Lipid-Based Nano-Delivery for Oral Administration of Poorly Water Soluble Drugs (PWSDs): Design, Optimization and in Vitro Assessment PDF Download
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Author: Mohsin Kazi Publisher: ISBN: Category : Medicine Languages : en Pages :
Book Description
Currently, more than 90% of compounds identified are water insoluble and or poorly water soluble, which is a bottle neck in the development of many new drug candidates. These poorly soluble drug molecules are difficult to formulate using conventional approaches and are associated with numerous formulation-related performance issues. Formulating these compounds using lipid-based systems is one of the rapidly growing interests and suitable drug delivery strategies. Lipid formulations such as self-emulsifying/microemulsifying/nanoemulsifying drug delivery systems (SEDDS/SMEDDS/SNEDDS) have been attempted in many researches to improve the bioavailability and dissolution rate for their better dispersion properties. One of the greatest advantages of incorporating the poorly soluble drug into such formulation products is their spontaneous emulsion and or microemulsion/nanoemulsion formation in aqueous media. The performance and ongoing advances in manufacturing technologies have rapidly introduced lipid-based drug formulations as commercial products into the marketplace with several others in clinical development. The current chapter aims to present the characteristics feature, development and utilization of oral lipid-based nanoformulations within the drug delivery regime. The content of the chapter also provides an insight into the in vitro evaluation of lipid-based nanosystems and their limitations.
Author: Mohsin Kazi Publisher: ISBN: Category : Medicine Languages : en Pages :
Book Description
Currently, more than 90% of compounds identified are water insoluble and or poorly water soluble, which is a bottle neck in the development of many new drug candidates. These poorly soluble drug molecules are difficult to formulate using conventional approaches and are associated with numerous formulation-related performance issues. Formulating these compounds using lipid-based systems is one of the rapidly growing interests and suitable drug delivery strategies. Lipid formulations such as self-emulsifying/microemulsifying/nanoemulsifying drug delivery systems (SEDDS/SMEDDS/SNEDDS) have been attempted in many researches to improve the bioavailability and dissolution rate for their better dispersion properties. One of the greatest advantages of incorporating the poorly soluble drug into such formulation products is their spontaneous emulsion and or microemulsion/nanoemulsion formation in aqueous media. The performance and ongoing advances in manufacturing technologies have rapidly introduced lipid-based drug formulations as commercial products into the marketplace with several others in clinical development. The current chapter aims to present the characteristics feature, development and utilization of oral lipid-based nanoformulations within the drug delivery regime. The content of the chapter also provides an insight into the in vitro evaluation of lipid-based nanosystems and their limitations.
Author: David J. Hauss Publisher: CRC Press ISBN: 1420017268 Category : Medical Languages : en Pages : 370
Book Description
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
Author: Kazi Mohsin Publisher: ISBN: Category : Drugs Languages : en Pages : 558
Book Description
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.
Author: Sabyasachi Maiti Publisher: BoD – Books on Demand ISBN: 9535131214 Category : Medical Languages : en Pages : 186
Book Description
The goal of any novel drug delivery system is to provide therapeutic benefits to the patients by increasing duration of drug action, reducing dosing frequency, and controlling drug release rate at the target site, thereby reducing unwanted side effects. Advanced Technology for Delivering Therapeutics is a reference book that covers recent developments in the field of drug delivery science and technology. The purpose of this book is to bring together descriptions of some selective technologies including new and promising nanotechnology currently being investigated for drug delivery applications. This book is a useful source of information for graduate and post-graduate students of pharmacy and biomedical science; pharmaceutical
Author: Amit Kumar Nayak Publisher: Elsevier ISBN: 0323972462 Category : Medical Languages : en Pages : 759
Book Description
Dosage Forms, Formulation Developments and Regulations, Volume One in the Recent and Future Trends in Pharmaceutics series, explores aspects of pharmaceutics, with an original approach focused on technology, novelties and future trends in the field. The book discusses the most recent developments in pharmaceutical preformulation and formulation studies, biopharmaceutics and novel pharmaceutical formulations, regulatory affairs, and good manufacturing practices. Exciting areas such as formulation strategies, optimization techniques, the biopharmaceutical classification system, and pharmaceutical aerosols are included. The field of pharmaceutics is highly dynamic and rapidly expanding day-by-day, so it demands a variety of amplified efforts for designing and developing pharmaceutical processes and formulation strategies. This is an essential reference for researchers in academia and industry as well as advanced graduate students in pharmaceutics. Examines trends and recent technologies in dosage, formulation and regulation Contains contributions from leading experts in academia, research, industry and regulatory agencies Includes high-quality illustrations, flow charts and tables for easy understanding of concepts Discusses practical examples and research case studies
Author: Kathy Wai Yu Lee Publisher: ISBN: Category : Languages : en Pages : 458
Book Description
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.
Author: Claire Louise McEvoy Publisher: ISBN: Category : Languages : en Pages : 500
Book Description
This thesis has explored the use of lipid-based formulations (LBF) to enhance the oral bioavailability of the cholesteryl ester transfer protein (CETP) inhibitor CP-532,623, used here as a model poorly water soluble drug (PWSD), and the impact of dispersion and digestion on formulation performance. A particular focus has been the use of the in vitro lipid digestion model as a tool to predict the oral bioavailability of PWSDs, by investigating the relationship between drug solubilisation after in vitro digestion and in vivo exposure after oral administration.Dispersion and digestion of LBFs are both events that challenge the solubilisation of a co-administered drug. The data show that the development of LBFs can be informed by the dispersion and solubilisation properties of individual excipients after in vitro digestion. Different patterns of solubilisation were observed with changes in the type of excipient employed. Lipids and lipophilic co-surfactants retained drug in an oily phase but were nonetheless resistant to drug precipitation. Hydrophilic surfactants (particularly Kolliphor RH 40) maintained higher drug solubilisation levels after digestion, a characteristic that was maintained within composite formulations containing Kolliphor and additional excipients. Conversely, co-solvents supported high initial drug loading, but provided no ongoing solubilisation when introduced to aqueous media. A series of formulations based on medium chain (MC) lipids and were initially developed to provide for effective drug loading and good dispersion properties. Assessment of these MC-LBFs using the in vitro digestion model revealed varying degrees of susceptibility to precipitation during in vitro digestion, and a broad correlation between drug solubilisation after in vitro digestion and drug absorption after oral administration in beagle dogs.Subsequent modification of the formulations to include long chain (LC) lipids rather than MC lipids generally resulted in higher levels of CP-532,623 solubilisation after in vitro digestion. In all cases the LBFs greatly enhanced in vitro solubilisation and in vivo oral bioavailability of CP-532,623 in fasted beagle dogs when compared to a simple powder formulation. Within related groups of formulations in vitro solubilisation on lipid digestion was also found to correlate with in vivo exposure. Notably, formulations based on LC-LBFs required higher levels of drug solubilisation to achieve similar levels of in vivo exposure, when compared to MC-LBFs. Re-evaluation of the in vitro data to measure drug supersaturation rather than drug solubilisation, however, resulted in improved correlations, especially for formulations containing a common surfactant. Thus, formulations containing Kolliphor RH 40 were absorbed more readily at lower supersaturation levels than formulations containing polysorbate 80 or vitamin E TPGS. The data suggest that the degree of drug solubilisation and supersaturation during in vitro lipid digestion provides some indication of formulation performance but that this alone is insufficient to completely explain patterns of drug absorption. Further investigations into the factors contributing to the high bioavailability obtained in beagle dogs also suggested that drug absorption from LBFs may vary in beagle and greyhound dogs, with drug absorption typically being higher in beagles.In summary, the studies presented here further demonstrate the utility of the in vitro digestion model in formulation development. In conjunction with solubility studies, calculation of drug supersaturation, and characterisation of the physical state of precipitated drug, in vitro lipolysis tests provide useful in vitro indicators of formulation performance. Interestingly, the current studies suggest that whilst the overall patterns of in vitro-in vivo correlation that have previously been described in the literature, may be maintained, they appear to exist in parallel with excipient specific effects on drug absorption and bioavailability. Thus, in addition to concentration or thermodynamic activity, the nature of the solubilised phases formed on lipid formulation digestion appears to be a significant driver of differences in patterns of drug absorption from LBF.
Author: Navnit Shah Publisher: Springer ISBN: 1493915983 Category : Medical Languages : en Pages : 702
Book Description
This volume offers a comprehensive guide on the theory and practice of amorphous solid dispersions (ASD) for handling challenges associated with poorly soluble drugs. In twenty-three inclusive chapters, the book examines thermodynamics and kinetics of the amorphous state and amorphous solid dispersions, ASD technologies, excipients for stabilizing amorphous solid dispersions such as polymers, and ASD manufacturing technologies, including spray drying, hot melt extrusion, fluid bed layering and solvent-controlled micro-precipitation technology (MBP). Each technology is illustrated by specific case studies. In addition, dedicated sections cover analytical tools and technologies for characterization of amorphous solid dispersions, the prediction of long-term stability, and the development of suitable dissolution methods and regulatory aspects. The book also highlights future technologies on the horizon, such as supercritical fluid processing, mesoporous silica, KinetiSol®, and the use of non-salt-forming organic acids and amino acids for the stabilization of amorphous systems. Amorphous Solid Dispersions: Theory and Practice is a valuable reference to pharmaceutical scientists interested in developing bioavailable and therapeutically effective formulations of poorly soluble molecules in order to advance these technologies and develop better medicines for the future.
Author: Ana Catarina Silva Publisher: Mdpi AG ISBN: 9783036515502 Category : Languages : en Pages : 352
Book Description
The use of lipid-based nanosystems, including lipid nanoparticles (solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC)), nanoemulsions, and liposomes, among others, is widespread. Several researchers have described the advantages of different applications of these nanosystems. For instance, they can increase the targeting and bioavailability of drugs, improving therapeutic effects. Their use in the cosmetic field is also promising, owing to their moisturizing properties and ability to protect labile cosmetic actives. Thus, it is surprising that only a few lipid-based nanosystems have reached the market. This can be explained by the strict regulatory requirements of medicines and the occurrence of unexpected in vivo failure, which highlights the need to conduct more preclinical studies. Current research is focused on testing the in vitro, ex vivo, and in vivo efficacy of lipidbased nanosystems to predict their clinical performance. However, there is a lack of method validation, which compromises the comparison between different studies. This book brings together the latest research and reviews that report on in vitro, ex vivo, and in vivo preclinical studies using lipid-based nanosystems. Readers can find up-todate information on the most common experiments performed to predict the clinical behavior of lipid-based nanosystems. A series of 15 research articles and a review are presented, with authors from 15 different countries, which demonstrates the universality of the investigations that have been carried out in this area.
Author: Mohsin Kazi
Author: Mohsin Kazi
Author: David J. Hauss
Author: Kazi Mohsin
Author: Sabyasachi Maiti
Author: Linda Joy Solomon
Author: Amit Kumar Nayak
Author: Kathy Wai Yu Lee
Author: Claire Louise McEvoy
Author: Navnit Shah
Author: Ana Catarina Silva