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1.
Nat Commun ; 11(1): 4450, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895379

RESUMO

Hollow multishelled structures (HoMSs), with relatively isolated cavities and hierarchal pores in the shells, are structurally similar to cells. Functionally inspired by the different transmission forms in living cells, we studied the mass transport process in HoMSs in detail. In the present work, after introducing the antibacterial agent methylisothiazolinone (MIT) as model molecules into HoMSs, we discover three sequential release stages, i.e., burst release, sustained release and stimulus-responsive release, in one system. The triple-shelled structure can provide a long sterility period in a bacteria-rich environment that is nearly 8 times longer than that of the pure antimicrobial agent under the same conditions. More importantly, the HoMS system provides a smart responsive release mechanism that can be triggered by environmental changes. All these advantages could be attributed to chemical diffusion- and physical barrier-driven temporally-spatially ordered drug release, providing a route for the design of intelligent nanomaterials.


Assuntos
Antibacterianos/administração & dosagem , Preparações de Ação Retardada/administração & dosagem , Portadores de Fármacos/química , Nanoestruturas/química , Antibacterianos/farmacocinética , Preparações de Ação Retardada/farmacocinética , Difusão , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Microesferas , Tiazóis/administração & dosagem , Tiazóis/farmacocinética
2.
Paediatr Drugs ; 22(5): 561-570, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32776159

RESUMO

OBJECTIVE: This was a single-dose, one-period, multicenter, pharmacokinetic (PK) study to evaluate the PK of methylphenidate (MPH) hydrochloride multilayer extended-release capsules (MPH-MLR) in preschool children aged 4 to < 6 years, previously diagnosed with attention-deficit/hyperactivity disorder (ADHD), and on a stable dose of MPH. METHODS: Preschool-aged children (N = 10) received a single oral dose of MPH-MLR (10, 15, or 20 mg) sprinkled over applesauce; a dose equivalent to their pre-enrollment daily dose of MPH. Blood samples for the measurement of MPH concentrations were obtained pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 h post-dose. No structural model was assumed in the derivation of PK values for analysis. Maximum plasma concentration (Cmax), area under the concentration-time curve (AUC), elimination half-life, clearance (CL), and volume of distribution (Vd) data were compared with a historical group of older children aged 6-11 years (N = 11) and analyzed by bodyweight. Safety (adverse event monitoring, vital signs, electrocardiogram, clinical laboratory testing, physical examination) was assessed. RESULTS: Mean dose-normalized Cmax and area under the curve to the last measurable observation (AUC0-t) values were similar across dose groups, ranging from 0.67 ng/mL/mg (MPH 15 mg) to 0.81 ng/mL/mg (MPH 10 mg) for Cmax/dose, and from 7.80 h × ng/mL/mg (MPH 20 mg) to 8.92 h × ng/mL/mg (MPH 10 mg) for AUC0-t/dose. PK results were integrated into a previously described pharmacostatistical population PK model. Visual predictive check plots showed greater variability in the 6- to 11-year-old group than the 4- to < 6-year-old group, and CL increased with increasing body weight in a greater than dose-proportional manner. Mean CL, normalized for body weight, was constant for all dose groups, ranging from 4.88 L/h/kg to 5.80 L/h/kg. Median time to Cmax ranged from 2.00 to 3.00 h post-dose, and overall, dose-normalized Cmax concentrations indicated greater systemic exposures of MPH-MLR in preschool children aged 4 to < 6 years compared with children aged 6-11 years. Children aged 4 to < 6 years had a lower Vd than children aged 6-11 years. There were no unexpected safety signals. CONCLUSION: The PK of MPH-MLR in preschool children demonstrated the biphasic absorption profile described earlier in older children, and the PK profile in children with ADHD aged 4 to < 6 years was similar to the profile in those aged 6-11 years, apart from a lower Vd and relatively higher systemic MPH levels for children in the preschool group. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02470234.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/sangue , Estimulantes do Sistema Nervoso Central/farmacocinética , Metilfenidato/farmacocinética , Adulto , Peso Corporal , Cápsulas , Estimulantes do Sistema Nervoso Central/efeitos adversos , Estimulantes do Sistema Nervoso Central/sangue , Criança , Pré-Escolar , Preparações de Ação Retardada/efeitos adversos , Preparações de Ação Retardada/farmacocinética , Feminino , Humanos , Masculino , Metilfenidato/efeitos adversos , Metilfenidato/sangue , Modelos Biológicos
3.
Int J Nanomedicine ; 15: 5377-5387, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32848384

RESUMO

Background: Periodontal pathogenic bacteria promote the destruction of periodontal tissues and cause loosening and loss of teeth in adults. However, complete removal of periodontal pathogenic bacteria, at both the bottom of the periodontal pocket and the root bifurcation area, remains challenging. In this work, we explored a synergistic antibiotic and photothermal treatment, which is considered an alternative strategy for highly efficient periodontal antibacterial therapy. Methods: Mesoporous silica (MSNs) on the surface of Au nanobipyramids (Au NBPs) were designed to achieve the sustained release of the drug and photothermal antibacterials. The mesoporous silica-coated Au NBPs (Au NBPs@SiO2) were mixed with gelatin methacrylate (GelMA-Au NBPs@SiO2). Au NBPs@SiO2 and GelMA-Au NBPs@SiO2 hybrid hydrogels were characterized, and the drug content and photothermal properties in terms of the release profile, bacterial inhibition, and cell growth were investigated. Results: The GelMA-Au NBPs@SiO2 hybrid hydrogels showed controllable minocycline delivery, and the drug release rates increased under 808 nm near-infrared (NIR) light irradiation. The hydrogels also exhibited excellent antibacterial properties, and the antibacterial efficacy of the antibiotic and photothermal treatment was as high as 90% and 66.7% against Porphyromonas gingivalis (P. gingivalis), respectively. Moreover, regardless of NIR irradiation, cell viability was over 80% and the concentration of Au NBPs@SiO2 in the hybrid hydrogels was as high as 100 µg/mL. Conclusion: We designed a new near-infrared light (NIR)-activated hybrid hydrogel that offers both sustained release of antibacterial drugs and photothermal treatment. Such sustained release pattern yields the potential to rapidly eliminate periodontal pathogens in the periodontal pocket, and the photothermal treatment maintains low bacterial retention after the drug treatment.


Assuntos
Antibacterianos/farmacologia , Hidrogéis/química , Hidrogéis/farmacologia , Porphyromonas gingivalis/efeitos dos fármacos , Animais , Antibacterianos/química , Antibacterianos/farmacocinética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Liberação Controlada de Fármacos , Ouro/química , Hidrogéis/farmacocinética , Hidrogéis/efeitos da radiação , Lasers , Metacrilatos/química , Camundongos , Minociclina/química , Minociclina/farmacocinética , Minociclina/farmacologia , Nanoestruturas/química , Doenças Periodontais/tratamento farmacológico , Doenças Periodontais/microbiologia , Fototerapia/métodos , Dióxido de Silício/química
4.
Int J Nanomedicine ; 15: 5603-5612, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32848390

RESUMO

Introduction: Organ transplantation is a critically important procedure, which requires immune modulation by using immunosuppressants. Development of nanoparticles is an emerging and beneficial engineering process to increase the dissolution rate of poorly soluble immunosuppressants as well as to provide controlled release for better therapeutic outcomes. Method: Currently, the nanoprecipitation method was employed to fabricate ß-cyclodextrin (ßCD) facilitated mycophenolate mofetil (MMF)-loaded solid lipid nanoparticles (SLNPs). The prime objectives of the study included, improvement of the dissolution profile of poorly aqueous soluble drug and controlled release from the SLNs to provide steady state drug concentration. Drug release from the prepared SLNs was assessed in two different media, ie, acidic buffer at pH 1.2 and phosphate buffer at pH 7.2 using USP dissolution apparatus for 12 h, followed by the evaluation of drug release mechanism and pattern by applying kinetic models. Results: Justifiably, in acidic medium, the release was found to be 12% more (68%) in comparison to that in basic medium (56%). However, in both dissolution media, drug release was independent of initial concentration (R2>0.95) with non-Fickian type of diffusion mechanism. The outcomes of the study have exhibited that prepared formulations were in nanosized range (80-170 nm) with a net charge of ±23 charge on their surface. They possessed fairly uniform surface with acceptable polydispersity index (0.23±0.09). Scanning electron microscopy (SEM) analysis illustrated that the nanoparticles had uniform particle size and shape. Discussion: The findings show potential applications of the nanoparticles and the method for the development of SLNPs in controlled release of MMF for better therapeutic outcomes. Conclusively, the prepared SLNPs were well designed in nanosized ranges and justifying the once daily controlled release formulation dose of MMF to enhance patient compliance.


Assuntos
Portadores de Fármacos/química , Imunossupressores/farmacocinética , Ácido Micofenólico/farmacocinética , Nanopartículas/química , Disponibilidade Biológica , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Difusão , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Imunossupressores/química , Lipídeos/química , Microscopia Eletrônica de Varredura , Ácido Micofenólico/química , Nanopartículas/administração & dosagem , Tamanho da Partícula , Solubilidade , beta-Ciclodextrinas/química
5.
AAPS PharmSciTech ; 21(5): 195, 2020 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-32666354

RESUMO

The objective of this study was to develop a dissolution test in order to establish an in vitro-in vivo correlation (IVIVC) model for desvenlafaxine succinate monohydrate (DVSM) extended release (ER) tablets. The in vitro release characteristics of the drug were determined using USP apparatus 1 at 75 rpm, with volume of HCl pH 1.2, acetate buffer solution (ABS) pH 4.5, or phosphate buffer solution (PBS) pH 6.8. In vivo plasma concentrations and pharmacokinetic parameters in healthy volunteers were obtained from a bioequivalence study. The similarity factors f1 and f2 were used to compare the dissolution data. The IVIVC model was developed using fraction dissolved and fraction absorbed of the reference product. For predictability, the results showed that the percentage prediction error (%PE) value of Cmax was 7.63%. The observed low prediction error for Cmax demonstrated that the IVIVC model was valid for this parameter.


Assuntos
Succinato de Desvenlafaxina/administração & dosagem , Inibidores da Recaptação de Serotonina e Norepinefrina/administração & dosagem , Comprimidos , Adulto , Área Sob a Curva , Preparações de Ação Retardada/farmacocinética , Succinato de Desvenlafaxina/farmacocinética , Meia-Vida , Humanos , Técnicas In Vitro , Masculino , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacocinética , Solubilidade , Adulto Jovem
6.
Pharm. pract. (Granada, Internet) ; 18(2): 0-0, abr.-jun. 2020. tab, graf
Artigo em Inglês | IBECS | ID: ibc-194054

RESUMO

OBJECTIVE: To determine the accuracy, variability, and weight uniformity of tablet subdivision techniques utilized to divide the tablets of five drug products that are commonly prescribed for use as half tablets in Jordan. METHODS: Ten random tablets of five commonly subdivided drug products were weighed and subdivided using three subdivision techniques: hand breaking, kitchen knife, and tablet cutter. The five commonly subdivided drug products (warfarin 5 mg, levothyroxine 50 μg, levothyroxine 100 μg, candesartan 16 mg, and carvedilol 25 mg) were weighed. The weights were analyzed for acceptance, accuracy, and variability. Weight variation acceptance criteria were adopted in this work as a tool to indicate the properness of the subdivision techniques used to produce acceptable half tablets. Other relevant physical characteristics of the five products such as tablet shape, dimensions, face curvature, score depth, and crushing strength were measured. RESULTS: All tablets were round in shape, had weights that ranged between 100.63 mg (standard deviation=0.99) and 379.04 mg (standard deviation=3.00), and had crushing strengths that ranged between 23.29 N (standard deviation=3.58)and 103.35 N (standard deviation=14.98). Both candesartan and carvedilol were bi-convex in shape with an extent of face curvature equal to about 33%. In addition, percentage score depth of the tablets had a range between 0% and 24%. The accuracy and variability of subdivision varied according to the subdivision technique used and tablet characteristics. Accuracy range was between 81% and 109.8%. Moreover, the relative standard deviation was between 1.5% and 17.4%. Warfarin 5 mg subdivided tablets failed the weight variation test regardless of the subdivision technique used. Subdivision by hand produced half tablets that were acceptable for levothyroxine 50 μg and levothyroxine 100 μg. Subdivision by knife produced half tablets that were acceptable only for candesartan tablets. However, the tablet cutter produced half tablets that passed the weight variation test for four out of the five drug products tested in this study. CONCLUSIONS: The tablet cutter performed better than the other subdivision techniques used. It produced half tablets that passed the weight uniformity test for four drug products out of the five


No disponible


Assuntos
Humanos , Comprimidos/uso terapêutico , Autoadministração , Prescrições de Medicamentos , Reprodutibilidade dos Testes , Comprimidos/química , Tecnologia Farmacêutica/métodos , Erros de Medicação/prevenção & controle , Jordânia , Comprimidos/farmacocinética , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética
7.
AAPS PharmSciTech ; 21(5): 161, 2020 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488427

RESUMO

Development of generic extended-release (ER) formulations is challenging. Especially under fed conditions, the risk of failure in bioequivalence trials is high because of long gastric residence times and susceptibility to food effects. We describe the development of a generic trazodone ER formulation that was aided with a biorelevant dissolution evaluation. Trazodone hydrochloride 300-mg monolithic matrix tablets were dissolved both in USP and EMA compliant conditions and in the StressTest device that simulated both physicochemical and mechanical conditions of the gastrointestinal passage. The final formulation was tested against the originator, Trittico XR 300 mg, in a randomized cross-over bioequivalence trial with 44 healthy volunteers, in agreement with EMA guidelines. Initially developed formulations dissolved trazodone similarly to the originator under standard conditions (f2 factor above 50), but their dissolution kinetics differed significantly in the biorelevant tests. The formulation was optimized by the addition of low-viscosity hypromellose and mannitol. The final formulation was approved for the bioequivalence trial. Calculated Cmax were 1.92 ± 0.77 and 1.92 ± 0.63 [µg/mL], AUC0-t were 27.46 ± 8.39 and 29.96 ± 9.09 [µg∙h/mL], and AUC0-∞ were 28.22 ± 8.91 and 30.82 ± 9.41 [µg∙h/mL] for the originator and test formulations, respectively. The 90% confidence intervals of all primary pharmacokinetic parameters fell within the 80-125% range. In summary, biorelevant dissolution tests supported successful development of a generic trazodone ER formulation pharmaceutically equivalent with the originator under fed conditions. Employment of biorelevant dissolution tests may decrease the risk of failure in bioequivalence trials of ER formulations.


Assuntos
Desenvolvimento de Medicamentos , Inibidores de Captação de Serotonina/administração & dosagem , Trazodona/administração & dosagem , Adulto , Área Sob a Curva , Química Farmacêutica , Estudos Cross-Over , Preparações de Ação Retardada/farmacocinética , Feminino , Humanos , Masculino , Inibidores de Captação de Serotonina/farmacocinética , Solubilidade , Equivalência Terapêutica , Trazodona/farmacocinética
8.
J Pharmacokinet Pharmacodyn ; 47(3): 189-198, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32435882

RESUMO

To face SARS-CoV-2 pandemic various attempts are made to identify potential effective treatments by repurposing available drugs. Among them, indomethacin, an anti-inflammatory drug, was shown to have potent in-vitro antiviral properties on human SARS-CoV-1, canine CCoV, and more recently on human SARS-CoV-2 at low micromolar range. Our objective was to show that indomethacin could be considered as a promising candidate for the treatment of SARS-CoV-2 and to provide criteria for comparing benefits of alternative dosage regimens using a model-based approach. A multi-stage model-based approach was developed to characterize % of recovery and viral load in CCoV-infected dogs, to estimate the PK of indomethacin in dog and human using published data after administration of immediate (IR) and sustained-release (SR) formulations, and to estimate the expected antiviral activity as a function of different assumptions on the effective exposure in human. Different dosage regimens were evaluated for IR formulation (25 mg and 50 mg three-times-a-day, and 25 mg four-times-a-day), and SR formulation (75 mg once and twice-a-day). The best performing dosing regimens were: 50 mg three-times-a-day for the IR formulation, and 75 mg twice-a-day for the SR formulation. The treatment with the SR formulation at the dose of 75 mg twice-a-day is expected to achieve a complete response in three days for the treatment in patients infected by the SARS-CoV-2 coronavirus. These results suggest that indomethacin could be considered as a promising candidate for the treatment of SARS-CoV-2 whose potential therapeutic effect need to be further assessed in a prospective clinical trial.


Assuntos
Antivirais/administração & dosagem , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Cálculos da Dosagem de Medicamento , Indometacina/administração & dosagem , Indometacina/uso terapêutico , Modelos Biológicos , Pneumonia Viral/tratamento farmacológico , Animais , Antivirais/farmacocinética , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/virologia , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/uso terapêutico , Cães , Humanos , Indometacina/farmacocinética , Pandemias , Pneumonia Viral/virologia , Carga Viral/efeitos dos fármacos
9.
Rev. psiquiatr. infanto-juv ; 37(1): 29-33, ene.-mar. 2020.
Artigo em Espanhol | IBECS | ID: ibc-193562

RESUMO

El Trastorno obsesivo-compulsivo constituye una patología grave e incapacitante. El tratamiento de primera línea no consigue una remisión completa en casi la mitad de los pacientes. En adultos se ha demostrado la utilidad del tratamiento coadyuvante con aripiprazol en estos casos. En adolescentes la evidencia al respecto es escasa, aunque se han publicado algunos resultados prometedores. Tampoco se dispone de evidencia suficiente sobre la eficacia y seguridad de los antipsicóticos inyectables de liberación prolongada en población adolescente, por lo que sólo se recomiendan en trastornos psicóticos con respuesta insuficiente por falta de adherencia. Sin embargo, algunos autores proponen extender su utilización a otras patologías. Se presenta el caso de una paciente adolescente con trastorno obsesivocompulsivo resistente al tratamiento de primera línea, en la que la utilización coadyuvante de aripiprazol inyectable de liberación prolongada permite un buen control de la clínica obsesiva y contribuye a evitar nuevas descompensaciones


Obsessive-compulsive disorder is a severe and disabling pathology. First-line treatment does not achieve full remission in almost half of patients. In adults, the efficacy of the adjuvant treatment with aripiprazole has been demonstrated in these cases. There is not enough evidence in the adolescent population, although some promising results have been published. Scant evidence is available on the efficacy and safety of long-acting injectable antipsychotics in adolescents. Their use is recommended only in psychotic disorders with insufficient response due to lack of adherence. However, some authors suggest their use in other pathologies. The case of an adolescent patient with obsessive-compulsive disorder resistant to first-line treatment is presented. The adjuvant use of long-acting injectable aripiprazole allows for good control of the obsessive symptoms and helps prevent future episodes


Assuntos
Humanos , Feminino , Adolescente , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Aripiprazol/administração & dosagem , Sertralina/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Injeções Intramusculares/métodos , Aripiprazol/farmacocinética , Sertralina/farmacocinética , Exacerbação dos Sintomas
10.
Nature ; 579(7799): 421-426, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32188939

RESUMO

Bioorthogonal chemistry capable of operating in live animals is needed to investigate biological processes such as cell death and immunity. Recent studies have identified a gasdermin family of pore-forming proteins that executes inflammasome-dependent and -independent pyroptosis1-5. Pyroptosis is proinflammatory, but its effect on antitumour immunity is unknown. Here we establish a bioorthogonal chemical system, in which a cancer-imaging probe phenylalanine trifluoroborate (Phe-BF3) that can enter cells desilylates and 'cleaves' a designed linker that contains a silyl ether. This system enabled the controlled release of a drug from an antibody-drug conjugate in mice. When combined with nanoparticle-mediated delivery, desilylation catalysed by Phe-BF3 could release a client protein-including an active gasdermin-from a nanoparticle conjugate, selectively into tumour cells in mice. We applied this bioorthogonal system to gasdermin, which revealed that pyroptosis of less than 15% of tumour cells was sufficient to clear the entire 4T1 mammary tumour graft. The tumour regression was absent in immune-deficient mice or upon T cell depletion, and was correlated with augmented antitumour immune responses. The injection of a reduced, ineffective dose of nanoparticle-conjugated gasdermin along with Phe-BF3 sensitized 4T1 tumours to anti-PD1 therapy. Our bioorthogonal system based on Phe-BF3 desilylation is therefore a powerful tool for chemical biology; our application of this system suggests that pyroptosis-induced inflammation triggers robust antitumour immunity and can synergize with checkpoint blockade.


Assuntos
Preparações de Ação Retardada/administração & dosagem , Neoplasias Mamárias Experimentais/imunologia , Piroptose/imunologia , Animais , Cumarínicos/administração & dosagem , Cumarínicos/química , Cumarínicos/metabolismo , Cumarínicos/farmacocinética , Preparações de Ação Retardada/química , Preparações de Ação Retardada/metabolismo , Preparações de Ação Retardada/farmacocinética , Feminino , Proteínas de Fluorescência Verde/administração & dosagem , Proteínas de Fluorescência Verde/química , Proteínas de Fluorescência Verde/metabolismo , Proteínas de Fluorescência Verde/farmacocinética , Células HeLa , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/química , Imunoconjugados/metabolismo , Imunoconjugados/farmacocinética , Inflamassomos/imunologia , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Oligopeptídeos/administração & dosagem , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Oligopeptídeos/farmacocinética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Proteínas/administração & dosagem , Proteínas/química , Proteínas/metabolismo , Proteínas/farmacocinética , Silanos/administração & dosagem , Silanos/química , Silanos/metabolismo , Silanos/farmacocinética , Linfócitos T/imunologia , Trastuzumab/administração & dosagem , Trastuzumab/química , Trastuzumab/metabolismo , Trastuzumab/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
11.
AAPS PharmSciTech ; 21(3): 93, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32076885

RESUMO

To explore the potential utility of combination of hydrophilic matrix with membrane-controlled technology, the present study prepared tablets of a water-soluble model drug (ambroxol hydrochloride), through process of direct compression and spray coating. Single-factor experiments were accomplished to optimize the formulation. In vivo pharmacokinetics was then performed to evaluate the necessity and feasibility of further development of this simple process and low-cost approach. Various release rates could be easily obtained by adjusting the viscosity and amount of hypromellose, pore-former ratios in coating dispersions and coating weight gains. Dissolution profiles of coated tablets displayed initial delay, followed by near zero-order kinetics. The pharmacokinetic study of different formulations showed that lag time became longer as the permeability of coating membrane decreased, which was consistent with the in vitro drug release trend. Besides, in vitro/in vivo correlation study indicated that coated tablets exhibited a good correlation between in vitro release and in vivo absorption. The results, therefore, demonstrated that barrier-membrane-coated matrix formulations were extremely promising for further application in industrialization and commercialization.


Assuntos
Ambroxol/síntese química , Ambroxol/farmacocinética , Expectorantes/síntese química , Expectorantes/farmacocinética , Interações Hidrofóbicas e Hidrofílicas , Animais , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/farmacocinética , Cães , Avaliação Pré-Clínica de Medicamentos/métodos , Liberação Controlada de Fármacos , Derivados da Hipromelose/síntese química , Derivados da Hipromelose/farmacocinética , Permeabilidade , Distribuição Aleatória , Solubilidade , Comprimidos , Viscosidade
12.
Sci Rep ; 10(1): 1964, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029776

RESUMO

Trazodone hydrochloride (TRH) is a lipophilic drug which is used effectively as an antidepressant. Its poor solubility and short half-life represent an obstacle for its successful use. Nanocapsules with biodegradable polymeric shell are successful drug delivery systems for controlling the release of drugs. To enhance the entrapment of lipophilic drugs, oils can be added forming a lipophilic core in which the drug is more soluble. The aim of this study was to enhance the efficacy of TRH and prolong its action by formulating it into lipid core polymeric shell nanocapsules. Nanocapules were prepared using nanoprecipitation technique. All prepared formulations were in nano size range and negatively charged. The TRH entrapment efficiency (EE%) in lipid core nanocapsules was up to 74.8 ± 0.5% when using Labrafac lipophile as a lipid core compared to only 55.7 ± 0.9% in lipid free polymeric nanospheres. Controlled TRH release was achieved for all prepared formulations. Forced swim test results indicated the significant enhancement of antidepressant effect of the selected TRH loaded Labrafac lipophile core nanocapsules formulation compared to control and TRH dispersion in phosphate buffer. It is concluded that lipid core nanocapsules is a promising carrier for the enhancement of TRH efficacy.


Assuntos
Antidepressivos/administração & dosagem , Depressão/tratamento farmacológico , Portadores de Fármacos/química , Nanocápsulas/química , Trazodona/administração & dosagem , Animais , Antidepressivos/farmacocinética , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Modelos Animais de Doenças , Composição de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Injeções Intraperitoneais , Lipídeos/química , Masculino , Camundongos , Tamanho da Partícula , Poliésteres/química , Solubilidade , Trazodona/farmacocinética
13.
Mater Sci Eng C Mater Biol Appl ; 108: 110466, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31923948

RESUMO

Essentially, the human body can release in different disease conditions specific biomolecules such as histamines when the body encounters a toxic substance, antibodies which are part of the body's natural immune response or nitric oxide as a cardiovascular signalling molecule. Design and development of "intelligent" delivery systems able to release the therapeutic agent only in the presence of bioactive compounds was presented here. Poly(N-isopropylacrylamide-co-N-(3-aminopropyl)methacrylamide)) (poly(NIPAAm-co-APM)) was synthesized as an exciting pH/temperature sensitive copolymer. Under physiological conditions (pH = 7.4), the APM in copolymer is in the ionized state (pKa = 8.7), highly hydrophilic and therefore the copolymer loses thermosensitive properties. Remarkably, after electrostatic interactions of APM with specific biomolecules, the copolymer restores the thermosensitive property. Thus, the microgels synthesized from this copolymer are in the "inactivated" state at normal physiological pH and temperature (pH = 7.4 and T = 36 °C). In the presence of specific biomolecules, microgels undergo "activation", shrink and expel mechanically a certain amount of drug. It must be mentioned that the pH-sensitive component plays the role of a biosensor, the biomolecule acts as a triggering agent, and the poly(NIPAAm) represents the delivery component (actuator). MTT tests showed that poly(NIPAAm-co-APM) microspheres are completely devoid of toxicity; moreover, the rabbit dermal fibroblasts vastly adhere to the surface of microspheres.


Assuntos
Derme/metabolismo , Portadores de Fármacos , Fibroblastos/metabolismo , Teste de Materiais , Animais , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Derme/citologia , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Fibroblastos/citologia , Concentração de Íons de Hidrogênio , Coelhos
14.
Mater Sci Eng C Mater Biol Appl ; 108: 110432, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31923974

RESUMO

Coaxial electrospinning with the ability to use simultaneously two separate solvents provides a promising strategy for drug delivery. Nevertheless, controlled release of hydrophilic and sensitive therapeutics from slow biodegradable polymers is still challenging. To address this gap, we fabricated core-sheath fibers for dual delivery of lysozyme, as a model protein, and phenytoin sodium as a small therapeutic molecule. The sheath was processed by a gelatin solution while the core fibers were fabricated from an aqueous gelatin/PVA solution. Microstructural studies by transmission and scanning electron microscopy reveal the formation of homogeneous core-sheath nanofibers with an outer and inner diameter of 180 ± 48 nm and 106 ± 30 nm, respectively. Thermal gravimetric analysis determines that the mass loss of the core-sheath fibers fall between the mass loss values of individual sheath and core fibers. Swelling studies indicate higher water absorption of the core-sheath mat compared to the separate sheath and core membranes. In vitro drug release studies in Phosphate Buffered Saline (PBS) determine sustained release of the therapeutics from the core-sheath structure. The release trails three stages including non-Fickian diffusion at the early stage followed by the Fickian diffusion mechanism. The present study shows a useful approach to design core-sheath nanofibrous membranes with controlled and programmable drug release profiles.


Assuntos
Gelatina , Muramidase , Nanofibras/química , Fenitoína , Álcool de Polivinil , Animais , Linhagem Celular , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Gelatina/química , Gelatina/farmacologia , Camundongos , Muramidase/química , Muramidase/farmacocinética , Muramidase/farmacologia , Fenitoína/química , Fenitoína/farmacocinética , Fenitoína/farmacologia , Álcool de Polivinil/química , Álcool de Polivinil/farmacologia
15.
Mater Sci Eng C Mater Biol Appl ; 108: 110459, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31924031

RESUMO

In this work, a new pH-responsive nanohybrid carrier was prepared with chelating ZnO-dopamine (Zn-d) on the surface of graphene oxide. Doxorubicin (DOX) as a model drug was loaded on the resulted nanohybrid. The characteristics of Zn-d-rGO nanohybrid (NH) determined using Fourier transformed infrared spectroscopy (FT-IR), X-ray Diffraction spectroscopy (XRD), UV-Visible spectroscopy, Scanning Electron Microscope (SEM), EDX and AFM. The BET analysis showed a specific surface area of 37.16 m2/g and the obtained nanohybrid indicated a high loading capacity of DOX up to 99.7%, and the release profile displayed a pH-dependent discharge in the acidic environment for14 days. The cytotoxicity of the prepared nanohybrid was measured against T47D and MCF10A cells and it confirmed that as-prepared nanohybrid has high toxicity against cancer cells and lower effect against human breast cell. Meanwhile, the prepared nanohybrids showed well antimicrobial activity against gram-positive and negative bacteria. The obtained results showed that the prepared nanohybrid (Zn-d-rGO) could potentially be used as a safe carrier for drug delivery systems.


Assuntos
Antibacterianos , Quelantes , Dopamina , Doxorrubicina , Portadores de Fármacos , Grafite , Nanopartículas/química , Óxido de Zinco , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Linhagem Celular Tumoral , Quelantes/química , Quelantes/farmacocinética , Quelantes/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Dopamina/química , Dopamina/farmacocinética , Dopamina/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Grafite/química , Grafite/farmacocinética , Grafite/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Óxido de Zinco/química , Óxido de Zinco/farmacocinética , Óxido de Zinco/farmacologia
16.
Mater Sci Eng C Mater Biol Appl ; 108: 110455, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31924042

RESUMO

An amphiphilic biodegradable branched copolymer, mPEG-b-PLGA-g-OCol, was synthesized by grafting copolymer (methoxy polyethylene glycol)-b-Poly (l,d-lactic-co-glycolic acid) (mPEG-b-PLGA) on oligomeric collagen (OCol), to form a branched structure with mPEG-b-PLGA as side chain and OCol as backbone. mPEG-b-PLGA and mPEG-b-PLGA-g-OCol were both amphipathic and can self-assemble into micelles in aqueous solution. The mPEG-b-PLGA-g-OCol micelles showed pH-sensitive behaviors and the particle size below 100 nm in slightly acidic environment such as tumor tissue milieu interieur to perform passive targeting. Observed by SEM, when the solution pH increased from 5 to 9, the morphology of mPEG-b-PLGA-g-OCol micelles changed from small spheres to larger ones to rings. For biodegradable mPEG-b-PLGA-g-OCol, the micelles will gradually degrade in body. Further, doxorubicin (DOX) was effectively loaded in the micelles with drug loading and encapsulation efficiency of 3.48% and 25.8%, respectively. To evaluate antineoplastic effect of DOX-laden micelles in vitro, MTT test, flow cytometry and CLSM were performed and found that DOX-laden micelles exhibited higher cellular proliferation inhibition against HeLa cells. These features indicated that the mPEG-b-PLGA-g-OCol micelles were potential drug carrier for cancer therapy.


Assuntos
Plásticos Biodegradáveis , Portadores de Fármacos , Micelas , Plásticos Biodegradáveis/síntese química , Plásticos Biodegradáveis/química , Plásticos Biodegradáveis/farmacocinética , Plásticos Biodegradáveis/farmacologia , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Poliésteres/síntese química , Poliésteres/química , Poliésteres/farmacocinética , Poliésteres/farmacologia , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia
17.
Mater Sci Eng C Mater Biol Appl ; 108: 110194, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31923931

RESUMO

The thermal, physical, and morphological properties of diphenhydraminium ibuprofenate ([DIP][IBU]) adsorbed onto mesoporous silica (SiO2-60 Šand SiO2-90 Å) from solution were determined. The thermal, physical, and morphological properties of [DIP][IBU] supported on silica were determined. The adsorption of [DIP][IBU] on the pores and surface of silica was proven by N2 adsorption/desorption isotherms. Additionally, release profiles were determined for all systems, and the antinociceptive activity of neat [DIP][IBU] and [DIP][IBU] supported on silica were determined. The interaction of [DIP][IBU] and silica was dependent on pore size, with the formation of a [DIP][IBU] monolayer on SiO2-60 and a multilayer on SiO2-90. The release profile was sustained and slow and dependent on the pore size of the silica, in which the smaller the pore size, the faster the release. The nociceptive evaluation showed that [DIP][IBU] presents a greater (99.21 ±â€¯0.85%) antinociceptive effect than the ibuprofen (46 ±â€¯4.3%). Additionally, [DIP][IBU] on SiO2-60 (90 ±â€¯5.8%) had a greater antinociceptive effect than on SiO2-90 (73 ±â€¯13.2%), which indicates that in vivo tests are in accordance with the in vitro experiments.


Assuntos
Analgésicos , Ibuprofeno , Dor/tratamento farmacológico , Dióxido de Silício , Analgésicos/química , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Avaliação Pré-Clínica de Medicamentos , Ibuprofeno/análogos & derivados , Ibuprofeno/química , Ibuprofeno/farmacocinética , Ibuprofeno/farmacologia , Masculino , Camundongos , Dor/metabolismo , Dor/fisiopatologia , Porosidade , Dióxido de Silício/química , Dióxido de Silício/farmacocinética , Dióxido de Silício/farmacologia
18.
Mater Sci Eng C Mater Biol Appl ; 108: 110337, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31923987

RESUMO

Biodegradable, biocompatible and non-toxic polymer-based nanoparticles are the novel nanotherapeutic tool which is used for adsorption and encapsulation drugs. Extended release formulation of Norfloxacin antibiotic, chemotherapeutic agent model, drug in the form of encapsulated and loaded poly (lactic acid) nanocomposites-based Titanium dioxide (PLA/TiO2) was developed. Nanocomposites were prepared using different contents (1, 3, 5 wt %) and morphologies of TiO2 (spheres (S), rods (R). The dispersion of TiO2 was aided by ultrasonic technique followed by solution casting method. The morphology, particle size, crystallite size and composition of the nanocomposites were examined by SEM, TEM, XRD and FTIR. The crystallinity and thermal behavior of the nanocomposites were characterized by DSC and TGA. NOR was loaded onto TiO2 nanospheres (NOR@TiO2 (S)) and the optimum conditions for loading was investigated. Pseudo-second order model was the more adequate to represent the kinetic data. The equilibrium data followed Freundlich adsorption isotherm and the adsorption process was exothermic. NOR@TiO2 (S) was encapsulated into PLA and in vitro release behavior of drug was compared with NOR adsorbed into PLA (NOR@PLA) and nanocomposites (NOR@PLA/TiO2) using different pH (6.7, 7.4) media. To study the mechanism of NOR release, first order, Higuchi, Hixon Crowell and Korsmeyer-Peppas models were applied on the experimental results. The cytotoxicity of the loaded nanocomposites using MTT assay was studied against HepG 2, MCF-7, HCT 116, PC-3, Hela, WI-38 and WISH cells. The encapsulated (NOR@ 5S/En PLA) showed the highest cytotoxic efficacy with moderate effect on normal cells. Moreover, the nanocomposites have great potential against Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Salmonella and Klebsiella pneumonia. NOR@ PLA/TiO2 nanocomposites showed better antibacterial efficacy than NOR encapsulated nanocomposites. The nanocomposites could be effective vehicles for the sustained delivery of toxic anticancer drug.


Assuntos
Antineoplásicos , Nanocompostos , Neoplasias/tratamento farmacológico , Norfloxacino , Poliésteres , Titânio , Anti-Infecciosos/química , Anti-Infecciosos/farmacocinética , Anti-Infecciosos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Células HCT116 , Células HeLa , Células Hep G2 , Humanos , Células MCF-7 , Nanocompostos/química , Nanocompostos/uso terapêutico , Neoplasias/metabolismo , Neoplasias/patologia , Norfloxacino/química , Norfloxacino/farmacocinética , Norfloxacino/farmacologia , Células PC-3 , Poliésteres/química , Poliésteres/farmacocinética , Poliésteres/farmacologia , Titânio/química , Titânio/farmacocinética , Titânio/farmacologia
19.
Drug Dev Ind Pharm ; 46(2): 318-328, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31976771

RESUMO

Uncontrolled distribution of nanoparticles (NPs) within the body can significantly decrease the efficiency of drug therapy and is considered among the main restrictions of NPs application. The aim of this study was to develop a depot combination delivery system (CDS) containing fingolimod loaded poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) NPs dispersed into a matrix of oleic acid-grafted-aminated alginate (OA-g-AAlg) to minimize the nonspecific biodistribution (BD) of PHBV NPs. OA-g-AAlg was synthesized in two step; First, Alg was aminated by using adipic dihydrazide (ADH). The degree of hyrazide group substitution of Alg was determined by trinitro-benzene-sulfonic acid (TNBS) assay. Second, OA was attached to AAlg through formation of an amide bond. Chemical structure of OA-g-AAlg was confirmed with FTIR and HNMR spectroscopy. Furthermore, rheological properties of OA-g-AAlg with different grafting ratios were evaluated. In-vitro release studies indicated that 47% of fingolimod was released from the CDS within 28 days. Blood and tissue samples were analyzed using liquid chromatography/tandem mass spectrometry following subcutaneous (SC) injection of fingolimod-CDS into Wistar rats. The elimination phase half-life of CDS-fingolimod was significantly higher than that of fingolimod (∼32 d vs. ∼20 h). To investigate the therapeutic efficacy, lymphocyte count was assessed over a 40 day period in Wistar rats. Peripheral blood lymphocyte count decreased from baseline by 27 ± 8% in 2 days after injection. Overall, the designed CDS represented promising results in improving the pharmacokinetic properties of fingolimod. Therefore, we believe that this sustained release formulation has a great potential to be applied to delivery of various therapeutics.


Assuntos
Alginatos/química , Cloridrato de Fingolimode/química , Nanopartículas/química , Poliésteres/química , Animais , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Cloridrato de Fingolimode/farmacocinética , Cloridrato de Fingolimode/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Masculino , Ratos , Ratos Wistar , Distribuição Tecidual
20.
Carbohydr Polym ; 227: 115333, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31590864

RESUMO

The gold nanoparticles surface was modified by thioglycolic acid ligand and their surface was coated by the chitosan-grafted-poly(N-vinylcaprolactam) (chitosan-g-PNVCL) copolymer. The cisplatin anticancer drug was loaded into the synthesized nanocarriers and its performance was investigated for the treatment of MCF-7 breast cancer cells in vitro. The synthesized nanoparticles were characterized using FTIR, DLS, TEM, SEM, EDX and TGA analysis. The lower critical solution temperature (LCST) of PNVCL/chitosan and PNVCL/chitosan coated gold nanoparticles were found to be 38 and 39 °C, respectively. The cisplatin loading efficiency, cisplatin release from nanoparticles at different temperatures and pH values as well as the pharmacokinetic studies were examined. The maximum cisplatin release from nanoparticles was achieved at T > LCST (42 °C) and pH of 5. The Korsemeyer-Peppas model was best described the cisplatin release from nanoparticles. The maximum MCF cell death was found to be 92% using cisplatin loaded-gold/TGA/chitosan-g-PNVCL nanoparticles under an induction heating system.


Assuntos
Antineoplásicos , Caprolactama/análogos & derivados , Quitosana , Cisplatino , Ouro , Nanopartículas Metálicas , Polímeros , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Caprolactama/administração & dosagem , Caprolactama/química , Caprolactama/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Quitosana/administração & dosagem , Quitosana/química , Quitosana/farmacocinética , Cisplatino/administração & dosagem , Cisplatino/química , Cisplatino/farmacocinética , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Liberação Controlada de Fármacos , Ouro/administração & dosagem , Ouro/química , Humanos , Células MCF-7 , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/química , Polímeros/administração & dosagem , Polímeros/química , Polímeros/farmacocinética
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