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1.
Int J Pharm ; 557: 135-144, 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30594685

RESUMO

To improve the penetration and accumulation of anti-inflammatory drugs in colitis tissue, we functionalized the surface of porous poly(lactic-co-glycolic acid) nanoparticles (NPs) using pluronic F127 (PF127) and loaded curcumin (CUR) into the resulting NPs to obtain porous PF127-functionalized CUR-loaded NPs (porous PF127-NPs). These NPs had an average hydrodynamic diameter of about 270 nm with a highly monodisperse size distribution, slightly negative surface charge and controllable CUR release profile. It was found that they had good biocompatibility and yielded a much higher cellular uptake rate of CUR than porous CUR-loaded NPs without PF127 modification (porous NPs). In addition, porous PF127-NPs showed a greater capacity to inhibit the major pro-inflammatory cytokines (IL-6, IL-12 and TNF-α) secreted from lipopolysaccharide-activated macrophages than porous NPs and non-porous PF127-NPs. In vivo experiments suggested that porous PF127-NPs achieved the best therapeutic outcomes against ulcerative colitis (UC) in mice compared with porous NPs and non-porous PF127-NPs. Our results clearly demonstrate that these fabricated porous PF127-NPs show a great promise as an efficient CUR nanocarrier for UC therapy.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Curcumina/administração & dosagem , Portadores de Fármacos/administração & dosagem , Nanopartículas/administração & dosagem , Poloxâmero/administração & dosagem , Ácido Poliglicólico/administração & dosagem , Administração Oral , Animais , Colite Ulcerativa/induzido quimicamente , Sulfato de Dextrana , Feminino , Lipopolissacarídeos/farmacologia , Camundongos , Células RAW 264.7
2.
Int J Pharm ; 548(1): 698-706, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30031864

RESUMO

Oxytocin is a promising candidate for the treatment of social-deficit disorders such as Autism Spectrum Disorder, but oxytocin cannot readily pass the blood-brain barrier. Moreover, oxytocin requires frequent dosing as it is rapidly metabolized in blood. We fabricated four polymeric nanoparticle formulations using poly(lactic-co-glycolic acid) (PLGA) or bovine serum albumin (BSA) as the base material. In order to target them to the brain, we then conjugated the materials to either transferrin or rabies virus glycoprotein (RVG) as targeting ligands. The formulations were characterized in vitro for size, zeta potential, encapsulation efficiency, and release profiles. All formulations showed slightly negative charges and sizes ranging from 100 to 278 nm in diameter, with RVG-conjugated BSA nanoparticles exhibiting the smallest sizes. No formulation was found to be immunogenic or cytotoxic. The encapsulation efficiency was ≥75% for all nanoparticle formulations. Release studies demonstrated that BSA nanoparticle formulation exhibited a faster initial burst of release compared to PLGA particles, in addition to later sustained release. This initial burst release would be favorable for clinical dosing as therapeutic effects could be quickly established, especially in combination with additional sustained release to maintain the therapeutic effects. Our size and release profile data indicate that RVG-conjugated BSA nanoparticles are the most favorable formulation for brain delivery of oxytocin.


Assuntos
Encéfalo/metabolismo , Portadores de Fármacos , Nanopartículas , Ocitocina , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Glicoproteínas/administração & dosagem , Glicoproteínas/química , Ácido Láctico/administração & dosagem , Ácido Láctico/química , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/química , Óxido Nítrico/metabolismo , Ocitocina/administração & dosagem , Ocitocina/química , Ácido Poliglicólico/administração & dosagem , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Vírus da Raiva , Soroalbumina Bovina/administração & dosagem , Soroalbumina Bovina/química , Transferrina/administração & dosagem , Transferrina/química , Proteínas Virais/administração & dosagem , Proteínas Virais/química
3.
Int J Pharm ; 548(1): 522-529, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30017818

RESUMO

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor. Despite available therapeutic options, the prognosis for patients with GBM remains very poor. We hypothesized that the intra-operative injection of a photopolymerizable hydrogel into the tumor resection cavity could sustain the release of the anti-cancer drug paclitaxel (PTX) encapsulated in poly (lactic-co-glycolic acid) (PLGA) nanoparticles and prevent GBM recurrence. The tumor was resected 13 days after implantation and a pre-gel solution composed of polyethylene glycol dimethacrylate (PEG-DMA) polymer, a photoinitiator and PTX-loaded PLGA nanoparticles (PTX PLGA-NPs) was injected into the tumor resection cavity. A solid gel filling the whole cavity was formed immediately by photopolymerization using a 400 nm light. PTX in vitro release study showed a burst release (11%) in the first 8 h and a sustained release of 29% over a week. In vitro, U87 MG cells were sensitive to PTX PLGA-NPs with IC50 level of approximately 0.010 µg/mL. The hydrogel was well-tolerated when implanted in the brain of healthy mice for 2 and 4 months. Administration of PTX PLGA-NPs-loaded hydrogel into the resection cavity of GBM orthotopic model lead to more than 50% long-term survival mice (150 days) compared to the control groups (mean survival time 52 days). This significant delay of recurrence is very promising for the post-resection treatment of GBM.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Hidrogéis/administração & dosagem , Nanopartículas/administração & dosagem , Paclitaxel/administração & dosagem , Animais , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/cirurgia , Linhagem Celular Tumoral , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Liberação Controlada de Fármacos , Feminino , Glioblastoma/cirurgia , Humanos , Hidrogéis/química , Período Intraoperatório , Ácido Láctico/administração & dosagem , Ácido Láctico/química , Metacrilatos/administração & dosagem , Metacrilatos/química , Camundongos , Nanopartículas/química , Paclitaxel/química , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Ácido Poliglicólico/administração & dosagem , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico
4.
Fish Shellfish Immunol ; 80: 651-654, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29859314

RESUMO

Recently, chitosan-based nanoparticles with mucoadhesive properties emerged as a strategy for mucosal drug release. This study aimed to characterize the interaction of mucoadhesive system chitosancoated PLGA nanoparticles (NPMA) with fish external mucus. NP suspensions with fluorescent probe were prepared and characterized by size, polydispersity, zeta potential and pH measures. In post-exposure fish were observed an increase in fluorescence imaging over time and it was significantly influenced by NPMA concentration. We also observed the main predominance the fluorescence in the spleen, followed by liver, gill and other tissues. The use of mucoadhesive nanocarriers becomes an alternative for administration of drugs and immunomodulators in immersion systems since the nanosystem can adhere to the mucosal surface of the fish with little residual effect in the water.


Assuntos
Quitosana/administração & dosagem , Portadores de Fármacos/administração & dosagem , Nanopartículas/administração & dosagem , Ácido Poliglicólico/administração & dosagem , Adesividade , Animais , Quitosana/química , Portadores de Fármacos/química , Corantes Fluorescentes/administração & dosagem , Brânquias/metabolismo , Imunomodulação , Fígado/metabolismo , Membrana Mucosa/química , Nanopartículas/química , Ácido Poliglicólico/química , Baço/metabolismo , Peixe-Zebra
5.
Vaccine ; 36(28): 4070-4076, 2018 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-29859800

RESUMO

One of the economically important diseases in the poultry industry is Marek's disease (MD) which is caused by Marek's disease virus (MDV). The use of current vaccines provides protection against clinical signs of MD in chickens. However, these vaccines do not prevent the transmission of MDV to susceptible hosts, hence they may promote the development of new virulent strains of MDV. This issue persuaded us to explore alternative approaches to control MD in chickens. Induction of innate responses at the early stage of life in the chicken may help to prevent or reduce MDV infection. Further, prophylactic use of Toll-like receptor ligands (TLR-Ls) has been shown to generate host immunity against infectious diseases. In this regard, encapsulation of TLR-Ls in Poly(d, l-lactic-co-glycolic acid) (PLGA) may further enhance host responses by controlled release of TLR-Ls for an extended period. Hence, in the current study, protective effects of encapsulated TLR4 and TLR21 ligands, LPS and CpG, respectively, were investigated against MD. Results indicated that administration of encapsulated CpG and LPS first at embryonic day (ED) 18, followed by post-hatch at 14 days-post infection (dpi) intramuscularly, diminished tumor incidence by 60% and 42.8%, respectively at 21dpi compared to the MDV only group. In addition, analysis of cytokine gene profiles of interferon (IFN)-α, IFN-ß, IFN-γ, inducible nitric oxide synthase (iNOS), interleukin (IL)-1ß, IL-18 and IL-10 in spleen and bursa of Fabricius at different time points suggests that TLR-Ls possibly triggered host responses through the expression of IL-1ß and IL-18 to reduce tumor formation. However, further studies are needed to explore the role of these pro-inflammatory cytokines and other influencing elements like lymphocytes in the hindrance of tumor development by TLR-Ls treatment in chickens.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Ácido Láctico/administração & dosagem , Doença de Marek/prevenção & controle , Nanopartículas/administração & dosagem , Ácido Poliglicólico/administração & dosagem , Receptores Toll-Like/agonistas , Animais , Galinhas , Citocinas/análise , Imunidade Inata , Incidência , Lipopolissacarídeos/administração & dosagem , Doença de Marek/epidemiologia , Oligodesoxirribonucleotídeos/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Resultado do Tratamento
6.
Biol Pharm Bull ; 41(6): 937-943, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29863082

RESUMO

In the development of drugs for intra-articular administration, sustained-release formulations are desirable because it is difficult to maintain the effect of conventional injections due to immediate drug leakage from the joint cavity. In this study, a sustained-release poly(lactic-co-glycolic acid) (PLGA) microsphere formulation for intra-articular administration containing indocyanine green (ICG) as a model drug was prepared to follow its fate after intra-articular administration in rats with a real-time in-vivo imaging system. ICG administered as an aqueous solution leaked from the joint cavity in a short time and was excreted outside the body within 1-3 d. However, ICG in the sustained-release formulation was retained in the joint cavity and released for 2 weeks. Next, a sustained-release formulation containing PLGA microspheres in a hyaluronic acid (HA) gel formulation was prepared. After gradual release in two stages, we could achieve sustained release for a longer period. It is considered that a combination formulation of PLGA microspheres and HA gel can significantly improve the sustained release of a drug administered into the knee joint.


Assuntos
Ácido Hialurônico/administração & dosagem , Ácido Láctico/administração & dosagem , Ácido Poliglicólico/administração & dosagem , Animais , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Esquema de Medicação , Composição de Medicamentos , Liberação Controlada de Fármacos , Géis , Ácido Hialurônico/química , Injeções Intra-Articulares , Articulação do Joelho , Ácido Láctico/química , Masculino , Microesferas , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos Sprague-Dawley
7.
Curr Drug Deliv ; 15(8): 1204-1215, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29866006

RESUMO

OBJECTIVE: The incredibly serious problem of Hepatitis B is virus-related chronic liver disease. The conventional preventive treatment of Hepatitis B requires booster dose, which requires repeated administration of the vaccine to the subject. Thus, there is a need to develop a formulation which can eliminate the need of frequent dosing and enhance patient's acquiescence. To prepare single dose nanovaccine of HBsAg by utilizing central composite design for optimization and interaction of independent variables effects on measured response. METHODS: Nanovaccines were characterized for particle size, morphology, integrity, internalization, proliferation response and haemocompatibility. Nanoparticles at single and multiple doses were compared with booster dose of alum-HBsAg vaccine and measure the immunological marker and cytokine (interleukin-2 and interferon-Y) levels by ELISA techniques in BALB/c mice. RESULTS: The designed nanoparticles were found to have nanometric size, high entrapment efficiency and retained antigen integrity. Nanoparticles showed maximum proliferation and efficiently internalized by lymph and spleen cell without eliciting significant toxicity and haemocampatible. CONCLUSION: The comparable data of anti-HBsAg titre between nanovaccine and alum adsorbed HBsAg demonstrated that single dose of nanoparticles is sufficient for production of immunoglobulin plus cytokine levels, maintain immunogenicity at longer period of time and eliminate the booster dose. Nanovaccines trigger immune responses and showing adjuvant properties.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Compostos de Alúmen/administração & dosagem , Antígenos da Hepatite B/administração & dosagem , Imunização/métodos , Ácido Láctico/administração & dosagem , Nanopartículas/administração & dosagem , Ácido Poliglicólico/administração & dosagem , Adjuvantes Imunológicos/química , Compostos de Alúmen/química , Animais , Proliferação de Células/efeitos dos fármacos , Composição de Medicamentos , Liberação Controlada de Fármacos , Eritrócitos/efeitos dos fármacos , Feminino , Hemólise/efeitos dos fármacos , Antígenos da Hepatite B/química , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Interferon gama/imunologia , Interleucina-2/imunologia , Ácido Láctico/química , Linfócitos/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Agregação Plaquetária/efeitos dos fármacos , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico
8.
Int J Pharm ; 547(1-2): 24-30, 2018 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-29800738

RESUMO

A delivery system based on poly(lactic-co-glycolic acid) polymer (PLGA) microparticles has been developed for parenteral administration of the local anesthetic prilocaine in its free base form. Both drug-free and drug-loaded microparticles, prepared by a double-emulsion-evaporation method, were characterized for mean size by Laser Diffraction Analysis, while their morphology was investigated by scanning electron microscopy. The preparation technique allowed obtainment of homogeneous microparticles of about 25 µm diameter, suitable for subcutaneous administration. The encapsulation efficiency, determined by both direct and indirect methods, was around 36-38%. Differential Scanning Calorimetry was used to characterize the solid state of the raw materials, assess drug-polymer compatibility and miscibility and highlight possible modifications of the components induced by the preparation method. In vitro release studies showed a sustained release profile, with about 80% of drug released after the first 24 h. The anesthetic effect of the formulation was evaluated in vivo on rats, according to the test of cutaneous trunci muscle reflex. Administration of prilocaine base as PLGA microparticles allowed to significantly enhance both extent (60% AUC increase) and duration (100% increase) of the anesthetic effect in the animal model, in comparison with the equivalent dose of prilocaine hydrochloride aqueous solution.


Assuntos
Anestésicos Locais/administração & dosagem , Portadores de Fármacos , Ácido Láctico/administração & dosagem , Ácido Poliglicólico/administração & dosagem , Prilocaína/administração & dosagem , Anestésicos Locais/química , Animais , Varredura Diferencial de Calorimetria , Composição de Medicamentos , Liberação Controlada de Fármacos , Ácido Láctico/química , Masculino , Microscopia Eletrônica de Varredura , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiologia , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Prilocaína/química , Ratos Sprague-Dawley , Reflexo/efeitos dos fármacos
9.
Int J Pharm ; 546(1-2): 272-278, 2018 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-29753905

RESUMO

Polymer microparticles are widely used as acellular drug delivery platforms in regenerative medicine, and have emerging potential as cellular scaffolds for therapeutic cell delivery. In the clinic, PLGA microparticles are typically administered intramuscularly or subcutaneously, with the clinician and clinical application site determining the precise needle gauge used for delivery. Here, we explored the role of needle diameter in microparticle delivery yield, and develop a modified viscosity formulation to improve microparticle delivery across a range of clinically relevant needle diameters. We have identified an optimal biocompatible formulation containing 0.25% pluronic F127 and 0.25% carboxymethyl cellulose, which can increase delivery payload to 520% across needle gauges 21-30G, and note that needle diameter impacts delivery efficacy. We use this formulation to increase the delivery yield of PLGA microparticles, and separately, PLGA-cell scaffolds supporting viable mesenchymal stem cells (MSCs), demonstrating the first in vitro delivery of this cell scaffold system. Together, these results highlight an optimal formulation for the delivery of microparticle and microparticle-cell scaffolds, and illustrate how careful choice of delivery formulation and needle size can dramatically impact delivery payload.


Assuntos
Ácido Láctico/administração & dosagem , Células-Tronco Mesenquimais , Ácido Poliglicólico/administração & dosagem , Carboximetilcelulose Sódica/administração & dosagem , Carboximetilcelulose Sódica/química , Sobrevivência Celular , Terapia Baseada em Transplante de Células e Tecidos , Humanos , Ácido Láctico/química , Agulhas , Poloxâmero/administração & dosagem , Poloxâmero/química , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Viscosidade
10.
Int J Pharm ; 547(1-2): 10-23, 2018 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-29751140

RESUMO

Resistance to antiepileptic drugs (AEDs) is a major clinical problem. The overexpression of P-glycoprotein (Pgp), one of the main transporters limiting the entry of xenobiotics into the brain, is among the factors contributing to the AED resistance. Presently, there is no consensus on the interaction of carbamazepine (CBZ) with the Pgp. This study investigates the effect of the Pgp inhibitor verapamil on the anticonvulsant effect of CBZ and its nanoparticulate formulation in the rat model of isoniazid-induced epilepsy. Verapamil significantly increased the anticonvulsant effect of CBZ and reduced its effective dose by at least 30% (from 30 mg/kg to 20 mg/kg). Binding of carbamazepine to the poloxamer 188-coated PLGA nanoparticles enabled a 30-fold increase of its anticonvulsive effect, as compared to the free drug. The inhibition of Pgp did not influence the effectivity of carbamazepine encapsulated in nanoparticles.


Assuntos
Anticonvulsivantes/administração & dosagem , Carbamazepina/administração & dosagem , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Nanopartículas/administração & dosagem , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Encéfalo/fisiopatologia , Carbamazepina/química , Carbamazepina/farmacocinética , Carbamazepina/uso terapêutico , Relação Dose-Resposta a Droga , Sistemas de Liberação de Medicamentos , Epilepsia Resistente a Medicamentos/induzido quimicamente , Epilepsia Resistente a Medicamentos/fisiopatologia , Eletrocorticografia , Isoniazida , Ácido Láctico/administração & dosagem , Ácido Láctico/química , Ácido Láctico/farmacocinética , Ácido Láctico/uso terapêutico , Masculino , Nanopartículas/química , Nanopartículas/uso terapêutico , Poloxâmero/administração & dosagem , Poloxâmero/química , Poloxâmero/farmacocinética , Poloxâmero/uso terapêutico , Ácido Poliglicólico/administração & dosagem , Ácido Poliglicólico/química , Ácido Poliglicólico/farmacocinética , Ácido Poliglicólico/uso terapêutico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos Wistar , Verapamil/farmacologia
11.
Drug Des Devel Ther ; 12: 711-719, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29670329

RESUMO

Background: Norquetiapine (N-desalkyl quetiapine, NQ) is an active metabolite of quetiapine with stable pharmacokinetic and pharmacological properties. However, its short half-life is a drawback for clinical applications, and long-acting formulations are required. Purpose: The objectives of this study were to prepare improved entrapment efficiency NQ freebase microspheres by the solvent evaporation method with poly(d,l-lactic-co-glycolic acid) (PLGA) as a release modulator and to evaluate their physicochemical and in vitro/in vivo release properties. Methods: NQ freebase PLGA (1:5 w/w) formulations were prepared by the oil-in-water (o/w) emulsion-solvent evaporation method. A solution of the drug and PLGA in 9:1 v/v dichloromethane:ethanol was mixed with 0.2% polyvinyl alcohol and homogenized at 2,800 rpm. The emulsion was stirred for 3 h to dilute and evaporate the solvent. After that, the resulting product was freeze-dried. Drug-loading capacity was measured by the validated RP-HPLC method. The surface morphology of the microspheres was observed by scanning electron microscopy (SEM), and the physicochemical properties were evaluated by differential scanning calorimetry, powder X-ray diffraction, and Fourier-transform infrared spectroscopy particle size distribution. The in vitro dissolution test was performed using a rotary shaking bath at 37°C, with constant shaking at 50 rpm in sink condition. Results: The NQ freebase microspheres prepared by o/w emulsion-solvent evaporation showed over 30% efficiency. NQ was confirmed to be amorphous in the microspheres by powder X-ray diffraction and differential scanning calorimetry. Special chemical interaction in the microspheres was not observed by FT-IR. The in vitro dissolution test demonstrated that the prepared microspheres' release properties were maintained for more than 20 days. The in vivo test also confirmed that the particles' long acting properties were maintained. Therefore, good in vitro-in vivo correlation was established. Conclusion: In this study, NQ freebase-PLGA microspheres showed potential for the treatment of schizophrenia for long-periods.


Assuntos
Dibenzotiazepinas/farmacocinética , Ácido Láctico/farmacocinética , Microesferas , Ácido Poliglicólico/farmacocinética , Animais , Dibenzotiazepinas/administração & dosagem , Dibenzotiazepinas/química , Ácido Láctico/administração & dosagem , Ácido Láctico/química , Tamanho da Partícula , Ácido Poliglicólico/administração & dosagem , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos , Ratos Sprague-Dawley , Espectroscopia de Infravermelho com Transformada de Fourier , Propriedades de Superfície
12.
Int J Pharm ; 543(1-2): 300-310, 2018 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-29608954

RESUMO

Restoration of the Chol homeostasis in the Central Nervous System (CNS) could be beneficial for the treatment of Huntington's Disease (HD), a progressive, fatal, adult-onset, neurodegenerative disorder. Unfortunately, Chol is unable to cross the blood-brain barrier (BBB), thus a novel strategy for a targeted delivery of Chol into the brain is highly desired. This article aims to investigate the production of hybrid nanoparticles composed by Chol and PLGA (MIX-NPs) modified with g7 ligand for BBB crossing. We described the impact of ratio between components (Chol and PLGA) and formulation process (nanoprecipitation or single emulsion process) on physico-chemical and structural characteristics, we tested MIX-NPs in vitro using primary hippocampal cell cultures evaluating possible toxicity, uptake, and the ability to influence excitatory synaptic receptors. Our results elucidated that both formulation processes produce MIX-NPs with a Chol content higher that 40%, meaning that Chol is a structural particle component and active compound at the same time. The formulation strategy impacted the architecture and reorganization of components leading to some differences in Chol availability between the two types of g7 MIX-NPs. Our results identified that both kinds of MIX-NPs are efficiently taken up by neurons, able to escape lysosomes and release Chol into the cells resulting in an efficient modification in expression of synaptic receptors that could be beneficial in HD.


Assuntos
Colesterol/química , Sistemas de Liberação de Medicamentos , Glicopeptídeos/química , Ácido Láctico/química , Nanopartículas/química , Ácido Poliglicólico/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Colesterol/administração & dosagem , Embrião de Mamíferos , Glicopeptídeos/administração & dosagem , Hipocampo/citologia , Ácido Láctico/administração & dosagem , Nanopartículas/administração & dosagem , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Poloxâmero/química , Ácido Poliglicólico/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Álcool de Polivinil/química , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo , Tensoativos/administração & dosagem , Tensoativos/química
13.
Eur J Pharm Sci ; 119: 171-178, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29653177

RESUMO

Cryptococcus neoformans is one of the most lethal fungi causing mortality across the globe. Immuno-competent patients and patients taking immuno-suppressive medications are extremely susceptible to its infection. For effective removal of cryptococcal burden, there is an urgent need for new forms of therapy. In the present study, we have explored the potential effects of amphotericin B (AMB) and fluconazole (FLC) in combination, against cryptococcosis in Swiss albino mice. To enhance the therapeutic potential of the tested drugs, they were entrapped into fibrin microspheres; a dual delivery vehicle comprising of poly-lactide co-glycolide (PLGA) microsphere that was additionally encapsulated into the fibrin cross-linked plasma bead. Dynamics of fibrin microspheres included survival and fungal burden in lung, liver and spleen of treated mice. While each drug was effective in combination or alone, prominent additive potential of AMB and FLC were clearly observed when used in fibrin microsphere. Significant reduction in fungal burden and increase in survival rate of AMB + FLC-fibrin microspheres treated mice shows an extensive accessibility of both tested drugs without any side-effects. A full potential of two-drug combination encapsulated in fibrin microspheres proposes an effective approach of safe delivery to the target site in their intact form and decrease the drug associated toxicities.


Assuntos
Anfotericina B/administração & dosagem , Antifúngicos/administração & dosagem , Criptococose/tratamento farmacológico , Fluconazol/administração & dosagem , Anfotericina B/química , Anfotericina B/uso terapêutico , Animais , Antifúngicos/química , Antifúngicos/uso terapêutico , Cryptococcus neoformans/efeitos dos fármacos , Cryptococcus neoformans/crescimento & desenvolvimento , Combinação de Medicamentos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Fluconazol/química , Fluconazol/uso terapêutico , Ácido Láctico/administração & dosagem , Ácido Láctico/química , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Microesferas , Ácido Poliglicólico/administração & dosagem , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico
14.
Curr Drug Deliv ; 15(7): 1020-1027, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29493454

RESUMO

BACKGROUND: Apocynin has become a drug of choice in NADPH oxidase induced pathological conditions. Hyperoxaluria is one such pathological condition where NADPH oxidase is involved in eliciting renal injury. OBJECTIVE: Recently apocynin has shown to reverse the transcriptome profile of the NADPH oxidaseassociated genes and reduced oxidative burden in hyperoxaluric animals. The poor solubility of this drug creates certain apprehensions about its bioavailability. PLGA (Poly Lactic co-Glycolic Acid) encapsulation of drug nanoparticles have showed to induce sustain release and henceforth enhance the efficiency and bioavailability of drugs. Therefore, the present study is aimed to envisage a novel approach of synthesizing apocynin doped PLGA nanoparticles. METHODS: The PLGA nanoparticles (both unloaded and loaded) were prepared using solvent extraction method and analyzed for size and stability by Dynamic Light Scattering (DLS), TEM (transmission electron microscopy) and zeta potential. Furthermore, the drug release and encapsulation efficiency of the drug was calculated in vitro. RESULTS: The nanoencapsulation formed was stable with desired size (217-259 nm) and posses a controlled drug release of 20%. Further this nanoencapsulation was explored for its potential to reduce hyperoxaluric manifestations in rats given ethylene glycol with ammonium chloride for 9 days. CONCLUSION: In comparison to free apocynin, it was found that nanoparticles containing apocynin showed moderately better results in vivo by maintaining serum urea and createnine levels. These nanoparticles can be used in diseases where a sustained release of apocynin is required.


Assuntos
Acetofenonas/administração & dosagem , Hiperoxalúria/tratamento farmacológico , Ácido Láctico/administração & dosagem , NADPH Oxidases/antagonistas & inibidores , Nanopartículas/administração & dosagem , Ácido Poliglicólico/administração & dosagem , Acetofenonas/química , Acetofenonas/uso terapêutico , Animais , Creatinina/sangue , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/uso terapêutico , Liberação Controlada de Fármacos , Hiperoxalúria/sangue , Hiperoxalúria/urina , Rim/efeitos dos fármacos , Rim/metabolismo , Ácido Láctico/química , Ácido Láctico/uso terapêutico , Masculino , NADPH Oxidases/metabolismo , Nanopartículas/química , Nanopartículas/uso terapêutico , Oxalatos/sangue , Oxalatos/urina , Ácido Poliglicólico/química , Ácido Poliglicólico/uso terapêutico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos Wistar , Resultado do Tratamento , Ureia/sangue
15.
Int J Pharm ; 542(1-2): 47-55, 2018 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-29501738

RESUMO

Oral administration of insulin increases patient comfort and could improve glycemic control thanks to the hepatic first passage. However, challenges remain. The current approach uses poly (d, lactic-co-glycolic) acid (PLGA) nanoparticles (NPs), an effective drug carrier system with a long acting profile. However, this system presents a bioavailability of less than 20% for insulin encapsulation. In this context, physico-chemical parameters like surface charge could play a critical role in NP uptake by the intestinal barrier. Therefore, we developed a simple method to modulate NP surface charge to test its impact on uptake in vitro and finally on NP efficiency in vivo. Various NPs were prepared in the presence (+) or absence (-) of polyvinyl alcohol (PVA), sodium dodecyl sulfate (SDS), and/or coated with chitosan chloride. In vitro internalization was tested using epithelial culture of Caco-2 or using a co-culture (Caco-2/RevHT29MTX) by flow cytometry. NPs were then administered by oral route using a pharmaceutical complex vector (100 or 250 UI/kg) in a diabetic rat model. SDS-NPs (-42 ±â€¯2 mV) were more negatively charged than -PVA-NPs (-22 ±â€¯1 mV) and chitosan-coated NPs were highly positively charged (56 ±â€¯2 mV) compared to +PVA particles (-2 ±â€¯1 mV), which were uncharged. In the Caco-2 model, NP internalization was significantly improved by using negatively charged NPs (SDS NPs) compared to using classical NPs (+PVA NPs) and chitosan-coated NPs. Finally, the efficacy of insulin SDS-NPs was demonstrated in vivo (100 or 250 UI insulin/kg) with a reduction of blood glucose levels in diabetic rats. Formulation of negatively charged NPs represents a promising approach to improve NP uptake and insulin bioavailability for oral delivery.


Assuntos
Portadores de Fármacos/administração & dosagem , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Nanopartículas/administração & dosagem , Dodecilsulfato de Sódio/administração & dosagem , Animais , Disponibilidade Biológica , Glicemia/análise , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/uso terapêutico , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Insulina/química , Insulina/farmacocinética , Insulina/uso terapêutico , Ácido Láctico/administração & dosagem , Ácido Láctico/química , Ácido Láctico/farmacocinética , Ácido Láctico/uso terapêutico , Masculino , Nanopartículas/química , Nanopartículas/uso terapêutico , Ácido Poliglicólico/administração & dosagem , Ácido Poliglicólico/química , Ácido Poliglicólico/farmacocinética , Ácido Poliglicólico/uso terapêutico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos Wistar , Dodecilsulfato de Sódio/química , Dodecilsulfato de Sódio/farmacocinética , Dodecilsulfato de Sódio/uso terapêutico , Propriedades de Superfície
16.
Eur J Pharm Sci ; 118: 24-31, 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29555501

RESUMO

For patient convenience, sustained release Adefovir Poly-d,l-lactic-co-glycolic acid (PLGA) microspheres were formulated to relieve the daily use of the drug which is a problem for patients treated from chronic hepatitis-B. PLGA microspheres were prepared and characterized by entrapment efficiency, particle size distribution and scanning electron microscopy (SEM). In-vitro release and in-vivo studies were carried out. Factors such as drug: polymer ratio, polymer viscosity and polymer lactide content were found to be important variables for the preparation of PLGA Adefovir microspheres. Fourier transform infrared (FTIR) analysis and differential scanning calorimetry (DSC) were performed to determine any drug-polymer interactions. One way analysis of variance (ANOVA) was employed to analyze the pharmacokinetic parameters after intramuscular injection of the pure drug and the selected PLGA microspheres into rats. FTIR and DSC revealed a significant interaction between the drug and the polymer. Reports of SEM before and after 1 and 24 h release showed that the microspheres had nonporous smooth surface even after 24 h release. The entrapment efficiency ranged between 55.83 and 86.95% and in-vitro release studies were continued for 16, 31 and 90 days. The pharmacokinetic parameters and statistical analysis showed a significant increase in the Tmax, AUC0-t and MRT, and a significant decrease in the Cmax of the tested formulation (p < 0.05). Results demonstrated that PLGA Adefovir microspheres could be used for long-term treatment of chronic hepatitis-B instead of the daily dose used by the patient.


Assuntos
Adenina/análogos & derivados , Antivirais/administração & dosagem , Sistemas de Liberação de Medicamentos , Ácido Láctico/administração & dosagem , Microesferas , Organofosfonatos/administração & dosagem , Ácido Poliglicólico/administração & dosagem , Adenina/administração & dosagem , Adenina/sangue , Adenina/química , Adenina/farmacocinética , Animais , Antivirais/sangue , Antivirais/química , Antivirais/farmacocinética , Liberação Controlada de Fármacos , Hepatite B Crônica/tratamento farmacológico , Ácido Láctico/química , Ácido Láctico/farmacocinética , Masculino , Organofosfonatos/sangue , Organofosfonatos/química , Organofosfonatos/farmacocinética , Tamanho da Partícula , Ácido Poliglicólico/química , Ácido Poliglicólico/farmacocinética , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos
17.
Eur J Pharm Sci ; 118: 32-39, 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29551530

RESUMO

Tumor pH detection and pH value change monitoring have been of great interest in the field of nanomedicine. In this study, a pH-sensitive near-infrared fluorescence probe SiRB (Si-rhodamine and Boronic acid group) was synthesized by introducing a boronic acid group into the silicon rhodamine structure. ICG (Indocyanine green) as the fluorescence internal standard and SiRB were loaded into PLGA (poly lactic-co-glycolic acid) to form PLGA-SiRB-ICG nanoparticle. The experiments showed that the size of the nanoparticle was about 90 nm, which can reach tumor passively by enhancing permeability and retention effect. PLGA in the acidic environment will accelerate the release of cleavage, and the fluorescence ratio of the two probes can reflect the specific pH value in the tumor. The results indicated that the nanoparticle could quantitatively measure the pH value of the tumor site, which is expected to be used in tumor research and treatment.


Assuntos
Corantes Fluorescentes/administração & dosagem , Nanopartículas/administração & dosagem , Neoplasias/química , Animais , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/química , Sobrevivência Celular/efeitos dos fármacos , Fluorescência , Corantes Fluorescentes/química , Humanos , Concentração de Íons de Hidrogênio , Verde de Indocianina/administração & dosagem , Verde de Indocianina/química , Ácido Láctico/administração & dosagem , Ácido Láctico/química , Células MCF-7 , Camundongos , Microscopia Confocal , Nanopartículas/química , Neoplasias/metabolismo , Imagem Óptica , Ácido Poliglicólico/administração & dosagem , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Rodaminas/administração & dosagem , Rodaminas/química , Silício/administração & dosagem , Silício/química
18.
Curr Drug Deliv ; 15(8): 1193-1203, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29557743

RESUMO

OBJECTIVE: Formulation of injectable In situ forming implant (ISI) systems of lornoxicam for dental and postoperative pain management to decrease dosing frequency and increase patient compliance. METHODS: Polymeric in situ implant solutions were prepared using different concentrations and inherent viscosities of Poly-DL-lactide (PDL) or DL-lactide/glycolide copolymer (PDLG) using 22X4 factorial experimental design. Nonpolymeric systems were prepared using different concentrations of lipids like cetyl alcohol and stearyl alcohol and also sucrose acetate isobutyrate (SAIB) using 32 factorial experimental design. In vitro release study, rheological measurement, syringeability assessment and effect of γ-sterilization were used for evaluation of the prepared formulae. In vivo pharmacokinetic study of lornoxicam from the most optimum formula was conducted in a rabbit model using HPLC analysis of blood samples. RESULTS: Polymeric systems showed high burst release followed by very slow release rate over 72 hours. Formula I 24 (containing SAIB 80% (w/w)) showed relatively low burst release followed by diffusion controlled release pattern, low viscosity, Newtonian flow behavior and good syringeability. γ- sterilization had no significant effect on the in vitro release and the physical nature of the most optimum formula. In vivo study concluded that intramuscularly injected In situ implant formula I 24 showed prolonged release pattern compared to the marketed product which was indicated by the increased Tmax and the extended mean residence time. CONCLUSION: Lornoxicam ISI systems could be promising as convenient injectable sustained release delivery systems for dental and postoperative pain management.


Assuntos
Anti-Inflamatórios não Esteroides , Implantes de Medicamento , Piroxicam/análogos & derivados , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/sangue , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacocinética , Liberação Controlada de Fármacos , Álcoois Graxos/administração & dosagem , Álcoois Graxos/química , Injeções , Masculino , Dor Pós-Operatória/tratamento farmacológico , Piroxicam/administração & dosagem , Piroxicam/sangue , Piroxicam/química , Piroxicam/farmacocinética , Poliésteres/administração & dosagem , Poliésteres/química , Ácido Poliglicólico/administração & dosagem , Ácido Poliglicólico/química , Coelhos , Viscosidade
19.
Int J Pharm ; 542(1-2): 232-241, 2018 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-29559330

RESUMO

It is difficult to effectively eradicate C. albicans using traditional antifungal agents, mainly because the low permeability of the C. albicans cell wall creates strong drug resistance. The aim of this study was to investigate the synergistic fungicidal effect and the underlying mechanisms of low-frequency and low-intensity ultrasound combined with a treatment of amphotericin B-loaded nanoparticles (AmB-NPs) against C. albicans. AmB-NPs were prepared by a poly(lactic-co-glycolic acid) (PLGA) double emulsion method. C. albicans was treated by AmB-NPs combined with 42 kHz ultrasound irradiation at an intensity of 0.30 W/cm2 for 15 min. The results demonstrate that the application of ultrasound enhanced the antibacterial effectiveness of AmB-NPs (P < 0.01), and the antifungal efficiency increased significantly with increasing AmB concentration of drug-loaded nanoparticles under ultrasonic irradiation. Additionally, the mycelial morphology of C. albicans suffered from the most severe damage and loss of normal microbial morphology after the combined treatment of AmB-NPs and ultrasound, as revealed by electron microscope. Furthermore, we verified the safe use of low-frequency ultrasound on exposed skin and discussed the potential mechanism of ultrasound enhanced fungicidal activity. The results reveal that the mechanism may be associated with the ultrasound cavitation effect and an increase in intracellular reactive oxygen species.


Assuntos
Anfotericina B/administração & dosagem , Antifúngicos/administração & dosagem , Candida albicans/efeitos dos fármacos , Candida albicans/efeitos da radiação , Nanopartículas/administração & dosagem , Ondas Ultrassônicas , Anfotericina B/química , Animais , Antifúngicos/química , Candida albicans/metabolismo , Candida albicans/ultraestrutura , Ácido Láctico/administração & dosagem , Ácido Láctico/química , Camundongos , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Nanopartículas/química , Ácido Poliglicólico/administração & dosagem , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Espécies Reativas de Oxigênio/metabolismo , Pele/efeitos da radiação , Sonicação
20.
AAPS PharmSciTech ; 19(4): 1652-1661, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29516291

RESUMO

Etoposide-loaded poly(lactic-co-glycolic acid) implants were developed for intravitreal application. Implants were prepared by a solvent-casting method and characterized in terms of content uniformity, morphology, drug-polymer interaction, stability, and sterility. In vitro drug release was investigated and the implant degradation was monitored by the percent of mass loss. Implants were inserted into the vitreous cavity of rabbits' eye and the in vivo etoposide release profile was determined. Clinical examination and the Hen Egg Test-Chorioallantoic Membrane (HET-CAM) method were performed to evaluate the implant tolerance. The original chemical structure of the etoposide was preserved after incorporation in the polymeric matrix, which the drug was dispersed uniformly. In vitro, implants promoted sustained release of the drug and approximately 57% of the etoposide was released in 50 days. In vivo, devices released approximately 63% of the loaded drug in 42 days. Ophthalmic examination and HET-CAM assay revealed no evidence of toxic effects of implants. These results tend to show that etoposide-loaded implants could be potentially useful as an intraocular etoposide delivery system in the future.


Assuntos
Implantes de Medicamento/metabolismo , Etoposídeo/metabolismo , Ácido Láctico/metabolismo , Ácido Poliglicólico/metabolismo , Corpo Vítreo/metabolismo , Animais , Galinhas , Implantes de Medicamento/administração & dosagem , Implantes de Medicamento/química , Etoposídeo/administração & dosagem , Etoposídeo/química , Injeções Intravítreas , Ácido Láctico/administração & dosagem , Ácido Láctico/química , Masculino , Ácido Poliglicólico/administração & dosagem , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Coelhos , Corpo Vítreo/efeitos dos fármacos
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