applications of modified release during the preclinical stage - weijia zheng, astrazeneca

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

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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


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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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


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


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


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


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


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


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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Impact of Pore Diameter on Drug Load and Release Rate MCM41 MSP

12

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


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


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


• 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


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


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


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


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


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


Acknowledgements

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•  Early Teams in Pharm Dev-Boston, Macclesfield, Mölndal