Liposomal Formulations of Inflammatory Bowel Disease Drugs: Local versus Systemic Drug Delivery in a Rat Model

Based on adherence to intestinal mucosa, intralumenally administered liposomal formulations of 5-aminosalicylate (5-ASA) and 6-mercaptopurine (6-MP) were studied for their potential to enhance local drug delivery to intestinal tissue for the treatment of inflammatory bowel disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41509/1/11095_2005_Article_5376.pd

Targeting of therapeutics to diseased intestinal tissue in inflammatory bowel disease.

Current therapies for inflammatory bowel disease (IBD) fail to address disease pathogenesis, providing only symptomatic alleviation, and lack organ specificity, with most of the drug reaching the systemic circulation rather than being targeted locally to the diseased intestine. The objective of this research project was to study two novel approaches to IBD therapy; adenoviral gene delivery and local liposomal drug delivery after intralumenal administration. Caco-2 cells in in vitro models of mucosal wound healing, ex vivo intestinal biopsy cultures and an in vitro M-cell model were employed to study interactions of adenoviral vectors and intestinal epithelium. Transgene expression was quantified by biophotonic imaging. The rat was used as an animal model for investigation of intestinal absorption and metabolism of the model compound, 6-mercaptopurine, administered in solution or as a liposomal formulation, coupled with HPLC and liquid scintillation counting bioanalytical methods. It was determined that restituting intestinal epithelial cells are transfected much more efficiently by adenoviral vectors than their healthy, confluent counterparts. The effect appears to be related to integrin and CAR expression by the restituting cells, associated with the migration process. Significant differences in adenoviral transduction of Caco-2 cells and M-cells compared to other epithelia cell types were observed. Liposomal formulation of 6-mercaptopurine, despite mucosal adherence, did not prove advantageous in terms of local delivery compared to solution. This is in contrast to previous studies with a 5-aminosalicylic acid liposomal formulation. The differences can be explained by the different physicochemical properties and absorption characteristics of the two drugs. This study suggests that gastrointestinal epithelium, in disorders such as IBD where epithelial restitution takes place, represents a valid target for gene transfer. As gastrointestinal gene delivery is still in its infancy, liposomal formulations that offer an increased drug residence time at the inflamed intestinal tissue due to mucosal adherence are an attractive alternative to traditionally used controlled/delayed release formulations of small drug molecules. However, drug physicochemical properties and intestinal absorption characteristics will dictate the potential for these formulations.Ph.D.Health and Environmental SciencesPharmaceutical sciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/124708/2/3150234.pd

Physiologically Based Absorption Modeling to Impact Biopharmaceutics and Formulation Strategies in Drug Development—Industry Case Studies

In recent years, there has been a significant increase in use of physiologically based pharmacokinetic models in drug development and regulatory applications. Although most of the published examples have focused on aspects such as first-in-human (FIH) dose predictions or drug–drug interactions, several publications have highlighted the application of these models in the biopharmaceutics field and their use to inform formulation development. In this report, we present 5 case studies of use of such models in this biopharmaceutics/formulation space across different pharmaceutical companies. The case studies cover different aspects of biopharmaceutics or formulation questions including (1) prediction of absorption prior to FIH studies; (2) optimization of formulation and dissolution method post-FIH data; (3) early exploration of a modified-release formulation; (4) addressing bridging questions for late-stage formulation changes; and (5) prediction of pharmacokinetics in the fed state for a Biopharmaceutics Classification System class I drug with fasted state data. The discussion of the case studies focuses on how such models can facilitate decisions and biopharmaceutic understanding of drug candidates and the opportunities for increased use and acceptance of such models in drug development and regulatory interactions

DISSOLUTION AND TRANSLATIONAL MODELING STRATEGIES ENABLING PATIENT-CENTRIC PRODUCT DEVELOPMENT M-CERSI WORKSHOP SUMMARY REPORT

Abstract On May 15th -17th 2017, the US Food and Drug Administration (FDA) and the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) held a workshop at the University of Maryland's Center of Excellence in Regulatory Science and Innovation (M-CERSI), Baltimore campus to discuss the role of dissolution testing and translational modeling and simulation in enabling patient-centric drug product development. This three-day event was attended by roughly 120 scientists from international regulatory agencies, major global pharmaceutical companies and academia. The recognition of patient-centric drug product development by the FDA and the scientific community is not a new concept, and yet, the number of submissions containing data that link product quality attributes to in vivo performance in order to enhance drug product understanding appears stagnant. In this regard, one of the areas of focus of the workshop was to discuss the gaps in knowledge and challenges that the scientific community is facing to establish this in vitro-in vivo link. The first day of the meeting focused on the role of dissolution testing to guide formulation candidate selection, to assess and to mitigate biopharmaceutics risks, and as a quality control tool. On the second day, approaches to establish a link between in vitro testing and in vivo drug product performance were presented. Overall success rates and challenges in establishing in vitro – in vivo correlations (IVIVC) via traditional and modern physiologically based pharmacokinetic (PBPK) modeling and simulation approaches were discussed. Day 3 provided an opportunity for regulatory agencies and industry to discuss their expectations for establishing clinically relevant drug product specifications. After the morning presentations, afternoon breakout sessions served as platforms for the discussion of key and controversial topics. The meeting concluded with a commitment to continue the dialogue between regulators, industry and academia to advance overall product quality understanding

Human intestinal fluid layer separation: The effect on colloidal structures & solubility of lipophilic compounds

In addition to individual intestinal fluid components, colloidal structures are responsible for enhancing the solubility of lipophilic compounds. The present study investigated the link between the ultrastructure of fed state human intestinal fluids (FeHIF) and their solubilizing capacity for lipophilic compounds, taking into account interindividual variability. For this purpose, FeHIF samples from 10 healthy volunteers with known composition and ultrastructure were used to determine the solubility of four lipophilic compounds. In light of the focus on solubility and ultrastructure, the study carefully considered the methodology of solubility determination in relation to colloid composition and solubilizing capacity of FeHIF. To determine the solubilizing capacity of human and simulated intestinal fluids, the samples were saturated with the compound of interest, shaken for 24 h, and centrifuged. When using FeHIF, solubilities were determined in the micellar layer of FeHIF, i.e. after removing the upper (lipid) layer (standard procedure), as well as in total FeHIF (without removal of the upper layer). Compound concentrations were determined using HPLC-UV/fluorescence. To link the solubilizing capacity with the ultrastructure, all human and simulated fluids were imaged using transmission electron microscopy (TEM) before and after centrifugation and top layer (lipid) removal. Comparing the ultrastructure and solubilizing capacity of individual FeHIF samples demonstrated a high intersubject variability in postprandial intestinal conditions. Imaging of FeHIF after removal of the upper layer clearly showed that only micellar structures remain in the lower layer. This observation suggests that larger colloids such as vesicles and lipid droplets are contained in the upper, lipid layer. The solubilizing capacity of most FeHIF samples substantially increased with inclusion of this lipid layer. The relative increase in solubilizing capacity upon inclusion of the lipid layer was most pronounced in samples that contained mainly vesicles alongside the micelles. Current fed state simulated intestinal fluids do not contain the larger colloids observed in the lipid layer of FeHIF and can only simulate the solubilizing capacity of the micellar layer of FeHIF. While the importance of drug molecules solubilized in the micellar layer of postprandial intestinal fluids for absorption has been extensively demonstrated previously, the in-vivo relevance of drug solubilization in the lipid layer is currently unclear. In the dynamic environment of the human gastrointestinal tract, drug initially entrapped in larger postprandial colloids may become available for absorption upon lipid digestion and uptake. The current study, demonstrating the substantial solubilization of lipophilic compounds in the larger colloids of postprandial intestinal fluids, warrants further research in this field.status: publishe

Using mechanistic modeling approaches to support bioequivalence assessments for oral products

This report summarizes the proceedings for Day 1 Session 3 of the 2-day public workshop entitled "Best Practices for Utilizing Modeling Approaches to Support Generic Product Development," a jointly sponsored workshop by the US Food and Drug Administration (FDA) and the Center for Research on Complex Generics (CRCG) in the year 2022. The aims of this workshop were to discuss how to modernize approaches for efficiently demonstrating bioequivalence (BE), to establish their role in modern paradigms of generic drug development, and to explore and develop best practices for the use of modeling and simulation approaches in regulatory submissions and approval. The theme of this session is mechanistic modeling approaches supporting BE assessments for oral drug products. As a summary, with more successful cases of PBPK absorption modeling being developed and shared, the general strategies/frameworks on using PBPK for oral products are being formed; this will help further evolvement of this area. In addition, the early communications between the industry and the agency through appropriate pathways (e.g., pre-abbreviated new drug applications (pre-ANDA) meetings) are encouraged, and this will speed up the successful development and utility of PBPK modeling for oral products. Graphical Abstract: [Figure not available: see fulltext.]