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1.
J Control Release ; 349: 1045-1051, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35868358

RESUMO

Drug delivery to the suprachoroidal space (SCS®) has become a clinical reality after the 2021 FDA approval of CLS-TA, a triamcinolone acetonide injectable suspension for suprachoroidal use (XIPERE®), administered via a microneedle-based device, the SCS Microinjector®. Suprachoroidal (SC) delivery facilitates targeting, compartmentalization, and durability of small molecule suspensions, thereby potentially addressing some of the efficacy, safety, and treatment burden limitations of current retinal therapies. Herein, the design features of the SCS Microinjector are reviewed, along with the biomechanics of SC drug delivery. Also presented are preclinical evaluations of SC small molecule suspensions from 4 different therapeutic classes (plasma kallikrein inhibitor, receptor tyrosine kinase inhibitor, corticosteroid, complement factor D inhibitor), highlighting their potential for durability, targeted compartmentalization, and acceptable safety profiles following microinjector-based SC delivery. The clinical evaluations of the safety, tolerability and efficacy of SC delivered triamcinolone further supports potential of SC small molecule suspensions as a clinically viable strategy for the treatment of chorioretinal diseases. Also highlighted are current limitations, key pharmacological considerations, and future opportunities to optimize the SC microinjector platform for safe, effective, and potentially long-acting drug delivery for the treatment of chorioretinal disorders.


Assuntos
Corioide , Triancinolona Acetonida , Fator D do Complemento/farmacologia , Calicreína Plasmática/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Suspensões
2.
J Ocul Pharmacol Ther ; 38(6): 459-467, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35404132

RESUMO

Purpose: To compare ocular pharmacokinetics (PK), systemic absorption, and injectability of triamcinolone acetonide (TA) suprachoroidal (SC) and intravitreal (IVT) suspensions. Methods: New Zealand White (NZW) rabbits received a bilateral injection of 4 mg TA injectable suspension, TRI (TRIESENCE ®; Alcon) through either microneedle-based SC or standard IVT injection. Another group of NZW rabbits received a bilateral SC injection (4 mg) of either TRI or a proprietary TA suspension for SC use, CLS-TA (Clearside Biomedical). Blood and ocular tissues were analyzed for TA over 3 months. Separately, injectability of TRI and CLS-TA through a proprietary SC delivery system (SCS Microinjector®; Clearside Biomedical) was compared using microinjector syringe-plunger glide force measurement. Results: Suprachoroidal delivery of TRI, compared with IVT-TRI, resulted in ∼12-fold higher exposure in the retinal pigment epithelium-choroid-sclera, and comparable exposure in the retina. Conversely, SC-TRI, compared to IVT-TRI, resulted in 460-, 34-, and 22-fold lower exposure in the lens, iris-ciliary body, and vitreous humor, and negligible exposure in the aqueous humor. SC injection of either CLS-TA or TRI resulted in comparable and sustained ocular TA levels. Plasma TA levels were generally undetectable in both studies. A significantly greater and more variable glide force was measured for TRI vs. CLS-TA. Conclusions: Suprachoroidal delivery of TA enabled high and durable TA levels targeted to the chorioretina with limited anterior segment exposure. SC delivery of either CLS-TA or TRI resulted in comparable ocular PK profiles with low systemic exposure; however, CLS-TA required lower and less variable glide force than TRI, potentiating more consistent, controlled administration.


Assuntos
Glucocorticoides , Triancinolona Acetonida , Animais , Corioide , Coelhos , Retina , Suspensões
3.
Transl Vis Sci Technol ; 10(7): 19, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34128964

RESUMO

Purpose: Axitinib, a tyrosine kinase inhibitor, is a potent inhibitor of vascular endothelial growth factor (VEGF) receptors -1, -2 and -3. Suprachoroidal (SC) delivery of axitinib, combined with pan-VEGF inhibition activity of axitinib, has the potential to provide additional benefits compared to the current standard of care with intravitreal anti-VEGF-A agents. This study evaluated the ocular pharmacokinetics and systemic disposition of axitinib after SC administration in rabbits. Methods: Rabbits received axitinib as either a single SC injection (0.03, 0.10, 1.00, or 4.00 mg/eye; n = 4/group) or a single intravitreal injection (1 mg/eye; n = 4/group) in three separate studies. Axitinib concentrations were measured in several ocular compartments and in plasma at predetermined timepoints for up to 91 days. The pharmacokinetics parameters were estimated by noncompartmental analysis. Results: A single SC injection of axitinib suspension (1 mg/eye) resulted in an 11-fold higher mean axitinib exposure in the posterior eye cup, compared with intravitreal injection. Sustained levels of axitinib in the retinal pigment epithelium-choroid-sclera (RCS) and retina were observed throughout the duration of studies after a single SC axitinib injection (0.1 and 4.0 mg/eye), with low exposure in the vitreous humor, aqueous humor, and plasma. Axitinib levels in the RCS were 3 to 5 log orders higher than the reported in vitro (VEGF receptor-2 autophosphorylation inhibition) 50% inhibitory concentration value after 0.1 and 4.0 mg/eye dose levels throughout the 65-day and 91-day studies, respectively. Conclusions: This study demonstrates that SC axitinib suspension has a favorable pharmacokinetics profile with potential as a long-acting therapeutic candidate targeted to affected choroid and retinal pigment epithelium in neovascular age-related macular degeneration. Translational Relevance: Suprachoroidal axitinib suspension has potential to decrease the treatment burden in neovascular age-related macular degeneration, as a long-acting therapeutic candidate, and could yield greater efficacy, as a potent tyrosine kinase pan-VEGF inhibitor, compared with current standard anti-VEGF-A therapies.


Assuntos
Corioide , Fator A de Crescimento do Endotélio Vascular , Animais , Axitinibe , Injeções Intravítreas , Coelhos , Retina
4.
Pharmaceutics ; 13(2)2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33671815

RESUMO

Suprachoroidal drug delivery technology has advanced rapidly and emerged as a promising administration route for a variety of therapeutic candidates, in order to target multiple ocular diseases, ranging from neovascular age-related macular degeneration to choroidal melanoma. This review summarizes the latest preclinical and clinical progress in suprachoroidal delivery of therapeutic agents, including small molecule suspensions, polymeric entrapped small molecules, gene therapy (viral and nonviral nanoparticles), viral nanoparticle conjugates (VNCs), and cell therapy. Formulation customization is critical in achieving favorable pharmacokinetics, and sustained drug release profiles have been repeatedly observed for multiple small molecule suspensions and polymeric formulations. Novel therapeutic agents such as viral and nonviral gene therapy, as well as VNCs, have demonstrated promise in animal studies. Several of these suprachoroidally-administered therapies have been assessed in clinical trials, including small molecule suspensions of triamcinolone acetonide and axitinib, viral vector RGX-314 for gene therapy, and VNC AU-011. With continued drug delivery research and optimization, coupled with customized drug formulations, suprachoroidal drug delivery may address large unmet therapeutic needs in ophthalmology, targeting affected tissues with novel therapies for efficacy benefits, compartmentalizing therapies away from unaffected tissues for safety benefits, and achieving durability to relieve the treatment burden noted with current agents.

5.
Transl Vis Sci Technol ; 9(13): 21, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33364076

RESUMO

Purpose: This study evaluated ocular tolerability and transfectability of nonviral DNA nanoparticles (DNPs) after microneedle-based suprachoroidal (SC) administration, in comparison to subretinal (SR) administration. Methods: The DNPs consisted of a single copy of plasmid DNA with a polyubiquitin C/luciferase transcriptional cassette compacted with 10 kDa PEG-substituted lysine 30-mer peptides (CK30PEG10k). New Zealand White rabbits (n = 4 per group) received a unilateral SC injection (0.1 mL via a microneedle technique) of ellipsoid-shaped DNPs, rod-shaped DNPs, or saline (negative control). A cohort of rabbits (n = 4) also received a single unilateral SR injection (0.05 mL via a transvitreal approach) of rod-shaped DNPs. At day 7, luciferase activity was measured in the retina and retinal pigment epithelium (RPE)-choroid via bioluminescence assay. A cohort of rabbits received a SC injection of analogous DNPs to assess spread of DNP injectate in the suprachoroidal space (SCS) via optical coherent tomography and histology. Results: Suprachoroidal injection of DNPs resulted in reversible opening of the SCS circumferentially and posteriorly and was generally well tolerated, with no significant ocular examination score changes, intraocular pressure abnormalities, or changes in electroretinography amplitudes on day 7 compared to the baseline. High luciferase activity was observed in the retina and RPE-choroid of eyes that received SC DNPs (rod and ellipsoid shape) and SR DNPs (rod shape) compared to controls. The mean luciferase activity in RPE-choroid and retina was comparable between SC and SR administrations. Transfection in the RPE-choroid was approximately 10-fold higher than in the retina after either SC or SR administration of DNPs. Conclusions: Suprachoroidal and SR administration of DNPs resulted in comparable transfection of retina and RPE-choroid. Translational Relevance: Suprachoroidal delivery of DNPs offers the potential to precisely target chorioretinal tissues while avoiding surgical risks associated with SR injection, and it may offer an office-based nonsurgical gene therapy option for the treatment of retinal diseases.


Assuntos
Nanopartículas , Epitélio Pigmentado da Retina , Animais , Corioide , DNA , Coelhos , Retina
6.
Expert Opin Investig Drugs ; 29(9): 935-945, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32657172

RESUMO

INTRODUCTION: Integrins are a family of multi-functional cell-adhesion molecules, heterodimeric receptors that connect extracellular matrix (ECM) to actin cytoskeleton in the cell cortex, thus regulating cellular adhesion, migration, proliferation, invasion, survival, and apoptosis. Consequently, integrins play a role in inflammation, angiogenesis and fibrosis. AREAS COVERED: This review examines individual anti-integrin agents in terms of their chemical nature, route of administration, and anti-integrin action. It also provides a summary of preclinical and clinical studies. Current clinical candidates include risuteganib, THR-687, and SF-0166, which have shown promise in treating diabetic macular edema (DME) and/or age-related macular degeneration (AMD) in early clinical studies. Preclinical candidates include SB-267268, AXT-107, JNJ-26076713, Cilengitide and Lebecetin, which exhibit a decrease in retinal permeability, angiogenesis and/or choroidal neovascularization (CNV). EXPERT OPINION: Anti-integrin therapies show potential in treating retinal diseases. Anti-integrin agents tackle the multi-factorial nature of diabetic retinopathy (DR) and AMD and show promise as injectable and topical agents in preclinical and early clinical studies. Integrin inhibition has potential to serve as primary therapy, adjunctive therapy to anti-vascular endothelial growth factor agents, or secondary therapy in refractory cases.


Assuntos
Neovascularização de Coroide/tratamento farmacológico , Integrinas/antagonistas & inibidores , Doenças Retinianas/tratamento farmacológico , Animais , Neovascularização de Coroide/fisiopatologia , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/fisiopatologia , Desenvolvimento de Medicamentos , Humanos , Degeneração Macular/tratamento farmacológico , Degeneração Macular/fisiopatologia , Edema Macular/tratamento farmacológico , Edema Macular/fisiopatologia , Doenças Retinianas/fisiopatologia
7.
J Ocul Pharmacol Ther ; 36(6): 384-392, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32255727

RESUMO

Retinal gene therapy is a rapidly growing field with numerous clinical trials underway, and route of delivery is a critical contributor to its success. Subretinal administration, which involves pars plana vitrectomy in the operating room, offers targeted delivery to retinal-pigment epithelium cells and photoreceptors. Due to the immune-privileged nature of the subretinal space, the risk of an immune reaction against viral capsid antigens is minimized, an advantage of subretinal administration in patients with preexisting neutralizing antibodies. Intravitreal administration, with fewer procedure-related complications, is challenged by potential immune response and incomplete vector penetration through the internal limiting membrane. However, novel vectors, optimized by "directed evolution" may address these issues. Nonsurgical in-office suprachoroidal gene delivery offers the potential for greater surface-area coverage of the posterior segment compared to focal subretinal injection, and is not hindered by the internal limiting membrane. However, the vector must pass through multiple layers to reach the targeted retinal layers, and there is a risk of immune response. This review highlights recent developments, challenges, and future opportunities associated with viral and nonviral suprachoroidal gene delivery for the treatment of chorioretinal diseases. While ocular tolerability and short-term effectiveness of suprachoroidal gene delivery have been demonstrated in preclinical models, durability of gene expression, long-term safety, potential systemic exposure, and effective delivery to the macula require further exploration. Although the safety and efficacy of suprachoroidal gene delivery are yet to be proven in clinical trials, further optimization could facilitate nonsurgical in-office suprachoroidal gene therapy.


Assuntos
Doenças da Coroide/terapia , Efusões Coroides/genética , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Doenças Retinianas/terapia , Animais , Proteínas do Capsídeo/imunologia , Proteínas do Capsídeo/uso terapêutico , Efusões Coroides/metabolismo , Ensaios Clínicos como Assunto , Técnicas de Transferência de Genes , Cobaias , Haplorrinos , Injeções Intravítreas/métodos , Camundongos , Modelos Animais , Nanopartículas/administração & dosagem , Células Fotorreceptoras de Vertebrados/efeitos dos fármacos , Coelhos , Ratos , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Propriedades de Superfície/efeitos dos fármacos , Suínos , Vitrectomia/métodos
8.
Expert Opin Investig Drugs ; 29(3): 237-244, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31985300

RESUMO

Introduction: Plasma kallikrein is a  mediator of vascular leakage and inflammation. Activation of plasma kallikrein can induce features of diabetic macular edema (DME) in preclinical models. Human vitreous shows elevated plasma kallikrein levels in patients with DME. Because of the incomplete response of some patients to anti-VEGF agents, and the treatment burden associated with frequent dosing, there is still considerable need for VEGF-independent targeted pathways.Areas covered: This review covers the role of plasma kallikrein in the pathogenesis of DME and the therapeutic potential of plasma kallikrein inhibitors. It discusses early clinical studies of plasma kallikrein pathway modulation for DME, which have been associated with some improvement in visual acuity but with limited improvement in macular edema. This review also highlights KVD001, which is furthest along the development pathway, THR-149, which has recently completed a phase 1 study, and oral agents under development.Expert opinion: Plasma kallikrein inhibitors have a potential role in the treatment of DME, with mixed functional/anatomic results in early clinical trials. Given the large unmet need in DME treatment, further studies are warranted.


Assuntos
Retinopatia Diabética/tratamento farmacológico , Edema Macular/tratamento farmacológico , Calicreína Plasmática/antagonistas & inibidores , Animais , Retinopatia Diabética/fisiopatologia , Desenvolvimento de Medicamentos , Drogas em Investigação/farmacologia , Humanos , Edema Macular/fisiopatologia , Calicreína Plasmática/metabolismo
9.
Expert Opin Investig Drugs ; 28(10): 861-869, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31513439

RESUMO

Introduction: The Tie-2/Angiopoietin pathway is a therapeutic target for the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Activation of Tie-2 receptor via Ang-1 maintains vascular stability to limit exudation. Ang-2, a competitive antagonist to Ang-1, and VE-PTP, an endothelial-specific phosphatase, interfere with the Tie-2-Ang-1 axis, resulting in vascular leakage. Areas covered: Faricimab, a bispecific antibody that inhibits VEGF-A and Ang-2, is in phase 3 trials for nAMD and DME. Nesvacumab is an Ang-2 inhibitor; when coformulated with aflibercept, it failed to show benefit over aflibercept monotherapy in achieving visual gains in phase 2 studies of nAMD and DME. ARP-1536 is an intravitreally administered VE-PTP inhibitor undergoing preclinical studies. AKB-9778 is a subcutaneously administered VE-PTP inhibitor that, when combined with monthly ranibizumab, reduced DME more effectively than ranibizumab monotherapy in a phase 2 study. AKB-9778 monotherapy did not reduce diabetic retinopathy severity score compared to placebo. AXT107, currently in the preclinical phase, promotes conversion of Ang-2 into a Tie-2 agonist and blocks signaling through VEGFR2 and other receptor tyrosine-kinases. Expert opinion: Tie-2/Angiopoietin pathway modulators show promise to reduce treatment burden and improve visual outcomes in nAMD and DME, with potential to treat cases refractory to current treatment modalities.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Retinopatia Diabética/tratamento farmacológico , Degeneração Macular/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Angiopoietina-1/antagonistas & inibidores , Angiopoietina-2/antagonistas & inibidores , Animais , Retinopatia Diabética/fisiopatologia , Humanos , Degeneração Macular/fisiopatologia , Edema Macular/tratamento farmacológico , Edema Macular/fisiopatologia , Receptor TIE-2/efeitos dos fármacos , Receptor TIE-2/metabolismo , Transdução de Sinais/efeitos dos fármacos
10.
SLAS Discov ; 22(10): 1239-1245, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28787579

RESUMO

Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) is becoming an important technology to determine the distribution of drugs and their metabolites in the tissue of preclinical species after dosing. Interest in IMS is growing in the ophthalmology field, but little work to this point has been done to investigate ocular drug transit using this technology. Information on where and how a drug is distributing through the eye is important in understanding efficacy and whether it is reaching the desired target tissue. For this study, ocular distribution of brimonidine was investigated in rabbits following topical administration. Brimonidine has been shown to lower intraocular pressure and is approved to treat glaucoma, the second leading cause of blindness in the world. We have developed IMS methods to assess transit of topically administered brimonidine from the anterior to the posterior segment of rabbit eyes. Using IMS, brimonidine was detected in the cornea, aqueous humor, iris, and posterior segments of the eye. The distribution of brimonidine suggests that the route of transit following topical administration is mainly through the uvea-scleral route. This study demonstrates that IMS can be applied to assess ocular transit and distribution of topically administered drugs.


Assuntos
Tartarato de Brimonidina/farmacologia , Olho/efeitos dos fármacos , Imageamento Tridimensional , Espectrometria de Massas , Animais , Coelhos , Processamento de Sinais Assistido por Computador , Fatores de Tempo
11.
J Med Chem ; 60(13): 5717-5735, 2017 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-28621538

RESUMO

The highly specific S1 serine protease factor D (FD) plays a central role in the amplification of the complement alternative pathway (AP) of the innate immune system. Genetic associations in humans have implicated AP activation in age-related macular degeneration (AMD), and AP dysfunction predisposes individuals to disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). The combination of structure-based hit identification and subsequent optimization of the center (S)-proline-based lead 7 has led to the discovery of noncovalent reversible and selective human factor D (FD) inhibitors with drug-like properties. The orally bioavailable compound 2 exerted excellent potency in 50% human whole blood in vitro and blocked AP activity ex vivo after oral administration to monkeys as demonstrated by inhibition of membrane attack complex (MAC) formation. Inhibitor 2 demonstrated sustained oral and ocular efficacy in a model of lipopolysaccharide (LPS)-induced systemic AP activation in mice expressing human FD.


Assuntos
Fator D do Complemento/antagonistas & inibidores , Via Alternativa do Complemento/efeitos dos fármacos , Prolina/análogos & derivados , Prolina/farmacologia , Administração Oral , Animais , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Síndrome Hemolítico-Urêmica Atípica/imunologia , Fator D do Complemento/imunologia , Complexo de Ataque à Membrana do Sistema Complemento/antagonistas & inibidores , Complexo de Ataque à Membrana do Sistema Complemento/imunologia , Feminino , Haplorrinos , Humanos , Macaca fascicularis , Degeneração Macular/tratamento farmacológico , Degeneração Macular/imunologia , Masculino , Camundongos , Prolina/administração & dosagem , Prolina/farmacocinética
12.
Nat Commun ; 8: 14837, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28332616

RESUMO

Protein drugs that neutralize vascular endothelial growth factor (VEGF), such as aflibercept or ranibizumab, rescue vision in patients with retinal vascular diseases. Nonetheless, optimal visual outcomes require intraocular injections as frequently as every month. Here we report a method to extend the intravitreal half-life of protein drugs as an alternative to either encapsulation or chemical modifications with polymers. We combine a 97-amino-acid peptide of human origin that binds hyaluronan, a major macromolecular component of the eye's vitreous, with therapeutic antibodies and proteins. When administered to rabbit and monkey eyes, the half-life of the modified proteins is increased ∼3-4-fold relative to unmodified proteins. We further show that prototype long-acting anti-VEGF drugs (LAVAs) that include this peptide attenuate VEGF-induced retinal changes in animal models of neovascular retinal disease ∼3-4-fold longer than unmodified drugs. This approach has the potential to reduce the dosing frequency associated with retinal disease treatments.


Assuntos
Bevacizumab/administração & dosagem , Ranibizumab/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Doenças Retinianas/tratamento farmacológico , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacocinética , Animais , Bevacizumab/química , Bevacizumab/farmacocinética , Modelos Animais de Doenças , Feminino , Meia-Vida , Humanos , Ácido Hialurônico/química , Injeções Intravítreas , Macaca fascicularis , Masculino , Coelhos , Ranibizumab/química , Ranibizumab/farmacocinética , Receptores de Fatores de Crescimento do Endotélio Vascular/química , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/farmacocinética , Doenças Retinianas/metabolismo
13.
J Pharm Sci ; 104(12): 3997-4001, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26524700

RESUMO

Drugs possessing the ability to bind to melanin-rich tissue, such as the eye, are linked with higher ocular exposure, and therefore have the potential to affect the efficacy and safety profiles of therapeutics. A high-throughput melanin chromatographic affinity assay has been developed and validated, which has allowed the rapid melanin affinity assessment for a large number of compounds. Melanin affinity of compounds can be quickly assigned as low, medium, or high melanin binders. A high-throughput chromatographic method has been developed and fully validated to assess melanin affinity of pharmaceuticals and has been useful in predicting ocular tissue distribution in vivo studies. The high-throughput experimental approach has also allowed for a specific training set of 263 molecules for a quantitative structure-affinity relationships (QSAR) method to be developed, which has also been shown to be a predictor of ocular tissue exposure. Previous studies have reported the development of in silico QSAR models based on training sets of relatively small and mostly similar compounds; this model covers a broader range of melanin-binding affinities than what has been previously published and identified several physiochemical descriptors to be considered in the design of compounds where melanin-binding modulation is desired.


Assuntos
Olho/metabolismo , Melaninas/metabolismo , Preparações Farmacêuticas/metabolismo , Simulação por Computador , Relação Quantitativa Estrutura-Atividade
14.
AAPS PharmSciTech ; 11(4): 1526-40, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20976577

RESUMO

Injectable lipid emulsions, for decades, have been clinically used as an energy source for hospitalized patients by providing essential fatty acids and vitamins. Recent interest in utilizing lipid emulsions for delivering lipid soluble therapeutic agents, intravenously, has been continuously growing due to the biocompatible nature of the lipid-based delivery systems. Advancements in the area of novel lipids (olive oil and fish oil) have opened a new area for future clinical application of lipid-based injectable delivery systems that may provide a better safety profile over traditionally used long- and medium-chain triglycerides to critically ill patients. Formulation components and process parameters play critical role in the success of lipid injectable emulsions as drug delivery vehicles and hence need to be well integrated in the formulation development strategies. Physico-chemical properties of active therapeutic agents significantly impact pharmacokinetics and tissue disposition following intravenous administration of drug-containing lipid emulsion and hence need special attention while selecting such delivery vehicles. In summary, this review provides a broad overview of recent advancements in the field of novel lipids, opportunities for intravenous drug delivery, and challenges associated with injectable lipid emulsions.


Assuntos
Emulsões Gordurosas Intravenosas/química , Ácidos Graxos Essenciais/química , Nutrição Parenteral , Triglicerídeos/química , Estado Terminal , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Emulsões Gordurosas Intravenosas/metabolismo , Emulsões Gordurosas Intravenosas/farmacocinética , Ácidos Graxos Essenciais/metabolismo , Ácidos Graxos Essenciais/farmacocinética , Humanos , Infusões Intravenosas , Veículos Farmacêuticos/química , Solubilidade , Triglicerídeos/metabolismo , Triglicerídeos/farmacocinética
15.
J Ocul Pharmacol Ther ; 26(2): 137-46, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20415622

RESUMO

PURPOSE: The purpose of this study was to evaluate partitioning into and transport across posterior segment tissues (sclera, retinal pigment epithelium (RPE)-choroid) of AL-4940, the active metabolite of angiostatic cortisene anecortave acetate (AL-3789). METHODS: Transport of [(14)C]-AL-4940 was measured through RPE-choroid-sclera (RCS) and sclera, excised from Dutch Belted pigmented rabbits' eyes, in the directions of scleral to vitreal (S-->V) and vitreal to scleral (V-->S) for 3 h at 37 degrees C using Ussing chambers. Tissue integrity was monitored by transepithelial electrical resistance (TEER), potential difference (PD), and biochemical assay (LDH). Partitioning in RPE-choroid and sclera was determined separately for both [(14)C]-AL-4940 and [(14)C]-AL-3789. Mathematical analysis for bilaminate membranes used partitioning and transport data to derive diffusion coefficients for 2 tissue layers sclera and RPE-choroid. RESULTS: Partitioning of drug in tissue was comparable for both [(14)C]-AL-4940 and [(14)C]-AL-3789. Partition coefficients of drug in tissue were 2.2 for sclera and about 4 for RPE-choroid. Permeability through sclera alone was about 3 x 10(-5) cm/s and about 1 x 10(-5) cm/s through the RCS tissue, irrespective of the direction of transport (S-->V) or (V-->S). Results from bioelectrical and biochemical evaluation of tissue with modified LDH assay provided evidence that the RCS tissue preparation remained viable during the period of transport study. CONCLUSIONS: The thin RPE-choroid layer contributes significantly to resistance to drug transport, and diffusivity in this layer is 10 times less than in sclera. This experimental scheme is proposed as an important component for the development of a general ocular physiologically based pharmacokinetic model.


Assuntos
Inibidores da Angiogênese/metabolismo , Corioide/metabolismo , Hidrocortisona/análogos & derivados , Pregnadienodiois/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Esclera/metabolismo , Animais , Transporte Biológico Ativo , Cultura em Câmaras de Difusão , Impedância Elétrica , Hidrocortisona/metabolismo , Potenciais da Membrana , Modelos Teóricos , Coelhos
16.
Int J Pharm ; 358(1-2): 168-76, 2008 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-18417304

RESUMO

The objective of this research was to functionally characterize sodium-dependent vitamin C transporter (SVCT) in MDCK-MDR1 cells and to study the effect of substituted benzene derivatives on the intracellular accumulation of ascorbic acid (AA). Mechanism of AA uptake and transport was delineated. Uptake of [(14)C]ascorbic acid ([(14)C]AA) was studied in the absence and presence of excess unlabelled AA, anion transporter inhibitors, and a series of mono- and di-substituted benzenes. Transepithelial transport of [(14)C]AA across polarized cell membrane has been studied for the first time. Role of cellular protein kinase-mediated pathways on the regulation of AA uptake has been investigated. The cellular localizations of SVCTs were observed using confocal microscopy. Uptake of AA was found to be saturable with a K(m) of 83.2muM and V(max) of 94.2pmol/min/mg protein for SVCT1. The process was pH, sodium, temperature, and energy-dependent. It was under the regulation of cellular protein kinase C (PKC) and Ca(2+)/CaM mediated pathways. [(14)C]AA uptake was significantly inhibited in the presence of excess unlabelled AA and a series of electron-withdrawing group, i.e., halogen- and nitro-substituted benzene derivatives. AA appears to translocate across polarized cell membrane from apical to basal side (A-B) as well as basal to apical side (B-A) at a similar permeability. It appears that SVCT1 was mainly expressed on the apical side and SVCT2 may be located on both apical and basal sides. In conclusion, SVCT has been functionally characterized in MDCK-MDR1 cells. The interference of a series of electrophile-substituted benzenes on the AA uptake process may be explained by their structural similarity. SVCT may be targeted to facilitate the delivery of drugs with low bioavailability by conjugating with AA and its structural analogs. MDCK-MDR1 cell line may be utilized as an in vitro model to study the permeability of AA conjugated prodrugs.


Assuntos
Ácido Ascórbico/metabolismo , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Simportadores/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Transporte Biológico Ativo , Linhagem Celular , Permeabilidade da Membrana Celular , Interpretação Estatística de Dados , Cães , Metabolismo Energético/fisiologia , Humanos , Concentração de Íons de Hidrogênio , Microscopia Confocal , Transdução de Sinais/fisiologia , Sódio/fisiologia , Transportadores de Sódio Acoplados à Vitamina C , Especificidade por Substrato
17.
Int J Pharm ; 355(1-2): 210-9, 2008 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-18207340

RESUMO

The primary objective of this study was to investigate the expression of a specialized carrier-mediated system for folic acid and to delineate its uptake mechanism and intracellular trafficking in a human derived retinoblastoma cell line (Y-79). Uptake of [3H]Folic acid was determined at various concentrations, pH, temperatures, in the absence of sodium and chloride ions and in the presence of structural analogs, methyltetrahydro folate (MTF) and methotrexate (MTX), vitamins, membrane transport and metabolic inhibitors to delineate the mechanism of uptake. Kinetics of uptake was studied in the presence of various intracellular regulatory pathways; protein kinases A and C (PKA and PKC), protein tyrosine kinase (PTK) and calcium-calmodulin modulators. Reverse transcription polymerase chain reaction (RT-PCR) was performed to confirm the molecular identity of folate carrier systems. The uptake was found to be linear up to 30min. The rate of uptake followed saturation kinetics with apparent Km of 8.29+/-0.74nM, 17.03+/-1.98nM and 563.23+/-115.2nM and Vmax of 393.47+/-9.33, 757.58+/-26.21 and 653.17+/-31.7fmol/(minmg) protein for folic acid, MTF and MTX, respectively. The process was chloride, temperature and energy dependent but sodium and pH independent; inhibited by the structural analogs MTF and MTX but not by structurally unrelated vitamins. Membrane transport inhibitors did not affect the uptake of [3H]Folic acid, however endocytic inhibitor, colchicine, significantly inhibited the [3H]Folic acid uptake indicating the involvement of receptor mediated endocytosis process. PKC, PTK and Ca2+/calmodulin pathways appeared to play important roles in the regulation of folic acid uptake. Molecular evidence of the presence of folate receptor (FR) precursor was identified by RT-PCR analysis. This research work demonstrated, for the first time, the functional and molecular existence of a specialized high affinity carrier-mediated system for folic acid uptake, in human retinoblastoma cells.


Assuntos
Ácido Fólico/administração & dosagem , Ácido Fólico/metabolismo , Neoplasias da Retina/metabolismo , Retinoblastoma/metabolismo , Vitaminas/administração & dosagem , Vitaminas/metabolismo , Antimetabólitos/farmacologia , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Interpretação Estatística de Dados , Portadores de Fármacos , Transferência de Energia , Inibidores Enzimáticos/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Cinética , Proteínas de Membrana Transportadoras/metabolismo , Proteína Quinase C/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Especificidade por Substrato , Temperatura
18.
J Ocul Pharmacol Ther ; 23(4): 321-34, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17803430

RESUMO

PURPOSE: The overall aim of this research work was to evaluate a series of dipeptide monoester prodrugs of an antiviral agent, ganciclovir (GCV), for oligopeptide transporter-targeted transscleral drug delivery to rabbit retina. METHODS: The permeability and enzymatic hydrolysis of dipeptide monoester GCV prodrugs were evaluated using freshly excized rabbit retinal pigment epithelium (RPE)-choroidsclera (RCS) and sclera tissue preparations. Affinity and transport mechanism of these prodrugs and their translocation across RCS were investigated through competitive inhibition studies of [(3)H]glycylsarcosine with the prodrugs. RESULTS: The transport of glycylsarcosine was found to be saturable (K(m) = 1.21 +/- 0.41 mM, V(max) = 15.89 +/- 1.54 pmoles/min/cm(2)), pH, temperature, and energy dependant. Dipeptides, angiotensin converting enzyme inhibitors, and a beta-lactum antibiotic strongly inhibited the transport of glycylsarcosine indicating the functional presence of oligopeptide transport (OPT) system on the RPE. Dipeptide prodrugs (valine-valine-GCV, glycine-valine-GCV, and tyrosine-valine-GCV), and valine-GCV demonstrate a high enzymatic stability and affinity toward the retinal OPT system. The transport of the prodrugs was significantly inhibited ( approximately 50%) in the presence of glycylsarcosine. The rank order of scleral permeability was Gly-Val-GCV approximately GCV>Val-GCV>Tyr-Val-GCV approximately Val-Val-GCV. The RCS permeability values of Val-GCV (3.29 +/- 0.09 x 10(6)cm/s), Val-Val-GCV (4.14 +/- 0.33 x 10(6)cm/s), Gly-Val-GCV (3.40 +/- 0.47 x 10(6)cm/s) and Tyr-Val-GCV (3.08 +/- 0.29 x 10(6)cm/s) were two-fold higher than that of GCV (1.61 +/- 0.06 x 10(6)cm/s). CONCLUSIONS: The dipeptide monoester GCV prodrugs, owning to higher lipophilicity and OPT-mediated translocation across RPE, appear to be promising candidates in the treatment of ocular cytomegalovirus infections following an episcleral administration.


Assuntos
Antivirais/farmacocinética , Sistemas de Liberação de Medicamentos , Ganciclovir/farmacocinética , Retina/metabolismo , Animais , Antivirais/administração & dosagem , Transporte Biológico , Proteínas de Transporte/metabolismo , Corioide/metabolismo , Dipeptídeos/administração & dosagem , Dipeptídeos/farmacocinética , Ganciclovir/administração & dosagem , Ganciclovir/análogos & derivados , Técnicas In Vitro , Masculino , Oligopeptídeos/metabolismo , Epitélio Pigmentado Ocular/metabolismo , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Coelhos , Esclera/metabolismo , Relação Estrutura-Atividade
19.
Int J Pharm ; 336(2): 233-40, 2007 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-17207946

RESUMO

Saquinavir (SQV) was the first human immuno-virus-1 (HIV-1) protease inhibitor approved by FDA. However, P-glycoprotein (P-gp), an efflux pump limits its oral and brain bioavailabilities. The objective of this study is to investigate whether prodrug modification of SQV to dipeptide prodrugs Valine-Valine-Saquinavir (Val-Val-SQV) and Glycine-Valine-Saquinavir (Gly-Val-SQV) targeting intestinal peptide transporter can enhance intestinal permeability of SQV by circumventing P-gp mediated efflux. Single pass intestinal perfusion experiments in rat jejunum were performed to calculate the absorption rate constant and intestinal permeability of SQV, Val-Val-SQV and Gly-Val-SQV. Equimolar concentration (25 microM) of SQV, Val-Val-SQV and Gly-Val-SQV were employed in the perfusion studies. Perfusion experiments were also carried out in the presence of cyclosporine (10 microM) and glycyl-sarcosine (20 mM). Absorption rate constants in rat jejunum (ka) for SQV, Val-Val-SQV and Gly-Val-SQV were found to be 14.1+/-3.4x10(-3), 65.8+/-4.3x10(-3), and 25.6+/-5.7x10(-3) min(-1), respectively. Enhanced absorption of Val-Val-SQV and Gly-Val-SQV relative to SQV can be attributed to their translocation by the peptide transporter in the jejunum. Significant permeability enhancement of SQV across rat jejunum was observed in the presence of cyclosporine 10 microM (P-gp inhibitor). However, permeability of Val-Val-SQV was unchanged in the presence of cyclosporine suggesting lack of any interaction of the prodrug with efflux pump. Intestinal absorption of Val-Val-SQV was significantly inhibited in the presence of gly-sar indicating the involvement of peptide transporter in intestinal absorption. In conclusion, peptide transporter targeted prodrug modification of P-gp substrates could lead to shielding of these drug molecules from efflux pumps.


Assuntos
Inibidores da Protease de HIV/farmacocinética , Pró-Fármacos/farmacocinética , Saquinavir/análogos & derivados , Saquinavir/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Disponibilidade Biológica , Transporte Biológico , Estabilidade de Medicamentos , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/química , Absorção Intestinal , Jejuno/metabolismo , Masculino , Permeabilidade , Pró-Fármacos/síntese química , Pró-Fármacos/química , Ratos , Ratos Sprague-Dawley , Saquinavir/síntese química , Saquinavir/química
20.
J Ocul Pharmacol Ther ; 22(4): 231-41, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16910863

RESUMO

PURPOSE: The aim of this study was to determine vitreal pharmacokinetics of a series of dipeptide monoester ganciclovir (GCV) prodrugs and to study their interaction with the retinal peptide transporter. METHODS: New Zealand albino male rabbits were selected as the animal model. Ocular microdialysis technique was employed to delineate the pharmacokinetics of GCV, L-valine-GCV and dipeptide monoester GCV prodrugs (L-valine-L-valine, L-tyrosine-L-valine, and L-glycine- L-valine) following intravitreal administration. RESULTS: Val-GCV and Val-Val-GCV inhibited retinal uptake of [3H]Gly-Sar by 43% and 37%, respectively, suggesting that these prodrugs may be substrates of the retinal peptide transport system. Val-GCV and Gly-Val-GCV were observed to be the most stable GCV prodrugs in vitreous humor. All GCV prodrugs were rapidly converted to GCV in retinal homogenates. Vitreal pharmacokinetic studies suggest that Val-GCV and Val-Val-GCV are rapidly eliminated from the vitreous chamber, compared to GCV, whereas Gly-Val-GCV is eliminated at a much slower rate. Retinal GCV concentrations generated from all three prodrugs, at the end of 5 h, were almost equivalent and were almost twice that following intravitreal administration of GCV. Gly-Pro, however, did not demonstrate any effect on retinal uptake of Val-GCV or Gly-Val-GCV. CONCLUSIONS: Considering retinal GCV concentrations generated and vitreal pharmacokinetic profiles, Gly-Val-GCV appears to be a lead candidate for further in vivo evaluation against human cytomegalovirus (HCMV) retinitis.


Assuntos
Antivirais/farmacocinética , Dipeptídeos/farmacocinética , Ganciclovir/farmacocinética , Pró-Fármacos/farmacocinética , Corpo Vítreo/metabolismo , Animais , Biotransformação , Corioide/metabolismo , Cromatografia Líquida de Alta Pressão , Ganciclovir/análogos & derivados , Masculino , Coelhos , Retina/metabolismo , Distribuição Tecidual
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