Pharmaceutical Sciences Update

EDITOR’S NOTE: Selected abstracts from recent issues of the Journal of Pharmaceutical Sciences, which is published by John Wiley & Sons on behalf of the American Pharmacists Association. For more on these studies and others, go to http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1520-6017.

Formation of a polymer drug matrix and eventual release of drug molecule from the matrix.

Fatty acid and water-soluble polymer-based controlled release drug delivery system

Sustained release capsule formulations based on three components—drug, water-soluble polymer, and water-insoluble fatty acid—were developed. Theophylline, acetaminophen, and glipizide, representing a wide spectrum of aqueous solubility, were used as model drugs. Povidone and hydroxypropyl cellulose were selected as water-soluble polymers. Stearic acid and lauric acid were selected as water-insoluble fatty acids. Fatty acid, polymer, and drug mixture was filled into size #0 gelatin capsules and heated for two hours at 50°C. The drug particles were trapped into molten fatty acid and released at a controlled rate through pores created by the water-soluble polymer when capsules were exposed to an aqueous dissolution medium. Manipulation of the formulation components enabled release rates of glipizide and theophylline capsules to be similar to commercial Glucotrol® XL tablets and Theo-24® capsules, respectively. The capsules also exhibited satisfactory dissolution stability after exposure to 30°C/60% relative humidity (RH) in open petri dishes and to 40°C/75% RH in closed high-density polyethylene bottles. A computational fluid dynamic-based model was developed to quantitatively describe the drug transport in the capsule matrix and the drug release process. The simulation results showed a diffusion-controlled release mechanism from these capsules.
Desai D, Kothari S, Chen W, et al. Fatty acid and water-soluble polymer-based controlled release drug delivery system. J Pharm Sci. 2011;100(5):1900-1912. Correspondence to Divyakant Desai, Research and Development, Bristol-Myers Squibb Company, New Brunswick, N.J. 08903-0191. Telephone: (732) 227-6458; divyakant.desai@bms.com.

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Unfolding of mAb1 and mAb2 with GuHCl. (a) Steady-state equilibrium measurement and (b) kinetic unfolding of mAb1.

Evaluation of a non-Arrhenius model for therapeutic monoclonal antibody aggregation

Understanding antibody aggregation is of great significance for the pharmaceutical industry. We studied the aggregation of five different therapeutic monoclonal antibodies (mAbs) using size-exclusion chromatography-high-performance liquid chromatography (SEC-HPLC), fluorescence spectroscopy, electron microscopy, and light scattering methods at various temperatures with the aim of gaining insight into the aggregation process and developing models of it. In particular, we find that the kinetics can be described by a second-order model and are non-Arrhenius. Thus, we developed a non-Arrhenius model to connect accelerated aggregation experiments at high temperature to long-term storage experiments at low temperature. We evaluated our model by predicting mAb aggregation and comparing it with long-term behavior. Our results suggest that the number of monomers and mAb conformations within aggregates vary with the size and age of the aggregates and that only certain sizes of aggregates are populated in the solution. We also proposed a kinetic model based on conformational changes of proteins and monomer peak loss kinetics from SEC-HPLC. This model could be employed for a detailed analysis of mAb aggregation kinetics.
Kayser V, Chennamsetty N, Voynov V, et al. Evaluation of a non-Arrhenius model for therapeutic monoclonal antibody aggregation. J Pharm Sci. 2011;100(7):2526-2542. Correspondence to Bernhardt L. Trout, Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Mass. 02139. Telephone: 617-258-5021; trout@mit.edu.

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Structure of lamivudine.

Biowaiver monographs for immediate release solid oral dosage forms: lamivudine

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing lamivudine as the only active pharmaceutical ingredient were reviewed. The solubility and permeability data of lamivudine, as well as its therapeutic index, its pharmacokinetic properties, data indicating excipient interactions, and reported BE/bioavailability (BA) studies were taken into consideration. Lamivudine is highly soluble, but its permeability characteristics are not well defined. Reported BA values in adults ranged from 82% to 88%. Therefore, lamivudine is assigned to the biopharmaceutics classification system (BCS) class III, noting that its permeability characteristics are near the border of BCS class I. Lamivudine is not a narrow therapeutic index drug. Provided that (a) the test product contains only excipients present in lamivudine IR solid oral drug products approved in the International Conference on Harmonization or associated countries in usual amounts and (b) the test product as well as the comparator product fulfill the BCS dissolution criteria for very rapidly dissolving, a biowaiver can be recommended for new lamivudine multisource IR products and major post-approval changes of marketed drug products.
Strauch S, Jantratid E, Dressman JB, et al. Biowaiver monographs for immediate release solid oral dosage forms: lamivudine. J Pharm Sci. 2011;100(6):2054-2063. Correspondence to D. M. Barends, RIVM—National Institute for Public Health and the Environment, Bilthoven, The Netherlands. Telephone: 31-30-2744209; dirk.barends@rivm.nl.

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Optical microscopy (a and b) and SEM (c and d) images of curcumin-loaded PLGA microparticles prepared by conventional solvent evaporation and homogenization technique; (a and c) after washing with water; (b and d) after washing with 10% (w/v) Tween 80. For (a and b), magnification is 400× and bar is 10 μm. For (c and d), magnification is 5000× and bar is 10 μm.

Highly loaded, sustained-release microparticles of curcumin for chemoprevention

Curcumin, a dietary polyphenol, has preventive and therapeutic potential against several diseases. Because of the chronic nature of many of these diseases, sustained-release dosage forms of curcumin could be of significant clinical value. However, the extreme lipophilicity and instability of curcumin are significant challenges in its formulation development. The objectives of this study were to fabricate an injectable microparticle formulation that can sustain curcumin release over a one-month period and to determine its chemopreventive activity in a mouse model. Microparticles were fabricated using poly(d, l-lactide-co-glycolide) polymer. A conventional emulsion solvent evaporation method of preparing microparticles resulted in crystallization of curcumin outside of microparticles and poor entrapment (∼1%, w/w loading). Rapid solvent removal using a vacuum dramatically increased drug entrapment (∼38%, w/w loading; 76% encapsulation efficiency). Microparticles sustained curcumin release over four weeks in vitro, and the drug release rate could be modulated by varying the polymer molecular weight and/or composition. A single subcutaneous dose of microparticles sustained curcumin liver concentration for nearly a month in mice. Hepatic glutathione-s-transferase and cyclooxygenase-2 activities, biomarkers for chemoprevention, were altered following treatment with curcumin microparticles. The results of these studies suggest that sustained-release microparticles of curcumin could be a novel and effective approach for cancer chemoprevention.