No description available.

<p dir="ltr">Opioid use disorder (OUD) presents a challenging and nuanced condition with potential for debilitating social and physical consequences. Patients with OUD have access to treatment options, but they may encounter issues such as diversion, invasiveness, or poor adherence. With over 2.5 million adults in the US experiencing OUD as of 2021, the need for an OUD treatment that overcomes these challenges is clear. One available treatment method is Sublocade®, a PLGA-based in situ forming implant (ISFI) that releases buprenorphine. This treatment shows promise due to its physician administered extended release design, which addresses many current issues in OUD treatment. However, the practicality of this treatment remains a challenge due to its monthly injection requirement. To address this, we investigated how altering ISFI components impacts the timeframe of buprenorphine release from a PLGA-based ISFI. Our focus was on evaluating factors that lead to extended buprenorphine release while maintaining zero-order release. We varied polymer-to-solvent ratios, drug percentage, and solvent composition, assessing their effects through drug release studies. We also conducted SEM imaging and swelling/erosion studies to evaluate polymer behavior and implant microstructure, gaining further insights into drug release mechanisms. Our drug release studies revealed that higher buprenorphine content in the implant significantly reduced total drug release and linearized drug release patterns. Decreasing the polymer-to-solvent ratio similarly linearized drug release and reduced drug burst, although the overall amount of drug released over time remained similar. Introducing Triacetin (TA) as a solvent helped reduce drug burst and maintain release linearity in lower drug content implants. In higher drug content implants, TA appeared to increase drug release over time, likely due to degradation processes indicated by high swelling and increased degradation observed in SEM imaging. Erosion studies showed less implant erosion with higher drug loading, aligning with release study observations. In conclusion, solvent type and drug content significantly influence buprenorphine release in ISFI systems and should be carefully considered when designing extended release systems similar to Sublocade®.</p>

<p>Pancreatic ductal adenocarcinoma is an especially deadly disease having the lowest 5-year survival rate of any major cancer at just 11%. As in many cancers, systemically-delivered chemotherapy forms the backbone of clinical treatment. However, limitations of systemic delivery exacerbated by the unique desmoplastic and avascular microenvironment surrounding the pancreatic tumor cells result in the failed efficacy of current treatments. The high stromal content in the microenvironment, which is especially overabundant in hyaluronic acid, is thought to physically impede drug perfusion into the tissue. Thus, there is clearly a <strong>critical need</strong> to develop novel treatments for pancreatic ductal adenocarcinoma that can overcome these drug delivery barriers. Long-acting injectable implants offer an attractive drug delivery method that can provide <em><strong>sustained</strong></em> drug release directly at the <em><strong>local</strong></em> targeted site, rather than transient, systemic release. Here we use in situ forming implants (ISFIs), which are a low-viscosity solution outside of the body but transition into a solid drug-eluting depot after injection into an aqueous environment. Our <strong>objective</strong> is to develop and characterize an ISFI that can provide sustained release of bioactive hyaluronidase for use as an intratumoral injection to degrade hyaluronic acid in pancreatic tumors. This work was accomplished in four aims. First, a method was developed using diffusion-weighted MRI for noninvasive characterization of the implants. Second, because hyaluronidase is a protein drug, we studied factors affecting protein release from ISFIs, focusing on external factors of the injection site. Third, we showed that basic salt additives can be used to neutralize the acidic environment created by the implants which may improve protein stability. Finally, we formulated an implant to provide sustained release of hyaluronidase and demonstrated retention of its bioactivity both <em>in vitro</em> and <em>ex vivo</em>.</p>

Le développement de nouveaux systèmes pour l’administration de médicaments par la voie transcutanée ne cesse de susciter un intérêt croissant pour élaborer de nouvelles stratégies visant à traverser la barrière du stratum corneum et transporter efficacement les agents thérapeutiques à travers la peau. Bien que l’administration par voie orale soit la plus favorable chez les patients, une faible biodisponibilité est souvent rencontrée pour certains médicaments et notamment pour les produits biopharmaceutiques. Ainsi, la peau représente un site accessible et pratique pour l’absorption de médicaments, mais détient un potentiel encore sous-estimé comme voie alternative à l’administration par voie orale. La conception de systèmes d'administration parentérale prolongée de médicaments capables de contrôler la libération du médicament au long terme et réduire la fréquence d’administration des médicaments pourrait présenter une option de traitement attrayante. Parmi les systèmes d’implants se formant in situ, les implants d’organogel offrent de nombreux avantages pour libérer au long terme une grande variété de molécules médicamenteuses et notamment des substances actives lipophiles piégées dans les huiles gélifiées. Cependant si l’objectif visé est une administration minimalement invasive et rapide de substances actives, les timbres de microaiguilles dissolvant dans la peau seraient d’un grand intérêt en raison de leur auto-administration, leur sécurité d’emploi et leur capacité à administrer des médicaments à base de peptides. Malgré les effets bénéfiques de ces deux nouveaux systèmes d’administration, les rôles exacts de la composition des organogels et des paramètres géométriques des microaiguilles hydrosolubles sur la libération de médicaments restent peu explorés. Le premier objectif principal de cette thèse était de déterminer l’effet de la composition des organogels se formant in situ par rapport au pourcentage massique en organogélifiant de bas poids moléculaire (acide 12-hydroxystéarique, 12-HSA) et de l’ajout de tensioactif (polysorbate 80) dans le système sur le taux de libération de substances actives hydrophile (acyclovir) et lipophile (clotrimazole). De plus, l'influence des paramètres de composition de ces organogels sur l'induction d'effets toxiques au niveau des fibroblastes de prépuce humain a également été étudiée. Pour ce faire, des systèmes d’organogel formant un dépôt sous-cutané à base de 12-HSA ont été développés en utilisant une faible quantité de solvant organique miscible à l’eau (N-méthyl-2-pyrrolidone) en tant qu’agent inhibant partiellement la gélation, favorisant ainsi l’injection des formulations. Au contact du milieu aqueux, les molécules de 12-HSA ont précipité en immobilisant simultanément l’huile et la substance active en son sein. Une augmentation du pourcentage massique en 12-HSA a conduit à une augmentation de la résistance du gel à la déformation grâce à la formation d’une structure de réseau en trois dimensions complexe. Cependant, l’ajout de polysorbate 80 dans le système a conduit à une structure plus fluide (de faible résistance) diminuant la capacité d’injectabilité des formulations et augmentant l’érosion du gel en surface. Ce dernier phénomène étant amplifié avec un plus faible pourcentage massique en 12-HSA. Les organogels de 12-HSA ont montré diminuer significativement les taux de libération au long terme de l’acyclovir comparé aux formulations de clotrimazole in vitro et ex vivo à travers la peau de porc excisé. La toxicité cellulaire était dépendante du pourcentage massique en 12-HSA et du type de culture cellulaire utilisée. En effet, les effets cytotoxiques étaient plus élevés en augmentant la quantité de 12-HSA dans l’implant pour une sensibilité plus élevée dans la culture cellulaire tridimensionnelle que dans celle bidimensionnelle. Ces résultats semblent néanmoins influencés par le type d’huile utilisé et son potentiel cytotoxique. Le deuxième objectif principal de cette thèse était de déterminer l’effet de la hauteur des microaiguilles en forme de pyramide et solubles dans l’eau sur le taux de libération d’un peptide modèle, le growth hormone-releasing peptide-6 (GHRP-6). À cet effet, les microaiguilles ont été préparées par micro-moulage à l’aide de deux polymères biocompatibles hydrosolubles approuvés par la Food and Drug Agency (FDA), l’alcool polyvinylique (PVA) et polyvinylpyrrolidone (PVP). Les timbres de microaiguilles ainsi développés permettaient de pénétrer efficacement dans la peau de porc tout en libérant la molécule encapsulée à l’interface entre l’épiderme et le derme supérieur. La quantification du GHRP-6 dans différentes matrices (peau, microaiguilles, plasma) a pu être réalisée grâce à une méthode analytique robuste et sensible utilisant la chromatographie liquide ultra performance couplée à la spectrométrie de masse en tandem. Les études de libération du GHRP-6 ex vivo sur la peau de porc ont montré que le taux de libération du GHRP-6 était plus élevé au long terme pour une hauteur en aiguille plus grande (800 µm contre 500 µm) tout en permettant d’augmenter l’encapsulation du GHRP-6 dans le système. En conclusion, ces résultats suggèrent que les organogels de 12-HSA pourraient constituer une approche prometteuse pour l’administration prolongée de substance active et notamment celles hydrophiles. Toutefois, les formulations développées devront être efficaces in vivo tout en minimisant les effets toxiques par l’utilisation d’huiles plus biocompatibles. Pour une libération rapide de substances actives, les timbres de microaiguilles représentent une avenue très prometteuse notamment pour les médicaments innovants de nature peptidique. Leur efficacité pour la libération de GHRP-6 et de leurs dérivés azapeptides devra être confirmée lors d’études in vivo (pharmacocinétique, pharmacodynamique, biodistribution), ce qui pourrait constituer une avancée dans l’administration de thérapie à base de peptides pour la gestion de l’inflammation chronique. / The development of novel transcutaneous drug delivery systems has gained increasing interest, with the focus on overcoming the stratum corneum barrier and efficiently transport therapeutic agents through the skin. Although oral administration is the most favorable route for patients, low bioavailability is often reported for certain drugs and especially for biopharmaceuticals. Accordingly, the skin represents an accessible and convenient site for drug absorption, but has yet to fully achieve its potential as an alternative to oral delivery. The design of parenteral sustained drug delivery systems capable of controlling long-term delivery of drugs and reducing the frequency of drug administration could present an attractive treatment option. Among in situ forming implants, in situ forming organogels offer many advantages such as controlled-release of a wide variety of drug molecules over a longer period of time, including lipophilic active substances trapped within gelled oil solutions. However, if the objective is the rapid administration of active substances, minimally invasive, dissolving microneedle patches would be of great interest due to their self-administration, their safety and their ability to deliver peptide-based drugs. Despite the beneficial effects of these two new delivery systems, the exact roles of the composition of organogels and geometrical parameters of microneedles on drug delivery are largely understudied. The first main objective of this thesis was to determine the effect of the composition of in situ forming organogels with respect to the organogelator concentration (12-hydroxystearic acid, 12-HSA) and the addition of a nonionic surfactant (polysorbate 80) to the system on the release rate of a hydrophilic (acyclovir) and a lipophilic (clotrimazole) active substances. In addition, the toxic effects of these organogels of different compositions on human foreskin fibroblasts were also studied. To do so, 12-HSA-based organogel systems forming a depot in the subcutaneous tissue have been developed using a small amount of water-miscible organic solvent (N-methyl-2-pyrrolidone) as an agent that can partially inhibit gelation, thus enhancing injectability of the formulations. Upon contact with aqueous medium, 12-HSA molecules precipitated simultaneously immobilizing the oil and the active substance therein. An increase in the concentration of 12-HSA led to an increase in the resistance of the gel to deformation thanks to the formation of a complex three-dimensional network structure. However, the addition of polysorbate 80 to the system resulted in fluid-matrix organogel (weak gel) decreasing the syringability of the formulations while increasing the erosion of the gel on the surface. The latter phenomenon is also intensified with a lower concentration of 12-HSA. 12-HSA organogels have been shown to significantly decrease acyclovir release rates for a longer time period in vitro and ex vivo through excised pig skin compared to clotrimazole formulations. Cellular cytotoxicity was dependent on the concentration of 12-HSA and the type of cell culture used. Indeed, the cytotoxic effects were higher by increasing the concentration of 12-HSA in the implant for a higher sensitivity in the three-dimensional cell culture than in the two-dimensional one. However, these results seem to be influenced by the type of oil used and its cytotoxic potential. The second main objective of this thesis was to determine the effect of dissolving pyramidal microneedles height on the release rate of a model peptide, the growth hormone-releasing peptide-6 (GHRP-6). For this purpose, the microneedles were prepared by micromolding process using two water-soluble biocompatible polymers approved by the Food and Drug Agency (FDA), poly(vinyl alcohol) (PVA) and polyvinylpyrrolidone (PVP). The microneedle patches allowed the microneedles to efficiently penetrate pig skin while releasing the encapsulated molecule at the interface between the epidermis and upper dermis. The quantification of GHRP-6 in different matrices (skin, microneedles, plasma) was achieved using a robust and sensitive analytical method using ultra performance liquid chromatography - tandem mass spectrometry. Ex vivo GHRP-6 release studies on pig skin showed that the release rate of GHRP-6 was higher over time for high-height microneedle (800 µm vs. 500 µm) while increasing the amount of GHRP-6 loaded in microneedles. In conclusion, these results suggest that 12-HSA organogels could constitute a promising approach as a sustained-release dosage form of active substances and in particular hydrophilic ones. However, the formulations developed must be effective in vivo while minimizing toxic effects through the use of more biocompatible oils. For a rapid release of drugs, microneedle patches represent a very promising avenue, in particular for emerging peptide drugs. Their efficacy for the release of GHRP-6 and azapeptide derivatives of GHRP-6 needs to be confirmed using in vivo studies (pharmacokinetic, pharmacodynamic, biodistribution), which may represent a breakthrough in the transdermal delivery of therapeutic peptides for the management of chronic inflammation.