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Vaginal inserts that can be used on demand before or after sex may be a desirable human immunodeficiency virus (HIV) prevention option for women. We recently showed that inserts containing tenofovir alafenamide fumarate (TAF, 20â mg) and elvitegravir (EVG, 16â mg) were highly protective against repeated simian/human immunodeficiency virus (SHIV) vaginal exposures when administered to macaques 4 hours before or after virus exposure (93% and 100%, respectively). Here, we show in the same macaque model that insert application 8 hours or 24 hours after exposure maintains high efficacy (94.4% and 77.2%, respectively). These data extend the protective window by TAF/EVG inserts and inform their clinical development for on-demand prophylaxis in women.
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Adenina , Alanina , Fármacos Anti-HIV , Quinolonas , Síndrome de Imunodeficiência Adquirida dos Símios , Tenofovir , Animais , Tenofovir/administração & dosagem , Tenofovir/análogos & derivados , Feminino , Quinolonas/administração & dosagem , Quinolonas/farmacologia , Alanina/administração & dosagem , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Fármacos Anti-HIV/administração & dosagem , Adenina/análogos & derivados , Adenina/administração & dosagem , Adenina/farmacologia , Adenina/uso terapêutico , Vagina/virologia , Vagina/efeitos dos fármacos , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , Administração Intravaginal , Macaca mulatta , Modelos Animais de DoençasRESUMO
Current antibody (Ab) therapies require development of stable formulations and an optimal delivery system. Here, we present a new strategy to create a single-administration long-lasting Ab-delivery microarray (MA) patch, which can carry high doses of thermally stabilized Abs. The MA fabricated by an additive three-dimensional manufacturing technology can be fully embedded into the skin via a single application to deliver doses of Abs at multiple programmable time points, thus sustaining Ab concentrations in systemic circulation. We developed an MA formulation that stabilized and delivered human immunoglobulins (hIg) in a time-controlled manner while maintaining their structure and functionality. As an example, the b12 Abâa broadly neutralizing Ab against HIV-1âmaintained antiviral activity in vitro after MA manufacturing and heat exposure. Pharmacokinetic studies of MA patch-delivered hIg in rats successfully provided a proof of concept for concurrent and time-delayed Ab delivery. These MA patches codeliver different Abs, providing a tool for expanded protection against viral infections or combination HIV therapy and prevention.
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Anticorpos , Infecções por HIV , Humanos , Ratos , Animais , Pele , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controleRESUMO
The purpose of this investigation is to design and synthesize novel pentablock (PB) copolymer (PB-1: PCL-PLA-PEG-PLA-PCL) based nanoformulations suspended in a thermosensitive gelling copolymer (PB-2: mPEG-PCL-PLA-PCL-PEGm) termed as composite nanoformulation. The composite nanoformulation was prepared to provide a sustained delivery of macromolecules over a longer duration with negligible burst release effect. The delivery system was designed to be utilized for the treatment of posterior segment ocular diseases such as age-related (wet) macular degeneration, diabetic retinopathy, and diabetic macular edema. The novel PB copolymers were characterized for their functional groups by Fourier transform infrared spectroscopy, molecular weight and purity by (1)H NMR spectroscopy, and gel permeation chromatography. X-ray diffraction analysis was used to determine the crystallinity of copolymers. The size distribution of PB-1 nanoparticles (NPs) prepared using emulsification-solvent evaporation method was found to be â¼150 nm analyzed by nanoparticle tracking analysis. The % encapsulation efficiency and % drug loading were found to be 66.64% w/w ± 1.75 and 18.17% w/w ± 0.39, respectively, (n = 3). Different weight percentages (15 and 20 wt %) of the PB-2 copolymer have been utilized for in vitro release studies of IgG-Fab from composite nanoformulation. A negligible burst release with continuous near zero-order release has been observed from the composite nanoformulation analyzed up to 80 days. In vitro cell viability and biocompatibility studies performed on ocular (human corneal epithelial and retinal pigment epithelium) and mouse macrophage (RAW 264.7) cell lines showed that the synthesized PB copolymer based composite nanoformulations were safe for clinical applications. On the basis of the results observed, it is concluded that PB copolymer based composite nanoformulations can serve as a platform for ocular delivery of therapeutic proteins. In addition, the composite nanoformulation may provide minimal side effects associated with frequent intravitreal injections.
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Injeções Intravítreas/métodos , Nanopartículas/química , Poliésteres/química , Polietilenoglicóis/química , Polímeros/química , Animais , Linhagem Celular , Sobrevivência Celular/fisiologia , Cromatografia em Gel , Composição de Medicamentos/métodos , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Células RAW 264.7 , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios XRESUMO
It is hypothesized that thiolated chitosan (TCS) core/shell nanofibers (NFs) can enhance the drug loading of tenofovir, a model low molecular weight and highly water-soluble drug molecule, and improve its mucoadhesivity and in vivo safety. To test this hypothesis, poly(ethylene oxide) (PEO) core with TCS and polylactic acid (PLA) shell NFs are fabricated by a coaxial electrospinning technique. The morphology, drug loading, drug release profiles, cytotoxicity and mucoadhesion of the NFs are analyzed using scanning and transmission electron microscopies, liquid chromatography, cytotoxicity assays on VK2/E6E7 and End1/E6E7 cell lines and Lactobacilli crispatus, fluorescence imaging and periodic acid colorimetric method, respectively. In vivo safety studies are performed in C57BL/6 mice followed by H&E and immunohistochemical (CD45) staining analysis of genital tract. The mean diameters of PEO, PEO/TCS, and PEO/TCS-PLA NFs are 118.56, 9.95, and 99.53 nm, respectively. The NFs exhibit smooth surface. The drug loading (13%-25%, w/w) increased by 10-fold compared to a nanoparticle formulation due to the application of the electrospinning technique. The NFs are noncytotoxic at the concentration of 1 mg/mL. The PEO/TCS-PLA core/shell NFs mostly exhibit a release kinetic following Weibull model (r2 = 0.9914), indicating the drug release from a matrix system. The core/shell NFs are 40-60-fold more bioadhesive than the pure PEO based NFs. The NFs are nontoxic and noninflammatory in vivo after daily treatment for up to 7 days. Owing to their enhanced drug loading and preliminary safety profile, the TCS core/shell NFs are promising candidates for the topical delivery of HIV/AIDS microbicides such as tenofovir.
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Quitosana/química , Inflamação/tratamento farmacológico , Nanofibras/química , Nanopartículas/química , Inibidores da Transcriptase Reversa/farmacologia , Compostos de Sulfidrila/química , Tenofovir/farmacologia , Animais , Células Cultivadas , Quitosana/administração & dosagem , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Feminino , Humanos , Inflamação/patologia , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Nanofibras/administração & dosagem , Nanopartículas/administração & dosagem , Inibidores da Transcriptase Reversa/química , Tenofovir/químicaRESUMO
PURPOSE: It is hypothesized that docetaxel (Doc)-loaded hyaluronic acid (HA)-polyethylene glycol/poly(ε-caprolactone)-grafted oily core nanocapsules (NCs) can enhance the drug cytotoxicity and uptake in CD44 expressing breast cancer (BC) cells (MDA-MB 231). METHODS: NCs were prepared, optimized and characterized by dynamic light scattering, transmission electron microscopy (TEM), and powder X-ray diffraction (PXRD). In vitro cytotoxicity tests [MTS, level of reactive oxygen species (ROS) and level of reduced glutathione (GSH)] were performed in BC cells. The contribution of CD44 to the NCs cellular uptake was elucidated using an anti CD44 antibody blockage and a CD44 negative NIH3T3 cell line. RESULTS: The optimum formulation of Doc-loaded HA oily core NCs had respective mean diameter, polydispersity, and drug encapsulation efficiency of 224.18 nm, 0.32, and 60.38%. The NCs appeared spherical with low drug crystallinity, while the drug release data fitted to first order equation. Compared to that of ungrafted NCs, the cytotoxicity of Doc-loaded HA-grafted NCs was significantly enhanced (p<0.05). A decrease of the intracellular level of ROS was reversely correlated with that of GSH. Interestingly, the cellular internalization of HA-grafted NCs mediated CD44 was dramatically enhanced (3 to 4-fold) with respect to the absence of specific biomarker or targeting ligand. CONCLUSIONS: The use of HA-grafted NCs enhanced the selective drug payload, cytotoxicity and uptake in MDA-MB 231 cells. Therefore, it could be a promising template for safe and effective delivery of Doc and similar chemotherapeutic agents in cancer cells.
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Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Neoplasias da Mama/tratamento farmacológico , Ácido Hialurônico/química , Nanocápsulas/química , Taxoides/administração & dosagem , Taxoides/farmacocinética , Animais , Antineoplásicos/farmacologia , Mama/efeitos dos fármacos , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Docetaxel , Feminino , Humanos , Camundongos , Células NIH 3T3 , Nanocápsulas/ultraestrutura , Espécies Reativas de Oxigênio/metabolismo , Taxoides/farmacologiaRESUMO
HIV/AIDS remains a global public health issue, and products available for the prevention of HIV infections are limited, especially those for short-acting, on-demand, user-controlled applications. Topical inserts are products that can be applied vaginally or rectally and have been explored as drug delivery systems. To fill the gap in the HIV prevention product pipeline, CONRAD has developed a topical insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG), two potent and synergistic antiretrovirals, as a simple, low-cost, and discreet option that can be self-administered vaginally and/or rectally, before and after coitus. In this review, we have described the development path of the TAF/EVG insert up to its current point in clinical testing, highlighting findings from acceptability, preclinical safety, pharmacokinetics, and efficacy evaluations and early clinical studies. In summary, the TAF/EVG inserts are stable, easy to manufacture, low-cost, acceptable, and show highly promising preclinical and clinical results for on-demand topical pre- or post-exposure HIV prevention.
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Transdermal administration remains an active research and development area as an alternative route for long-acting drug delivery. It avoids major drawbacks of conventional oral (gastrointestinal side effects, low drug bioavailability, and need for multiple dosing) or parenteral routes (invasiveness, pain, and psychological stress and bio-hazardous waste generated from needles), thereby increasing patient appeal and compliance. This review focuses on the current state of long-acting transdermal drug delivery, including adhesive patches, microneedles, and molecularly imprinted polymeric systems. Each subsection describes an approach including key considerations in formulation development, design, and process parameters with schematics. An overview of commercially available conventional (adhesive) patches for long-acting drug delivery (longer than 24 h), the reservoir- and matrix-type systems under preclinical evaluation, as well as the advanced transdermal formulations, such as the core-shell, nanoformulations-incorporated and stimuli-responsive microneedles, and 3D-printed and molecularly imprinted polymers that are in development, is also provided. Finally, we elaborated on translational aspects, challenges in patch formulation development, and future directions for the clinical advancement of new long-acting transdermal products.
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Administração Cutânea , Preparações de Ação Retardada , Sistemas de Liberação de Medicamentos , Humanos , Animais , Adesivo Transdérmico , Agulhas , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/químicaRESUMO
The purpose of this study was to develop and validate a rapid, sensitive, and specific reversed-phase high-performance liquid chromatography method for the quantitative determination of native tenofovir (TNF) for various applications. Different analytical performance parameters such as linearity, precision, accuracy, limit of quantification (LOQ), limit of detection (LOD), and robustness were determined according to International Conference on Harmonization (ICH) guidelines. A Bridge™ C18 column (150 × 4.6 mm, 5 µm) was used as stationary phase. The retention time of TNF was 1.54 ± 0.03 min (n = 6). The assay was linear over the concentration range of 0.1-10 µg/mL. The proposed method was sensitive with LOD and LOQ values equal to 50 and 100 ng/mL, respectively. The method was accurate with percent mean recovery from 95.41% to 102.90% and precise as percent RSD (relative standard deviation) values for intra-day, and inter-day precision were less than 2%. This method was utilized for the estimation of molar absorptivity of TNF at 259 nm (ε(259) = 12,518 L/mol/cm), calculated from linear regression analysis. The method was applied for determination of percentage of encapsulation efficiency (22.93 ± 0.04%), drug loading (12.25 ± 1.03%), in vitro drug release profile in the presence of enzyme (43% release in the first 3 h) and purification analysis of hyaluronic acid-based nanomedicine.
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Adenina/análogos & derivados , Ácido Hialurônico/análise , Nanomedicina/métodos , Organofosfonatos/análise , Adenina/análise , Adenina/química , Cromatografia Líquida de Alta Pressão/métodos , Ácido Hialurônico/química , Limite de Detecção , Nanomedicina/normas , Organofosfonatos/química , Reprodutibilidade dos Testes , Tenofovir , Fatores de TempoRESUMO
INTRODUCTION: Poor or inconsistent adherence to daily oral pre-exposure prophylaxis (PrEP) has emerged as a key barrier to effective HIV prevention. The advent of potent long-acting (LA) antiretrovirals (ARVs) in conjunction with advances in controlled release technologies has enabled LA ARV drug delivery systems (DDS) capable of providing extended dosing intervals and overcome the challenge of suboptimal drug adherence with daily oral dosing. AREAS COVERED: This review discusses the current state of the LA PrEP field, recent advances, and emerging technologies, including ARV prodrug modifications and new DDS. Technological challenges, knowledge gaps, preclinical testing considerations, and future directions important in the context of clinical translation and implementation of LA HIV PrEP are discussed. EXPERT OPINION: The HIV prevention field is evolving faster than ever and the bar for developing next-generation LA HIV prevention options continues to rise. The requirements for viable LA PrEP products to be implemented in resource-limited settings are challenging, necessitating proactive consideration and product modifications during the design and testing of promising new candidates. If successfully translated, next-generation LA PrEP that are safe, affordable, highly effective, and accepted by both end-users and key stakeholders will offer significant potential to curb the HIV pandemic.
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Síndrome da Imunodeficiência Adquirida , Fármacos Anti-HIV , Infecções por HIV , Profilaxia Pré-Exposição , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Sistemas de Liberação de MedicamentosRESUMO
Raloxifene (RLX) is a second-generation selective estrogen receptor modulator approved for the prevention of invasive breast cancer in women. Oral therapy of RLX requires daily intake and is associated with side effects that may lead to low adherence. We developed a weekly transdermal delivery system (TDS) for the sustained delivery of RLX to enhance the therapeutic effectiveness, increase adherence, and reduce side effects. We evaluated the weekly transdermal administration of RLX using passive permeation, chemical enhancers, physical enhancement techniques, and matrix- and reservoir-type systems, including polymeric gels. In vitro permeation studies were conducted using vertical Franz diffusion cells across dermatomed human skin or human epidermis. Oleic acid was selected as a chemical enhancer based on yielding the highest drug delivery amongst the various enhancers screened and was incorporated in the formulation of TDSs and polymeric gels. Based on in vitro results, both Eudragit- and colloidal silicon dioxide-based transdermal gels of RLX exceeded the target flux of 24 µg/cm2/day for 7 days. An infinite dose of these gels delivered 326.23 ± 107.58 µg/ cm2 and 498.81 ± 14.26 µg/ cm2 of RLX in 7 days, respectively, successfully exceeding the required target flux. These in vitro results confirm the potential of reservoir-based polymeric gels as a TDS for the weekly administration of RLX.
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This study explored the development of cross-linked gels to potentially provide a physical barrier to vaginal sperm transport for contraception. Two types of gels were formulated, a physically cross-linked iota-carrageenan (Ci) phenylboronic acid functionalized hydroxylpropylmethyacrylate copolymer (PBA)-based (Ci-PBA) gel, designed to block vaginal sperm transport. The second gel was pH-shifting cross-linked Ci-polyvinyl alcohol-boric acid (Ci-PVA-BA) gel, designed to modulate its properties in forming a viscoelastic, weakly cross-linked transient network (due to Ci gelling properties) on vaginal application (at acidic pH of ~3.5-4.5) to a more elastic, densely cross-linked (due to borate-diol cross-linking) gel network at basic pH of 7-8 of seminal fluid, thereby acting as a physical barrier to motile sperm. The gels were characterized for dynamic rheology, physicochemical properties, and impact on sperm functionality (motility, viability, penetration). The rheology data confirmed that the Ci-PBA gel was formed by ionic interactions whereas Ci-PVA-BA gel was chemically cross-linked and became more elastic at basic pH. Based on the screening data, lead gels were selected for in vitro sperm functionality testing. The in vitro results confirmed that the Ci-PBA and Ci-PVA-BA gels created a barrier at the sperm-gel interface, providing sperm blocking properties. For preclinical proof-of-concept, the Ci-PBA gels were applied vaginally and tested for contraceptive efficacy in rabbits, demonstrating only partial efficacy (40-60%). Overall, the in vitro and in vivo results support the development and further optimization of cross-linked gels using commercially available materials as vaginal contraceptives.
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BACKGROUND: Topical on-demand forms for HIV pre-exposure prophylaxis (PrEP) may be a desirable alternative for people that prefer not to use daily PrEP. CONRAD has developed inserts containing tenofovir alafenamide (TAF) and elvitegravir (EVG) for on-demand vaginal or rectal pericoital use. We assessed the pharmacokinetics (PK) and pre-exposure efficacy of rectally applied TAF/EVG inserts in macaques. METHODS: PK was assessed in 12 pigtailed macaques. Tenofovir (TFV) and EVG levels were assayed in rectal biopsies and secretions, and tenofovir-diphosphate (TFV-DP) levels in biopsies and peripheral blood mononuclear cells (PBMC). Drug biodistribution was evaluated in 10 animals at necropsy 4 h post-dosing. For efficacy assessments, one or two TAF/EVG inserts were administered to macaques (n = 6) 4 h before repeated rectal SHIV162p3 challenges. FINDINGS: One TAF/EVG insert resulted in rapid and high EVG and TFV-DP in rectal tissue 4 h after application. Adding a second insert led to a 10-fold increase in EVG and TFV-DP in rectal tissue. Efficacy of one and two TAF/EVG inserts were 72.6% (CI 24.5%-92.6%) and 93.1% (CI 73.3%-99.2%), respectively. INTERPRETATION: Although high TFV-DP and EVG levels were observed with one rectal TAF/EVG insert, it only conferred partial protection from rectal SHIV challenges. Adding a second insert led to an increase in TFV and EVG in rectal tissues resulting in higher (>90%) efficacy. These results highlight the high efficacy of TAF/EVG inserts as topical on-demand rectal PrEP, as well as the need for appropriate drug coverage in the deep rectum and colon to achieve high protection. FUNDING: The work related to animal studies was funded by CDC intramural funds and an interagency agreement between CDC and USAID (USAID/CDC IAA AID-GH-T-15-00002). The work related to the insert formulation was funded by U.S. PEPFAR through USAID under a Cooperative Agreement (AID-OAA-A-14-00010) with CONRAD/Eastern Virginia Medical School. The findings and conclusions of this manuscript are those of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention (CDC), USAID, President's Emergency Plan for AIDS Relief (PEPFAR), Eastern Virginia Medical School (EVMS), or the US government.
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Fármacos Anti-HIV , Infecções por HIV , Animais , Feminino , Fármacos Anti-HIV/uso terapêutico , Leucócitos Mononucleares , Macaca , Distribuição Tecidual , Infecções por HIV/tratamento farmacológico , Alanina/uso terapêutico , Tenofovir , Fumaratos/uso terapêuticoRESUMO
BACKGROUND: Vaginal products for HIV prevention that can be used on-demand before or after sex may be a preferable option for women with low frequency or unplanned sexual activity or who prefer not to use daily or long-acting pre-exposure prophylaxis (PrEP). We performed dose ranging pharmacokinetics (PK) and efficacy studies of a vaginally applied insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG) in macaques under PrEP or post-exposure prophylaxis (PEP) modalities. METHODS: PK studies were performed in 3 groups of pigtailed macaques receiving inserts with different fixed-dose combinations of TAF and EVG (10/8, 20/16 and 40/24 mg). PrEP and PEP efficacy of a selected insert was investigated in a repeat exposure vaginal SHIV transmission model. Inserts were administered 4 h before (n = 6) or after (n = 6) repeated weekly SHIV exposures. Infection outcome was compared with macaques receiving placebo inserts (n = 12). FINDINGS: Dose ranging studies showed rapid and sustained high drug concentrations in vaginal fluids and tissues across insert formulations with minimal dose proportionality. TAF/EVG (20/16 mg) inserts were selected for efficacy evaluation. Five of the 6 animals receiving these inserts 4 h before and 6/6 animals receiving inserts 4 h after SHIV exposure were protected after 13 challenges (p = 0.0088 and 0.0077 compared to placebo, respectively). The calculated PrEP and PEP efficacy was 91.0% (95% CI = 32.2%-98.8%) and 100% (95% CI = undefined), respectively. INTERPRETATION: Inserts containing TAF/EVG provided high protection against vaginal SHIV infection when administered within a 4 h window before or after SHIV exposure. Our results support the clinical development of TAF/EVG inserts for on-demand PrEP and PEP in women. FUNDING: Funded by CDC intramural funds, an interagency agreement between CDC and USAID (USAID/CDC IAA AID-GH-T-15-00002), and by the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) through the U.S. Agency for International Development (USAID) under a Cooperative Agreement (AID-OAA-A-14-00010) with CONRAD/Eastern Virginia Medical School.
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Fármacos Anti-HIV , Infecções por HIV , Profilaxia Pré-Exposição , Animais , Feminino , Adenina , Fármacos Anti-HIV/uso terapêutico , Fumaratos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Macaca , Tenofovir/uso terapêuticoRESUMO
Nanotechnology and microfabrication approaches are playing instrumental roles in the development of innovative technologies to fight human diseases. Because of promising in vitro and preclinical outcomes, micro-/nanorobots (MNRs), are increasingly being considered for personalized and precision therapeutic diagnoses, sensing, drug delivery, and surgery. Today, designing MNR-based devices to improve the safety and efficacy of drugs for targeted cells and tissues represents a novel and promising area of therapeutic development. Progress has primarily been due to many scientific breakthroughs made in design, fabrication, and operational technologies, which greatly enhanced the capabilities of MNRs to meet the requirements of biomedical applications. This review focuses on the development and emerging biomedical applications of micro-/nanostructures encompassing nanoswimmers, nanoengines, 3D-motion nanomachines, and biologically inspired microbots, nanofish, nanorockets, etc. Promising applications of these novel devices in various therapeutic areas are discussed. We examine the impacts of the rapid progress made in developing these novel devices for drug delivery applications. We also summarize the current fabrication, scale-up development and clinical translational challenges and the main roadblocks that need to be overcome, particularly those related to patient safety and personalized medicine approaches, areas that require the design of safe innovative materials. As MNRs are new, scientists should systematically investigate their behavior, functionality, biocompatibility, toxicity, biodistribution, and efficacy before considering any potential clinical evaluations, while also ensuing that they comply with ethical principles. Although still an emerging area, MNRs are steadily becoming a realistic prospect as vital future therapeutic tools for a vast array of biomedical applications.
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Nanoestruturas , Preparações Farmacêuticas , Humanos , Microtecnologia , Nanotecnologia , Distribuição TecidualRESUMO
Tenofovir alafenamide (TAF) is a potent prodrug of tenofovir (TFV) for HIV prophylaxis, and HIV and HBV treatment. Compared to oral daily doses, transdermal administration of TAF may be more advantageous for long-term adherence by offering sustained drug delivery and reduced dosing frequency. Here, we described the plasma pharmacokinetics (PK) of an optimized once-weekly suspension transdermal delivery system (TDS) for TAF (96 mg/25 cm2 of TDS) in female hairless rats. Over the study period, the TAF TDS delivered an overall low level of TAF (median: 1.43 [0.02-3.28] ng/mL) and a sustained level of the stable metabolite and parent drug, TFV. Relative to the projected exposure corresponding to six-day oral daily doses, a comparable TAF exposure but a substantially lower TFV exposure was resulted from the TAF TDS, suggesting a lower risk of TFV-associated adverse effects. TAF, TFV, and phosphorylated TFVs (TFV-monophosphate and diphosphate) were found distributed in vaginal tissue, the portal of entry for HIV during male-to-female sexual transmission. Skin adhesion and tolerance were acceptable given the animal model used. PK evaluation of the TAF TDS in hairless rats demonstrates the proof of concept that transdermal delivery can be an alternative route for a sustained, once-weekly systemic delivery of TAF.
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Adenina/análogos & derivados , Antivirais/administração & dosagem , Antivirais/farmacocinética , Adenina/administração & dosagem , Adenina/sangue , Adenina/farmacocinética , Adenina/toxicidade , Administração Cutânea , Administração Oral , Alanina , Animais , Antivirais/sangue , Antivirais/toxicidade , Preparações de Ação Retardada , Esquema de Medicação , Composição de Medicamentos , Feminino , Injeções Intravenosas , Estudo de Prova de Conceito , Ratos Pelados , Tenofovir/análogos & derivados , Distribuição Tecidual , Adesivo Transdérmico , Vagina/metabolismoRESUMO
The clinical development of cell therapies is revealing that extracellular vesicles (EVs) may become very instrumental as subcellular therapeutic adjuncts in human medicine. EVs are released by various types of cells, grown in culture, such as mesenchymal stromal cells, or obtained from patients or allogeneic donors. Some EV populations (especially species of exosomes and shed microvesicles) exhibit inherent roles in cell-cell communication, thanks to their ca. 30~1000-nm nanosize and the physiological expression of cell-specific markers on their lipid bilayer membranes. Biomedical engineers are now attempting to exploit this cellular crosstalk capacity to use EVs as smart drug delivery systems that display substantial benefits in targeting, safety, and pharmacokinetics compared to synthetic nanocarriers. In parallel, the development of a set of nano-instrumentation, biochemical tools, and preclinical assays needed for optimal characterization of both naïve and drug-loaded EVs is ongoing. Although many hurdles remain, owing to the complexity of EV populations, translation of this "subcellular therapy" platform into reality is at hand and may soon change the landscape of the therapeutic arsenal in place to treat human degenerative and metabolic pathologies as well as diseases like cancer. This article provides objective opinions, balanced between unrealistic hopes of the capacity of EVs to resolve multiple clinical issues and concrete hurdles that have to be overcome to ensure that EVs are not lost in the translation phase, so that EVs can fulfill their promise by becoming a reliable therapeutic modality.
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Terapia Baseada em Transplante de Células e Tecidos/métodos , Sistemas de Liberação de Medicamentos/métodos , Vesículas Extracelulares/fisiologia , Nanomedicina/métodos , Animais , Biomarcadores/metabolismo , Comunicação Celular , Exossomos/química , Exossomos/fisiologia , Vesículas Extracelulares/metabolismo , Humanos , Neoplasias/metabolismo , Neoplasias/terapia , Doenças Neurodegenerativas/terapia , Distribuição Tecidual , Pesquisa Translacional BiomédicaRESUMO
Nanocarriers (synthetic/cell-based have attracted enormous interest for various therapeutic indications, including neurodegenerative disorders. A broader understanding of the impact of nanomedicines design is now required to enhance their translational potential. Nanoformulations in vivo journey is significantly affected by their physicochemical properties including the size, shape, hydrophobicity, elasticity, and surface charge/chemistry/morphology, which play a role as an interface with the biological environment. Understanding protein corona formation is crucial in characterizing nanocarriers and evaluating their interactions with biological systems. In this review, the types and properties of the brain-targeted nanocarriers are discussed. The biological factors and nanocarriers properties affecting their in vivo behavior are elaborated. The compositional description of cell culture and biological matrices, including proteins potentially relevant to protein corona built-up on nanoformulation especially for brain administration, is provided. Analytical techniques of characterizing nanocarriers in complex matrices, their advantages, limitations, and implementation challenges in industrial GMP environment are discussed. The uses of orthogonal complementary characterization approaches of nanocarriers are also covered.
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Encéfalo/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Doenças Neurodegenerativas/tratamento farmacológico , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Humanos , NanomedicinaRESUMO
Microvesicles (MVs) are subcellular physiological vehicles present in all body fluids that mediate the transfer of intercellular information within biological systems and contribute to healthy conditions. MVs have lipid bilayer membranes decorated with multiple ligands that can interact with receptors on target cells, rendering them as promising candidates for targeted delivery. The biotechnology and cell therapy industries are developing MV-based preparations that use this subcellular therapeutic machinery (in a naïve or modified state) for regenerative medicine, as substitutes for intact cell therapy, and as intelligent targeted drug delivery carriers. However, significant production challenges must be overcome before MVs scale-up development, clinical translation, and routine therapeutic application can be realized. The unique expertise developed in the biotechnology industry should facilitate market access to MV-based therapeutics. In this review, the roles of biotechnology and cell therapy industries to manufacture MVs as inherent therapeutic agents or drug delivery systems are summarized. The manufacturing, development, characterization, and regulatory challenges for successful translation are discussed.
Assuntos
Biotecnologia/métodos , Vesículas Extracelulares/metabolismo , Terapia de Alvo Molecular/métodos , Medicina Regenerativa/métodos , Tecnologia Farmacêutica/métodos , Biotecnologia/tendências , Humanos , Medicina Regenerativa/tendências , Tecnologia Farmacêutica/tendênciasRESUMO
The development of topical inserts for the prevention of sexually transmitted infections (STIs), particularly human immunodeficiency virus (HIV), represents a promising alternative to oral and parenteral pre-exposure prophylaxis (PrEP) dosage forms. They may be used for vaginal and/or rectal administration of a variety of agents with antiviral activity. Topical inserts deliver drugs to the portal of viral entry, i.e., the genital or rectal mucosa, with low systemic exposure, and therefore are safer and have fewer side effects than systemic PrEP agents. They may dissolve fast, releasing the active drugs within minutes of insertion, or slowly for long-acting drug delivery. Furthermore, they are user-friendly being easy to administer, discreet and highly portable. They are also economical and easy to manufacture at scale and to distribute, with excellent stability and shelf-life. Altogether, topical inserts represent a particularly promising form of drug delivery for HIV and STI prevention. Highlighted within this review are end-user acceptability research dedicated to understanding preferred attributes for this form of drug delivery, advantages and disadvantages of the formulation platform options, considerations for their development, clinical assessment of select placebo prototypes, future directions, and the potential impact of this dosage form on the HIV prevention landscape.
RESUMO
Advances in polymer synthetic approaches have significantly enhanced the ability to rationally design the block copolymers with tailor-made functionality and variable molecular weight. Hence, block copolymers have been extensively applied in the formulation of nanostructure materials. Owing to their amphiphilic characteristics, block copolymers can generate different nanostructures, providing easy adjustability of their size, stability and surface chemistry. In this review, block copolymer classification, synthesis, characterization, stimuli-responsive behavior and nanostructure applications are summarized. Although block copolymers hold great potential for improving the therapeutic efficacy of drugs, a comprehensive delivery potential of these systems has not been fully exploited. Thus, an outlook on future developments on block-copolymer-based assemblies are further discussed. The new developments in block copolymers are expected to contribute significantly to the field of polymeric nanomedicine.