Browsing by Subject "Drug delivery systems"

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Cellular and molecular evaluation of oral delivery systems for chemotherapeutic agents
(2004-05) Blanchette, James Otto, 1976-; Peppas, Nicholas A., 1948-
The development of carriers to deliver a variety of cancer therapeutics orally would represent a significant advance in the treatment of this disease. This delivery system is based on hydrophilic polymer carriers to deliver therapeutic agents to the upper region of the small intestine in response to the pH increase when passing from the stomach. Methacrylic acid (MAA) and ethylene glycol (EG) combined in a 1:1 molar ratio were reacted to form P(MAA-g-EG) nanospheres by UV-initiated free radical polymerization. MAA and EG were chosen to give the nanospheres pH-responsive swelling behavior and mucoadhesive properties as has been shown by previous work in our lab with oral delivery of proteins. Bleomycin, chosen as a chemotherapeutic agent with desirable properties, was loaded into the nanospheres by in situ polymerization or imbibition. Release studies were carried out in conditions modeling the gastrointestinal tract. Results showed that bleomycin is preferentially released at a higher pH due to the increased mesh size of the swollen hydrogel carrier. The potential cytotoxicity of bleomycin on the small intestine was investigated with the use of Caco-2 cells (human colon adenocarcinoma). Studies done with bleomycin concentrations ranging from 0.01 – 1.0 mg/ml showed maintenance of both viability and proliferation in treated cells compared to control cells. The presence of the nanospheres decreases the transepithelial electrical resistance (TER) across Caco-2 cell monolayers. This decrease is thought to be the result of calcium binding by the nanospheres and removal of calcium aids transport of bleomycin across a Caco-2 model of the intestinal epithelium. Bleomycin efficacy studies show activity of the drug against a DLD-1 cell (human colon carcinoma) tumor model following loading and release from the nanospheres.
Design, synthesis, and evaluation of synthetic particulate delivery systems in DNA and protein vaccine delivery
(2006) Kasturi, Sudhir Pai; Roy, Krishnendu
Vaccination is not only a medical marvel in terms of unparalleled importance in safeguarding health but also considered to be one of the most economical and safe medical intervention strategies. Radical changes have taken place in vaccine development in recent times with modern approaches laying heavy emphasis on safety and rapid turn around times for new vaccines. Recombinant subunit protein vaccines and DNA vaccines are considered to be the future generation of vaccines. Genetic immunization which involves host inoculation of bacterially derived plasmid DNA encoding for proteins (antigens) derived from disease causing pathogens has emerged as a safer, cost effective alternative to the use of recombinant viruses. Experts believe that genetic immunization could be the first application towards the use of nucleic acids as a biopharmaceutical drug. Although extensive research in animal models has shown significant promise in terms of generating strong and potent balance of humoral and cell mediated immunity, the translation to human clinical trials has been disappointing. The use of synthetic delivery systems to enhance the potency of nucleic acid based (DNA) vaccines and recombinant purified protein vaccines have opened new directions in safer, yet effective modalities of vaccination. The overall goal of this project was to engineer synthetic polymer based delivery systems to enhance the potency of protein and DNA vaccines. We have synthesized hybrid polymeric PLGA microparticles; surface modified by chemical conjugation of polycations such as branched and linear poly (ethyleneimine) PEI and with solvent free Atmospheric Plasma Glow discharge (APG) based approaches. Extensive characterization demonstrates that our formulations; a) have excellent reproducibility, b) are efficiently taken up by phagocytic cells, c) have endo/phagosomal escape facilitating properties, d) are non toxic to cells, and e) have improved transfection efficiencies at early time points in phagocytic cells in vitro. We have also demonstrated that these formulations considerably enhance potency of cancer genetic vaccines without the use of known immune potentiators in mice models in vivo. The potential to include known soluble adjuvants in our design can have far reaching effects in realizing combinatorial vaccine and adjuvant delivery systems for cures in cancer and infectious diseases.
Enhancing the delivery of poorly water soluble drugs using particle engineering technologies
(2006-12) Sinswat, Prapasri, 1972-; Williams, Robert O., 1956-; Johnston, Keith P., 1955-
Improvement in the bioavailability of poorly water-soluble drugs via pulmonary delivery of nanoparticles
(2009-08) Yang, Wei; Williams, Robert O., 1956-; Johnston, Keith P., 1955-
High throughput screening techniques that are routinely used in modern drug discovery processes result in a higher prevalence of poorly water-soluble drugs. Such drugs often have poor bioavailability issues due to their poor dissolution and/or permeability to achieve sufficient and consistent systemic exposure, resulting in sub-optimal therapeutic efficacies, particularly via oral administration. Alternative formulations and delivery routes are demanded to improve their bioavailability. Nanoparticulate formulations of poorly water-soluble drugs offer improved dissolution profiles. The physiology of the lung makes it an ideal target for non-invasive local and systemic drug delivery for poorly water-soluble drugs. In Chapter 2, a particle engineering process ultra-rapid freezing (URF) was utilized to produce nanostructured aggregates of itraconazole (ITZ), a BCS class II drug, for pulmonary delivery with approved biocompatible excipients. The obtained formulation, ITZ:mannitol:lecithin (1:0.5:0.2, w/w), i.e. URF-ITZ, was a solid solution with high surface area and ability to achieve high magnitude of supersaturation. An aqueous colloidal dispersion of URF-ITZ was suitable for nebulization, which demonstrated optimal aerodynamic properties for deep lung delivery and high lung and systemic ITZ levels when inhaled by mice. The significantly improved systemic bioavailability of inhaled URF-ITZ was mainly ascribed to the amorphous morphology that raised the drug solubility. The effect of supersaturation of amorphous URF-ITZ relative to nanocrystalline ITZ on bioavailability following inhalation was evaluated in Chapter 3. The nanoparticulate amorphous ITZ composition resulted in a significantly higher systemic bioavailability than for the nanocrystalline ITZ composition, as a result of the higher supersaturation that increased the permeation. In Chapter 4, pharmacokinetics of inhaled nebulized aerosols of solubilized ITZ in solution versus nanoparticulate URF-ITZ colloidal dispersion were investigated, under the hypothesis that solubilized ITZ can be absorbed faster through mucosal membrane than the nanoparticulate ITZ. Despite similar ITZ lung deposition, the inhaled solubilized ITZ demonstrated significantly faster systemic absorption across lung epithelium relative to nanoparticulate ITZ in mice, due in part to the elimination of the phase-to-phase transition of nanoparticulate ITZ.
In vitro and in vivo behavior of insulin delivery systems based on poly(ethylene glycol)-grafted poly(methacrylic acid) hydrogels
(2005) Kavimandan, Nikhil Jayant; Peppas, Nicholas A., 1948-
Developing oral insulin formulations for the treatment of diabetes can greatly improve the quality of life of the patients. Many different approaches have been investigated to address the problems associated with oral insulin delivery, but the bioavailability of oral insulin is still low, even in some of the most successful formulations. Insulin is rapidly degraded by the enzymes in the GI tract and is not transported across the epithelial barrier easily. The oral insulin formulation developed in this work makes use of complexation hydrogels for oral delivery of insulin bioconjugates. The insulin bioconjugates synthesized in this work consist of insulin bound to transferrin molecule which can be uptaken by the epithelial cells. These conjugates can increase the permeability of insulin across the epithelial barrier by receptor-mediated transcytosis. The transferrin in the conjugate is also shown to stabilize insulin in the presence of intestinal enzymes. Use of complexation hydrogels for delivery of insulin-transferrin conjugate may greatly increase the bioavailability of oral insulin. This is because, the complexation hydrogels are known to exhibit characteristics that make them ideal candidates for oral protein delivery. For example, it is shown in this work that the hydrogels can increase the retention of the therapeutic protein in the small intestine. They can also inhibit the degradation of insulin in the GI tract. Thus, combination of these two approaches provides an innovative platform for oral insulin delivery.
Influence of drug-polymer interactions on the processing and functionality of anionic polymeric targeted drug delivery systems
(2002-12) Bruce, Lisa Diane; McGinity, James W.
Investigation of cellulose ether polymers in controlled drug delivery
(2001-08) Mahaguna, Vorapann; Williams, Robert O., 1956-
Cellulose ethers are widely used in a variety of pharmaceutical applications. The purpose of this research was to investigate the use of cellulose ether polymers to formulate different oral pharmaceutical dosage forms, and to control the release of active ingredient from the specific drug delivery system over an extended period of time. In this study, applications of the cellulose ether polymer in matrix tablets and multiparticulate dosage forms, were investigated. Specifically, ethylcellulose (EC) used in aqueous polymeric coating, and hydroxypropyl methylcellulose (HPMC) used in hydrophilic matrix tablets, were investigated in this study. Formulations and processing parameters were developed and optimized in order to achieve the desirable rate of drug release from each drug delivery system. For the matrix tablet system, an efficient method to achieve complete recovery of alprazolam from powder blends and tablets containing HPMC was developed and qualified. Formulation parameters, including tablet size, polymer levels, excipient type and level, molecular weight type of HPMC, and dissolution media, were investigated and optimized during development of the drug delivery systems. Finally, two oral controlled release tablet formulations (containing different molecular weight types of HPMC) with equivalent dissolution profiles were developed and used for in vivo bioequivalence study. Molecular weight types of HPMC did not influence in vitro or in vivo performance of controlled release tablets and provided bioequivalent results in both fed and fasted states. For the multiparticulate system, the amount of drug release from EC coated matrix beads was influenced by drug type, plasticization, water-soluble additive, and curing condition. Optimum curing conditions were determined in order to ensure complete film coalescence without disrupting film integrity. Additionally, the amount of theophylline released from EC coated beads was manipulated by the inclusion of different types and levels of water-soluble additives. As found for both controlled release drug delivery systems, formulation and processing parameters must be investigated and optimized in order to achieve desirable release profiles and stabilize the amount of drug released throughout the shelf-life of the product.
The modification of insulin to enhance oral delivery systems
(2009-05) Kanzelberger, Melissa Ann; Peppas, Nicholas A., 1948-
While a number of PEGylated proteins have been studied for injectable applications and reviewers have used this data to speculate possible oral delivery improvements, a detailed investigation of PEGylated insulin for oral delivery and the development of an optimized pH-sensitive carrier for PEGylated insulin conjugates had yet to be accomplished. In order to proceed with oral delivery study, improvements in yield, with respect to previous PEGylation methods were necessary to enable the completion of high throughput drug delivery studies. Subsequently, a reaction scheme for the covalent attachment of PEG to insulin using nitrophenyl carbonate-PEG was developed. It was demonstrated that this reaction occurred at a 1:1 ratio and was site specific at the B29Lys position. A P(MAA-g-EG) hydrogel carrier was developed to optimize loading and release behavior for PEGylated insulin. It was demonstrated that the density and length of polymer grafts affected both loading and release behavior of PEGylated insulin. The best performing grafted polymers had a 3:1 methacrylic acid: ethylene glycol (MAA:EG) ratio and achieved loading efficiencies from 96% to nearly 100%. With respect to release, polymer particles containing fewer, but longer grafts shown to release faster than polymers with shorter grafts with the same MAA:EG ratio. Finally, the effects of PEGylation on intestinal absorption was investigated using an intestinal epithelial model as well as a rat model. It was demonstrated that PEGylated insulin in the presence of P(MAA-g-EG) microparticles did not significantly alter the tight junctions over unmodified insulin. However, the conjugate permeabilities across the membrane were reduced. The pharmacological availability (PA) was then verified by injecting the insulin conjugates subcutaneously in fasted Sprague-Dawley rats. It was determined that PEG 1000 insulin (1KPI) had a PA roughly equivalent to insulin, while it was reduced by 59% for 2KPI and by 81% for 5KPI. The effectiveness of utilizing PEGylated insulin as an oral drug delivery candidate was evaluated with a closed loop intestinal study, in which PEGylated insulin or insulin in solution was delivered directly to the jejunum. It was shown that 1KPI and insulin performed identically; with a pharmacological availability of 0.56%. 2KPI, however improved the pharmacological availability of insulin by 2.8 times. These results demonstrate that PEGylation holds promise for improving the oral delivery of proteins.
Molecular design of advanced oral protein delivery systems using complexation hydrogels
(2006) Wood, Kristy Marie; Peppas, Nicholas A., 1948-
A novel class of pH sensitive complexation hydrogels composed of methacrylic acid and functionalized poly(ethylene glycol) tethers, referred to as P(MAA-g-EG) WGA, was investigated as an oral protein delivery system. The PEG tethers were functionalized with wheat germ agglutinin (WGA), a lectin that can bind to carbohydrates in the intestinal mucosa, to improve residence time of the carrier and absorption of the drug at the delivery site. P(MAA-g-EG) WGA created a specific mucoadhesive interaction between mucin and WGA in in vitro experiments. In addition, it improved the overall adhesion of the carrier by 17% to a cellular monolayer, as compared to P(MAA-g-EG). Administration of P(MAA-g-EG) WGA to a rat small intestine demonstrated that 99% of the microparticles still remained in the rat small intestine after 1 hour. These results confirmed that functionalizing P(MAA-g-EG) with WGA improved the mucoadhesive properties of the carrier. Insulin was effectively entrapped within the polymer network with a loading efficiency of 74%. Release studies with insulin-loaded P(MAA-g-EG) WGA showed that the carrier released less than 10% of the insulin at pH 3.2 after 60 minutes and 70% of the insulin at pH 7.0 after 60 minutes. These studies confirmed that P(MAA-g-EG) WGA can protect insulin in the low pH of the stomach and that the pH change between the stomach and the small intestine can be used as a physiologic trigger to quickly release insulin. The ability of P(MAA-g-EG) WGA to improve insulin absorption was investigated in two different intestinal epithelial models and an animal model. In the Caco-2 cells, P(MAA-g-EG) WGA improved insulin permeability by 9-fold as compared to an insulin only solution. P(MAA-g-EG) WGA was also evaluated in a mucussecreting culture that contained Caco-2 and HT29-MTX cells. Insulin permeability was increased by 5-fold in the presence of P(MAA-g-EG) WGA. The final study determined bioavailability of insulin-loaded P(MAA-g-EG) WGA when administered to a rat small intestine. Bioavailability of insulin was 11.9% for insulin-loaded P(MAA-g-EG) WGA, which is a vast improvement over the 0.5% bioavailability of an insulin only solution. Overall, it is clear that P(MAA-gEG) WGA holds great promise as an oral insulin delivery system.
Nanoimprint lithography based fabrication of size and shape-specific, enzymatically-triggered nanoparticles for drug delivery applications
(2008-05) Glangchai, Luz Cristal Sanchez, 1977-; Roy, Krishnendu; Shi, Li, Ph. D.
Our ability to precisely manipulate size, shape, and composition of nanoscale carriers is essential for controlling their in-vivo transport, biodistribution, and drug release mechanism. Shape-specific, "smart" nanoparticles that deliver drugs or imaging agents to target tissues primarily in response to disease-specific or physiological signals could significantly improve therapeutic care of complex diseases. Current methods in nanoparticle synthesis do not allow such simultaneous control over particle size, shape, and environmentally-triggered drug release, especially at the sub-100 nm range. In this dissertation, we discuss the development of high-throughput nanofabrication techniques using synthetic and biological macromers (peptides) to produce highly monodisperse nanoparticles, as well as enzymatically-triggered nanoparticles, of precise sizes and shapes. We evaluated thermal nanoimprint lithography (ThNIL) and step and flash imprint lithography (SFIL) as two possible fabrication techniques. We successfully employed ThNIL and SFIL for fabricating nanoparticles and have extensively characterized the SFIL fabrication process, as well as the properties of the imprinted biopolymers. Particles as small as 50 nm were fabricated on silicon wafers and harvested directly into aqueous buffer using a biocompatible, one-step release technique. These methods provide a novel way to fabricate biocompatible nanoparticles with precise size and geometry. Furthermore, we developed an enzyme-degradable material system and demonstrated successful encapsulation and enzyme-triggered release of antibodies and nucleic acids from these imprinted nanoparticles; thus providing a potential means for disease-controlled delivery of biomolecules. Finally, we evaluated the bioactivity of the encapsulated therapeutics in-vitro. The development of the SFIL method for fabrication of biocompatible nanocarriers has great potential in the drug delivery field for its ability to create monodisperse particles of pre-designed geometry and size, and to incorporate stimulus-responsive release mechanisms. This research provides the potential to broaden the study of how particle size and shape affect the biodistribution of drugs within the body.
Physical and chemical properties of rapid-release systems prepared by a thermal granulation technique
(2002-12) Koleng, John Joseph; McGinity, James W.
The physicochemical properties of rapid-release drug delivery systems prepared by the thermal granulation of fine powder pharmaceutical compositions using hot-melt extrusion (HME) were investigated. Thermal processing represents an alternative production technique to the traditional methods of wet granulation or dry granulation. Acetaminophen (APAP) was thermally granulated with polyethylene glycol (PEG) or poloxamer. APAP was demonstrated to be thermally stable. The molecular weight, dissolution rate, and aqueous viscosity of the thermal binders influenced APAP dissolution. Additionally, APAP dissolution was dependent upon the thermal binder concentration and the properties of the filler excipient. The most rapid dissolution was obtained with 15% polyethylene glycol and soluble filler excipients. viii APAP dissolution was more rapid from a thermally granulated composition than from a wet granulated formulation. Ibuprofen (IBU) was thermally granulated using the drug as a melt binder. IBU stability was demonstrated to be dependent upon temperature and duration of exposure. Granule particle size, tablet hardness, and filler excipient influenced the dissolution of IBU. Thermally granulated IBU tablets were prepared that provided similar dissolution rates to commercially available products. Tocofersolan (TPGS) was used to thermally granulate phenylbutazone (PBZ) and diphenhydramine HCl (DPH). PBZ was oxidized by TPGS, and oxidation was dependent upon TPGS concentration, temperature, and duration of exposure. Ascorbic acid was found to inhibit the TPGS-mediated oxidation of PBZ. DPH did not exhibit oxidation in the presence of TPGS. Although the thermal binder and the addition of ascorbic acid influenced PBZ dissolution, greater than 80% dissolution was obtained at 15 minutes. DPH dissolution from tablets containing either PEG or TPGS was complete within 10 minutes. HME was successfully employed to thermally granulate rapid-release systems. The thermal stability and compatibility of the drug and excipients must be evaluated to determine the appropriate thermal binder and extrusion conditions. Thermal binder concentration, granule particle size, and functional excipients must be optimized to provide the desired physical properties of the drug product
Physicochemical and mechanical characterization of hot-melt extruded dosage forms
(2003) Crowley, Michael McDonald; McGinity, James W.
The physicochemical and mechanical properties and the mechanisms of drug release from drug delivery systems prepared by hotmelt extrusion were investigated. The influence of processing conditions and the thermal properties of the polymeric retardants was also studied. The stability of polyethylene oxide (PEO) in sustained release tablets prepared by hot-melt extrusion was investigated. The chemical stability of PEO was found to be dependent on the storage and processing temperature, the screw speed and the molecular weight of the polymer. Lower molecular weight PEO MW = 100,000 (PEO 100K) was demonstrated to be a suitable processing aid for PEO 1M. Vitamin E, Vitamin E Succinate and Vitamin E TPGS were found to be suitable stabilizers for PEO; however, ascorbic acid was shown to degrade the polymer in solution. Drug release rates from hot-melt extruded tablets stabilized with antioxidants were found to be dependent on the hydrophilic nature of the antioxidant. The physicochemical properties and mechanism of drug release from ethyl cellulose matrix tablets containing a water soluble drug (guaifenesin) were investigated. Tablets were prepared by direct compression and hot-melt extrusion techniques. The drug dissolution and release kinetics were determined and the tablet pore characteristics, tortuosity, thermal properties and surface morphologies were studied. The tortuosity was measured directly by a novel technique that allows for the calculation of diffusion coefficients in 3 experiments. The Higuchi diffusion model, percolation theory and polymer free volume theory were applied to the dissolution data to explain the release properties of drug from the matrix systems. Films containing PEO and two model drugs (guaifenesin and ketoprofen) were prepared by hot-melt extrusion. Both guaifenesin and ketoprofen were stable during the extrusion process. Wide angle X-ray diffraction suggested that guaifenesin crystallized from the melt upon cooling, but ketoprofen formed a solid solution. Crystallization of guaifenesin on the surface of the film could be observed using scanning electron microscopy at all concentrations studies, but did not reveal ketoprofen crystallization until reaching the 15% level. Guaifenesin and ketoprofen were found to decrease the drive load, increase the stability of polyethylene oxide and plasticize the polymer during extrusion. The percent elongation decreased with increasing guaifenesin concentrations, but increased with increasing ketoprofen concentrations. Both guaifenesin and ketoprofen decreased the tensile strength of the film.
Properties of polymeric drug delivery systems prepared by hot-melt extrusion
(2002) Zhu, Yucun; McGinity, James W.
The purpose of this research project was to investigate the physicochemical and drug release properties of polymeric drug delivery systems prepared by hot-melt extrusion containing either highly water-soluble drugs or a poorly water-soluble drug. The properties of processed materials were characterized by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), stability indicating RP- HPLC assay, dissolution studies, scanning electron microscopy (SEM), X-ray diffractometry, electronic torque rheometry, Zeta potential particle size analysis, and helium pycnometry. Chlorpheniramine maleate (CPM), diltiazem hydrochloride (DTZ), indomethacin (IDM), and the excipients were thermally and chemically stable following hot-melt extrusion. CPM decreased the glass transition temperature (Tg) of Eudragit RS PO and exhibited a solid-state plasticization effect. CPM and IDM were in the amorphous state and DTZ was in the crystalline state following hot-melt extrusion processing. Triethyl citrate (TEC) facilitated the hot-melt extrusion process by decreasing the Tg and the melt viscosity of Eudragit RS PO. However, the thermal lubricant, glyceryl monostearate (GMS), only decreased the melt viscosity of the Eudragit RS PO. The CPM release rate constant decreased in the order from tablets prepared by direct compression, hot-melt granulation, and hot-melt extrusion. This was due to an increase in the intermolecular binding and entanglement between drug molecules and polymer molecules that occurred during thermal processing. Post- processing thermal treatment of the hot-melt extrudates had a minimal effect on decreasing the drug release rate since the hot-melt extrusion process enhanced the entanglement of the drug and polymer to a greater extent. Drug release rates from both DTZ and CPM hot-melt extrudates increased with an increase in the TEC level in the formulations, while DTZ release from the Eudragit RS 30D coated pellets decreased with an increase of TEC in the coating layer. This could be attributed to the fact that a continuous polymeric structure was formed following hot-melt extrusion regardless of the TEC level. However, for the film coated pellets, coalescence of the polymer particles was enhanced with higher levels of TEC. Due to the lower solubility of IDM, no significant difference in drug release was observed in the IDM hot-melt extrudated granules containing 0%, 4%, and 8% TEC.