title: The Development of a Novel Controlled Release Drug Delivery System

authors: Babu, Kavitha Mary Vadakkel

subjects: Controlled Release Drug Delivery

abstract: The aim of this research was to formulate, characterise and assess the feasibility of a novel drug delivery system known as the in situ gelling matrix (ISGM) where a hydrophilic polymer is suspended in a non-aqueous solvent that converts into a gel when injected subcutaneously or intramuscularly thus giving a controlled release matrix for a drug.  Although the concept has been patented with claims that this kind of drug delivery is achievable in theory for a wide variety of candidate substances, actual formulation studies for making a commercially viable product for this technology are completely lacking in practice.   The research embodied in this thesis addresses this lack.  Initial studies involved conducting a biocompatibility study using the HET-CAM (hens egg test - chorioallantoic membrane) test on a range of possible ingredients for the delivery system.  The materials deemed biocompatible were then carried through to a screening process where the physical stability of the hydrophilic polymers in non-aqueous solvents was monitored.  It was found that the hydrophilic polymers tested sedimented rapidly in the non-aqueous solvents indicating such a system was not physically stable.  Consequently, density-inducing or viscosity-inducing agents were added to the non-aqueous solvents to retard the sedimentation rate.  The addition of polycarbophil, a viscosity-inducing agent, clearly increased the viscosity of the system.  However, undesirable formation of polycarbophil globules occurred during the manufacturing process, which caused batch-to-batch variations in the viscosity of the continuous phase. Various manufacturing methods were tested before arriving at the optimum procedure to prevent globule formation using a high speed dispersion tool.  A final physical sedimentation analysis of candidate continuous phases and hydrophilic polymers was conducted for determining the ideal combination of ingredients to use in the system.  These investigations finally led to the adoption of an optimum mix of components consisting of 10% (w/w) hydroxypropyl methylcellulose (HPMC) (the hydrophilic polymer) suspended in a continuous phase of propylene glycol (the non-aqueous solvent) containing 0.67% (w/w) polycarbophil (the viscosity inducing agent).

Using this mix of components, the in situ gelling matrix system was then subjected to various characterisation studies including infrared (IR), differential scanning calorimetry (DSC), ultraviolet-visible (UV-Vis) spectrophotometry and redispersion studies.  The chemical stability of the hydrophilic polymer and the continuous phase (the non-aqueous solvent and polycarbophil) was monitored and were found to be chemically stable over a 9 month period.  

The feasibility of the in situ gelling matrix technology as a controlled release device was assessed using the drug propranolol.  In vitro drug release studies were conducted using a custom-built dissolution apparatus.  The effect of various parameters such as the concentration of the hydrophilic gelling agent on the drug release rate was investigated.  Increasing the concentration of the gelling agent in the formulation resulted in a slower rate of release.  The drug release data were modelled using the Higuchi relationship and a power law relationship to compare the effects of the various parameters on the release rate

Stability studies on the drug in the in situ gelling matrix system were carried out by storing samples in accelerated ageing conditions of 40 C / 75% relative humidity for 4 weeks.  During this time, the samples were analysed each week by high performance liquid chromatography (HPLC).  These demonstrated that no apparent drug degradation had occurred over the 4-week period. This indicates that the drug propranolol in the in situ gelling matrix system is stable under ambient conditions for at least 4 weeks.  

The results of this study demonstrated that the in situ gelling matrix technology is potentially viable as a drug delivery system and provide a practical methodology for the commercial development of such systems.

text: The Development of a Novel Controlled Release Drug Delivery System The aim of this research was to formulate, characterise and assess the feasibility of a novel drug delivery system known as the in situ gelling matrix (ISGM) where a hydrophilic polymer is suspended in a non-aqueous solvent that converts into a gel when injected subcutaneously or intramuscularly thus giving a controlled release matrix for a drug.  Although the concept has been patented with claims that this kind of drug delivery is achievable in theory for a wide variety of candidate substances, actual formulation studies for making a commercially viable product for this technology are completely lacking in practice.   The research embodied in this thesis addresses this lack.  Initial studies involved conducting a biocompatibility study using the HET-CAM (hens egg test - chorioallantoic membrane) test on a range of possible ingredients for the delivery system.  The materials deemed biocompatible were then carried through to a screening process where the physical stability of the hydrophilic polymers in non-aqueous solvents was monitored.  It was found that the hydrophilic polymers tested sedimented rapidly in the non-aqueous solvents indicating such a system was not physically stable.  Consequently, density-inducing or viscosity-inducing agents were added to the non-aqueous solvents to retard the sedimentation rate.  The addition of polycarbophil, a viscosity-inducing agent, clearly increased the viscosity of the system.  However, undesirable formation of polycarbophil globules occurred during the manufacturing process, which caused batch-to-batch variations in the viscosity of the continuous phase. Various manufacturing methods were tested before arriving at the optimum procedure to prevent globule formation using a high speed dispersion tool.  A final physical sedimentation analysis of candidate continuous phases and hydrophilic polymers was conducted for determining the ideal combination of ingredients to use in the system.  These investigations finally led to the adoption of an optimum mix of components consisting of 10% (w/w) hydroxypropyl methylcellulose (HPMC) (the hydrophilic polymer) suspended in a continuous phase of propylene glycol (the non-aqueous solvent) containing 0.67% (w/w) polycarbophil (the viscosity inducing agent).

Using this mix of components, the in situ gelling matrix system was then subjected to various characterisation studies including infrared (IR), differential scanning calorimetry (DSC), ultraviolet-visible (UV-Vis) spectrophotometry and redispersion studies.  The chemical stability of the hydrophilic polymer and the continuous phase (the non-aqueous solvent and polycarbophil) was monitored and were found to be chemically stable over a 9 month period.  

The feasibility of the in situ gelling matrix technology as a controlled release device was assessed using the drug propranolol.  In vitro drug release studies were conducted using a custom-built dissolution apparatus.  The effect of various parameters such as the concentration of the hydrophilic gelling agent on the drug release rate was investigated.  Increasing the concentration of the gelling agent in the formulation resulted in a slower rate of release.  The drug release data were modelled using the Higuchi relationship and a power law relationship to compare the effects of the various parameters on the release rate

Stability studies on the drug in the in situ gelling matrix system were carried out by storing samples in accelerated ageing conditions of 40 C / 75% relative humidity for 4 weeks.  During this time, the samples were analysed each week by high performance liquid chromatography (HPLC).  These demonstrated that no apparent drug degradation had occurred over the 4-week period. This indicates that the drug propranolol in the in situ gelling matrix system is stable under ambient conditions for at least 4 weeks.  

The results of this study demonstrated that the in situ gelling matrix technology is potentially viable as a drug delivery system and provide a practical methodology for the commercial development of such systems.

year: 2007

title: Confiscation of Terrorist Funds: Can the EU Be a Useful Model for ASEAN?

authors: Tofangsaz, Hamed

subjects: terrorism

abstract: The counter-terrorist financing regime has been developed and diffused rapidly since the 9/11 attacks. The two central components of the regime are criminalization of acts of financing and confiscation of terrorist funds. These measures, which duplicate US laws on terrorist financing, have been designed to impose liability on, and confiscate assets and property of, those who finance or associate with terrorism regardless of whether there is a link between their act of financing or associating and a terrorist act. In the absence of such connection between the offense of terrorist financing and its subsequent crime of terrorism, a question arises: What is the legal basis for imposing liability on suspected financers and confiscating their assets and
property? This ambiguity has never been properly addressed by the creators of the regime or by those who promote the regime. This paper explores whether and how this ambiguity has been addressed at the regional level among the Member States of the Association of South East Asian Nations (ASEAN) where the agenda of countering terrorism has been largely shaped by external actors, mainly the Western states and international organizations established and controlled by them. Considering the fact that counter-terrorism has entered the agenda in the political dialogue between the EU and ASEAN, it is worth examining whether EU laws and policies on terrorist financing offer themselves as a model for ASEAN to emulate. The paper concludes that the EU, a value-based community, has failed to deal with the issue of terrorist financing effectively. This has resulted in draconian and unjustified overreach of the forfeiture laws and policies which, in many ways, are inconsistent with the rule of law, human rights, democratic values and good governance.

text: Confiscation of Terrorist Funds: Can the EU Be a Useful Model for ASEAN? The counter-terrorist financing regime has been developed and diffused rapidly since the 9/11 attacks. The two central components of the regime are criminalization of acts of financing and confiscation of terrorist funds. These measures, which duplicate US laws on terrorist financing, have been designed to impose liability on, and confiscate assets and property of, those who finance or associate with terrorism regardless of whether there is a link between their act of financing or associating and a terrorist act. In the absence of such connection between the offense of terrorist financing and its subsequent crime of terrorism, a question arises: What is the legal basis for imposing liability on suspected financers and confiscating their assets and
property? This ambiguity has never been properly addressed by the creators of the regime or by those who promote the regime. This paper explores whether and how this ambiguity has been addressed at the regional level among the Member States of the Association of South East Asian Nations (ASEAN) where the agenda of countering terrorism has been largely shaped by external actors, mainly the Western states and international organizations established and controlled by them. Considering the fact that counter-terrorism has entered the agenda in the political dialogue between the EU and ASEAN, it is worth examining whether EU laws and policies on terrorist financing offer themselves as a model for ASEAN to emulate. The paper concludes that the EU, a value-based community, has failed to deal with the issue of terrorist financing effectively. This has resulted in draconian and unjustified overreach of the forfeiture laws and policies which, in many ways, are inconsistent with the rule of law, human rights, democratic values and good governance.

year: 2017

title: Is the web being used to speak our language?

authors: Keegan, Te Taka Adrian Gregory

subjects: WWW

abstract: This paper presents results from extensive surveys of the usage of Maori language on the World Wide Web(www, Web) conducted in 1998 and 2002. Issues both supportive and detrimental relating to the use and publication of indigenous languages in the WWW will be highlighted. Specifically: how is the WWW being used to articulate the Maori language?

text: Is the web being used to speak our language? This paper presents results from extensive surveys of the usage of Maori language on the World Wide Web(www, Web) conducted in 1998 and 2002. Issues both supportive and detrimental relating to the use and publication of indigenous languages in the WWW will be highlighted. Specifically: how is the WWW being used to articulate the Maori language?

year: 2004