Multiple dose regimens are frequently required to optimize therapy; however, such therapy is frequently undermined by poor patient adherence. In fact, patient adherence is inversely related to the number of doses a patient is asked to take each drug. Consequently, great efforts are under way to develop drug delivery systems that are able to release drugs over an extended time interval; this could offer considerable benefits including reducing administration frequency. This dissertation describes multiple dose platforms designed to deliver a variety of drugs as a single oral administration are described in this dissertation. We believe these drug delivery systems can be used to enhance patient compliance and achieve better therapeutic outcomes. We developed and tested a novel gastroretentive pulsatile drug delivery platform. This platform could deliver multiple unit doses of a drug in a pulsatile pattern and be controlled by dissolution/erosion of a lag-time interval layer. The platform was designed to be retained in the stomach whilst pulsing drug at various timed intervals. This would allow each dose of the drug to release above or within an optimized absorption window over an extended period of time. To assure the robustness and reproducibility of the platform, various in vitro dissolution studies and physical stability tests were performed and evaluated through drug release characteristics, buoyancy, and structural integrity evaluations. The applicability of the novel multiple dose platform was demonstrated by providing repeated release profiles of ciprofloxacin and verapamil in a single, once-daily delivery system. Ultimately, this dissertation demonstrates that a novel multiple dose platform could be a suitable alternative dosing strategy for a variety of drugs to improve patient adherence and treatment efficacy. / text

Formulation intervention, through the application of processing technologies, is a requirement for enabling therapy for the vast majority of drugs. Without these enabling technologies, poorly soluble drugs may not achieve therapeutic concentrations in the blood or tissue of interest. Conversely, freely soluble and/or rapidly cleared drugs may require frequent dosing resulting in highly cyclic tissue concentrations. During the last several years, thermal processing techniques, such as melt mixing, spray congealing, sintering, and hot-melt extrusion (HME), have evolved rapidly. Several new technologies, specifically dry powder coating, injection molding, and KinetiSol® dispersing (KSD), have been adapted to the pharmaceutical arena. Co-rotating twin screw extrusion is routinely applied for the purposes of dissolving poorly soluble drugs into glassy polymers to prepare amorphous solid dispersions, which create supersaturated drug concentrations in the gastro-intestinal tract. A potentially more advantageous alternate geometry, counter-rotating twin screw extrusion was evaluated for preparation of model amorphous solid dispersion and was observed to be more efficient in forming a solid solution and reduced the thermal stress on the drug. HME and KSD processes were utilized to prepare two phase systems consisting of a lipid, glyceryl behenate, and a polymeric amorphous solid dispersion intended to provide both controlled release of drug and supersaturated drug concentrations in the release medium. Such systems are challenging due to the potential for crystallization of the drug within the dosage form during release, which was observed to be influenced by lipophilicity and porosity of the formulation, as well as the surface area to volume ratio of the system. High molecular weight cellulose based glassy dispersions were prepared using a weakly basic model drug by KSD, which when formulated into tablets were optimized to provide either immediate or approximately 2 hours of controlled release under the pH conditions simulating the environment of the stomach. Without formulation intervention in the external phase of the tablet, these compositions gel, muting drug release and missing the drug absorption window. Compositions optimized by an in vitro dissolution test were compared to a lower molecular weight HME prepared commercial product in a beagle dog model and observed to have statistically similar bioavailability, and in one case improved variability. A modified twin screw extrusion machine was utilized to develop a continuous granulation process capable of producing granules that do not require subsequent grinding or sizing. This novel process, which employs previously un-reported temperature profiles, produces lipid based granules that when compressed into tablets produce a controlled release of tramadol hydrochloride, which were not susceptible to alcohol induced dose dumping. / text

The influence of water soluble and insoluble stabilizing excipients on the physical stability of coated dosage forms was investigated in this study. The effect of the excipients on the thermal and physico-mechanical properties, and water vapor permeability of free films was studied, as was the influence of these excipients on the physical stability and release kinetics of coated pellets. The effect of water-soluble proteins, bovine serum albumin (BSA) and Type B gelatin, on the physical aging of Eudragit[trademark] RS/RL 30 D films was investigated. It was found that ionic interactions occurred above the isoelectric point of BSA and caused unstable films which showed accelerated decreases in drug release rate. The adjustment of the pH of the dispersion below the isoelectric point of BSA resulted in electrostatic repulsive charges that stabilized the drug release rate from coated dosage forms at both ambient and accelerated conditions. The addition of gelatin to the coating dispersion increased the drug release rate due to the formation of gel-domains through which the drug was able to easily diffuse. The influence of silicon dioxide on the stability of Eudragit[trademark] RS/RL 30 D films was investigated. Colloidal grades showed enhanced incorporation in the acrylic matrix; however, unstable films were formed. The addition of silicon dioxide with a larger particle size increased the permeability of the film and stabilization in drug release rate was attributed to constant water vapor permeability values of free films. The influence of ethylcellulose on the physical aging of Eudragit[trademark] NE 30 D coated pellets was studied. The two polymers were found to be substantially immiscible and the drug release rate of coated pellets was constant at both ambient and accelerated conditions which correlated to stabilizations in both the physico-mechanical properties and water vapor permeability of free films. Blending both Eudragit[trademark] NE 30 D and RS 30 D resulted in the formation of coherent films without the need of plasticizer. The two polymers were found to be miscible and both films and coated dosage forms were stable when stored below the glass transition temperature of the polymer blend. When films were stored above this temperature, instabilities occurred as a result of the further coalescence and densification of the polymer blend.

Thesis (MTech. degree in Pharmaceutical Sciences)--Tshwane University of Technology, 2010. / Investigates the absorption enchancing properties of N-trimethyl chitosan chloride (TMC) and monocaprin (MC), individually and in combination, on the permeability of insulin across the Caco-2 intestinal epothelial cell line.

I developed a system to release multiple growth factors from PEGylated fibrin gels with varying profiles to induce vasculogenesis from embedded human MSCs. Zero-order release can be obtained by conjugating a growth factor with a homobifunctional, amine-reactive, PEG derivative. Growth factors can be entrapped during thrombin-mediated crosslinking and released rapidly. Growth factors with physical affinity for fibrinogen or fibrin can be sequestered within the matrix and released via degradation and/or disassociation. PDGF-BB was loaded via entrapment while TGF-β1 was sequestered through a combination of physical affinity and conjugation. The affinity of TGF-β1 and fibrinogen had never been previously examined or quantified. I aimed to determine the Ka and Kd between TGF-β1 and fibrinogen through a variety of assays. Binding ELISAs were developed for TGF-β1 and fibronectin, a protein associated with fibrin gels, and TGF-β1 and fibrinogen. However, background was high due to insufficient blocking agents. Other assays explored included western blots, surface plasmon resonance, and radiolabeled TGF-β1 with limited success. The affect of TGF-β1 on human MSC differentiation towards vascular cell phenotypes was examined both in 2D and fibrin gels embedded with MSCs. With exposure to TGF-β1, MSC proliferation was significantly inhibited in both 2D and within fibrin gels indicating that loaded TGF-β1 maintained bioactivity for at least 7 days. Gene expression of MSCs exposed to TGF-β1 demonstrated inhibited endothelial cell differentiation and stimulated smooth muscle cell differentiation. However, confocal and light microscopy indicated that endothelial cell differentiation is maintained with TGF-β1 loaded PEGylated fibrin gels. The system developed is highly modular and can be applied to other tissue engineering systems. Furthermore, other growth factors could be incorporated to promote vascular cell differentiation. / text

Η παρούσα εργασία μελετά την ανάπτυξη ενός ευέλικτου συστήματος αντιμικροβιακής προστασίας για εφαρμογή σε είδη ρουχισμού και υφάσματα οικιακής χρήσης. Πιο συγκεκριμένα αναπτύχθηκαν διασυνδεδεμένα πολυμερικά νανοσφαιρίδια πολυστυρολίου-διβινυλοβενζολίου στα οποία ενσωματώθηκε Triclosan, μία ευρέος φάσματος εμπορική αντιμικροβιακή ουσία. Σημειώνεται ότι στο πλαίσιο ανάσχεσης των ενδονοσοκομειακών λοιμώξεων η ανάπτυξη αντιμικροβιακών νοσοκομειακών στολών, σεντονιών και άλλων σχετικών κλωστοϋφαντουργικών προϊόντων αποτελούν τις τελευταίες δεκαετίες αντικείμενο έντονου επιστημονικού ενδιαφέροντος. Το μέγεθος των νανοσωματιδίων βρέθηκε μετά από εξέταση με ηλεκτρονική μικροσκοπία σάρωσης (SEM) και δυναμική σκέδαση φωτός (DLS) να κυμαίνεται μεταξύ 35-350 nm ανάλογα την σύσταση. H θερμική συμπεριφορά τους μελετήθηκε μέσω διαφορικής θερμιδομετρίας σάρωσης (DSC) και διαπιστώθηκε σημείο τήξεως στους ~425 οC. Χρησιμοποιώντας την φασματοσκοπία UVVis προσδιορίστηκε ο πραγματικός εγκλωβισμός του αντιμικροβιακού στο σύστημα κατά μέσο όρο σε ποσοστό ~72% του ονομαστικού και παρακολουθήθηκε ο ρυθμός αποδέσμευσης του σε διαλύματα αιθανόλης-νερού. Επιπλέον, τα σφαιρίδια που όπως διαπιστώθηκε παρουσιάζουν χαρακτηριστικά ελεγχόμενης αποδέσμευσης ενσωματώθηκαν σε μήτρες πολυπροπυλενίου οι οποίες υπό την μορφή φιλμ εφελκύστηκαν μονοαξονικά. Τέλος κάνοντας χρήση της δονητικής φασματοσκοπίας Raman εκτιμήθηκε ο μοριακός προσανατολισμός που επιβλήθηκε στα εφελκυσμένα φιλμ και συσχετίσθηκε με την παρατηρούμενη μείωση που επιτεύχθηκε στην κινητική αποδέσμευσης της εγκλωβισμένης δραστικής ουσίας. Το πρώτο κεφάλαιο της παρούσας εργασίας ασχολείται με το πρόβλημα της μικροβιακής επιμόλυνσης υφασμάτων, τις διάφορες λύσεις που έχουν προταθεί κατά καιρούς και τέλος αναλύει τον στόχο της παρούσας εργασίας. Στο δεύτερο κεφάλαιο επεξηγείται η έννοια της ελεγχόμενης αποδέσμευσης και περιγράφονται οι διάφορες κατηγορίες συστημάτων ελεγχόμενης χορήγησης μαζί με χαρακτηριστικά παραδείγματα. Τα νανοσωματίδια, η σύστασή, οι μοναδικές ιδιότητες, οι εφαρμογές και οι διάφοροι τρόποι σύνθεσης και χαρακτηρισμού τους συζητούνται στο τρίτο κεφάλαιο. Το τέταρτο κεφάλαιο αναφέρει πληροφορίες για τα υλικά και επεξηγεί τις τεχνικές που χρησιμοποιήθηκαν στην σύνθεση, την επεξεργασία και τον χαρακτηρισμό των νανοσωματιδίων και των μιγμάτων τους. Τέλος στο πέμπτο κεφάλαιο παρουσιάζονται τα αποτελέσματα των πειραμάτων που πραγματοποιήθηκαν και ακολουθεί ο σχολιασμός τους. / The present thesis studies the development of a versatile system of antimicrobial protection for use in clothing and household products. In particular Triclosan incorporated crosslinked polystyrenedinylbenzene nanobeads were developed; triclosan is a widely used antimicrobial agent. It is noted that the health hazards arising during nosocomial treatment due to infections caused by microbial pathogens and the means to protect oneself against such threats have become the subject of many research activities during the last few decades. The size of the nanoparticles after examination with scanning electron microcopy (SEM) and dynamic light scattering (DLS) was found to vary between 35-350 nm depending on the system formulation. Their thermal behavior was studied with differential scanning calorimetry (DSC) and their melting point was measured at ~425 oC. Using UV-Vis spectroscopy the real encapsulation efficiency of the antimicrobial in the system was determined at ~72% and its release kinetics were studied in a water-ethanol solution. The nanobeads possess controlled release properties; they were furthermore incorporated into polypropylene matrixes which were uniaxially drawn in film form. Finally utilizing polarized Raman spectra, the draw induced molecular orientation of the films was correlated to the relevant variation of the related antimicrobial release kinetics. The first chapter of the present thesis reviews the textile microbial infections and the various solutions that have been proposed showing up the specific research goal targeted. In the second chapter the meaning of controlled release is explained and the basic system categories involved are presented along with characteristic examples. The nanoparticles, their composition, special attributes, applications, synthesis and characterization techniques are the subject of the third chapter. The fourth chapter reports information about the materials and the methods used in the synthesis, postprocessing and characterization of the nanoparticles and their blends. Finally the last chapter presents the experimental results and relevant comments.

No description available.

Bone defects treatment and reconstructive surgery continues to increase at a significant rate. Current bone defect treatments are autotransplantation, allograft, and xenografts create many problems such as, inflammation, infection and chronic pain. Moreover, allografts and xenografts arouse immune rejection. These problems have led to development of controlled release system for use as alternatives to autografts, allografts and xenografts in bone repair. There have been many approaches for sustained drug delivery in local bone regeneration using biodegradable polymers and osteotropic biomolecules. This dissertation presents new approaches that apply intermittent drug delivery for local bone regeneration. In the first, the osteotropic molecules simvastatin (Sim) or parathyroid hormone (PTH) were released with intermittent profiles. In the second, alternating delivery of Sim and PTH as well as alternating release of the antimicrobial agent cecropin B (CB) with Sim or PTH. An association polymer system of cellulose acetate phthalate (CAP) and Pluronic F-127 (PF-127) was used for the delivery vehicle. Each device showed discrete peaks in release profiles and lasted more than 10 days. Release profiles could be controlled by altering surface area exposed to aqueous environment, number of layers, loading, and blending ratios. Cells were cultured with sustained or intermittent exposure to Sim or PTH at various concentrations, and alternating exposure to CB and Sim or PTH and to Sim and PTH at different concentrations. Low dose Sim and PTH treatments stimulated higher osteoblastic activity than observed in control cultures. Furthermore, intermittent delivery was more effective than sustained exposure. In vivo, newly formed bone was found in animals implanted with both blank Sim-loaded devices. However, a greater anabolic effect was seen for Sim release devices. Further, intermittent release devices stimulated the greatest woven bone thickness, total bone area, and lamellar bone area. These results suggest that intermittent release devices containing a single molecule, Sim or PTH, and alternating release devices containing multiple molecules, CB with Sim or PTH, possess promising potential as a treatment for local bone regeneration.

Spinal fusion is used to treat diseases or disorders of the spine by fusing together two or more vertebrae. Two associated risks with spinal fusion are infection and blood loss. Administration of tranexamic acid is used to prevent blood loss, and transfusions are given following blood loss. Surgical site infections are prevented with vancomycin powder spread into the surgical wound, while established infections are treated by debridement and delivery of antibiotics for 4 to 6 weeks. The present research explored an alternate method to prevent and treat blood loss or infection in spinal fusion. Poly(lactic-co-glycolic acid) (PLGA) microspheres was used to encapsulate vancomycin for 42 days to treat infection. Vancomycin encapsulated in gelatin microspheres had a controlled release of 7 days to prevent infection. Tranexamic acid was dissolved into phosphate-buffered saline or carboxymethylcellulose to provide a release of 6 hours to prevent blood loss after surgery. The microspheres and tranexamic acid were delivered to a target region using a water based spray system. The spray system demonstrated the delivery and distribution of drugs to a target region. The microsphere spray system is capable of spraying drugs onto a target region to prevent or treat blood loss and infection over time.

Diabetes has become a nationwide epidemic affecting 18.2 million Americans, and the incidence is expected to increase 122% by the year 2025. The dyslipidemia associated with type 2 diabetes—low HDL-C; high TG; and small, dense LDL-C—contributes to the 2 to 4 times greater risk of individuals with diabetes to have a major cardiovascular event. Niacin, a B vitamin, and aerobic exercise have been shown separately to favorably alter the lipid profile. The present study examined a combination therapy of Niaspan®, an extended-release formulation of niacin, and 16 weeks of aerobic exercise in 23 individuals with type 2 diabetes. The dosage of Niaspan® began at 500 mg/day and increased 500 mg/day every 4 weeks up to a maximum dose of 2000 mg/day. Subjects were advised to gradually progress their frequency, intensity, and duration of aerobic exercise until they were expending at least 1500 kilocalories by week 8. Subjects were instructed to make no changes to their diet or diabetes medication regimen. Lipoproteins and subfractions and selected measures of physical fitness were examined before and after the 16 week intervention. Following the 16 week intervention period, there were significant changes (p<0.05) in HDL-C (+28%), TG (-19%), VLDL-C (-12%), and LDL-C (-9%). There were also significant changes in the larger, more buoyant subfractions HDL2 (+48%), VLDL2 (-15%) and LDL1 (-48%). Other subfractions that are smaller and more dense also changed favorably: HDL3 (+24%) and LDL4 (-15%). Although there was no significant weight loss in this population as a result of the intervention, there were significant changes in submaximal heart rate (124.9±17.6 vs. 116.7±16.3 bpm) and resting systolic (136.8±17.5 vs. 128.3±13.8 mmHg) and diastolic (80.3±12.5 vs. 73.2±9.8 mmHg) blood pressure, adaptations that occur with improvement in physical fitness. There were no changes in fasting plasma glucose or glycosylated hemoglobin, contradicting any deterioration in glucose control. Therefore, the combination of Niaspan® and aerobic exercise is effective at altering the lipid profile in individuals with type 2 diabetes. In addition, this intervention is safe in that it does not adversely affect glucose control. / School of Physical Education, Sport, and Exercise Science