Rheological characterization of pharmaceutical semisolids is of importance as it provides fundamental information required for the assessment of some of the final properties of a product such as viscosity, elasticity, quality and storage stability. The effect of formulation variables on product characteristics such as consistency and correlation of consumer evaluation of consistency can also be attained. (Ramachandran et al., 1999) This study focussed on using rheological techniques to fully characterize the properties of various semisolid formulations being developed or produced at a South African-based generic pharmaceutical company. Various tests were employed to characterize the semisolid dosage forms (creams and ointments), including continuous shear tests such as flow and viscosity curves and yield point measurements, oscillatory tests such as amplitude and frequency sweeps, as well as step and temperature ramp tests. A method to determine justifiable and meaningful viscosity specifications was developed, where excellent reproducibility of results were obtained when compared to the single-point viscosity determinations usually used. An evaluation as to whether rheology can be utilized as an assessment tool for product stability revealed varying results, with the oscillation-frequency sweep test displaying modest predictive capabilities. Observable differences in rheological character were found when evaluating ointment formulations exhibiting deviating quality characteristics. When analysing the effect of varying processing parameters, namely, cooling rate and mixing speed, during the manufacture of a cream, statistically significant rheological differences were obtained, while a thorough characterization of a scale-up procedure was also achieved upon analysis of various rheological properties.

University of Macau / Institute of Chinese Medical Sciences

Part I. Following a general historical review of the development of drug targeting, critical evaluations were made of current targeted drug delivery systems. Based on the results shown by previous studies, magnetic albumin microspheres containing adriamycin is one of the most promising targetable delivery systems for the treatment of solid tumors. It was also apparent that the pharmacokinetics of drugs associated with magnetic albumin microspheres had not been determined. A systematic study of the multiple variables involved in albumin microsphere preparation was completed to identify to what extent these variables affected the microsphere size distribution. The results of this investigation led to an optimal method of microsphere preparation. Information obtained from the above studies was applied to the production of magnetic albumin microspheres containing adriamycin suitable for in vivo use. The problems of separation and quantitation of adriamycin and adriamycinol in biological matrices were investigated using ion-pairing high pressure liquid chromatography. An optimized chromatographic system was presented for the analysis of these compounds in rat serum and tissues. The disposition of adriamycin following administration as magnetic albumin microspheres and as a solution was studied by monitoring adriamycin concentrations in multiple rat tissues for forty-eight hours after administration. The magnetic dosage form was targeted to a predefined tail segment with a magnetic field strength of 8000 G applied for 30 min after dosing. A physiological pharmacokinetic model was used to describe the disposition of adriamycin after both dosage forms. The model developed following adriamycin administration as a solution served as the foundation for the model for adriamycin when it was administered as the magnetic dosage form. Part II. The present investigation was designed to characterize the kinetics of ibuprofen in plasma and synovial fluid, which in the past, has been flawed by inadequate study protocols. After administration of a single dose and at steady-state, ibuprofen concentrations were measured simultaneously in plasma and synovial fluid obtained from eight patients with rheumatoid arthritis. The extent of accumulation of ibuprofen in each fluid was determined. The degree of ibuprofen protein binding in plasma and synovial fluid was also determined and related to its kinetic behavior.

Thesis (M.S.)--University of Wisconsin. / Includes indexes. Bibliography: p. 67-144.

Liposomes have important potential as drug delivery vehicles. However, in order to realize this potential, much basic research is required to elucidate the interactions experienced by liposomes in vivo. In this thesis two aspects of these interactions are investigated: the influence of vesicle size and lipid composition on the biodistribution observed in vivo; and the interaction of liposomes with plasma proteins. In order to determine the in vivo behavior of liposomal systems, a new vesicle marker is synthesized (¹²⁵I-tyraminyl-inulin, ¹²⁵ITI) and tested in vivo. It is shown that this probe satisfies the necessary criteria for an accurate marker of liposome behavior, and is superior to probes used by other workers in terms of accuracy, convenience, high specific activity, low tissue quenching and cost. The use of ¹²⁵ITI as a vesicle marker allows accurate measurements to be made with lower doses of liposomes than previously employed. The influence of vesicle size, composition, and dose on the blood residency times, leakage and tissue distributions of vesicles was therefore investigated at these lower doses, employing a cannulation procedure to monitor vesicles. It is demonstrated that the clearance of vesicles from the circulation exhibits biphasic kinetics. The relative number of vesicles cleared during the early phase (halflife <20 min) is decreased by increasing the vesicle dose or decreasing the size. The behavior of small vesicles produced by extrusion is also investigated, and the in vivo behavior of these systems is shown to be equivalent to conventional sonicated systems. The second part of this thesis investigates the binding of plasma proteins to vesicles in vitro. It is shown that vesicles bind a large number of plasma components and that the binding is strongly dependent on the surface charge of the vesicle. Some of the proteins have been tentatively identified with 2-D electrophoresis and several were positively identified via immuno- autoradiography. A hypothesis is advanced regarding the role of plasma proteins in the fate of liposomes in vivo. / Medicine, Faculty of / Biochemistry and Molecular Biology, Department of / Graduate

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

Several polymer systems including P(MAA-g-EG) and P(MAA-co-NVP) with crosslinking agents TEGDMA and PEGDMA1000, monomer-to-solvent ratios of 67:33, 60:40, and 50:50, and particle sizes of <75 microns, 90-150 microns, and 150-212 microns were synthesized for use with protein-transporter conjugates. All synthesized systems were characterized by SEM which demonstrated the visual size, surface features, and surface textures of the polymer microparticles. Insulin-transferrin and calcitonin-transferrin conjugates were successfully synthesized using the protein crosslinker SPDP, binding the two proteins with a disulfide bond. The multi-step conjugation reactions used to create the conjugates were analyzed by the use of UV spectroscopy and HPLC to ensure the quality of the final products. In both conjugation reactions, the final product yield was found to be over 70%. The in vitro loading and release characteristics for insulin-transferrin and calcitonin-transferrin were separately investigated. By testing loading and release using a number of different polymer systems with different synthesis parameters, it was possible to optimize the hydrogel carriers for use with each of the conjugates independently. Upon optimization, the ideal system for use with insulin-transferrin and calcitonin-transferrin was found to be P(MAA-g-EG) microparticles of <75 microns formed using a PEGDMA1000 crosslinker and a 50:50 monomer-to-solvent ratio for both conjugates through separate optimization processes. This optimized polymer carrier was found to release upwards of 50% of loaded insulin-transferrin conjugate and near 90% of loaded calcitonin-transferrin conjugate. The insulin-transferrin conjugate was further evaluated through the use of cellular and animal models. Using cellular models, the insulin-transferrin conjugate was shown to increase transport relative to insulin by a factor of 7, achieving an apparent permeability of 37 x 10⁹ cm/s. Also, in the presence of polymer microparticles, the insulin-transferrin conjugate increased transport by a factor of 14 times relative to insulin, achieve an apparent permeability of 72.8 x 10⁹ cm/s. The presence of the microparticles near the cells was found to improve conjugate transport by nearly 100%. The preliminary animal studies verified the successful synthesis of the insulin-transferrin conjugate as well as demonstrated the bioactivity of the insulin portion of the molecule by achieving a drop in blood glucose level upon subcutaneous injection. / text

Co-trimoxazole, a combination of a 5-to-l ratio of Sulphamethoxazole (SMZ) and Trimethoprim (TMP) , is a highly effective, broad-spectrum antibacterial agent. Since its introduction in 1968, it has been extensively used in infections of the respiratory and urinary tracts. Co-trimoxazole was developed by the systematic investigation of a series of compounds whose mechanism of action was already known. As early as 1950 synergy between sulphonamides and 2,4-diaminopyrimidines was reported. This was to be expected as both groups of drugs exert their antibacterial activity by interfering with the same biochemical pathway in bacteria. TMP was chosen from among many 2,4-diaminopyrimidines tested because of its good antibacterial activity and low toxicity. SMZ was chosen from the sulphonamides available for combination with TMP because of similarity of their biological half-lives. The widespread use of the combination coupled with the fact that monitoring of the levels of all drugs in the body is becoming increasingly important has stimulated research into rapid and efficient methods for the analysis of TMP and SMZ in biological fluids. Another consequence of the immense popularity of the combination is the appearance on the market of several generic preparations of Co-trimoxazole. It is now generally recognized that drug products from different manufacturers which are chemically equivalent may not be therapeutically equivalent. This is due to the fact that the absorption rate and/or bioavailability (extent of absorption) of a poorly soluble drug may be markedly affected by its release rate from the product and by its subsequent dissolution rate in gastrointestinal fluids. Hence bioequivalence of these various products should be established

The use of the oral route of administration for the treatment of young children with antibiotics can at times be problematic since, factors such as nausea, vomiting, taste and/or smell, in addition to the challenges associated with the administration of suspensions, may contribute to poor patient compliance. In such cases, the use of the rectal route of administration may be appropriate. Therefore, suppositories containing 250 mg azithromycin (AZI) were manufactured and assessed for potential as an antibiotic suppository dosage form. Suppositories, containing AZI dihydrate were manufactured by the fusion method, using different grades of PEG, Witepsol® and Suppocire® bases. The rate and extent of AZI release was evaluated using USP apparatus I, and samples were analyzed using a validated HPLC method. Differences in the rate and extent of AZI release were observed with the greatest amount of AZI being released from PEG formulations. The rate and extent of AZI release from formulations manufactured using fatty bases were influenced by physicochemical properties, such as melting rate and hydroxyl value, of the bases. In addition drug partitioning appeared to favor the lipid phase and had a negative impact on AZI release characteristics. Two different formulation approaches were used in an attempt to increase the rate and extent of AZI release from fatty base formulations. The use of surfactants significantly increased AZI release from formulations manufactured with fatty bases with high hydroxyl values. The use of urea or Povidone K25 in combination with AZI as a physical mixture or solid dispersion did not increase the rate and extent of AZI release from the fatty suppositories, to any significant extent. The mechanism of drug release was evaluated using several mathematical models, including the Higuchi, Korsmeyer- eppas, Zero and, First order models. In addition, in vitro dissolution profiles were characterized by the difference and similarity factors, f1 and f2 and by use of the Gohel similarity factor, Sd. AZI release kinetics were best described by the Higuchi and Korsmeyer-Peppas models and the values of the release exponent, n, revealed that drug release was a consequence of the combined effects of AZI diffusion, rate of melting of the base and partitioning of the drug which can be considered to be anomalous release.

Over the past few decades many researchers have investigated the utility of in vitro - in vivo correlations for the assessment of dosage forms. These investigations are, however, dependent on reproducible dissolution data and well conducted biostudies in order to establish meaningful and robust correlations. Despite the fact that the establishment of such correlations is perhaps idealistic, considerable interest has still been shown in this area of research. Various Controlled/Modified Release Dosage Forms (CMRD's) of theophylline, a weakly basic drug, and indomethacin, a weakly acidic drug, were assessed in order to establish in vitro - in vivo correlations. Dissolution rate studies were carried out using either the USP basket or paddle apparatus. The dissolution rate studies were conducted in a range of dissolution media of varying pH. Bioavailability studies were conducted on the dosage forms used by the Biopharmaceutics Research Institute at Rhodes University. The results of these biostudies were kindly made available for use in this research project. Type A correlations were established using a mathematical simulation process whereby expected in vivo responses are simulated and compared to actual profiles obtained for the dosage forms. In order to perform the simulations the dissolution rate profiles were stripped and using linear regression and the methods of residuals the dissolution rate order and the relevant dissolution rates were obtained. The results of the s imulations indicated that the in vivo serum concentration-time curves could be accurately predicted for the theophylline dosage forms but to a lesser extent, for the indomethacin formulations. The dissolution rate studies indicated that the paddle method is a suitable method for dissolution rate studies of theophylline CMRD's, although it appeared that the optimum pH of the dissolution medium was formulation dependent. Dissolution rate studies conducted on indomethacin formulations indicated that the USP specified basket method for extended-release indomethacin formulations was not able to distinguish between two formulations which exhibited different in vivo profiles. The conversion to the paddle method was, however, able to highlight the differences between these formulations. The use of three dimensional topographs to depict dissolution rate profiles was demonstrated for formulations of both theophylline and indomethacin. The topographs enabled the successful differentiation between bioinequivalent formulations. The dissolution rate profiles were also fitted to the Wei bull equation and the parameters obtained from this were compared to the Weibull parameters obtained from the in vivo absorption plots obtained using the Wagner-Nelson method. The results indicated that the Weibull function was suitable to describe both the in vivo and in vitro data. The following recommendations for the preformulation dissolution studies of weakly acidic and weakly basic drugs are proposed. The dissolution rate studies of weakly acid drugs, such as indomethacin, should be carried out over a range of pH utilising the paddle apparatus. Three dimensional topographs based on the dissolution data should be constructed and used as a comparative tool for different formulations. Based on these comparisons the appropriate formulation can then be selected for a pilot scale in vivo bioavailability study. The dissolution rate studies of weakly basic drugs, such as theophylline, should be carried out over a range of pH utilising the paddle apparatus. The dissolution data should then be used to simulate the expected in vivo profile and on this basis the appropriate formulation selected for a pilot scale bioavailability study. The above approach to the preformulation studies of new CMRO's would allow for the more careful selection of new dosage forms and could thus eliminate costly and unnecessary bioavailability studies performed on inferior formulations.