<p> The ability of chitosan and tripolyphosphate to form an ionic crosslinked material and its effectiveness in sustained release formulations has been reported. However, key issues commonly observed with these formulations include inefficiencies and inaccuracies in the drug loading as well as an inability to achieve complete release of drug. Acetaminophen, as a model drug, was added to various chitosan-tripolyphosphate crosslinked powders to assess the sustained release characteristics when drug is added extragranularly as opposed to during the crosslinking process, which is the most common procedure for drug addition in prior literature. The influence of various process and formulation variables including chitosan concentration, chitosan:tripolyphosphate ratio, temperature, ionic strength, and pH was assessed. Design of experiments allowed the identification of factors and two factor interactions that have significant effects on particle size and size distribution, yield, zeta potential, true density, and drug release. Statistical model equations were successfully used to manufacture optimized chitosan-tripolyphosphate crosslinked powders with various properties for further evaluation. Analysis of the compressibility of the optimized powders revealed that the crosslinked powders had enhanced compression properties when compared to chitosan powder. Environmental scanning electron microscopy revealed a correlation between the rigidity and density of the powders and corresponding capabilities for enhanced sustained release. Analysis of the moisture sorption and desorption isotherms from dynamic vapor sorption analysis revealed various types and levels of water present and a correlation between the quantity of water internally absorbed during sorption and desorption and sustained release capability. Chitosan-tripolyphosphate crosslinked powder can be manufactured with optimized properties that allow desired sustained drug release profiles while simultaneously serving as the primary diluent for solid oral dosage forms.</p><p>

<p> The aims of this research was to evaluate the partial crystallinity of two BCS class II drugs (Ketoconazole and Chlorpropamide) when prepared as solid-dispersions with three viscosity grades of Ethyl -Cellulose (EC7, EC45, or EC100 cP). Two processes were explored for preparing the dispersions; namely, spray drying, and, co-precipitation induced by non-solvent addition. The partial crystallinity of the formulations was evaluated using Differential Scanning Calorimetry, with crystal enthalpy values of 103.4 J/G for Ketoconazole and 98.8 J/G for Chlorpropamide (from literature). Both formulation processes yielded free-flowing white powders with a size range of 3 to 49 &mu;m. Control formulations with no EC content showed crystal enthalpies ranging from 83-97%, suggesting practically no amorphous stabilization in the absence of Ethyl Cellulose. The co-precipitation process was ineffective in preparing amorphous formulations for Ketoconazole, as crystal enthalpies ranged from 82-100%. For Chlorpropamide, however, the efficiency of the co-precipitation process improved with the viscosity grade of the Ethyl Cellulose, with EC7, EC45, and EC100 showing % crystalline enthalpies of 98, 76, and 51% respectively. The progressive decrease in crystal enthalpies suggested a corresponding increase in the amorphous forms of these drugs. Spray-dried formulations prepared with EC7 showed practically no crystalline enthalpies for both Ketoconazole and Chlorpropamide, suggesting that these drugs were almost entirely trapped in their amorphous state, and would expect to show higher solubility upon dissolution. Overall, this research shows that spray-drying with low viscosity grade Ethyl Cellulose such as EC7 is an optimal approach for the preparation of amorphous solid-dispersions of BCS Class II drugs.</p><p>

University of Macau / Institute of Chinese Medical Sciences

University of Macau / Institute of Chinese Medical Sciences

<p> Application of learn-apply paradigm in drug development and clinical therapeutics increases efficiency and supports decision making. The current research highlights the role of pharmacometrics to inform trial design and propose individualized management of chemotherapy induced peripheral neuropathy (CIPN) in oncology. </p><p> The first project focuses on learning from early clinical trial of veliparib to inform future investigations. Population pharmacokinetics and exposure-response analyses were conducted to evaluate the contribution of intrinsic and extrinsic factors on veliparib PK, and assess the adequacy of veliparib dosing for the future trial. A 28% increase in AUC with mild renal impairment increases mucositis by only 7%, thus supporting the inclusion of patients with mild renal impairment in future trials without the need of dose adjustment. Exposure-response for efficacy (objective response rate and overall survival) and safety (mucositis) along with in vitro IC50 information supported 80 mg BID dose for veliparib. Multivariate exposure-response analysis provided supportive evidence to further evaluate veliparib in patients with myeloproliferative neoplasms and with 14 day treatment duration. </p><p> The second project proposes a novel strategy based on precision therapeutics for the management of CIPN in clinical setting. An indirect response model with linear drug effect was able to describe the longitudinal-CIPN data reasonably well for paclitaxel, nab-paclitaxel and ixabepilone. The model was utilized to identify an early time point of 3 months that predicted later time course of CIPN (concordance probability ~ 75%). Utilizing the dose-CIPN model, a novel strategy to use patients own early CIPN data to predict their future CIPN time course was proposed. 'CIPN management dosing card' and 'CIPN precision therapeutics tool' were developed to prospectively manage CIPN in patients who may be at risk of developing CIPN later in the therapy. For paclitaxel, nab-paclitaxel and ixabepilone, the proposed CIPN management dosing card resulted in 61%, 48% and 35% fewer patients with CIPN after 6 cycles as compared to administering cycle 3 doses for 4^th, 5^th and 6^th chemotherapy cycle. With CIPN precision therapeutics tool, oncologists can visualize the predicted CIPN time course and tailor the dosing to manage CIPN in an individual patient based on overall benefit/risk.</p>

N-Acetylneuraminic acid (NeuAc) is a sialic acid which constitutes terminal positions in glycoproteins and glycolipids. It is part of the antigenic determinant of many forms of cancer (S. Hakomori, Chem. Phys. Lipids. 42, 209 (1986)) and hence a cancer "vaccine" could be made from an appropriate multivalent macromolecular form of NeuAc. To explore the possibility of inducing anti-NeuAc antibodies, we have synthesized polyvalent conjugates of $\alpha$NeuAc or NeuAc$\alpha$2-3Gal$\beta$1-4Glc (sialyl2-3lactose) on protein carriers. This was accomplished by reductive amination with 2-oxoethyl $\alpha$-NeuAc or with the concealed aldehyde of the reducing sugar (glucose) onto the lysine residues of the proteins Bovine Serum Albumin (BSA) and Tetanus Toxoid (TT). A new procedure involving a Michael-type addition employed the $\epsilon$-amino groups of the lysine residues in a 1,4 nucleophilic addition to the acrylamide functional group in two derivatives of NeuAc; the N-acryloylaminoethylthiopropyl glycoside, and the N-acryloylsialyl2-3lactosylamine. This technique does not require the use of reagents and was performed under mild basic conditions. Polyacrylamide copolymers were also synthesized by radical co-polymerization of acrylamide with NeuAc monomers, providing a polymer (Mw $\approx$ 100 kDa) with pendant NeuAc. Reactive monomers giving different spacer arms between the sugar and the polymer backbone were developed, including the allyl glycoside, a more reactive N-acryloylaminoethylthiopropyl glycoside and several lactose derivatives. The polymers were found to have a better shelf life than the proteins, and had the advantage of sharing only the NeuAc moiety. Some of the NeuAc/protein conjugates were used to immunize rabbits, and the antibodies formed were screened with polyacrylamide copolymers with pendant NeuAc. The polymer with spacer was found to react better with the antibodies in immunoprecipitation and enzyme-linked immunosorbent assay (ELISA). Inhibition of ELISA experiments were done using synthesized derivatives of NeuAc to determine the binding specificity of the antibodies. It was found that the antibodies recognized the glycerol side chain, acid function, spacer, and to a lesser extent, the acetamido function of NeuAc. The same methodology was used to map the binding site of the lectin from Triticum vulgaris (called Wheat germ agglutinin, WGA) which binds NeuAc. Nuclear magnetic resonance (nmr) studies were undertaken to determine the acidity constants (pK$\sb{\rm a}$) and conformation of several NeuAc derivatives. Also studied was the lactone of NeuAc$\alpha$2-3Gal$\beta$1-4Glc which is believed to be responsible for the immunogenicity of certain cancer cells (T. Dohi, G. Nores and S. Hakomori, Cancer Res. 48, 5680 (1988)). This work was complemented by molecular modelling using MM2. A model was proposed for the conformation of the lactone which is consistent with the n.m.r. evidence.

The tetrasaccharide sialyl Lewisx (SLex) is the smallest recognizable ligand for selectins. The binding of SLe x to the selectins triggers the inflammatory cascade and recruits leukocytes to the injured cells. Chronic and acute inflammatory diseases result from the over-recruitment of leukocytes leading to damage of normal cells. Carbohydrate-based mimetics, maintaining functionality while improving stability, binding affinity and structural simplicity, are ideal candidates for anti-inflammatory drugs. Sialyl Lewisx glycomimetics were synthesized using two different convergent approaches. Each synthesis used an enzyme-resistant alpha-carbon-linked fucosyl moiety (C-glycoside) to replace the unstable anomeric oxygen linkage of the natural ligand. One synthetic route coupled a rigid proline ring to the fucosyl carboxylic acid derivative made from L-fucose to form one branch of the mimetic. The second branch was synthesized by coupling modified amines to form functionalized peptide chains of various lengths. The second convergent approach used novel olefin metathesis chemistry in the preparation to orchestrate a stereoselective cis-alkene bond formation extending from the fucosyl branch of the synthetic pathway. (Abstract shortened by UMI.)

A novel synthetic strategy for the potential analogue 17 of the immunosuppressive agents subglutinols A (3) and B ( 4) was investigated. Neither of these molecules, nor any analogues, have been synthesized previously. The route selected employed a cis -isopropylidene control group in the tether to facilitate the key synthetic step, an intramolecular Diels-Alder reaction. This approach afforded the tricyclic core of 18 in an efficient and direct manner. The Diels-Alder precursor 20 was constructed from D-isoascorbic acid (24), vinylmagnesium chloride (22), and 4-iodo-3-methoxymethoxymethyl-penta-1,3-diene (21). The synthesis of the lactone 19 and the attempts to remove the MOM group from 18 were also investigated. Unfortunately, however, the final target analogue 17 was not realized due to unsuccessful attempts at removing the MOM group from 18. Thus, an efficient route to the decalin core was established, though the coupling of the lactone 19 awaits further study.

No description available.

The syntheses of 8-amino-16-azadispiro[6.1.6.2]heptadecan-16-one and its 8-chloroacetyl derivative are reported. The compounds were characterized by their infrared spectra and by elemental analysis of the latter compound. Data is presented for the attempted reaction of dimethylaminoacetic acid with 7-amino-14-azadispiro[5.1.5.2]pentadecan-15-one and 8-amino-16-azadispiro-[6.1.6.2]heptadecan-17-one using dicyclohexylcarbodiimide as the condensing reagent. The reduction of the product obtained from the latter reaction is described. The addition of the ß-dimethylaminoethyl group to the 8-amino dispiro compound named above, in the presence of sodamide was also tried. A ß-dimethylaminoethyl derivative of 7,14-diazadispiro[5.1.5.2]penta-decane was synthesized by the lithium aluminum hydride reduction of the pentadecan-15-one analog. A correct elemental analysis was obtained for the unsaturated compound but the reduced derivative was identified only by its infrared spectrum. It was not determined whether substitution had occurred at the secondary or the lactam nitrogen. The reaction of chloroacetyl chloride with 7,14-diazadispiro[5.1.5.2]pentadecan-15-one using a variety of reaction conditions is described. Data is also presented for the attempted purification of the product obtained from the latter reaction; both thin layer and column chromatography were employed. The condensation reaction of 1-amino-cycloheptanecarbonitrile in the presence of sodium ethoxide and a trace of moisture does not yield the expected 8,16-diazadispiro[6.1.6.2]heptadecan-17-one. / Pharmaceutical Sciences, Faculty of / Graduate