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Clinical Relevance of Drug Release Testing James E. Polli [email protected] October 3, 2016 Outline • In vitro dissolution in development • Experimental findings – Volume – Food effect – Surfactant effect Two of the Most Common Complaints about In Vitro Dissolution • Too sensitive (i.e. over discrimination) • Not sensitive enough (i.e. not discriminating enough) • Opportunities – Regulatory relief – Methods development/standardization of more challenging dissolution problems (e.g. BCS class 2) Comments of Dr. M. Pernarowski • “Dissolution methodology exists. It is an exercise in futility. It is a necessity. It is all things to some; very little to others. Why then do we determine the dissolution characteristics of tablets and capsules …? Comments of Dr. M. Pernarowski • “… First, we determine dissolution times to insure biological availability. The state of the art is far from perfect and it is for this reason that we must hedge and state that dissolution per se is no guarantee of therapeutic efficacy. At the same time, I do not think it wise to continually argue that dissolution has no in vivo significance. This is simply a mis-statement of facts and tends to downgrade the importance of the technique. Comments of Dr. M. Pernarowski • “…[Secondly] A discriminating method for the determination of dissolution characteristics is an excellent research tool. … Products with poor dissolution characteristics are obviously poor candidates for the market place or for clinical trials. … Unfortunately, the converse is not always true. … Laboratory tricks whose sole purpose is to increase the rate of solution are … not always a guarantee that the formulated product will be biologically available. Comments of Dr. M. Pernarowski • “[Thirdly] Lastly, … various methods are now being used to control manufactured products. Such a control method is more capable of detecting difference between products … and different lots of the same product than is the traditional disintegration test.” Use of Surfactant: What do we want? Complications • Attaining complete dissolution and sink conditions – Enhanced drug solubility (e.g. via additional surfactant) tends to reduce dissolution test sensitivity. • Same EVERYTHING across dose strengths – Historical tendency to prefer the same test methods and same specs, even though different doses can result in a fundamental change in the dissolution problem. • A higher dose may dissolve slower or to a lesser extent, than lower dose. Effect of Dosage Form Size on Dissolution T Higuchi (1961). Rate of release of medicaments from ointment bases containing drugs in suspension. J Pharm Sci 50:874-874. Dissolution in Formulation Design re-assess initial effort in vivo dissolution in vivo performance prediction Roles of In Vitro Dissolution • Product development tool • QC test • Clinically relevant assessment tool [a/k/a in vivo performance test] – Meaning? • A measure of in vivo dissolution – As assessed by deconvolution of PK profile when absorption is dissolutionlimited? Need for a Second In Vitro Dissolution Method • QC test – Use: current application in batch-to-batch consistency • Clinically relevant assessment tool [a/k/a in vivo performance test] – Meaning? – Use: Product development tool; SUPAC-type situations Biopharmaceutic Risk from 2009-2012 32 NDAs vs 4 INDs n=25 oral solid dosage forms From: Dr Sandra Suarez Sharp, “FDA’s Experience on IVIVC-New Drug Products”, PQRI Workshop on Application of IVIVC in Formulation Development, September 5-6, 2012. Meaning of “In Vivo Performance” • • • • In vivo dissolution (profile) In vivo absorption (profile) In vivo pharmacokinetic profile Sensitive to efficacy or safety • All above are related, but lack of clarity is a barrier. • Do we want in vitro dissolution to predict first-pass metabolism? • We have to be careful about what we expect of in vitro dissolution. Lack of clarity detracts from reliable utility of in vitro dissolution. • IVIVR – in vitro dissolution – in vivo absorption relationship – Absorption = dissolution + permeation Status Quo • Organizations will often not pursue approaches that lack utility in drug development or lack high regulatory certainty. • Status quo – Stakeholders know current strength/limitations of in vitro dissolution – Budget • No requirement for “biostudies with several formulations” • Uncertain elements – Budget – Acceptable role of modeling and simulation Dissolution in Development • “Our boss, who is not a dissolution person, thinks our lab is problematic. Our results from using well-known ‘biorelevent media’ do not agree with in vivo PK.” Novel In Vitro Dissolution Methods • Two major elements – Apparatus and operating conditions – Media • Apparati – Compendial – Two or more “lumen” compartments (e.g. stomach and duodenum per ASD model) – Systems with “absorption compartment” (e.g. biphasic systems to mimic absorption during dissolution for low solubility drugs to avoid “too much” surfactant) Outline • In vitro dissolution in development • Experimental findings – Volume – Food effect – Surfactant effect Recent FDA Guidance 2015 Dissolution Guidance 2015 BCS Biowaiver Guidance In Vivo Dissolution Volume • Low solubility drugs : in vitro dissolution volume will impact in vitro performance of dosage form • Volume of water available for dissolution in vivo is << 900mL Mudie, D.M.; Murray,K.; Hoad, C.L.; Pritchard, S.E.; Garnett, M.C.; Amidon, G.L.; Gowland, P.A.; Spiller, R.C.; Amidon,G.E.; Marciani, L. Quantification of Gastrointestinal Liquid Volumes and Distribution Following a 240 mL Dose of Water in the Fasted State. 2014, 11, 3039−3047. Lamotrigine • • • • • Lamotrigine: BCS Class 2b drug Dose: 100mg At pH 4.5: exhibited both 3-fold and 10fold sink conditions in each 500 mL and 900 mL dissolution volumes At pH 1.2: exhibited 3-fold sink conditions, but not 10-fold sink conditions At pH 6.8: did not exhibit either 3-fold or 10-fold sink conditions pH Solubility (mg/mL) Volume to dissolve label amount (mL) Volume for 10fold sink conditions (mL) Volume for 3fold sink conditions (mL) 1.2 1.09 91.7 917 275 4.5 2.53 39.5 395 119 6.8 0.210 476 4760 1430 Volume % Dissolved in 15 min % Dissolved in 30 min 500 ml 900 ml 500ml 900ml 500ml 900ml 92.2 101.2 93.5 99.7 54.0 68.7 94.9 101.0 95.5 101.6 69.1 85.5 f2 (5-15min) f2 (5-30min) 47.2 56.4 58.0 59.2 47.0 42.0 Outline • In vitro dissolution in development • Experimental findings – Volume – Food effect – Surfactant effect In vitro Lipolysis Model Fe-Lipolysis/Fa-Lipolysis Danazol Amiodarone Ivermectin +ve food effect is > 30% AUC enhancement in the presence of food Bioavailability Enhancement Fe-Lipolysis/Fa-Lipolysis Drug AUC0-15 min ratio AUC0-30 min ratio (SEM) (SEM) in vivo AUC ratio (SEM) Danazol 2.28 (0.10) 2.46 (0.07) ≈ 3.00 Amiodarone 13.0 (0.2) 10.5 (0.3) ≈ 2.30 Ivermectin 8.35 (0.10) 8.13 (0.03) ≈ 3.00 Raman S and Polli JE (2016): Prediction of Positive Food Effect: Bioavailability Enhancement of BCS Class II Drugs. DOI: 10.1016/j.ijpharm.2016.04.013. Int. J. Pharm. 506:110-115. FeSSIF-V2L/FaSSIF-V2L Danazol Amiodarone Ivermectin +ve food effect is > 30% AUC enhancement in the presence of food Lipolysis Imaging Using AFM Lipolysis Time Course Analysis on AFM t = 0 min t = 5 min t = 15 min t = 30 min Electron Source Lipolysis Imaging Using cryo-TEM e- ee- e- ee2-D Image Colloids embedded in vitreous ice Magnetic Lens Fe-Lipolysis Analysis on cryo-TEM t = 0 min Colloidal structures observed: (a) unilamellar and multilamellar vesicles (b) lipid droplets Fe-Lipolysis Analysis on cryo-TEM t = 5 min Colloidal structures observed: (a) & (c) unilamellar and multilamellar vesicles (b) lipid droplets (d) micelles Fe-Lipolysis Analysis on cryo-TEM t = 10 min Colloidal structures observed: (a) unilamellar and multilamellar vesicles (b) lipid droplets (c) micelles Fe-Lipolysis Analysis on cryo-TEM Time (min) Danazol Colloidal particles observed 0 Lipid droplets, vesicles, micelles 5 Lipid droplets, vesicles, micelles, protein aggregates 10 Lipid droplets, vesicles, micelles, protein aggregates 15 Lipid droplets, vesicles, micelles 30 Lipid droplets, vesicles, micelles • Vesicles and micelles are primarily responsible for solubilization. • Highest amount solubilized is 10 min onwards Outline • In vitro dissolution in development • Experimental findings – Volume – Food effect – Surfactant effect Wood’s Apparatus G.D. Lehmkuhl and J.L. Hudson. Flow and mass transfer near enclosed rotating disc: experiment. Chem Engin Sci 26:1601-1613, 1971. Levich Equation J D 0.62 DD2 3 1 6w1 2 D • JD is the flux of the dissolving drug • DD is the diffusivity of free drug in the stagnant diffusion layer • v is the kinematic viscosity of the stagnant diffusion layer • w is the rotational speed of the Wood apparatus disk • [D] is the concentration of the drug at the surface of the tablet, which is assumed to be the aqueous drug solubility Objective • To assess the contributions of surfactant-mediated solubility and micellar diffusivity on the ability of surfactant to enhance drug dissolution. • Balakrishnan, A., Rege, B.D., Amidon, G.L., and Polli, J.E. (2004): Surfactant-mediated dissolution: contributions of solubility enhancement and relatively low micelle diffusivity. J. Pharm. Sci. 93:2064-2075. Model Development Model f m DD2 3M f 1 2 3 f f DD • f is the degree of surfactant-mediated dissolution enhancement • fm is the fraction of drug in micelle and ff is the fraction of free drug • DD and DD-M are the diffusivities of free drug and drug-loaded micelles, respectively. Influence of micelle diffusivity • If • If DD M DD M 23 DM = 0.1, D DD DD= 0.05, 23 D D DD2 3M = 0.215 23 D D = 0.136 Enhancement of griseofulvin solubility and dissolution by SDS and CTAB Fold Enhancement 120 Solubility Enhancement 105 90 Dissolution Enhancement 75 60 45 30 15 0 10mM SDS 20mM SDS 40mM SDS 60mM SDS Surfactant 6.67mM CTAB 13.32mM CTAB 20mM CTAB Observed versus predicted dissolution enhancement of griseofulvin by SDS and CTAB Observed Fold Enhancement 31 26 21 16 f m DD2 3M f 1 23 f f DD 11 6 1 1 6 11 16 21 Predicted Fold Enhancem ent SDS (closed circles) and CTAB (open circles) 26 31 Outline • In vitro dissolution in development • Experimental findings – Volume – Food effect – Surfactant effect