Innovative Strategies in the Design of in situ Forming Implants: Optimizing Workflow and Sustained Release for the Treatment of Neglected Tropical Diseases

Clarice Sombra de Medeiros

doi:10.21996/bdcc99aa-2bb1-45ef-b514-23b60cd46307

Innovative Strategies in the Design of in situ Forming Implants: Optimizing Workflow and Sustained Release for the Treatment of Neglected Tropical Diseases

Bidragets oversatte titel: Innovative strategier til design af in situ dannende implantater: Optimering af workflow (procesforløb) og langtidsvirkende lægemiddelfrigivelse til behandling af negligerede tropesygdomme

Clarice Sombra de Medeiros

Publikation: Afhandling › Ph.d.-afhandling

25 Downloads (Pure)

Abstract

Den første del af dette forskningsprojekt fokuserede på en omfattende præformuleringsundersøgelse med levonorgestrel (LNG) som modellægemiddel for at evaluere virkningen af leverandørvariationer på faststofegenskaberne af LNG-råmaterialer. Høj konsistens på tværs af leverandører blev bekræftet ved hjælp af flere analytiske teknikker; kildevariabilitet påvirker ikke signifikant fremstillingen af nye langtidsvirkende injicerbare (LAI) formuleringer, der indeholder LNG. Efterfølgende flyttede forskningen fokus modoptimering af udviklingsarbejdsgange ved at undersøge virkningen af at implementere fokuseret ultralydbehandling for at accelerere opnåelsen af termodynamisk ligevægt i polære aprotiske opløsningsmidler, såsom N-methyl-2-pyrrolidon (NMP). Denne innovative tilgang reducerede inkubationstiderne for modellægemidlerne atovaquon (ATQ), praziquantel (PZQ) og proguanil (PRG) betydeligt, hvorved laboratoriegennemstrømningen forbedredes. Efterfølgende undersøgelser blev udført for at vurdere indflydelsen af amfifile additiver på lægemiddelopløselighed og dermed på lægemiddelbelastningskapaciteten af in situ-dannende implantater (ISFI'er). Resultaterne indikerede, at poloxamerer, når de opløses i ren NMP, overvejende eksisterer som unimerer eller store aggregater, hvorved micelledannelse hæmmes. Derudover blev der observeret en antagonistisk effekt, hvilket førte til en reduktion i modellægemidlernes tilsyneladende opløselighed, uanset type og koncentration af overfladeaktivt stof.

Den anden del af undersøgelsen fokuserede på at undersøge virkningen af at inkorporere hydrofobe ionparringskomplekser (HIP) i ISFI'er på samtidig levering af lægemidler med forskellige fysisk-kemiskeegenskaber. Faststofkarakterisering af de to lægemiddel-ISFI'er bekræftede dannelsen af HIP-komplekser mellem ATQ og PRG fri base. Desuden blev det observeret, at formuleringsparametre, herunder valg af opløsningsmiddel, polymerkoncentration og polymermolekylvægt (Mw), væsentligt påvirker dynamikken i faseinversion og implantatmikrostruktur, hvorved lægemiddelfrigivelsen in vivo påvirkes. Dannelsen af HIPkomplekser forbedrede ATQ-eksponeringen markant ved at hæmme for tidlig omkrystallisation, hvilket ellers ville føre til en meget langsom opløsningsbegrænset absorption. Derudover viste farmakokinetiske studier udført på Sprague-Dawley-rotter vedvarende terapeutiske plasmakoncentrationer af både ATQ og PRG imindst seks uger efter en enkelt subkutan administration.

Afslutningsvis demonstrerer resultaterne af denne forskning potentialet af HIP-loaded ISFI'er tilvedvarende samtidig levering af antimalariamidler og fremhæver den grundlæggende rolle, sompræformuleringsstudier spiller i det rationelle design af nye langtidsvirkende injicerbare (LAI) formuleringer.

Bidragets oversatte titel	Innovative strategier til design af in situ dannende implantater: Optimering af workflow (procesforløb) og langtidsvirkende lægemiddelfrigivelse til behandling af negligerede tropesygdomme
Originalsprog	Engelsk
Bevilgende institution	Syddansk Universitet
Vejledere/rådgivere	Holm, René, Hovedvejleder Christensen, Lars Porskjær, Bivejleder
Dato for forsvar	26. jun. 2026
Udgiver	Syddansk Universitet. Det Naturvidenskabelige Fakultet
DOI	https://doi.org/10.21996/bdcc99aa-2bb1-45ef-b514-23b60cd46307
Status	Udgivet - 8. jun. 2026

Note vedr. afhandling

Afhandlingen kan læses på SDUs bibliotek. 

Finansiering

This research project has received funding from the Novo Nordisk Foundation under the grant agreement No. 0068744.

Dokumenter og links

10.21996/bdcc99aa-2bb1-45ef-b514-23b60cd46307Licens: Kun læseadgang

Open Access VersionForlagets udgivne version, 9,84 MBLicens: Kun læseadgang

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Errata List

2 Tidsskriftartikel

Accelerating thermodynamic solubility determination in organic solvents via focused ultrasonication  
de Medeiros, C. S., Palani, O., Christensen, L. P. & Holm, R., 2026, I: Journal of Drug Delivery Science and Technology. 125, 7 s., 108711.
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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Preformulation studies of levonorgestrel: A supplier variation analysis
de Medeiros, C. S., Pedersen, M. I., Sørensen, M. D. M., Hopper, C., Hedegaard, M. A. B., Qi, S., Vinarov, Z. & Holm, R., 1. aug. 2026, I: European Journal of Pharmaceutical Sciences. 223, 12 s., 107562.
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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Citationsformater

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title = "Innovative Strategies in the Design of in situ Forming Implants: Optimizing Workflow and Sustained Release for the Treatment of Neglected Tropical Diseases",

abstract = "The first part of this research project focused on a comprehensive preformulation study using levonorgestrel (LNG) as a model drug to evaluate the impact of the supplier variation on the solidstate properties of LNG raw materials. High consistency across suppliers was confirmed using multiple analytical techniques, source variability does not significantly impact the manufacturing of novel long-acting injectable (LAI) formulations containing LNG. Subsequently, the research shifted focus towards optimizing development workflows by examining the impact of implementing focused ultrasonication to accelerate the attainment of thermodynamic equilibrium in polar aprotic solvents, such as N-methyl-2-pyrrolidone (NMP). This innovative approach significantly reduced the incubation periods for the model drugs atovaquone (ATQ), praziquantel (PZQ), and proguanil (PRG),thereby enhancing laboratory throughput. Subsequent investigations were conducted to assess the influence of amphiphilic additives on drug solubilization and, consequently, on the drug loading capacity of in situ forming implants (ISFIs). The findings indicated that when dissolved in pure NMP, poloxamers predominantly exist as unimers or large aggregates, thereby inhibiting micelle formation. Furthermore, an antagonistic effect was observed, i.e., a reduction in the apparent solubility of themodel drugs, regardless of the surfactant type and concentration. The second part focused on investigating the impact of incorporating hydrophobic ion pairing(HIP) complexes within ISFIs on the co-delivery of drugs with distinct physicochemical properties. Solid-state characterization (i.e., X-ray powder diffraction and infrared spectroscopy) of the dualdrug ISFIs confirmed the formation of HIP complexes between ATQ and PRG base. Furthermore, it was observed that formulation parameters, including the choice of solvent, polymer concentration, and polymer molecular weight (Mw), substantially influence the dynamics of phase inversion and implant microstructure, thereby affecting the in vivo drug release. The formation of HIP complexes markedly enhanced ATQ exposure by inhibiting premature recrystallization, which would otherwise result in a very slow dissolution-limited absorption. Moreover, pharmacokinetic studies conducted on Sprague-Dawley rats demonstrated sustained therapeutic plasma concentrations of both ATQ and PRG for at least six weeks following a single subcutaneous administration. In conclusion, the findings of this research project demonstrate the potential of HIP-loaded ISFIs for the sustained co-delivery of antimalarials, highlighting the fundamental role of preformulation studies in the rational design of novel long-acting injectable (LAI) formulations.",

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ER -

Innovative Strategies in the Design of in situ Forming Implants: Optimizing Workflow and Sustained Release for the Treatment of Neglected Tropical Diseases

Abstract

Note vedr. afhandling

Finansiering

Dokumenter og links

SDU link

Andre filer og links

Fingeraftryk

Relaterede publikationer

Accelerating thermodynamic solubility determination in organic solvents via focused ultrasonication

Preformulation studies of levonorgestrel: A supplier variation analysis

Citationsformater

Accelerating thermodynamic solubility determination in organic solvents via focused ultrasonication  