Medical

Poorly Soluble Drugs

Author: Gregory K. Webster

Publisher: CRC Press

ISBN:

Category: Medical

Page: 728

View: 167

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.
Medical

Formulating Poorly Water Soluble Drugs

Author: Robert O. Williams III

Publisher: Springer

ISBN:

Category: Medical

Page: 779

View: 449

The objective of this volume is to consolidate within a single text the most current knowledge, practical methods, and regulatory considerations pertaining to formulations development with poorly water-soluble molecules. A pharmaceutical scientist’s approach toward solubility enhancement of a poorly water-soluble molecule typically includes detailed characterization of the compound’s physiochemical properties, solid-state modifications, advanced formulation design, non-conventional process technologies, advanced analytical characterization, and specialized product performance analysis techniques. The scientist must also be aware of the unique regulatory considerations pertaining to the non-conventional approaches often utilized for poorly water-soluble drugs. One faced with the challenge of developing a drug product from a poorly soluble compound must possess at minimum a working knowledge of each of the abovementioned facets and detailed knowledge of most. In light of the magnitude of the growing solubility problem to drug development, this is a significant burden especially when considering that knowledge in most of these areas is relatively new and continues to develop

Poorly Soluble Drugs

Author: Lino Messana

Publisher:

ISBN:

Category:

Page: 300

View: 493

Solubility is the property of a solid, liquid, or gaseous chemical substance called solute to dissolve in a solid, liquid, or gaseous solvent to form a homogeneous solution of the solute in the solvent. The solubility of a substance fundamentally depends on the solvent used as well as on temperature and pressure. The extent of solubility of a substance in a specific solvent is measured as the saturation concentration where adding more solute does not increase its concentration in the solution. Solubility also plays a major role for other dosage forms like parenteral formulations as well. Many newly proposed drugs suffer from poor water solubility, thus presenting major hurdles in the design of suitable formulations for administration to patients. Consequently, the development of techniques and materials to overcome these hurdles is a major area of research in pharmaceutical companies. This book provides a comprehensive overview of currently used formulation strategies for hydrophobic drugs discusses the main instrumentation, operation principles and theoretical background, with a focus on critical formulation features and clinical studies. It provides a comprehensive assessment of the application of fundamental principles of dissolution and drug release testing to poorly soluble compounds and formulations. Over 40% of new chemical entities developed in pharmaceutical industry are practically insoluble in water. These poorly water soluble drugs having slow drug absorption leads to inadequate and variable bioavailability and gastrointestinal mucosal toxicity. For orally administered drugs solubility is the most important one rate limiting parameter to achieve their desired concentration in systemic circulation for pharmacological response. Problem of solubility is a major challenge for formulation scientist. The improvement of drug solubility thereby its oral bioavailability remains one of the most challenging aspects of drug development process especially for oral-drug delivery system.
Philosophy

Hot-melt extrusion with poorly soluble drugs

Author: Jessica Albers

Publisher: Cuvillier Verlag

ISBN:

Category: Philosophy

Page: 156

View: 823

Hot-melt extrusion with poorly soluble drugs is a challenging method to enhance the solubility. The formation of solid dispersions, specifically of glassy solid solutions, wherein the drug is dispersed on a molecular basis in an inert carrier, leads to metastable systems that have advantageous dissolution behaviour but suffer from physical stability problems. To date, there is poor understanding of the solid state structure, the mechanism by which dissolution enhancement occurs, the stability on storage and in dissolution, and the processing to solid dosage forms. The hot-melt extrusion process is influenced by several parameters. The right coordination of these parameters is decisive for the production of solid dispersions and thus, the success in solubility enhancement. The solid state and the viscosity of the extrudates can be controlled by the temperature of the barrels. Besides the configuration of the screw and the temperature profile of the barrel, the design of the die plate represents the third important extrusion parameter. By keeping the dead storage capacity at a minimum, an early solidification and thus a blockage of the dies can be prevented. Due to shear forces evolving in the extruder barrel and the ability of the drug to dissolve in the molten carrier before reaching the melting temperature, the process temperature can be kept below the melting point of the substances. Basic butylated methacrylate copolymer is a suitable carrier to enhance the solubility of the poorly water-soluble drug celecoxib in a hot-melt extrusion process. The best solubility enhancement can be obtained by dispersing the drug in the molten carrier on a molecular basis and thus, to form glassy solid solutions. The solid state characteristics of the solid dispersion can be revealed by DSC analysis and interpretation of the corresponding glass transitions. Such systems may contain a drug load of up to 60% and are stable at increased temperature and humidity which is due to the very low water uptake of the components. Glassy solid solutions of celecoxib and basic butylated methacrylate copolymer have a fast dissolution rate and result in a 58 fold supersaturated solution. The mechanism of drug release from these glassy solid solutions is carrier-controlled and governed by dissolution. The enhancement of the dissolution rate is based on improved solubility and wettability. Basic butylated methacrylate copolymer interacts chemically with celecoxib in an acid-base reaction. The hot-melt extrusion process is highly dependent on the physicochemical properties of the compounds and their miscibility in the molten state. The use of basic butylated methacrylate copolymer as solubility enhancing carrier in hot-melt extrusion cannot be transferred easily to all drugs. Depending on the properties of the drug, specifically the melting point and the pKa, basic butylated methacrylate copolymer can be a useful carrier in glassy solid solution formation, but might be insufficient for solubility improvement. The formation of a glassy solid solution evolves from interactions between the drug and the carrier. Bonds can differ in their strength and can be advantageous or disadvantageous for a fast dissolution. Furthermore, decomposition processes can occur, when processing the drug at high temperatures. Thus, each formulation has to be analyzed separately. The interpretation of the chemical structure, the calculation of solubility parameters, the determination of melting temperatures and enthalpies, and the performance of molecular dynamics simulations are tools to predict the miscibility of drugs and carriers for the formulation of solid dispersions. A combined approach of tools predicting miscibility is highly appropriate, as no single technique may yield all the required information. Nevertheless, the evaluation of the melting behaviour via DSC has the highest impact. Hot-melt extruded glassy solid solutions can be processed into solid dosage forms. The mechanical energy input through milling and zabletting has no influence on the solid-state stability. The solution-state stability can be achieved by adding HPMC to the external phase. The filling of capsules with milled hot-melt extrudates is a promising technique to obtain solid dosage forms from glassy solid solutions. By the extensive analysis of the hot-melt extrusion process, the interactions of the compounds, the thermal characteristics, and the dissolution mechanism of the resulting systems, it is possible to predict the extrusion process in an early stage of development and to improve the dissolution of poorly soluble drugs.
Medical

Emulsions and Nanosuspensions for the Formulation of Poorly Soluble Drugs

Author: Rainer H. Müller

Publisher: CRC Press

ISBN:

Category: Medical

Page: 396

View: 795

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.
Medical

Water-Insoluble Drug Formulation, Third Edition

Author: Ron Liu

Publisher: CRC Press

ISBN:

Category: Medical

Page: 736

View: 900

Properties and Formulation: From Theory to Real-World Application Scientists have attributed more than 40 percent of the failures in new drug development to poor biopharmaceutical properties, particularly water insolubility. Issues surrounding water insolubility can postpone or completely derail important new drug development. Even the much-needed reformulation of currently marketed products can be significantly affected by these challenges. More recently it was reported that the percentage increased to 90% for the candidates of new chemical entities in the discovery stage and 75% for compounds under development. In the most comprehensive resource on the topic, this third edition of Water-Insoluble Drug Formulation brings together a distinguished team of experts to provide the scientific background and step-by-step guidance needed to deal with solubility issues in drug development. Twenty-three chapters systematically describe the detailed discussion on solubility theories, solubility prediction models, the aspects of preformulation, biopharmaceutics, pharmacokinetics, regulatory, and discovery support of water-insoluble drugs to various techniques used in developing delivery systems for water-insoluble drugs. This book includes more than 15 water-insoluble drug delivery systems or technologies, illustrated with case studies and featuring oral and parenteral applications. Highlighting the most current information and data available, this seminal volume reflects the significant progress that has been made in nearly all aspects of this field. The aim of this book is to provide a handy reference for pharmaceutical scientists in the handling of formulation issues related to water-insoluble drugs. In addition, this book may be useful to pharmacy and chemistry undergraduate students and pharmaceutical and biopharmaceutical graduate students to enhance their knowledge in the techniques of drug solubilization and dissolution enhancement.
Science

Drug Delivery Strategies for Poorly Water-Soluble Drugs

Author: Dionysios Douroumis

Publisher: John Wiley & Sons

ISBN:

Category: Science

Page: 648

View: 806

Many newly proposed drugs suffer from poor water solubility,thus presenting major hurdles in the design of suitableformulations for administration to patients. Consequently, thedevelopment of techniques and materials to overcome these hurdles is a major areaof research in pharmaceutical companies. Drug Delivery Strategies for Poorly Water-Soluble Drugs providesa comprehensive overview of currently used formulation strategiesfor hydrophobic drugs, including liposome formulation, cyclodextrindrug carriers, solid lipid nanoparticles, polymeric drugencapsulation delivery systems, self–microemulsifying drugdelivery systems, nanocrystals, hydrosol colloidal dispersions,microemulsions, solid dispersions, cosolvent use, dendrimers,polymer- drug conjugates, polymeric micelles, and mesoporous silicananoparticles. For each approach the book discusses the maininstrumentation, operation principles and theoretical background,with a focus on critical formulation features and clinical studies. Finally, the bookincludes some recent and novel applications, scale-upconsiderations and regulatory issues. Drug Delivery Strategies for Poorly Water-Soluble Drugs is anessential multidisciplinary guide to this important area of drugformulation for researchers in industry and academia working indrug delivery, polymers and biomaterials.
Medical

Prediction of biological membrane penetration of poorly soluble drugs using surface activity profiling

Author: Anna Christine Petereit

Publisher: Cuvillier Verlag

ISBN:

Category: Medical

Page: 202

View: 360

Since combinatorial chemistry and high throughput screening have become a common technique in the drug discovery phase the number of compounds being considered has increased frequently. These structures are often characterized by high molecular weight, high lipophilicity and low solubility in aqueous and physiological media. Due to the generally poor bioavailability, new in vitro techniques were needed for screening of pharmacokinetic properties. An important parameter for these screening methods is the implementation at an early state of drug discovery phase, to find potential lead structures, before investment costs become significant. The established in vitro methods for the prediction of membrane interaction are not reliable especially for poorly soluble compounds. A new method that is fast and easy to use, requires only small amounts of NCE and which can provide more reliable predictions is needed. In this study, a new screening technique based on surface activity profiling for the prediction of oral drug absorption was evaluated with special emphasis on the predictability of biological membrane interaction of poorly soluble drug compounds. It was demonstrated that drug absorption through a bilayer membrane can be modeled by the orientation of compounds at the air/water interface. Thus amphilicity of a drug is generally related to both oral absorption and blood brain barrier penetration. In turn, amphiphilicity is influenced by the lipophilicity, size and charge distribution of a drug. Surface activity profiling was determined by analysis of surface pressure profiles using the Gibbs adsorption isotherm. The surface activity measurements were carried out using a multichannel tensiometer Delta 8, which was developed by Kibron to be utilized in conjugation high throughput screening in early drug discovery processes. For this study two test sets were analyzed, one for the prediction of gastrointestinal wall interaction and the second for the prediction of the penetration behavior at the blood brain barrier. Both test sets consist of drug compounds with a wide range of absorption properties and consist mainly of compounds with poor water solubility. Since the drugs characteristics varied, they were classified according to water solubility and surface activity and a sample preparation method for each group was established. For the prediction of oral drug absorption, three different methods were established to model the interaction of compound and gastrointestinal wall. For drug compounds with solubility above 1mmol/L the traditional shake-flask method enabled the determination of the amphiphilic properties of drug compounds in pure aqueous media. Compounds with solubility below 1mmol/L tend to not to exhibit any increase in surface activity. Thus surface tension measurements of compounds, which exhibited a limited surface activity due to poor aqueous solubility, were conducted from stock solutions prepared with various organic solvents. Mainly polar organic solvents were used. A mixture of DMSO and DMF resulted in the best combination of properties: the intensive solubility enhancing effect of DMF and the lower intrinsic surface activity of DMSO. The polar solvent ruptured the water clusters, so that highly lipophilic structures had a higher affinity to the solvent and higher concentrations could be obtained. For these compounds higher maximum surface pressure were generated than was possible in pure aqueous media. The surface pressure data were correlated with the fraction absorbed values in vivo However it was found that poor water solubility is not the only limiting step to exhibiting any surface activity. Some compounds were showed no surface activity in either solvent system. Therefore a micelle vehicle method was established using short chain phospholipids to mimic the gastrointestinal wall. It could be concluded from the results, that non surface active drugs can interact with the phospholipids micelle vehicle in a way analogous to their interaction with the membrane bilayer. The relative critical micelle concentration was correlated with the fraction absorbed of this test set. A sample preparation schema based on the three types of drugs was established. This schema enabled us to predict the absorbance of slightly soluble and poorly soluble drugs with acceptable reliability for early compound screening. For the prediction of blood brain barrier penetration using surface activity profiling as analyzing method, a test set with very poorly soluble characteristics was chosen. The sample preparation method was based on a strictly aqueous approach using the ‘shake flask’ method. The surface tension measurements enabled correlation of the amphiphilic properties of the very poorly soluble drug compounds with BBB uptake. From the aqueous surface pressure profiles and the determination of physicochemical parameters, it was found that blood brain barrier is more likely when a drug provides a small cross-sectional area, As, at the interface. The cross-sectional area is the only parameter which is independent from the maximal concentration in aqueous media and it is particularly suitable for lower solubility compounds. In summary, it was shown that amphilicity is related to biological membrane interaction in the human body and that surface activity profiling with appropriate sample preparation can be used as a reliable screening tool for the prediction of oral drug absorption of poorly soluble drugs. Furthermore an in vitro screening method of blood-brain-barrier penetration was established.

Enhancement of the Dissolution of a Poorly Water Soluble Drug

Author: Sachin Kumar

Publisher: LAP Lambert Academic Publishing

ISBN:

Category:

Page: 112

View: 583

Up to 40% of new chemical entities discovered by the pharmaceutical industry today are poorly soluble or lipophilic compounds. The solubility issues complicating the delivery of these new drugs also affect the delivery of many existing drugs. Poorly water-soluble drugs show unpredictable absorption, since their bioavailability depends upon the dissolution in the gastrointestinal tract. The dissolution characteristics of poorly soluble drugs can be enhanced by several methods. Among these methods, solid dispersions (SDs) and cyclodextrins (CDs) have been extensively studied to improve solubility, dissolution, and bioavailability of various drugs. The present manuscript reveals the significance and methodology of enhancing solubility of a poorly water soluble drug which can be useful to apply for other poorly water soluble drugs.
Medical

Oral Lipid-Based Formulations

Author: David J. Hauss

Publisher: CRC Press

ISBN:

Category: Medical

Page: 368

View: 677

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 of major significance, the pharmaceutical industry has been slow to apply and further develop this technology. This title provides a comprehensive summary of the theoretical and practical aspects of oral lipid-based formulations for use in industry, and provides further insights into a developing technology expected to assume increasing prominence in years to come.

Enhancement of Solubilization & Bioavailability of Poorly Soluble Drug

Author: Amit Chaudhary

Publisher: LAP Lambert Academic Publishing

ISBN:

Category:

Page: 52

View: 964

The aim of this work is to improve the solubilization and bioavailability of poorly soluble drugs by using various approaches like physical, chemical and others modifications or techniques. The solubility of a solute is the maximum quantity of solute that can dissolve in a certain quantity of solvent or quantity of solution at a specified temperature. Solubility is one of the important parameter to achieve desired concentration of drug in systemic circulation for pharmacological response to be shown. Drug efficacy can be severely limited by poor aqueous solubility and some drugs also show side effects due to their poor solubility. There are many techniques which are used to enhance the aqueous solubility. The ability to increase aqueous solubility can thus be a valuable aid to increasing efficiency and/or reducing side effects for certain drugs. This is true for parenterally, topically and orally administered solutions. Physical modifications techniques like media milling/ nanocrystal technology, cryogenic technology, supercritical fluid process, modification of the crystal habit, complexation, micellar technologies, chemical modifications etc.

In-Vitro In-Vivo Correlation (IVIVC) for Poorly Soluble Drugs

Author: Attia Afzal

Publisher: LAP Lambert Academic Publishing

ISBN:

Category:

Page: 208

View: 744

The pharmaceutical industries are hungry to speed up formulation development process. In Vitro-In Vivo Correlation (IVIVC) modeling fulfills this objective efficiently. The objective of this book is to provide a systematic approach to develop level A correlation for the poorly soluble drugs leading to development of a suitable dosage forms of biopharmaceutical classification System (BCS) Class II drugs by reducing time and cost i.e. research and development (R & D) work. This book is also helpful for the postgraduate students of pharmacy and allied sciences to get basic guidelines for pre-clinical and clinical studies of developed formulations.
Medical

Solubility enhancement of poorly water-soluble drugs by solid dispersion

Author: Adela Kalivoda

Publisher: Cuvillier Verlag

ISBN:

Category: Medical

Page: 198

View: 594

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.
Medical

Recent trends in solubility and bioavailability enhancement for poorly water-soluble drugs

Author: 최한곤

Publisher: 한양대학교 출판부

ISBN:

Category: Medical

Page: 100

View: 593

난용상 약물의 용해도 및 생체[이용율 증진에 대한 최근 연구동향을 모아 발간하고자 함 1. Silymarin-loaded solid nanoparticles with excellent hepatic protection: physicochemical characterization and in vivo evaluation. 2. The Influence of Bile Salt on the Chemotherapeutic Response of Docetaxel-loaded Thermosensitive Nanomicelles. 3. Enhanced oral bioavailability of fenofibrate using polymeric nanoparticulated systems: Physicochemical characterization and in vivo investigation. 4. Tumor-targeting. pH-sensitive nanoparticles for docetaxel delivery to drug-resistant cancer cells. 5. Comparative study on solid self-nanoemulsifying drug delivery and solid dispersion system for enhanced solubility and bioavailability of ezetimibe. 6. Novel electrosprayed nanospherules for enhanced aqueous solubility and oral bioavailability of poorly water-soluble fenofibrate. 7. Receptor-targeted. drug-loaded. functionalized graphene oxides for chemotherapy and photothermal therapy. 8. Progressive slowdown/prevention of cellular senescence by CD9-targeted delivery of rapamycin using lactose-wrapped calcium carbonate nanoparticles. 9. Optimization and physicochemical characterization of a cationic lipid-phosphatidylcholine mixed emulsion formulated as a highly efficient vehicle that facilitates adenoviral gene transfer. 10. Combination of NIR therapy and regulatory T cell modulation using layer-by-layer hybrid nanoparticles for effective cancer photoimmunotherapy. 11. Cyclic RGD-conjugated Pluronic® blending system for active. targeted drug delivery. 12. Transferrin-Conjugated Polymeric Nanoparticle for Receptor-Mediated Delivery of Doxorubicin in Doxorubicin-Resistant Breast Cancer Cells. 13. Self-microemulsifying drug delivery system (SMEDDS) for improved oral delivery and photostability of methotrexate. 14. Comparison of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol-loaded self-emulsifying granule and solid self-nanoemulsifying drug delivery system: powder property. dissolution and oral bioavailability. 15. Liposomal Formulations for Nose-to-Brain Delivery: Recent Advances and Future Perspectives. 16. Development of folate-functionalized zein nanoparticles for ligand-directed delivery of paclitaxel.