Human-Veterinary Technology Benefits and Crossovers for Vet and Human Patients Professor David Brayden UCD School of Veterinary Medicine Principal Investigator , SFI Medical Devices Centre (CURAM) AAPS-CRS Workshop: Animal Health Drug R&D: Formulation, Delivery and Development to Market Topics • Principles of controlled release for vet med • Transdermal patches/sprays, inhalers and oral delivery • Devices for large animals - a unique evolution based on species differences in physiology • Relevance of species-specific drug transporters for drug-drug interactions Production versus companion animals Clients Environment Number treated per environment $ value Treatment decision Challenges Farmed animals Business Numerous Current/ future market value Balance between Cost constraints Ease of use immediate and Tissue residues future value Companion animals Home One or two Priceless Compassionate Convenience Compliance Oral not easy Nasal impossible Adapted from M. Rathbone, CRS, 2008 Vet routes and examples Route Examples Gastrointestinal Liquids (solutions, suspensions) Pastes Solids (tablets, powders, granules, pre-mixes) Devices (balling guns, gastro-retention) Formulation (taste masking, modified release) Topical Dips, spot-ons, sprays, patches, collars Pulmonary Anaesthetics, aerosols Parenteral I.V, I.M, implants, depot preps (excipients, stabilizing agents, buffers, chelators) Ocular and periodontal Eye-drops, inserts, hydrogels, (localized delivery of non-antibiotic and antibiotic anti-microbial drugs) Reproductive tract Applicators, sponges, controlled internal drug release (CIDR) devices, pessaries, implants Other Intra mammary infusions, intrathecal, ear implants Brayden, D. J., et al (2010). Handbook of Exp. Pharmacology. 199:79-112 One molecule illustrates most vet routes Crossover 1 Crossover 1: Fentanyl patches in dogs Fentanyl (ng/ml) 10 IV Patch removed 1 .1 0 12 24 36 48 60 72 Time(hours) 84 96 Bellei, E. et al, JVPT, 2011 34:437-41 Papich, M. & Riviere, J. (2001) ADDR 50: 175-203 Transdermal Duragesicâ in Dogs (50 µg/hr) Oxycodone equine patches • • • • • Integrated Animal Health (Australia) TPM® technology from Phosphagenics Based on phosphorylated vitamin E as permeation enhancer (Crossover 2) Replace phenylbutazone in horses with shin sores, but relies on local delivery hypothesis www.thoroughbredracing.com/articles/smallpain-relief-patch-could-be-safe-alternative-bute Transdermal fentanyl solution • Recuvyra™ (Elanco, Acrux) EMA-approved 2011, FDAapproved 2012 • Fentanyl 50mg/ml solution: metered dose transdermal spray for post-op control of pain giving 4 day relief • Enhancers: octyl salicylate /isopropyl alcohol Photo: Elanco Martinez, SA et al. (2014). JVPT 37:394-405. Unique to vets: Spot-on anti-parasitics-fipronil mg /g: 1 day mg /g : 56 days 308 7 31 2 Back Leg Brayden, D. J., et al (2010). Handbook of Exp. Pharmacology. 199:79-112 Needle-free injectors-devices lead by skin physiology and economics AFLURIA® Flu Vaccine with PharmaJet's Needle-Free Injector http://pharmajet.com/product/ Vaccines and antibiotics in production animals (crossover 3) http://www.pulse-nfs.com/products/livestock-products/ Topical veterinary drug delivery: selected Formulation Species Example Spot-on: oily base solution feline/canine Fipronil (Frontline Top Spot®, Merial) Spot-on: alcohol base feline/canine Selemectin (Revolution®, Pfizer Animal Health) Spot-on: oily base solution feline/canine Imidacloprid (Advantage®, Bayer) Pour-on: dilute isopropanol bovine Ivermectin (Ivomec® Pour-On, solution Merial) Flea-collar: vinyl matrix resin feline/canine Tetrachlorvinphos (Rabon®, Hartz) Transdermal reservoir patch canine Fentanyl opiate (human Duragesic50® patch, J & J, off-label use) Brayden, D. J., et al (2010). Handbook of Exp. Pharmacology. 199:79-112 Inhalers for small animals and humans http://www.youtube.com/watch ?v=eDxyUWG7MCE (Trudell Medical International) • Nebulizer principle (crossover 4) • Design differences reflect species Aeroneb-Go® (Aerogen Ltd) From Exubera®(2007) to Afrezza® (2014) Selam JL. J Diab Sci Technology 2008;2(1):311-315. Neumiller JJ, Campbell RK. Biodrugs 2010; 24(3):165-172. Santos Cavaiola T & Edelman S (2014).Clin Ther. 36:1275-1289. Insulin delivery to cats by inhalation (cross-over 5) Inhaled saline (IS), insulin 15 U/kg (I15), iinsulin 25 U/kg (I25) versus IV insulin (IV) Glucose concentrations in individual cats after inhaled insulin (25 U/kg). Arrows indicate when dextrose was given De Clue et al. (2008) J. Feline Med. Surgery 10, 519-522 Gastro-retentive systems: production animals Ivermectin Tablet Partition High density Semi-permeable shell Ivomec® SR bolus, Merial Flow Paratect-flex® (Zoetis) Alvinerie et al, 1999 Res. Vet Sci. 66, 57-61 Gastro-retentive systems: human (no cross-over) Designed to drip feed into small intestine to access window in jejunum Suits stable, short half life molecules binding to low capacity saturable carriers Gabapentin L-dopa Riboflavin Captopril Davis, SS. (2005) DDT, 10: 249-257 Oral delivery in cats and dogs (limited-cross-over) • Flavoured chewables • Palatability agents, yeast, pork liver difficult to incorporate in tablets without humidity management and costly packaging • Solution flavourings (honey) can change odour and flavour during stability • Chemical analysis challenges Oral microneedle capsules for insulin delivery for humans? Crossover 6 http://newsoffice.mit.edu/2014/microne edles-drug-delivery-capsule-1001 Traverso, G. J. Pharm Sci (2014) DOI 10.1102/jps 24182 Human versus vet: intra-vaginal delivery (no cross-over) CIDR-B® PRID® Malcolm et al (2010) Control of oestrus for large animal reproduction management Great interest in microbicides for HIV Engineered for different species from biocompatible materials with CR progesterone Long-acting CR injectables Formulation / Product Comment Recombinant bovine somatotropin SR from an oil-based sterile suspension, dosed (Posilac®, Elanco) for increased feed every 14 days (non-EU) efficiency and milk yield Florfenicol antibiotic (Nuflor®, Schering- Solution in non-aqueous vehicle; solubility Plough) for respiratory disease and foot- controlled; 1-2 times in 48 hours rot Vitamin B12 entrapped in microspheres First vet product using PLG microspheres; single or for lambs on cobalt-deficient pasture i.m. injection releasing B12 over many weeks (SMARTShot-TM B12, AgResearch, NZ) Injectable steroid implants for growth Pellets containing range of growth stimulants promotion. (estrogenic or androgenic) injected into back of ear Non EU ) Long-acting ivermectin (IVOMEC®, Merial) Solid-dispersion of ivermectin and castor oil injection as a prophylactic endectocide for crushed to make aqueous suspension; 60 day sheep persistence Long-acting oxytetracycline-poly(ethylene) Injected (i.v, i.m., s.c) daily up to 4 days. Reduced glycol, (Bio-Mycin® 200, ) for respiratory diseases clearance. Similar technology, different rationale (cross-over 7) PLG microspheres Sucrose acetate isobuyrate gels Vitamin B12 (Sheep) Leuprolide (Human) Efflux pumps in human/vet: cross-over 8 GI Renal tubules Hepatocytes Blood BBB Ivermectin and P-gp Mealey et al, 2001 www.vetmed.wsu.edu/depts -VCPL/test.aspx Nobmann et al, 2001 Functional assay for P-gp substrates A-B B-A Verapamil Griffin, J. et al, (2005) JVPT, 28: 257-265 Importance of canine P-gp defect • A large animal KO model in addition to mdr1a -/- mice • Showed that BBB Pgp is likely to be of more importance than Pgp in the gut for PK • Identified competing substrates that led to relevant DDI • Investigation of P-gp inhibition in canine cancer resistance? Drugs requiring altered dosing in P-gp KO dogs Drug Toxicity Dose change Ivermectin Neurologic Safe at heartworm dose Selamectin, milbemycin, moxidectin Neurologic Safe at heartworm dose Loperamide (diarrhea) Sedation, death Avoid Erythromycin Neurologic Use other antibiotics ACP (sedative, pre-op) Deeper/longer sedation 50% reduction Butorphanol (analgesic, pre-op) Deeper/longer sedation 50% reduction Vincristine, vinblastin, doxirubicin (cancer) More bone marrow suppression; GI toxicity 30% reduction Emodepside (dewormer) Neurologic Avoid Spinosad (insecticide) Neurologic with ivermectin Avoid ivermectin Table drawn in part from information on: www.vetmed.wsu.edu/deptsVCPL/drugs.aspx BCRP (ABCG2) Mealey, JVPT, 2011 Medical devices (cross-over 9) ? “A 'cartridge' concept employed www.biomedtrix.com/elbow.php http://canadawestvets.com/are -you-hip-to-joint-replacement in the TATE total elbow replacement device for dogs, according to Prof. Deborah Kochevar (Tufts Vet School), is being applied to the design of joint prostheses for humans, for instance. Likewise, a modified dog hip prosthesis will hit the European market for human use” http://www.qmed.com/mpmn/medtechpulse/medicaldevice-design-going-dogs Cancer studies in dogs (cross-over 10) Paoloni M, Khanna C. (2008) Nat Rev Cancer. 8:147-56 . …..implications for ‘nano’ delivery of cancer drugs Why is there so little leveraging of DDS between human and vet? • • • • • • • Altered drug PK and PD between species, breeds Physiological differences Markets for vet drugs are more limited Few specialist vet DDS companies Route of administration priorities differ Vet research: device-led Human research: formulation, biology-led Conclusions • Veterinary drug delivery technologies are highly innovative with many successful examples • Goals of production and companion animal CR technologies are different and transferability is limited by physiological differences • Study of efflux transporters in dogs and cats is yielding useful information on potential drug-drug interactions • Medical devices and spontaneous canine cancers offer rationale for two-way collaboration Acknowledgements • Science Foundation Ireland Cluster funding • Pfizer Animal Health (Zoetis) for funding the selamectin P-gp studies at UCD • Ref: Brayden, D. J., Oudot, E., & Baird, A. W. (2010). Drug delivery systems in domestic animal species. In: Handbook of Experimental Pharmacology. Ed. Lees, P., Cunningham, F. and Elliot, J. Ed. Springer, New York.