Long acting

23 Pages·2016·3.15 MB·English

by  Computing Services

Long acting (LA) drug delivery in TB treatment
Andrew Owen, Ph.D. FRSB. FBPhS.
Professor of Pharmacology
Department of Molecular and Clinical Pharmacology
University of Liverpool, UK
How to define “long-acting”?
The term is traditionally applied in a disease- and/or drug-specific manner
(e.g. Insulin glargine is termed LA for once daily administration and the term
‘ultra-LA’ for insulin Degludec is now being introduced).
Route of delivery Oral Parenteral Implant / Device
Dosing frequency ≥ 1 week ≥ 1month ≥ 6months
Owen and Rannard. ADDR. 2016
Technologies being explored across indications to
achieve long-acting delivery
Injectables Devices
Owen and Rannard. ADDR. 2016
Non-adherence as a driver for development of
long-acting medicines
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Time (days)
• Directly Observed Therapy (DOT) was estimated to account for up to 75% of
healthcare provider costs for TB treatment1
• The current WHO End TB Strategy2 contains “supportive treatment supervision
by treatment partners”. Many TB programs still use DOT.
• DOT not shown to be significantly superior to self-administered treatment2
1Steffen R, Menzies D, Oxlade O, et al. Patients’ costs and cost-effectiveness of tuberculosis treatment in and non-DOTS facilities in Rio de Janeiro, Brazil. PLoSOne. 2010;5:1–7.
2World Health Organization. The End TB Strategy. Global strategy and targets for tuberculosis prevention, care and control after 2015. 2014. www.who.int/tb/post2015_strategy/en/.
High drug potency underpins the LA approach
Dose and release rate as critical
factors in LA delivery
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K = 0.023 hr-1
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Time (hr)
Nanotechnologies being explored in drug delivery
Solid Drug Nanoparticles (SDNs; aka nanocrystals, nanosuspensions, nanodispersio
“Bottom-Up” “Top-Down”
Particles in liquid
Breaking large
Precipitation of
solids
solutions
Nanocarrier systems (extremely diverse in composition)
Lipid-based carriers polymer-based carriers Inorganic carriers Biological
Grinding Pharmaceuticals
• Physical fracturing of “large” fragments to generate small particles
– Micronisation (Dry or air-jet milling - sizes 1-5µm)
– Wet bead (or nano) Milling - <1µm
• Attrition techniques
– Limited to materials with specific
properties (eg Crystalline, high melting
point)
– Limited access to approved excipients
– Impurities from milling agents
– Correlation between processing time
or energy input and particle size
• BUT successful in new medicine
development
Liverpool ETFD formation of nanosuspensions
(Being employed as part of R01AI114405)

Two solvents
APIs and excipients dissolved
In vitro In Silico In Vivo
McDonald et al. Adv HealthcMater. 2013 Sep 1. doi: 10.1002/adhm.201300280.