Introduction
The efficacy of a drug depends on its solubility and absorption
into the systemic circulation and its availability at the site of action. Poorwater solubility of a
drug is associated with variability in its absorption. Such variability can lead to reduced efficacy of
the drug (due to poor absorption) or unwanted side effects (due to increased absorption). Variability
in the bioavailability of a drug impacts on patient compliance, disease management and quality of
life. It is estimated that approximately 50% of existing therapeutic agents have poor
solubility and that many emerging leads from pharma drug discovery programs have solubility
limitations which hinder their development. Improving the solubility of a drug may therefore lead
to improvement in the variability of drug levels in systemic circulation, resulting in an
enhancement of new therapeutics and a reduction in the required therapeutic dose. The
problem of poor solubility is further exacerbated when the drug is formulated as an immediate
release tablet or dose form in particular for the fast disintegrating tablet dose forms which
require a fast dispersibility in the aqueous environment or oral cavity.
Poor solubility and poor oral bioavailability have been addressed
in the pharmaceutical industry using a number of strategies; changing the physiochemical
properties of the drug, complexing the drug with cyclodextrins, or formulating the drug in lipid
excipients or, more commonly, by conversion of the drug into a higher energy polymorphic form or an
amorphous form. While these techniques have been used in the formulation of oral solids
and products, a number of these strategies have inherent stability issues as a result of drug
re-crystallisation or reconversion to the less soluble polymorphic form resulting in a loss of
efficacy. More recently, particle size reduction of the drug into nanosized crystals has
been developed to increase the surface area of the drug and hence its solubility. Unfortunately
the increase in surface area of the particles impacts on the solid state properties of the drug
such as flowability thereby limiting their processability into solid dose forms. A significant
limitation of small nanosized particles is the inherent level of agglomeration which reduces the solubility
and dissolution of the particles from the final solid dose forms.
The School of Pharmacy at the Royal College of Surgeons in Ireland
has addressed the above shortcomings by developing a novel formulation concept to overcome
solubility limitations of therapeutic agents and allows these drugs to be formulated into
oral solid dose forms from
which it can be released rapidly and effectively. This novel
formulation approach involves formulating the drug as a solid drug dispersion comprising of fine
drug crystals of diameter <20 microns dispersed in a matrix consisting of a disintegrant
preferably a superdisintegrant. This dispersion is formulated by spray drying and provides excellent
rheological properties while maintaining the crystalline nature and stability of the drug. As
the crystals are homogenously dispersed through an inherently disintegrating matrix, the
particles of the solid dispersion break up rapidly and easily in an aqueous environment, releasing the
small crystals of drug for rapid dissolution and absorption. In addition the dispersions have
improved flow properties which makes
them suitable for processing into various oral solid dose forms including
capsules, tablets and fast dissolving tablets. RCSI’s novel dispersions are produced
using aqueous systems and are applicable to a wide range of therapeutic agents including generic
compounds as well as new therapeutic compounds and for administration to human or veterinary
medicines.
Technology
Approximately 50% of marketed drugs and a similar proportion of
drugs in the corporate pharma pipeline present solubility issues. Enhancing solubility
represents a major and important opportunity for the pharmaceutical industry with
potential benefits of improved efficacy, safety and better patient compliance. RCSI’s new
crystalline solid dispersion formulation technology offers a novel solution to enhance drug
solubility and to maximize development of existing and new therapeutics for application in
various oral dose formats.
Applications
RCSI’s technology is currently under development with a number of
poorly soluble pharmaceutical actives including the lipid lowering agent
simvastatin The spray dried crystalline solid dispersions have good to excellent flow properties and have
been processed by direct compression into oral tablets which rapidly disperses within 10-20
seconds to release the drug.
Advantages
·
Versatile technology suitable for the development of enhanced
products for veterinary
medicines, OTC, Rx medicines and line
extensions;
·
New proprietary technology which uses spray drying and offers ease
of processing and scale
up;
·
Aqueous based processing hence environment friendly and does not
result in drug
solubilisation with potential conversion to unstable amorphous
form;
·
Enhanced redispersibility and dose form stability compared to
current commercially
available products.
Contacts:
Dr. Gearóid Tuohy, RCSI Technology Transfer, 123 St Stephen’s
Green, Dublin 2, Ireland; email:
gearoidtuohy@rcsi.ie Tel: +353 1
4022362
Dr Aoife Gallagher, RCSI Technology Transfer, 123 St Stephen’s
Green, Dublin 2, Ireland; email:
aoifegallagher1@rcsi.ie. Tel: +353 1
4022394;
Principle Investigator:
Dr. Zeibun Ramtoola, School of Pharmacy, Royal College of Surgeons,
123 St Stephen’s Green, Dublin 2,
Ireland. Email: zramtoola@rcsi.ie Tel: +353 1 40228626 or +353 1
4022498