Graduation date: 1996

The topical application of many substances, including drugs, enzymes, moisturizers and fragrances, contributes largely to the cosmetic and pharmaceutical industries. These components are often volatile in nature and dissipate in a matter of hours. When considering the different types of slow release systems, an overwhelming variety of these systems is available. Each one of the systems is unique in a way, and is designed to perform a particular function, whether it facilitates the controlled release of an active into the body via the skin surface (transdermal delivery) or whether it reduces the rate of loss of an active from the skin surface to the surrounding environment. For the purpose of this study, a previously existing fixative formulation which is believed to reduce the rate of loss of an active component to the environment, through film formation on the skin surface, was investigated. Alternative ingredients or components were incorporated together with the original fixative formulation ingredients into an experimental design which investigates the effect of each group of the components present. 18 formulations with various concentrations of the components within the groups and specified upper and lower limits for each component were formulated. The fixative properties of the formulations were analysed through the incorporation of a fixed amount of a simple fragrance molecule, 4- methoxybenzaldehyde, into each formulation and evaporation studies were conducted in an environmental room at 28±1° C over a period of 5 hours followed by gas chromatography analysis and finally data analyses using statistical methods. The most efficient fixative formulation was established using regression analysis. The fragrance compound in this formulation was found to evaporate at a rate of 0.47 g/L per hour. The least efficient fixative formulation lead to the loss of 0.78 g/L of the fragrance component per hour. From the calculated fragrance concentrations, the rate constant for each individual fixative formulation could be calculated and response surface 8 modelling by backward regression was used in order to determine how each component contributes to the rate of loss of the fragrance compound. Since the sum of the original ingredient and its alternative was constant, each of the original ingredients was coupled directly to its alternative and no conclusion could be made about the contribution of individual components. By increasing the concentration of Hydroxypropylcellulose (HPC) 100K and its alternative HPC 140K, while keeping the effects of the other components constant, a decrease in the rate of fragrance loss was observed. The same conclusion could be made when increasing the concentrations of PEG-12 Dimethicone and its alternative cetyl dimethicone (decreases the evaporation rate). An interaction took place between HPC 100K and PEG-12 dimethicone and their alternatives. The negative effect was, however, not as strong as the combined positive effect on the rate of fragrance loss of the individual components HPC and PEG-12 dimethicone. Evidence suggested that the removal of the components polyvinylpyrrolidone and its alternative, polyurethane-32 (Baycusan® C1003), would improve the effectiveness of the fixative formulation in terms of its slow release properties. A confirmation experiment established that the exclusion of these components from the fixative formulation does improve the “slow release” properties thereof. A larger, more intricate design is required to investigate the effect of each one of the individual components and where the sum of the components (original and its alternative) is not constant.

Controlled release formulations deliver an active ingredient over an extended period of time. It is an ideal dosage form for an active ingredient with a short elimination half-life. An active ingredient with a short elimination half-life would be released in small portions over an extended period of time and thus less frequent administration is necessary and this improve patient compliance. Other advantages of these formulations include: decreased side effects, constant drug levels in the blood, improvement in treatment efficiency and reduction in cost of administration. Controlled release beads are formulated in such a way that the active ingredient is embedded in a matrix of insoluble substance like chitosan; the dissolving drug then has to find its way through the pores of the matrix into the surrounding medium. The chitosan matrix swells to form a gel, the drug then has to first dissolve in the matrix and diffuse through the outer surface into the surrounding medium. Chitosan is a biocompatible, biodegradable polymer of natural origin. It has mucoadhesive properties as well as the ability to manipulate the tight junctions in the epithelium membrane and these properties have qualified chitosan as an effective drug carrier in controlled release dosage forms. The effect of a modern controlled release polymer namely Kollidon® SR in combination with chitosan on drug release was investigated. Ketoprofen was chosen as model drug. Ketoprofen is an anti-inflammatory drug that causes gastrointestinal side effects in conventional dosage forms. Ketoprofen has a short elimination half-life of 2.05 ± 0.58 h and this characteristic makes it an ideal candidate for use in a controlled release formulation. The aim of this study was to achieve controlled release and minimize gastrointestinal effects of ketoprofen with chitosan particles. Kollidon® SR was used as polymer because it exhibits pH independent release characteristics and previous studies have shown potential for this combination. Chitosan beads and chitosan-Kollidon® SR beads, as well as chitosan granules and chitosan-Kollidon® SR granules, were prepared and investigated as potential controlled release formulations. Chitosan beads were prepared through the inotropic gelation method using tripolyphosphate as a cross linking agent. Granules were prepared through wet granulation using 2% v/v acetic acid as the granulating fluid or by dissolving ketoprofen in ethanol and Kollidon® SR in 2-pyrrolidinone and using the solution as granulating fluid. Kollidon® SR was added in concentrations of 0.25, 0.5 and 1% (w/v) in the bead formulations and concentrations of 1, 5 and 10% (w/w) in the granule formulations. The beads and granules were characterised by evaluating the following properties: morphology, drug loading and drug release. Additionally swelling and friability tests were also conducted on the bead formulations. The cross linking times of the bead formulations were varied to investigate the effect of cross linking time on the characteristics of the beads. Chitosan-Kollidon® SR beads showed promising results for controlled release formulations and ketoprofen were released over an extended period of time. Drug loading of the plain chitosan beads was 74.65 ± 0.71% and it was noted that the inclusion of Kollidon® SR in the beads resulted in an increase in drug loading and the formulation containing 1% (w/v) Kollidon® SR, cross linked for 30 minutes had a drug loading of 77.38 ± 0.01%. Drug loading of the beads that were cross linked for a longer time were slightly lower which is an indication that some of the drug might have leached out during cross linking. The degree of swelling was promising with some beads swelling to a degree of 2.5 in phosphate buffer solution pH 5.6. Granules had a drug loading between 81.73 ± 1.53% and 93.30 ± 0.50%. Ketoprofen release from the beads and the granules in PBS pH 7.40 at 37 °C over a period of 6 hours were investigated. The bead formulations were more effective in achieving controlled release and it was noted that the bead formulations that was cross linked for a longer period was more efficient in achieving controlled release. The granules did not form a matrix and were not effective in achieving controlled release. Controlled release of ketoprofen were achieved and the results show potential for chitosan-Kollidon® SR formulations in the future. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

Monodispersed nanoparticles of poly-N-isopropylacrylamide-co-allylamine (PNIPAM-co-allylamine) and PNIPAM-co-acrylic acid (AA) have been synthesized and used as building blocks for creating three-dimensional networks. The close-packed PNIPAM-co-allylamine and PNIPAM-co-AA nanoparticles were stabilized by covalently bonding neighboring particles at room temperature and at neutral pH; factors which make these networks amicable for drug loading and release. Controlled release studies have been performed on the networks using dextran markers of various molecular weights as model macromolecular drugs. Drug release was quantified under various physical conditions including a range of temperature and molecular weight. These nanoparticle networks have several advantages over the conventional bulk gels for controlling the release of biomolecules with large molecular weights. Monodispersed nanoparticles of poly-N-isopropylacrylamide-co-allylamine (PNIPAM-co-allylamine) can self-assemble into crystals with a lattice spacing on the order of the wavelength of visible light. By initiating the crystallization process near the colloidal crystal melting temperature, while subsequently bonding the PNIPAM-co-allylamine particles below the glass transition temperature, a nanostructured hydrogel has been created. The crystalline hydrogels exhibit iridescent patterns that are tunable by the change of temperature, pH value or even protein concentration. This kind of soft and wet hydrogel with periodic structures may lead to new sensors, devices, and displays operating in aqueous solutions, where most biological and biomedical systems reside. The volume-transition equilibrium and the interaction potential between neutral PINPAM particles dispersed in pure water were investigated by using static and dynamic light-scattering experiments. From the temperature-dependent size and energy parameters, the Sutherland-like potential provides a reasonable representation of the inter-particle potential for PNIPAM particles in swollen and in collapsed phases. An aqueous dispersion of PNIPAM particles can freeze at both high and low temperatures. At low temperatures, the freezing occurs at a large particle volume fraction, similar to that in a hard-sphere system; while at high temperature, the freezing occurs at low particle concentrations, driven by the strong van der Waals attraction due to the collapsed microgel particles. The calculated phase diagram has been confirmed semi-quantitatively by experiments.

A papaína é uma enzima proteolítica extraída do látex das folhas e frutos do mamão verde adulto. Tem sido amplamente utilizada como agente debridante de escaras e cicatrizante de feridas. No entanto, apresenta baixa estabilidade, o que limita seu uso a formulações de manipulação extemporânea ou de curto prazo de validade. O objetivo deste trabalho foi incorporar a papaína em uma matriz polimérica de modo a obter um sistema de liberação controlada do fármaco. Polímeros de aplicação médica foram selecionados e inicialmente avaliados quanto à sua citotoxicidade. Os polímeros não-citotóxicos foram submetidos ao ensaio de irritação cutânea primária in vivo em animais, para avaliar sua capacidade de causar irritação na pele humana. Diversas membranas foram preparadas com os polímeros considerados adequados para aplicação biomédica para incorporação da papaína. As membranas preparadas com 2% de papaína foram selecionadas para serem submetidas ao ensaio de liberação com células de difusão de Franz. Parte dessas membranas foi irradiada com raios γ na dose de 25 kGy para esterilização do material. As membranas irradiadas e não-irradiadas foram testadas simultaneamente a fim de verificar se a radiação γ interferiria no perfil de liberação do fármaco. Os resultados do ensaio de liberação indicaram que o fármaco é liberado de maneira constante durante as 12 horas iniciais do experimento. A análise, por Microscopia Eletrônica de Varredura, das membranas irradiadas revelou que as membranas formadas são bastante densas e que seus poros são pequenos. / Papain is a proteolytic enzyme extracted from the latex of green papaya leaves and fruits. It has been widely used as debridant for scars and wound healing agent. However, papain presents low stability, which limits its use to extemporaneous or short shelf life formulations. The purpose of this study was to entrap papain into a polymeric matrix in order to obtain a drug delivery system. Polymers of medical application were selected and firstly assessed for cytotoxicity. Non-cytotoxic polymers were evaluated for primary cutaneous irritation test in vivo in animals, in order to verify if they are able to cause irritation to human skin. Many membranes were prepared with the polymers considered suitable for biomedical application for papain entrapment. Membranes containing 2% papain were selected to be evaluated in the releasing test using Fanz diffusion cells. Some of these membranes were irradiated by γ rays with 25 kGy dose for material sterilization. Irradiated and non-irradiated membranes were simultaneously assessed in order to verify if γ radiation interferes on drug releasing profile. Results obtained from releasing test indicated the drug is released in a constant manner over 12 hours in the beginning of the experiment. Scanning Eletronic Microscopy analysis of the irradiated membranes revealed that membranes are very dense and its pores are small.

Because of its high specific strength, durability, and biocompatibility, titanium is a widely used material for orthopedic implants. However, its insufficient binding with the surrounding bone tissue regularly leads to stress shielding, bone resorption and implant loosening. A promising solution to improve adhesion is to modify the implant surface chemistry and topography by coating it with a protein-eluting polyelectrolyte complex. Bone morphogenetic protein 2 (BMP-2), a potent osteoconductive growth factor, was adsorbed onto the surface of anodized titanium, and polyelectrolyte multilayer (PEM) coatings prepared from solutions of poly-L-histidine (PLH) and poly(methacrylic acid) (PMAA) were built on top of the BMP-2. The effect of solution pH during the deposition process was investigated. High levels of BMP-2 released over several months were achieved. Approximately 2 μg/cm² of BMP-2 were initially adsorbed on the anodized titanium and a pH-dependent release behavior was observed, with more stable coatings assembled at pH = 6-7. Three different diffusion regimes could be determined from the release profiles: an initial burst release, a sustained release regime and a depletion regime. Mass adsorption monitoring using quartz crystal microbalance with dissipation monitoring (QCM-D) showed that PLH was adsorbed in greater quantities than PMAA, and that more mass was adsorbed per bilayer as the number of bilayers grew. Moreover, the pH of the water used during the rinsing step significantly impacted the composition of the multilayer. Atomic force microscopy (AFM) and contact angle analysis (CAA) were used to determine the topography and surface energy of the PEMs. No visible change was observed in surface morphology as the assembly pH was varied, whereas the surface energy decreased for samples prepared at more basic pH. These variations indicate that the influence of the initial BMP-2 layer can be felt throughout the PEM and impact its surface structure.

This thesis describes evaluation of a gastric retention device (GRD) developed at Oregon State University. The device was originally fabricated from Xanthan gum and Locust bean gum. A modified gastric retention device containing other additives was developed and investigated in this work. The modified device was evaluated in vitro for swelling and dissolution properties using riboflavin as a model drug. Different shapes and sizes of GRDs were tested in dogs to study the gastric retention potential of these devices. The effect of the device on food emptying from the stomach in dogs was also investigated. Endoscopic studies in dogs also showed that the device swells rapidly and considerably in gastric fluid. The bioavailability of riboflavin from three different size GRDs was determined in six fasted human volunteers and compared to an immediate release formulation. The biostudy indicated that the bioavailability of riboflavin from a large size GRD was more than triple that measured after administration of the immediate release formulation. Deconvolution was used to determine gastric residence time of the different size GRDs. A new colonic delivery system made of acetaminophen loaded beads produced by extrusion and spheronization and coated with different ratios of pectin and ethylcellulose coating solutions in a spray coating apparatus was also developed in this work. Such beads release their drug content in the colon due to susceptibility of pectin in the outer coat to enzymatic action of colonic bacteria. The new delivery system was evaluated in vitro by conducting release studies in different dissolution media to mimic transit times, pH and enzyme conditions in the gastrointestinal tract. The gastrointestinal transit behavior of drug beads was also assessed by conducting gamma-scintigraphic studies in dogs. The bioavailability and pharmacokinetic parameters of acetaminophen from several colonic delivery system formulations were determined in human volunteers and compared to the immediate release commercial product Tylenol®. A selected pectin-ethylcellulose coat formulation in the ratio 1:3 was further evaluated in six volunteers under both fed and fasting conditions and was found to be effective and to provide sustained drug release in the colon over a period of 12 hours. / Graduation date: 2003

Acetaminophen has been safely used for analgesia for many years. Literature suggests that a plasma acetaminophen level of 5��g/ml is necessary to maintain analgesic relief in humans. Current dosing regiments are inconvenient (every 4-6 hours) and do not maintain this minimum plasma level. Simulations were conducted to examine various doses and input rates for sustained release formulations of acetaminophen. Once parameters were selected from the simulations, sample formulations were prepared and tested using standard dissolution techniques. Investigations into dose/size relationships, hydroxypropylmethylcellulose (HPMC) percentage for erosion matrix tablets, compression force, tablet shape, tablet divisibility, and granulation methods were performed for non-disintegrating hydrophilic matrix tablets. Tablets containing 5% and 7.5% HPMC were selected for pharmacokinetic study in 10 healthy human subjects. Tylenol Extra Strength and Tylenol Extended Relief tablets were administered as control formulations. Pharmacokinetic fitting of the kinetic profiles of all four formulations were performed using Win Nonlin. The formulations were best described by a 1-compartment open model with first order input and first order elimination. The 5% HPMC sustained release acetaminophen formulation was selected for Phase II clinical trials. Patients with osteoarthritis of the knee were recruited for a double blind crossover study of 5% HPMC sustained release acetaminophen formulations and immediate release acetaminophen. Patients received two tablets of study medication, four times a day for 4 weeks. After a seven day wash-out period patients were then crossed over to the other treatment. Patients were evaluated using a twelve question questionnaire and the time to walk 50 feet was measured. Thirty patients were enrolled in the study and seventeen patients completed the study. The sustained release formulations were statistically superior to the baseline treatments in reducing pain level, decreasing disability, and improving the duration of pain relief. Additional, larger scale studies are needed to confirm these findings. / Graduation date: 2000

This thesis describes 1) development of a gastric retention device (GRD) to increase gastric retention time of certain drugs, 2) product formulations of an immediate release itraconazole and controlled-release ketoprofen. GRD was fabricated from crosslinked carbohydrate polymers. Rate and extent of hydration of the film in water and in simulated gastric fluid, compressibility of film, shape of the film, and in vivo gastric transit time in the stomach of dog were used as tools to evaluate gastric retention properties. Hydration studies were carried out at 37��C. Evaluation of the device containing radio-opaque agents, in dogs for gastric retention was carried out with the help of X-rays. The device was found to stay in the stomach of dogs for at least 10 hours. GRD containing amoxicillin trihydrate caplets were evaluated in a human. The area under the excretion rate curve was found to increase by 30% when compared to without the device. A successful development of a formulation of water insoluble itraconazole, without the use of organic solvents, was achieved with modifications from eutectic mixture techniques. Solubilization of the drug was achieved in polyethylene glycol of higher molecular weight. A series of formulations made by varying the amounts ingredients therein, were evaluated for dissolution profile in comparison with the reference, Sporanox��. Effect of molecular weights of PEG and types of PEG were evaluated for desired drug dissolution. Preliminary study from 6 subjects under the conditions of fasting and fed indicated that bioavailability from the new formulation was increased slightly when compared to the reference. This may be correlated to difference in the rate of in vitro dissolution, where the new formulation has initial faster dissolution. A controlled-release formulation of ketoprofen was also developed using a diffusion-controlled polymer, which was coated onto the drug beads. Release of drugs from such beads is controlled by the thickness of the coat. Thickness of the coat was evaluated by SEM and was correlated to the desired in vitro drug release in comparison to the reference Oruvail��. A three-way cross over study involving the new formulation and two marketed products in 12 subjects under fasting conditions indicated that there was a significant difference between the new product and marketed products, so as to be considered non-bioequivalent. Use of In Vitro-In Vivo Correlations and Convolution- Deconvolution relations predicted desired in vitro drug dissolution in a subsequent modification of the formulation. / Graduation date: 1999

This thesis describes a novel "Tablet-in-a-Bottle" oral suspension formulation. Ingredients with unstable physical or chemical characteristics can be placed in a core tablet, and then dry compression coated with an outer layer which provides separation from other components. The new suspension formulation comprises fast disintegrating clavulanic acid (KCA) tablets with a powder mixture containing amoxicillin. Hardness, friability, flow properties and weight uniformity of tablets for three different formulations were investigated and were all improved in a third formulation. Stability tests under different humidities were conducted. Amoxicillin and clavulanic acid in the new formulations showed the same stabilities when compared with the marketed product Augmentin��. Preliminary pharmacokinetics and bioavailability of one new formulation were evaluated by comparing in vitro release rates and in vivo urinary excretion rates. In vitro dissolution studies were carried out according to the USP XXIII paddle method. The new formulation showed faster release rates during the first hour when stirring speed was 25 rpm. However, when 75 rpm stirring speed was applied, the dissolution profiles for the new formulation and the reference marketed product were identical. A randomized two-way crossover bioequivalence study was designed to evaluate the bioavailabilities. Cmax, Tmax and AUC[subscript o--->t] of amoxicillin were within ��20% of the reference pharmacokinetic values. However, Cmax and Tmax of clavulanate were not within ��20%. Bioeqivalence between this new suspension formulation and the marketed product (Augmentin��) were evaluated using a two one-sided t-test. There is not sufficient statistical support with this test to conclude that the two products are bioequivalent. However, this is most likely due to small sample size and high intersubject variation and statistical support for bioequivalence is expected in a larger study group. / Graduation date: 1998