Laser-assisted fabrication of silicone-based patches for transdermal drug release – Labricon

The structure of the oxidized layer will be investigated by SEM, AFM, IR and Raman spectroscopy. The transport properties of the membranes can be varied in continuous manner from semi-permeable to impermeable, via the application of different intensity and duration of the radiation. The permittivity of the interfaces will be quantified by the diffusion rate through the interface into liquid receiving media (phosphate buffer) with the use of the Franz cell. The less traditional approaches, such as diffusion in humidity-controlled synthetic skin system (Cai et al 2012) , and confocal microscopy measurement of the diffusion profiles of the model drugs (e.g. Rhodamine B) in PDMS receiving layer will be also applied for the characterization of the interface barrier properties. Prototypes of the patches of different architectures will be tested. In the monolayer patches, the single PDMS layer, topped by an impermeable strongly oxidized film, will serve silultaneously the adhesive layer, the drug reservoir, and the mechanical support. In more complicated architectures, these functions will be assigned to different consequtive layers. The adhesive layer and the drug reservoir layer will be separated by semi-permeable interface, and the drug reservoir layer will be topped by the impermeable interface. The pressure-sensitive adhesion will be provided by low degree of crosslinking of the corresponding layer. At the advanced stage of the project, we will work with real drugs models. Similar drugs than the ones used in the marketed transdermal drug delivery devices will be used. Two different model drugs such as scopolamine and oestradiol will be used. The determination of the release profiles will be explored with the use of the Franz cells, and the syntetic skin system (Cai et al. 2012). A dissolution bath apparatus 2 with mini vessels will be also used to perform the release test for patches. The patches will be fixed in the baskets and placed at the bottom of the vessel in pH 6.8 phosphate buffer. The concentration of the model drugs in the solution will be measured using isocratic reversed phase liquid HPLC. The fraction of drug release will be calculated from the total amount of drug in the patch. To analyze the active ingredients and to see if they are degraded by the irradiation, we shall make an assay by a double mass liquid chromatography (HPLC MS/MS). This will measure the active ingredient and any impurities (degradation products). In vivo tests will be performed on nude rats (without hair). These tests will be carried out in the animal clinics of the University of Strasbourg and in particular at the laboratory animal house of the Faculty of Pharmacy. The in vivo tests will be performed after writing a referral that has been validated by the regulatory authorities.

The first half of the project period was devoted to the study of the possibility to create the effective diffusion barrier at the surface of a PDMS film by the infrared laser irradiation. The effectiveness of the barrier was tested with the use of a model drug, Rhodamin B, which is known for its solubility in the polymer. The irradiation parameters were optimized in terms of the laser power, speed of the laser beam displacement along the sample, number of the irradiation repetitions, and the distance of the sample surface from the focal plane of the laser lense. The optimisation challenge consisted in finding the window of parameters which provide the formation of the highly crosslinked layer of the surface of the elastomer without the ablation of the polymer. We have found that the optimal irradiation conditions correspond to strong defocussing of the laser, and simultaneous increasing the laser power. In order to limit the number of the optimization parameters, the laser displacement speed was kept constant, as well as the raster resolution. The presence of the strongly crosslinked barrier layer was detected by the scanning electron microscopy (SEM), and by the change of the adhesivity of the irradiated surface. The barrier properties were investigated by the confocal microscopy, and by the spectrophophotometric measurements of the Rhodamin B concentration in water media applied to the irradiated side of the RhB-containing PDMS patches. Apart of the laser irradiation treatment of the PDMS, we have explored the formation of the barrier layer with the use of plasma polymerisation in collaboration with the Functional Polymers Engineering Group of IS2M. The barrier layer was formed on the surface of the patches at the plasma polymerisation of hexamethyldisiloxane in the pulsed plasma regime. Also, the PDMS barrier layer was formed by the ion beam irradiation at the ICube laboratory CNRS/INSA, in collaboration with the group of D. Muller. The samples were irradiated by Ar ion beams using the Van der Graaf ion accelerator. The laser irradiation treatment and the plasma polymerisation provide very similar barrier properties, reducing the model drug diffusion from the patch to the level which is below 10% of that of the control sample during 3 days, that correspond well to the typical period of a patch wearing. In contrary, ion beam irradiation provided only moderate blocking of the model drug diffusion, and the effectiveness of the barrier seems to be not satisfactory for all the irradiation doses.

The formulation of patches containing active pharmaceutical ingredients to prevent the development of neurodegenerative diseases of the brain will improve the quality of patients suffering from these diseases. Neurodegenerative diseases include Alzheimer's disease, Hungtington's disease, multiple sclerosis and Parkinson's disease. In 2015, 46.8 million people worldwide suffered from dementia. If current trends continue by 2030, that number could reach 74.7 million and by 2050, 131.5 million people. Neurodegenerative diseases produce the symptoms of dementia by causing cells in the spinal cord and brain to die. Losing these cells and their functions means a reduced ability to control movement, make effective decisions, and remember memories. Neurodegeneration is devastating because there is no simple way to regenerate these types of cells. Two active pharmaceutical ingredients - trazadone, usually prescribed for depression, and dibenzoylmethane, currently being tested as an anti-cancer drug - also have the property of slowing neurodegenerative diseases, including dementia. The combination, within a single patch or two separate patches, should be able to prevent damage to brain cells and restore memory function in mice, while reducing the signs of shrinking brain. The advantage of such patch formulations for patients affected by these neurodegenerative diseases is to be able to easily support this type of treatment for life unlike tablets or injectables to be taken daily, without mentioning gastrointestinal intolerances linked to these active ingredients following oral administration. Although these treatments are very unlikely to cure them completely, being able to stop their progress will change these neurodegenerative diseases such as Alzheimer's so that it can become bearable for the patient and the caregiver.

A research article is in course of preparation.

Silicone-based transdermal drug delivery patches are currently used in a wide range of pharmaceutical applications from hormone therapy to central nervous system related pathologies. However, their production has relatively high technology barrier, impacting their price and limiting their utilization. We aim to resolve this problem by developing a novel simple and cost-effective approach to the patches fabrication, based on infrared laser irradiation of polydimethylsiloxane layers. In previous works (Qi et al 2018, Tomba et al 2019) it was shown that intense irradiation can generate a few microns thick strongly oxidized layer on the surface of the PDMS films, without the films ablation. Preliminary experiments have shown that these films might serve as the barrier for the diffusion of small molecules in the elastomer matrix. This opens the way to create patches as the sequence of PDMS layer separated by the laser-oxidized interfaces of different permeability for the drugs.
The structure of the oxidized layer will be investigated by SEM, AFM, IR and Raman spectroscopy. The transport properties of the membranes can be varied in continuous manner from semi-permeable to impermeable, via the application of different intensity and duration of the radiation. The permeability of the interfaces will be quantified by the diffusion rate through the interface into liquid receiving media (phosphate buffer) with the use of the Franz cell. The less traditional approaches, such as diffusion in humidity-controlled synthetic skin system (Cai et al 2012) , and confocal microscopy measurement of the diffusion profiles of the model drugs (e.g. Rhodamine B) in PDMS receiving layer will be also applied for the characterization of the interface barrier properties.
Prototypes of the patches of different architectures will be tested. In the monolayer patches, the single PDMS layer, topped by an impermeable strongly oxidized film, will serve simultaneously the adhesive layer, the drug reservoir, and the mechanical support. In more complicated architectures, these functions will be assigned to different consecutive layers. The adhesive layer and the drug reservoir layer will be separated by asemi-permeable interface, and the drug reservoir layer will be topped by the impermeable interface. The pressure-sensitive adhesion will be provided by low degree of crosslinking of the corresponding layer.
At the advanced stage of the project, we will work with real drugs models. Similar drugs than the ones used in the marketed transdermal drug delivery devices will be used. Two different model drugs such as scopolamine and oestradiol will be used. The determination of the release profiles will be explored with the use of the Franz cells, and the synthetic skin system (Cai et al. 2012). A dissolution bath apparatus 2 with mini vessels will be also used to perform the release test for patches. The patches will be fixed in the baskets and placed at the bottom of the vessel in pH 6.8 phosphate buffer. The concentration of the model drugs in the solution will be measured using isocratic reversed phase liquid HPLC. The fraction of drug release will be calculated from the total amount of drug in the patch. To analyze the active ingredients and to see if they are degraded by the irradiation, we shall make an assay by a double mass liquid chromatography (HPLC MS/MS). This will measure the active ingredient and any impurities (degradation products).
In vivo tests will be performed on nude rats (without hair). These tests will be carried out in the animal clinics of the University of Strasbourg and in particular at the laboratory animal house of the Faculty of Pharmacy. The in vivo tests will be performed after writing a referral that has been validated by the regulatory authorities.