astellas formulation development for global health
TRANSCRIPT
Astellas Formulation Development
for Global Health
Feb 29, 2016 Yu Hasegawa
CSR group, Corporate Planning Astellas Pharma Inc.
Agenda
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Pediatric Formulation Development for Praziquantel Drug Delivery System for AMR
Current commercial tablet
PZQ new ODT 150 mg tablet
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
Points for Praziquantel Pediatric Formulation
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Astellas Formulation Technologies (1/2)
WOWTAB (Without Water Tablets) Anytime & anywhere Anybody
TIP (Temporary Insoluble Polymer) Taste-masking
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Drug coreSalting-out layer(Salting-out agents + water-soluble polymers)
Water-penetration control layer (Water-insoluble materials)
Oral-disintegratingtablets
Phase Change ofWater-soluble Polymers
Salting-outagents
Saliva Drug
From mouth to pharynges In the GI-tractIn the oral cavity
Figure 2. Schematic description of expected phenomena after administration 4
Affordable & Sustainable
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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
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
~ 10 sec.
30 ~ 60 sec.
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Example: Unmet Medical Needs for Pediatrics
http://bpca.nichd.nih.gov/prioritization/status/Documents/Priority_List_07082014.pdf Source: Best Pharmaceuticals for Children Act (BPCA) Priority List of Needs in Pediatric Therapeutics, NIH
Identified Therapeutic Area Gaps in Knowledge/Labeling
Type of Study and/or Scientific Needs
Infectious Diseases: • HIV: antiretrovirals • TB: isoniazid • Trypanosomiasis: benznidazole,
nifurtimox • Parasitic infections: albendazole • Malaria: mefloquine, sulfadoxine-
pyrimethamine, chlorproguanil-dapsone
• Taste-masking technologies
• Orally dissolvable dosage forms that do not require water
• Heat-stable and light-stable dosage forms
• Safety data for excipients
• Improving the technology and designs of child-friendly/easy- to-swallow dosage forms of drugs to improve adherence and effectiveness
• NICHD-FDA Formulations Platform
Hematology: hydroxyurea
Oncology: 6-mercaptopurine, methotrexate, prednisone, isotretinoin
Spasticity: baclofen
Hypothyroidism: 1-thyroxine
Agenda
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Pediatric Formulation Development for Praziquantel Drug Delivery System for AMR
Better drug adherence L.B. Baradell, A. Fitton, Artesunate Drugs 50 (1995) 714/741
Better bioavailability and better efficacy E. E. Chinaeke et al Drug Deliv, 2015; 22(5): 652–665
Sustained-release Tab. / Adherence / AMR
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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
Minimize AMR Risk?
Astellas Formulation Technologies (2/2)
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
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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.
Summary
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Astellas has a lot of novel formulation technologies and drug delivery systems. Such technologies should be modified to more cost-effective and easy-to-producible method so that factories in developing countries can sustainably manufacture products. Drug delivery systems could minimize AMR risks.
Astellas can take on challenges of global health by utilizing our expertise and experience in formulation development.
Our Technology
Our Approach
Possibility
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Appendix
OCAS
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♦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
Mean plasma drug levels in human (n=24)
Time (h) 0 6 12 18 24
Pla
sma
leve
l (n
g/m
l)
0
5
10
15
20
25
30
fast fed
OCASTM application to tamsulosin ♦No food-effect ♦low plasma peak/trough ♦High dose tolerance
Schematic description of gelling and drug release of OCAS and conventional gel-forming matrix (CG) in gastrointestine
OCAS for Nicardipine Hydrochloride
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12 10 8 6 4 2 0 0
20
40
60
80
100
Time (h)
% re
leas
ed
Nic-CG
Nic-OCAS
G2h = 8.2%
G2h = 79.6%
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Nic-OCAS Nic-CG
10 8 6 4 2 0 0
20
40
60
80
Time (h)
Pla
sma
leve
l (ng
/ml)
Nic release profiles by paddle method at 200 rpm in JP 2nd fluid
Plasma levels after oral dosing of Nic at a dose of 160 mg/body to fasted dogs (n=6, mean)
OCAS-Select
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Time
drug r
elea
se
gel layer core
(cross section)
Schematic diagram of gel formation/drug release in GI tract
outer layer: gel-forming polymer gel-forming enhancer core tablet: drug freely erodible filler
CODES
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CODES releases the drug by utilizing the action of microflora.
DrugLactulose Stomach
Small Intestine
Colon
organic acids
DrugLactulose
DrugLactulose
Drug release
DrugLactulose
microflora
Cationic polymerEnteric polymer
< 103
< 103
1010 - 1013
Concentration of bacteria
pH 1 - 3.5
6 - 7
5.5 - 7
PEER
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Image of absorption enhancement mechanism lumen
mucosa
mucus
components in GI-tract
drugs
absorption enhancer
PEER prevent the interaction between drugs and components in GI-tract
Absorption enhancer often damage to mucosa.
drugs
Mean plasma levels of model drug
0
10
20
30
40
0 1 2 3 4 5 6 7 8
Time (h)
Pla
sma
conc.(ng/
mL)
Conv.
PEER
Cmax AUC Tmax(ng/mL) (ng*h/mL) (h)
Conv. 2.9±1.0 8.6±3.2 1.3±0.7PEER 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)