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Long-acting injectable (LAI) formulations can provide several advantages over the more traditional oral formulation as drug product opportunities. LAI formulations can achieve sustained drug release for extended periods of time, which results in less frequent dosing requirements leading to higher patient adherence and more optimal therapeutic outcomes. This review article will provide an industry perspective on the development and associated challenges of long-acting injectable formulations. The LAIs described herein include polymer-based formulations, oil-based formulations, and crystalline drug suspensions. The review discusses manufacturing processes, including quality controls, considerations of the Active Pharmaceutical Ingredient (API), biopharmaceutical properties and clinical requirements pertaining to LAI technology selection, and characterization of LAIs through in vitro, in vivo and in silico approaches. Lastly, the article includes a discussion around the current lack of suitable compendial and biorelevant in vitro models for the evaluation of LAIs and its subsequent impact on LAI product development and approval.
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Antipsicóticos , Esquizofrenia , Humanos , Antipsicóticos/uso terapêutico , Esquizofrenia/tratamento farmacológico , Preparações de Ação Retardada , Injeções , Liberação Controlada de FármacosRESUMO
Imaging-based characterization of polymeric drug-eluting implants can be challenging due to the microstructural complexity and scale of dispersed drug domains and polymer matrix. The typical evaluation via real-time (and accelerated in vitro experiments not only can be very labor intensive since implants are designed to last for 3 months or longer, but also fails to elucidate the impact of the internal microstructure on the implant release rate. A novel characterization technique, combining multi-scale high resolution three-dimensional imaging, was developed for a mechanistic understanding of the impact of formulation and manufacturing process on the implant microstructure. Artificial intelligence-based image segmentation and imaging analytics convert "visualized" structural properties into numerical models, which can be used to calculate key parameters governing drug transport in the polymer matrix, such as effective permeability. Simulations of drug transport in structures constructed on the basis of image analytics can be used to predict the release rates for the drug-eluting implant without running lengthy experiments. Multi-scale imaging approach and image-based characterization generate a large amount of quantitative structural information that are difficult to obtain experimentally. The direct-imaging based analytics and simulation is a powerful tool and has potential to advance fundamental understanding of drug release mechanism and the development of robust drug-eluting implants.
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Implantes de Medicamento/farmacocinética , Liberação Controlada de Fármacos , Composição de Medicamentos/métodos , Imageamento Tridimensional , Microscopia Eletrônica de Varredura , Polímeros , Tomografia Computadorizada por Raios XRESUMO
The emergence of new active pharmaceutical ingredient (API) polymorphs in pharmaceutical development presents significant risks. Even with thorough polymorph screening, new pathways toward alternate crystal phases can present themselves over the course of formulation development; thus, further improvements in phase screening methods are needed. Herein, a case study is presented of a thermodynamically stable crystalline phase of the HIV drug Islatravir (MK-8591, EFdA) that was not isolated from initial pharmaceutical polymorph screening. In total, five Islatravir phases are identified: one monohydrate and four anhydrate phases. The new phase, anhydrate form IV, was unexpectedly discovered during hot melt extrusion (HME) process development of polymeric implant drug product formulations while probing extreme manufacturing process conditions (elevated shear forces). X-ray diffraction (XRD), differential scanning calorimetry (DSC), and solid-state nuclear magnetic resonance (ssNMR) were utilized as principal tools to identify the new polymorph. The result suggests that HME introduces conditions that may allow a thermodynamically stable crystalline phase to form and these conditions are not necessarily captured by routine pharmaceutical polymorph screening. Subsequent investigations identified procedures to generate the new anhydrate phase without HME equipment by the use of special thermal procedures. It is found that for a crystalline hydrate phase the rate of water loss as well as water entrapment in a heating vessel play a crucial role in phase conversions into different anhydrate polymorphs. Further, the polymer involved in the HME manufacturing process also plays a critical role in the phase conversion, likely by coating the API microparticles and thereby altering the phase conversion kinetics. Strategies presented herein to mimic phase changes during formulation manufacture hold promise for the identification of thermodynamically stable anhydrate forms in earlier stages of pharmaceutical development.
Assuntos
Desoxiadenosinas/química , Preparações Farmacêuticas/química , Varredura Diferencial de Calorimetria/métodos , Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Desenvolvimento de Medicamentos/métodos , Tecnologia de Extrusão por Fusão a Quente/métodos , Temperatura Alta , Polímeros/química , Solubilidade/efeitos dos fármacos , Termodinâmica , Difração de Raios X/métodosRESUMO
Although researchers have examined eating disorders in female athletes, few such studies have been done with athletes who are retired, and even fewer have been quantitative. Thus, the authors empirically tested an established eating disorder theoretical model with 218 former NCAA Division-I female collegiate athletes who had been retired for 2-6 years. In retirement, participants completed measures of general sociocultural pressures related to body and appearance, thin-ideal internalization, body dissatisfaction, dietary restraint, negative affect, and bulimic symptomatology. Through structural equation modeling, the authors examined the direct and indirect relationships among the latent variables while controlling for body mass index and years since retirement. The model fit the data well, supporting the hypothesized direct and indirect relationships among the variables and explaining 54% of the variance in bulimic symptomatology. Despite no longer being exposed to sport pressures that contribute to eating disorders, female athletes experience such symptoms long into retirement.
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Regimen adherence remains a major hurdle to the success of daily oral drug regimens for the treatment and prevention of human immunodeficiency virus (HIV) infection. Long-acting drug formulations requiring less-frequent dosing offer an opportunity to improve adherence and allow for more forgiving options with regard to missed doses. The administration of long-acting formulations in a clinical setting enables health care providers to directly track adherence. MK-8591 (4'-ethynyl-2-fluoro-2'-deoxyadenosine [EFdA]) is an investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI) drug candidate under investigation as part of a regimen for HIV treatment, with potential utility as a single agent for preexposure prophylaxis (PrEP). The active triphosphate of MK-8591 (MK-8591-TP) exhibits protracted intracellular persistence and, together with the potency of MK-8591, supports its consideration for extended-duration dosing. Toward this end, drug-eluting implant devices were designed to provide prolonged MK-8591 release in vitro and in vivo Implants, administered subcutaneously, were studied in rodents and nonhuman primates to establish MK-8591 pharmacokinetics and intracellular levels of MK-8591-TP. These data were evaluated against pharmacokinetic and pharmacodynamic models, as well as data generated in phase 1a (Ph1a) and Ph1b clinical studies with once-weekly oral administration of MK-8591. After a single administration in animals, MK-8591 implants achieved clinically relevant drug exposures and sustained drug release, with plasma levels maintained for greater than 6 months that correspond to efficacious MK-8591-TP levels, resulting in a 1.6-log reduction in viral load. Additional studies of MK-8591 implants for HIV treatment and prevention are warranted.
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Desoxiadenosinas/uso terapêutico , Portadores de Fármacos/química , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Inibidores da Transcriptase Reversa/uso terapêutico , Animais , Fármacos Anti-HIV , Desoxiadenosinas/química , HIV-1/efeitos dos fármacos , HIV-1/patogenicidade , Macaca mulatta , Masculino , Polímeros/química , Ratos , Ratos Wistar , Inibidores da Transcriptase Reversa/químicaRESUMO
BACKGROUND: The latent reservoir in resting CD4(+) T cells presents a major barrier to HIV cure. Latency-reversing agents are therefore being developed with the ultimate goal of disrupting the latent state, resulting in induction of HIV expression and clearance of infected cells. Histone deacetylase inhibitors (HDACi) have received a significant amount of attention for their potential as latency-reversing agents. RESULTS: Here, we have investigated the in vitro and systemic in vivo effect of panobinostat, a clinically relevant HDACi, on HIV latency. We showed that panobinostat induces histone acetylation in human PBMCs. Further, we showed that panobinostat induced HIV RNA expression and allowed the outgrowth of replication-competent virus ex vivo from resting CD4(+) T cells of HIV-infected patients on suppressive antiretroviral therapy (ART). Next, we demonstrated that panobinostat induced systemic histone acetylation in vivo in the tissues of BLT humanized mice. Finally, in HIV-infected, ART-suppressed BLT mice, we evaluated the effect of panobinostat on systemic cell-associated HIV RNA and DNA levels and the total frequency of latently infected resting CD4(+) T cells. Our data indicate that panobinostat treatment resulted in systemic increases in cellular levels of histone acetylation, a key biomarker for in vivo activity. However, panobinostat did not affect the levels of cell-associated HIV RNA, HIV DNA, or latently infected resting CD4(+) T cells. CONCLUSION: We have demonstrated robust levels of systemic histone acetylation after panobinostat treatment of BLT humanized mice; and we did not observe a detectable change in the levels of cell-associated HIV RNA, HIV DNA, or latently infected resting CD4(+) T cells in HIV-infected, ART-suppressed BLT mice. These results are consistent with the modest effects noted in vitro and suggest that combination therapies may be necessary to reverse latency and enable clearance. Animal models will contribute to the progress towards an HIV cure.
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Fármacos Anti-HIV/uso terapêutico , Linfócitos T CD4-Positivos/virologia , DNA Viral/metabolismo , HIV-1/efeitos dos fármacos , Ácidos Hidroxâmicos/uso terapêutico , Indóis/uso terapêutico , RNA Viral/metabolismo , Latência Viral/efeitos dos fármacos , Acetilação , Animais , Fármacos Anti-HIV/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/genética , HIV-1/fisiologia , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Camundongos , Camundongos Transgênicos , Panobinostat , RNA Viral/sangue , Ativação Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacosRESUMO
Polymer based carriers that aid in endosomal escape have proven to be efficacious siRNA delivery agents in vitro and in vivo; however, most suffer from cytotoxicity due in part to a lack of selectivity for endosomal versus cell membrane lysis. For polymer based carriers to move beyond the laboratory and into the clinic, it is critical to find carriers that are not only efficacious, but also have margins that are clinically relevant. In this paper we report three distinct categories of polymer conjugates that improve the selectivity of endosomal membrane lysis by relying on the change in pH associated with endosomal trafficking, including incorporation of low pKa heterocycles, acid cleavable amino side chains, or carboxylic acid pH sensitive charge switches. Additionally, we determine the therapeutic index of our polymer conjugates in vivo and demonstrate that the incorporation of pH responsive elements dramatically expands the therapeutic index to 10-15, beyond that of the therapeutic index (less than 3), for polymer conjugates previously reported.
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Concentração de Íons de Hidrogênio , Polímeros/uso terapêutico , RNA Interferente Pequeno/uso terapêutico , Animais , Polímeros/química , Polímeros/farmacocinética , RNA Interferente Pequeno/química , RNA Interferente Pequeno/farmacocinética , RatosRESUMO
BACKGROUND: Islatravir (MK-8591) is a deoxyadenosine analog in development for the treatment and prevention of HIV-1 infection. An islatravir-eluting implant could provide an additional option for pre-exposure prophylaxis (PrEP). SETTING: Previous data support a threshold islatravir triphosphate concentration for PrEP of 0.05 pmol/10 6 cells in peripheral blood mononuclear cells. Prototype islatravir-eluting implants were previously studied to establish general tolerability and pharmacokinetics (PKs) of islatravir relative to the threshold level. METHODS: In this randomized, double-blind, placebo-controlled, phase 1 trial, a next-generation radiopaque islatravir-eluting implant (48 mg, 52 mg, or 56 mg) or placebo implant was placed for a duration of 12 weeks in participants at low risk of HIV infection. Safety and tolerability, as well as PK for islatravir parent and islatravir triphosphate from plasma and peripheral blood mononuclear cells, were assessed throughout placement and 8 weeks after removal. RESULTS: In total, 36 participants (8 active and 4 placebo per dose arm) were enrolled and completed this study. Implants were generally well tolerated, with no discontinuations due to an adverse event, and no clear dose-dependence in implant-related adverse events. No clinically meaningful relationships were observed for changes in laboratory values, vital signs, or electrocardiogram assessments. Mean islatravir triphosphate levels at day 85 (0.101-0.561 pmol/10 6 cells) were above the PK threshold for all dose levels. CONCLUSION: Islatravir administered using a subdermal implant has the potential to be an effective and well-tolerated method for administering PrEP to individuals at risk of acquiring HIV-1.
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Infecções por HIV , HIV-1 , Profilaxia Pré-Exposição , Humanos , Infecções por HIV/tratamento farmacológico , Profilaxia Pré-Exposição/métodos , Leucócitos Mononucleares , Desoxiadenosinas/uso terapêutico , Método Duplo-CegoRESUMO
We conducted a qualitative evaluation of Bodies in Motion (BIM), a dissonance, mindful self-compassion-based program that addresses the unique experiences and needs of female athletes with respect to their bodies and their well-being. Using semi-structured interviews, 12 collegiate female athletes (retired 2 - 6 years) reflected and provided feedback on the enduring impact of BIM on their body image, relationship to food and exercise, and overall psychological well-being. Through thematic analysis, we found that these retired athletes, extending from their initial program learning, reported increased awareness of sport and societal messages and their impact on body image, shifted perspectives in their view of themselves and their bodies, and used learned skills to manage body image in their lives. Further, with the passage of time, athletes emphasized how what they had learned in BIM remained essential as they navigated challenging life transitions, such as their retirement from collegiate sports. Our findings indicate that the benefits female athletes report accruing in the immediate aftermath of BIM remain with them, even growing and becoming more salient as they continue to reflect on the program and its impact on their body awareness and how they navigate their lives as women and former athletes.
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Aposentadoria , Esportes , Feminino , Humanos , Aposentadoria/psicologia , Satisfação Pessoal , Imagem Corporal/psicologia , Atletas/psicologia , Esportes/psicologiaRESUMO
ABSTRACT: This article highlights the need to screen survivors of traumatic orthopedic injuries for postinjury symptoms associated with stressor-related disorders such as acute stress disorder and posttraumatic stress disorder, including pain, sleep disturbances, anxiety, and depression. The authors discuss the presentation of these postinjury symptoms, the instruments used to screen for each, the various pharmacological and nonpharmacological treatments, and the nursing implications for managing postinjury symptoms in traumatic orthopedic injury survivors.
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Saúde Mental , Transtornos de Estresse Pós-Traumáticos , Ansiedade , Depressão/diagnóstico , Humanos , Dor/etiologia , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Sobreviventes/psicologiaRESUMO
Introduction: Drug eluting implants offer patient convenience and improved compliance through less frequent dosing, eliminating repeated, painful injections and providing localized, site specific delivery with applications in contraception, ophthalmology, and oncology.Areas covered: This review provides an overview of available implant products, design approaches, biodegradable and non-biodegradable polymeric materials, and fabrication techniques with a focus on commercial applications and industrial drug product development. Developing trends in the field, including expanded availability of suitable excipients, development of novel materials, scaled down manufacturing process, and a wider understanding of the implant development process are discussed and point to opportunities for differentiated drug eluting implant products.Expert opinion: In the future, long-acting implants will be important clinical tools for prophylaxis and treatment of global health challenges, especially for infectious diseases, to reduce the cost and difficulty of treating chronic indications, and to prolong local delivery in difficult to administer parts of the body. These products will help improve patient safety, adherence, and comfort.
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Sistemas de Liberação de Medicamentos , Preparações Farmacêuticas , Desenvolvimento de Medicamentos , Implantes de Medicamento , Excipientes , HumanosRESUMO
Islatravir (MK-8591) is a highly potent type 1 human immunodeficiency virus (HIV-1) nucleoside reverse transcriptase translocation inhibitor with a long intracellular half-life that is in development for the prevention and treatment of HIV-1. We conducted a randomized, double-blind, placebo-controlled, phase 1 trial in adults without HIV-1 infection. Participants received islatravir or placebo subdermal implants for 12 weeks and were monitored throughout this period and after implant removal. The co-primary end points were safety and tolerability of the islatravir implant and pharmacokinetics, including concentration at day 85, of islatravir triphosphate in peripheral blood mononuclear cells (PBMCs). Secondary end points included additional pharmacokinetic parameters for islatravir triphosphate in PBMCs and the plasma pharmacokinetic profile of islatravir. Based on preclinical data, two doses were assessed: 54 mg (n = 8, two placebo) and 62 mg (n = 8, two placebo). The most frequently reported adverse events were mild-to-moderate implant-site reactions (induration, hematoma, pain). Throughout the 12-week trial, geometric mean islatravir triphosphate concentrations were above a pharmacokinetic threshold of 0.05 pmol per 106 PBMCs, which was estimated to provide therapeutic reverse transcriptase inhibition (concentration at day 85 (percentage of geometric coefficient of variation): 54 mg, 0.135 pmol per 106 cells (27.3); 62 mg, 0.272 pmol per 106 cells (45.2)). Islatravir implants at both doses were safe and resulted in mean concentrations above the pharmacokinetic threshold through 12 weeks, warranting further investigation of islatravir implants as a potential HIV prevention strategy.
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Fármacos Anti-HIV/administração & dosagem , Desoxiadenosinas/administração & dosagem , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/administração & dosagem , Adulto , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Desoxiadenosinas/efeitos adversos , Desoxiadenosinas/farmacocinética , Método Duplo-Cego , Infecções por HIV/genética , Infecções por HIV/virologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , HIV-1/patogenicidade , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Placebos , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/farmacocinética , Replicação Viral/efeitos dos fármacosRESUMO
In pharmaceutical development alternative drug delivery modalities are being increasingly employed. One example is an implant, which achieves gradual drug release in patients over a period of many months or years. Due to the complexity of these long-acting formulations, advanced physical characterization methods are desirable as screening tools during protracted formulation development. Imaging methods are of particular interest due to their ability to interrogate the structure and composition of implants spatially across multiple length scales (macro, micro, nano). In this work, spatiochemical imaging is shown to interrogate many crucial drug product attributes of solid implants: overall implant structure, drug distribution, micro-domain size and orientation, agglomeration, porosity and defects, drug/excipient interface, dissolution process, and release mechanism. Imaging methods facilitate a detailed understanding of the process/structure correlation to inform on formulation selection, process parameter optimization, and batch consistency. Numerous case studies of implant applications with imaging are discussed. Methods utilized are X-ray computed tomography (XRCT), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS) imaging, and Raman microscopy. The imaging data is complemented with solid-state nuclear magnetic resonance (ssNMR). Altogether, these examples demonstrate that complementary imaging methods are highly effective for analyzing complex and novel pharmaceutical modalities such as solid implants.
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Preparações Farmacêuticas , Liberação Controlada de Fármacos , Humanos , Microscopia Eletrônica de Varredura , Próteses e Implantes , Espectrometria por Raios XRESUMO
Alternative formulations of entecavir, a once daily oral hepatitis B antiretroviral, may improve treatment adherence by patients. We explored the use of biocompatible polymers to control entecavir dissolution in two formats suitable for subcutaneous implantation. Hot melt extrudates were prepared by extruding entecavir-polymer blends at specified weight ratios. Dip-coated tablets were prepared by compressing entecavir in a multi-tip tooling. Tablets were dip-coated in solutions of polymer and dried. In rodents, entecavir-poly(caprolactone) extrudates demonstrated >180â¯days of continuous drug release, although below the estimated efficacious target input rate. Drug pharmacokinetic profiles were tunable by varying the polymer employed and implant format. The rank order trends of drug input rates observed in vitro were observed in vivo in the detected plasma concentrations of entecavir. In all dose groups entecavir was not tolerated locally at the site of administration where adverse event severity correlated with drug input rate. These polymer-based implantable formats have applicability to long-acting formulations of high solubility compounds beyond entecavir.
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Antivirais/química , Antivirais/farmacologia , Guanina/análogos & derivados , Hepatite B/tratamento farmacológico , Animais , Química Farmacêutica/métodos , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Excipientes/química , Feminino , Guanina/química , Guanina/farmacologia , Masculino , Polímeros/química , Ratos , Ratos Wistar , Solubilidade/efeitos dos fármacos , Comprimidos/química , Comprimidos/farmacologiaRESUMO
Since their introduction over 50 years ago, polyurethanes have been applied to nearly every industry. This review describes applications of polyurethanes to the development of modified release drug delivery. Although drug delivery research leveraging polyurethanes has been ongoing for decades, there has been renewed and substantial interest in the field in recent years. The chemistry of polyurethanes and the mechanisms of drug release from sustained release dosage forms are briefly reviewed. Studies to assess the impact of intrinsic drug properties on release from polyurethane-based formulations are considered. The impact of hydrophilic water swelling polyurethanes on drug diffusivity and release rate is discussed. The role of pore formers in modulating drug release rate is examined. Finally, the value of assessing mechanical properties of the dosage form and approaches taken in the literature are described.
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Strawberry pallidosis-associated virus (SPaV) was found closely associated with pallidosis disease. The modes of transmission of the virus were studied, including pollen, seed (achene), and whitefly transmission. Three whitefly species were tested for their ability to transmit SPaV, but only the greenhouse whitefly, Trialeurodes vaporariorum, was identified as a vector of the virus. Testing strawberries for SPaV and Beet pseudo yellows virus (BPYV), a second crinivirus associated with pallidosis disease, in strawberry-producing areas in North America confirmed a high incidence of both viruses in areas where high populations of whiteflies were present. Infection rates as high as 90% for SPaV and 60% for BPYV were observed when plants exhibiting decline symptoms were tested. Lower rates of infection were found in regions where whiteflies were absent or found in low numbers. The role of these criniviruses in the strawberry decline observed over the past few years along the western coast of North America was examined.
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The realization of polymer conjugate-based RNA delivery as a clinical modality requires the development and optimization of novel formulations. Although many literature examples of polymer conjugate-based SiRNA delivery systems exist, the protocols described herein represent a robust and facile way of screening any poly(amine)-based polymer system for SiRNA delivery. In this chapter, we describe the synthetic methods used to prepare poly(amide) polymers using a controlled polymerization method, as well as the preparation of the resulting targeted SiRNA polymer conjugates. In addition, detailed methods are provided for the characterization of the biodegradable poly(peptides) as well as the polymer conjugate that ensues.
Assuntos
Portadores de Fármacos/química , Fígado/metabolismo , Nylons/química , RNA Interferente Pequeno/química , Aminas/química , Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Hepatócitos/metabolismo , Fígado/citologia , Nylons/síntese química , Nylons/metabolismo , Ornitina/química , Fenilalanina/química , Polietilenoglicóis/química , RNA Interferente Pequeno/metabolismo , Succinimidas/química , Sulfetos/químicaRESUMO
Peptides are an important class of endogenous ligands that regulate key biological cascades. As such, peptides represent a promising therapeutic class with the potential to alleviate many severe disease states. Despite their therapeutic potential, peptides frequently pose drug delivery challenges to scientists. This review introduces the physicochemical, biophysical, biopharmaceutical, and formulation developability aspects of peptides pertinent to the drug discovery-to-development interface. It introduces the relevance of these properties with respect to the delivery modalities available for peptide pharmaceuticals, with the parenteral route being the most prevalent route of administration. This review also presents characterization strategies for oral delivery of peptides with the aim of illuminating developability issues with the drug candidate. A brief overview of other routes of administration, including inhaled, transdermal, and intranasal routes, is provided as these routes are generally preferred by patients over injectables. Finally, this review presents formulation techniques to mitigate some of the developability obstacles associated with peptide delivery. The authors emphasize opportunities for the thoughtful application of pharmaceutical science to the development of peptide drugs and to the general advancement of this promising class of pharmaceuticals.
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Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Peptídeos/administração & dosagem , Química Farmacêutica/métodos , Vias de Administração de Medicamentos , Humanos , Preferência do PacienteRESUMO
A series of amphiphilic, biodegradable polypeptide copolymers were prepared for the delivery of siRNA (short interfering ribonucleic acid). The molecular weight (or polymer chain length) of the linear polymer was controlled by reaction stoichiometry for the 11.5, 17.2, and 24.6 kDa polypeptides, and the highest molecular weight polypeptide was prepared using a sequential addition method to obtain a polypeptide having a molecular weight of 38.6 kDa. These polymers were used to prepare polymer conjugate systems designed to target and deliver an apolipoprotein B (ApoB) siRNA to hepatocyte cells and to help delineate the effect of polymer molecular weight or polymer chain length on siRNA delivery in vivo. A clear trend in increasing potency was found with increasing molecular weight of the polymers examined (at a constant polymer:siRNA (w/w) ratio), with minimal toxicity found. Furthermore, the biodegradability of these polymer conjugates was examined and demonstrates the potential of these systems as siRNA delivery vectors.
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Apolipoproteínas B/genética , Ornitina/química , Peptídeos/administração & dosagem , Fenilalanina/química , Polímeros/administração & dosagem , RNA Interferente Pequeno/administração & dosagem , Animais , Feminino , Fígado/metabolismo , Peso Molecular , Peptídeos/química , Polímeros/química , RNA Mensageiro/genética , RNA Interferente Pequeno/química , Ratos Sprague-DawleyRESUMO
The greatest challenge standing in the way of effective in vivo siRNA delivery is creating a delivery vehicle that mediates a high degree of efficacy with a broad therapeutic window. Key structure-activity relationships of a poly(amide) polymer conjugate siRNA delivery platform were explored to discover the optimized polymer parameters that yield the highest activity of mRNA knockdown in the liver. At the same time, the poly(amide) backbone of the polymers allowed for the metabolism and clearance of the polymer from the body very quickly, which was established using radiolabeled polymers to demonstrate the time course of biodistribution and excretion from the body. The fast degradation and clearance of the polymers provided for very low toxicity at efficacious doses, and the therapeutic window of this poly(amide)-based siRNA delivery platform was shown to be much broader than a comparable polymer platform. The results of this work illustrate that the poly(amide) platform has a promising future in the development of a siRNA-based drug approved for human use.