PLGA Based Drug Carrier and Pharmaceutical Applications

Poly(lactic-co-glycolic acid) (PLGA) is one of the most successful polymers used for producing therapeutic devices, such as drug carriers (DC). PLGA is one of the few polymers that the Food and Drug Administration (FDA) has approved for human administration due to its biocompatibility and biodegradability. In recent years, DC produced with PLGA has gained enormous attention for its versatility in transporting different type of drugs, e.g., hydrophilic or hydrophobic small molecules, or macromolecules with a controlled drug release without modifying the physiochemical properties of the drugs. These drug delivery systems have the possibility/potential to modify their surface properties with functional groups, peptides, or other coatings to improve the interactions with biological materials. Furthermore, they present the possibility to be conjugated with specific target molecules to reach specific tissues or cells. They are also used for different therapeutic applications, such as in vaccinations, cancer treatment, neurological disorder treatment, and as anti-inflammatory agents. This book aims to focus on the recent progress of PLGA as a drug carrier and their new pharmaceutical applications

Production of functional pharmaceutical nano/micro-particles by solvent displacement method using advanced micro-engineered dispersion devices

The rapid advancement of drug delivery systems (DDS) has raised the possibility of using functional engineered nano/micro-particles as drug carriers for the administration of active pharmaceutical ingredients (APIs) to the affected area. The major goals in designing these functional particles are to control the particle size, the surface properties and the pharmacologically active agents release in order to achieve the site-specification of the drug at the therapeutically optimal rate and dose regimen. Two different equipment (i.e. glass capillary microfluidic device and micro-engineered membrane dispersion cell) were utilised in this study for the formation of functional nano/micro-particles by antisolvent precipitation method. This method is based on micromixing/direct precipitation of two miscible liquids, which appear as a straightforward method, rapid and easy to perform, does not require high stirring rates, sonication, elevated temperatures, surfactants and Class 1 solvents can be avoided. Theoretical selection of a good solvent and physicochemical interaction between solvent-water-polymer with the aid of Bagley s two-dimensional graph were successfully elucidated the nature of anti-solvent precipitation method for the formation of desired properties of functional pharmaceutical nano/micro-engineered particles. For the glass capillary microfluidic experiment, the organic phase (a mixture of polymer and tetrahydrofuran/acetone) was injected through the inner glass capillary with a tapered cross section culminated in a narrow orifice. The size of nanoparticles was precisely controlled by controlling phase flow rates, orifice size and flow configuration (two- phase co-flow or counter-current flow focusing). The locations at which the nanoparticles would form were determined by using the solubility criteria of the polymer and the concentration profiles found by numerical modelling. This valuable results appeared as the first computational and experimental study dealing with the formation of polylactide (PLA) and poly(ε-caprolactone) (PCL) nanoparticles by nanoprecipitation in a co-flow glass capillary device. The optimum formulations and parameters interactions involved in the preparation of paracetamol encapsulated nanoparticles (PCM-PCL NPs) using a co-flow microfluidic device was successfully simulated using a 25-full factorial design for five different parameters (i.e. PCL concentration, orifice size, flow rate ratios, surfactant concentration and paracetamol amount) with encapsulation efficiency and drug loading percentage as the responses. PCM-loaded composite NPs composed of a biodegradable poly(ᴅ,ʟ-lactide) (PLA) polymer matrix filled with organically modified montmorillonite (MMT) nanoparticles were also successfully formulated by antisolvent nanoprecipitation in a microfluidic co-flow glass capillary device. The incorporation of MMT in the polymer matrix improved the drug encapsulation efficiency and drug loading, and extended the rate of drug release in simulated intestinal fluid (pH 7.4). The encapsulation of MMT and PCM in the NPs were well verified using transmission electron microscopy (TEM), energy dispersive x-ray spectroscopy (EDS), x-ray diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR). PCL drug-carrier nanoparticles were also produced by rapid membrane micromixing combined with nanoprecipitation in a stirred cell employing novel membrane dispersion. The size of the NPs was precisely controlled by changing the aqueous-to-organic volumetric ratio, stirring rate, transmembrane flux, the polymer content in the organic phase, membrane type and pore morphologies. The particle size decreased by increasing the stirring rate and the aqueous-to-organic volumetric ratio, and by decreasing the polymer concentration in the aqueous phase and the transmembrane flux. The existence of the shear stress peak within a transitional radius and a rapid decline of the shear stress away from the membrane surface were revealed by numerical modelling. Further investigation on the PCL nanoparticles loaded immunosuppressive rapamycin (RAPA) drug were successfully synthesised by anti-solvent nanoprecipitation method using stainless steel (SS) ringed micro-engineered membrane. Less than 10 µm size of monohydrate piroxicam (PRX) micro-crystals also was successfully formed with the application of anti-solvent precipitation method combined with membrane dispersion cell that has been utilised in the formation of functional engineered nanoparticles. This study is believed to be a new insight into the development of integrated membrane crystallisation system

NANOCRYSTALS OF CHEMOTHERAPEUTIC AGENTS FOR CANCER THERANOSTICS: DEVELOPMENT AND IN VITRO AND IN VIVO EVALUATION

The majority of pharmacologically active chemotherapeutics are poorly water soluble. Solubilization enhancement by the utilization of organic solvents often leads to adverse side effects. Nanoparticle-based cancer therapy, which is passively targeted to the tumor tissue via the enhanced permeation and retention effect, has been vastly developed in recent years. Nanocrystals, which exist as crystalline and carry nearly 100% drug loading, has been explored for delivering antineoplastic agents. Additionally, the hybrid nanocrystal concept offers a novel and simple way to integrate imaging agents into the drug crystals, enabling the achievement of theranostics. The overall objective of this dissertation is to formulate both pure and hybrid nanocrystals, evaluate their performance in vitro and in vivo, and investigate the extent of tissue distribution and tumor accumulation in a murine model. Pure and hybrid nanocrystals of several model drugs, including paclitaxel (PTX), camptothecin, and ZSTK474, were precipitated by the antisolvent method in the absence of stabilizer, and their size was further minimized by homogenization. The nanocrystals of PTX, which is the focus of the study, had particle size of approximately 200 nm and close-to-neutral surface charge. Depending on the cell type, PTX nanocrystals exerted different level of cytotoxicity. In human colon and breast cancer xenograft models, nanocrystals yielded similar efficacy as the conventional formulation, Taxol, at a dose of 20 mg/kg, yet induced a reduced toxicity. Biodistribution study revealed that 3H-PTX nanocrystals were sequestered rapidly by the macrophages upon intravenous injection. Yet, apparent toxicity was not observed even after four weekly injections. The sequestered nanocrystals were postulated to be released slowly into the blood circulation and reached the tumor. Tritium-labeled-taxol, in contrast, was distributed extensively to all the major organs, inducing systemic toxicity as observed in significant body weight loss. The biodistribution results obtained from radioactive analysis and whole-body optical imaging was compared. To some degree, the correlation was present, but divergence in the quantitative result, due to nanocrystal integrity and limitations associated with the optical modality, existed. Despite their promising properties, nanocrystal suspensions must be securely stabilized by stealth polymers in order to minimize opsonization, extend blood-circulation time, and efficiently target the tumor

NASA Thesaurus. Volume 2: Access vocabulary

The NASA Thesaurus -- Volume 2, Access Vocabulary -- contains an alphabetical listing of all Thesaurus terms (postable and nonpostable) and permutations of all multiword and pseudo-multiword terms. Also included are Other Words (non-Thesaurus terms) consisting of abbreviations, chemical symbols, etc. The permutations and Other Words provide 'access' to the appropriate postable entries in the Thesaurus

Organically Modified Inorganic Nanoparticles for Halochromic Ionophores and Nucleic Acids

In this dissertation, four nanoparticle reaction schemes were developed as substrates for halochromic dyes or nucleic acids. The reaction schemes include the use of two substrates: silica nanoparticles and halloysite nanotubes. The protocols can incorporate silica (SiO2) nanoparticles and halloysite aluminosilicate (AlO2SiO2) nanotubes due to the presence of silane groups on the surface of either substrate. The reaction schemes are presented along with detailed protocols which were written to facilitate both reproducibility and to serve as an aid to further study and for easy modification of the protocol to suit a researcher\u27s needs. The data is discussed in the materials section to annotate the stages of synthesis as well as the response of the nanoparticles to varying conditions of pH in both a broad range and a near neutral range. The first particle scheme was designed to create a particle to measure pH using neutral red, a halochromic ionophore with sensitivity to near neutral pH values. Neutral red has a primary amine which is not required for its halochromic response but is suitable for covalent binding to an aldehyde. The particle synthesis involved functionalization of the inorganic silica surface with an amine. This amine was then covalently bound to a dialdehyde, glutaraldehyde, creating an imine and resulted in a terminal aldehyde functional group on the surface of the particle. The final step of the synthesis was to bind neutral red by its primary amine to the aldehyde functional group. This created a pH sensitive nanoparticle. The particles were stable and did not exhibit leaching or loss of dye. The particles were sensitive to near neutral pH and observation of UV-vis spectra they could be used to discern changes in pH at a large range by observation of the spectral bands of the protonated and deprotonated states of the halochromic dye. The second particle developed was a derivation of the first particle. Instead of using a dialdehyde to link two amines, a silane coupling agent was used to provide aldehydes to the surface of the particles. The aldehyde functional group was then linked to the amine functional group of the halochromic dye, neutral red. This protocol produced stable nanoparticles with pH sensitivity, was steps shorter, required fewer reagents, which reduced the cost of development and increased the facility of the protocol. The third particle developed used an organosilane cross linking agent to produce nanoparticles made of covalently bound silica and the halochromic dyes, neutral red and Nile blue. The particles were highly responsive to changes in pH. Analysis of UV-vis spectral data showed a broad sensitivity to pH by changes in the spectral bands. The fourth particle developed used the reaction scheme from the second particle. The surface of the inorganic particles was functionalized with aldehyde groups. The aldehyde modified particles were then shown to have the ability to covalently bind nucleic acids and nitrogenous bases. The synthesis of these particles is presented along with the supporting data. Further areas of study and possible future work are discussed

NASA Thesaurus. Volume 1: Hierarchical listing

There are 16,713 postable terms and 3,716 nonpostable terms approved for use in the NASA scientific and technical information system in the Hierarchical Listing of the NASA Thesaurus. The generic structure is presented for many terms. The broader term and narrower term relationships are shown in an indented fashion that illustrates the generic structure better than the more widely used BT and NT listings. Related terms are generously applied, thus enhancing the usefulness of the Hierarchical Listing. Greater access to the Hierarchical Listing may be achieved with the collateral use of Volume 2 - Access Vocabulary

NASA thesaurus. Volume 2: Access vocabulary

The Access Vocabulary, which is essentially a permuted index, provides access to any word or number in authorized postable and nonpostable terms. Additional entries include postable and nonpostable terms, other word entries, and pseudo-multiword terms that are permutations of words that contain words within words. The Access Vocabulary contains 40,738 entries that give increased access to the hierarchies in Volume 1 - Hierarchical Listing

NASA thesaurus. Volume 1: Hierarchical Listing

There are over 17,000 postable terms and nearly 4,000 nonpostable terms approved for use in the NASA scientific and technical information system in the Hierarchical Listing of the NASA Thesaurus. The generic structure is presented for many terms. The broader term and narrower term relationships are shown in an indented fashion that illustrates the generic structure better than the more widely used BT and NT listings. Related terms are generously applied, thus enhancing the usefulness of the Hierarchical Listing. Greater access to the Hierarchical Listing may be achieved with the collateral use of Volume 2 - Access Vocabulary and Volume 3 - Definitions

NASA thesaurus. Volume 2: Access vocabulary

The access vocabulary, which is essentially a permuted index, provides access to any word or number in authorized postable and nonpostable terms. Additional entries include postable and nonpostable terms, other word entries and pseudo-multiword terms that are permutations of words that contain words within words. The access vocabulary contains almost 42,000 entries that give increased access to the hierarchies in Volume 1 - Hierarchical Listing

NASA Thesaurus. Volume 1: Alphabetical listing

The NASA Thesaurus -- Volume 1, Alphabetical Listing -- contains all subject terms (postable and nonpostable) approved for use in the NASA scientific and technical information system. Included are the subject terms of the Preliminary Edition of the NASA Thesaurus (NASA SP-7030, December 1967); of the NASA Thesaurus Alphabetical Update (NASA SP-7040, September 1971); and terms approved, added or changed through May 31, 1975. Thesaurus structuring, including scope notes, a generic structure with broader-term/narrower-term (BT-NT) relationships displayed in embedded hierarchies, and other cross references, is provided for each term, as appropriate