Implementation of a fully integrated continuous manufacturing line for direct compression and coating at a commercial pharmaceutical facility - Part 1: Operational considerations and control strategy.

We implement a fully integrated continuous manufacturing (CM) line for direct compression and coating of a pharmaceutical oral solid dosage form in a commercial production facility. In this first paper of a two-part series, we describe process design and operational choices made to introduce CM using infrastructure originally intended for batch operations. Consistent with lean manufacturing principles, we select equipment, facilities, and novel process analytical technologies that meet production agility goals alongside an existing batch process.

Application of in vitro transmucosal permeability, dose number, and maximum absorbable dose for biopharmaceutics assessment during early drug development for intraoral delivery.

Intraoral (IO) administration is a unique route that takes advantage of transmucosal absorption in the oral cavity to deliver a drug substance locally or systemically. IO delivery can also enhance or enable oral administration, providing a better therapeutic benefit/safety risk profile for patient compliance. However, there are relatively few systematic biopharmaceutics assessments for IO delivery to date.

Electrostatic interactions of monoclonal antibodies with subcutaneous tissue.

Aim: The majority of the subcutaneously injected monoclonal antibodies already on the market achieve 50-65% bioavailability, yet the fate of the portion that is lost remains unknown. This consistently incomplete systemic absorption affects the efficacy, safety and overall cost of the drug product. There are many potential factors that might influence the absorption, such as charge, hydrophobicity, formulation variables and the depth and volume of the injection.

Decoupling the role of image size and calorie intake on gastric retention of swelling-based gastric retentive formulations: pre-screening in the dog model.

Gastric retention is postulated as an approach to improve bioavailability of compounds with narrow absorption windows. To elucidate the role of image size on gastric retention and pharmacokinetics, formulations with different image sizes and swelling kinetics but similar dissolution rates were designed and imaged in dogs. Diet had a clear effect, with increasing calorific intake prolonging retention in the dog model.

Pharmacokinetic and pharmacodynamic evaluation of a novel in situ forming poly(ethylene glycol)-based hydrogel for the controlled delivery of the camptothecins.

Inadequate drug delivery, due to problems associated with achieving constant therapeutic blood levels, has hampered the use of anticancer agents of the camptothecin (CPT) class. The objective of the current studies was to develop a depot delivery system for the water-soluble analog of CPT, topotecan (TPT). In this study, a 2-phase drug depot consisting of TPT-loaded liposomes entrapped in a poly(ethylene glycol) hydrogel was designed.

Membrane transport of camptothecin: facilitation by human P-glycoprotein (ABCB1) and multidrug resistance protein 2 (ABCC2).

Background: The purpose of the present study was to continue the investigation of the membrane transport mechanisms of 20-(S)-camptothecin (CPT) in order to understand the possible role of membrane transporters on its oral bioavailability and disposition.

Methods: The intestinal transport kinetics of CPT were characterized using Caco-2 cells, MDCKII wild-type cells and MDCKII cells transfected with human P-glycoprotein (PGP) (ABCB1) or human multidrug resistance protein 2 (MRP2) (ABCC2). The effects of drug concentration, inhibitors and temperature on CPT directional permeability were determined.

A hydrogel prepared by in situ cross-linking of a thiol-containing poly(ethylene glycol)-based copolymer: a new biomaterial for protein drug delivery.

A new poly(ethylene glycol)-based copolymer containing multiple thiol (-SH) groups was cross-linked in situ to form a polymer hydrogel under mild conditions. No organic solvent, elevated temperature, or harsh pH is required in the formulation or patient administration processes, making it particularly useful for delivery of fragile therapeutics, such as proteins. The in vitro release of fluorescein-labeled bovine serum albumin and the in vivo release of the model proteins, erythropoietin, RANTES and three PEG-conjugated RANTES derivatives showed sustained release for 2-4 weeks and demonstrated prolonged biological activity of the released proteins in animals.

Enhancing the anticancer efficacy of camptothecin using biotinylated poly(ethylene glycol) conjugates in sensitive and multidrug-resistant human ovarian carcinoma cells.

Background: Camptothecin (CPT) is an anticancer agent that kills cells by converting DNA topoisomerase I into a DNA-damaging agent. Although CPT and its derivatives are now being used to treat tumors in a variety of clinical protocols, the low water solubility of the drug and its unique pharmacodynamics and reactivity in vivo limit its delivery to cancer cells. To increase the anticancer efficacy of CPT a special drug delivery system is needed.