Astellas Formulation Development for Global Health Feb 29, 2016 Yu Hasegawa CSR group, Corporate Planning Astellas Pharma Inc.
Agenda Pediatric Formulation Development for Praziquantel Drug Delivery System for AMR 2
Points for Praziquantel Pediatric Formulation Easy intake for children Small-size tablet Taste canceling Oral disintegrating tablet (ODT) Optimization for developing countries Less susceptible to tropical climate Stable production and distribution - Easy production at local site - Simple formula ingredients Low cost of development Current commercial tablet PZQ new ODT 150 mg tablet 3
Astellas Formulation Technologies (1/2) WOWTAB (Without Water Tablets) Anytime & anywhere Anybody TIP (Temporary Insoluble Polymer) Taste-masking Oral-disintegrating tablets Drug core Salting-out layer (Salting-out agents + water-soluble polymers) Water-penetration control layer (Water-insoluble materials) In the oral cavity Saliva From mouth to pharynges Salting-out agents In the GI-tract Drug Phase Change of Water-soluble Polymers Figure 2. Schematic description of expected phenomena after administration 4 4
Key for Formulation Tech. Transfer Innovative Formulation Technologies Require special technologies, devices & skills (Factory in developed countries) ODT: WOWTAB (High-speed disintegration) Taste: Masking with coating ~ 10 sec. Affordable & Sustainable Easy production & simple formula ingredients with lower cost General manufacturing method, devices & excipient (Factory in developing countries) ODT: WOWTAB-like (Middle-speed disintegration) Taste: Cancelling with excipient 30 ~ 60 sec. 5
Example: Unmet Medical Needs for Pediatrics Identified Therapeutic Area Infectious Diseases: HIV: antiretrovirals TB: isoniazid Trypanosomiasis: benznidazole, nifurtimox Parasitic infections: albendazole Malaria: mefloquine, sulfadoxinepyrimethamine, chlorproguanildapsone Hematology: hydroxyurea Oncology: 6-mercaptopurine, methotrexate, prednisone, isotretinoin Spasticity: baclofen Hypothyroidism: 1-thyroxine Gaps in Knowledge/Labeling Taste-masking technologies Orally dissolvable dosage forms that do not require water Heat-stable and light-stable dosage forms Safety data for excipients Type of Study and/or Scientific Needs Improving the technology and designs of childfriendly/easy- toswallow dosage forms of drugs to improve adherence and effectiveness NICHD-FDA Formulations Platform Source: Best Pharmaceuticals for Children Act (BPCA) Priority List of Needs in Pediatric Therapeutics, NIH http://bpca.nichd.nih.gov/prioritization/status/documents/priority_list_07082014.pdf 6
Agenda Pediatric Formulation Development for Praziquantel Drug Delivery System for AMR 7
Sustained-release Tab. / Adherence / AMR More frequency and/or longer duration of drug administration could result in worse drug adherence. Cockman J, et al: Determinants of non-compliance with short term antibiotic regimens. Brit Med J 295: 814-818,1987 Longer duration of administration with lower dose has higher risk of AMR occurrence than shorter duration with higher dose. Bergman AB & Werner RJ: Failure of children to receive penicillin by mouth. N Engl J Med 268: 1334-1338, 1963 Sustained-release tablet: Less frequency with proper dose Better drug adherence Better bioavailability and better efficacy L.B. Baradell, A. Fitton, Artesunate Drugs 50 (1995) 714/741 E. E. Chinaeke et al Drug Deliv, 2015; 22(5): 652 665 Minimize AMR Risk? 8
Astellas Formulation Technologies (2/2) The technologies below can control drug levels in blood (have impacts on PK/PD parameter) with less frequency of administration. Thus, such drug delivery systems have a possibility in minimizing AMR risks through better adherence and better bioavailability. Need to consider whether AS concept can be applied or not. Depends on compound characteristics and mechanism of AMR occurrence. OCAS (Oral Controlled Absorption System) Novel controlled-release formulation OCAS-select Timed-release system avoiding drug-drug interaction CODES (Colon-Targeted Delivery System) Colon delivery tablet PEER Absorption improvement 9
Summary Astellas can take on challenges of global health by utilizing our expertise and experience in formulation development. Our Technology Astellas has a lot of novel formulation technologies and drug delivery systems. Our Approach Such technologies should be modified to more cost-effective and easy-to-producible method so that factories in developing countries can sustainably manufacture products. Possibility Drug delivery systems could minimize AMR risks. 10
Thank you for your attention! Contact: yu.hasegawa@astellas.com 11
Appendix 12
OCAS once-daily controlled-release technology for oral dosing rapid gelation of polymer matrix enabling constant drug release in the whole GI, even in the colon where little water exists Schematic description of gelling and drug release of OCAS and conventional gel-forming matrix (CG) in gastrointestine Mean plasma drug levels in human (n=24) 30 Plasma level (ng/ml) 25 20 15 10 5 0 fast fed 0 6 12 18 24 Time (h) OCAS TM application to tamsulosin No food-effect low plasma peak/trough High dose tolerance 13
OCAS for Nicardipine Hydrochloride % released Nic release profiles by paddle method at 200 rpm in JP 2nd fluid 100 80 60 40 20 Nic-OCAS G 2h = 79.6% Nic-CG G 2h = 8.2% Plasma level (ng/ml) 80 60 40 20 Plasma levels after oral dosing of Nic at a dose of 160 mg/body to fasted dogs (n=6, mean) Nic-OCAS Nic-CG 0 0 2 4 6 Time (h) 8 10 12 0 0 2 4 6 Time (h) 8 10 12 14
OCAS-Select Schematic diagram of gel formation/drug release in GI tract outer layer: gel-forming polymer gel-forming enhancer core tablet: drug freely erodible filler drug release gel layer core (cross section) Time 15
CODES CODES releases the drug by utilizing the action of microflora. Enteric polymer Cationic polymer ph 1-3.5 Drug Lactulose Stomach 6-7 Drug Lactulose Small Intestine < 10 3 5.5-7 Drug Lactulose organic acids microflora 10 10-10 13 < 10 3 Drug Lactulose Drug release Colon Concentration of bacteria 16
PEER Image of absorption enhancement mechanism lumen mucus mucosa Absorption enhancer often damage to mucosa. absorption enhancer drugs PEER prevent the interaction between drugs and components in GI-tract components in GI-tract drugs Mean plasma levels of model drug Plasma conc.(ng/ml) 40 30 20 10 0 Conv. PEER 0 1 2 3 4 5 6 7 8 Time (h) Cmax AUC Tmax (ng/ml) (ng*h/ml) (h) Conv. 2.9±1.0 8.6±3.2 1.3±0.7 PEER 37.4±11.6 * 64.5±22.2 * 0.6±0.3 * (mean ± SD, n=12 in dogs) *; significantly different from conv. (p<0.05) 17