ASSESSING THE DRUG RELEASE FROM NANOFORMULATIONS WHEN, WHY AND HOW?

Transcription

1 ASSESSING THE DRUG RELEASE FROM NANOFORMULATIONS WHEN, WHY AND HOW? Matthias G. Wacker, PhD Pharma Test Workshop Series 2016 NANOTECHNOLOGY IN THE PHARMACEUTICAL INDUSTRY

2 DRUG RELEASE FROM NANOFORMULATIONS Dissolution rate increases with surface area (Noyes-Whitney) Rising saturation solubility for small particles occurs (Ostwald ripening) Nanocrystals are synthesized to achieve high dissolution pressure Burst release is a common problem of nanocarrier technology Surface area

3 DRUG RELEASE TESTING Quality control Testing dosage forms in a standardized setup Detecting different formulation qualities from batch to batch Biorelevant release testing Discriminating between different formulations Simulating physiological environment Predicting the in vivo performance of dosage forms (IVIVC) In vitro digestion testing of nanomaterials Investigating material degradation in biorelevant medium Simulating physiological environment

4 QUALITY CONTROL Discriminating between batch qualities in a low-cost procedure with simple medium composition Detect changes in manufacturing process, excipients or stability issues Short release interval and automated setup where possible Source: Pharmatest Apparatebau GmbH

5 BIORELEVANT RELEASE TESTING Simulate physiological environment, e.g. by using biorelevant media containing physiological dissolution enhancers (proteins, bile salts) Simulate effects that were be observed in vivo (e.g. gastric emptying) Predict in vivo data based on in vitro experiments Source: Pharmatest Apparatebau GmbH; AGW

6 IN VITRO DIGESTION MODELS Confirming particle size properties to characterize nanomaterials after exposure to biorelevant media Detect particle dissolution, aggregation or degradation in biorelevant media Comply with EU and US guidelines Dynamic light scattering Powder diffration AFM Particle size Electron microscopy TEM Analytical ultracentrifugation SEM Field flow fractionation

7 DRUG RELEASE MEDIA Quality control Aqueous buffer media Surfactants and other excipients to support dissolution process Biorelevant release testing Physiological fluids (e.g. blood, plasma, intestinal fluids) Simulated physiological fluids In vitro digestion models Physiological fluids optimized to monitor degradation Enzymes and proteins Optimized to allow size measurement from medium

8 DRUG RELEASE MEDIA FOR NANOFORMULATIONS Medium Setup for drug release Reference Human plasma Non-compendial flow-through cell setup (Gido, Langguth et al. 1993; Gido, Langguth et al. 1994) HEPES buffer 7.4 Phosphate buffer saline 7.4 Phosphate buffer 7.4 supplemented with fetal calf serum (10-90%) Phosphate buffer 7.4 supplemented with fetal calf serum (50%) Dialysis bag (USP2) Reverse dialysis bag (USP2) Flow-through cell(usp4) with A4D adapter Modified basket (USP1) (Bhardwaj and Burgess 2010) (Abdel-Mottaleb and Lamprecht 2011) Dispersion releaser (USP2) (Janas, Dressman et al. 2013) Dispersion releaser (USP2) (Villa Nova, Janas et al.) FaSSGF / FaSSIF / FaSSIF V2 FeSSGF / FeSSIF / FeSSIF V2 FaSSIF V2 USP apparatus 2 with syringe filters USP apparatus 2 with syringe filters Juenemann, Jantratid et al. ( )2010 (Beyer, Moosmann et al. 2015)

9 METHODOLOGY FOR DRUG RELEASE TESTING Nanoformulations require optimized separation technology Methods must discriminate between nanoparticles and dispersed drug molecules Careful sampling is required to detect drug release without disrupting formulation structure Methodology for drug release testing includes Sample and separate Dialysis

10 SAMPLE AND SEPARATE Separation techniques such as mechanical filtration or solid phase extraction are applied Both methods may affect stability of the carrier Accurate selection of filter pore size, SPE or filter material and medium Adsorption Separation (Cut-off) Disruption

11 SAMPLE AND SEPARATE Mechanical filtration devices Careful selection of filter membrane and pore size required Not applicable to sensitive formulations such as micelles, liposomes, emulsions Relevant for solubility-driven release Applicable to many peroral IR nanocrystal formulations

12 SAMPLE AND SEPARATE Biorelevant release test of microsized fenofibrate by applying sample and separate with syringe filters of different pore sizes Microparticle are well-separated by different filter pore sizes Source: Juenemann et al. 2011, Eur. J. Pharm. Biopharm.

13 SAMPLE AND SEPARATE Release samples collected with nanoparticles from FaSSIF Only one filter reflects equilibrium solubility of fenofibrate over 24 h Filter pore size Source: Juenemann et al. 2011, Eur. J. Pharm. Biopharm.

14 SAMPLE AND SEPARATE Solid particle formulation of poorly soluble compound TMP001 (logp=10,417) Microparticle formulation and nanoparticle formulation Free drug Nanoformulation Microformulation Setup USP2/syringe filter 0.1 µm ph 6.8 Medium FaSSIF V2 Source: Beyer et al. 2015, Pharm Res

15 SAMPLE AND SEPARATE Solid phase extraction Affinity-based separation technique SPE column must have poor affinity to formulation excipients Applicable to some core-loaded liposome formulations Requires careful validation to separate excipient and API by affinity Source: Guillnot et al. 2015, Pharm Res

16 DIALYSIS Separation by dialysis in combination with the compendial equipment such as USP apparatus 2 (paddle) or USP apparatus 4 (flow-through cell) Sensitive when k1 << k2 k2 is higher for compounds with moderate or good solubility k1 k2 Source: Ashtikar et al. 2016, J Pharm Pharmacol (In preparation)

17 DIALYSIS Evaluating different membranes in a continously monitored dialysis setup (optimal data collection) Membrane transport for one compound comparing CE and RC membranes Calculation of k2 from the release profile Source: Xie et al. 2015; Int J Pharm

18 DIALYSIS Same pore size but different membrane materials Sensitivity of measurement with cellulose ester (CE) is much higher than with RC (regenerated cellulose) Pore size and membrane material are essential Source: Xie et al. 2015; Int J Pharm

19 DIALYSIS Membrane transport k2 needs to quick when release rate is high Comparing dialysis techniques needs to be done with fast and slow-releasing drug delivery systems Source: Xie et al. 2015; Int J Pharm

20 DIALYSIS Dialysis bag Dialysis membrane closed by two clamps Poor membrane penetration and partitioning High variability at high dissolution rates Works well for slow-releasing dosage forms or drugs with moderate or good solubility Source: Ashtikar et al (In preparation)

21 DIALYSIS Flow-through cell USP4 allows release testing in open-loop and closed loop systems Sotax offers the A4D adapter for nanoformulations High cell-to-cell variability in flow rate when used at a pumping rates of below 1 ml/min Works well for API with moderate or good solubility and/or high flow rate (low k2) No evaporation in open-loop configuration Source: Ashtikar et al (In preparation); European Pharmacopeia;

22 DIALYSIS Investigation of Dexamethasone liposomes in different systems compared to A4D Sink conditions were applied Reduced sensitivity especially when release rate is high Source: Bhardwaj et al. 2010, Int J Pharm

23 DIALYSIS Dispersion releaser USP2 is a robust standard setup used for quality control of IR formulations Pharma Test offers the dispersion releaser High sensitivity for fluctuations in release rate Works well for compounds with poor, moderate and good solubility (high k2) Evaporation occurs in long-term experiments Source: Ashtikar et al (In preparation); Janas and Wacker 2013, DE

24 DIALYSIS Parenteral polymeric micelle formulation of poorly soluble API (logp=9,57) Batch-to-batch reproducibility in quality control Formulation highly sensitive to shear forces Batch 1 Batch 2 Setup USP2/dispersion releaser ph 7.4 Medium phosphate buffer saline foetal calf serum 10% Source: Villa Nova et al. 2015, Int J Pharm

25 DIALYSIS Dialysis bag vs. dispersion releaser tested with free compound assuring sink conditions Solid particle formulation with sustained release properties Free drug, dispersion releaser Free drug, dialysis bag / SR formulation 1 /2 Setup USP2 / dialysis bag or dispersion releaser ph 7.2 Medium phosphate buffer saline 10% FCS Source: Janas et al (In preparation)

26 DIALYSIS Sampling from inner compartment during dialysis-based release test Particle aggregation and dissolution effects after administration Biorelevant media specifically designed to monitor degradation but to allow size measurement F1-4 0h 24 h Water Medium 1-2 Medium nm Source: Modified from Janas et al. 2013, AAPS Annual Meeting & Exposition

27 SUMMARY Nanoformulations have high dissolution pressure compared to other formulations Release rate can be quantified by sample and separate or dialysis Sample and separate approaches require careful sampling to avoid shear forces and forced extraction Dialysis requires additional care in membrane selection and needs to be optimized to increase membrane transport Biorelevant release testing can also be employed for nanomaterial testing to comply with EU guidelines

28 NANOMETRX NanoMetrX is a Fraunhofer IME project setting up methodology for testing nanomaterials, e.g. Analytical technology identifying nanomaterials Analytical technology identifying degradation and dissolution behavior Analytical technology identifying routes of release Open platform is provided to all manufacturers

29 NANOMETRX Submit a sample without participating in NanoMetrX Submit a sample free of charge Retain all rights Analytical technologies provided on a fee-for-service basis Submit a sample with participating in NanoMetrX Join the collaboration and support NanoMetrX financially and with your infrastructure Use our methodology for your products free of charge

30 ACKNOWLEDGEMENTS Dr. Mukul Ashtikar Dr. Bassam Al Meslmani Susanne Beyer Monica Villa Nova Christine Janas Aline Moosmann Xie Li Laura Jablonka Manuela Thurn Prof. Dr. Jennifer Dressman Prof. Dr. Marcos Bruschi Prof. Dr. Michael Parnham