenntnisse dieser Arbeit vielversprechend, da gezeigt wird, dass das Freisetzungsprofil der Extrudate leicht beeinflusst und an spezifische Anforderungen angepasst werden kann. Weitere Untersuchungen sind notwendig, um das Konzept und die Relevanz der Ergebnisse in vivo zu überprüfen.
Oral Drug Absorption, Second Edition thoroughly examines the special equipment and methods used to test whether drugs are released adequately when administered orally. The contributors discuss methods for accurately establishing and validating in vitro/in vivo correlations for both MR and IR formulations, as well as alternative approaches for MR an
