Cerebrospinal fluid (CSF) penetration and the pharmacokinetics of vancomycin were studied after c... more Cerebrospinal fluid (CSF) penetration and the pharmacokinetics of vancomycin were studied after continuous infusion (50 to 60 mg/kg of body weight/day after a loading dose of 15 mg/kg) in 13 mechanically ventilated patients hospitalized in an intensive care unit. Seven patients were treated for a sensitive bacterial meningitis and the other six patients, who had a severe concomitant neurologic disease with intracranial hypertension, were treated for various infections. Vancomycin CSF penetration was significantly higher ( P < 0.05) in the meningitis group (serum/CSF ratio, 48%) than in the other group (serum/CSF ratio, 18%). Vancomycin pharmacokinetic parameters did not differ from those obtained with conventional dosing. No adverse effect was observed, in particular with regard to renal function.
Cerebrospinal fluid (CSF) penetration and the pharmacokinetics of vancomycin were studied after c... more Cerebrospinal fluid (CSF) penetration and the pharmacokinetics of vancomycin were studied after continuous infusion (50 to 60 mg/kg of body weight/day after a loading dose of 15 mg/kg) in 13 mechanically ventilated patients hospitalized in an intensive care unit. Seven patients were treated for a sensitive bacterial meningitis and the other six patients, who had a severe concomitant neurologic disease with intracranial hypertension, were treated for various infections. Vancomycin CSF penetration was significantly higher ( P < 0.05) in the meningitis group (serum/CSF ratio, 48%) than in the other group (serum/CSF ratio, 18%). Vancomycin pharmacokinetic parameters did not differ from those obtained with conventional dosing. No adverse effect was observed, in particular with regard to renal function.
AG337 (Thymitaq) is an antitumor compound synthesized by Agouron Pharmaceuticals, Inc., using pro... more AG337 (Thymitaq) is an antitumor compound synthesized by Agouron Pharmaceuticals, Inc., using protein structure-based drug design. AG337 is a hydrochloride salt with a molecular formula of C 14 H 12 N 4 OS‚2HCl. This compound was subjected to thermal analyses, Karl Fischer titrimetry, powder X-ray diffractometry, scanning electron microscopy, and FTIR. On the basis of the Karl Fischer and thermogravimetric analysis, it was concluded to be a dihydrate. The differential scanning calorimetric studies revealed, that on heating, AG337 dehydrates and form a metastable form with a melting point of 213°C followed by crystallization into a stable form at 261°C. This stable form was finally melted at 312°C with decomposition. On the basis of the FTIR and HPLC studies, it was concluded that the final exothermic peak at 320°C was due to sample decomposition. The powder X-ray diffraction studies confirmed the existence of these two polymorphs of AG337. Scanning electron microscopic studies revealed that the crystal habits of both the polymorphs were quite different. FTIR spectra of both the polymorphs showed pronounced difference in the range of 600−1800 cm-1 .
Aim: A polymeric in situ gelling delivery system for localized and sustained delivery to jawbone ... more Aim: A polymeric in situ gelling delivery system for localized and sustained delivery to jawbone infections was developed. Materials & methods: In situ gelling delivery systems were prepared using either Poly(dl-lactic acid) or chitosan and Pluronic F127/Pluronic F68. Metronidazole nanoparticles were prepared using poly(dl-lactide-co-glycolide) or chitosan. Poly(dl-lactide-co-glycolide) was used for microparticles. Particles were characterized for size, charge and morphology. Results: Viscosity and yield stress of the gels were 0.4 Pa.s and 2 Pa, respectively, with 70% cell viability over 72 h. Around 90% of loaded metronidazole was released at a sustained rate over 1 week. Conclusion: Use of appropriate amount of nano/microparticles in the gel resulted in a sustained release over a period of 1 week – needed for jawbone infection.
Abstract Polymersomes are self-assembled polymeric vesicles prepared from amphiphilic block-copol... more Abstract Polymersomes are self-assembled polymeric vesicles prepared from amphiphilic block-copolymers. This chapter provides an overview of their composition, preparation, and characterization as well as their similarities and differences from liposomes. The recent developments and uses of polymersomes in drug delivery and other biomedical applications are further emphasized. Polymersomes development for drug delivery includes approaches for synthesis of novel block-copolymers, their assembly, and drug loading. Various surface modification strategies have been used for their targeting. Internal and external stimuli have been studied for controlling the release of drugs from polymersomes. In addition to drug delivery, the biomedical applications of polymersomes include diagnostics, polymersome-based nanoreactors, and the development of artificial cells (especially artificial erythrocytes) for scientific or clinical use. While none of these developments are in clinical use yet, they show a great promise for drug and gene delivery, imaging, blood substitution, and tissue engineering in the near future.
Journal of Drug Delivery Science and Technology, 2019
Tyr-Leu-Arg sequence was assembled directly onto the surface of spraydried chitosan microparticle... more Tyr-Leu-Arg sequence was assembled directly onto the surface of spraydried chitosan microparticles using solid-phase peptide synthesis with Fmoc chemistry. Both targeted and scrambled peptides were cleaved from chitosan with enzymatic digestion, isolated using reversed-phase HPLC, then identified with LC/MS/MS and amino acid analysis. Particles with conjugated peptides and fluorescentlabeled were characterized for binding with A549 (cancer) and WI-26 VA4 (normal) lung cells using flow cytometry and confocal microscopy. The purity of peptide synthesis was in the range of 74-77%. The cell binding studies revealed that particles modified with the peptide bind to lung cancer cells 8.3 times higher than the normal lung cells. The binding potential of surface-modified targeted particles to the tumor cells was compared with scrambled and unmodified ones and was found to be significantly different. The binding was 7.3-7.5-fold higher than the scrambled and unmodified particles, respectively. Modification of chitosan particles with direct assembly of Ala-Glu-Tyr-Leu-Arg peptide on their surface enhanced their targeting potential to lung cancer cells and could be used as a potential carrier for delivery and therapy. This approach can further be utilized for assembly of other short peptide ligands on micro-or nanoparticulate systems for tumor targeting.
Light-induced drug release has been explored as a strategy for externally modulating the release ... more Light-induced drug release has been explored as a strategy for externally modulating the release of drug from delivery systems. This study reports the development of a solid lipid nanoparticulate system (SLN) for paclitaxel (PTX), where photosensitizer-mediated oxidation of lipids was used as a mechanism for controlling the drug release. Low-intensity (23 mW/cm 2) near-infrared (around 730 nm) illumination was externally applied as the light source. Paclitaxel release was less than 10% within 4 hrs from these SLN and was 8-fold higher after application of light at time zero. The other advantages of this approach include the use of ascorbic acid as an antioxidant for enhancing the release and storage stability of the delivery system. Antioxidant like ascorbic acid in the SLN decrease the degradation of lipid by 8-fold within 4 months of storage. Presence of ascorbic acid and light illumination of SLN containing PTX further decreased the IC50 by 2 times in A549 cells. The uniqueness of this approach allows the possibility of external modulation to achieve pulsatile release from the delivery system. The light used in the NIR spectral range of 700-850 nm, which has the greatest tissue penetration ability, with a low intensity will be safe for normal tissues.
Hydrogen sulfide (H2S) targets both underlying factors in glaucoma pathogenesis by reducing eleva... more Hydrogen sulfide (H2S) targets both underlying factors in glaucoma pathogenesis by reducing elevated intraocular pressure (IOP) and providing retinal neuroprotection, whereas the current clinical approaches targets only reducing IOP. Therefore, H2S could be a potential superior candidate for glaucoma pharmacotherapy. However, H2S could be toxic in a concentration greater than 200 μM and its donors are unstable in water. Therefore, this study investigated the preparation and characterization of a non-aqueous in situ gelling sustained-release delivery system for H2S donors. The delivery system was prepared by dissolving GYY 4137, a H2S donor, in poly lactide-co-glycolide polymer (PLGA) (Resomer® RG 502H) solution prepared by dissolving polymer in a mixture of benzyl alcohol and benzyl benzoate in a ratio of 7:3, respectively. The GYY 4137 formulation was characterized for syringeability/injectability, change in pH and tonicity, moisture content, GYY 4137 degradation, and toxicity usin...
The objective of this study was to develop a novel chitosan-glyceryl monooleate (GMO) in situ gel... more The objective of this study was to develop a novel chitosan-glyceryl monooleate (GMO) in situ gel system for sustained drug delivery and targeting. The delivery system consisted of 3% (w/v) chitosan and 3% (w/v) GMO in 0.33 M citric acid. In situ gel was formed at a biological pH. In vitro release studies were conducted in Sorensen's phosphate buffer (pH 7.4) and drugs were analyzed either by HPLC or spectrophotometry. Characterization of the gel included the effect of cross-linker, determination of diffusion coefficient and water uptake by thermogravimetric analysis (TGA). Mucoadhesive property of the gel was evaluated in vitro using an EZ-Tester. Incorporation of a cross-linker (glutaraldehyde) retarded the rate and extent of drug release. The in vitro release can further be sustained by replacing the free drug with drug-encapsulated microspheres. Drug release from the gel followed a matrix diffusion controlled mechanism. Inclusion of GMO enhanced the mucoadhesive property of chitosan by threeto sevenfold. This novel in situ gel system can be useful in the sustained delivery of drugs via oral as well as parenteral routes.
Pharmaceutics: Basic Principles and Application to Pharmacy Practice is a valuable textbook cover... more Pharmaceutics: Basic Principles and Application to Pharmacy Practice is a valuable textbook covering the basic science as well as the role and application of pharmaceutics within pharmacy practice. Based on curricular guidelines mandated by the American Council for Pharmacy Education (ACPE), this book incorporates laboratory skills by identifying portions of each principle that can be used in a clinical setting. In this way, instructors are able to demonstrate their adherence to ACPE standards and objectives simply by using this book. A companion website for students and instructors further enhance the didactic content for students by including practice questions and answers and videos that feature difficult processes and procedures. Essential resources for instructors are also available and include chapter PowerPoint slides and full-color images. Full of practical examples and case studies for experiential learning, Pharmaceutics enables students to gain the scientific foundation to understand drug physicochemical properties, practical aspects of dosage forms and drug delivery systems, and the biological applications of drug administration. It features chapter objectives and chapter summaries that illustrate and reinforce key ideas. It is designed to meet curricular guidelines for pharmaceutics and laboratory skills mandated by the Accreditation Council for Pharmacy Education (ACPE). Companion website features resources for students and instructors, including videos illustrating difficult processes and procedures and practice questions and answers. Instructor resources include Powerpoint slides and a full-color image bank.
Methods and Findings in Experimental and Clinical Pharmacology, 2003
In a previous study, we showed evidence that oxidative stress induced by hydrogen peroxide (H2O2)... more In a previous study, we showed evidence that oxidative stress induced by hydrogen peroxide (H2O2) can inhibit the release of [3H]-D-aspartate from the bovine isolated retina, in vitro. The aim of the present study was to investigate the effect of H2O2 on glutamate and glycine levels in the bovine retina and vitreous humor, ex vivo. Furthermore, we examined whether inhibition of catalase activity with 3-amino-triazole had any effect on the concentrations of these amino acids in the posterior segment of the bovine eye. Whole eye organ cultures were prepared by incubating tissues in oxygenated Krebs solution at 37 masculine C for 30 min. After incubation, H2O2 (1-100 microM) or sterile distilled water was injected intravitreally into each eye. Thirty minutes after injection, the retina and vitreous humor were removed for analysis of glutamate and glycine by high performance liquid chromatography (HPLC) with fluorescence detection. Exogenously applied H2O2 (1-100 microM) caused a concentration-related decrease in both glutamate and glycine levels in the bovine retina. Furthermore, while H2O2 (1-10 microM) caused a concentration-dependent decrease in glycine levels in the vitreous humor, it had no significant effect on glutamate levels. The catalase inhibitor, 3-amino-triazole (10 mM), caused a significant reduction in both glutamate and glycine levels in the bovine retina, ex vivo. Likewise, 3-AT caused an attenuation in both glutamate and glycine concentration in the vitreous humor. We conclude that oxidative stress induced by H2O2 can alter the release and/or availability of amino acids in the posterior segment of bovine eyes.
Uncontrolled exposure to radiation from possible nuclear battlefields, outer space travel or acci... more Uncontrolled exposure to radiation from possible nuclear battlefields, outer space travel or accidents at nuclear power plants presents the greatest threat and challenge to the civilized world today. The consequences of ionizing radiation, either from intentional or unintentional ...
Critical Reviews in Therapeutic Drug Carrier Systems, 2009
Paclitaxel (PTX) is a potent anticancer agent whose clinical usefulness is marred by a delivery p... more Paclitaxel (PTX) is a potent anticancer agent whose clinical usefulness is marred by a delivery problem that is caused by its unfavorable pharmacokinetic and physical properties. Paclitaxel is currently formulated in a mixture of Cremophor EL and ethanol, which is diluted 5-20 times with normal saline or 5% dextrose prior to administration via slow infusion to avoid precipitation in plasma. Many adverse reactions to the PTX formulation have been reported because of the presence of Cremophor EL, including hypersensitivity reactions, nephrotoxicity, and neurotoxicity. Cremophor EL also causes vasodilation, labored breathing, lethargy, hypotension, and leaching of plasticizers, such as diethylhexylpthalate, from the polyvinylchloride infusion bags/sets. Significant research efforts have been conducted to develop an alternative formulation approach to increase the aqueous solubility of PTX without using Cremophor, thereby decreasing its toxicity. This article reviews the various investigated formulation approaches including pastes; liposomes; conjugates with antibodies, peptides, and fatty acids; nanospheres and microspheres; cyclodextrin complexes; emulsions; mucoadhesive gel; prodrugs; and nanoparticulate systems. The pros and cons of each approach are also discussed. Finally, this review concludes with a discussion of nanoparticulate delivery, which is the most promising PTX delivery system of the future because it incorporates the benefits of other approaches such as conjugation, complexation, and prodrugs.
The in vitro release of a drug from topical formulations depends on the concentration of the drug... more The in vitro release of a drug from topical formulations depends on the concentration of the drug in the formulation, the solubility of the drug in the base, the diffusion coefficient of the drug in the vehicle, and the partition coefficient of the drug between the vehicle, and the release medium. Incorporation of both complexing agents and cosolvents into such formulations has been used to enhance the in vitro release of a drug from topical formulations. In this investigation, a novel approach to enhance the in vitro release of benzocaine from different ointment formulations has been introduced. In this study, benzocaine was microencapsulated using gelatin−acacia complex coacervation technique. Various weight fractions of the coacervate, 5, 10, and 20% (w/w), were incorporated into both oleaginous and absorption bases. The in vitro release characteristics of benzocaine from the resulting ointments were studied using a modified USP Dissolution Apparatus 2. A plot of the cumulative amount of drug released (7−8%) per unit surface area versus (time) 1/2 was linear. Microscopic studies of the formulations revealed that the coacervates maintained their integrity in the formulation during the preparation and storage of the dosage form. Differential scanning calorimetric (DSC) studies indicated that the drug existed in the crystalline state in all formulations including those at a low drug load (0.5% w/w). DSC was also used to determine the solubility of the drug in the formulation. The rate and extent of drug release was higher in the absorption base as compared to the oleaginous base.
Ultra-long-acting integrase strand transfer inhibitors were created by screening a library of mon... more Ultra-long-acting integrase strand transfer inhibitors were created by screening a library of monomeric and dimeric dolutegravir (DTG) prodrug nanoformulations. This led to an 18-carbon chain modified ester prodrug nanocrystal (coined NM2DTG) with the potential to sustain yearly dosing. Here, we show that the physiochemical and pharmacokinetic (PK) formulation properties facilitate slow drug release from tissue macrophage depot stores at the muscle injection site and adjacent lymphoid tissues following single parenteral injection. Significant plasma drug levels are recorded up to a year following injection. Tissue sites for prodrug hydrolysis are dependent on nanocrystal dissolution and prodrug release, drug-depot volume, perfusion, and cell-tissue pH. Each affect an extended NM2DTG apparent half-life recorded by PK parameters. The NM2DTG product can impact therapeutic adherence, tolerability, and access of a widely used integrase inhibitor in both resource limited and rich settings...
The classically used nontargeted chemotherapeutic approach to pancreatic cancer has a dual drawba... more The classically used nontargeted chemotherapeutic approach to pancreatic cancer has a dual drawback of suboptimal drug delivery at the target site and the systemic side effects produced by the unfettered exposure of the drug to healthy tissue. This study has the objective of developing novel poly(2-ethyl-2-oxazoline) (PETOX)-based long circulating liposomes loaded with gemcitabine and irinotecan for the treatment of pancreatic ductal adenocarcinoma, with a juxtaposition to PEGylated and uncoated liposomes. A PETOX −cholesteryl chloroformate lipopolymer conjugate (PETOX-ChC) with a carbonate linkage was prepared and characterized by 1 H NMR, FTIR, and DSC. Liposomes were prepared using the thin film hydration technique followed by freeze-thaw and membrane extrusion methods. Liposome characterization includes particle size determination, zeta potential determination using a zetameter, and structural elucidation using 31 P NMR and cryo-TEM. The PETOXylated liposomes showed a particle size of 180.1 ± 2.2 nm and a zeta potential of − 33.63 ± 1.23 mV. The liposomal combination therapy of gemcitabine and irinotecan was found to have an IC 50 value 39 times lower in comparison to the drug combination in solution, while the PEGylated and PETOXylated liposomes showed IC 50 values 1.6 times lower and 2 times lower than that of uncoated liposomes, respectively, against Mia PaCa II pancreatic cancer cell line. The PEGylated and PETOXylated liposomes showed 4.1 and 5.4 times slower macrophagial uptake in vitro in comparison to the uncoated liposomes respectively. The PEGylated liposomes showed 11% higher in vitro macrophagial uptake in comparison to PETOXylated liposomes.
Low-Intensity Light-Induced Drug Release from a Dual Delivery System Comprising of a Drug Loaded ... more Low-Intensity Light-Induced Drug Release from a Dual Delivery System Comprising of a Drug Loaded Liposome and a Photosensitive Conjugate This study reports the development of a binary drug delivery system consisting of charged liposomes and an oppositely charged peptide-photosensitizer conjugate. Liposomes were prepared with phosphadityl-L-serine as a negatively charged lipid. Calcein, a fluorophore marker, and doxorubicin, an anticancer drug, were used as model hydrophilic loads. The conjugate consisted of a positively charged arginine-rich peptide synthesized by solid-phase peptide synthesis, and a phthalocyanine derivative with characteristic absorption around 685 nm. Illumination of the binary system with far-red light of 12-15 mW/cm 2 intensity resulted in 5 to 15-fold increase in release of payloads from the liposomes. The mechanism of drug release was based on photosensitized oxidation of lipids destabilizing the liposomal membrane. The cytotoxicity of the liposomes loaded with doxorubicin was tested on B16-F10 melanoma and Y79 retinoblastoma cells. The cytotoxicity of the illuminated binary system in melanoma cell line was significantly higher as compared to the system without illumination. The components of the binary system can be individually prepared and stored with greater storage stability. However, their combination will allow for substantial release of hydrophilic payload from the liposomes under externally applied light.
The objective of this study was to develop a nanodelivery system containing a mucoadhesive polyme... more The objective of this study was to develop a nanodelivery system containing a mucoadhesive polymer hyaluronic acid (HA) for oral delivery. Metformin was used as a model drug. Blank and drug-loaded HA nanostructures were prepared by precipitation method and characterized for particle size (PS), zeta potential (ZP), physical stability (over 65 days), surface morphology, moisture content, and physical state of the drug in the nanostructures. The cytotoxicity and hemolysis potential of the delivery system was assessed in Caco-2 cells and whole human blood, respectively. The in vitro release of metformin and its uptake in Caco-2 cells was evaluated using high-performance liquid chromatography. Ex vivo permeability of metformin was measured through goat intestinal membrane. The nanoparticles were physically stable and neutrally charged with an average PS of 114.53 ± 12.01 nm. This nanodelivery system existed as nanofibers containing metformin in a crystalline state. This delivery system released the drug rapidly with > 50% of metformin released within 1 h. Cellular uptake studies on Caco-2 cells indicated higher uptake of metformin from nanoparticle as compared to metformin in solution, up to first 45 min. Ex vivo permeability studies on the other hand showed a higher metformin permeability from solution relative to that from nanoparticles through the goat intestinal membrane. Metformin nanoparticles were non-toxic at therapeutic concentrations in Caco-2 cells and showed no hemolytic effect to RBCs. This study indicates the preparation, characterization, as well as the potential use of HA nanostructures for oral delivery.
Cerebrospinal fluid (CSF) penetration and the pharmacokinetics of vancomycin were studied after c... more Cerebrospinal fluid (CSF) penetration and the pharmacokinetics of vancomycin were studied after continuous infusion (50 to 60 mg/kg of body weight/day after a loading dose of 15 mg/kg) in 13 mechanically ventilated patients hospitalized in an intensive care unit. Seven patients were treated for a sensitive bacterial meningitis and the other six patients, who had a severe concomitant neurologic disease with intracranial hypertension, were treated for various infections. Vancomycin CSF penetration was significantly higher ( P < 0.05) in the meningitis group (serum/CSF ratio, 48%) than in the other group (serum/CSF ratio, 18%). Vancomycin pharmacokinetic parameters did not differ from those obtained with conventional dosing. No adverse effect was observed, in particular with regard to renal function.
Cerebrospinal fluid (CSF) penetration and the pharmacokinetics of vancomycin were studied after c... more Cerebrospinal fluid (CSF) penetration and the pharmacokinetics of vancomycin were studied after continuous infusion (50 to 60 mg/kg of body weight/day after a loading dose of 15 mg/kg) in 13 mechanically ventilated patients hospitalized in an intensive care unit. Seven patients were treated for a sensitive bacterial meningitis and the other six patients, who had a severe concomitant neurologic disease with intracranial hypertension, were treated for various infections. Vancomycin CSF penetration was significantly higher ( P < 0.05) in the meningitis group (serum/CSF ratio, 48%) than in the other group (serum/CSF ratio, 18%). Vancomycin pharmacokinetic parameters did not differ from those obtained with conventional dosing. No adverse effect was observed, in particular with regard to renal function.
AG337 (Thymitaq) is an antitumor compound synthesized by Agouron Pharmaceuticals, Inc., using pro... more AG337 (Thymitaq) is an antitumor compound synthesized by Agouron Pharmaceuticals, Inc., using protein structure-based drug design. AG337 is a hydrochloride salt with a molecular formula of C 14 H 12 N 4 OS‚2HCl. This compound was subjected to thermal analyses, Karl Fischer titrimetry, powder X-ray diffractometry, scanning electron microscopy, and FTIR. On the basis of the Karl Fischer and thermogravimetric analysis, it was concluded to be a dihydrate. The differential scanning calorimetric studies revealed, that on heating, AG337 dehydrates and form a metastable form with a melting point of 213°C followed by crystallization into a stable form at 261°C. This stable form was finally melted at 312°C with decomposition. On the basis of the FTIR and HPLC studies, it was concluded that the final exothermic peak at 320°C was due to sample decomposition. The powder X-ray diffraction studies confirmed the existence of these two polymorphs of AG337. Scanning electron microscopic studies revealed that the crystal habits of both the polymorphs were quite different. FTIR spectra of both the polymorphs showed pronounced difference in the range of 600−1800 cm-1 .
Aim: A polymeric in situ gelling delivery system for localized and sustained delivery to jawbone ... more Aim: A polymeric in situ gelling delivery system for localized and sustained delivery to jawbone infections was developed. Materials & methods: In situ gelling delivery systems were prepared using either Poly(dl-lactic acid) or chitosan and Pluronic F127/Pluronic F68. Metronidazole nanoparticles were prepared using poly(dl-lactide-co-glycolide) or chitosan. Poly(dl-lactide-co-glycolide) was used for microparticles. Particles were characterized for size, charge and morphology. Results: Viscosity and yield stress of the gels were 0.4 Pa.s and 2 Pa, respectively, with 70% cell viability over 72 h. Around 90% of loaded metronidazole was released at a sustained rate over 1 week. Conclusion: Use of appropriate amount of nano/microparticles in the gel resulted in a sustained release over a period of 1 week – needed for jawbone infection.
Abstract Polymersomes are self-assembled polymeric vesicles prepared from amphiphilic block-copol... more Abstract Polymersomes are self-assembled polymeric vesicles prepared from amphiphilic block-copolymers. This chapter provides an overview of their composition, preparation, and characterization as well as their similarities and differences from liposomes. The recent developments and uses of polymersomes in drug delivery and other biomedical applications are further emphasized. Polymersomes development for drug delivery includes approaches for synthesis of novel block-copolymers, their assembly, and drug loading. Various surface modification strategies have been used for their targeting. Internal and external stimuli have been studied for controlling the release of drugs from polymersomes. In addition to drug delivery, the biomedical applications of polymersomes include diagnostics, polymersome-based nanoreactors, and the development of artificial cells (especially artificial erythrocytes) for scientific or clinical use. While none of these developments are in clinical use yet, they show a great promise for drug and gene delivery, imaging, blood substitution, and tissue engineering in the near future.
Journal of Drug Delivery Science and Technology, 2019
Tyr-Leu-Arg sequence was assembled directly onto the surface of spraydried chitosan microparticle... more Tyr-Leu-Arg sequence was assembled directly onto the surface of spraydried chitosan microparticles using solid-phase peptide synthesis with Fmoc chemistry. Both targeted and scrambled peptides were cleaved from chitosan with enzymatic digestion, isolated using reversed-phase HPLC, then identified with LC/MS/MS and amino acid analysis. Particles with conjugated peptides and fluorescentlabeled were characterized for binding with A549 (cancer) and WI-26 VA4 (normal) lung cells using flow cytometry and confocal microscopy. The purity of peptide synthesis was in the range of 74-77%. The cell binding studies revealed that particles modified with the peptide bind to lung cancer cells 8.3 times higher than the normal lung cells. The binding potential of surface-modified targeted particles to the tumor cells was compared with scrambled and unmodified ones and was found to be significantly different. The binding was 7.3-7.5-fold higher than the scrambled and unmodified particles, respectively. Modification of chitosan particles with direct assembly of Ala-Glu-Tyr-Leu-Arg peptide on their surface enhanced their targeting potential to lung cancer cells and could be used as a potential carrier for delivery and therapy. This approach can further be utilized for assembly of other short peptide ligands on micro-or nanoparticulate systems for tumor targeting.
Light-induced drug release has been explored as a strategy for externally modulating the release ... more Light-induced drug release has been explored as a strategy for externally modulating the release of drug from delivery systems. This study reports the development of a solid lipid nanoparticulate system (SLN) for paclitaxel (PTX), where photosensitizer-mediated oxidation of lipids was used as a mechanism for controlling the drug release. Low-intensity (23 mW/cm 2) near-infrared (around 730 nm) illumination was externally applied as the light source. Paclitaxel release was less than 10% within 4 hrs from these SLN and was 8-fold higher after application of light at time zero. The other advantages of this approach include the use of ascorbic acid as an antioxidant for enhancing the release and storage stability of the delivery system. Antioxidant like ascorbic acid in the SLN decrease the degradation of lipid by 8-fold within 4 months of storage. Presence of ascorbic acid and light illumination of SLN containing PTX further decreased the IC50 by 2 times in A549 cells. The uniqueness of this approach allows the possibility of external modulation to achieve pulsatile release from the delivery system. The light used in the NIR spectral range of 700-850 nm, which has the greatest tissue penetration ability, with a low intensity will be safe for normal tissues.
Hydrogen sulfide (H2S) targets both underlying factors in glaucoma pathogenesis by reducing eleva... more Hydrogen sulfide (H2S) targets both underlying factors in glaucoma pathogenesis by reducing elevated intraocular pressure (IOP) and providing retinal neuroprotection, whereas the current clinical approaches targets only reducing IOP. Therefore, H2S could be a potential superior candidate for glaucoma pharmacotherapy. However, H2S could be toxic in a concentration greater than 200 μM and its donors are unstable in water. Therefore, this study investigated the preparation and characterization of a non-aqueous in situ gelling sustained-release delivery system for H2S donors. The delivery system was prepared by dissolving GYY 4137, a H2S donor, in poly lactide-co-glycolide polymer (PLGA) (Resomer® RG 502H) solution prepared by dissolving polymer in a mixture of benzyl alcohol and benzyl benzoate in a ratio of 7:3, respectively. The GYY 4137 formulation was characterized for syringeability/injectability, change in pH and tonicity, moisture content, GYY 4137 degradation, and toxicity usin...
The objective of this study was to develop a novel chitosan-glyceryl monooleate (GMO) in situ gel... more The objective of this study was to develop a novel chitosan-glyceryl monooleate (GMO) in situ gel system for sustained drug delivery and targeting. The delivery system consisted of 3% (w/v) chitosan and 3% (w/v) GMO in 0.33 M citric acid. In situ gel was formed at a biological pH. In vitro release studies were conducted in Sorensen's phosphate buffer (pH 7.4) and drugs were analyzed either by HPLC or spectrophotometry. Characterization of the gel included the effect of cross-linker, determination of diffusion coefficient and water uptake by thermogravimetric analysis (TGA). Mucoadhesive property of the gel was evaluated in vitro using an EZ-Tester. Incorporation of a cross-linker (glutaraldehyde) retarded the rate and extent of drug release. The in vitro release can further be sustained by replacing the free drug with drug-encapsulated microspheres. Drug release from the gel followed a matrix diffusion controlled mechanism. Inclusion of GMO enhanced the mucoadhesive property of chitosan by threeto sevenfold. This novel in situ gel system can be useful in the sustained delivery of drugs via oral as well as parenteral routes.
Pharmaceutics: Basic Principles and Application to Pharmacy Practice is a valuable textbook cover... more Pharmaceutics: Basic Principles and Application to Pharmacy Practice is a valuable textbook covering the basic science as well as the role and application of pharmaceutics within pharmacy practice. Based on curricular guidelines mandated by the American Council for Pharmacy Education (ACPE), this book incorporates laboratory skills by identifying portions of each principle that can be used in a clinical setting. In this way, instructors are able to demonstrate their adherence to ACPE standards and objectives simply by using this book. A companion website for students and instructors further enhance the didactic content for students by including practice questions and answers and videos that feature difficult processes and procedures. Essential resources for instructors are also available and include chapter PowerPoint slides and full-color images. Full of practical examples and case studies for experiential learning, Pharmaceutics enables students to gain the scientific foundation to understand drug physicochemical properties, practical aspects of dosage forms and drug delivery systems, and the biological applications of drug administration. It features chapter objectives and chapter summaries that illustrate and reinforce key ideas. It is designed to meet curricular guidelines for pharmaceutics and laboratory skills mandated by the Accreditation Council for Pharmacy Education (ACPE). Companion website features resources for students and instructors, including videos illustrating difficult processes and procedures and practice questions and answers. Instructor resources include Powerpoint slides and a full-color image bank.
Methods and Findings in Experimental and Clinical Pharmacology, 2003
In a previous study, we showed evidence that oxidative stress induced by hydrogen peroxide (H2O2)... more In a previous study, we showed evidence that oxidative stress induced by hydrogen peroxide (H2O2) can inhibit the release of [3H]-D-aspartate from the bovine isolated retina, in vitro. The aim of the present study was to investigate the effect of H2O2 on glutamate and glycine levels in the bovine retina and vitreous humor, ex vivo. Furthermore, we examined whether inhibition of catalase activity with 3-amino-triazole had any effect on the concentrations of these amino acids in the posterior segment of the bovine eye. Whole eye organ cultures were prepared by incubating tissues in oxygenated Krebs solution at 37 masculine C for 30 min. After incubation, H2O2 (1-100 microM) or sterile distilled water was injected intravitreally into each eye. Thirty minutes after injection, the retina and vitreous humor were removed for analysis of glutamate and glycine by high performance liquid chromatography (HPLC) with fluorescence detection. Exogenously applied H2O2 (1-100 microM) caused a concentration-related decrease in both glutamate and glycine levels in the bovine retina. Furthermore, while H2O2 (1-10 microM) caused a concentration-dependent decrease in glycine levels in the vitreous humor, it had no significant effect on glutamate levels. The catalase inhibitor, 3-amino-triazole (10 mM), caused a significant reduction in both glutamate and glycine levels in the bovine retina, ex vivo. Likewise, 3-AT caused an attenuation in both glutamate and glycine concentration in the vitreous humor. We conclude that oxidative stress induced by H2O2 can alter the release and/or availability of amino acids in the posterior segment of bovine eyes.
Uncontrolled exposure to radiation from possible nuclear battlefields, outer space travel or acci... more Uncontrolled exposure to radiation from possible nuclear battlefields, outer space travel or accidents at nuclear power plants presents the greatest threat and challenge to the civilized world today. The consequences of ionizing radiation, either from intentional or unintentional ...
Critical Reviews in Therapeutic Drug Carrier Systems, 2009
Paclitaxel (PTX) is a potent anticancer agent whose clinical usefulness is marred by a delivery p... more Paclitaxel (PTX) is a potent anticancer agent whose clinical usefulness is marred by a delivery problem that is caused by its unfavorable pharmacokinetic and physical properties. Paclitaxel is currently formulated in a mixture of Cremophor EL and ethanol, which is diluted 5-20 times with normal saline or 5% dextrose prior to administration via slow infusion to avoid precipitation in plasma. Many adverse reactions to the PTX formulation have been reported because of the presence of Cremophor EL, including hypersensitivity reactions, nephrotoxicity, and neurotoxicity. Cremophor EL also causes vasodilation, labored breathing, lethargy, hypotension, and leaching of plasticizers, such as diethylhexylpthalate, from the polyvinylchloride infusion bags/sets. Significant research efforts have been conducted to develop an alternative formulation approach to increase the aqueous solubility of PTX without using Cremophor, thereby decreasing its toxicity. This article reviews the various investigated formulation approaches including pastes; liposomes; conjugates with antibodies, peptides, and fatty acids; nanospheres and microspheres; cyclodextrin complexes; emulsions; mucoadhesive gel; prodrugs; and nanoparticulate systems. The pros and cons of each approach are also discussed. Finally, this review concludes with a discussion of nanoparticulate delivery, which is the most promising PTX delivery system of the future because it incorporates the benefits of other approaches such as conjugation, complexation, and prodrugs.
The in vitro release of a drug from topical formulations depends on the concentration of the drug... more The in vitro release of a drug from topical formulations depends on the concentration of the drug in the formulation, the solubility of the drug in the base, the diffusion coefficient of the drug in the vehicle, and the partition coefficient of the drug between the vehicle, and the release medium. Incorporation of both complexing agents and cosolvents into such formulations has been used to enhance the in vitro release of a drug from topical formulations. In this investigation, a novel approach to enhance the in vitro release of benzocaine from different ointment formulations has been introduced. In this study, benzocaine was microencapsulated using gelatin−acacia complex coacervation technique. Various weight fractions of the coacervate, 5, 10, and 20% (w/w), were incorporated into both oleaginous and absorption bases. The in vitro release characteristics of benzocaine from the resulting ointments were studied using a modified USP Dissolution Apparatus 2. A plot of the cumulative amount of drug released (7−8%) per unit surface area versus (time) 1/2 was linear. Microscopic studies of the formulations revealed that the coacervates maintained their integrity in the formulation during the preparation and storage of the dosage form. Differential scanning calorimetric (DSC) studies indicated that the drug existed in the crystalline state in all formulations including those at a low drug load (0.5% w/w). DSC was also used to determine the solubility of the drug in the formulation. The rate and extent of drug release was higher in the absorption base as compared to the oleaginous base.
Ultra-long-acting integrase strand transfer inhibitors were created by screening a library of mon... more Ultra-long-acting integrase strand transfer inhibitors were created by screening a library of monomeric and dimeric dolutegravir (DTG) prodrug nanoformulations. This led to an 18-carbon chain modified ester prodrug nanocrystal (coined NM2DTG) with the potential to sustain yearly dosing. Here, we show that the physiochemical and pharmacokinetic (PK) formulation properties facilitate slow drug release from tissue macrophage depot stores at the muscle injection site and adjacent lymphoid tissues following single parenteral injection. Significant plasma drug levels are recorded up to a year following injection. Tissue sites for prodrug hydrolysis are dependent on nanocrystal dissolution and prodrug release, drug-depot volume, perfusion, and cell-tissue pH. Each affect an extended NM2DTG apparent half-life recorded by PK parameters. The NM2DTG product can impact therapeutic adherence, tolerability, and access of a widely used integrase inhibitor in both resource limited and rich settings...
The classically used nontargeted chemotherapeutic approach to pancreatic cancer has a dual drawba... more The classically used nontargeted chemotherapeutic approach to pancreatic cancer has a dual drawback of suboptimal drug delivery at the target site and the systemic side effects produced by the unfettered exposure of the drug to healthy tissue. This study has the objective of developing novel poly(2-ethyl-2-oxazoline) (PETOX)-based long circulating liposomes loaded with gemcitabine and irinotecan for the treatment of pancreatic ductal adenocarcinoma, with a juxtaposition to PEGylated and uncoated liposomes. A PETOX −cholesteryl chloroformate lipopolymer conjugate (PETOX-ChC) with a carbonate linkage was prepared and characterized by 1 H NMR, FTIR, and DSC. Liposomes were prepared using the thin film hydration technique followed by freeze-thaw and membrane extrusion methods. Liposome characterization includes particle size determination, zeta potential determination using a zetameter, and structural elucidation using 31 P NMR and cryo-TEM. The PETOXylated liposomes showed a particle size of 180.1 ± 2.2 nm and a zeta potential of − 33.63 ± 1.23 mV. The liposomal combination therapy of gemcitabine and irinotecan was found to have an IC 50 value 39 times lower in comparison to the drug combination in solution, while the PEGylated and PETOXylated liposomes showed IC 50 values 1.6 times lower and 2 times lower than that of uncoated liposomes, respectively, against Mia PaCa II pancreatic cancer cell line. The PEGylated and PETOXylated liposomes showed 4.1 and 5.4 times slower macrophagial uptake in vitro in comparison to the uncoated liposomes respectively. The PEGylated liposomes showed 11% higher in vitro macrophagial uptake in comparison to PETOXylated liposomes.
Low-Intensity Light-Induced Drug Release from a Dual Delivery System Comprising of a Drug Loaded ... more Low-Intensity Light-Induced Drug Release from a Dual Delivery System Comprising of a Drug Loaded Liposome and a Photosensitive Conjugate This study reports the development of a binary drug delivery system consisting of charged liposomes and an oppositely charged peptide-photosensitizer conjugate. Liposomes were prepared with phosphadityl-L-serine as a negatively charged lipid. Calcein, a fluorophore marker, and doxorubicin, an anticancer drug, were used as model hydrophilic loads. The conjugate consisted of a positively charged arginine-rich peptide synthesized by solid-phase peptide synthesis, and a phthalocyanine derivative with characteristic absorption around 685 nm. Illumination of the binary system with far-red light of 12-15 mW/cm 2 intensity resulted in 5 to 15-fold increase in release of payloads from the liposomes. The mechanism of drug release was based on photosensitized oxidation of lipids destabilizing the liposomal membrane. The cytotoxicity of the liposomes loaded with doxorubicin was tested on B16-F10 melanoma and Y79 retinoblastoma cells. The cytotoxicity of the illuminated binary system in melanoma cell line was significantly higher as compared to the system without illumination. The components of the binary system can be individually prepared and stored with greater storage stability. However, their combination will allow for substantial release of hydrophilic payload from the liposomes under externally applied light.
The objective of this study was to develop a nanodelivery system containing a mucoadhesive polyme... more The objective of this study was to develop a nanodelivery system containing a mucoadhesive polymer hyaluronic acid (HA) for oral delivery. Metformin was used as a model drug. Blank and drug-loaded HA nanostructures were prepared by precipitation method and characterized for particle size (PS), zeta potential (ZP), physical stability (over 65 days), surface morphology, moisture content, and physical state of the drug in the nanostructures. The cytotoxicity and hemolysis potential of the delivery system was assessed in Caco-2 cells and whole human blood, respectively. The in vitro release of metformin and its uptake in Caco-2 cells was evaluated using high-performance liquid chromatography. Ex vivo permeability of metformin was measured through goat intestinal membrane. The nanoparticles were physically stable and neutrally charged with an average PS of 114.53 ± 12.01 nm. This nanodelivery system existed as nanofibers containing metformin in a crystalline state. This delivery system released the drug rapidly with > 50% of metformin released within 1 h. Cellular uptake studies on Caco-2 cells indicated higher uptake of metformin from nanoparticle as compared to metformin in solution, up to first 45 min. Ex vivo permeability studies on the other hand showed a higher metformin permeability from solution relative to that from nanoparticles through the goat intestinal membrane. Metformin nanoparticles were non-toxic at therapeutic concentrations in Caco-2 cells and showed no hemolytic effect to RBCs. This study indicates the preparation, characterization, as well as the potential use of HA nanostructures for oral delivery.
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Papers by Alekha Dash