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1.
Drug Dev Ind Pharm ; 46(1): 122-134, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31860373

RESUMO

Objective: Development of stimuli-responsive intelligent drug delivery system (based on a polysaccharide, glucuronoxylan [GX]) with on-off switching properties under physiological conditions.Significance: As GX exhibits high swelling index and stimuli-responsive swelling/de-swelling properties, therefore, this material appeared highly useful to design pH, solvent and ionic stress-sensitive oral tablet formulations, which offered on-off switching properties. In this way, we could design intelligent/smart drug delivery systems for levosulpiride (LS) and theophylline (TF) with valuable pharmaceutical properties.Methods: GX-based tablet formulations were explored for stimuli-responsive, reversible swelling-deswelling behavior, dynamic swelling, and its kinetics. Tablet surface and channeling after swelling were observed using scanning electron microscopy (SEM). Drug release study was performed mimicking the physiological conditions like pH and transit time of gastrointestinal tract (GIT). Radiographic images of tablet path (in vivo) were recorded.Results: GX-based formulations exhibited high swelling in deionized water (DW), pH 6.8 and 7.4 while negligible swelling at pH 1.2. SEM images discovered the presence of microcracks and nanopores on the surface of tablets and showed channeling after swelling of tablets in DW. Sustained drug release was observed and found directly proportional to the concentration of GX in the formulations with negligible release at pH 1.2. In vivo radiographic evaluation indicated the retention of tablets in GIT for 7 h. Hemocompatibility studies showed the non-thrombogenic and non-hemolytic nature of GX.Conclusions: GX-based smart/stimuli-responsive formulations can control/sustain the release of drugs in GIT.


Assuntos
Preparações de Ação Retardada/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Polissacarídeos/química , Xilanos/química , Administração Oral , Preparações de Ação Retardada/química , Liberação Controlada de Fármacos , Cinética , Polissacarídeos/farmacologia , Comprimidos , Xilanos/farmacologia
2.
Carbohydr Polym ; 227: 115351, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31590861

RESUMO

Surfactants have been used as a tool to improve the properties of polymeric nanoparticles (NPs) and to increase the rate of hydrophobic drug release by means of these nanoparticles. In this context, this study evaluated the effect of lecithin on the characteristics of chitosan (CHI) and chondroitin sulfate (CS) nanoparticles, when applied in curcumin (Curc) release. CHI/CS NPs and CHI/CS/Lecithin NPs were prepared by the ionic gelation method, both as standards and containing curcumin. Simultaneous conductimetric and potentiometric titrations were employed to optimize the interaction between the polymers. NPs with hydrodynamic diameter of ∼130 nm and zeta potential of +60 mV were obtained and characterized by HRTEM; their pore size and surface area were also analyzed by BET method, DLS, FTIR, XPS, and fluorescence spectroscopy techniques to assess morphological and surface properties, stability and interaction between polymers and to quantify the loading of drugs. The final characteristics of NPs were directly influenced by lecithin addition, exhibiting enhanced encapsulation efficiency of curcumin (131.8 µg curcumin per mg CHI/CS/Lecithin/Curc NPs). The release of curcumin occurred gradually through a two-stage process: diffusion-controlled dissolution and release of curcumin controlled by dissolution of the polymer. However, the release of curcumin in buffer solution at pH 7.4 was achieved faster in CHI/CS/Lecithin/Curc NPs than in CHI/CS/Curc NPs. in vitro cytotoxic activity evaluation of the curcumin was determined by the MTT assay, observing that free curcumin and curcumin nanoencapsulated in CHI/CS/Curc and CHI/CS/Lecithin/Curc NPs reduced the viability of MCF-7 cells in the 72 h period (by 28.4, 36.0 and 30.7%, P < 0.0001, respectively). These results indicate that CHI/CS/Lecithin NPs have more appropriate characteristics for encapsulation of curcumin.


Assuntos
Quitosana/química , Sulfatos de Condroitina/química , Curcumina/química , Lecitinas/química , Nanopartículas/química , Sobrevivência Celular/efeitos dos fármacos , Quitosana/administração & dosagem , Sulfatos de Condroitina/administração & dosagem , Curcumina/administração & dosagem , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Liberação Controlada de Fármacos , Humanos , Lecitinas/administração & dosagem , Células MCF-7 , Nanopartículas/administração & dosagem
3.
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
4.
Drug Deliv ; 26(1): 1049-1057, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31691602

RESUMO

Doxorubicin (DOX) is widely used in the chemotherapy of a wide range of cancers. However, intravenous administration of DOX causes toxicity to most major organs which limits its clinical application. DOX-loaded drug delivery system could provide a continuous sustained-release of drugs and enables high drug concentrations at the target site, while reducing systemic toxicity. Additionally, local chemotherapy with DOX may be a promising approach for lowering post-surgical recurrence of cancer. In this study, the sustained-release DOX-loaded implants were prepared by melt-molding method. The implants were characterized with regards to drug content uniformity, micromorphology and drug release profiles. Furthermore, differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) analyses were carried out to investigate the drug-excipient compatibility. To determine the local penetration of DOX in liver, the minipigs received intrahepatic implantation of DOX-loaded implants by abdominal surgery. UPLC-MS/MS method was used to detect the concentration of DOX in liver tissues. Our results suggested that DOX-loaded implants delivered high doses of drug at the implantation site for a prolonged period and provided valuable information for the future clinical applications of the DOX-loaded implants.


Assuntos
Doxorrubicina/administração & dosagem , Doxorrubicina/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Varredura Diferencial de Calorimetria/métodos , Cromatografia Líquida de Alta Pressão/métodos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Excipientes/química , Feminino , Fígado/efeitos dos fármacos , Masculino , Próteses e Implantes , Ratos , Ratos Wistar , Suínos , Porco Miniatura , Espectrometria de Massas em Tandem/métodos
5.
Dermatol Surg ; 45(11): 1401-1405, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31658188

RESUMO

BACKGROUND: Current treatment options for rosacea include topical agents, oral therapies, phototherapy using lasers, or intense pulsed light (IPL). Combination therapy for rosacea often yields better results than monotherapy. The safety of laser/light treatments in combination with systemic doxycycline has been questioned because of the theoretical risk of photosensitivity. OBJECTIVE: The purpose of this study was to assess the incidence of phototoxicity or photosensitivity in rosacea patients receiving concomitant laser or light treatments and systemic doxycycline. METHODS: Treatment records of 36 patients receiving laser/light treatments while also being treated with standard dose or anti-inflammatory dose of doxycycline were retrospectively reviewed. RESULTS: No adverse reactions related to doxycycline combined with laser/light therapy were reported. Specifically, no photosensitivity or sensitivity to wavelengths in the pulsed dye laser (PDL), or IPL range was observed in this cohort. All patients achieved some degree of clearance. CONCLUSION: The results of this retrospective study demonstrate that doxycycline used in conjunction with laser or nonlaser light therapy is a valid combination therapy for improving signs and symptoms of rosacea. No photosensitivity reactions were observed to commonly used IPL or PDL devices.


Assuntos
Antibacterianos/efeitos adversos , Doxiciclina/efeitos adversos , Terapia de Luz Pulsada Intensa/efeitos adversos , Terapia com Luz de Baixa Intensidade/efeitos adversos , Rosácea/terapia , Administração Cutânea , Adolescente , Adulto , Idoso , Antibacterianos/administração & dosagem , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/efeitos adversos , Doxiciclina/administração & dosagem , Feminino , Humanos , Terapia de Luz Pulsada Intensa/instrumentação , Terapia de Luz Pulsada Intensa/métodos , Lasers de Corante/efeitos adversos , Terapia com Luz de Baixa Intensidade/métodos , Masculino , Pessoa de Meia-Idade , Transtornos de Fotossensibilidade/diagnóstico , Transtornos de Fotossensibilidade/etiologia , Estudos Retrospectivos , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Resultado do Tratamento , Adulto Jovem
6.
J Enzyme Inhib Med Chem ; 34(1): 1590-1596, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31581863

RESUMO

Oral colon administration system has become a new method to treat intestinal diseases. The implementation of colon drug delivery system is restricted by many aspects, including physical and chemical properties, drug delivery mode, gastrointestinal physiological factors, and so on. Delivery methods to overcome these challenges revolve around the mechanisms of drug delivery, including the use of rational dosage forms to avoid the complex pH environment, and the prevention of drug release and absorption in the upper digestive tract.


Assuntos
Colo , Portadores de Fármacos/química , Administração Oral , Animais , Colo/metabolismo , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Portadores de Fármacos/administração & dosagem , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Microbioma Gastrointestinal , Humanos , Concentração de Íons de Hidrogênio , Enteropatias/tratamento farmacológico , Polímeros/química
7.
Artif Cells Nanomed Biotechnol ; 47(1): 3961-3975, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31588802

RESUMO

Ion-complementary self-assembling peptides have potential in delivering hydrophobic drugs. This study involved two self-assembling peptides, RADA16-I and RVDV16-I, of which RVDV16-I was a novel self-assembling peptide with different hydrophobic side chains designed from RADA16-I. The purpose of this study was to observe the interaction between different self-assembling peptides and emodin through fluorescence spectrophotometry, CD, SEM and AFM; to construct a preliminary suspension in-situ hydrogel delivery system for emodin with the self-assembling peptides; and to investigate the drug-loading and drug-releasing properties of the self-assembling peptides on emodin. The results showed that both peptides can interact with emodin and the interaction was dominated by hydrophobic interaction. The aqueous solutions of both self-assembling peptides can form relatively stable suspensions with emodin under mechanical stirring, and the suspension can form in-situ hydrogel under physiological condition. In vitro release of emodin from the hydrogels showed a manner of sustained release to some extent. Cell viability studies showed inherent proliferation inhibiting effects of emodin on tumor cells was maintained or enhanced through the in-situ hydrogels. The self-assembling peptides RADA16-I and RVDV16-I had showed promising drug-loading and drug-releasing performance for hydrophobic drugs. It is reasonable to exploit self-assembling peptides as drug carriers for their great potential to improve delivery of hydrophobic drugs.


Assuntos
Antineoplásicos/química , Preparações de Ação Retardada/química , Emodina/química , Hidrogéis/química , Peptídeos/química , Células A549 , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Emodina/administração & dosagem , Emodina/farmacologia , Células Hep G2 , Humanos , Hidrogéis/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Suspensões
8.
Transplant Proc ; 51(9): 2971-2973, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31607620

RESUMO

BACKGROUND: An extended-release formulation of tacrolimus designed for once-daily administration (LCP-TAC) is a new prolonged-release tacrolimus (TAC-PR) formulation using a drug delivery technology designed to enhance the bioavailability of drugs compared with TAC-PR. The aim of this study was to retrospectively compare de novo administration of LCP-TAC and TAC-PR for therapeutic trough levels and daily dosage during the first 30 days after first liver transplant (LT). METHODS: A total of 35 patients submitted to first LT between 2016 and 2018 were retrospectively enrolled: 16 received LCP-TAC, while 19 received TAC-PR as de novo immunosuppression. Patients were analyzed for daily dosage and trough levels at postoperative days (PODs) 3, 7, 15, and 30. RESULTS: The initial dose of tacrolimus did not differ between LCP-TAC and TAC-PR (mean, 5.19 [SD, 1.72] mg/d vs mean, 5.26 [SD, 1.91] mg/d, P = .90). On PODs 7, 15, and 30 the daily dosage was statistically lower for LCP-TAC compared with TAC-PR (mean, 5.44 [SD, 2.06] mg/d vs mean, 7.68 [SD, 2.91] mg/d, P = .01; mean, 5.33 [SD, 2.23] mg/d vs mean, 8.82 [SD, 2.35] mg/d, P < .001; and mean, 5.38 [SD, 2.50] mg/d vs mean, 9.81 [SD, 3.78] mg/d, P < .001, respectively). The therapeutic trough levels were significantly higher for LCP-TAC on POD 3 (mean, 5.05 [SD, 3.58] ng/mL vs mean, 2.42 [SD, 2.75] ng/mL, P = .03) and POD 5 (mean, 7.35 [SD, 5.12] ng/mL vs mean, 4.17 [SD, 2.05] ng/mL, P = .04), while no differences were found on PODs 7, 15, and 30.The percentage of patients on POD 3 achieving a trough level higher than 6 ng/mL was higher for LCP-TAC than TAC-PR (40% vs 13%, P = .05). CONCLUSIONS: LCP-TAC after LT is safe and might enhance bioavailability, reducing the amount of drug necessary to achieve therapeutic trough levels compared with TAC-PR.


Assuntos
Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Transplante de Fígado , Tacrolimo/administração & dosagem , Tacrolimo/farmacocinética , Adulto , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Feminino , Humanos , Imunossupressão/métodos , Imunossupressores/sangue , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tacrolimo/sangue
9.
AAPS PharmSciTech ; 20(8): 320, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31646399

RESUMO

The in vitro drug release in an aqueous medium is a critical performance metric for a sustained release drug product. During long-term release studies, drugs may degrade in the release medium, and such degradation can lead to errors in drug release quantitation. Using dexamethasone as a model drug and LC-MS/MS methods employing dexamethasone-d4 as an internal standard, this study identified that dexamethasone can degrade into 13 major degradation products in phosphate buffered saline (PBS) as a function of time, temperature (25, 37, and 45°C), and light exposure. A putative scheme for dexamethasone degradation pathways in PBS has been proposed. In proof-of-concept studies, the analytical method was used to quantitate dexamethasone and its degradation products during in vitro release studies with sustained release dexamethasone-poly(D,L-lactide-co-glycolide) (PLGA) implants incubated in phosphate buffer saline (PBS). Further, mathematical approaches were developed to estimate drug release from implants after accounting for drug degradation in PBS. The LC-MS/MS analytical method and the mathematical approaches developed could be used for assessing the stability and/or release of dexamethasone during manufacturing, storage, and use of various dosage forms.


Assuntos
Anti-Inflamatórios/farmacocinética , Dexametasona/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Água/metabolismo , Anti-Inflamatórios/administração & dosagem , Cromatografia Líquida/métodos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Dexametasona/administração & dosagem , Implantes de Medicamento , Liberação Controlada de Fármacos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacocinética , Espectrometria de Massas em Tandem/métodos
10.
J Nanobiotechnology ; 17(1): 99, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31530285

RESUMO

BACKGROUND: Combined therapy has demonstrated to be an effective strategy for cancer therapy. Herein, an injectable hydrogel based on the genetically engineered polypeptide and hollow gold nanoshells (HAuNS) has been developed for chemo-photothermal therapy of HepG2 tumor. METHODS: PC10A/DOX/HAuNS nanogel was prepared with layer-by-layer through the adsorption of DOX and PC10A successively. DOX with positive charge and PC10A with negative charge were coated step by step onto the surface of negatively charged HAuNS. The multifunctional hydrogel PC10A/DOX/HAuNS were prepared via dissolving hybrid PC10A/DOX/HAuNS nanogel in polypeptide PC10A. Chemotherapy drug DOX in the PC10A/DOX/HAuNS hydrogel was absorbed on the HAuNS and directly embedded in the PC10A hydrogel, which contributes to sequentially release of the drug. Specifically, DOX adsorbed on the HAuNS could be released slowly for sustainable chemotherapy. RESULTS: The PC10A/DOX/HAuNS hydrogel could pass 26-gauge needle without clogging, indicating that it is injectable. In addition, the PC10A/DOX/HAuNS hydrogel possessed outstanding photothermal effect and photothermal stability. In both in vitro cell and in vivo tumor-bearing mice experiments, a remarkably enhance tumor inhibition was observed by the combined therapy of chemo-photothermal therapy compared with photothermal therapy or chemotherapy alone. CONCLUSIONS: The combined chemotherapy and photothermal therapy of PC10A/DOX/HAuNS hydrogels could significantly improve the therapeutic effect. Therefore, the multifunctional hydrogel PC10A/DOX/HAuNS is promising to provide a new strategy for sustained chemo-photothermal therapy.


Assuntos
Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Ouro/química , Hidrogéis/administração & dosagem , Hidrogéis/química , Nanoconchas/química , Animais , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Portadores de Fármacos/química , Células Hep G2 , Humanos , Masculino , Camundongos , Nanosferas/química , Fototerapia/métodos
11.
J Mater Sci Mater Med ; 30(9): 106, 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31502009

RESUMO

With the advantage of handy process, random pattern skin flaps are generally applied in limb reconstruction and wound repair. Apelin-13 is a discovered endogenous peptide, that has been shown to have potent multiple biological functions. Recently, thermosensitive gel-forming systems have gained increasing attention as wound dressings due to their advantages. In the present study, an apelin-13-loaded chitosan (CH)/ß-sodium glycerophosphate (ß-GP) hydrogel was developed for promoting random skin flap survival. Random skin flaps were created in 60 rats after which the animals were categorized to a control hydrogel group and an apelin-13 hydrogel group. The water content of the flap as well as the survival area were then measured 7 days post-surgery. Hematoxylin and eosin staining was used to evaluate the flap angiogenesis. Cell differentiation 34 (CD34) and vascular endothelial growth factor (VEGF) levels were detected by immunohistochemistry and Western blotting. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were assessed by enzyme linked immunosorbent assays (ELISAs). Oxidative stress was estimated via the activity of tissue malondialdehyde (MDA) and superoxide dismutase (SOD). Our results showed that CH/ß-GP/apelin-13 hydrogel could not only reduce the tissue edema, but also improve the survival area of flap. CH/ß-GP/apelin-13 hydrogel also upregulated levels of VEGF protein and increased mean vessel densities. Furthermore, CH/ß-GP/apelin-13 hydrogel was shown to significantly inhibit the expression of TNF-α and IL-6, along with increasing the activity of SOD and suppressing the MDA content. Taken together, these results indicate that this CH/ß-GP/apelin-13 hydrogel may be a potential therapeutic way for random pattern skin flap.


Assuntos
Sobrevivência de Enxerto/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/administração & dosagem , Peptídeos e Proteínas de Sinalização Intercelular/farmacocinética , Transplante de Pele/métodos , Pele/efeitos dos fármacos , Temperatura Ambiente , Animais , Temperatura Corporal/fisiologia , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Hidrogéis/administração & dosagem , Hidrogéis/farmacocinética , Masculino , Malondialdeído/metabolismo , Necrose/patologia , Necrose/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Pele/metabolismo , Pele/patologia , Fenômenos Fisiológicos da Pele/efeitos dos fármacos , Retalhos Cirúrgicos/fisiologia , Retalhos Cirúrgicos/transplante
12.
Eur J Pharm Biopharm ; 144: 132-138, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31521716

RESUMO

Novel treatment methods for obesity are urgently needed due to the increasing global severity of the problem. Gastrointestinal hormones, such as GLP-1 and PYY, are secreted by the enteroendocrine cells, playing a critical role in regulating food intake. Digested nutrients trigger the secretion of these hormones, which have a very short half-life. α-Linolenic acid (αLA) has been shown to stimulate GLP-1 secretion, however, chemical instability and fast uptake in the small intestine hinder its use in body weight management. We developed a novel delivery system based on inorganic mesoporous particles for αLA to increase secretion of gastrointestinal peptides. αLA was loaded to thermally hydrocarbonized porous silicon particles (THCPSi). 47.9 ±â€¯3.84% and 30.7 ±â€¯2.86% of αLA was released during 6 h from 3.0% and 9.2% loading degree (w/w) samples in vitro, respectively. Native αLA (50 µM) significantly increased GLP-1 secretion from enteroendocrine STC-1 and GLUTag cell lines. αLA loaded THCPSi significantly and dose dependently stimulated GLP-1 secretion from STC-1 cells, whereas empty particles did not. We demonstrated in vitro that THCPSi particles have the potential to be used as a controlled delivery system for nutrients such as αLA, increasing GLP-1 secretion. Our results justify further in vivo investigations.


Assuntos
Preparações de Ação Retardada/administração & dosagem , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Intestino Delgado/metabolismo , Ácido alfa-Linoleico/administração & dosagem , Animais , Linhagem Celular , Sistemas de Liberação de Medicamentos/métodos , Camundongos , Peptídeos/metabolismo , Silício/química
13.
Parasit Vectors ; 12(1): 433, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492168

RESUMO

BACKGROUND: The safety of ProHeart® 12 (PH 12; extended-release injectable suspension; 10% moxidectin in glyceryl tristearate microspheres) was evaluated in four studies using Beagle dogs and one study using ivermectin-sensitive Collies. The recommended dose is 0.5 mg/kg subcutaneously once yearly. METHODS: Study 1: safety margin was evaluated as 3 treatments of PH 12 (0× (control); 1× (recommended dose); 3× (3 times recommended dose) and 5× (5 times recommended dose) in 12 months via clinical observations, body weights, food consumption, injection site observations, physical examinations, moxidectin tissue assay, pharmacokinetics, and clinical and anatomic pathology. Study 2: safety in breeding-age males was demonstrated by semen testing at 14-day intervals from Day 7 to Day 91 post-treatment (0× or 3×). Study 3: reproductive safety in females was demonstrated by monitoring dams and litters following treatments (0× or 3×) administered during breeding, gestation, or lactation. Study 4: safety in dogs surgically implanted with adult heartworms was evaluated by clinical and laboratory monitoring following treatment with 0× or 3× administered 61 days post-implantation. Study 5: safety in ivermectin-sensitive dogs (120 µg/kg SC) was by clinical monitoring for 1 week after administering 1×, 3× or 5×. RESULTS: Study 1: slight swelling clinically detectable at some 3× and 5× injection sites was characterized microscopically as granulomatous inflammation, like tissue responses to medical implants, interpreted as non-adverse. Pharmacokinetics were dose-proportional and there was little or no systemic accumulation. Residual moxidectin mean (range) at 1× injection sites after 1 year was 16.0% (0.045-37.6%) of the administered mass. Studies 2 and 3: no effects were identified in reproductive indices (females) or semen quality characteristics (males). Study 4: PH 12 produced marked reductions in circulating microfilariae and lower numbers of adult heartworms, but no adverse clinical signs were identified. Study 5: there were no abnormal clinical signs at 1×, 3× or 5× overdoses of PH 12 in ivermectin-sensitive dogs. CONCLUSIONS: PH 12 has a > 5× safety margin in both normal and ivermectin-sensitive dogs, has no effects on canine reproduction, and is well tolerated in heartworm-positive dogs. The only treatment-related finding was non-adverse, granulomatous inflammation at the injection site.


Assuntos
Antinematódeos/efeitos adversos , Preparações de Ação Retardada/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Injeções/efeitos adversos , Macrolídeos/efeitos adversos , Suspensões/efeitos adversos , Animais , Antinematódeos/administração & dosagem , Preparações de Ação Retardada/administração & dosagem , Doenças do Cão/tratamento farmacológico , Cães , Hidropericárdio/tratamento farmacológico , Macrolídeos/administração & dosagem , Suspensões/administração & dosagem , Resultado do Tratamento
14.
Biomater Sci ; 7(10): 4060-4074, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31475710

RESUMO

Combined photothermal-chemotherapy guided by multimodal imaging is a promising strategy for cancer diagnosis and treatment. Multifunctional nanoparticles, such as those comprising organic and inorganic compounds, have been extensively investigated for combined photothermal-chemotherapy; however, their application is still limited by their potential long-term toxicity and lack of contrast properties. To solve these problems, in this study, a new type of multifunctional nanoparticle for combined photothermal-chemotherapy guided by dual-modality imaging was prepared with endogenous melanin by multistep emulsification to enhance tumor ablation. The nanoparticles were coated with poly(lactide-co-glycolic acid) (PLGA) and loaded with paclitaxel (PTX), encapsulated melanin and perfluoropentane (PFP). The materials in the nanoparticles were endogenous, ensuring high stability, biocompatibility, and biosafety. Nanoparticles irradiated with a laser, which induced their phase transformation into microbubbles, exhibited high photothermal conversion efficiency, thereby achieving photoacoustic (PA)/ultrasound (US) dual-modality imaging to determine tumor location, boundary, and size and to monitor drug distribution. Furthermore, optical droplet vaporization (ODV) of the nanoparticles could trigger the release of PTX; thus, these nanoparticles are a useful drug carrier. In vivo and in vitro experiments revealed that a strong synergistic antitumor effect was achieved by combining the photothermal properties of the nanoparticles with a chemotherapy drug. Importantly, the cavitation, thermoelastic expansion, and sonoporation caused by the phase transformation of the nanoparticles could directly damage the tumors. These processes also promoted the release, penetration and absorption of the drug, further enhancing the effect of combined photothermal-chemotherapy on tumor suppression. Therefore, the multifunctional nanoparticles prepared in this study provide a new strategy of using endogenous materials for controlled near-infrared (NIR)-responsive drug release and combined photothermal-chemotherapy guided by multimodal imaging.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Fluorcarbonetos/administração & dosagem , Melaninas/administração & dosagem , Nanopartículas/administração & dosagem , Neoplasias/terapia , Paclitaxel/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Animais , Antineoplásicos Fitogênicos/farmacocinética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Terapia Combinada , Preparações de Ação Retardada/administração & dosagem , Feminino , Fluorcarbonetos/farmacocinética , Células Endoteliais da Veia Umbilical Humana , Humanos , Melaninas/farmacocinética , Camundongos Endogâmicos BALB C , Neoplasias/metabolismo , Paclitaxel/farmacocinética , Técnicas Fotoacústicas , Fototerapia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacocinética , Distribuição Tecidual , Ultrassonografia
15.
Colloids Surf B Biointerfaces ; 182: 110388, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31369955

RESUMO

MRSA infections are a major global healthcare problem associated with high morbidity and mortality. The application of novel materials in antibiotic delivery has efficiently contributed to the treatment of MRSA infections. The aim of the study was to develop novel hyaluronic acid-oleylamine (HA-OLA) conjugates with 25-50% degrees of conjugation, for application as a nano-drug carrier with inherent antibacterial activity. The biosafety of synthesized novel HA-OLA conjugates was confirmed by in vitro cytotoxicity assay. Drug carrying ability of HA-OLA conjugates was confirmed by 26.1-43.12% of vancomycin (VCM) encapsulation in self-assembled polymersomes. These polymersomes were dispersed in nano-sized range (196.1-360.9 nm) with a negative zeta potential. Vancomycin loaded polymersomes were found to have spherical and bilayered morphology. The VCM loaded polymersomes displayed sustained drug release for 72 h. In vitro studies showed moderate antibacterial activity for HA-OLA conjugates against both S. aureus and MRSA with minimum inhibitory concentration (MIC) of 500 µg/mL. The VCM loaded HA-OLA polymersomes displayed four-fold lower MIC (1.9 µg/mL) than free VCM (7.8 µg/mL) against MRSA. Furthermore, synergism was observed for VCM and HA-OLA against MRSA. Flow cytometry showed 1.8-fold higher MRSA cell death in the population for VCM loaded polymersomes relative to free drug, at concentration of 1.95 µg/mL. Bacterial cell morphology showed that the drug loaded polymersomes had stronger impact on MRSA membrane, compared to free VCM. These findings suggest that, HA-OLA conjugates are promising nano-carriers to function as antibiotic delivery vehicles for the treatment of bacterial/MRSA infections.


Assuntos
Aminas/química , Sistemas de Liberação de Medicamentos/métodos , Ácido Hialurônico/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Polímeros/química , Vancomicina/administração & dosagem , Antibacterianos/administração & dosagem , Antibacterianos/química , Antibacterianos/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Liberação Controlada de Fármacos , Células HEK293 , Células HeLa , Humanos , Células MCF-7 , Meticilina/farmacologia , Staphylococcus aureus Resistente à Meticilina/fisiologia , Testes de Sensibilidade Microbiana , Vancomicina/química , Vancomicina/farmacocinética
16.
Int J Pharm ; 569: 118589, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31386880

RESUMO

Polymer microcapsules offer a possibility of storing increased amounts of drugs. Appropriate design and composition of the microcapsules allow tuning of the drug-release process. In this paper, we report on synthesis of hydrogel microcapsules sensitive to temperature and pH and degradable by glutathione and hydrogen peroxide. Microcapsules were based on thermo-responsive poly(N-isopropylacrylamide) and degradable cystine crosslinker, and were synthesized by applying precipitation polymerization. Such way of polymerization was appropriately modified to limit the crosslinking in the microcapsule center. This led to a possibility of washing out the pNIPA core at room temperature and the formation of a capsule. Microcapsules revealed rather high drug-loading capacity of ca. 17%. The degradation of the microcapsules by the reducing agent (GSH) and the oxidizing agent (H2O2) was confirmed by using the DLS, UV-Vis, SEM and TEM techniques. Depending on pH and concentration of the reducing/oxidizing agents a fast or slow degradation of the microcapsules and a burst or long-term release of doxorubicin (DOX) were observed. The DOX loaded microcapsules appeared to be cytotoxic against A2780 cancer cells similarly to DOX alone, while unloaded microcapsules did not inhibit proliferation of the cells.


Assuntos
Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Hidrogéis/administração & dosagem , Antineoplásicos/química , Cápsulas , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Doxorrubicina/química , Liberação Controlada de Fármacos , Glutationa/farmacologia , Humanos , Hidrogéis/química , Peróxido de Hidrogênio/farmacologia , Concentração de Íons de Hidrogênio , Temperatura Ambiente
17.
Drug Dev Ind Pharm ; 45(11): 1777-1787, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31418598

RESUMO

Development of extended release oral formulations of dexketoprofen trometamol (DT), a rapidly eliminated drug with high solubility, poses a great challenge especially when a portion of the dose is to be absorbed from the colon. In this study, site-specific release-retardant mini-matrix tablets (SSRRMTs) were developed and functionally coated with pH-responsive materials to achieve a site-specific delivery of DT at the duodenojejunal (DSRRMT) and ileocecal (ISRRMT) regions. Stomach-specific coated mini-tablets (SSCMTs) were manufactured for immediate release of about 16% of the daily dose of DT in the stomach. The SSCMT, DSRRMT, and ISRRMT were combined into a solid dosage form (C-SSRRMT tablets or capsules) to achieve the required linear release profile for once daily administration of DT. The SSRRMT and C-SSRRMT formulations were evaluated for the physical properties, in vitro-disintegration and in vitro dissolution and proved to be consistent with the pharmacopeial specifications. The in vitro release profiles of both C-SSRRMT tablets and capsules showed a constant release rate of about 6 mg/h and were similar to that of the theoretical target linear release profile. The pharmacokinetic study using human volunteers showed the bioequivalence of a single oral dose of C-SSRRMT capsules compared to three-successive oral doses of the immediate release market tablets with less ups and downs in the drug levels. The C-SSRRMT capsules formulation, may therefore, constitute an advance in the extended oral delivery of DT without the lack of efficacy and the adverse events frequently encountered in multiple daily dosing of the immediate release tablets.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Preparações de Ação Retardada/farmacocinética , Cetoprofeno/análogos & derivados , Trometamina/farmacocinética , Administração Oral , Adulto , Anti-Inflamatórios não Esteroides/administração & dosagem , Área Sob a Curva , Estudos Cross-Over , Preparações de Ação Retardada/administração & dosagem , Esquema de Medicação , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Voluntários Saudáveis , Humanos , Absorção Intestinal , Mucosa Intestinal/metabolismo , Cetoprofeno/administração & dosagem , Cetoprofeno/farmacocinética , Masculino , Solubilidade , Comprimidos , Equivalência Terapêutica , Trometamina/administração & dosagem
18.
Drug Dev Ind Pharm ; 45(11): 1725-1739, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31432703

RESUMO

Objective and methods: This study predicted the nature of chitosan interactions and effects of this interaction on drug release mechanism in simvastatin-loaded chitosan nanoformulation using molecular docking, spectroscopic and thermal analysis. Significance: This work explains in depth the molecular mechanism of simvastatin and chitosan bond formation in nanoformulation. Results: The effective encapsulation and sustain release properties of chitosan were indicated by increase in melting endotherm of simvastatin. Intermolecular hydrogen bond between third hydroxyl group pyranone ring of simvastatin and amino group of chitosan represented the stability of active lactone moiety that was not cleaved during formulation which is prerequisite for biological activity. UV-vis spectroscopic characterization, shift in infrared vibration wavenumber of simvastatin and chitosan, ligand titration, 1HNMR and 13C-NMR analyses confirmed this interaction pattern. The pharmacokinetic evaluation in mouse model revealed the sustain release property of nanoformulation. Conclusion: Thus formation of intermolecular hydrogen bond in nanoformulation contributed to modified physicochemical properties and improved in vivo performance of simvastatin.


Assuntos
Quitosana/química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Hiperlipidemias/tratamento farmacológico , Sinvastatina/farmacocinética , Administração Oral , Animais , Colesterol na Dieta/administração & dosagem , Colesterol na Dieta/efeitos adversos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Modelos Animais de Doenças , Esquema de Medicação , Composição de Medicamentos , Feminino , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/etiologia , Camundongos , Simulação de Acoplamento Molecular , Nanopartículas/química , Tamanho da Partícula , Espectroscopia de Prótons por Ressonância Magnética , Sinvastatina/administração & dosagem , Espectroscopia de Infravermelho com Transformada de Fourier
19.
J Vet Cardiol ; 24: 58-63, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31405555

RESUMO

INTRODUCTION: The objective of the present study was to evaluate the pharmacokinetics of a compounded sustained-release procainamide formulation in normal dogs. ANIMALS: Six healthy, purpose-bred mixed-breed dogs participated in the study. METHODS: In phase I, two dogs were administered oral procainamide (30 mg/kg), and plasma was obtained to determine plasma concentration ranges and duration. In phase II, six dogs were administered procainamide (30 mg/kg by mouth every 12 hours) to determine the pharmacokinetics of sustained-release procainamide. Serum procainamide concentration was determined using an immunochemistry assay. RESULTS: No adverse clinical effects were noted in any of the dogs studied. The average maximum serum concentration, average serum concentration, and average minimum serum concentration were 10.17, 7.13, and 3.07 µg/mL, respectively. The average time over a 12-h period during which procainamide concentration exceeded 12 µg/mL was 2.35 h, was between 4 and 12 µg/mL was 7.19 h, and was less than 4 µg/mL was 2.46 h. The average times at maximum concentration and minimum concentration were 18.67 and 12.25 h, respectively. CONCLUSIONS: Administration of sustained-release procainamide twice daily achieved targeted plasma concentrations in most dogs. Evaluation of serum trough concentrations should be considered owing to interanimal variability to confirm that serum concentrations are within the reported therapeutic range for an individual patient.


Assuntos
Antiarrítmicos/farmacocinética , Preparações de Ação Retardada/farmacocinética , Cães/metabolismo , Procainamida/farmacocinética , Administração Oral , Animais , Antiarrítmicos/administração & dosagem , Antiarrítmicos/sangue , Preparações de Ação Retardada/administração & dosagem , Cães/sangue , Feminino , Masculino , Procainamida/administração & dosagem , Procainamida/sangue , Valores de Referência
20.
J Agric Food Chem ; 67(38): 10604-10613, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31466448

RESUMO

The aim of this study was to investigate the dipeptidyl peptidase-IV (DPP-IV) inhibition and metabolic stability of a casein-derived peptide Val-Pro-Tyr-Pro-Gln (VPYPQ) and its fragments as well as their release from casein following hydrolysis. Results showed that VPYPQ was the most potent DPP-IV inhibitory peptide among them with an IC50 value of 41.45 µM. This might be due to its two internal Pro residues at positions 2 and 4. Moreover, VPYPQ was resistant to hydrolysis by gastrointestinal enzymes and was relatively more stable to hydrolysis by DPP-IV and peptidases in plasma compared with its fragments. Additionally, oral administration of VPYPQ at a dose of 90 µmol/kg body weight could reduce the postprandial blood glucose levels in mice. More importantly, VPYPQ could be released efficiently from casein following hydrolysis by a combination of papain and in vitro digestion, reaching up to 3211.15 µg/g. Therefore, VPYPQ was a promising casein-derived DPP-IV inhibitor.


Assuntos
Caseínas/química , Preparações de Ação Retardada/química , Inibidores da Dipeptidil Peptidase IV/química , Peptídeos/química , Animais , Biocatálise , Glicemia/metabolismo , Preparações de Ação Retardada/administração & dosagem , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Teste de Tolerância a Glucose , Humanos , Hidrólise , Camundongos , Peptídeo Hidrolases/química , Peptídeo Hidrolases/metabolismo , Peptídeos/administração & dosagem , Ratos , Ratos Sprague-Dawley
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