{"id":{"repo_id":"cork","oai_identifier":"oai:cora.ucc.ie:10468/18463"},"canonical_url":"https://search.dev.ndltd.org/etd/cork/oai:cora.ucc.ie:10468/18463","repository":{"repo_id":"cork","name":"University College Cork","base_url":"https://cora.ucc.ie/server/oai/request"},"display":{"title":"Preclinical evaluation of dissolvable microarray patches for allergy treatment: key factors governing in vitro and in silico assessment","abstract":"Allergic diseases continue to pose a significant global health challenge, highlighting the need for more effective, patient-friendly therapeutic approaches. Although antihistamines remain the cornerstone of allergy treatment, their conventional oral administration is limited by extensive first-pass metabolism and unpredictable pharmacokinetics. Skin delivery represents a promising alternative, with innovative platforms such as dissolvable microarray patches (MAP), offering the potential for targeted local and systemic drug effects. However, no dissolvable MAP have yet reached the market. Despite significant advances in early MAP development (e.g. materials, fabrication), critical gaps remain in understanding the factors that influence preclinical performance. These gaps are particularly evident in in vitro and in silico studies, where the lack of predictive, MAP-specific translational models remains a major limitation. To address these limitations, this thesis aimed to enhance the preclinical evaluation of dissolvable MAP by systematically investigating the physicochemical, biopharmaceutical, and pharmacokinetic factors that govern skin deposition and the bioavailability of antihistamines delivered via dissolvable MAP. To establish a foundation for this investigation, a theoretical analysis of the scientific principles underpinning preclinical evaluation specific to MAP systems was first conducted. This comprehensive assessment of the skin environment and its implications to in vitro MAP performance revealed several critical yet overlooked factors—including media composition, skin model selection, and the therapeutic efficacy of the released drug—all of which require careful consideration in experimental design. With the theoretical groundwork established, thesis then focused on investigating how the physicochemical properties of a drug influence MAP design and performance. Two antihistamines—chlorpheniramine maleate (CPM) and loratadine (LOR)—were incorporated into MAP using distinct micromoulding methods (drug solution diffusion vs molten drug) and formulation types (polymer-based vs drug-only). The final formulations, CPM MAP (70 mg/ml in 15% w/v PVP/VA) and drug-only LOR MAP, demonstrated optimal physical, chemical, and mechanical properties. Furthermore, in vitro release and in vitro permeation testing protocols were optimised to evaluate biopharmaceutical performance, with particular emphasis on media composition and skin model selection. Results demonstrated that the composition of the in vitro release medium significantly affects the release profile of the lipophilic LOR, as well as the permeation and skin deposition profiles of both lipophilic LOR and hydrophilic CPM delivered via MAP. To better simulate the physiological conditions of the skin, proposed is the use of a biorelevant artificial interstitial fluid as the in vitro release medium for both MAP formulations, supplemented with a non-ionic surfactant to maintain sink conditions for lipophilic LOR. Additionally, evaluation of skin models revealed that neonatal porcine skin overestimates CPM and LOR permeability, whereas adult porcine skin more accurately reflects their permeability in human skin. To further investigate biopharmaceutical factors, in vitro safety and efficacy studies were conducted using human skin cell models to assess the selected drugs and formulations. Cytotoxicity testing in dermal fibroblasts and epidermal keratinocytes confirmed that both drugs were non-toxic to the most prevalent skin cell types across a range of concentrations, including those representative of MAP dose. Efficacy was evaluated based on the ability of MAP-delivered antihistamines to inhibit histamine release from mast cells, which play a central role in dermal allergic responses. LOR demonstrated a concentration-dependent and statistically significant inhibition of histamine release compared to controls, supporting its potential for targeted dermal delivery, whereas CPM showed no such effect. In the final chapter of this thesis, the pharmacokinetic behaviour following MAP administration was investigated using in silico approach, through the development of physiologically based pharmacokinetic model adapted from the MoBi® platform. This model was specifically tailored for dissolvable MAP by integrating microneedle geometry and experimentally derived in vitro release profile. Following careful optimisation of input parameters, the model successfully predicted skin-layer distribution and permeation of CPM and LOR under in vitro conditions, as well as the systemic exposure of itraconazole in vivo after MAP applications. These results support its potential as a valuable translational tool in early-stage MAP development. In conclusion, this research has significantly advanced our understanding of the complex factors influencing drug behaviour in the skin following MAP application. Through the development of two distinct MAP formulations incorporating CPM and LOR, we comparatively evaluated how the physicochemical, biopharmaceutical, and pharmacokinetic properties of these drugs impact skin distribution, systemic absorption, and therapeutic efficacy. The in vitro and in silico models were specifically designed to capture the complex interactions between MAP and the skin environment, offering mechanistic insights into their effects on MAP performance. Findings of this thesis emphasise the critical importance of considering these interconnected factors in preclinical MAP research, providing a solid foundation for advancing clinical studies and accelerating the translation of MAP technologies into clinical applications.","abstract_html":"Allergic diseases continue to pose a significant global health challenge, highlighting the need for more effective, patient-friendly therapeutic approaches. Although antihistamines remain the cornerstone of allergy treatment, their conventional oral administration is limited by extensive first-pass metabolism and unpredictable pharmacokinetics. Skin delivery represents a promising alternative, with innovative platforms such as dissolvable microarray patches (MAP), offering the potential for targeted local and systemic drug effects. However, no dissolvable MAP have yet reached the market. Despite significant advances in early MAP development (e.g. materials, fabrication), critical gaps remain in understanding the factors that influence preclinical performance. These gaps are particularly evident in in vitro and in silico studies, where the lack of predictive, MAP-specific translational models remains a major limitation. To address these limitations, this thesis aimed to enhance the preclinical evaluation of dissolvable MAP by systematically investigating the physicochemical, biopharmaceutical, and pharmacokinetic factors that govern skin deposition and the bioavailability of antihistamines delivered via dissolvable MAP. To establish a foundation for this investigation, a theoretical analysis of the scientific principles underpinning preclinical evaluation specific to MAP systems was first conducted. This comprehensive assessment of the skin environment and its implications to in vitro MAP performance revealed several critical yet overlooked factors—including media composition, skin model selection, and the therapeutic efficacy of the released drug—all of which require careful consideration in experimental design. With the theoretical groundwork established, thesis then focused on investigating how the physicochemical properties of a drug influence MAP design and performance. Two antihistamines—chlorpheniramine maleate (CPM) and loratadine (LOR)—were incorporated into MAP using distinct micromoulding methods (drug solution diffusion vs molten drug) and formulation types (polymer-based vs drug-only). The final formulations, CPM MAP (70 mg/ml in 15% w/v PVP/VA) and drug-only LOR MAP, demonstrated optimal physical, chemical, and mechanical properties. Furthermore, in vitro release and in vitro permeation testing protocols were optimised to evaluate biopharmaceutical performance, with particular emphasis on media composition and skin model selection. Results demonstrated that the composition of the in vitro release medium significantly affects the release profile of the lipophilic LOR, as well as the permeation and skin deposition profiles of both lipophilic LOR and hydrophilic CPM delivered via MAP. To better simulate the physiological conditions of the skin, proposed is the use of a biorelevant artificial interstitial fluid as the in vitro release medium for both MAP formulations, supplemented with a non-ionic surfactant to maintain sink conditions for lipophilic LOR. Additionally, evaluation of skin models revealed that neonatal porcine skin overestimates CPM and LOR permeability, whereas adult porcine skin more accurately reflects their permeability in human skin. To further investigate biopharmaceutical factors, in vitro safety and efficacy studies were conducted using human skin cell models to assess the selected drugs and formulations. Cytotoxicity testing in dermal fibroblasts and epidermal keratinocytes confirmed that both drugs were non-toxic to the most prevalent skin cell types across a range of concentrations, including those representative of MAP dose. Efficacy was evaluated based on the ability of MAP-delivered antihistamines to inhibit histamine release from mast cells, which play a central role in dermal allergic responses. LOR demonstrated a concentration-dependent and statistically significant inhibition of histamine release compared to controls, supporting its potential for targeted dermal delivery, whereas CPM showed no such effect. In the final chapter of this thesis, the pharmacokinetic behaviour following MAP administration was investigated using in silico approach, through the development of physiologically based pharmacokinetic model adapted from the MoBi® platform. This model was specifically tailored for dissolvable MAP by integrating microneedle geometry and experimentally derived in vitro release profile. Following careful optimisation of input parameters, the model successfully predicted skin-layer distribution and permeation of CPM and LOR under in vitro conditions, as well as the systemic exposure of itraconazole in vivo after MAP applications. These results support its potential as a valuable translational tool in early-stage MAP development. In conclusion, this research has significantly advanced our understanding of the complex factors influencing drug behaviour in the skin following MAP application. Through the development of two distinct MAP formulations incorporating CPM and LOR, we comparatively evaluated how the physicochemical, biopharmaceutical, and pharmacokinetic properties of these drugs impact skin distribution, systemic absorption, and therapeutic efficacy. The in vitro and in silico models were specifically designed to capture the complex interactions between MAP and the skin environment, offering mechanistic insights into their effects on MAP performance. Findings of this thesis emphasise the critical importance of considering these interconnected factors in preclinical MAP research, providing a solid foundation for advancing clinical studies and accelerating the translation of MAP technologies into clinical applications.","abstract_has_math":false,"creators":["Railic, Maja"],"institution":"University College Cork","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Vucen, Sonja","Crean, Abina"],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025","date_published":"2025","updated_at":"2026-07-24T01:47:55Z","subjects":["Dissolvable microarray patches","Antihistamines","Transdermal drug delivery","In vitro–in silico modelling","Preclinical evaluation"],"languages":["en"],"rights":["© 2025, Maja Railic."],"rights_urls":["https://creativecommons.org/licenses/by/4.0/"],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/10468/18463","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Vucen, Sonja","Crean, Abina"]},{"key":"dc:creator","label":"Author","values":["Railic, Maja"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2026-01-26T11:21:36Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2026-01-26T11:21:36Z"]},{"key":"dc:date.issued","label":"Date","values":["2025"]},{"key":"dc:publisher","label":"Institution","values":["University College Cork"]},{"key":"dc:type","label":"Dc Type","values":["Doctoral thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["PhD - Doctor of Philosophy"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Dissolvable microarray patches","Antihistamines","Transdermal drug delivery","In vitro–in silico modelling","Preclinical evaluation"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["© 2025, Maja Railic."]},{"key":"dc:rights.uri","label":"Rights URI","values":["https://creativecommons.org/licenses/by/4.0/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/10468/18463"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Allergic diseases continue to pose a significant global health challenge, highlighting the need for more effective, patient-friendly therapeutic approaches. Although antihistamines remain the cornerstone of allergy treatment, their conventional oral administration is limited by extensive first-pass metabolism and unpredictable pharmacokinetics. Skin delivery represents a promising alternative, with innovative platforms such as dissolvable microarray patches (MAP), offering the potential for targeted local and systemic drug effects. However, no dissolvable MAP have yet reached the market. Despite significant advances in early MAP development (e.g. materials, fabrication), critical gaps remain in understanding the factors that influence preclinical performance. These gaps are particularly evident in in vitro and in silico studies, where the lack of predictive, MAP-specific translational models remains a major limitation. To address these limitations, this thesis aimed to enhance the preclinical evaluation of dissolvable MAP by systematically investigating the physicochemical, biopharmaceutical, and pharmacokinetic factors that govern skin deposition and the bioavailability of antihistamines delivered via dissolvable MAP. To establish a foundation for this investigation, a theoretical analysis of the scientific principles underpinning preclinical evaluation specific to MAP systems was first conducted. This comprehensive assessment of the skin environment and its implications to in vitro MAP performance revealed several critical yet overlooked factors—including media composition, skin model selection, and the therapeutic efficacy of the released drug—all of which require careful consideration in experimental design. With the theoretical groundwork established, thesis then focused on investigating how the physicochemical properties of a drug influence MAP design and performance. Two antihistamines—chlorpheniramine maleate (CPM) and loratadine (LOR)—were incorporated into MAP using distinct micromoulding methods (drug solution diffusion vs molten drug) and formulation types (polymer-based vs drug-only). The final formulations, CPM MAP (70 mg/ml in 15% w/v PVP/VA) and drug-only LOR MAP, demonstrated optimal physical, chemical, and mechanical properties. Furthermore, in vitro release and in vitro permeation testing protocols were optimised to evaluate biopharmaceutical performance, with particular emphasis on media composition and skin model selection. Results demonstrated that the composition of the in vitro release medium significantly affects the release profile of the lipophilic LOR, as well as the permeation and skin deposition profiles of both lipophilic LOR and hydrophilic CPM delivered via MAP. To better simulate the physiological conditions of the skin, proposed is the use of a biorelevant artificial interstitial fluid as the in vitro release medium for both MAP formulations, supplemented with a non-ionic surfactant to maintain sink conditions for lipophilic LOR. Additionally, evaluation of skin models revealed that neonatal porcine skin overestimates CPM and LOR permeability, whereas adult porcine skin more accurately reflects their permeability in human skin. To further investigate biopharmaceutical factors, in vitro safety and efficacy studies were conducted using human skin cell models to assess the selected drugs and formulations. Cytotoxicity testing in dermal fibroblasts and epidermal keratinocytes confirmed that both drugs were non-toxic to the most prevalent skin cell types across a range of concentrations, including those representative of MAP dose. Efficacy was evaluated based on the ability of MAP-delivered antihistamines to inhibit histamine release from mast cells, which play a central role in dermal allergic responses. LOR demonstrated a concentration-dependent and statistically significant inhibition of histamine release compared to controls, supporting its potential for targeted dermal delivery, whereas CPM showed no such effect. In the final chapter of this thesis, the pharmacokinetic behaviour following MAP administration was investigated using in silico approach, through the development of physiologically based pharmacokinetic model adapted from the MoBi® platform. This model was specifically tailored for dissolvable MAP by integrating microneedle geometry and experimentally derived in vitro release profile. Following careful optimisation of input parameters, the model successfully predicted skin-layer distribution and permeation of CPM and LOR under in vitro conditions, as well as the systemic exposure of itraconazole in vivo after MAP applications. These results support its potential as a valuable translational tool in early-stage MAP development. In conclusion, this research has significantly advanced our understanding of the complex factors influencing drug behaviour in the skin following MAP application. Through the development of two distinct MAP formulations incorporating CPM and LOR, we comparatively evaluated how the physicochemical, biopharmaceutical, and pharmacokinetic properties of these drugs impact skin distribution, systemic absorption, and therapeutic efficacy. The in vitro and in silico models were specifically designed to capture the complex interactions between MAP and the skin environment, offering mechanistic insights into their effects on MAP performance. Findings of this thesis emphasise the critical importance of considering these interconnected factors in preclinical MAP research, providing a solid foundation for advancing clinical studies and accelerating the translation of MAP technologies into clinical applications."]},{"key":"dc:format.mimetype","label":"Dc Format Mimetype","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Preclinical evaluation of dissolvable microarray patches for allergy treatment: key factors governing in vitro and in silico assessment"]}]}],"canonical_facts":{"dc:contributor.advisor":["Vucen, Sonja","Crean, Abina"],"dc:creator":["Railic, Maja"],"dc:date.accessioned":["2026-01-26T11:21:36Z"],"dc:date.available":["2026-01-26T11:21:36Z"],"dc:date.issued":["2025"],"dc:description.abstract":["Allergic diseases continue to pose a significant global health challenge, highlighting the need for more effective, patient-friendly therapeutic approaches. Although antihistamines remain the cornerstone of allergy treatment, their conventional oral administration is limited by extensive first-pass metabolism and unpredictable pharmacokinetics. Skin delivery represents a promising alternative, with innovative platforms such as dissolvable microarray patches (MAP), offering the potential for targeted local and systemic drug effects. However, no dissolvable MAP have yet reached the market. Despite significant advances in early MAP development (e.g. materials, fabrication), critical gaps remain in understanding the factors that influence preclinical performance. These gaps are particularly evident in in vitro and in silico studies, where the lack of predictive, MAP-specific translational models remains a major limitation. To address these limitations, this thesis aimed to enhance the preclinical evaluation of dissolvable MAP by systematically investigating the physicochemical, biopharmaceutical, and pharmacokinetic factors that govern skin deposition and the bioavailability of antihistamines delivered via dissolvable MAP. To establish a foundation for this investigation, a theoretical analysis of the scientific principles underpinning preclinical evaluation specific to MAP systems was first conducted. This comprehensive assessment of the skin environment and its implications to in vitro MAP performance revealed several critical yet overlooked factors—including media composition, skin model selection, and the therapeutic efficacy of the released drug—all of which require careful consideration in experimental design. With the theoretical groundwork established, thesis then focused on investigating how the physicochemical properties of a drug influence MAP design and performance. Two antihistamines—chlorpheniramine maleate (CPM) and loratadine (LOR)—were incorporated into MAP using distinct micromoulding methods (drug solution diffusion vs molten drug) and formulation types (polymer-based vs drug-only). The final formulations, CPM MAP (70 mg/ml in 15% w/v PVP/VA) and drug-only LOR MAP, demonstrated optimal physical, chemical, and mechanical properties. Furthermore, in vitro release and in vitro permeation testing protocols were optimised to evaluate biopharmaceutical performance, with particular emphasis on media composition and skin model selection. Results demonstrated that the composition of the in vitro release medium significantly affects the release profile of the lipophilic LOR, as well as the permeation and skin deposition profiles of both lipophilic LOR and hydrophilic CPM delivered via MAP. To better simulate the physiological conditions of the skin, proposed is the use of a biorelevant artificial interstitial fluid as the in vitro release medium for both MAP formulations, supplemented with a non-ionic surfactant to maintain sink conditions for lipophilic LOR. Additionally, evaluation of skin models revealed that neonatal porcine skin overestimates CPM and LOR permeability, whereas adult porcine skin more accurately reflects their permeability in human skin. To further investigate biopharmaceutical factors, in vitro safety and efficacy studies were conducted using human skin cell models to assess the selected drugs and formulations. Cytotoxicity testing in dermal fibroblasts and epidermal keratinocytes confirmed that both drugs were non-toxic to the most prevalent skin cell types across a range of concentrations, including those representative of MAP dose. Efficacy was evaluated based on the ability of MAP-delivered antihistamines to inhibit histamine release from mast cells, which play a central role in dermal allergic responses. LOR demonstrated a concentration-dependent and statistically significant inhibition of histamine release compared to controls, supporting its potential for targeted dermal delivery, whereas CPM showed no such effect. In the final chapter of this thesis, the pharmacokinetic behaviour following MAP administration was investigated using in silico approach, through the development of physiologically based pharmacokinetic model adapted from the MoBi® platform. This model was specifically tailored for dissolvable MAP by integrating microneedle geometry and experimentally derived in vitro release profile. Following careful optimisation of input parameters, the model successfully predicted skin-layer distribution and permeation of CPM and LOR under in vitro conditions, as well as the systemic exposure of itraconazole in vivo after MAP applications. These results support its potential as a valuable translational tool in early-stage MAP development. In conclusion, this research has significantly advanced our understanding of the complex factors influencing drug behaviour in the skin following MAP application. Through the development of two distinct MAP formulations incorporating CPM and LOR, we comparatively evaluated how the physicochemical, biopharmaceutical, and pharmacokinetic properties of these drugs impact skin distribution, systemic absorption, and therapeutic efficacy. The in vitro and in silico models were specifically designed to capture the complex interactions between MAP and the skin environment, offering mechanistic insights into their effects on MAP performance. Findings of this thesis emphasise the critical importance of considering these interconnected factors in preclinical MAP research, providing a solid foundation for advancing clinical studies and accelerating the translation of MAP technologies into clinical applications."],"dc:format.mimetype":["application/pdf"],"dc:identifier.uri":["https://hdl.handle.net/10468/18463"],"dc:language.iso":["en"],"dc:publisher":["University College Cork"],"dc:rights":["© 2025, Maja Railic."],"dc:rights.uri":["https://creativecommons.org/licenses/by/4.0/"],"dc:subject":["Dissolvable microarray patches","Antihistamines","Transdermal drug delivery","In vitro–in silico modelling","Preclinical evaluation"],"dc:title":["Preclinical evaluation of dissolvable microarray patches for allergy treatment: key factors governing in vitro and in silico assessment"],"dc:type":["Doctoral thesis"],"dc:type.qualificationlevel":["Doctoral"],"dc:type.qualificationname":["PhD - Doctor of Philosophy"]},"updated_at":"2026-07-24T01:47:55Z"}