Nanoparticles-in-film for the combined vaginal delivery of anti-HIV microbicide drugs.
Combining two or more antiretroviral drugs in one medical product is an interesting but challenging strategy for developing topical anti-HIV microbicides. We developed a new vaginal delivery system comprising the incorporation of nanoparticles (NPs) into a polymeric film base - NPs-in-film - and tested its ability to deliver tenofovir (TFV) and efavirenz (EFV). EFV-loaded poly(lactic-co-glycolic acid) NPs were incorporated alongside free TFV into fast dissolving films during film manufacturing. The delivery system was characterized for physicochemical properties, as well as genital distribution, local and systemic 24h pharmacokinetics (PK), and safety upon intravaginal administration to mice. NPs-in-film presented suitable technological, mechanical and cytotoxicity features for vaginal use. Retention of NPs in vivo was enhanced both in vaginal lavages and tissue when associated to film. PK data evidenced that vaginal drug levels rapidly decreased after administration but NPs-in-film were still able to enhance drug concentrations of EFV. Obtained values for area-under-the-curve for EFV were around one log10 higher than those for the free drugs in aqueous vehicle (phosphate buffered saline). Film alone also contributed to higher and more prolonged local drug levels as compared to the administration of TFV and EFV in aqueous vehicle. Systemic exposure to both drugs was low. NPs-in-film was found to be safe upon once daily vaginal administration to mice, with no significant genital histological changes or major alterations in cytokine/chemokine profiles being observed. Overall, the proposed NPs-in-film system seems to be an interesting delivery platform for developing combination vaginal anti-HIV microbicides.
CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde & Instituto Universitário de Ciências da Saúde, Gandra, Portugal.
Cassilda
C
Cunha-Reis
i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.
Alexandra
A
Machado
UCIBIO, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
Luísa
L
Barreiros
i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.
Francisca
F
Araújo
i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.
Rute
R
Nunes
CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde & Instituto Universitário de Ciências da Saúde, Gandra, Portugal.
Vítor
V
Seabra
Laboratório de Tecnologia Farmacêutica, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
Domingos
D
Ferreira
UCIBIO, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
Marcela A
MA
Segundo
CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde & Instituto Universitário de Ciências da Saúde, Gandra, Portugal; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.
Bruno
B
Sarmento
CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde & Instituto Universitário de Ciências da Saúde, Gandra, Portugal; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal. Electronic address: j.dasneves@ineb.up.pt.
José
J
das Neves
D000282:Administration, Intravaginal; D000480:Alkynes; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D048588:Benzoxazines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003521:Cyclopropanes; D004337:Drug Carriers / Q000737:chemistry; D004338:Drug Combinations; D016503:Drug Delivery Systems; D005260:Female; D019344:Lactic Acid / Q000737:chemistry; D051379:Mice; D053758:Nanoparticles; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D000068698:Tenofovir / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D014018:Tissue Distribution
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D004337:Drug Carriers; D004338:Drug Combinations; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D000068698:Tenofovir; C098320:efavirenz
Efavirenz (PubChem CID: 64139); HIV/AIDS; Hypromellose (PubChem CID: 57503849); Nanotechnology; Pharmacokinetics; Pre-exposure prophylaxis; Safety; Tenofovir (PubChem CID: 464205); Vaginal drug administration