RESUMEN
HIV continues to affect millions of men and women worldwide. The development of long-acting injectables for HIV prevention can overcome adherence challenges with daily oral prevention regimens by reducing dosing frequency and stigma. We previously developed an ultra-long-acting injectable, biodegradable, and removeable in situ forming implant (ISFI) with cabotegravir (CAB) that demonstrated protection after multiple rectal SHIV challenges in female macaques. Here, we sought to further characterize CAB ISFI pharmacokinetics (PK) in mice by assessing the effect of dose and number of injections on CAB PK, time to completion of CAB release and polymer degradation, long-term genital tissue PK, and CAB PK tail after implant removal. CAB concentrations in plasma were above the benchmark for protection for 11-12 months with proportionality between dose and drug exposure. CAB ISFI exhibited high concentrations in vaginal, cervical, and rectal tissues for up to 180 days. Furthermore, depots were easily retrievable up to 180 days post-administration with up to 34% residual CAB and near complete (85%) polymer degradation quantified in depots ex vivo. After depot removal, results demonstrated a median 11-fold decline in CAB plasma concentrations across all doses. Ultimately, this study provided critical PK information for the CAB ISFI formulation that could aid in its future translation to clinical studies.
RESUMEN
Only condoms are proven to protect against both HIV and unplanned pregnancy, however, poor user acceptability and lack of partner cooperation impede effectiveness. We developed an injectable ultra-long-acting, biodegradable, and removable in-situ forming implant (ISFI) as multipurpose prevention technology (MPT). MPT ISFIs co-formulated an antiretroviral (dolutegravir (DTG)) or cabotegravir (CAB)), and a hormonal contraceptive (etonogestrel (ENG) or medroxyprogesterone acetate (MPA)). All formulations were well-tolerated in mice with no signs of chronic local or systemic inflammation. Plasma CAB and DTG concentrations were above 4× PA-IC90 for 90 days with zero-order and diffusion-controlled absorption, respectively, and no differences when co-formulated with either hormone. Plasma ENG and MPA concentrations were quantifiable for 90 days. Complete removal of CAB/MPA ISFIs resulted in MPA concentrations falling below the limit of quantification after 24 h post-removal, but incomplete CAB elimination from plasma. Collectively, we demonstrated the ability to co-formulate antiretrovirals with contraceptives in an ISFI that is well-tolerated with sustained plasma concentrations up to 90 days.
Asunto(s)
Infecciones por VIH , Embarazo no Planeado , Embarazo , Humanos , Femenino , Ratones , Animales , Infecciones por VIH/prevención & controlRESUMEN
Globally, there are 20 million adolescent girls and young women living with HIV who have limited access to long-acting, effective, women-controlled preventative methods. Additionally, although there are many contraceptive methods available, globally, half of all pregnancies remain unintended. Here we report the first 3D-printed multipurpose prevention technology (MPT) intravaginal ring (IVR) for HIV prevention and contraception. We utilized continuous liquid interface production (CLIP™) to fabricate MPT IVRs in a biocompatible silicone-based resin. Etonogestrel (ENG), ethinyl estradiol (EE), and islatravir (ISL) were loaded into the silicone poly(urethane) IVR in a controlled single step drug loading process driven by absorption. ENG/EE/ISL IVR promoted sustained release of drugs for 150 days in vitro and 14 days in sheep. There were no adverse MPT IVR-related findings of cervicovaginal toxicity or changes in vaginal biopsies or microbiome community profiles evaluated in sheep. Furthermore, ISL IVR in macaques promoted sustained release for 28 days with ISL-triphosphate levels above the established pharmacokinetic benchmark of 50-100 fmol/106 PBMCs. The ISL IVR was found to be safe and well tolerated in the macaques with no observed mucosal cytokine changes or alterations in peripheral CD4 T-cell populations. Collectively, the proposed MPT IVR has potential to expand preventative choices for young women and girls.
Asunto(s)
Infecciones por VIH , Embarazo no Planeado , Embarazo , Humanos , Femenino , Animales , Ovinos , Preparaciones de Acción Retardada , Administración Intravaginal , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Macaca , Impresión TridimensionalRESUMEN
Ultra-long-acting delivery platforms for HIV pre-exposure prophylaxis (PrEP) may increase adherence and maximize public health benefit. We report on an injectable, biodegradable, and removable in-situ forming implant (ISFI) that is administered subcutaneously and can release the integrase inhibitor cabotegravir (CAB) above protective benchmarks for more than 6 months. CAB ISFIs are well-tolerated in female mice and female macaques showing no signs of toxicity or chronic inflammation. In macaques, median plasma CAB concentrations exceed established PrEP protection benchmarks within 3 weeks and confer complete protection against repeated rectal SHIV challenges. Implant removal via a small incision in 2 macaques at week 12 results in a 7- to 48-fold decrease in plasma CAB levels within 72 hours. Modeling to translate CAB ISFI dosing suggests that a 3 mL injection would exceed protective benchmarks in humans for over 5 months post administration. Our results support the clinical advancement of CAB ISFIs for ultra-long-acting PrEP in humans.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Inhibidores de Integrasa VIH , Profilaxis Pre-Exposición , Humanos , Femenino , Animales , Ratones , Macaca , Piridonas , Inhibidores de Integrasa VIH/uso terapéutico , Recto , Profilaxis Pre-Exposición/métodos , Infecciones por VIH/prevención & control , Infecciones por VIH/tratamiento farmacológico , Fármacos Anti-VIH/uso terapéuticoRESUMEN
Influenza affects millions of people worldwide and can result in severe sickness and even death. The best method of prevention is vaccination; however, the seasonal influenza vaccine often suffers from low efficacy and requires yearly vaccination due to changes in strain and viral mutations. More conserved universal influenza antigens like M2 ectodomain (M2e) and the stalk region of hemagglutinin (HA stalk) have been used clinically but often suffer from low antigenicity. To increase antigenicity, universal antigens have been formulated using nano/microparticles as vaccine carriers against influenza. Utilizing polymers, liposomes, metal, and protein-based particles, indicators of immunity and protection in mouse, pig, ferrets, and chicken models of influenza have been shown. In this review, seasonal and universal influenza vaccine formulations comprised of these materials including their physiochemical properties, fabrication, characterization, and biologic responses in vivo are highlighted. The review is concluded with future perspectives for nano/microparticles as carrier systems and other considerations within the universal influenza vaccine delivery landscape. Graphical Abstract.
Asunto(s)
Sistemas de Liberación de Medicamentos , Vacunas contra la Influenza/administración & dosificación , Gripe Humana/prevención & control , Animales , Antígenos Virales/inmunología , Química Farmacéutica/métodos , Modelos Animales de Enfermedad , Humanos , Vacunas contra la Influenza/inmunología , Gripe Humana/inmunología , Gripe Humana/virología , Microesferas , Nanopartículas , Orthomyxoviridae/inmunología , Orthomyxoviridae/aislamiento & purificación , Vacunación/métodosRESUMEN
In-situ forming implants (ISFIs) represent a simple, tunable, and biodegradable polymer-based platform for long-acting drug delivery. However, drugs with different physicochemical properties and physical states in the polymer-solvent system exhibit different drug release kinetics. Although a few limited studies have been performed attempting to elucidate these effects, a large, systematic study has not been performed until now. The purpose of this study was to characterize the in vitro drug release of 12 different small molecule drugs with differing logP and pKa values from ISFIs. Drug release was compared with polymer degradation as measured by lactic acid (LA) release and change in poly(DL-lactide-co-glycolide) (PLGA) molecular weight (MW) measured by size exclusion chromatography with multi-angle laser light scattering (SEC-MALS). Drug physical state and morphology were also measured using differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). Together, these results demonstrated that hydrophilic drugs have higher burst release at 24 h (22.8-68.4%) and complete drug release within 60 days, while hydrophobic drugs have lower burst release at 24 h (1.8-18.9%) and can sustain drug release over 60-285 days. Overall, drug logP and drug physical state in the polymer-solvent system are the most important factors when predicting the drug release rate in an ISFI for small-molecule drugs. Hydrophilic drugs exhibit high initial burst and less sustained release due to their miscibility with the aqueous phase, while hydrophobic drugs have lower initial burst and more sustained release due to their affinity for the hydrophobic PLGA. Additionally, while hydrophilic drugs seem to accelerate the degradation of PLGA, hydrophobic drugs on the other hand seem to slow down the PLGA degradation process compared with placebo ISFIs. Furthermore, drugs that were in a crystalline state within the ISFI drugs exhibited more sustained release compared with amorphous drugs.
RESUMEN
There is a high global prevalence of HIV, sexually transmitted infections (STIs), and unplanned pregnancies. Current preventative daily oral dosing regimens can be ineffective due to low patient adherence. Sustained release delivery systems in conjunction with multipurpose prevention technologies (MPTs) can reduce high rates of HIV/STIs and unplanned pregnancies in an all-in-one efficacious, acceptable, and easily accessible technology to allow for prolonged release of antivirals and contraceptives. The concept and development of MPTs have greatly progressed over the past decade and demonstrate efficacious technologies that are user-accepted with potentially high adherence. This review gives a comprehensive overview of the latest oral, parenteral, and vaginally delivered MPTs in development as well as drug delivery formulations with the potential to advance as an MPT, and implementation studies regarding MPT user acceptability and adherence. Furthermore, there is a focus on MPT intravaginal rings emphasizing injection molding and hot-melt extrusion manufacturing limitations and emerging fabrication advancements. Lastly, formulation development considerations and limitations are discussed, such as nonhormonal contraceptive considerations, challenges with achieving a stable coformulation of multiple drugs, achieving sustained and controlled drug release, limiting drug-drug interactions, and advancing past preclinical development stages. Despite the challenges in the MPT landscape, these technologies demonstrate the potential to bridge gaps in preventative sexual and reproductive health care.