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Oral Bioavailability Dosage Form Solutions Low aqueous solubility resulting in poor oral bioavailability of drug candidates is an increasingly common challenge for the pharmaceutical industry. An estimated 60% to 70% of compounds in early development have poor bioavailability due to low solubility, representing a significant loss in economic and therapeutic opportunity. Capsugel Dosage Form Solutions has developed a patented delivery platform based on spray-dried dispersions (SDDs), which is available for license. SDD Functionality and Advantages Technology Overview •Enhanced oral bioavailability of poorly water-soluble compounds by attaining and sustaining a supersaturated concentration of drug in the gastrointestinal environment for biologically relevant time frames An SDD is a single-phase, amorphous molecular dispersion of a drug in a polymer matrix. SDDs are prepared by dissolving drug and polymer in an organic solvent and then spray-drying the solution. The formulation and process conditions are chosen to quickly evaporate the solvent from the droplets, allowing insufficient time for phase separation or crystallization. •A solid, shelf-stable drug form that avoids crystallization or phase separation of amorphous drug and is suitable for delivery using suspensions or traditional solid dosage forms such as tablets and capsules Capsugel Dosage Form Solutions formulates SDDs using a number of commercially available polymers, including hydroxypropyl methylcellulose acetate succinate (HPMCAS). Due to the high glass-transition temperature and low water sorption of HPMCAS, “homogeneous” SDDs made from this polymer have robust physical stability, allowing long-term storage over a wide range of conditions without amorphous phase separation or crystallization of the drug, which could negatively affect performance. These properties also allow SDDs to have higher drug loadings than solid dispersions manufactured with more-hydrophilic polymers. For some drugs and some problem statements, alternate polymers, or polymers and surfactants, are used to provide optimal performance and acceptable stability. •A reproducible, controllable, and scalable manufacturing process that can be used from discovery to commercial production •A technology that is broadly applicable to structurally diverse insoluble compounds across a wide range of physical properties [Compound] ( µ g/mL) 70 60 50 SDD (HPMCAS) Crystalline drug Spray-dried PVP dispersion Amorphous drug 40 30 20 10 0 0 30 60 90 Time (min) Figure 1. In Vitro Concentration Profiles Over Time for an HPMCAS SDD, Spray-Dried PVP Dispersion, Amorphous Drug, and Crystalline Drug in Simulated Intestinal Fluid (Test Concentration = 100 μg/mL) The amorphous drug in an SDD is in a high-energy state relative to crystalline drug. When placed into an aqueous solution, SDDs dissolve to a drug concentration well above the solubility of the drug’s crystalline form. Interaction of the drug with the polymer inhibits conversion of the drug to a lower-energy form. The higher drug concentration provides the driving force for rapid absorption of the drug. Because of the strong interaction of HPMCAS with a wide variety of drugs, the performance of these SDD formulations is often superior to that of other dispersion systems, such as those based on polyvinyl pyrrolidone (PVP). Figure 1 shows concentrationversus-time profiles for an example HPMCAS SDD, a spray-dried PVP dispersion, amorphous drug, and crystalline drug. Performance SDDs can be prepared from compounds with a broad range of physicochemical properties, including: •Aqueous solubilities as low as 0.001 μg/mL 700 Plasma Concentration (ng/mL) Capsugel Dosage Form Solutions has formulated more than 1,000 compounds as SDDs for in vivo testing. In addition, more than 80 compounds have been formulated as SDDs and manufactured at Capsugel Dosage Form Solutions for advancement to Phase 1 through Phase 3 clinical trials. 600 500 400 200 100 0 0 •Log P values from 1 to more than 8 •Melting points from 0°C to 300°C and greater •Acidic, basic, or neutral composition SDD absorption enhancement relative to crystalline drug ranges from around 2-fold to more than 50-fold. Figure 2 shows clinical results for plasma concentration versus time for an HPMCAS SDD and crystalline drug. Stability SDD (HPMCAS) Crystalline drug 300 6 12 18 24 Time (hr) Figure 2. Clinical Pharmacokinetic Profiles for SDD and Crystalline Drug Dosed to Healthy Volunteers (Dose = 200 mg, Fasted State; Aqueous Solubility = 1.3 μg/mL; Crystalline Drug Size = 5 μm) results in low bulk drug requirements for early-stage testing and rapid turnaround times to support fast-paced projects. Safety SDDs with shelf lives of more than 2 years have been consistently demonstrated. Proven physical-stability models allow reliable identification of stable formulations from short-term data. An extensive safety package addressing chronic oral use of HPMCAS is available in an FDA Type V Drug Master File for reference when using Capsugel Dosage Form Solutions SDD technology. Manufacturability Progressible Dosage Forms SDD manufacturing has been reproducibly demonstrated at scales from milligrams to metric tons, enabling production of developmental quantities through Phase 3 clinical supplies and product launch. Process development, technology transfer, and scale-up are successfully achieved using a comprehensive set of experimental tools and fundamental models. This The excellent stability and physical properties of SDDs makes them well-suited to suspensions and traditional solid dosage forms such as tablets and capsules. Capsugel Dosage Form Solutions also has extensive experience in developing and manufacturing immediate- and controlled-release dosage forms for SDDs. About Capsugel Dosage Form Solutions Capsugel’s Dosage Form Solutions business unit solves customers’ most pressing product development challenges, including bioavailability enhancement, modified release, abuse deterrence, biotherapeutic processing, and inhalation formulation. We utilize an integrated product development approach ensuring that our clients can rely on one partner from design to commercial scale production of innovative drug product intermediates and finished dosage forms. Capsugel Dosage Form Solutions accelerates and improves product development through an array of technologies including lipids and liquids, spray-dried dispersions, hotmelt extrusion, and through specialized manufacturing including FDA/ MHRA-accredited finished dosage sites that can handle highly potent, controlled substance, hormonal and oncology compounds. High quality science and engineering is core to our offering at each stage of the product development cycle and has enabled the successful advancement of hundreds of compounds. For more information on our oral bioavalability technology contact us at [email protected], visit capsugel.com, or reach a Capsugel representative directly at: Europe, Middle East & Africa: +44 (0) 150 644 8080 | North America: +1 (541) 382-4100 Capsugel will use reasonable efforts to include accurate and up-to-date information on this brochure but makes no warranties or representations of any kind as to its accuracy or completeness. The entire contents of this brochure are subject to copyright protection. Copyright © 2014 Capsugel Belgium NV. All rights reserved. GMCN 201409018