Near-infrared induced release for localized on-demand drug delivery

By non-invasive external triggering of drug release from an implant, pulsewise administration can be realized according to the patient’s needs and at specific locations in the human body. In comparison to more traditional delivery forms (e.g. oral or by injection), externally triggered drug release potentially offers the advantage of increased patient compliance due to easy and painless dosing, higher bioavailability, and lower doses of potent drugs, thereby reducing the toxic side effects commonly associated with systemic administration. The main focus in this thesis is on externally triggered on-demand release of relatively small drug molecules using the large change in diffusivity occurring near the glass transition temperature (Tg) of a polymer matrix. When the polymer is in the glassy state (T <Tg), the entrapped drug is virtually immobile, while in the rubbery state (T > Tg) the high amount of free volume and flexibility of the polymer chains allows diffusion of the drug out of the implant. The rate of diffusion greatly depends on the size, shape and flexibility of the drug, as well as its relation to the flexibility of the polymer chain. To a certain extent, these phenomena can be described by the free volume theory (FVT). However, the FVT has mainly been applied to describe diffusion of relatively small solutes in rubbery polymer-solute systems, whereas only a limited amount of research has dealt with its application to large solutes, such as drug molecules. Chapter 5 demonstrates that to use the FVT for diffusion of larger molecules approaching the size of polymer jumping units, a better understanding of polymer/drug dynamics is required.Non-invasive thermal triggering of drug release is achieved using near-infrared radiation (NIR), bordering on visible red light in the electromagnetic spectrum. The low absorption of water and tissue chromophores in this region allows for a relatively high penetration of NIR into the human body of up to several centimeters, making it attractive for biomedical applications. Since most polymers do not intrinsically absorb NIR, an NIR-absorbing compound is required. Here, a quaterrylenebis(dicarboximide) derivative, exhibiting a maximum in absorption around 780 nm, is incorporated into polymer matrices by conventional polymer processing techniques without affecting the Tg. UV-Visible spectroscopy reveals the formation of face-to-face stacked molecular aggregates on incorporation of this dye by solvent casting, which can be suppressed by incorporation or post-processing at elevated temperature. Although dye aggregation affects the absorption spectrum, the absorption at the wavelength of the NIR-source can effectively be controlled by increasing the dye concentration. Using a 785 nm NIR-laser, initial heating rates of over 3ºC s-1 and steady state temperature increases as high as 80ºC are reached. To investigate the effect of NIR-dye distribution on heat generation inside the polymer matrix in aqueous environment, a finite element (FE) model for NIR-induced heating is developed. Since the main resistance to mass transfer is located at the polymer/water interface, heat generation should mainly be located at the surface of the implant. Coating the implant with a dye containing layer therefore yields the best combination of high surface temperatures without exposing the inside of the implant to excessive temperatures. The FE-model is subsequently used to estimate the temperatures that can be achieved in vivo using NIR, taking into account scattering and absorption by skin and subcutaneous tissue. Compared to aqueous environment (in vitro), higher temperatures are induced in vivo due to a lower amount of heat dissipation. By using an insulating layer, the tissue can be protected from high temperatures, thus preventing tissue damage from occurring and enabling NIR-induced drug release. Experimentally, both in vitro and in vivo, repeated and reproducible on-off release of ibuprofen is demonstrated by non-invasive selective heating of a polylactide implant using near-infrared radiation, attaining on-off ratios in excess of 1,000. Supersaturation of the implant ensures replenishment of released ibuprofen by partial dissolution of the drug crystals providing a constant concentration of ibuprofen dissolved in the polymer and, consequently, a constant driving force for release. Although the large plasticizing effect of ibuprofen lowers the Tg of the polymer to about 0ºC (i.e. the bulk polymer is in a rubbery state), release of ibuprofen at body temperature is extremely low, attributed to the spontaneous formation of a glassy surface layer. Drug release can thus be controlled by changing the temperature of this switching layer around Tg. In addition, this self-sealing mechanism provides an intrinsic safety precaution, as rupture of the implant will not result in dose dumping. The simple design of an implant based on the glass transition switch thus offers an appealing drug delivery system. It should be realized, however, that strict requirements are imposed on the polymer, and that new solubility and diffusivity data needs to be generated for each new drug/polymer combination. Although the Tg can be effectively used to switch on and off the release of ‘simple’ drug molecules, controlling release of large molecules, such as peptide drugs, is impossible. For this reason, an alternative mechanism is explored based on the reversible swelling capability of a hydrogel around the so-called lower critical solution temperature (LCST). A drug reservoir is covered by a thermoresponsive composite membrane, consisting of a microporous polymeric support and a hydrogel graft layer. Above the LCST of the hydrogel (on-state), the shrunken state of the graft layer appears to only partially cover the membrane, allowing protein permeation through the uncovered pores. Provided the grafting degree is high enough, the swollen hydrogel covers the membrane completely below the LCST (off-state), thus preventing protein permeation. In this way, reversible on/off-switching of protein permeation through a thermoresponsive composite membrane with negligible permeation in the off-state is demonstrated. The on-demand release mechanism proposed in this thesis is based on switching the membrane surface coverage rather than previously reported switches based on effective pore size or hydrogel mesh size, thus allowing for higher fluxes in the on-state, since permeation is not limited by pore-narrowing. Both the Tg- and the LCST-concept permit long-term and patient-friendly administration of a wide variety of medicines, ranging from systemic dosing of drugs with low oral bioavailability to drugs required locally. This thesis presents a proof of principle for on-demand drug delivery using a laser as NIR-source. From a commercial point of view, it is expected that the use of cheaper light emitting diodes (LEDs) in the NIR range can lead to the design of hand-held devices suitable for near-infrared induced drug delivery in both a clinical and home environment

On-demand drug delivery from polymeric implants by external triggering

In this contribution, a novel on demand drug delivery concept based on polymeric implants is presented. The simple combination of drug substance and polymer matrix was found to result in a robust and reproducible on demand drug delivery device that can be switched by temp. High switching ratios (several hundreds) were found in repetitive (up to 5) on demand drug dosing. In addn., the use of several other noninvasive triggers was explored. Finally, the potential of this novel drug delivery technol. will be demonstrated by in vivo on demand drug delivery

On-demand drug delivery from polymeric implants by external triggering

In this contribution, a novel on demand drug delivery concept based on polymeric implants is presented. The simple combination of drug substance and polymer matrix was found to result in a robust and reproducible on demand drug delivery device that can be switched by temp. High switching ratios (several hundreds) were found in repetitive (up to 5) on demand drug dosing. In addn., the use of several other noninvasive triggers was explored. Finally, the potential of this novel drug delivery technol. will be demonstrated by in vivo on demand drug delivery

Pore-covered thermoresponsive membranes for repeated on-demand drug release

Reversible on/off-switching of bovine serum albumin (BSA) permeation through a thermoresponsive composite membrane with negligible permeation in the off-state is demonstrated. UV-photografting of poly(N-isopropylacrylamide) onto a poly(ethylene terephthalate) microfiltration membrane results in a hydrogel graft layer on the irradiated side of the membrane only. The amount of hydrogel grafted onto the membrane can be controlled by the amount of crosslinker. Above the lower critical solution temperature (LCST) of the hydrogel (on-state), the shrunken state of the graft layer appears to only partially cover the membrane, allowing BSA permeation through the uncovered pores. Provided the grafting degree is high enough, the swollen hydrogel covers the membrane completely below the LCST (off-state), thus preventing BSA permeation. The on-demand release mechanism proposed here is based on switching the membrane surface coverage rather than previously reported switches based on effective pore size or hydrogel mesh size. The main advantage of our mechanism is that higher fluxes can be achieved in the on-state, since permeation is not limited by pore-narrowing

Pore-covered thermoresponsive membranes for repeated on-demand drug release

Reversible on/off-switching of bovine serum albumin (BSA) permeation through a thermoresponsive composite membrane with negligible permeation in the off-state is demonstrated. UV-photografting of poly(N-isopropylacrylamide) onto a poly(ethylene terephthalate) microfiltration membrane results in a hydrogel graft layer on the irradiated side of the membrane only. The amount of hydrogel grafted onto the membrane can be controlled by the amount of crosslinker. Above the lower critical solution temperature (LCST) of the hydrogel (on-state), the shrunken state of the graft layer appears to only partially cover the membrane, allowing BSA permeation through the uncovered pores. Provided the grafting degree is high enough, the swollen hydrogel covers the membrane completely below the LCST (off-state), thus preventing BSA permeation. The on-demand release mechanism proposed here is based on switching the membrane surface coverage rather than previously reported switches based on effective pore size or hydrogel mesh size. The main advantage of our mechanism is that higher fluxes can be achieved in the on-state, since permeation is not limited by pore-narrowing

Externally triggered glass transition switch for localized on-demand drug delivery

want a new drug dose: External on-demand laser triggering is used in a drug-delivery concept, with on/off ratios in excess of 1000/1. The switching mechanism involves the glass transition of hydrophobic polymers with a large change in diffusivity. Formation of a glassy surface layer of the implant in the off state plays a key role, resulting in negligible off-release. (Picture: data points indicate ibuprofen concentration)