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Applications of Modified Release during the Preclinical Stage
Weijia Zheng May 8, 2014 Controlled & Modified Drug Release, Philadelphia, PA Pharmaceutical Development AstraZeneca Pharmaceutical LP
Weijia Zheng| 8 May 2014
Outline
• Importance of modified release at the preclinical stage • Common challenges • Approaches to achieve modified release profiles
- Routes of administration - Formulation approaches - Devices
• Conclusions
2
Weijia Zheng| 8 May 2014
Achieving Optimal Exposure at the Preclinical Stage
• Importance of achieving optimal exposure - Understand PK-PD, efficacy and target engagement - Enable early hypothesis testing - Allow early safety signal searching - Facilitate compound selection
• Advantages of modified release - Reduce dose frequency, animal stress and cost - Enable delivery of short half-life compounds - Minimize peak/trough fluctuations - Increase target coverage and improve efficacy - Reduce side effects caused by high Cmax
3 Minimal effective level
Toxic level
Weijia Zheng| 8 May 2014
Common Challenges in the Preclinical Stage
• Suboptimal PK and physicochemical properties - Poor solubility and/or permeability - High clearance and short half-life - Inadequate stability
• Limited information on targeted profile - PK-PD - Efficacy drivers (Cmax, AUC…) - Safety concerns
• Limited compound availability and short timeline - Minimal formulation development and optimization
• Limited formulation approaches - Technical feasibility during drug discovery stage - Suitable for rodent dosing
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Weijia Zheng| 8 May 2014
Preclinical Approaches for Achieving Modified Release
• Route of administration - IV infusion - IP - SC
• Preclinical formulation approaches - In situ gels - Mesoporous silica particles - Micro and nano suspensions
• Devices - Minipumps
Weijia Zheng| 8 May 2014
Routes of Administration Route Principles Formulation Advantages Limitations
IV infusion Drug administration through the intravenous route at a constant rate
- Solution - Emulsion - Nanosuspension
- Ability to modulate plasma profile by infusion rate and duration
- Need surgically prepared animal - Difficult for rodents especially mice
IP Injection to the peritoneal cavity and absorption to mesenteric vessels
- Solution - Suspension
- Minimize GI instability and gut metabolism - High dose volume
- Doesn’t avoid hepatic first pass effect - Tolerability issues with chronic dosing with suspensions
SC Administration to subcutaneous tissues and absorption to capillaries beneath skin into systemic circulation
- Solution - Suspension - Gel - Implant
-Avoid first pass effect - Achieve sustained release due to slow absorption
-Low dosing volume - Risk of local irritation
Weijia Zheng| 8 May 2014
In Situ Hydrogels
• Hydrogel: 3D networks of water soluble polymers • In situ
• Liquid in formulation, solid or semisolid depot after administration
• Phase transition triggered by chemical or physical processes • Routes of administration
• SC, Oral, IV, IM, transdermal, ophthalmic, rectal, vaginal
• Advantages - Avoid surgical procedures - Provide prolonged local and systemic exposure - Suitable for both solutions and suspensions
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D.Y. Ko et al. Progress in Polymer Science 38 (2013) 672– 701
Adapted from: www.chemeng.tsinghua.edu.cn
Weijia Zheng| 8 May 2014
ReGel®: ABA triblock copolymer of PLGA and PEG
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Rat PK from Insulin ReGel® Following SC Administration
Y.J. Kim et al. Pharm. Res. 18 2001 548-550 K.D. Fower et al. Drug Development & Delivery 2003. Vol 3, No. 5
• Drug release controlled by diffusion from and degradation of the polymer (1-4 wks) • Biodegradable and biocompatible
Weijia Zheng| 8 May 2014
In Situ Gel with Nanocrystals for Sustained Release
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Z. Lin et al. Journal of Controlled Release 174 (2014) 161–170
PTX-NCs-Gel
PTX-NCs Taxol
In vitro release
Efficacy
%drug remained after 20 days
• In situ gels with suspensions enable
- Sustained release for poorly solubles - Prolonged drug release and retention - Improved efficacy
Weijia Zheng| 8 May 2014
Mesoporous Silica Particles (MSP)
• Ordered porous structures of SiO2 • Key properties
- High surface area (600-1000m2/g) - Narrow particle size distribution (10-1000nm)
- Pore size (2-50nm) - Good biocompatibility - Surface functionalization
• Applications - Controlled release - Enhance exposure for poorly solubles - Targeting - Combination therapy
10 C. Ge´rardin et al. Chem. Soc. Rev., 2013, 42, 4217-4255
Material Matters 2008, 3, 17-18
Weijia Zheng| 8 May 2014
MSP Modified Release
• Drug loading - Through weak non-covalent interactions
• hydrogen bonding, physical adsorption, electrostatic interaction, and p–p stacking
- Methods • solvent and melt
• Controlling release via diffusion • Drug load and release impacted by
- Guest molecule size and solubility - Surface functionalization - Surface area - Pore diameter and volume
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Weijia Zheng| 8 May 2014
Impact of Pore Diameter on Drug Load and Release Rate MCM41 MSP
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0
50
100
150
200
250
300
350
400
1.5 nm 1.6 nm 1.9 nm 2.5 nm
1.5 nm 1.6 nm 1.9 nm 2.5 nm
Pore size (nm)
Dru
g Lo
ad (m
g)
• Increased drug load and release rate with an increased pore diameter
M. Vallet-Regí, Chem. Eur. J., 2006, 12, 5934–5943
Weijia Zheng| 8 May 2014
MSP Surface Functionalization
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Dp [nm]
load [mg g−1]
release time [h]
MCM-41 2.5 337 48
MCM-41 aminopropyl 1.7 270 213
Impact on Release Rate
D. Arcos, M. Vallet-Regı´ Acta Materialia 61 (2013) 890–911
M. Vallet-Regí, Chem.–Eur. J., 2006, 12, 5934–5943
Weijia Zheng| 8 May 2014
Enhance Dissolution by MPS Fenofibrate-Loaded MPS
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Solvent Melting
• Dissolution enhancement observed from MPS with 20-33% drug load • Enhanced dissolution due to amorphousization and nanosizing • No dissolution enhancement at high drug loadings due to crystallization
F. Uejo et al. A. J. of Pharm. Sci. 8 (2013) 329-335
Weijia Zheng| 8 May 2014
• Micro suspensions - Suitable for oral, SC, IP administrations - Challenging for amorphous materials with a limited amount
• Nano suspensions - Suitable for oral, SC (including minipump), IP and IV - Need stabilizer(s) to control Ostwald ripening
• Advantages - Enable high dose for poorly solubles - Improve tolerability
• Reduce solvents for solubilization • Reduce Cmax driven toxicity
• Limitations/cautions - Physical stability - Can impact bio-distribution via IV
Micro and Nano Suspensions
Weijia Zheng| 8 May 2014
Nanosuspension Preparation Methods on Small Scale
• Precipitation - Dissolve API in organic solvent (1-10%) and rapidly ppt into aqueous phase
with stabilizers - Suitable for small amount of API (5mg) - Typically produce amorphous suspension
• Ultrasonication crystallization - Suitable for small amount of API - Can produce crystalline suspension
• Wet milling and high pressure homogenization - Defragmentation and deagglomeration via mechanic force - Crystalline suspension - Can achieve high concentration - Challenging with a very small scale
Solution
Controlled ppt. by
anti-solvent
Milling or homogenization
Bottom up Top down
Nanosuspension
Weijia Zheng| 8 May 2014
R. Rabinow et al. International Journal of Pharmaceutics 339 (2007) 251–260
Sustained Itraconazole IV Nanosupesions
Rat PK
• Nanosuspension provided more prolonged exposure • Nanosuspension decreased Cmax, and reduced acute toxicity • Nanosuspension enhanced efficacy by prolonging exposure and enabling
higher dose
Tolerability
Weijia Zheng| 8 May 2014
Osmotic Pumps
• Uses the osmotic pressure of drug or other solutes for controlled delivery of drugs
• Types
• Oral • Implantable (SC,IP)
• Advantages
• Zero order release • Provide flexibility to explore dose schedule and PK/PD
• Various models available to cover range of volume, rate and duration (1day -6 wks)
• Formulations
• Solution • Suspensions
Weijia Zheng| 8 May 2014
Achieving Prolonged Exposure by Minipump
IP administration SC minipump administration
K. Zhang et al. Mol Cancer Ther 2008 7 (4)
Formulation: 30% PEG400 in 5% dextrose
Weijia Zheng| 8 May 2014
Conclusions
• Achieving optimal exposure and coverage during the early drug discovery stage is challenging but critical for early hypothesis testing, ensuring efficient compound design, selection and risk assessment
• Various routes of administration, formulation approaches and devices can be explored and combined to achieve modified release and a desirable PK profile
• Understanding the impact of early enabling formulation approaches on clinical and commercial development is necessary
Weijia Zheng| 8 May 2014
Acknowledgements
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• Early Teams in Pharm Dev-Boston, Macclesfield, Mölndal