The poor response of patients to high-dose chemotherapy commonly associated with the treatment of solid tumors has led to research efforts in the development of implants for the delivery of drug directly to solid tumors. In order to prevent surgical complications associated with the placement of an implant at the site of the tumor, efforts have been made to develop implants which form at the site of the tumor. This study aimed to develop an In Situ Forming Implant (ISFI) which was responsive to temperature and able to form an implant when injected into the body and to release drug over a period exceeding one month. To this end, a thermoresponsive polymer, poly(methyl vinyl ether) was selected and following preformulation studies to assess release and gelation temperature, a Design of Experiments approach was utilised to formulate an optimal formulation. Fourteen formulations were prepared according to a Face-Centred Central Composite Design selected and were assessed for gelation temperature, ease of injectability and Mean Dissolution Time. Utilising the experimental values obtained, regression models for each of the outcomes were generated. The optimal formulation was then determined by selecting the appropriate targets for each of the responses in the design. The optimal formulation was able to gel at body temperature, could be injected into the body and showed release of entrapped chemotherapeutic, methotrexate for a period exceeding one month. pH-responsive microparticles were also formulated and optimized using a Face-Centred Central Composite Design. Optimized particles were then loaded into the optimized ISFI and displayed faster release of the entrapped drug than with the dispersed drug. In vitro testing of the ISFI was conducted against solid tumor forming cells and in vivo testing was conducted in healthy Sprague-Dawley rats. A few rats developed toxicity to methotrexate after 6 days, however, low quantities of drug were found in the plasma. In addition, drug was present in the surrounding tissue in a high concentration even after 10 days.

Thesis (M.Pharm.)--University of the Witwatersrand, Faculty of the Health Sciences, 2013. / The oral route presents the most convenient, least invasive and thus the most widely used route for the administration of drugs but displays inherent impediments, related to both the drugs used and the gastrointestinal tract itself, resulting in diminished bioavailability of drugs. Additionally, development of new drug molecules is difficult, expensive, time-consuming and their approval and success is not guaranteed. Development of novel controlled Multiparticulate Oral Drug Delivery Systems (MODDS) aims to address these issues by employing existing drugs and enhancing their oral bioavailibility and safety, thus improving clinical efficacy in many disease states. Multiparticulate drug delivery systems are specialized controlled drug delivery systems that comprise of many discrete units, each loaded with a fraction of the total dose and each possessing the ability to release entrapped drug independently, thus preventing dose dumping and allowing diverse applications within a single dosage form. However, novel drug delivery systems possess disadvantages in that they may be expensive, difficult to reproduce on a large-scale and frequently use synthetic polymers that may not be disintegrated nor excreted to a sufficient extent in vivo. Starch, a natural polymer, is widely available, inexpensive, and biocompatible and can be modified in various ways. Starch is thus available in several forms and compositions, including commercial multiparticulates, allowing it to be used for the development of an effective controlled MODDS. The essential aim of the study was to functionalize the inert, inexpensive, commercially available, food-grade multiparticulates derived from sago or tapioca starch and employ the multiparticulates as a Starch-Based Platform (SBP) in a MODDS. Following characterization of both starch-based multiparticulates, the sago multiparticulates were selected as the SBP and preliminary optimization of drug entrapment employing diphenhydramine (DPH) as the model drug was conducted using a Box-Behnken experimental design. The pre-optimized formulation displayed superior Drug Entrapment Efficiency (DEE= 59.354%, R2=0.9257 when compared to the predicted DEE), but demonstrated poor control of drug release. Thus, alternate drugs displaying varying physicochemical characteristics were evaluated and sulfasalazine (SSZ) was ultimately selected as the model drug for the study. Various modifications of the SBP were attempted with epichlorohydrin-facilitated crosslinking followed by SSZ loading and finally secondary epichlorohydrin crosslinking conferring the best control of drug release coupled with satisfactory drug entrapment and excellent SBP structural stability. The formulation procedure was optimized using a Face Centered Central Composite Design by evaluating the effects of varying the drug loading time (DLT) and secondary crosslinking time (CLT) on the responses of DEE and Mean Dissolution Time (MDT). The optimum formulation conditions was established as DLT=8 hours and CLT=8 hours with predicted DEE and MDT of 40.78% and 171.696 minutes, respectively. Formulation, scaling up and analysis of the optimized SBP revealed that gelatinization and crosslinking had occurred throughout the SBP resulting in incorporation of SSZ into the structure of the SBP, both at the surface and at the core of the SBP. Experimental DEE values for the optimized and scaled-up formulations demonstrated close correlation to the predicted DEE with R2 values of 0.9813 and 0.9893, respectively. The modifications imparted during optimization caused coalescence of the surface starch granules and resulted in a decrease in surface area and porosity of the SBP. This in turn affected the drug release resulting in MDT values of 163.972 and 166.011 minutes, which translated into R2 values of 0.9550 and 0.9669 for the optimized and scaled-up formulations, respectively. Drug release from the optimized SBP formulation was found to fit the Higuchi model best with Quasi-fickian diffusion occurring in simulated gastric fluid and anomalous drug transport in simulated intestinal fluid resulting in an overall anomalous drug transport mechanism of drug release. In vivo SSZ release throughout the gastrointestinal tract was determined directly by measuring plasma SSZ concentrations and indirectly by measuring the plasma concentrations of 5-Acetyl Salicylic Acid (5-ASA) and N-Acetyl-5-ASA and displayed general correlation to the in vitro SSZ behavior determined previously. Furthermore, the in vivo SSZ release of the optimized SBP formulation was compared to a conventional commercially available SSZ formulation, Salazopyrin® with the optimized SBP formulation displaying superior SSZ release characteristics and a vast improvement in the bioavailability of SSZ compared to Salazopyrin®.

The oral delivery of drugs has several disadvantages, particularly in pediatrics, geriatrics and other patients experiencing difficulty in swallowing tablets or capsules. A frequent approach to this problem is the use of liquid formulations or buccal drug delivery systems. However, with liquid formulations, many drugs have an undesirable solubility or stability in appropriate solvents and dosing accuracy is compromised due to the patient being required to measure doses. Current rapidly disintegrating buccal drug delivery systems, such as buccal tablets, are able to dissolve rapidly within the oral cavity; however the short residence time at the absorption surface is a limiting factor in the effectiveness of these delivery systems. Furthermore, buccal tablet and wafer systems tend to be brittle and fragile and hence require special protective packaging. A rapidly disintegrating, flexible, mucoadhesive fibrous matrix system (FMS) with drug-loaded electrospun fibers incorporated onto a polymeric backing film may be capable of overcoming some of the innate disadvantages of the non-invasive delivery of various drugs, especially those requiring a rapid onset of action. Various electrospinnable polymers were investigated for suitability in the development of the electrospun fibrous layer of the FMS, and it was determined that polyvinylalcohol (PVA) produced drug-loaded fibers with the most acceptable morphology and a desirable disintegration time. An ideal drug-loaded fiber formulation was obtained by design of experiments and employed in further investigations. The original model drug, zidovudine (AZT), exhibited less than 1% permeation after 90 minutes. Permeation was not adequately increased by penetration enhancers, and AZT was therefore tested against diphenhydramine (DPH), which exhibited 42-82% permeation after 5 minutes. The polymeric backing film layer was developed by investigating various film-forming polymers and methods of film or membrane preparation. Acceptable films were produced by film-casting of solutions containing combinations of PVA and hydroxypropylmethylcellulose (HPMC), and variables for an Experimental Design were obtained. The variables were fill volume (40-100mL), HPMC concentration (0-0.5%w/v) and concentration of glycerol (10-15%w/w of total polymer mass). The film layer was optimized according to a Box-Behnken experimental design, employing the responses disintegration time, work of adhesion, maximum detachment force, dissolution and ex vivo permeation. In vitro physicochemical and physicomechanical characterization, as well as ex vivo analysis, was performed on the optimized FMS in order to assess the suitability of the system for rapid oramucosal drug delivery. The FMS was deemed to be suitable for buccal drug delivery and able to overcome some of the inherent limitations of current drug delivery systems.

An oral proteomatrix drug delivery platform was formulated using pH responsive biostable polymers for slow release kinetics for the treatment of the neurodegenerative disease, multiple sclerosis (MS), which was the primary aim. After successful design and optimization for utilizing this system for MS, this system was further applied as a versatile platform for oral protein delivery. Interferon beta (INF- ) was selected as the oral treatment for MS. The fundamental effect of INF- in the treatment of MS is based on reducing the immune response that is directed against central nervous system myelin, i.e. the fatty sheath that surrounds and protects nerve fibers. Damage of nerve fibers, resulting in demyelination, consequently causes nerve impulses to be slowed or halted, thus producing symptoms of MS (Jongen et al., 2011). To date, INF- is effectively being used to treat MS subcutaneously or as intramuscular injections. These forms of administration have commonly been associated with multiple problems of pain, allergic reactions, poor patient compliance and chances of infection (Chiu et al., 2007). It was thus concluded to design an oral platform for the delivery of multiple protein therapeutic formulations. To prove the versatility of the proteomatrix system, two other demanding protein therapeutics for oral delivery, insulin and erythropoietin, were selected for further in vitro Box-Behnken series of formulations and in vivo analysis. By administration of these oral protein systems, a greater patient compliance can be achieved, thus enhancing the therapeutic profiles of patients with conditions of MS, diabetes and chronic renal failure resulting in chronic anemia. All studies consisted of in vitro drug release studies, characterization using specific analytical techniques for testing the mechanical properties, as well as the physicochemical characteristics of the copolymeric system. All proteins, INF- , insulin and erythropoietin, were analyzed in vivo using New Zealand White rabbits (NZW) with determination of the protein from serum obtained during regular blood sampling intervals.

Thesis (M.S.)--Boston University

Oral delivery of drugs is inundated by formulation challenges predominantly due to poor physicochemical properties of chemical entities resulting in anomalies in serum levels and inconsistent pharmacokinetics and pharmacodynamics. Similar challenges exist for nutraceutical products however, there has been a recent shift in research paradigms towards novel formulation strategies to render these agents invaluable complementary treatments. In this view, vitamin D has gained interest, however it’s effective therapeutic use is limited by low aqueous solubility, erratic inter-patient response, and inadequate formulation design. Cholecalciferol (D3), being a potent form of the vitamin, is widely supplemented and prescribed and was selected as the model agent for proof of concept in the design of a novel oral Drug Delivery System (DDS) in the current research. An ideal physiological milieu is often essential for intended performance of even advanced DDS’s. GIT topology may have an even greater impact on modified dosage forms compared to conventional dosage forms. The use of absorption and solubility enhancers is a tried and tested formulation strategy to improve bioavailability and efficacy of drugs with unfavourable physicochemical characteristics. Despite being an integral part of modern formulation design, these bioenhancers may prove only marginally effective in oral delivery unless the physiological state is considered during formulation. It was therefore imperative that the DDS designed in this investigation included measures to mitigate this effect and achieve robust efficacy regardless of the dynamic GIT condition. In addition, most nutraceuticals typically occur as multicomponent products, yet different combined BCS class vitamins may encounter erratic absorption due to differences in solubility and flocculation effects that impede dispersion in aqueous media. It is therefore imperative to formulate and evaluate a DDS containing more than one nutraceutical agent for greater “real-world” relevance instead of a single vitamin DDS formulation that has been pursued in past studies. The current work therefore set out to develop a DDS capable of orally delivering multiple nutraceutical actives and biological constituents from a single formulation framework with modifiable release kinetics and a unified release of synergistic vitamins, with D3 as the focus agent for enhanced oral bioavailability. Few researchers have investigated the use of multiple biological enhancers combined with synthetic carriers in a dosage form to aid nutraceutical delivery

Zeolites and mesoporous silica were used as drug delivery systems for the loading and release of small drug molecules, aspirin and 5-fluorouracil. Different parameters were varied such as aluminum content in the zeolite, effect of distribution of functional groups and the method of surface modification in case of mesoporous silica. The effect of the aforementioned variables was studied on drug loading and release from these microporous and mesoporous systems. The drug loaded materials were extensively characterized using various physical techniques such as powder X-ray diffraction, nitrogen isotherms, infrared spectroscopy, solid state NMR and thermogravimetric analysis. Quantum calculations and molecular dynamics simulations were performed in order to validate the experimental data and also to obtain a molecular level insight of the drugs inside the pores of the host materials. Drug templated synthesis of mesoporous silica was also carried out in the presence of aspirin as the template. The aspirin templated material was characterized by aforementioned techniques and showed a sustained drug release profile.

SDM is a process model, based on service marketing components, to position a service while concurrently being a service delivery management tool improving serviceen counter processes. Added to a service script, SDM can increase customer satisfaction, quality perception, voice levels and repurchase intentions in a general service encounter scenario as well as during episodes which include a failure. Addressing mishaps requires particular attention, since Consumer Complaint Behaviour research shows that most customers prefer to switch suppliers, rather than offer constructive feedback. This means that many service failures go unnoticed, with a large proportion of customers defecting. Since most services are performed in real time by service personnel, consistent quality output is a challenge. Therefore, occasional service failures are inevitable. Present research recognises this by offering suggestions, but does not present an integrated framework like SDM, using the presence of a customer during a service encounter as an unique opportunity to resolve issues on the spot. An elicitation process is used as a first step, attempting to improve voice and minimising lost feedback. Step two is a specific service recovery process, adapted to the failure type. SDM processes can also lead to a general increase of satisfaction and quality perception, regardless of whether or not there was a service failure. With satisfaction generally being regarded as an actual repurchase behaviour indicator, this may lead to increased sales turnover, while a higher quality perception may lead to a larger price premium tolerance and therefore higher profits. Higher service quality perceptions can also be used as a marketing positioning tool to differentiate a service from competitors. Data collected supported all hypotheses put forward in this thesis, showing statistically significant improvements on all key variables, including a satisfaction rating increase of 24percent when SDM was applied. In academic terms, the process model tested did not only link separate literature streams, but offered an integrated, proactive tool which is capable of operating in real time. Traditionally, academic models and their processes analyse results after an episode concludes, while SDM allows a provider to positively influence or manage satisfaction levels during the service delivery.

Thesis (Ph. D.)--University of Hong Kong, 2007. / Also available online.

Thesis (Ph. D.)--University of Hong Kong, 2007. / Title proper from title frame. Also available in printed format.