Browsing by Subject "drug delivery"

Now showing 1 - 4 of 4
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    Amphiphilic And Random Copolymers: Self Assembly And Application In Drug Delivery Formulations
    (2019-03) Tale, Swapnil
    One of the biggest challenges in the field of drug delivery is the development of a system that can deliver cargo to a specific organ or cell and improve the aqueous solubility of poorly water soluble drugs. Recently, amphiphilic and random polymers have attracted considerable attention from researchers in order to elucidate these issues. Amphiphilic polymers consist of both hydrophilic and hydrophobic segments. Amphiphilic polymers are not only limited to drug delivery applications but also have utility in products such as food, detergents, paints, and cosmetics etc. Random copolymers consist of two or more monomers, the chain can add these monomers in any order. The incorporation on monomers into chain based on numerous factors such as conditions used for polymerization, reactivity of one monomer towards another etc. which can follow order depend on reactivity of one monomer towards another. Random polymers are continuously finding applications in the formulation industry due to their ability to improve aqueous solubility of poorly water soluble drugs. This thesis highlights my work on 1) the self-assembly of amphiphilic polymers to form micelles, 2) the application of micelles in pharmaceutical formulation, 3) the use of amphiphilic polymers as excipients, and 4) the use of random copolymers to enhance aqueous solubility of model drugs. Chapter 2 describes the synthesis of trehalose-containing amphiphilic diblock terpolymers with increasing trehalose content in the hydrophilic segment of the terpolymers. A poly(ethylene-alt-propylene)–poly[(N,N-dimethylacrylamide)-grad-poly(6-deoxy-6-methacrylamido trehalose)] (PEP-P(DMA-g-MAT)) polymer was chosen as a model system. The PEP content of the system was deliberately kept low to trigger formation of micelles in solution. PEP-P(DMA-g-MAT) successfully self-assembled into micelles in water. When incubated in various salt and serum-containing media, these micelles exhibited excellent stability from aggregation. Due to their excellent stability, these nanocarriers can be further optimized for potential systemic drug delivery applications. Chapter 3 demonstrates the effect of forming solution state polymer assemblies (prior to spray drying) on drug dissolution and supersaturation maintenance of poorly water soluble drugs. Herein, we synthesized four model polymer excipients (amphiphilic diblock ter- and copolymers): PEP-P(DMA-grad-MAG) and PEP-PDMA, and their respective hydrophilic analogues, P(DMA-grad-MAG) and PDMA. Our study clearly showed that formation of micelles prior to spray drying enhanced the dissolution of poorly water soluble drugs. Therefore, using micelle structures in excipient formulations is a simple and controlled platform for oral drug delivery. Chapter 4 describes a new synthetic platform with Trehalose-based diblock terpolymers to increase the solubility of poorly water soluble drug candidates. This study reveals that the solubility of polymer matrices in dissolution media and increase in hydrogen bonding sites in polymer matrices are critically important to decrease drug crystallinity & maintaining super saturation concentration in dissolution media. Chapter 5 presents the solubility enhancement of a highly lipophilic drug, phenytoin via interaction with poly(N-isopropylacrylamide-co-vinylpyrrolidone) (P(NIPAAm-co-VP)). Chapter 6 explains a systematic approach to understand structure-property relationships between drugs and excipients. This study illustrates that the first step to design a new excipient for a drug is to study the crystallization mechanism of that drug. When the drug crystallization mechanism is known, it is necessary to incorporate groups in the excipient formulation that can interact and interfere with the drug crystallization process to increase and maintain its aqueous solubility.
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    Design of an Oxygen-Delivering Porous Chitosan Scaffold Encapsulated in a Calcium Alginate Hydrogel for Treatment of Hypoxic Wounds
    (2018-07) Kollaja, Benjamin
    Several oxygen-delivering wound dressings have been proposed in recent literature with the aim of improving healing outcomes of chronic wounds. Oxygen generation has been achieved in numerous ways, including the incorporation of peroxide salts and perfluorocarbons (PFCs) to provide oxygen-loading capacity. Here, we have designed a multilayer wound dressing composed of chitosan encapsulated in calcium alginate, incorporating calcium peroxide and PFCs to act as oxygen-generators and oxygen shuttles, respectively. We hypothesize that the combination of oxygen-generating CaO2 and oxygen-carrying PFCs will act synergistically to improve sustained oxygen delivery to the underlying wound and thus improve healing outcomes. Oxygen generation is quantified by fluorescence microscopy using aqueous tris(bipyridine)ruthenium (II) chloride in a closed flow system.
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    Formulation Effects on Immune Response to Nanocarriers Encapsulating TLR 7 Agonist
    (2019-08) Wang, Jiawei
    Abstract Recent decades have witnessed remarkable progress in cancer immunotherapy as an approach to enhancing host immune response against cancer. Particularly, a cancer vaccine comprised of antigen, vaccine adjuvant, and delivery system has gained widespread attention, which can elicit immune response by activating dendritic cells (DCs), the critical antigen-presenting cells (APCs) 1. In the past decades, nanoformulations have gained extensive attention as drug carriers for improved cancer immunotherapy. Imidazoquinoline-based toll-like receptor (TLR) 7 agonist, imiquimod (IMQ), a cytokine inducer, could elicit DC activation. TLR7 activation stimulates myeloid differentiation primary-response gene 88 (MyD88) signaling pathways, elicit DCs to upregulate costimulatory molecules, secrete type I interferons and pro-inflammatory cytokines, and stimulate T cell- mediated immune response 2. The development of a variety of nanoformulations as drug carriers, such as polymeric poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) and liposomes, has broadened the application of TLR7 agonist in cancer immunotherapy. However, an improved understanding of how formulation factors could influence the immune response to nanocarriers encapsulating TLR 7 agonist can drive the discovery of more efficient platforms to deliver TLR 7 agonist to immune system for enhanced cancer immunotherapy. In this thesis, we encapsulated IMQ in PLGA NPs that were either naturally anionic or modified with didodecyldimethylammonium bromide (DMAB) to generate cationic surface charge. In addition, 18:0 PC 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and 1,2-dioleoyl-3-trimethylammonium-propane (chloride salt) (DOTAP) were employed to formulate IMQ-loaded anionic DSPC liposomes and cationic DOTAP liposomes. These formulations were evaluated for in vitro DC activation and antigen presentation with a model antigen, ovalbumin (OVA), using bone marrow-derived dendritic cells (BMDCs) and DC 2.4 cell line. Cell viability assay showed that PLGA NPs and DSPC liposomes showed negligible cytotoxicity on BMDCs and DC 2.4 at low concentrations, whereas DMAB-PLGA NPs and DOTAP liposomes exhibited obvious cytotoxicity at relatively low concentrations. Also, anionic PLGA NPs were superior to other nanoformulations in eliciting costimulatory molecule expression by DCs, whereas cationic DOTAP liposomes were superior in inducing antigen presentation by DCs compared with other nanoformulations. Overall, our studies demonstrated that IMQ loaded PLGA NPs showed both better biocompatibility and stronger DC activation efficacy compared with other formulations. However, further studies are needed to understand the mechanism of formulation effects on immune response to nanocarriers encapsulating TLR 7 agonist. Definitely, the development of more efficient drug delivery systems encapsulating TLR agonists could contribute to vaccine-based cancer immunotherapy.
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    Tunable Polymers as Specialized Excipients for Oral Drug Delivery
    (2016-08) Ting, Jeffrey
    For the continued advancement of modern pills and tablets in oral drug administration, spray–dried dispersions (solid–solid mixtures of amorphous drugs and polymers) have the potential to elevate poor drug solubility by orders of magnitude through drug supersaturation, thereby enhancing the therapeutic potency, oral bioavailability, and safety of accessible, lifesaving medicines worldwide. However, drug formulation efforts of these materials often employ Edisonian trial–and–error tactics with limited molecular– level understanding of the underlying interactions between polymers and drugs. Herein, a rational approach to establish fundamental structure–property relationships is presented using well–defined, modular polymer platforms. Specifically, Chapters 3–5 describes the synthesis, characterization, and performance properties of a multicomponent acrylic polymer, inspired by hydroxypropyl methylcellulose acetate succinate (HPMCAS). By strategically varying the precise monomeric incorporation, microstructure, and chemical character of these HPMCAS analogs, we systematically examined how specific polymeric attributes produce stable, amorphous spray–dried dispersions with various hydrophobic drugs at increasing drug loadings. Chapter 6 extends these ideas for precision drug formulation, a concept that specialized polymers can be judiciously constructed around drugs of high therapeutic interest. High–throughput synthesis and screening tools expedited this process, akin to molecular evolution methods in biology and genetics; in vitro and in vivo results show the remarkable versatility and ability of designer polymers to controllably solubilize drugs. Altogether, this simple but universal approach combining synthetic and predictive ingredients enables the establishment of robust guidelines to meet unfulfilled needs in the pharmaceutical landscape.