Thursday, November 20
8:30 am Morning Coffee
Dissolution, Solubility and Bioavailability
9:00 Comments by Session Chairperson
9:15 Using Dissolution in Biorelevant Medium to Guide Formulation Selection
Jesse L. Kuiper, Ph.D., Senior Research Chemist, PAC PR & D, Merck Research Laboratories
Recent trends show an increasing fraction of new drug candidates that have poor aqueous solubility, creating a challenge to make formulations that maximize bioavailability and improve API delivery to the intended therapeutic target arises. To guide the development of formulations, which will be successful under in vivo conditions, it is important to have in-vitro dissolution methods that ideally reflect in vivo performance. Biorelevant dissolution media are designed to simulate gastrointestinal conditions, and provide a higher probability of success in establishing in vivo/in vitro relationships, thus guiding formulations of poorly soluble APIs. In this study, we conducted dissolution in Simulated Gastric Fluid (SGF) and Fasted State Simulated Intestinal Fluid (FaSSIF) to guide early phase formulation development. The results were critically compared with in vivo results from humans and animals to understand the scope and limitations of dissolution in biorelevant media.
9:45 Applications of Nonclinical In vitro and In vivo Models in the Development of Low Solubility Compounds: Key Issues and Considerations for Evaluating Formulations in Early Development
Gary Eichenbaum, Ph.D., J&J Pharmaceutical R&D, LLC
10:15 Solubilization Patterns and Implications for Formulation Design
John P. Rose, Ph.D., Research Computational Chemist, Biopharmaceutics & Drug Delivery, Eli Lilly & Co.
We present work designed to delineate patterns of solubilization behavior across a matrix of pharmaceutically relevant molecules and formulation vehicles. Measured solubilities, ranging from 0.1 to 65 mg/mL were acquired for 104 molecules in 88 diverse vehicles to generate an extensive collection of ~9000 solubility measurements. Solubility profiles or “fingerprints” for each molecule and vehicle were used in clustering methods to elucidate the predominant solubilization patterns. A computer model was built on the molecule cluster results to derive a “reduced” solubility fingerprint that describes the structure of solubilization space equivalently to the full fingerprint. Test results suggest that the model may provide an efficient means for guiding formulation exploration by grouping a large list of potential vehicles into classes of similar solubilization behavior.
10:45 Networking Coffee Break, Poster and Exhibit Viewing
11:15 Formulation Development for Preclinical and Clinical Studies
Vishal Saxena, Ph.D., Senior Scientist, TRD, Novartis Institute for BioMedical Research
Dosage form (formulation) plays a very important role in preclinical and clinical studies. In many disease areas, most of the new chemical entities have a poor aqueous solubility. These are often available in the amorphous and chemically impure form for in vitro enzyme assay, pharmacokinetic, pharmacological and toxicity studies in animal models. These molecules are often dosed as a suspension/solution and candidate selection is done based on results obtain during these studies. It is very important to select a physical form as early as possible so that same form can be used for preclinical studies and clinical studies. The change in physical form or formulation principle could significantly affect the bioavailability and stability of formulation. Selected candidate must be physically and chemically stable during formulation development process with desirable pharmacokinetic parameters. If bioavailability is significantly different than that obtained from preclinical studies, lot of efforts will be required in formulation development. Ultimately it will increase the time to develop formulation for first in human. This presentation will cover the different technologies for the success of new chemical entity from pre-formulation to drug delivery into clinic.
11:45 Materials Science: Integrated API and Drug Product Design
Keith Horspool, Ph.D., Senior Director, Pfizer, Inc.
This presentation will show how Pfizer, Inc. is incorporating form, formation and formulation into one organization to create integrated design from molecules through to dosage forms.
12:15 pm Modified Conventional Formulation Approaches for a Poorly Water Soluble Drug
Danping Li, Ph.D., Director, Formulation Development, Rib-X Pharmaceuticals
Strategy and methods to create micro-environmental conditions to enhance drug dissolution, and achieve super-saturation will be presented. The strategy involves selection of salts, drug surface area and excipients, which can enhance drug solubility and achieve super-saturation. It requires understanding the fundamentals of solubility and diffusion during dissolution and crystallization retardation. Case studies will also be presented.
12:45 Luncheon Technology Workshop (Sponsorships Available) or Lunch on Your Own
Delivery
2:00 Comments by Session Chairperson
2:10 BiotransportTM Technology for Converting Anticancer Injectables into Oral Dosing Forms
Valery Alakhov, Ph.D., Vice President, R&D and CSO, Supratek Pharma Inc.
Convenience of use and high dosing flexibility of oral cytotoxics has been proven, with the most known and successful example being capecytabine (Xeloda). However, converting injectable anticancer drugs into equivalent oral dosing forms remains a challengine task, mainly due to a low systemic absorption that is limited by ABC transporters that are highly expressed in the drug absorption sites, limited drug solubility, high rate of first pass drug metabolism, and, in some cases, saturability of the drug absorption rate related to a low transition time in the absorption site. We have developed a robust and flexible polymer-based technology that allows creating pharmaceutically acceptable compositions that are free of the above problems. The examples of such compositions and their clinical development models will be presented including topotecan with selectively increased absorption of lactone form, soluble and orally bioavailable paclitaxel, and magesterol actetate with increased transition time.
2:40 Delivery of siRNA: Opportunities and Challenges
Roger Adami, Ph.D., Associate Director, Molecular Pharmaceutics, MDRNA Inc.
Dicer and novel constructs provide highly effective siRNAs, particularly when combined with appropriate modifications. For maximal activity, potent siRNAs must be paired with highly effective delivery formulations. MDRNA is developing novel lipids to reduce toxicity and enable attachment for targeting entities. Peptide conjugates demonstrate activity; peptide-siRNA nanoparticles improve systemic delivery, and in combination with modified lipids, peptides increase siRNA payload. These delivery options are proving essential for developing siRNA therapeutics.
3:10 Networking Refreshment Break, Poster and Exhibit Viewing
3:40 Solving the Biopharmaceutical Stability Problem: Fast Dynamics as an Indicator of Protein Stability in Glass
Marcus T. Cicerone, Ph.D., Biomaterials Group Leader, NIST Polymers Division
In this presentation I will describe methods development work that is aimed at filling out the set of characterization tools needed to predict function of these protein-preserving glasses. This work, based largely on protein aggregation and chemical stability studies, results from neutron scattering and measurements of hydrogen bond network lifetimes, has already led to a much more complete picture of the important physical parameters that impact protein stability in the glass. The methods we are developing are relatively straightforward and simple to implement, and we believe that they show promise for significantly streamlining the lyophilization formulations process.
4:10 Formulation of Small Molecules for Optimum Inhalation Delivery
David Cipolla, Ph.D., Senior Director of Pharmaceutical Sciences, Aradigm Corporation
Most inhaled drugs are small molecules delivered by MDIs, DPIs or nebulizers to treat pulmonary diseases like asthma and COPD. This session will provide a tutorial on the factors that drive the formulation and device selection decision. Innovative formulations and delivery technology will be discussed. Two case studies will be shared including the development of an inhaled sustained release antibiotic to treat lung infections and inhaled nicotine for smoking cessation.
4:40 Closing Comments
5:00 End of "Drug Formulation" Conference