Sustained concentrations of active compound were maintained in vitro and in vivo for an oral and a parenteral dosage form respectively. The vehicle of a oral dosage form was modified and the molecular structure of a parenteral dosage form was modified. An oral dosage form was tested in vitro using dissolution apparatus. A parenteral dosage form was tested in vivo using rats. A new oral suspension dosage form for acetylsalicylic acid was compared to two controlled release forms and two immediate release dosage forms which are currently commercially available. A parenteral thrombomodulin analogue conjugated to polyethylene glycol was compared to the unconjugated thrombomodulin analogue. In each case the goal was to maintain sustained concentrations of active compound. / Graduation date: 1991

The benefits of controlled release drug delivery are important to the pharmaceutical industry. With a controlled release device, local administration of a drug is possible and release profiles can be created that remain within therapeutic limits for prolonged periods. Made from biodegradable and bioerodable polymers, unwanted side effects and the need of return trips for treatment diminish. However, a usable device must be free of organic solvents normally used to dissolve large drug molecules. Many of these solvents are toxic themselves. Therefore, steps must be taken to either remove residual solvent from the final device or limit their use during synthesis. Ideally, it is desirable to remove the organic solvents from the process entirely. Supercritical carbon dioxide (scCO2) has been used as a replacement for these solvents. Carbon dioxide is inexpensive, environmentally acceptable, and safe for use in human consumables. However, many drug molecules have very low solubility in scCO2, resulting in extended polymer impregnation times. An organic co-solvent can be used to increase drug solubility, leading to a more efficient polymer impregnation. Using only a small amount of organic co-solvent, a single phase stream is possible that results in significantly increased solubility. This meets the original task of limiting organic solvents in the process and increases efficiency over scCO2 alone. This study uses supercritical carbon dioxide with ethanol as a co-solvent. Ethanol increases the solubility of β-estradiol in scCO2 for impregnation into the glassy polymer polyvinylpyrrolidone (PVPP). Experimental conditions cover a range of temperatures from 40 °C to 50 °C and pressure up to 2500 psi. The effect of polymer swelling time on the sorption process is also studied. A dual mode sorption model describes the sorption of drug into the glassy polymer, and a plug flow and stirred tank compartmental model predicts breakthrough profiles. The determined sorption parameters allow analysis of polymer conformation and suggest optimum impregnation conditions.

Thesis (M.E.)--University of Waikato, 2008. / Title from PDF cover (viewed September 18, 2008) Includes bibliographical references (p. 66-70)

The use of controlled release dosage forms has increased significantly in recent years as they result in increased patient compliance and higher therapeutic efficiency. This research focused on the development of a once daily dosage form that could be used for the treatment of hypertension. Both a separate sustained release dosage of metoprolol tartrate and a combination dosage form that included both an immediate release hydrochlorothiazide and a sustained release metoprolol component, were developed and evaluated. A matrix tablet, consisting of an ethylcellulose ranulation of metoprolol tartrate compressed into a hydrophilic hydroxypropyl methylcellulose polymer matrix, effectively sustained metoprolol release over a 22-hour experimental period. A multiparticulate combination dosage form that consisted of six coated mini matrix tablets of metoprolol and a powder blend of hydrochlorothiazide packed into a gelatin capsule, displayed zero order release kinetics for metoprolol release over 22 hours (r2=0.9946). The release of hydrochlorothiazide was found to be comparable to that of a commercially available product tested. Differential Scanning Calorimetry was used to identify possible incompatibilities between MPTA and excipients initially, and long term stability testing was used to assess to behaviour of the dosage form. Dissolution testing of the dosage forms was performed using USP Apparatus III, which was found to be more discriminating between the batches assessed. Dissolution curves were evaluated for similarity and difference using f1 and f2 fit factors. Samples were analyzed using a high performance liquid chromatographic method that was developed and validated for the simultaneous determination of the compounds of interest. Various factors influencing drug release from the developed dosage forms were assessed and recommendations for further optimization of the formulation are made. Factors evaluated included the quantity of granulating fluid, matrix polymer content, drug load and process variables, including drying time and compression force. The influence of various coating levels on drug release was assessed and none of the levels assessed were found to adequately retarded drug release over a 22-hour period. Combinations of tablets coated to different levels allowed for the successful development of a sustained release metoprolol component, which could be included into the combination dosage form.

No description available.

No description available.

The aim of this research was to formulate, characterise and assess the feasibility of a novel drug delivery system known as the in situ gelling matrix (ISGM) where a hydrophilic polymer is suspended in a non-aqueous solvent that converts into a gel when injected subcutaneously or intramuscularly thus giving a controlled release matrix for a drug. Although the concept has been patented with claims that this kind of drug delivery is achievable in theory for a wide variety of candidate substances, actual formulation studies for making a commercially viable product for this technology are completely lacking in practice. The research embodied in this thesis addresses this lack. Initial studies involved conducting a biocompatibility study using the HET-CAM (hens egg test - chorioallantoic membrane) test on a range of possible ingredients for the delivery system. The materials deemed biocompatible were then carried through to a screening process where the physical stability of the hydrophilic polymers in non-aqueous solvents was monitored. It was found that the hydrophilic polymers tested sedimented rapidly in the non-aqueous solvents indicating such a system was not physically stable. Consequently, density-inducing or viscosity-inducing agents were added to the non-aqueous solvents to retard the sedimentation rate. The addition of polycarbophil, a viscosity-inducing agent, clearly increased the viscosity of the system. However, undesirable formation of polycarbophil globules occurred during the manufacturing process, which caused batch-to-batch variations in the viscosity of the continuous phase. Various manufacturing methods were tested before arriving at the optimum procedure to prevent globule formation using a high speed dispersion tool. A final physical sedimentation analysis of candidate continuous phases and hydrophilic polymers was conducted for determining the ideal combination of ingredients to use in the system. These investigations finally led to the adoption of an optimum mix of components consisting of 10% (w/w) hydroxypropyl methylcellulose (HPMC) (the hydrophilic polymer) suspended in a continuous phase of propylene glycol (the non-aqueous solvent) containing 0.67% (w/w) polycarbophil (the viscosity inducing agent). Using this mix of components, the in situ gelling matrix system was then subjected to various characterisation studies including infrared (IR), differential scanning calorimetry (DSC), ultraviolet-visible (UV-Vis) spectrophotometry and redispersion studies. The chemical stability of the hydrophilic polymer and the continuous phase (the non-aqueous solvent and polycarbophil) was monitored and were found to be chemically stable over a 9 month period. The feasibility of the in situ gelling matrix technology as a controlled release device was assessed using the drug propranolol. In vitro drug release studies were conducted using a custom-built dissolution apparatus. The effect of various parameters such as the concentration of the hydrophilic gelling agent on the drug release rate was investigated. Increasing the concentration of the gelling agent in the formulation resulted in a slower rate of release. The drug release data were modelled using the Higuchi relationship and a power law relationship to compare the effects of the various parameters on the release rate Stability studies on the drug in the in situ gelling matrix system were carried out by storing samples in accelerated ageing conditions of 40 C / 75% relative humidity for 4 weeks. During this time, the samples were analysed each week by high performance liquid chromatography (HPLC). These demonstrated that no apparent drug degradation had occurred over the 4-week period. This indicates that the drug propranolol in the in situ gelling matrix system is stable under ambient conditions for at least 4 weeks. The results of this study demonstrated that the in situ gelling matrix technology is potentially viable as a drug delivery system and provide a practical methodology for the commercial development of such systems.

Graduation date: 1995

Thesis (Ph. D.)--University of Washington, 1983. / Vita. Bibliography: leaves [202]-216.

Gastrointestinal (GI) transit data were collected using pigs as animal models. Density and size effects of non-disintegrating dosage forms on GI transit were investigated. Total GI transit times range from 2 to 33 days for 22 administrations of these nondisintegrating dosage forms. Pigs are found to not be an appropriate animal model for studying bioavailability or GI transit of non-disintegrating, non-erodible oral release dosage forms. Development of controlled release dosage forms where the mechanism of drug release is diffusion through polymeric membrane formed via film coating utilizing fluid-bed technology requires optimization of several processing and formulation variables. The influence of a processing variable (nozzle orifice opening) and a few formulation variables (individual vs. combination plasticizer, or a water-insoluble additive) on dissolution of a model drug (acetaminophen) spray coated with Aquacoat® were studied. Pharmacodynamic and pharmacokinetic information for a model drug (acetaminophen) and computer simulation were used to develop a dosage form with a 12 hour sustained release for oral administration to children and adults for maximum analgesic and antipyretic effect. Simulated plasma acetaminophen concentration-time curves were similar to observed bioavailability study profiles. In vitro and preliminary in vivo results from an adult human volunteer indicate that sustained therapeutic saliva acetaminophen concentration is possible using the newly developed acetaminophen molded tablet dosage form. The bioavailability of the new, oral controlled release acetaminophen molded tablet relative to a commercially available product (Extra-Strength Tylenol® caplet) was evaluated in 8 healthy, adult volunteers. Multiple doses of these two products were administered in a two-way cross-over design. Bioavailability of the new sustained release molded tablet is comparable to that of the immediate release product. Polymer coated acetaminophen beads were effective in maintaining saliva acetaminophen concentrations of 5 μ/ml over a 12 hour dosing interval. / Graduation date: 1991