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1.
Biomed Pharmacother ; 133: 111041, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378949

RESUMO

Poly (ADP-ribose) polymerase 1 (PARP1)-dependent cell death in the retinal pigment epithelium (RPE) is implicated in dry age-related macular degeneration (AMD). Although PARP1 inhibitors are available for treating dry AMD, their delivery route is not ideal for patients. The aim of this study was to test the efficacy of a novel PARP1-inhibitory compound (PIC) in vitro and in vivo. This study presents PIC, a novel small molecule, with superior efficacy to PARP1 inhibitors in the market. PIC demonstrated a distinctive inhibitory profile against PARP isotypes than the FDA-approved PARP1 inhibitors. PIC inhibited PARP1 activation at an IC50 of 0.41 ± 0.15 nM in an enzyme-based assay in vitro and at IC50 and EC50 in ARPE-19 cells of 0.11 ± 0.02 nM and 0.22 ± 0.02 nM, respectively, upon H2O2 insult. PIC also moderated mitochondrial fission and depolarization and maintained cellular energy levels under oxidative stress in ARPE-19 cells. Furthermore, PIC demonstrated good corneal penetration in a rat model, presenting PIC as a promising candidate for eye drop therapeutics for dry AMD. When PIC was administered as an eye drop formulation, RPE morphology was preserved, maintaining the thickness of the outer nuclear layers under sodium iodate (SI) treatment in rats. In SI-treated rabbits, eye drop administration of PIC also retained the structural and functional integrity when analyzed using funduscopy and electroretinogram. Collectively, our data portray PIC as an attractive treatment measure for dry AMD.


Assuntos
Degeneração Macular/tratamento farmacológico , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Administração Oftálmica , Animais , Antioxidantes/farmacologia , Linhagem Celular , Modelos Animais de Doenças , Humanos , Iodatos , Degeneração Macular/induzido quimicamente , Degeneração Macular/enzimologia , Degeneração Macular/patologia , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Absorção Ocular , Soluções Oftálmicas , Estresse Oxidativo/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Coelhos , Ratos Sprague-Dawley , Epitélio Pigmentado da Retina/enzimologia , Epitélio Pigmentado da Retina/patologia
2.
Ther Deliv ; 10(11): 737-747, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31718481

RESUMO

Pathologic posterior neovascularization of eye is a major cause of irreversible vision loss and limitations of therapeutics to be successfully delivered to back of the eye has been a main obstacle for its effective treatment. Current pharmacological treatment using anti-VEGF agents being delivered intravitreally are effective but complicated due to anatomical and physiological barriers, as well as administration of high and frequent doses. With expanding horizons of nanotechnology, it can be possible to formulate promising nanoscale delivery system to improve penetration and sustained the release of therapeutic in posterior segment of the eye. Taking into consideration advances in the field of nanoscale delivery systems, this special report focuses on emerging strategies and their applications for treatment of posterior ocular neovascularization.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Portadores de Fármacos/química , Nanopartículas/química , Neovascularização Retiniana/terapia , Adenoviridae/genética , Administração Oftálmica , Inibidores da Angiogênese/farmacocinética , Animais , Cegueira/etiologia , Cegueira/prevenção & controle , Barreira Hematoaquosa/metabolismo , Barreira Hematorretiniana/metabolismo , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Humanos , Terapia a Laser/métodos , Absorção Ocular , Permeabilidade , Fotoquimioterapia , Retina/metabolismo , Neovascularização Retiniana/complicações , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/genética , Baixa Visão/etiologia , Baixa Visão/prevenção & controle , Vitrectomia
3.
J Control Release ; 313: 96-105, 2019 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-31536731

RESUMO

Establishing bioequivalence (BE) of ophthalmic emulsions in the absence of in vivo data is challenging. In these emulsions, drug release is a complex process due to drug distribution among various phases which are difficult to characterize. The objective of this study is to investigate the process of drug distribution and mechanism of drug release in the context of formulation-associated variables. A previously reported kinetic method for determining drug partitioning was used to quantitatively evaluate the drug distribution within a simplified biphasic (emulsion) system employing cyclosporine and difluprednate as model drugs. The impacts of formulation variables, such as the amount of polysorbate 80, glycerin, and carbomer copolymer as well as the area of oil-water interface were investigated. Polysorbate 80 was found to have the greatest influence on the drug distribution. It enhanced both the rate and extent of the drug distribution from oil to aqueous phase. Glycerin was found to slightly reduce the rate and extent of drug distribution of cyclosporine into the aqueous phase, probably by suppressing the solubilization capability of the micelles. Carbomer slowed down the diffusion of drug into the oil phase and shifted the equilibrium drug distribution towards the aqueous phase. Furthermore, increase in the interfacial area significantly increased the rate of drug diffusion across the oil-aqueous interface but had negligible effect on the extent of drug distribution. It is noteworthy that the experimental setup utilized a planar interface rather than an interface with curvature, which may have slightly underestimated the influence of globule size on equilibrium drug distribution. The findings of this study give insight into the drug distribution and diffusion in complex ophthalmic emulsions and assist with formulation design as well as development of in vitro methods to support BE assessment of ophthalmic emulsions.


Assuntos
Ciclosporina/química , Portadores de Fármacos/química , Emulsões/química , Fluprednisolona/análogos & derivados , Soluções Oftálmicas/síntese química , Transporte Biológico , Ciclosporina/administração & dosagem , Difusão , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Olho , Fluprednisolona/administração & dosagem , Fluprednisolona/química , Glicerol/química , Cinética , Micelas , Modelos Biológicos , Absorção Ocular , Soluções Oftálmicas/administração & dosagem , Transição de Fase , Polissorbatos/química , Propriedades de Superfície , Água
4.
Mol Pharm ; 16(9): 3968-3976, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31348666

RESUMO

Lens is the avascular tissue in the eye between the aqueous humor and vitreous. Drug binding to the lens might affect ocular pharmacokinetics, and the binding may also have a pharmacological role in drug-induced cataract and cataract treatment. Drug distribution in the lens has been studied in vitro with many compounds; however, the experimental methods vary, no detailed information on distribution between the lens sublayers exist, and the partition coefficients are reported rarely. Therefore, our objectives were to clarify drug localization in the lens layers and establish partition coefficients for a wide range of molecules. Furthermore, we aimed to illustrate the effect of lenticular drug binding on overall ocular drug pharmacokinetics. We studied the distribution of 16 drugs and three fluorescent dyes in whole porcine lenses in vitro with imaging mass spectrometry and fluorescence microscopy techniques. Furthermore, we determined lens/buffer partition coefficients with the same experimental setup for 28 drugs with mass spectrometry. Finally, the effect of lenticular binding of drugs on aqueous humor drug exposure was explored with pharmacokinetic simulations. After 4 h, the drugs and the dyes distributed only to the outermost lens layers (capsule and cortex). The lens/buffer partition coefficients for the drugs were low, ranging from 0.05 to 0.8. On the basis of the pharmacokinetic simulations, a high lens-aqueous humor partition coefficient increases drug exposure in the lens but does not significantly alter the pharmacokinetics in the aqueous humor. To conclude, the lens seems to act mainly as a physical barrier for drug distribution in the eye, and drug binding to the lens affects mainly the drug pharmacokinetics in the lens.


Assuntos
Corantes Fluorescentes/farmacocinética , Cristalino/efeitos dos fármacos , Absorção Ocular/fisiologia , Preparações Farmacêuticas/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Animais , Humor Aquoso/efeitos dos fármacos , Humor Aquoso/metabolismo , Área Sob a Curva , Tampões (Química) , Corantes Fluorescentes/química , Cristalino/metabolismo , Microscopia de Fluorescência , Peso Molecular , Absorção Ocular/efeitos dos fármacos , Concentração Osmolar , Preparações Farmacêuticas/química , Suínos , Distribuição Tecidual , Corpo Vítreo/efeitos dos fármacos , Corpo Vítreo/metabolismo
5.
Kidney Int ; 96(3): 572-580, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31229276

RESUMO

Vascular endothelial growth factor (VEGF) inhibitors have emerged as powerful tools to treat malignant neoplasms and ocular diseases by virtue of their ability to inhibit angiogenesis. Recent data indicate that intravitreal injections of VEGF inhibitors can lead to significant systemic absorption as well as a measurable reduction of plasma VEGF activity. There is increasing evidence showing that vitreal absorption of these drugs is associated with cases of accelerated hypertension, worsening proteinuria, glomerular disease, thrombotic microangiopathy, and possible chronic renal function decline. In this review, the 3 most commonly used anti-VEGF agents-bevacizumab, ranibizumab, and aflibercept-are discussed, highlighting their intravitreal absorption and associated effects on the kidney as a target organ system. We provide clinical suggestions for clinicians to both better manage patients receiving anti-VEGF agents intravitreally and detect any putative systemic renal effects of these agents. While acknowledging the risks of aberrant retinal angiogenesis, it is important for clinicians to be aware of the potential for adverse renal risks with use of these agents.


Assuntos
Inibidores da Angiogênese/efeitos adversos , Retinopatia Diabética/tratamento farmacológico , Rim/efeitos dos fármacos , Proteinúria/induzido quimicamente , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacocinética , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Bevacizumab/farmacocinética , Humanos , Injeções Intravítreas , Rim/patologia , Absorção Ocular , Proteinúria/patologia , Ranibizumab/administração & dosagem , Ranibizumab/efeitos adversos , Ranibizumab/farmacocinética , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/farmacocinética , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo
6.
AAPS J ; 21(4): 65, 2019 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-31111305

RESUMO

Developing mathematical models to predict changes in ocular bioavailability and pharmacokinetics due to differences in the physicochemical properties of complex topical ophthalmic suspension formulations is important in drug product development and regulatory assessment. Herein, we used published FDA clinical pharmacology review data, in-house, and literature rabbit pharmacokinetic data generated for dexamethasone ophthalmic suspensions to demonstrate how the mechanistic Ocular Compartmental Absorption and Transit model by GastroPlus™ can be used to characterize ocular drug pharmacokinetic performance in rabbits for suspension formulations. This model was used to describe the dose-dependent (0.01 to 0.1%) non-linear pharmacokinetic in ocular tissues and characterize the impact of viscosity (1.67 to 72.9 cP) and particle size (5.5 to 22 µm) on in vivo ocular drug absorption and disposition. Parameter sensitivity analysis (hypothetical suspension particle size: 1 to 10 µm, viscosity: 1 to 100 cP) demonstrated that the interplay between formulation properties and physiological clearance through drainage and tear turnover rates in the pre-corneal compartment drives the ocular drug bioavailability. The quick removal of drug suspended particles from the pre-corneal compartment renders the impact of particle size inconsequential relative to viscosity modification. The in vivo ocular absorption is (1) viscosity non-sensitive when the viscosity is high and the impact of viscosity on the pre-corneal residence time reaches the maximum physiological system capacity or (2) viscosity sensitive when the viscosity is below a certain limit. This study reinforces our understanding of the interplay between physiological factors and ophthalmic formulation physicochemical properties and their impact on in vivo ocular drug PK performance in rabbits.


Assuntos
Simulação por Computador , Dexametasona/farmacocinética , Olho/metabolismo , Modelos Biológicos , Absorção Ocular , Animais , Disponibilidade Biológica , Dexametasona/administração & dosagem , Dexametasona/sangue , Relação Dose-Resposta a Droga , Humanos , Soluções Oftálmicas , Coelhos , Suspensões
7.
J Emerg Med ; 56(5): 519-522, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30879857

RESUMO

BACKGROUND: Coral snake bites from Micrurus fulvius and Micrurus tener account for < 1% of all snake bites in North America. Coral snake envenomation may cause significant neurotoxicity, including respiratory insufficiency, and its onset may be delayed up to 13 h. CASE REPORT: We present a unique patient encounter of M. tener venom exposure through the ocular mucous membranes and a small cutaneous bite, resulting in neurotoxicity. To our knowledge, this is the first reported case of systemic neurotoxicity associated with ocular contact with coral snake venom. Our patient developed rapid-onset skeletal muscle weakness, which is very uncommon for M. tener, along with cranial nerve deficits. Acquisition of antivenom was challenging, but our patient provides a rare report of resolution of suspected M. tener neurotoxicity after receiving Central American coral snake (Micrurus nigrocinctus) antivenom. Our patient subsequently developed serum sickness, a known delayed complication of antivenom. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The emergency physician should be aware that coral snake venom may be absorbed through different routes. Neurotoxicity and respiratory insufficiency may be fatal and onset may be delayed up to 13 h. North American Coral Snake Antivenom is in very limited supply, so non-Food and Drug Administration-approved alternative coral snake antivenoms may be used for patients demonstrating neurotoxicity. Emergency physicians should be proactive in contacting a toxicologist to procure antivenom, as well as consideration of adjunctive treatments, such as neostigmine. Furthermore, whole immunoglobulin G products, such as antivenom, may result in immediate and delayed reactions.


Assuntos
Antivenenos/farmacologia , Cobras Corais , Síndromes Neurotóxicas/tratamento farmacológico , Venenos de Serpentes/efeitos adversos , Animais , Antivenenos/uso terapêutico , Feminino , Humanos , Absorção Ocular , Centros de Controle de Intoxicações/organização & administração , Doença do Soro/etiologia , Mordeduras de Serpentes/tratamento farmacológico , Venenos de Serpentes/farmacologia , Polegar/lesões , Adulto Jovem
8.
Pharm Res ; 36(4): 54, 2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-30790065

RESUMO

In 2009, members of the ophthalmic research community held a joint meeting with members of the Food and Drug Administration (FDA) and the National Eye Institute (NEI) to define and describe the types of patient-focused drug development (PFDD) tools used in ophthalmology. Since then numerous reports have been published which indicate that many of the questionnaires used for patient-reported outcomes (PROs) in ophthalmic clinical development lack rigor and reliability according to modern methods. In 2017, the FDA began development of a series of four methodological guidances for sponsors of clinical trials on the significance of PFDD. The new guidances delineate the FDA's thinking and commitments under the Prescription Drug User Fee Act to implement a more structured approach to the assessment of risks and benefits in clinical trials. In these guidances, the FDA provides steps that drug and device manufacturers should follow, not only to obtain, but also to develop reliable and validated tools that measure patients' experience in clinical trials. Subsequent efforts have resulted in the development and validation of PROs specifically for ophthalmology. The purpose of this paper is to assesses the PROs currently used in ophthalmology and to provide practical strategies for incorporating them into clinical trials.


Assuntos
Ensaios Clínicos como Assunto/legislação & jurisprudência , Aprovação de Drogas/legislação & jurisprudência , Desenvolvimento de Medicamentos/legislação & jurisprudência , Descoberta de Drogas/legislação & jurisprudência , Oftalmopatias/tratamento farmacológico , Olho/efeitos dos fármacos , Regulamentação Governamental , Medidas de Resultados Relatados pelo Paciente , United States Food and Drug Administration/legislação & jurisprudência , Administração Oftálmica , Ensaios Clínicos como Assunto/métodos , Aprovação de Drogas/métodos , Composição de Medicamentos , Desenvolvimento de Medicamentos/métodos , Descoberta de Drogas/métodos , Determinação de Ponto Final , Olho/metabolismo , Olho/patologia , Olho/fisiopatologia , Oftalmopatias/metabolismo , Oftalmopatias/patologia , Oftalmopatias/fisiopatologia , Humanos , Absorção Ocular , Soluções Oftálmicas , Segurança do Paciente , Psicometria , Medição de Risco , Resultado do Tratamento , Estados Unidos
9.
J Pharm Biomed Anal ; 164: 337-344, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30415142

RESUMO

Sirolimus is regarded as one of the most effective immunosuppressants receiving extensive attention over the years, for which the ocular application needs further development in clinical keratoplasty. In order to study the transcorneal absorption effect of ophthalmic administration, there was a need to study the pharmacokinetics of drugs in aqueous humor. In this work, a validated and reliable HPLC-ESI-MS/MS method was established to study the pharmacokinetics of sirolimus nanoformulations in rabbit aqueous humor. The analysis conditions were as follows. Ascomycin was chosen as internal standard. After a simple precipitation extraction procedure, the aqueous humor samples were separated on a XBridge C18 column (4.6 mm × 150 mm, 3.5 µm, Waters Co., USA) with a mobile phase comprised of water (0.1% formic acid and 5 mM ammonium formate) and methanol (0.1% formic acid) at the ratio of 10:90 (v/v). The mass analysis was achieved by positive ionization with multiple reaction monitoring (MRM) mode. The highest response ion pairs m/z at 931.5→864.5 were chosen for sirolimus. The validated results showed that the calibration range was 0.3-100.6 ng/mL with r = 0.9997 (n = 6). The R.S.D. values of the intra- and inter-day precision were less than 11% and the average accuracy values were between 94.73%-100.20%. Besides, for reducing the consumption of rabbits and the variation of the data, we designed a consecutive sampling method in pharmacokinetic study, with only seven rabbits consumed for each formulation. In conclusion, the developed analysis method was more reliable and practical than previously reported experiments. Meanwhile, the validated method was successfully applied to study the pharmacokinetics of sirolimus micelle and sirolimus nanosuspension after ophthalmic administration.


Assuntos
Humor Aquoso/metabolismo , Imunossupressores/farmacocinética , Sirolimo/farmacocinética , Espectrometria de Massas em Tandem/métodos , Administração Oftálmica , Animais , Calibragem , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Imunossupressores/administração & dosagem , Micelas , Modelos Animais , Nanopartículas , Absorção Ocular , Coelhos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Sirolimo/administração & dosagem , Sirolimo/análise , Espectrometria de Massas por Ionização por Electrospray/instrumentação , Espectrometria de Massas por Ionização por Electrospray/métodos , Suspensões , Tacrolimo/administração & dosagem , Tacrolimo/análogos & derivados , Tacrolimo/análise , Tacrolimo/farmacocinética , Espectrometria de Massas em Tandem/instrumentação
10.
Int J Pharm ; 553(1-2): 386-397, 2018 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-30393167

RESUMO

Sertaconazole nitrate (STZ) is a poorly soluble antifungal drug commonly used for treating fungal skin infections. Introducing it as a new treatment option for the management of fungal keratitis, requires the development of a delivery system capable of targeting the infected cornea with an adequate STZ concentration. Hence, Sertaconazole nitrate loaded cubosomes (STZ-CUBs) were prepared, characterized and optimized based on a 33 central composite face-centred design. Optimized formulation (CUB-opt) showed maximum desirability (0.905), with solubilization efficiency (SE%) of 94.50 ±â€¯0.51%, particle size (PS) of 216.55 ±â€¯2.33 nm, polydispersity index (PDI) of 0.229 ±â€¯0.11 and zeta potential (ZP) of 34.00 ±â€¯6.93 mV. Under the transmission electron microscope, it showed discrete cubic shaped structures. Moreover, it exhibited a promising mucoadhesive behavior, terminal sterilization stability, and storage stability. Ex vivo corneal permeation study revealed its ability to enhance the steady state flux (Jss) and the permeability coefficient (KP) of STZ, compared to STZ-suspension. Finally, CUB-opt formulation was found to be safe on the corneal tissues in the in vivo corneal tolerance study, and demonstrated a superior corneal penetration power in the in vivo corneal uptake study.


Assuntos
Antifúngicos/administração & dosagem , Córnea/metabolismo , Imidazóis/administração & dosagem , Nanopartículas , Tiofenos/administração & dosagem , Adesividade , Administração Oftálmica , Animais , Antifúngicos/química , Antifúngicos/farmacocinética , Química Farmacêutica , Estabilidade de Medicamentos , Substituição de Medicamentos , Imidazóis/química , Imidazóis/farmacocinética , Masculino , Absorção Ocular , Tamanho da Partícula , Permeabilidade , Coelhos , Solubilidade , Tiofenos/química , Tiofenos/farmacocinética
11.
Int J Mol Sci ; 19(9)2018 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-30235809

RESUMO

Ocular drug delivery has been a major challenge for clinical pharmacologists and biomaterial scientists due to intricate and unique anatomical and physiological barriers in the eye. The critical requirement varies from anterior and posterior ocular segments from a drug delivery perspective. Recently, many new drugs with special formulations have been introduced for targeted delivery with modified methods and routes of drug administration to improve drug delivery efficacy. Current developments in nanoformulations of drug carrier systems have become a promising attribute to enhance drug retention/permeation and prolong drug release in ocular tissue. Biodegradable polymers have been explored as the base polymers to prepare nanocarriers for encasing existing drugs to enhance the therapeutic effect with better tissue adherence, prolonged drug action, improved bioavailability, decreased toxicity, and targeted delivery in eye. In this review, we summarized recent studies on sustained ocular drug/gene delivery and emphasized on the nanocarriers made by biodegradable polymers such as liposome, poly lactic-co-glycolic acid (PLGA), chitosan, and gelatin. Moreover, we discussed the bio-distribution of these nanocarriers in the ocular tissue and their therapeutic applications in various ocular diseases.


Assuntos
Administração Oftálmica , Portadores de Fármacos/química , Nanopartículas/química , Absorção Ocular , Animais , Plásticos Biodegradáveis/química , Plásticos Biodegradáveis/farmacocinética , Portadores de Fármacos/farmacocinética , Humanos , Injeções Intraoculares/métodos , Nanopartículas/metabolismo
12.
J Pharm Sci ; 107(12): 3089-3097, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30170009

RESUMO

Nepafenac is a water-insoluble nonsteroidal antiinflammatory drug that is available as an ophthalmic suspension (Nevanac®). Suspensions are undesirable for 2 reasons: they tend to cause foreign body sensation and lacrimation, which could limit residence time and drug bioavailability. This decreases the amount of time the drug has to reach the site of action, the cornea. Previously, we improved the solubility and ocular permeability of nepafenac by complexing the drug with hydroxypropyl-ß-cyclodextrin. In this study, we used the complex to formulate an ion-activated in situ gel system using sodium alginate, Protanal PH 1033, to increase the residence time and to reduce repeat eye drop instillation. Rheological properties of the formulations revealed that the viscosity of the optimized formulation was increased 30-fold when exposed to the simulated tear fluid (35°C). Permeation studies showed that the drug concentration of the in situ formulations were approximately 10 times higher than the commercial product, Nevanac® (p < 0.001). In addition, the in situ gel formulations had 5-fold higher concentrations of nepafenac retained in the cornea when compared to Nevanac® (p <0.001). Finally, ex vivo drug distribution studies in the porcine eye perfusion model revealed a higher drug retention in various ocular tissues such as cornea, sclera, retina, as compared to Nevanac®.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacocinética , Benzenoacetamidas/administração & dosagem , Benzenoacetamidas/farmacocinética , Portadores de Fármacos/química , Olho/metabolismo , Géis/química , Fenilacetatos/administração & dosagem , Fenilacetatos/farmacocinética , 2-Hidroxipropil-beta-Ciclodextrina/química , Administração Oftálmica , Alginatos/química , Animais , Anti-Inflamatórios não Esteroides/química , Benzenoacetamidas/química , Disponibilidade Biológica , Córnea/metabolismo , Absorção Ocular , Permeabilidade , Fenilacetatos/química , Solubilidade , Suínos , Viscosidade
13.
Int J Pharm ; 549(1-2): 249-260, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30077759

RESUMO

Development of efficient ocular drug delivery system for antifungal drugs becomes a must nowadays to face and eradicate the widely spread ophthalmic fungal infections. Itraconazole, a triazole antifungal, is struggling to penetrate the cornea and subsequently, its efficacy is limited. The aim of this study was to enhance itraconazole corneal penetration through utilizing the minimum surfactant amount in presence of ß-cyclodextrin which acted as a dissolution and permeation enhancer. ß-Cyclodextrin consolidated micellar dispersions (CCMD) were prepared after an initial screening to select the composition of surfactant(s). The preparation was done according to a modified melt dispersion technique. The prepared CCMD were characterized through the analysis of their particle size, zeta potential and solubilization efficiency. The optimum formula was chosen based on a factorial response surface analysis and it was composed of 17:1 w/w surfactant/drug, 30:1 w/w cyclodextrin/drug ratios and 0.02% polyethylene oxide. This formula was subjected to in vitro characterization including release, imaging by transmission electron microscope, mucoadhesion, stability, in addition to the determination of the minimum inhibitory concentration. Moreover, the ex vivo/in vivo permeation, safety and efficacy profiles were determined. The optimized CCMD formula was found to be significantly safe, stable, mucoadhesive and efficient to permeate the drug through rabbits' corneas. Consequently, the optimized CCMD formulation can be a promising, safe and efficient platform for the transcorneal delivery of lipophilic drugs including most antifungals.


Assuntos
Antifúngicos/administração & dosagem , Aspergilose/tratamento farmacológico , Córnea/efeitos dos fármacos , Excipientes/química , Infecções Oculares Fúngicas/tratamento farmacológico , Itraconazol/administração & dosagem , Ceratite/tratamento farmacológico , Absorção Ocular , beta-Ciclodextrinas/química , Adesividade , Administração Oftálmica , Animais , Antifúngicos/química , Antifúngicos/metabolismo , Aspergilose/metabolismo , Aspergilose/microbiologia , Aspergillus niger/efeitos dos fármacos , Aspergillus niger/crescimento & desenvolvimento , Córnea/metabolismo , Córnea/microbiologia , Modelos Animais de Doenças , Composição de Medicamentos , Liberação Controlada de Fármacos , Infecções Oculares Fúngicas/metabolismo , Infecções Oculares Fúngicas/microbiologia , Itraconazol/química , Itraconazol/metabolismo , Ceratite/metabolismo , Ceratite/microbiologia , Masculino , Micelas , Tamanho da Partícula , Permeabilidade , Coelhos , Solubilidade , Tecnologia Farmacêutica/métodos
14.
Libyan J Med ; 13(1): 1500347, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30045674

RESUMO

The purpose of this study is to prepare and characterize solid lipid nanoparticles (SLN) of N-Acetyl Carnosine (NAC) to treat cataract since surgery necessitates equipments and professional help. Cataract is believed to be formed by the biochemical approach where the crystalline eye proteins lose solubility and forms high molecular weight masses. Added advantages of SLN of NAC (henceforth referred as SLN-NAC) in the study are reduced size, sustained release and better corneal penetration of drug. The method of preparation of SLN-NAC by Mill's method is unique in itself. The size of the SLN-NAC was 75 ± 10 nm in the range of ideal for penetration. The in-vitro release study and the SLN-NAC formulations prepared with Mill's method demonstrated sustained release up to 24 h following an initial burst after 1 h. The zeta potential of the prepared formulation was -22.1 ± 1 mV. Corneal permeation studies using goat corneas indicate that SLN-NAC penetration rate was higher than those from NAC eye drops. Corneal hydration studies indicated that the formulation caused no harm to the corneal cells. Therefore it may be concluded that SLN-NAC may revolutionize cataract treatment and reversal by improving drug permeation, reducing toxicity and no damage to corneal tissue.


Assuntos
Carnosina/análogos & derivados , Catarata/tratamento farmacológico , Córnea/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/administração & dosagem , Administração Oftálmica , Animais , Carnosina/administração & dosagem , Técnicas de Cultura de Células , Linhagem Celular , Córnea/citologia , Preparações de Ação Retardada , Células Endoteliais/efeitos dos fármacos , Cabras , Humanos , Absorção Ocular , Tamanho da Partícula
15.
Toxicol Lett ; 292: 73-77, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29709424

RESUMO

TMAB001 is a humanized rabbit monoclonal antibody (mAb) designed to bind and neutralize human vascular endothelial growth factor (VEGF)-165. The purpose of the study was to investigate the pharmacokinetics (PK) and ocular tissue distribution after a single intravitreal (IVT) dose in rabbits and monkeys. Rabbits (2.5 mg/eye; n = 40) and monkeys (2.5 mg/eye; n = 12) received TMAB001 as a bilateral IVT dose. TMAB001 concentrations were measured in ocular tissues in all rabbits and monkeys by enzyme-linked immunosorbent assay (ELISA). TMAB001 and VEGF concentrations were measured in serum of monkeys by ELISA. Following a single bilateral IVT injection of TMAB001 2.5 mg/eye, the highest concentration was in vitreous humor, followed by retina and choroid, and the lowest concentration was in lens. In rabbits, TMAB001 was still detectable in ocular tissues at day 21 after single IVT dose, with the highest level in the vitreous humor and then retina, with longest t1/2 in aqueous humor and shortest t1/2 in choroid. In monkeys, tmax in serum was 43 h and t1/2 was approximately 5.5 days. Cmax in serum was much lower than that in vitreous, nearly 1/200. After IVT injection of TMAB001, total VEGF concentrations in serum and ocular tissues increased over time. VEGF concentration in retina and choroid increased over time, up to 336 h after administration. This study demonstrated that TMAB001 could reach the drug target sites-retina and choroid after a single bilateral IVT administration in rabbits and monkeys, with a long t1/2 in vitreous humor. TMAB001 also showed strong capability to neutralize VEGF. The study further confirmed that full-length antibodies can also efficiently diffuse and distribute in ocular tissues.


Assuntos
Inibidores da Angiogênese/farmacocinética , Anticorpos Monoclonais Humanizados/farmacocinética , Olho/metabolismo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/administração & dosagem , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Área Sob a Curva , Feminino , Meia-Vida , Injeções Intravítreas , Macaca mulatta , Masculino , Taxa de Depuração Metabólica , Absorção Ocular , Coelhos , Distribuição Tecidual , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/imunologia
16.
Eur J Pharm Sci ; 120: 133-141, 2018 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-29702232

RESUMO

The objective of this study was to systematically investigate the effects of surface active ophthalmic excipients on the corneal permeation of ophthalmic drugs using in vitro (HCE-T cell-based model) and ex vivo (freshly excised porcine cornea) models. The permeation of four ophthalmic drugs (i.e., timolol maleate, chloramphenicol, diclofenac sodium and dexamethasone) across in vitro and ex vivo corneal models was evaluated in the absence and presence of four commonly used surface active ophthalmic excipients (i.e., Polysorbate 80, Tyloxapol, Cremophor® EL and Pluronic® F68). The concentration and self-aggregation-dependent effects of surface active ophthalmic excipients on ophthalmic drug permeability were studied from the concentration region where only dissolved monomer molecules of surface active ophthalmic excipients exist, as well as the concentration region in which aggregates of variable size and dispersion are spontaneously formed. Neither the surface active ophthalmic excipients nor the ophthalmic drugs at all concentrations that were tested significantly affected the barrier properties of both corneal models, as assessed by transepithelial electrical resistance (TEER) monitoring during the permeability experiments. The lowest concentration of all investigated surface active ophthalmic excipients did not significantly affect the ophthalmic drug permeability across both of the corneal models that were used. For three ophthalmic drugs (i.e., chloramphenicol, diclofenac sodium and dexamethasone), depressed in vitro and ex vivo permeability were observed in the concentration range of either Polysorbate 80, Tyloxapol, Cremophor® EL or Pluronic® F68, at which self-aggregation is detected. The effect was the most pronounced for Cremophor® EL (1 and 2%, w/V) and was the least pronounced for Pluronic® F68 (1%, w/V). However, all surface active ophthalmic excipients over the entire concentration range that was tested did not significantly affect the in vitro and ex vivo permeability of timolol maleate, which is the most hydrophilic ophthalmic drug that was investigated. The results of the dynamic light scattering measurements point to the association of ophthalmic drugs with self-aggregates of surface active ophthalmic excipients as the potential mechanism of the observed permeability-depressing effect of surface active ophthalmic excipients. A strong and statistically significant correlation was observed between in vitro and ex vivo permeability of ophthalmic drugs in the presence of surface active ophthalmic excipients, which indicates that the observed permeability-altering effects of surface active ophthalmic excipients were comparable and were mediated by the same mechanism in both corneal models.


Assuntos
Epitélio Anterior/efeitos dos fármacos , Excipientes/administração & dosagem , Absorção Ocular/efeitos dos fármacos , Preparações Farmacêuticas/administração & dosagem , Tensoativos/administração & dosagem , Administração Oftálmica , Animais , Biofarmácia/métodos , Linhagem Celular , Cloranfenicol/administração & dosagem , Cloranfenicol/metabolismo , Dexametasona/administração & dosagem , Dexametasona/metabolismo , Diclofenaco/administração & dosagem , Diclofenaco/metabolismo , Composição de Medicamentos , Difusão Dinâmica da Luz , Impedância Elétrica , Epitélio Anterior/metabolismo , Excipientes/química , Feminino , Glicerol/administração & dosagem , Glicerol/análogos & derivados , Humanos , Masculino , Soluções Oftálmicas , Permeabilidade , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Poloxâmero/administração & dosagem , Polietilenoglicóis/administração & dosagem , Polissorbatos/administração & dosagem , Tensoativos/química , Sus scrofa , Tecnologia Farmacêutica/métodos , Fatores de Tempo , Timolol/administração & dosagem , Timolol/metabolismo
17.
AAPS PharmSciTech ; 19(4): 1647-1651, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29500761

RESUMO

Generic drug products are expected to have the same active pharmaceutical ingredient (API) (Q1) with the same content (Q2) and microstructure arrangement (Q3) as the innovator product. In complex oil-in-water emulsion drugs, the hydrophobic API is mainly formulated in oil droplets stabilized by surfactant and micelles composed of extra surfactant molecules. The API phase partition in oil and water (mainly micelle) is a critical quality attribute (CQA) of emulsion product in demonstrating physicochemical equivalence using difluprednate (DFPN) emulsion product Durezol® as a model, we developed a novel low-field benchtop NMR method to demonstrate its applicability in measuring DFPN phase partition for ophthalmic oil-in-water emulsion products. Low-field 19F spectra were collected for DFPN in formulation, in water phase and oil phase after separation from ultra-centrifugation. The NMR data showed the mass balance of DFPN before and after phase separation. The average water phase content of different Durezol® lots was 32 ± 3% with 1% variation from method reproducibility test. The partition results were 52 ± 2% for the in-house control products prepared in Q1/Q2 equivalence to Durezol® but by a different process. The significant difference in DFPN-phase partition between Durezol® and the in-house formulation demonstrated manufacture difference readily changed the API partition. The newly developed ultra-centrifugation and 19F NMR by benchtop instrument is a simple, robust, and sensitive analytical method for ophthalmic emulsion drug product development and control.


Assuntos
Imagem por Ressonância Magnética de Flúor-19/métodos , Fluprednisolona/análogos & derivados , Espectroscopia de Ressonância Magnética/métodos , Absorção Ocular , Ultracentrifugação/métodos , Água/análise , Emulsões , Fluprednisolona/análise , Fluprednisolona/química , Micelas , Tamanho da Partícula , Reprodutibilidade dos Testes , Tensoativos/análise , Tensoativos/química , Água/química
18.
Exp Eye Res ; 167: 118-121, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29246497

RESUMO

Peptide delivery to and through ocular sites is a growing field of research interest. However, several barriers restrict the permeation and bioavailability of these molecules to target tissues. The main pharmacological barriers of topical administration are the tear film, rapid drainage of the tear film, and poor corneal permeation. If the administered molecule is a peptide, instability and enzymatic degradation can be significant. Novel approaches such as the design and development of nanocarriers to overcome these drawbacks have been investigated with promising results. Therefore, in continuation of our previous study using a liposome-based (LP) formulation as topical drug delivery system, the aim of this work was to efficiently encapsulate a thrombospondin-1-derived peptide, KRFK, in this formulation and to assess peptide permeability through different ocular surface epithelia. LPs were prepared by the solvent evaporation technique and the labeled peptide FITC-KRFK was incorporated in the aqueous core. Different sonication times were used to optimize encapsulation efficiency. The selected formulation was further analyzed in terms of size, pH, osmolarity, and corneal epithelial cytotoxicity. The permeabilities of the LP-encapsulated and free labeled KRFK peptides were assessed with in vitro models of conjunctival and corneal epithelia. Our results provide a proof of concept that the LP formulation efficiently encapsulates the KRFK peptide and improves corneal permeation. Data reported in this study strongly support that this formulation could be a more effective therapeutic approach than free peptide instillation and warrant further analysis using experimental in vivo models.


Assuntos
Túnica Conjuntiva/metabolismo , Portadores de Fármacos , Epitélio Anterior/metabolismo , Lipossomos/química , Oligopeptídeos/administração & dosagem , Trombospondina 1/administração & dosagem , Administração Tópica , Animais , Disponibilidade Biológica , Linhagem Celular , Absorção Ocular , Oligopeptídeos/farmacocinética , Suínos
19.
Int J Pharm ; 529(1-2): 347-356, 2017 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-28673859

RESUMO

Inhibition of gene expression by nucleic acids is a promising strategy in the treatment of ocular diseases. However, intraocular delivery of nucleic acids to the posterior ocular tissues remains a great challenge due to the presence of various biological barriers. To circumvent this problem, we established a novel penetratin (P) modified poly(amidoamine) dendrimer (D)/hyaluronic acid (H) complex to deliver antisense oligonucleotides (ASOs, O). Complexes (D/O, HD/O and PHD/O) were easily prepared and modification layers (hyaluronic acid and penetratin) were respectively absorbed on the surface via electrostatic interaction. Complexes with different outer layers were characterized as spherical particles with reversed charges. In vitro cellular uptake of ASOs in PHD/O complex was significantly increased than those in other formulations. In vivo studies were carried out after topical instillation of the complexes in the conjunctival sac of mice. Compared with D/O and HD/O, PHD/O exhibited much more distribution in the posterior segment of the eyes and prolonged retention time of ASOs in retina for more than 8h. Taken together, these results indicated that PHD/O complex possessed substantially improved ocular permeability and distribution in the posterior ocular tissues. This work provided a promising noninvasive intraocular delivery strategy for nucleic acids via topical administration.


Assuntos
Proteínas de Transporte/química , Portadores de Fármacos/química , Oligonucleotídeos Antissenso/administração & dosagem , Administração Tópica , Animais , Linhagem Celular , Peptídeos Penetradores de Células , Dendrímeros/química , Humanos , Ácido Hialurônico/química , Camundongos , Camundongos Endogâmicos ICR , Absorção Ocular , Oligonucleotídeos
20.
Eur J Pharm Biopharm ; 119: 170-184, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28625688

RESUMO

Advances in nanotechnology have enabled solutions for challenging drug delivery targets. While the eye presents numerous emerging opportunities for delivery, analysis and sensing; issues persist for conventional applications. This includes liquid phase formulation localisation on the ocular surface once administered as formulated eye-drops; with the vast majority of dosage (>90%) escaping from the administered site due to tear production and various drainage mechanisms. The work presented here demonstrates a single needle electrohydrodynamic (EHD) engineering process to nano-coat (as an on demand and controllable fiber depositing method) the surface of multiple contact lenses rendering formulations to be stationary on the lens and at the bio-interface. The coating process was operational based on ejected droplet charge and glaucoma drug timolol maleate (TM) was used to demonstrate surface coating optimisation, bio-surface permeation properties (flux, using a bovine model) and various kinetic models thereafter. Polymers PVP, PNIPAM and PVP:PNIPAM (50:50%w/w) were used to encapsulate the active. Nano-fibrous and particulate samples were characterised using SEM, FTIR, DSC and TGA to confirm structural and thermal stability of surface coated formulations. More than 52% of nano-structured coatings (for all formulations) were <200nm in diameter. In vitro studies show coatings to exhibit biphasic release profiles; an initial burst release followed by sustained release; with TM-loaded PNIPAM coating releasing most drug after 24h (89.8%). Kinetic modelling (Higuchi, Korsmeyer-Peppas) was indicative of quasi-Fickian diffusion whilst biological evaluation demonstrates adequate ocular tolerability. Results from permeation studies indicate coated lenses are ideal to reduce dosing regimen, which in turn will reduce systemic drug absorption. Florescent microscopy demonstrated probe and probe embedded coating behaviour from lens surface in vitro. The multiple lens surface coating method demonstrates sustained drug release yielding promising results; suggesting both novel device and method to enhance drug activity at the eyes surface which will reduce formulation drainage.


Assuntos
Lentes de Contato , Córnea/efeitos dos fármacos , Córnea/metabolismo , Nebulizadores e Vaporizadores , Absorção Ocular/efeitos dos fármacos , Timolol/metabolismo , Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas Adrenérgicos beta/química , Antagonistas Adrenérgicos beta/metabolismo , Animais , Bovinos , Composição de Medicamentos , Absorção Ocular/fisiologia , Timolol/administração & dosagem , Timolol/química
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