RESUMO
Human immunodeficiency virus (HIV) continues to pose a serious threat to global health. Oral preexposure prophylaxis (PrEP), considered highly effective for HIV prevention, is the utilisation of antiretroviral (ARV) drugs before HIV exposure in high-risk uninfected individuals. However, ARV drugs are associated with poor patient compliance and pill fatigue due to their daily oral dosing. Therefore, an alternative strategy for drug delivery is required. In this work, two dissolving microneedle patches (MNs) containing either bictegravir (BIC) or tenofovir alafenamide (TAF) solid drug nanoparticles (SDNs) were developed for systemic delivery of a novel ARV regimen for potential HIV prevention. According to ex vivo skin deposition studies, approximately 11% and 50% of BIC and TAF was delivered using dissolving MNs, respectively. Pharmacokinetic studies in Sprague Dawley rats demonstrated that BIC MNs achieved a long-acting release profile, maintaining the relative plasma concentration above the 95% inhibitory concentration (IC95) for 3 weeks. For TAF MNs, a rapid release of drug and metabolism of TAF into TFV were obtained from the plasma samples. This work has shown that the proposed transdermal drug delivery platform could be potentially used as an alternative method to systemically deliver ARV drugs for HIV PrEP.
Assuntos
Administração Cutânea , Alanina , Fármacos Anti-HIV , Infecções por HIV , Agulhas , Profilaxia Pré-Exposição , Ratos Sprague-Dawley , Tenofovir , Animais , Tenofovir/administração & dosagem , Tenofovir/farmacocinética , Tenofovir/análogos & derivados , Alanina/farmacocinética , Alanina/administração & dosagem , Alanina/química , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Profilaxia Pré-Exposição/métodos , Infecções por HIV/prevenção & controle , Masculino , Adenina/administração & dosagem , Adenina/farmacocinética , Adenina/análogos & derivados , Adenina/química , Ratos , Nanopartículas/administração & dosagem , Nanopartículas/química , Liberação Controlada de Fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/química , Piridonas/administração & dosagem , Piridonas/farmacocinética , Sistemas de Liberação de Medicamentos , Piperazinas/farmacocinética , Piperazinas/administração & dosagem , Piperazinas/química , Ciclopropanos/administração & dosagem , Ciclopropanos/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Amidas/administração & dosagem , Amidas/farmacocinética , Amidas/químicaRESUMO
The control of COVID-19 across the world requires the formation of a range of interventions including vaccines to elicit an immune response and immunomodulatory or antiviral therapeutics. Here, we demonstrate the nanoparticle formulation of a highly insoluble drug compound, niclosamide, with known anti SARS-CoV-2 activity as a cheap and scalable long-acting injectable antiviral candidate.
Assuntos
Antivirais , Tratamento Farmacológico da COVID-19 , Niclosamida , SARS-CoV-2/efeitos dos fármacos , Antivirais/administração & dosagem , Antivirais/farmacologia , Humanos , Injeções Intramusculares , Nanopartículas , Niclosamida/administração & dosagem , Niclosamida/farmacologiaRESUMO
Suboptimal adherence to antiretroviral (ARV) therapy can lead to insufficient drug exposure leading to viral rebound and increased likelihood of resistance. This has driven the development of long-acting injectable (LAI) formulations which may mitigate some of these problems. Maraviroc (MVC) is an orally dosed CCR5 antagonist approved for use in patients infected with CCR5-trophic HIV-1. MVC prevents viral entry into host cells, is readily distributed to biologically relevant tissues and has an alternative resistance profile compared to more commonly used therapies. This makes a MVC LAI formulation particularly appealing for implementation in Pre-Exposure Prophylaxis (PrEP). A 70â¯wt% MVC-loaded nanodispersion stabilised with polyvinyl alcohol (PVA) and sodium 1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate (AOT) was prepared using emulsion-templated freeze-drying. In vitro release rate studies revealed over a 22% decrease in MVC release rate constant across a size selective membrane compared with an aqueous solution of MVC (<5% DMSO). Pharmacokinetic studies in rats were subsequently carried out following intramuscular injection of either the nanodispersion or an aqueous MVC preparation (<5% DMSO). Results demonstrated over a 3.4-fold increase in AUC0-∞ (1959.71 vs 567.17â¯ng.h ml), over a 2.6-fold increase in MVCs terminal half-life (t½) (140.69 vs 53.23â¯h) and MVC concentrations present up to 10-days. These data support development of a MVC LAI formulation with potential application in HIV therapy or prevention.
Assuntos
Inibidores da Fusão de HIV/administração & dosagem , Inibidores da Fusão de HIV/química , HIV-1/efeitos dos fármacos , Maraviroc/administração & dosagem , Maraviroc/química , Nanopartículas/administração & dosagem , Nanopartículas/química , Animais , Infecções por HIV/tratamento farmacológico , Injeções/métodos , Injeções Intramusculares/métodos , Masculino , Nanomedicina/métodos , Profilaxia Pré-Exposição/métodos , Ratos , Ratos WistarRESUMO
Oral drug administration remains the preferred approach for treatment of HIV in most patients. Maraviroc (MVC) is the first in class co-receptor antagonist, which blocks HIV entry into host cells. MVC has an oral bioavailability of approximately 33%, which is limited by poor permeability as well as affinity for CYP3A and several drug transporters. While once-daily doses are now the favoured option for HIV therapy, dose-limiting postural hypotension has been of theoretical concern when administering doses high enough to achieve this for MVC (particularly during coadministration of enzyme inhibitors). To overcome low bioavailability and modify the pharmacokinetic profile, a series of 70â¯wt% MVC solid drug nanoparticle (SDN) formulations (containing 30â¯wt% of various polymer/surfactant excipients) were generated using emulsion templated freeze-drying. The lead formulation contained PVA and AOT excipients (MVCSDNPVA/AOT), and was demonstrated to be fully water-dispersible to release drug nanoparticles with z-average diameter of 728â¯nm and polydispersity index of 0.3. In vitro and in vivo studies of MVCSDNPVA/AOT showed increased apparent permeability of MVC, compared to a conventional MVC preparation, with in vivo studies in rats showing a 2.5-fold increase in AUC (145.33 vs. 58.71â¯ngâ¯hâ¯ml-1). MVC tissue distribution was similar or slightly increased in tissues examined compared to the conventional MVC preparation, with the exception of the liver, spleen and kidneys, which showed statistically significant increases in MVC for MVCSDNPVA/AOT. These data support a novel oral format with the potential for dose reduction while maintaining therapeutic MVC exposure and potentially enabling a once-daily fixed dose combination product.
Assuntos
Maraviroc/administração & dosagem , Maraviroc/farmacocinética , Nanopartículas/administração & dosagem , Nanopartículas/metabolismo , Administração Oral , Animais , Disponibilidade Biológica , Células CACO-2 , Linhagem Celular Tumoral , Composição de Medicamentos/métodos , Emulsões/administração & dosagem , Emulsões/química , Emulsões/farmacocinética , Excipientes/química , Excipientes/farmacocinética , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Humanos , Masculino , Maraviroc/química , Nanopartículas/química , Ratos , Ratos Wistar , Distribuição TecidualRESUMO
The facile formation of drug nanoparticles in injectable/ingestible oils, of water-soluble antiretroviral tenofovir disoproxil fumarate, using a novel nanoprecipitation is presented with studies showing drug release into relevant aqueous media.
RESUMO
Chemoprophylaxis is currently the best available prevention from malaria, but its efficacy is compromised by non-adherence to medication. Here we develop a long-acting injectable formulation of atovaquone solid drug nanoparticles that confers long-lived prophylaxis against Plasmodium berghei ANKA malaria in C57BL/6 mice. Protection is obtained at plasma concentrations above 200 ng ml-1 and is causal, attributable to drug activity against liver stage parasites. Parasites that appear after subtherapeutic doses remain atovaquone-sensitive. Pharmacokinetic-pharmacodynamic analysis indicates protection can translate to humans at clinically achievable and safe drug concentrations, potentially offering protection for at least 1 month after a single administration. These findings support the use of long-acting injectable formulations as a new approach for malaria prophylaxis in travellers and for malaria control in the field.
Assuntos
Antimaláricos/uso terapêutico , Atovaquona/sangue , Atovaquona/uso terapêutico , Portadores de Fármacos/uso terapêutico , Malária/tratamento farmacológico , Malária/prevenção & controle , Plasmodium berghei/efeitos dos fármacos , Animais , Anopheles/parasitologia , Quimioprevenção/métodos , Modelos Animais de Doenças , Resistência a Medicamentos/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/uso terapêutico , Nanomedicina TeranósticaRESUMO
The new macromolecular architecture, hyperbranched polydendrons, are composed of a broad distribution of molecular weights and architectural variation; however, nanoprecipitation of these materials yields highly uniform, dendron-functional nanoparticles. By isolating different fractions of the diverse samples, the key role of the most highly branched structures in directing nucleation and growth has been explored and determined.
RESUMO
Botulinum neurotoxin is one of the deadliest biological toxins known to mankind and is able to cause the debilitating disease botulism. The rapid detection of the different serotypes of botulinum neurotoxin is essential for both diagnosis of botulism and identifying the presence of toxin in potential cases of terrorism and food contamination. The modes of action of botulinum neurotoxins are well-established in literature and differ for each serotype. The toxins are known to specifically cleave portions of the SNARE proteins SNAP-25 or VAMP; an interaction that can be monitored by electrochemical impedance spectroscopy. This study presents a SNAP-25 and a VAMP biosensors for detecting the activity of five botulinum neurotoxin serotypes (A-E) using electrochemical impedance spectroscopy. The biosensors are able to detect concentrations of toxins as low as 25 fg/mL, in a short time-frame compared with the current standard methods of detection. Both biosensors show greater specificity for their compatible serotypes compared with incompatible serotypes and denatured toxins.
Assuntos
Técnicas Biossensoriais , Toxinas Botulínicas/análise , Toxinas Botulínicas/química , Espectroscopia Dielétrica , Proteínas SNARE/química , SorogrupoRESUMO
Water soluble gold nanoparticles are coated with peptides bearing a dithiol surface active group for studies of lanthanide binding; characteristic red luminescence is observed upon europium binding to the nanoparticles.