Providing insight into pharmaceutical formulations

Transcription

1 Providing insight into pharmaceutical formulations Dr Steve Ward-Smith

2 Pharmaceutical Industry The average cost of developing a drug is reported to be approx $500 million, but up to 70% of new chemical entities do not generate enough revenue to recoup their R&D costs or don t even make the market. Maximizing the return on drugs that break even is an important objectives for pharmaceutical executives. The use of new drug delivery technologies and reformulation strategies to extend the time to peak sales and thus increase the return on their R&D investment. (Product Extension)

3 Trends in Drug Discovery Automation, high throughput processes, and technologies such as miniaturization. Researchers need to identify quickly and focus upon the most promising drug candidates at the earliest possible point in the drug discovery process. The challenge is to develop analytical methods to process the large amounts of data being generated at these early stages of development to arrive at the most suitable candidates for drug development.

4 Why characterise drugs? Absorption of drugs into the body controlled by size Control of micronising, blending and coating processes Particle size controls intake into the lungs for inhaler products Rheology of a topical cream affects its application onto the skin Shape of a particle affects the compaction (tableting) ability

5 Why do we need to do it? FDA Drug Control Institutes Return on investment Controlled manufacturing techniques Adverse events Patient care Optimisation of usage Product/Research & Development

6 Typical innovator pharma From discovery to drug.a decade in the making Time line for drug development for a typical Innovator company All these areas of development require the use of a Malvern technology at some stage or another

7 Typical generic pharma Steps and timelines in generic pharma 2 years and on the market Pre-formulation 2-3 months Prototype Development 4-6 months Scale Up 4-6 months ANDA filing 2-3 months FDA Approval 6-12 months Literature, patent search Innovator Characterization Excipient compatibility Optimize Excipients Select Manuf. Process Match dissolution profiles Stability Manufacture under cgmp Stability BE Bio-Equivalence Bio-Equivalence Failure

8 Developing the Manuf. Process Typical process flow and CQA s for Oral Solid Dose Raw Material & Dispense Pre-Blend Granulate Dry Mill De-Lump Blend Compress or Encapsulate Coating Ident. Particle Size Moisture Bulk Density Particle Size Granule Size Agglomerate Size Moisture Moisture Particle Size Particle Size BU Particle Size Bulk Density Moisture Flow CU Disintegration Dissolution Weight Thickness Hardness Friability Coating Uniformity Coating Thickness Dissolution Mass gain

9 Intralipid Emulsion Particle Size Distribution 12 Volume (%) Particle Size (µm)

10 z-average Diameter (nm) Cyclosporin Microemulsions Formulation 1 Formulation 2 Formulation 3 Formulation Time after sample preparation (hours)

11 Size and shape - Starch Quantitative difference in circularity between the two samples Could impact flowability and handling (hopper filling?)

12 Pharmaceutical Aerosols Why? Inhaled drug formulations Throat Deposition Impaction (>5µm) Upper Airways Sedimentation (1-5µm) Lung Deposition Diffusion (<2µm) Clive Washington: Particle size analysis in pharmaceutics and other industries: Theory and Practice p179 Ellis Horwood, 1992 ISBN:

13 Dry Powder Inhalers Actuation Comparison (Dv50) 120 Formulation A Formulation B 100 Dv50 / Microns Formulation A shows a higher fine particle fraction Time / sec

14 Particle size flow rate dependence for the unprocessed lactose powder

15 Particle size flow rate dependence for the Grindomix powder

16 Particle size flow rate dependence for the Mechofused powder

17 Changes to process leads to changes in aerosolisation behaviour Agglomerates are coated Agglomerates High Shear Blender + Mg Stearate Mechanofusion Each grain is dispersed and coated

18 Changes to process leads to changes in aerosolisation behaviour Agglomerates are coated Agglomerates High Shear Blender + Mg Stearate Mechanofusion Each grain is dispersed and coated

19 Acknowledgements My colleagues at Malvern Instruments, most notably Dr Paul Kippax