AN ORAL GHOST DELIVERY DEVICE FOR MACROMOLECULES Angus Rolland Hibbins A thesis ...

296 Pages·2014·10.01 MB·English

AN ORAL GHOST DELIVERY DEVICE FOR MACROMOLECULES

Angus Rolland Hibbins
A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, in
fulfilment of the requirements a Doctorate of Philosophy.

Supervisor:
Professor Viness Pillay, Department of Pharmacy and Pharmacology, University of the
Witwatersrand, South Africa

Co-Supervisor:
Associate Professor Yahya Essop Choonara, Department of Pharmacy and Pharmacology,
University of the Witwatersrand, South Africa

Co-Supervisor:
Dr. Lisa Clare du Toit, Department of Pharmacy and Pharmacology, University of the
Witwatersrand, South Africa

Johannesburg, 2014
DECLARATION

I, Angus Rolland Hibbins declare that this thesis is my own work and has been submitted for
the degree of Doctorate in Philosophy in the field of Pharmaceutics at the Faculty of Health
Sciences, University of the Witwatersrand (Johannesburg, South Africa). It has not been
submitted before for any degree or examination at this or any other University.

.......................
Signature

.......................
Date

i
RESEARCH PUBLICATIONS AND PRESENTATIONS

PUBLICATIONS
Orally Administered Therapeutic Peptide Delivery: Enhanced Absorption Through the Small
Intestine Using Permeation Enhancers (Review). Viness Pillay, Angus R. Hibbins, Yahya E.
Choonara, Lisa C. du Toit, Pradeep Kumar, Valance M.K. Ndesendo. International Journal of
Peptide Research and Therapeutics, Volume 18, Issue 3, Pages 259-280, April 2012.

Physicomechanical Characterisation and Optimization of EDTA-mPEG and Avicel®-EDTA-
mPEG In Situ Melt Dispersion Mini-Pellets (Research). Angus R. Hibbins, Yahya E.
Choonara, Lisa C. du Toit, Viness Pillay. AAPS PharmSciTech, Volume 14, Issue 3, Pages
935-949, September 2013.

pH Responsive Hydrogel Formulations for Oral Drug Delivery Applications: From Synthesis
to Physicomechanical and Physicochemical Evaluation Within the Phsiologically
Representative In Vitro Environments and Ex Vivo Performance in Isolated Porcine
Gastrointestinal Fluids (Research). Angus R. Hibbins, Yahya E. Choonara, Lisa C. du Toit,
Viness Pillay. Prepared.

The Box-Behnken Design of Optimizaed Eudragit® Coated Insulin Loaded Trimethyl
Chitosan mPEG-EDTA mini-pellet: From Synthesized Excipient Characterization to
Performance Analysis Within Biorelevant Dissolution Media and Isolated Porcine
Gastrointesitnal Fluids (Research). Angus R. Hibbins, Yahya E. Choonara, Lisa C. du Toit,
Pradeep Kumar, Viness Pillay. Prepared.

ii
PODIUM PRESENTATIONS
A Novel Ghost Drug Delivery Device for the Injection Free Administration of Salmon
Calcitonin. Angus R. Hibbins, Viness Pillay, Yahya E. Choonara, Lisa C. du Toit, Pradeep
Kumar. School of Therapeutic Sciences Research Day, University of the Witwatersrand,
August 2011.

iii
POSTER PRESENTATIONS
Improving New Chemical Entity Predications in Rat and Canine In Vitro Models –
Development of Biorelevant Media. Angus R. Hibbins, Giancarlo Francese, Frank H. Seiler.
Next Generation Scientist Internship Program 2012, Basel, Switzerland, September 2012.

Improving New Chemical Entity Predications in Rat and Canine In Vitro Models: Comparison
of Solubilities within Biorelevant Media. Angus R. Hibbins, Giancarlo Francese, Frank H.
Seiler. Science Forum, Basel, Switzerland, October 2012 (Closed Industrial Conference).

iv
PATENTS ARISING FROM THIS WORK

An Oral Ghost Delivery Device for the administration of macromolecules, patent reference
PTC:P63226PC00

v
INTERNSHIP

Next Generation Scientist Internship 2012
Program Director: Colin (Goonaseelan) Pillai, PhD
Leadership Mentor: Marcelo Gutierrez, PhD
Scientific Mentors: Giancarlo Francese, PhD
Frank H. Seiler, PhD
Time Period: 3 months
Scientific project: Developing dissolution media that is representative of the canine and rat
model

“This 3-month internship forms part of a Novartis program to build the next generation of
scientific leaders. Candidates in the program completed a drug discovery or clinical
development research project under the mentorship of a Novartis scientist, and presented
their research findings as a scientific poster during the Novartis Next Generation Scientist
Research Day event. Their skills development training included ≥70 hours of: presentation
and scientific event organisation. Each candidate was an active participant in structured,
interactive learning sessions on Pharmaceutical Research and Development topics,
including: Ethics, Social Responsibility, Intellectual Property, Drug Targets, Drug Regulation,
Technical Drug Development, Safety, Modeling and Simulation and Clinical Trials”

Colin Pillai (PhD) – Pharma Development (Basel, Switzerland)
Brigitta Tadmor (PhD) – NIBR (Cambridge, USA)
23 August 2012

vi
ABSTRACT

Recently, there has been an explosion of interest in developing biopharmaceutical
therapeutics for the treatment of life altering conditions. The main issue with the utilization of
biopharmaceutical therapeutics is the mode of administration. The Oral Ghost Drug Delivery
(OGDD) device could potentially enable the administration of these peptide therapeutics via
the oral route and significantly extend the application of these advanced therapeutic
compounds.

The OGDD device is a drug delivery platform that can permits the oral administration of
peptide therapeutics at a targeted location within the gastrointestinal tract. The OGDD is
composed of four entities: the non-responsive shell component, peptide therapeutic loaded
EDTA-mPEG trimethyl chitosan mini-pellet, Avicel®-EDTA-mPEG in situ hot melt dispersion
mini-pellet, pH responsive acrylamide-methacrylic acid hydrogel trigger mechanism. The
peptide therapeutic loaded EDTA-mPEG trimethyl chitosan was optimized with a Box-
Behnken design with the peptide insulin. For ethical and moral reasons, salmon calcitonin
was substituted for insulin during the in vivo assessment of the OGDD. The Avicel®-EDTA-
mPEG in situ hot melt dispersion mini-pellet and the pH responsive acrylamide-methylacrylic
acid hydrogel trigger mechanism was characterized with a textual analyzer with respect to
swelling properties in biorelevant dissolution fluid, USP dissolution fluid and isolated
gastrointestinal fluid. This analysis illustrates the impact of physiologically similar dissolution
fluid will not only impact the release or solubilisation of drug compounds but also the
physical behaviour of the drug containing matrix. In addition small molecular weight drug
compounds from biopharmaceutical classification system (BCS) I, II and III. The release of
these compounds from the hydrogel is not only impacted by the BSC class but also the
physical response of the drug matrix to these environments. Differential scanning calorimetry
was utilized for both the hydrogel and hot melt dispersion components of this device.

The oral administration of salmon calcitonin from the OGDD device was assessed in the
porcine model. The in vitro-in vivo correlation for the oral administration of salmon calcitonin
within different dissolution fluids and isolated porcine gastrointestinal fluids was conducted.
The biorelevant dissolution fluid of the canine model generated a closer in vivo-in vitro
correlation in comparison with USP and human biorelevant dissolution fluids. The utilization
of the OGDD device as a platform for the oral administration of peptide therapeutics was
achieved and the device is extremely customizable in a mathematically deterministic
manner.

vii
ACKNOWLEDEMENTS

Many individuals have contributed to the successful completion of this research and to them
I thank sincerely:

To my parents, Mrs. J.R. Hibbins and Mr. A.W. Hibbins, I thank you for the support, care and
love that if absent, the present research would not have been achieved.

To Mr. Pradeep Kumar, who assisted me greatly with some of the finer technical aspects of
my research and patient understanding of issues which occurred during development.

To Ms. Oluwatoyin A. Kolawole and Mr. Pius Fasinu for their insight and assistance with
general technical aspects of my research during the initial stages.

To my fellow students, Mr. Mpho Ngoepe, Mr. Felix Mashingaidze, Mr. Pierre Kondiah, Ms.
Teboho Kgesa, Ms. Martina Manikana, Mr. Maluta Mufamadi, Ms. Ameena Wadee, Mr.
Miles Braithwaite, Ms. Raeesa Moosa, Mr. Mershen Govender, Ms. Nonhlanhla Masina, and
Dr. Lomus Kumar Tomar, thank you for your assistance during my studies.

To Prof. Yahya E. Choonara and Ms. Lisa C. du Toit, thank you for your time, effort and
assistance throughout my research.

To the Central Animal Service staff at the University of Witwatersrand, Ms. Kershnee Chetty,
Ms. Lorraine Setimo, Ms. Amelia Ramakawwa, Ms. Mary-Anne Costello, Mr. Patrick Selahle
and Dr. Leith Meyer, my thanks for your assistance with my animal studies.

To my supervisor, Prof. Viness Pillay, for your vision, passion and understanding which
shaped and enhanced this research throughout my studies.

To the National Research Foundation (NRF), the Witwatersrand Financial Aid office and the
Department of Education (DEO) for the funding that enabled this research to be completed.

viii
DEDICATION

I dedicate this work to my parents, Ms. J.R. Hibbins and Mr. A.W. Hibbins, as they are the
sunlight which focuses my efforts.

ix