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1.
Int J Nanomedicine ; 15: 6007-6018, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32884260

RESUMO

Background: Skin pharmacokinetics is an indispensable indication for studying the drug fate after administration of transdermal drug delivery systems (TDDS). However, the heterogeneity and complex skin structured with stratum corneum, viable epidermis, dermis, and subcutaneous tissue inevitably leads the drug diffusion coefficient (Kp) to vary depending on the skin depth, which seriously limits the development of TDDS pharmacokinetics in full thickness skin. Methods: A multilayer geometry skin model was established and the Kp of drug in SC, viable epidermis, and dermis was obtained using the technologies of molecular dynamics simulation, in vitro permeation experiments, and in vivo microdialysis, respectively. Besides, finite element analysis (FEA) based on drug Kps in different skin layers was applied to simulate the paeonol nanoemulsion (PAE-NEs) percutaneous dynamic penetration process in two and three dimensions. In addition, PAE-NEs skin pharmacokinetics profile obtained by the simulation was verified by in vivo experiment. Results: Coarse-grained modeling of molecular dynamic simulation was successfully established and the Kp of PAE in SC was 2.00×10-6 cm2/h. The Kp of PAE-NE in viable epidermis and in dermis detected using penetration test and microdialysis probe technology, was 1.58×10-5 cm2/h and 3.20×10-5 cm2/h, respectively. In addition, the results of verification indicated that PAE-NEs skin pharmacokinetics profile obtained by the simulation was consistent with that by in vivo experiment. Discussion: This study demonstrated that the FEA combined with the established multilayer geometry skin model could accurately predict the skin pharmacokinetics of TDDS.


Assuntos
Administração Cutânea , Sistemas de Liberação de Medicamentos/métodos , Emulsões/farmacocinética , Epiderme/efeitos dos fármacos , Nanoestruturas/administração & dosagem , Acetofenonas/administração & dosagem , Acetofenonas/farmacocinética , Animais , Emulsões/administração & dosagem , Células Epidérmicas/efeitos dos fármacos , Análise de Elementos Finitos , Masculino , Microdiálise , Modelos Biológicos , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Absorção Cutânea/efeitos dos fármacos
2.
PLoS One ; 15(9): e0239506, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32976523

RESUMO

BACKGROUND: Low carnitine status may underlie the development of insulin resistance and metabolic inflexibility. Intravenous lipid infusion elevates plasma free fatty acid (FFA) concentration and is a model for simulating insulin resistance and metabolic inflexibility in healthy, insulin sensitive volunteers. Here, we hypothesized that co-infusion of L-carnitine may alleviate lipid-induced insulin resistance and metabolic inflexibility. METHODS: In a randomized crossover trial, eight young healthy volunteers underwent hyperinsulinemic-euglycemic clamps (40mU/m2/min) with simultaneous infusion of saline (CON), Intralipid (20%, 90mL/h) (LIPID), or Intralipid (20%, 90mL/h) combined with L-carnitine infusion (28mg/kg) (LIPID+CAR). Ten volunteers were randomized for the intervention arms (CON, LIPID and LIPID+CAR), but two dropped-out during the study. Therefore, eight volunteers participated in all three intervention arms and were included for analysis. RESULTS: L-carnitine infusion elevated plasma free carnitine availability and resulted in a more pronounced increase in plasma acetylcarnitine, short-, medium-, and long-chain acylcarnitines compared to lipid infusion, however no differences in skeletal muscle free carnitine or acetylcarnitine were found. Peripheral insulin sensitivity and metabolic flexibility were blunted upon lipid infusion compared to CON but L-carnitine infusion did not alleviate this. CONCLUSION: Acute L-carnitine infusion could not alleviated lipid-induced insulin resistance and metabolic inflexibility and did not alter skeletal muscle carnitine availability. Possibly, lipid-induced insulin resistance may also have affected carnitine uptake and may have blunted the insulin-induced carnitine storage in muscle. Future studies are needed to investigate this.


Assuntos
Carnitina/administração & dosagem , Ácidos Graxos não Esterificados/sangue , Ácidos Graxos não Esterificados/metabolismo , Resistência à Insulina/fisiologia , Lipídeos/administração & dosagem , Adulto , Carnitina/análogos & derivados , Carnitina/sangue , Estudos Cross-Over , Emulsões/administração & dosagem , Humanos , Bombas de Infusão , Insulina/sangue , Insulina/metabolismo , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Fosfolipídeos/administração & dosagem , Óleo de Soja/administração & dosagem , Adulto Jovem
3.
Int J Nanomedicine ; 15: 6503-6518, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922013

RESUMO

Objective: A non-lipolysis nanoemulsion (NNE) was designed to reduce the first-pass metabolism of raloxifene (RAL) by intestinal UDP-glucuronosyltransferases (UGTs) for increasing the oral absorption of RAL, coupled with in vitro and in vivo studies. Methods: In vitro stability of NNE was evaluated by lipolysis and the UGT metabolism system. The oral bioavailability of NNE was studied in rats and pigs. Finally, the absorption mechanisms of NNE were investigated by in situ single-pass intestinal perfusion (SPIP) in rats, Madin-Darby canine kidney (MDCK) cells model, and lymphatic blocking model. Results: The pre-NNE consisted of isopropyl palmitate, linoleic acid, Cremophor RH40, and ethanol in a weight ratio of 3.33:1.67:3:2. Compared to lipolysis nanoemulsion of RAL (RAL-LNE), the RAL-NNE was more stable in in vitro gastrointestinal buffers, lipolysis, and UGT metabolism system (p < 0.05). The oral bioavailability was significantly improved by the NNE (203.30%) and the LNE (205.89%) relative to the suspension group in rats. However, 541.28% relative bioavailability was achieved in pigs after oral NNE intake compared to the suspension and had two-fold greater bioavailability than the LNE (p < 0.05). The RAL-NNE was mainly absorbed in the jejunum and had high permeability at the intestine of rats. The results of both SPIP and MDCK cell models demonstrated that the RAL-NNE was absorbed via endocytosis mediated by caveolin and clathrin. The other absorption route, the lymphatic transport (cycloheximide as blocking agent), was significantly improved by the NNE compared with the LNE (p < 0.05). Conclusion: A NNE was successfully developed to reduce the first-pass metabolism of RAL in the intestine and enhance its lymphatic transport, thereby improving the oral bioavailability. Altogether, NNE is a promising carrier for the oral delivery of drugs with significant first-pass metabolism.


Assuntos
Absorção Fisico-Química , Emulsões/química , Lipólise , Nanopartículas/química , Cloridrato de Raloxifeno/metabolismo , Administração Oral , Animais , Disponibilidade Biológica , Transporte Biológico , Sobrevivência Celular , Cães , Emulsões/administração & dosagem , Feminino , Intestinos/fisiologia , Linfa/metabolismo , Células Madin Darby de Rim Canino , Masculino , Polietilenoglicóis , Ratos Sprague-Dawley , Tensoativos/química , Suínos
4.
Int J Nanomedicine ; 15: 5217-5226, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801687

RESUMO

Aim: Chronic use of oral nonsteroidal anti-inflammatory drugs (NSAIDs) is commonly associated with gastric irritation and gastric ulceration. Therefore, the aim of study was to develop a novel oral drug delivery system with minimum gastric effects and improved dissolution rate for aceclofenac (ACF), a model BCS class-II drug. Methods: Self-emulsifying drug delivery systems (SEDDS) were formulated to increase the solubility and ultimately the oral bioavailability of ACF. Oleic acid was used as an oil phase, Tween 80 (T80) and Kolliphor EL (KEL) were used as surfactants, whereas, polyethylene glycol 400 (PEG 400) and propylene glycol (PG) were employed as co-surfactants. Optimized formulations (F1, F2, F3 and F4) were analyzed for droplet size, poly dispersity index (PDI), cell viability studies, in vitro dissolution in both simulated gastric fluid and simulated intestinal fluid, ex vivo permeation studies and thermodynamic stability. Results: The optimized formulations showed mean droplet sizes in the range of 111.3 ± 3.2 nm and 470.9 ± 12.52 nm, PDI from 244.6 nm to 389.4 ± 6.51 and zeta-potential from -33 ± 4.86 mV to -38.5 ± 5.15 mV. Cell viability studies support the safety profile of all formulations for oral administration. The in vitro dissolution studies and ex vivo permeation analysis revealed significantly improved drug release ranging from 95.68 ± 0.02% to 98.15 ± 0.71% when compared with control. The thermodynamic stability studies confirmed that all formulations remain active and stable for a longer period. Conclusion: In conclusion, development of oral SEDDS might be a promising tool to improve the dissolution of BCS class-II drugs along with significantly reduced exposure to gastric mucosa.


Assuntos
Diclofenaco/análogos & derivados , Sistemas de Liberação de Medicamentos/métodos , Emulsões/química , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Disponibilidade Biológica , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Diclofenaco/administração & dosagem , Diclofenaco/farmacocinética , Liberação Controlada de Fármacos , Emulsões/administração & dosagem , Excipientes/química , Humanos , Masculino , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Polietilenoglicóis/química , Polissorbatos/química , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/farmacocinética , Ratos Sprague-Dawley , Solubilidade , Tensoativos/química
5.
Medicine (Baltimore) ; 99(27): e21155, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629751

RESUMO

BACKGROUND: Brucea javanica oil emulsion injection (BJOEI) has been widely applied as a promising adjunctive drug for colorectal carcinoma (CRC). However, the exact effects and safety of BJOEI remains controversial. In this study, we aimed to summarize the efficacy and safety of BJOEI for the treatment of advanced CRC through the meta-analysis, in order to provide scientific reference for the design of future clinical trials. METHODS: Eligible prospective controlled clinical trials were searched from PubMed, Cochrane Library, Google Scholar, Medline, Web of Science (WOS), Excerpt Medica Database (Embase), Chinese BioMedical Database (CBM), China Scientific Journal Database (VIP), China National Knowledge Infrastructure (CNKI) and Wanfang Database. Papers in English or Chinese published from January 2000 to May 2020 will be included without any restrictions. The clinical outcomes including therapeutic effects, quality of life (QoL), immune function and adverse events, were systematically evaluated.Study selection and data extraction will be performed independently by 2 reviewers. Review Manager 5.3 and Stata 14.0 were used for data analysis, and a fixed or random-effect model will be used depending upon the heterogeneity observed between trials. Subgroup and meta-regression analysis will be carried out depending on the availability of sufficient data. RESULTS: The results of this systematic review will be published in a peer-reviewed journal. CONCLUSION: Our study will draw an objective conclusion of the effects and safety of BJOEI for advanced CRC, and provide a helpful evidence for clinicians to formulate the best postoperative adjuvant treatment strategy for CRC patients.INPLASY registration number: INPLASY202060014.


Assuntos
Brucea/efeitos adversos , Quimioterapia Adjuvante/métodos , Neoplasias Colorretais/tratamento farmacológico , Emulsões/administração & dosagem , Estudos de Casos e Controles , China/epidemiologia , Neoplasias Colorretais/psicologia , Emulsões/uso terapêutico , Feminino , Humanos , Injeções/métodos , Masculino , Estudos Prospectivos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Segurança , Resultado do Tratamento
6.
AAPS PharmSciTech ; 21(4): 119, 2020 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-32318974

RESUMO

In the presented study, insight into the development and optimisation of the dry emulsion formulation and spray drying process is provided. The aim was to facilitate the dissolution of the poorly soluble, highly lipophilic drug, simvastatin, by forming spray-dried dry emulsion particles having adequate powder flow properties, while assuring sufficient drug content. Simvastatin and a mixture of caprylic, capric triglyceride and 1-oleoyl-rac-glycerol were employed as a model drug and solubilising oils, respectively. A matrix of the dry emulsions was composed at a fixed ratio mixture of mannitol and HPMC. Tween 20 was used in low amounts as the primary emulsion stabiliser. To facilitate process optimisation, a DoE surface response design was used to study the influence of formulation and process parameters on the particle size distribution, powder bulk properties, emulsion reconstitution ability, drug stability and process yield of spray-dried products. Two-fluid nozzle geometry was identified, studied and confirmed to be important for most product critical quality attributes. Models obtained after the study showed acceptable coefficients of determination and provided good insight in the relationship governing the process and product characteristics. Five model optimised products showed adequate process yield, suitable particle size distribution, good reconstitution ability and improved dissolution profile, when compared to a non-lipid-based tablet and the pure drug. However, the obtained dry emulsion powders exhibited poor flow character according to the Carr index. The optimised product was further analysed with NMR during lipolysis to gain insight into the species formed during digestion and the kinetics of their formation.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Emulsões/síntese química , Sinvastatina/síntese química , Tecnologia Farmacêutica/métodos , Fenômenos Químicos , Dessecação/métodos , Estabilidade de Medicamentos , Emulsões/administração & dosagem , Glicerídeos/administração & dosagem , Glicerídeos/síntese química , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/síntese química , Tamanho da Partícula , Polissorbatos/administração & dosagem , Polissorbatos/síntese química , Sinvastatina/administração & dosagem , Solubilidade , Comprimidos
7.
Int J Nanomedicine ; 15: 2027-2044, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32273700

RESUMO

Purpose: As one of the classic anti-Canidia albicans (CA) and vulvovaginal candidiasis (VVC) drugs, nystatin (NYS) is limited by poor water solubility and easy aggregation. Traditional NYS vaginal delivery formulations do not fully adapt to the specific environment of the vaginal cavity. The use of exopolysaccharides (EPS) has great application potential in emulsifiers, but its use has not been reported in nanoemulsions. In this work, an EPS/NYS nanoemulsion (ENNE) was developed to improve the activities of NYS against CA and VVC. Methods: The ENNE was prepared by ultrasonic method using EPS as an emulsifier, liquid paraffin oil as an oil phase, PEG400 as a co-emulsifier, and NYS as the loaded drug. ENNE preparation was optimized by response surface method. After optimization, in vitro and in vivo analysis of the anti-CA activity; animal experiments; staining with propidium iodide (PI), periodic acid-schiff (PAS), and hematoxylin-eosin (H&E); and cytokine experiments were performed to investigate the therapeutic ability against VVC. Results: The optimal formulation and preparation parameters of ENNE were determined as follows: EPS content of 1.5%, PEG400 content of 3.2%, NYS content of 700 µg/mL, paraffin oil content of 5.0%, ultrasonic time of 15 min, and ultrasonic amplitude of 35%. The ENNE showed an encapsulated structure with an average particle size of 131.1 ± 4.32 nm. ENNE exhibited high storage and pH stability, as well as slow release. The minimum inhibitory concentration (MIC) of ENNE against CA was only 0.125 µg/mL and the inhibition zone was 19.0 ± 0.5 mm, for greatly improved anti-CA effect. The prepared ENNE destroyed the membrane of CA cells, and exhibited good anti-CA effect in vivo and therapeutic ability against VVC. Conclusion: The results of this study will promote the application of EPS in nanotechnology, which should lead to new and effective local drug formulations for treating VVC.


Assuntos
Antifúngicos/administração & dosagem , Candidíase Vulvovaginal/tratamento farmacológico , Emulsões/química , Nanoestruturas/administração & dosagem , Nistatina/administração & dosagem , Administração Intravaginal , Animais , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Citocinas , Emulsificantes/química , Emulsões/administração & dosagem , Feminino , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Nanoestruturas/química , Nistatina/farmacologia , Tamanho da Partícula , Polietilenoglicóis/química , Polissacarídeos Bacterianos/química , Ultrassom/métodos
8.
Int J Nanomedicine ; 15: 2059-2070, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32273702

RESUMO

Purpose: Ferulic acid (FA) is a natural compound which is used to treat insomnia. However, its use is limited because of its poor oral bioavailability caused by extremely rapid elimination. The current study aimed to develop a self-microemulsifying drug delivery system (SMEDDS) to improve the oral delivery of FA and to enhance its hypnotic efficacy. Methods: FA-SMEDDS was prepared, and its morphology and storage stability were characterized. The formulation was also subjected to pharmacokinetic and tissue distribution studies in rats. The hypnotic efficacy of FA-SMEDDS was evaluated in p-chlorophenylalanine-induced insomnia mice. Results: FA-loaded SMEDDS exhibited a small droplet size (15.24 nm) and good stability. Oral administration of FA-SMEDDS yielded relative bioavailability of 185.96%. In the kidney, SMEDDS decreased the distribution percentage of FA from 76.1% to 59.4% and significantly reduced its metabolic conversion, indicating a reduction in renal elimination. Interestingly, FA-SMEDDS showed a higher distribution in the brain and enhanced serotonin levels in the brain, which extended the sleep time by 2-fold in insomnia mice. Conclusion: This is the first study to show that FA-loaded SMEDDS decreased renal elimination, enhanced oral bioavailability, increased brain distribution, and improved hypnotic efficacy. Thus, we have demonstrated that SMEDDS is a promising carrier which can be employed to improve the oral delivery of FA and facilitate product development for the therapy of insomnia.


Assuntos
Ácidos Cumáricos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Emulsões/administração & dosagem , Hipnóticos e Sedativos/administração & dosagem , Administração Oral , Animais , Disponibilidade Biológica , Ácidos Cumáricos/química , Ácidos Cumáricos/farmacocinética , Portadores de Fármacos/química , Emulsões/química , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/farmacocinética , Masculino , Camundongos , Ratos Wistar , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Solubilidade , Distribuição Tecidual
9.
Int J Nanomedicine ; 15: 2071-2083, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32273703

RESUMO

Background and Purpose: Adjuvant can reduce vaccine dosage and acquire better immune protection to the body, which helps to deal with the frequent outbreaks of influenza. Nanoemulsion adjuvants have been proved efficient, but the relationship between their key properties and the controlled release which greatly affects immune response is still unclear. The present work explores the role of factors such as particle size, the polydispersity index (PDI), stability and the safety of nanoemulsions by optimizing the water concentration, oil phase and modes of carrying, to explain the impact of those key factors above on adjuvant effect. Methods: Isopropyl myristate (IPM), white oil, soybean oil, and grape-kernel oil were chosen as the oil phase to explore their roles in emulsion characteristics and the adjuvant effect. ICR mice were immunized with an emulsion-inactivated H3N2 split influenza vaccine mixture, to compare the nanoemulsion's adjuvant with traditional aluminium hydroxide or complete Freund's adjuvant. Results: Particle size of all the nanoemulsion formed in our experiment ranged from 20 nm to 200 nm and did not change much when diluted with water, while the PDI decreased obviously, indicating that the particles tended to become more dispersive. Formulas with 80% or 85.6% water concentration showed significant higher HAI titer than aluminium hydroxide or complete Freund's adjuvant, and adsorption rather than capsule mode showed higher antigen delivery efficiency. As mentioned about oil phase, G (IPM), F (white oil), H (soybean oil), and I (grape-kernel oil) showed a decreasing trend in their adjuvant efficiency, and nanoemulsion G was the best adjuvant with smaller and uniform particle size. Conclusion: Emulsions with a smaller, uniform particle size had a better adjuvant effect, and the adsorption mode was generally more efficient than the capsule mode. The potential adjuvant order of the different oils was as follows: IPM > white oil > soybean oil > grape-kernel oil.


Assuntos
Adjuvantes Imunológicos/química , Sistemas de Liberação de Medicamentos/métodos , Emulsões/química , Vacinas contra Influenza/administração & dosagem , Nanoestruturas/química , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/farmacologia , Animais , Emulsões/administração & dosagem , Emulsões/farmacologia , Feminino , Vírus da Influenza A Subtipo H3N2 , Vacinas contra Influenza/imunologia , Camundongos Endogâmicos ICR , Óleos/química , Infecções por Orthomyxoviridae/prevenção & controle , Tamanho da Partícula , Óleo de Soja/química , Vacinas de Produtos Inativados , Água/química
10.
Int J Nanomedicine ; 15: 2391-2402, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32308390

RESUMO

Background: Oil-in-water drug nanoemulsion forms drug delivery systems with high oral bioavailability. The conventional fabrication methods of nanoemulsion are low energy emulsification methods and high energy emulsification methods. However, both two methods are not ideal for industrial production. The problem of low energy emulsification methods is the high dosage of surfactant and co-surfactant which has potential biosecurity issues. What is more, high energy emulsification methods have some disadvantages, like the destruction of drug components, the price of equipment and the difficulties of industrial production. Hence, there have been a few commercial drug nanoemulsions so far. Methods: In this work, we reported a novel method for the fabrication of stable and transparent drug nanoemulsion which contains hydrophilic drug rosuvastatin (ROS) calcium or hydrophobic drug silybinin (SYN) by using high-gravity rotating packed bed (RPB). The drug nanoemulsion was systematically characterized by droplet size, size distribution, stability and in vitro drug release as well as Caco-2 cells permeability. Results: Compared with the self-emulsification method (SE), high-gravity technology could reduce 75% amount of mixed surfactants. The as-prepared nanoemulsion exhibited a very narrow droplet size distribution with a size of 13.53 ± 0.53 nm and a polydispersity index of 0.073 ± 0.018. Meanwhile, the drug nanoemulsion was physicochemically stable at 25°C and 4°C for one-year storage. Furthermore, both ROS and SYN nanoemulsion displayed higher cell permeability and in vitro dissolution than that of commercial formulations. Conclusion: These results demonstrate that RPB can be a potential device to facilitate the industrial production of drug nanoemulsion.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Nanoestruturas/química , Administração Oral , Disponibilidade Biológica , Células CACO-2 , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Emulsões/administração & dosagem , Emulsões/química , Emulsões/farmacocinética , Humanos , Interações Hidrofóbicas e Hidrofílicas , Nanoestruturas/administração & dosagem , Tamanho da Partícula , Rosuvastatina Cálcica/administração & dosagem , Rosuvastatina Cálcica/química , Rosuvastatina Cálcica/farmacocinética , Silibina/administração & dosagem , Silibina/química , Silibina/farmacocinética , Tensoativos/química
11.
Life Sci ; 250: 117544, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32179072

RESUMO

Paeonol is a bioactive phenol present in Dioscorea japonica, Paeonia suffruticosa and Paeonia lactiflora. It is reported for various pharmacological activities. AIM: To review chemistry, pharmacokinetics, pharmacological activities as well as various formulations of paeonol. MATERIALS AND METHODS: A literature search was done using different search terms for paeonol by using different scientific databases like PubMed, Scopus and ProQuest. Scientific papers published during the period 1969 to 2019 were comprehensively reviewed. KEY FINDINGS: Researchers have synthesized methoxy, ethoxy, piperazine, chromonylthiazolidine, phenol-phenylsulfonyl, alkyl ether, aminothiazole, tryptamine hybrids and paeononlsilatie derivatives to enhance the stability of paeonol. These derivatives were synthesized and evaluated for in vitro series of biological activities like anti-inflammatory, tyrosinase inhibitory, neuroprotective, anticancer and antiviral activity. Regardless of valuable therapeutic potential, the clinical use of paeonol is restricted due to poor water solubility, low oral bioavailability, low stability and high volatility at room temperature. To enhance the bioavailability of paeonol various formulations are prepared and evaluated for its activity. Paeonol formulations can be categorized as conventional-tablets, topical gel and hydrogel; polymeric delivery system-microparticles, microsponges, dendrimers, nanocapsules, polymeric nanoparticles, nanospheres; lipid-based delivery systems-microemulsion, self-micro-emulsifying drug delivery, liposome, transethosomes, ethosomes, niosomes, proniosomes, lipid-based nanoparticles and nanoemulsion of paeonol. SIGNIFICANCE: Paeonol has a potential to be developed as a techno-commercial product with respect to its multi-faceted pharmacological properties. Even though in vitro and in vivo studies have been reported the important activities of paeonol, its commercial utilization requires extensive safety and efficacy data.


Assuntos
Acetofenonas/farmacologia , Acetofenonas/farmacocinética , Sistemas de Liberação de Medicamentos , Acetofenonas/administração & dosagem , Administração Oral , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Dendrímeros , Emulsões/administração & dosagem , Humanos , Hidrogéis , Concentração Inibidora 50 , Lipossomos , Nanocápsulas , Nanosferas , Polímeros , Relação Quantitativa Estrutura-Atividade , Absorção Cutânea , Solubilidade
12.
Int J Nanomedicine ; 15: 1101-1115, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32110010

RESUMO

Background: The clinical use of doxorubicin (DOX) is severely limited due to its cardiotoxicity. Thus, there is a need for prophylactic and treatment strategies against DOX-induced cardiotoxicity. Purpose: The purpose of this study was to develop a liquiritigenin-loaded submicron emulsion (Lq-SE) with enhanced oral bioavailability and to explore its efficacy against DOX-induced cardiotoxicity. Methods: Lq-SE was prepared using high-pressure homogenization and characterized using several analytical techniques. The formulation was optimized by central composite design response surface methodology (CCD-RSM). In vivo pharmacokinetic studies, biochemical analyses, reactive oxygen species (ROS) assays, histopathologic assays, and Western blot analyses were performed. Results: Each Lq-SE droplet had a mean particle size of 221.7 ± 5.80 nm, a polydispersity index (PDI) of 0.106 ± 0.068 and a zeta potential of -28.23 ± 0.42 mV. The area under the curve (AUC) of Lq-SE was 595% higher than that of liquiritigenin (Lq). Lq-SE decreased the release of serum cardiac enzymes and ameliorated histopathological changes in the hearts of DOX-challenged mice. Lq-SE significantly reduced oxidative stress by adjusting the levels of ROS, increasing the activity of antioxidative enzymes and inhibiting the protein expression of NOX4 and NOX2. Furthermore, Lq-SE significantly improved the inflammatory response through the mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NF-κB) signalling pathway and induced cardiomyocyte apoptosis. Conclusion: Lq-SE could be used as an effective cardioprotective agent against DOX in chemotherapy to enable better treatment outcomes.


Assuntos
Cardiotoxicidade/prevenção & controle , Doxorrubicina/efeitos adversos , Emulsões/química , Flavanonas/farmacologia , Administração Oral , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Disponibilidade Biológica , Cardiotônicos/farmacologia , Cardiotoxicidade/metabolismo , Emulsões/administração & dosagem , Feminino , Flavanonas/administração & dosagem , Flavanonas/farmacocinética , Coração/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Nus , Miocárdio/metabolismo , Miocárdio/patologia , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
13.
Int J Nanomedicine ; 15: 1161-1172, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32110014

RESUMO

Purpose: Nimodipine (NIMO) is used clinically to treat ischemic damage resulting from subarachnoid hemorrhage. However, clinical application of NIMO is limited by poor aqueous solubility and low safety. To overcome these limitations, a novel two-vial NIMO-loaded nanoemulsion (NIMO-TNE) was designed in this study. Methods: NIMO-TNE was prepared by mixing a nimodipine-polyethylene glycol 400 (NIMO-PEG400) solution and a commercially available 20% injectable blank nanoemulsion (BNE). Drug distribution in NIMO-TNE, physical stability, and dilution stability were evaluated in vitro, and pharmacokinetics and pharmacodynamics were evaluated in vivo. Safety was assessed using the hemolysis test and the intravenous irritation test, and acute toxicity of NIMO-TNE was compared with that of commercial Nimotop injection. Results: Drug loading (DL) in NIMO-TNE was enhanced 5-fold compared with that in Nimotop injection. The mean particle size of NIMO-TNE was 241.53 ± 1.48 nm. NIMO-TNE and NIMO-TNE diluted in 5% glucose injection and 0.9% sodium chloride was stable for a sufficient duration to allow for clinical use. In addition, NIMO-TNE exhibited a similar pharmacokinetic profile and similar brain ischemia reduction in a rat middle cerebral artery occlusion (MCAO) model compared to Nimotop injection. Furthermore, NIMO-TNE did not induce hemolysis at 37°C, and NIMO-TNE induced less intravenous irritation than Nimotop injection. Moreover, NIMO-TNE could be injected at a 23-fold higher dose than the LD50 of Nimotop injection with no obvious toxicity or side effects. Conclusion: NIMO-TNE is a promising formulation suitable for intravenous injection, is easy to prepare, and exhibits excellent safety.


Assuntos
Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Emulsões/administração & dosagem , Nimodipina/administração & dosagem , Animais , Portadores de Fármacos/administração & dosagem , Estabilidade de Medicamentos , Emulsões/química , Feminino , Infarto da Artéria Cerebral Média/tratamento farmacológico , Masculino , Camundongos Endogâmicos ICR , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Nimodipina/farmacocinética , Tamanho da Partícula , Polietilenoglicóis , Coelhos , Ratos Sprague-Dawley , Solubilidade , Distribuição Tecidual , Testes de Toxicidade Aguda
14.
Int J Nanomedicine ; 15: 1073-1094, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32103956

RESUMO

Purpose: This study demonstrated improved transdermal delivery of rifampicin-loaded cationic nanoemulsion gel to treat systemic and cutaneous tuberculosis using capmul, labrasol, and acconon, which exert anti-Mycobacterium activities. This approach enhanced drug permeation across the skin, increased therapeutic efficacy, and reduced dose-related side effects. Methods: Design Expert® was used to optimize formulations (Smix ratio and capmul as independent factors), which were prepared using a slow spontaneous titration method. The optimized nanoemulsion was incorporated into carbopol gel to allow for topical application and comparative assessments. Nanoemulsions and gels were evaluated for size, size distribution, shape, zeta potential, percent spread, viscosity, in vitro hemolysis, in vitro release, and ex vivo skin permeation and deposition. A mechanistic evaluation was performed using scanning electron microscopy. Furthermore, in vivo pharmacokinetic and irritation studies were performed. Results: The optimized cationic nanoemulsion (OCNE-1) was characterized by small particle size (≤100 nm), had optimal viscosity, percent spread, zeta potential, and percent drug release, and was hemocompatible. The OCNE-1T gel exhibited higher permeation flux (51.32 ± 0.5 µg/cm2 hr), permeation coefficient (2.566 ± 0.08 cm/hr), drug deposition (994.404 µg/cm2), and enhancement ratio (7.16) than those of the OCNE-1 nanoemulsion or drug solution. Scanning electron microscopy was used to characterize the mechanism of enhanced permeation. An In vivo study showed that the Cmax and area under the curve following transdermal application were 4.34- and 4.74-fold higher than those following oral administration. Conclusion: Transdermal delivery of rifampicin could be a promising alternative to conventional approaches to treat systemic and local tuberculosis, and other bacterial infections.


Assuntos
Antituberculosos/administração & dosagem , Emulsões/administração & dosagem , Rifampina/administração & dosagem , Tuberculose/tratamento farmacológico , Resinas Acrílicas/química , Administração Cutânea , Animais , Antituberculosos/farmacocinética , Antituberculosos/farmacologia , Disponibilidade Biológica , Caprilatos/química , Cátions/química , Emulsões/farmacologia , Excipientes/química , Géis/química , Géis/farmacologia , Glicerídeos/química , Mycobacterium/efeitos dos fármacos , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Tamanho da Partícula , Ratos Sprague-Dawley , Rifampina/farmacocinética , Rifampina/farmacologia , Pele/efeitos dos fármacos , Tuberculose Cutânea/tratamento farmacológico
15.
Anticancer Res ; 40(2): 689-694, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32014909

RESUMO

BACKGROUND/AIM: Piperine, a major alkaloid of the fruit of black pepper plants, selectively inhibits the growth of triple-negative breast cancer cells but its lipophilicity restricts possible clinical application. This study therefore determined the feasibility of encapsulating piperine in nanoparticles (NPs) to increase its solubility in an aqueous environment. MATERIALS AND METHODS: Piperine-loaded biodegradable methoxy poly(ethylene glycol)-poly(lactic-co-glycolic) acid copolymer-based NPs were produced by single emulsion solvent extraction and thin-film hydration. Growth and viability of triple-negative breast cancer (TNBC) cells were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Annexin-V-FLUOS/propidium iodide staining, respectively. RESULTS: Thin-film hydration was superior to single emulsion solvent extraction, yielding piperine-loaded NPs with an average size of 50 nm. Piperine-loaded NPs inhibited TNBC cell growth and induced apoptosis while sparing normal fibroblasts. CONCLUSION: It is feasible to deliver a cytotoxic concentration of piperine to TNBC cells via NPs with the potential for improved bioavailability and solubility in biological fluids.


Assuntos
Alcaloides/administração & dosagem , Benzodioxóis/administração & dosagem , Nanopartículas/administração & dosagem , Piperidinas/administração & dosagem , Alcamidas Poli-Insaturadas/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Alcaloides/química , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Benzodioxóis/química , Linhagem Celular Tumoral , Emulsões/administração & dosagem , Emulsões/química , Feminino , Humanos , Nanopartículas/química , Piperidinas/química , Poliésteres/administração & dosagem , Poliésteres/química , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Alcamidas Poli-Insaturadas/química , Neoplasias de Mama Triplo Negativas/patologia
16.
Colloids Surf B Biointerfaces ; 188: 110739, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31901623

RESUMO

This study aims to develop in situ microemulsion-gel (ME-Gel) obtained from hydroxypropyl methylcellulose (HPMC) films for transdermal administration of Zidovudine (AZT). Firstly, HPMC films containing propylene glycol (PG) and eucalyptus oil (EO) were obtained and characterized. Later, a pseudo-ternary phase diagram composed of water, EO, tween 80 and PG was obtained and one microemulsion (ME) with a similar proportion of the film components was obtained. ME was transformed in ME-Gel by the incorporation of HPMC. Finally, HPMC films were hydrated with Tween 80 solution to yield in situ ME-Gel and its effect on AZT skin permeation was compared with HPMC film hydrated with water (F5hyd). The results showed that the ME and ME-Gel presented a droplet size of 16.79 and 122.13 µm, respectively, polydispersity index (PDI) < 0.39 and pH between 5.10 and 5.40. The incorporation of HPMC resulted in viscosity about 2 times higher than the use of ME. The presence of AZT did not alter the formulation properties. The in situ ME-Gel promoted a two-fold increase in the permeated amount of AZT compared to F5hyd. The results suggest that it was possible to obtain an ME-Gel in situ from HPMC films and that its effect on transdermal permeation of AZT was significant.


Assuntos
Metilcelulose/química , Pró-Fármacos/química , Zidovudina/química , Administração Cutânea , Animais , Emulsões/administração & dosagem , Emulsões/química , Emulsões/metabolismo , Óleo de Eucalipto/administração & dosagem , Óleo de Eucalipto/química , Óleo de Eucalipto/metabolismo , Géis/administração & dosagem , Géis/química , Géis/metabolismo , Masculino , Metilcelulose/administração & dosagem , Metilcelulose/metabolismo , Tamanho da Partícula , Pró-Fármacos/administração & dosagem , Pró-Fármacos/metabolismo , Propilenoglicol/administração & dosagem , Propilenoglicol/química , Propilenoglicol/metabolismo , Ratos , Ratos Wistar , Pele/química , Pele/metabolismo , Absorção Cutânea , Propriedades de Superfície , Zidovudina/administração & dosagem , Zidovudina/metabolismo
17.
AAPS PharmSciTech ; 21(3): 80, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31975311

RESUMO

Bromocriptine mesylate (BCM), a dopaminergic agonist administered orally, exhibits retarded bioavailability owing to poor absorption and extreme first-pass metabolism. The objective of the current study was to develop, characterize, and statistically optimize BCM nanoemulsion (BCM-NE) loaded into a gel (BCM-NE gel) to evaluate its potential for improved permeation of BCM through the transdermal route, thereby improving its pharmacokinetic profile. BCM-NE was prepared by o/w spontaneous emulsification method and the effects of different formulation variables on the critical attributes of NE like globule size were investigated by implementing factorial design. The optimized formulation exhibited a mean globule size of 160 ± 6.5 nm, zeta potential of - 20.4 ± 1.23 mV, and drug content of 99.45 ± 1.9%. Ex vivo permeation studies across rat skin exhibited a significant enhancement in permeation, i.e., enhancement ratio (ER) of ~ 7.4 and 5.86 for BCM-NE and BCM-NE gel, respectively, when compared with aqueous BCM suspension gel. In vivo pharmacokinetic studies performed in rats demonstrated a higher and prolonged drug release of BCM from BCM-NE gel when compared to oral aqueous BCM suspension. The AUC0-t for BCM-NE gel and BCM suspension was found to be 562.54 ± 77.55 and 204.96 ± 51.93 ng/ml h, respectively. The relative bioavailability (%F) of BCM was shown to be enhanced 274% by BCM-NE gel. Histopathological studies demonstrated the safety and biocompatibility of the developed system. All the above results proved that the BCM-NE gel could be a superior and patient-compliant alternative to oral delivery in the management of PD.


Assuntos
Bromocriptina/administração & dosagem , Administração Cutânea , Animais , Bromocriptina/química , Bromocriptina/farmacocinética , Emulsões/administração & dosagem , Géis/química , Masculino , Nanotecnologia , Ratos , Ratos Wistar , Pele/metabolismo
18.
Nat Commun ; 11(1): 391, 2020 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959896

RESUMO

Red blood cells (RBCs) transport oxygen to tissues and remove carbon dioxide. Diffuse optical flowmetry (DOF) assesses deep tissue RBC dynamics by measuring coherent fluctuations of multiply scattered near-infrared light intensity. While classical DOF measurements empirically correlate with blood flow, they remain far-removed from light scattering physics and difficult to interpret in layered media. To advance DOF measurements closer to the physics, here we introduce an interferometric technique, surmounting challenges of bulk motion to apply it in awake humans. We reveal two measurement dimensions: optical phase, and time-of-flight (TOF), the latter with 22 picosecond resolution. With this multidimensional data, we directly confirm the unordered, or Brownian, nature of optically probed RBC dynamics typically assumed in classical DOF. We illustrate how incorrect absorption assumptions, anisotropic RBC scattering, and layered tissues may confound classical DOF. By comparison, our direct method enables accurate and comprehensive assessment of blood flow dynamics in humans.


Assuntos
Circulação Cerebrovascular/fisiologia , Modelos Biológicos , Córtex Pré-Frontal/fisiologia , Espalhamento de Radiação , Animais , Emulsões/administração & dosagem , Emulsões/farmacocinética , Eritrócitos/fisiologia , Emulsões Gordurosas Intravenosas/administração & dosagem , Estudos de Viabilidade , Humanos , Injeções Intravenosas , Interferometria/instrumentação , Interferometria/métodos , Luz , Camundongos , Método de Monte Carlo , Fosfolipídeos/administração & dosagem , Fosfolipídeos/farmacocinética , Córtex Pré-Frontal/irrigação sanguínea , Fluxo Sanguíneo Regional/fisiologia , Óleo de Soja/administração & dosagem , Óleo de Soja/farmacocinética
19.
Int J Nanomedicine ; 14: 8739-8751, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31806968

RESUMO

Objective: Nintedanib (NDNB) is a triple receptor tyrosine kinase inhibitor with poor solubility in neutral conditions and low bioavailability. A self-microemulsifying drug delivery system (SMEDDS) of NDNB was developed to improve drug solubility in physical conditions and absorption in vivo. Methods: The NDNB-SMEDDS formulation was optimized via pseudo-ternary phase diagrams. The physicochemical properties of NDNB-SMEDDS, viz., morphological observation, droplet size, stability, compatibility and in vitro release were investigated. The permeability of NDNB-SMEDDS was detected using both a Caco-2 cell monolayer in vitro and an intestinal perfusion study in vivo. Furthermore, the pharmacokinetic characteristics of NDNB-SMEDDS were evaluated. Results: The optimal formulation was composed of MCT as an oil phase, RH 40 as a surfactant and ethylene glycol as a co-surfactant. The average droplet size of the microemulsion was about 23 nm with good stability within 30 days. The formulation did not exhibit any obvious cytotoxic effect on Caco-2 cells. Permeability of nintedanib in a Caco-2 cell monolayer was enhanced by 2.8-fold upon incorporation in SMEDDS compared with the drug solution. The intestinal perfusion study demonstrated that the P app of NDNB-SMEDDS increased by 3.0-fold in the entire intestine and 3.2-fold in the colon in comparison with the drug solution. The pharmacokinetics study showed that the AUC of the NDNB-SMEDDS increased significantly. Conclusion: This study showed that the self-microemulsion formulations could improve the absorption of nintedanib, and can thus serve as a promising carrier for the oral delivery of nintedanib.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Emulsões/administração & dosagem , Indóis/administração & dosagem , Indóis/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Células CACO-2 , Liberação Controlada de Fármacos , Emulsões/química , Emulsões/farmacocinética , Etilenoglicol/química , Humanos , Masculino , Permeabilidade , Ratos Sprague-Dawley , Solubilidade , Tensoativos/química
20.
Drug Deliv ; 26(1): 1104-1114, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31735104

RESUMO

Nanoemulgels are composed of O/W nanoemulsion and hydrogels and are considered as ideal carriers for the transdermal drug delivery because these have high affinity to load hydrophobic drugs. The stable formulation of eprinomectin (EPR) is very challenging because of it is high hydrophobic nature. In this work, we have prepared EPR loaded nanoemulgel for the treatment of endo- and ectoparasites. The surface morphology of optimized formulations was characterized by scanning electron microscopy. Additionally, skin permeability and irritation tests were conducted for in vitro safety and in vivo skin retention and pearmeation test of EPR nanoemulgel were conducted for efficacy study. Obtained results indicated that the optimized formulation had good shear-thinning behavior, bioadhesiveness properties, and are nanosized droplets with porous internal structure, which are required for topical application. Furthermore, this formulation has showed good skin permeability in comparison to suspension and has no skin irritating property. Overall, the obtained results proved that nanoemulgel is a promising carrier for transdermal drug delivery and EPR nanoemulgel is a promising formulation for the treatment of endo- and ectoparasites.


Assuntos
Emulsões/química , Géis/química , Ivermectina/análogos & derivados , Pele/metabolismo , Administração Cutânea , Animais , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Emulsões/administração & dosagem , Géis/administração & dosagem , Ivermectina/administração & dosagem , Ivermectina/química , Masculino , Camundongos , Camundongos Endogâmicos ICR , Nanopartículas/química , Permeabilidade , Ratos , Ratos Sprague-Dawley , Absorção Cutânea
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