Oral Drug Delivery: What to learn from Imaging Studies? An update. Werner Weitschies University of Greifswald

Transcription

1 Oral Drug Delivery: What to learn from Imaging Studies? An update Werner Weitschies University of Greifswald 8th Global DDF Summit, Berlin, March 28, 2017

2 Outline Methodologies The classical role of imaging in biopharmaceutics Formulation development ( Seeing and disbelieving ) Impact of modern tools: Physiological imaging Understanding of physiological conditions at the site of drug delivery and absorption Generation of data sets for in vitro and in silico predictive tools

3 In vivo imaging techniques for biopharmaceutics Scintigraphy Requires labeling of drug delivery system with radioistope (Tc- 99m, In-111, Sm ) Magnetic Marker Monitoring (MMM), Magnetic Moment Imaging (MMI), pill tracking... Requires either labeling of drug delivery system with small amounts (MMM), large amounts (MMI) of ferromagnetic material or use of solid magnets as simulated dosage forms (pill tracking) Magnetic Resonance Imaging (MRI) No label or use of very small amounts of magnetic material Telemetric devices Camera(s): Given imaging ph: IntelliCap ph & pressure: SmartPill

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5 Classical applications of imaging in drug development Drug absorption site studies Scintigraphically controlled local drug delivery (IntelliCap) Determination of delivery system behaviour (preferentially in combination with pharmacokinetics) Transit (gastric emptying, small intestinal transit) Disintegration (immediate release, delayed release) Drug release: IVIVC Drug targeting (local or topical GI drug delivery) Drug development / Pharmaceutical development

6 Example: Scintigraphic images and GI transit overlay Avitriptan 150 mg labelled with Sm-153 % Activity in ROI Gastric Emptying Avitriptan ng/ml 40 Blood level 500 Jejunum Time (h) Marathe et al. Drug Metab Dispos :

7 C p (nmol/l) Postprandial felodipine plasma concentrations Proband 1 Proband 4 Proband 2 Proband 5 Proband 3 Proband Weitschies et al. J Control Rel t (min)

8 Classical imaging in biopharmaceutics: Problems Missing anatomical information: Discrimination of organs? Example: Sm-153 gives poor resolution (γ energy too low) Courtesy of Professor Clive Wilson

9 Classical imaging in biopharmaceutics: Problems Missing anatomical information: Discrimination of organs? Example: Anatomical variability Schiller et al., Aliment Pharmacol Ther :

10 Impact of modern tools: MRI Pros Anatomical imaging (organs visible) Environmental information ( spectroscopy ) Availability Safety Cons Low temporal resolution (transport dynamics?) Restricted body position (supine) Identification of dosage forms difficult

11 Applications of MRI in pharmaceutical development Determination of physiological conditions, e.g. gastric emptying colonic filling water distribution secretion dynamics. Transit studies (markers, dosage forms) incl. disintegration Functional interplays (e.g. water availability and drug absorption)

12 Characterization of stomach physiology

13 Characterization of gastric contents

14 Characterization of GI transit conditions Determination of the fluid volumes in the GI-tract under fasting and fed conditons. Is the small intestine a tube filled with water? Detection of capsules taken at different time points in the GI-tract of 12 healthy volunteers Are modified release dosage forms permanently in contact with intestinal water?

15 Magnetic Resonance Imaging (MRI) Dosage form : - Solid triglyceride (melting point >37 C; glycerol tripalmitate) - Identification by 1, 2 or 3 incorporated hydrogel pellets (diameter 2 mm) - Intake: 7 h (three dots), 4 h (two dots), 1 h (one dot) before imaging Schiller et al. Aliment Pharmacol Ther :

16 ?

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18 small intestine stomach ml ml minimum maximum median mean SD Schiller et al. Aliment Pharmacol Ther :

19 Water-contact of the capsules 19% 45% 14% 9% 77% 36% fasting within water in contact With water 1 h after meal without contact to water

20 Gastrointestinal (hydro)dynamics: Common belief in drug development

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23 Fasting intake conditions: The stomach How fast are the 240 ml swallowed with the dosage form emptied from the stomach and absorbed in the small intestine?

24 Hydrodynamic stomach model Garbacz et al. Eur. J. Pharm. Biopharm :

25 Fed intake conditions: The stomach What is inside the stomach after the FDA breakfast?

26 Volume (ml) Magnetic Gastric Resonance content volumes Imaging (MRI) Ingestion of 240 ml water Mean terminal volume change: 1.71 ± 0.26 ml/min 1w28 2w24 3m23 4m23 5w33 6w32 7m27 8m27 9m24 10w27 11m45 12m t (min) Koziolek et al. Mol Pharm :

27 Rapid emptying of water: Magenstrasse ( stomach road ) Magnetic Resonance Imaging (MRI) 0 s 36 s 72 s Maximum intensity projections of the stomach after ingestion of 240 ml of water (0 s indicates the starting point of drinking). 162 s 234 s Koziolek et al. Mol Pharm :

28 Rapid emptying of water: Magenstrasse ( stomach road ) Type I: Rapid intragastric disintegration/dissolution, evacuation of suspended/dissolved API with co-swallowed water via Magenstrasse Type II: Slow intragastric disintegration/dissolution, local enrichment due to poor gastric mixing (fundus region), evacuation ( wash out ) of suspended/dissolved API with later swallowed water via Magenstrasse Type III: Material mixed with gastric contents, evacuation with gastric chyme Koziolek et al. Adv. Drug Deliv. Rev. 2016

29 Fat fraction (%) Quantification of fat Magnetic Resonance Imaging (MRI) Proximal Distal Total t (min) Koziolek et al. Mol Pharm :

30 Fed Stomach Model Gastric mixing Site-dependent conditions inside the fed stomach 1 : Pylorus Low stress Little dosage form movement Gentle mixing Fundus High stress Intense dosage form movement Strong mixing Antrum Distal stomach Prox imal stomach Koziolek et al. Mol Pharm : A noise

31 Distribution of the capsules in the GI tract Fasting 1 h after meal Schiller et al. Aliment Pharmacol Ther :

32 Work in progress: gastro-ileal reflex Impact of stomach on deeper compartments of GI tract Gastric filling influences the filling of the colon Gastro-ileal reflex triggered by gastric wall distension and caloric stimulus T2w MRI of gastrointestinal fluids 20 min and 40 min after intake of 240 ml carbohydrate solution OrBiTo Task: MRI study in combination with probe drug sulfasalazine Correlation of gastric volume and caloric stimuli with colonic volumes and sulfapyridine occurrence in plasma

33 entrinsic TM DCC: Imaging results Example: MRI scans of capsule tracking 5 min: stomach 75 min: stomach 150 min: ileum 209 min: disintegration 3D reconstruction of capsule position at 5 min: Cooperation with Hassan Benameur & Aurelien Sivert (Capsugel)

34 MRI in biopharmaceutics: Future developments

35 Impact of modern tools: Telemetric systems Pill cam

36 Impact of modern tools: Telemetric systems IntelliCap

37 IntelliCap: ph stomach Fasting, n = 20 Koziolek et al. J Pharm Sci. 2014

38 SmartPill Fed intake conditions GE CA excretion time (h) clock time (h) 08:00 20:00 08:00 20:00 Subject 9; GE.. Gastric Emptying; CA.. Colon Arrival Koziolek et al. J. Control. Rel / Schneider et al. Eur. J. Pharm. Biopharm. 2016

39 What to learn from imaging studies? Classical imaging can act as a very helpful tool in formulation design. MRI as well as telemetric systems provide fundamental insights in GI physiology and the conditions at the sites of drug release and drug absorption. Understanding sources of variability

40 Outlook: Understanding sources of variability after i.m./s.c. injection Evert, Stefan Oswald, Werner Siegmund, Werner Weitschies* Probst (P = et placebo, al. J. Control. V = verum). Rel. 2016

41 Signal intensity in a.u. Outlook: Understanding sources of pk variability after i.m. injection of prednisolon (aqueous solution) Volume in mm³ Time in min ROI Volume Plasma concentration ROI signal intensity Concentration in ng/ml Time in min Time in min Probst et al. J. Control. Rel. 2016

42 Outlook: Understanding sources of variability after intraocular injection A: Low molecular (GadoSpin M, 936 Da) in vitreous model B: Middle weight molecular (GadoSpin D, Da) in vitreous model C: High molecular (GadoSpin P, Da) in vitreous model D: High molecular ( Da) in porcine eye Loch et al. Unpublished data

43 Thank you Spitzenforschung und Innovation in den Neuen Ländern Die Initiativen der zweiten Förderrunde