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1.
Zhongguo Zhong Yao Za Zhi ; 44(15): 3305-3311, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602887

RESUMO

To enhance in vitro dissolution of Cur by preparing Cur solid dispersions. The ability of HPMCAS-HF,HPMCAS-MF,HPMCAS-LF and PVPK30 to maintain supersaturated solution was investigated by supersaturation test. Amorphous solid dispersions were prepared by the solvent-evaporation method. The prepared samples were characterized using infrared spectroscopy( IR) and differential scanning calorimetry( DSC),and in vitro dissolution was investigated. DSC and IR results showed that in 1 ∶3 and 1 ∶9 solid dispersions,Cur was amorphously dispersed in the carrier,and the interaction existed between drug and carrier. The supersaturation test showed that the order of the ability of polymer to inhibit crystallization of Cur was MF>HF>LF>K30. The dissolution results showed that Cur-K30 amorphous solid dispersion had the highest drug release rate; Cur-K30 and Cur-LF amorphous solid dispersions had a quicker but not stable dissolution rate,and the drug concentration decrease after 4 h; Cur-MF and Cur-HF solid dispersions had a low dissolution,which however increased steadily,attributing to the strong ability of the polymers to inhibit the crystallization of Cur. HPMCAS could inhibit the degradation of Cur better than K30,especially MF and HF. The amorphous solid dispersions of cur significantly enhanced the dissolution of Cur and improved the chemical stability of Cur. This study can provide a basis for the rational selection of the polymer used for Cur solid dispersion.


Assuntos
Curcumina/química , Metilcelulose/análogos & derivados , Química Farmacêutica , Estabilidade de Medicamentos , Metilcelulose/química , Polímeros , Solubilidade
2.
Expert Opin Ther Pat ; 29(11): 891-907, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31603360

RESUMO

Introduction: Pharmacotherapy is limited by the inefficient drug targeting of non-healthy cells/tissues. In this pharmacological landscape, liposomes are contributing to the impulse given by Nanotechnology to optimize drug therapy. Areas covered: The analysis of the state-of-the-art in liposomal formulations for drug delivery purposes have underlined that lately published patents (since 2014) are exploring alternative compositions and ways to optimize the stability and drug loading content/release profile. These improvements are complemented by improved long-circulating structures and further liposome functionalizations, which have definitively opened the road for the (co-)delivery of therapeutics to the site of action. Liposomes are also contributing to new drug delivery approaches involving the generation of extracellular vesicles by targeted cells, while opening new ways to combine disease diagnosis and therapy (theranosis). Expert opinion: Patent publications on liposomal formulations have expanded new ways in drug delivery. New lipid compositions and strategies to optimize stability and drug vehiculization capabilities have settle solid pillars in liposome fabrication. Despite, their architecture has been satisfactorily adapted for combining passive and active drug targeting concepts, new inputs of liposomes into the disease arena should answer for: a simple/scalable/cost-effective formulation; a safe/stable/controllable formulation meeting quality control regulations; and, a confirmed therapeutic efficiency in clinical investigations.


Assuntos
Química Farmacêutica/métodos , Sistemas de Liberação de Medicamentos , Lipídeos/química , Animais , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Humanos , Lipossomos , Nanotecnologia/métodos , Patentes como Assunto
3.
J Agric Food Chem ; 67(41): 11331-11339, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31529945

RESUMO

Chiral pesticides are often produced and applied without distinguishing the difference of enantiomers, which sometimes leads to overuse and inaccurate risk assessment. Imazalil is a widely used chiral fungicide; its parent and major metabolite R14821 (imazalil-M) are usually detected in environmental and plant samples. The enantioselective bioactivity of imazalil enantiomers to seven typical pathogens (e.g., Fulvia fulva) was explored. S-(+)-Imazalil showed 3.00-6.59 times higher bioactivity than its antipode for selected pathogens. Molecular docking partly explained the mechanism of enantioselectivity in bioactivity. S-(+)-Imazalil had a stronger hydrophobic interaction and lower energy conformation with binding sites than R-(-)-imazalil. The acute toxicity of S-(+)-imazalil was 1.23-fold and 2.25-fold more than R-(-)-imazalil to P. subcapitata and D. magna, respectively. And, S-(+)-imazalil-M had 2.21-fold and 1.70-fold higher toxicity than R-(-)-imazalil-M to P. subcapitata and D. magna, respectively. However, R-(-)-imazalil was 1.21 times more toxic than S-(+)-imazalil to D. rerio. The enantioselective dissipation of imazalil and imazalil-M was explored under greenhouse conditions. High-effective S-(+)-imazalil preferentially enriched in leaf and fruit of tomato and cucumber, and no enantioselective degradation was found in soil. Imazalil-M enantiomers formed in cucumber, leaf of cucumber, and tomato, and the EF values fluctuated between 0.332 and 0.499. The results could provide information for more accurate assessment of imazalil; they implicated that using S-(+)-imazalil could reduce pesticide input and the risk to D. rerio.


Assuntos
Fungicidas Industriais/química , Imidazóis/química , Poluentes do Solo/química , Verduras/química , Poluentes Químicos da Água/química , Animais , Ascomicetos/efeitos dos fármacos , Clorófitas/efeitos dos fármacos , Cucumis sativus/química , Daphnia/efeitos dos fármacos , Estabilidade de Medicamentos , Frutas/química , Fungicidas Industriais/toxicidade , Imidazóis/toxicidade , Lycopersicon esculentum/química , Simulação de Acoplamento Molecular , Solo/química , Poluentes do Solo/toxicidade , Estereoisomerismo , Poluentes Químicos da Água/toxicidade
4.
Chem Pharm Bull (Tokyo) ; 67(9): 921-928, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474730

RESUMO

We studied the possibility of using ursodeoxycholic acid (UDCA) as an excipient to create an amorphous composite that can be administered to animals in preclinical studies of experimental drugs. Three UDCA-based amorphous samples composed of nifedipine (NIF), indomethacin (IND), and naproxen (NAP) were found by screening. The UDCA-based formulations were adjudged amorphous by solid-state analysis using X-ray powder diffraction and differential scanning calorimetry. In addition, amorphous samples of NIF-UDCA, IND-UDCA, and NAP-UDCA did not crystallize while in 1% methyl cellulose (MC) solution for 120 min, although an amorphous solid dispersion of NIF-poly(vinylpyrrolidone) (PVP) crystallized rapidly. The low hygroscopicity of UDCA helps NIF maintain an amorphous state in 1% MC solution. The UDCA-based amorphous composites can be administered as suspended formulations to animals in preclinical studies.


Assuntos
Composição de Medicamentos , Preparações Farmacêuticas/química , Ácido Ursodesoxicólico/química , Varredura Diferencial de Calorimetria , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Indometacina/química , Naproxeno/química , Nifedipino/química , Solubilidade
5.
Chem Pharm Bull (Tokyo) ; 67(9): 940-944, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474733

RESUMO

The photostability of three types of furosemide (FUR) cocrystal (FUR-caffeine, FUR-urea, and FUR-nicotinamide cocrystals) was studied under irradiation with a D65 fluorescent lamp. The coloration of the FUR-urea pellets was significantly faster than that of the intact FUR, whereas the coloration of FUR-nicotinamide was suppressed compared with that of intact FUR and the other cocrystals. In the case of FUR-urea, the chemical degradation of FUR increased by approximately 6.6% after irradiation for 90 d. On the other hand, FUR-nicotinamide showed better chemical stability, with only 1.3% of FUR degraded, which was significantly lower than the other cocrystals. The FUR-urea pellets showed a UV-Visible absorption spectrum similar to that of intact FUR, while the absorption range of FUR-nicotinamide shifted to a shorter wavelength. The light sensitivity of FUR-nicotinamide was improved because of the much lower emission of the D65 fluorescent lamp in the absorption range of the cocrystal.


Assuntos
Cafeína/química , Furosemida/química , Luz , Niacinamida/química , Ureia/química , Cristalização , Estabilidade de Medicamentos , Espectrofotometria
6.
Pharm Res ; 36(11): 153, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31482243

RESUMO

The purpose of this review is to discuss the challenges associated with the development of nanoparticle-based quality drug products in adhering to the principles of quality by design (QbD) and defining appropriate quality parameters towards successful product development. With the advent of nanotechnology into the pharmaceutical field, the novel field of nanomedicine was born. Due to their unique properties in terms of size, conformation and targeted delivery, nanomedicines are able to overcome many drawbacks of conventional medicine. As nano-sized formulations have made their way into more and more therapies, it has became clear that these very unique properties create hurdles for nanomedicines in successfully traversing the regulatory pathways and there is a need to develop nanomedicines in a more controlled and consistent fashion. The elements of a QbD methodology explained in this review enable the development of nano-based formulations in a way that maximizes the possibility of success. The identification of critical quality attributes (CQA) of the drug product and its intermediates are discussed in detail with a focus on nanomaterial-based formulations. In conclusion, QbD and the identification and specification of CQAs at its core are critical to the design, development and growth of nanomaterials in pharmaceuticals.


Assuntos
Desenvolvimento de Medicamentos/métodos , Nanocápsulas/química , Nanotecnologia/métodos , Animais , Preparações de Ação Retardada/química , Composição de Medicamentos , Estabilidade de Medicamentos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Nanomedicina , Resultado do Tratamento
7.
Int J Pharm Compd ; 23(5): 414-417, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31513540

RESUMO

Furosemide parenteral solutions are routinely used in our hospital. However, the stability in transparent syringes is unknown. In this study, transparent polypropylene syringes were filled with 8 mL and 50 mL of furosemide 5-mg/mL solution. The furosemide was analyzed by high-performance liquid chromatography and assays were performed up to 35 days of storage of the syringes at 4°C protected from light, plus 24 hours at 20°C exposed to daylight. In addition, the appearance and pH of the solutions were determined. A microbiological assay using tryptic soy broth was also performed. Both types of syringes remained colorless, clear, and free from visible particles throughout the study period. The pH did not change, and concentrations remained between 95% and 105% of the stated concentration. None of the syringes filled with culture media exhibited bacterial or fungal growth. In conclusion, ready-to-administer furosemide 5-mg/mL, 8-mL, and 50-mL polypropylene syringes are stable for up to 35 days when stored in a refrigerator at 4°C protected from light, plus 24 hours at 20°C unprotected from light. These results allow maximum storage time in stock and the ability of 24-hour continuous infusion at ambient room temperature without protecting the syringe against light.


Assuntos
Furosemida/química , Polipropilenos , Seringas , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Polipropilenos/química
8.
Cell Prolif ; 52(5): e12662, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31364793

RESUMO

OBJECTIVES: Pegaptanib might be a promising anti-tumour drug targeting VEGF to inhibit tumour vascular endothelial cell proliferation. However, the poor biostability limited its application. In this study, we took tetrahedron DNA nanostructures (TDNs) as drug nanocarrier for pegaptanib to explore the potent anti-angiogenesis and anti-tumour activity of this drug delivery system. MATERIALS AND METHODS: The successful synthesis of TDNs and pegaptanib-TDNs was determined by 8% polyacrylamide gel electrophoresis (PAGE), capillary electrophoresis and dynamic light scattering (DLS). The cytotoxicity of pegaptanib alone and pegaptanib-TDNs on HUVECs and Cal27 was evaluated by the cell count kit-8 (CCK-8) assay. The effect of pegaptanib and pegaptanib-TDNs on proliferation, migration and tube formation of HUVECs induced by VEGF was examined by CCK-8 assay, wound healing assay and tubule formation experiment. The cell binding capacity and serum stability were detected by flow cytometry and PAGE, respectively. RESULTS: Pegaptanib-TDNs had stronger killing ability than pegaptanib alone, and the inhibiting effect was in a concentration-dependent manner. What's more, pegaptanib-loaded TDNs could effectively enhance the ability of pegaptanib to inhibit proliferation, migration and tube formation of HUVECs induced by VEGF. These might attribute to the stronger binding affinity to the cell membrane and greater serum stability of pegaptanib-TDNs. CONCLUSIONS: These results suggested that pegaptanib-TDNs might be a novel strategy to improve anti-angiogenesis and anti-tumour ability of pegaptanib.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Aptâmeros de Nucleotídeos/farmacologia , Proliferação de Células/efeitos dos fármacos , Nanoestruturas/química , Neovascularização Fisiológica/efeitos dos fármacos , Inibidores da Angiogênese/química , Antineoplásicos/química , Aptâmeros de Nucleotídeos/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , DNA/química , Portadores de Fármacos/química , Estabilidade de Medicamentos , Células Endoteliais da Veia Umbilical Humana , Humanos , Fator A de Crescimento do Endotélio Vascular/farmacologia
9.
J Agric Food Chem ; 67(37): 10432-10447, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31466447

RESUMO

A composite nanogel was developed for cyanidin-3-O-glucoside (C3G) delivery by combining Maillard reaction and heat gelation. The starting materials utilized were ovalbumin, dextran, and pectin. C3G-loaded nanogel was spherical with a diameter of ∼185 nm, which was maintained over a wide range of pH and NaCl concentrations. The composite nanogel enhanced the chemical stability of C3G under accelerated degradation models and a simulated gastrointestinal tract. Clathrin-mediated, caveolae-mediated, and macropinocytosis-related endocytosis contributed to the higher cellular uptake of nano-C3G than that of free-C3G. The apparent permeability coefficients of C3G increased 2.16 times after nanoencapsulation. The transcytosis of the C3G-bearing nanogel occurred primarily through the clathrin-related pathway and macropinocytosis and followed the "common recycling endosomes-endoplasmic reticulum-Golgi complex-basolateral plasma membrane" route. Moreover, nano-C3G was more efficient in restoring the viability of cells and activities of endogenous antioxidant enzymes than free-C3G in oxidative models, which may be attributed to the former's high cellular absorption.


Assuntos
Antocianinas/química , Antocianinas/metabolismo , Antioxidantes/química , Antioxidantes/metabolismo , Portadores de Fármacos/química , Glucosídeos/química , Glucosídeos/metabolismo , Células CACO-2 , Composição de Medicamentos , Estabilidade de Medicamentos , Trato Gastrointestinal/metabolismo , Géis/química , Géis/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Absorção Intestinal , Modelos Biológicos , Nanopartículas/química , Nanopartículas/metabolismo , Tamanho da Partícula
10.
J Agric Food Chem ; 67(33): 9371-9381, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31379162

RESUMO

A major obstacle to the clinical use of curcumin (CUR) is its reduced bioavailability because of the drug's hydrophobic nature, low intestinal absorption, and rapid metabolism. In this study, a novel oral drug delivery system was constructed for improving the stability and enhancing mucoadhesion of CUR in the gastrointestinal (GI) tract. First, CUR was encapsulated in the bovine serum albumin nanoparticles (CUR-BSA-NPs). Then, N-acetyl cysteine (NAC)-modified CUR-BSA-NPs (CUR-NBSA-NPs) were obtained. The average particle size and zeta potential of CUR-NBSA-NPs were 251.6 nm and -30.66 mV, respectively; encapsulation efficiency and drug loading were 85.79 and 10.9%, respectively. CUR-NBSA-NPs exhibited a sustained release property and prominently enhanced stability in simulated GI conditions. Additionally, enhanced mucoadhesion of CUR-NBSA-NPs was also observed. An MTT study showed that the CUR-NBSA-NPs were safe for oral administration. Overall, NAC-modified BSA-NPs may potentially serve as an oral vehicle for improving CUR stability in the GI tract and enhancing mucoadhesion.


Assuntos
Acetilcisteína/química , Curcumina/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/instrumentação , Trato Gastrointestinal/metabolismo , Nanopartículas/química , Soroalbumina Bovina/química , Animais , Células CACO-2 , Bovinos , Curcumina/metabolismo , Estabilidade de Medicamentos , Humanos , Tamanho da Partícula
11.
Phys Chem Chem Phys ; 21(35): 19686-19694, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31469369

RESUMO

In this study the glass transition temperatures (Tgα and Tgß) in mesoporous silica-based amorphous drugs were characterized. For this purpose, mesoporous silica Parteck SLC (MPS) was loaded with the drugs ibuprofen and carvedilol, either below, at, or above the monomolecular drug loading capacities, i.e. the concentration at which the entire MPS surface is covered with a monolayer of drug molecules. The resulting amorphous forms were analysed using X-ray powder diffraction and the thermal behaviour was characterised with differential scanning calorimetry (DSC) and dynamic mechanical analysis (DMA). The drug monolayer did not contribute to the thermal signal in DSC. Using DMA however, it could be shown that the monolayer indeed exhibited a very weak Tgα, and that the temperature range of this transition did not differ from that of the quench cooled amorphous drugs. Theoretical ab initio molecular dynamics simulations revealed that the nature of hydrogen bonding geometry of the functional groups interacting with the MPS surface were similar to that of the respective crystalline drugs, which results in restricted molecular motions for those functional groups. On the other hand, the non-interacting parts of the molecules exhibited molecular motions similar to what is observed in pure amorphous drugs. As a result of the interactions of the monolayer with the MPS surface, the monomolecular drug layer did not reveal a Tgß. However, a Tgß was found at any drug-MPS ratios above the monomolecular drug loading capacity as a result of the excess drug which forms a "true" amorphous phase. Overall, this study demonstrated that drug molecules forming an amorphous monolayer on the surfaces of a mesoporous silica particle, even though they are restricted in their mobility, exhibit a Tgα, but lack a Tgß, whereas any excess drug confined in the MPS pores showed similar properties as the pure amorphous drug. These findings will help to increase the overall understanding of drug loaded MS systems, including their physical stability as well as release properties.


Assuntos
Vidro/química , Dióxido de Silício/química , Temperatura de Transição , Varredura Diferencial de Calorimetria , Carvedilol/química , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Ibuprofeno/química , Simulação de Dinâmica Molecular
12.
Int J Nanomedicine ; 14: 5017-5032, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371944

RESUMO

Background: Epigallocatechin gallate (EGCG), the major anti-inflammatory compound in green tea, has been shown to suppress osteoclast (OC) differentiation. However, the low aqueous solubility of EGCG always leads to poor bioavailability, adverse effects, and several drawbacks for clinical applications. Purpose: In this study, we synthesized EGCG-capped gold nanoparticles (EGCG-GNPs) to solve the drawbacks for clinical uses of EGCG in bone destruction disorders by direct reduction of HAuCl4 in EGCG aqueous solution. Methods and Results: The obtained EGCG-GNPs were negatively charged and spherical. Theoretical calculation results suggested that EGCG was released from GNPs in an acidic environment. Cellular uptake study showed an obviously large amount of intracellular EGCG-GNPs without cytotoxicity. EGCG-GNPs exhibited better effects in reducing intracellular reactive oxygen species levels than free EGCG. A more dramatic anti-osteoclastogenic effect induced by EGCG-GNPs than free EGCG was observed in lipopolysaccharide (LPS)-stimulated bone marrow macrophages, including decreased formation of TRAP-positive multinuclear cells and actin rings. Meanwhile, EGCG-GNPs not only suppressed the mRNA expression of genetic markers of OC differentiation but also inhibited MAPK signaling pathways. Furthermore, we confirmed that EGCG-GNPs greatly reversed bone resorption in the LPS-induced calvarial bone erosion model in vivo, which was more effective than applying free EGCG, specifically in inhibiting the number of OCs, improving bone density, and preventing bone loss. Conclusion: EGCG-GNPs showed better anti-osteoclastogenic effect than free EGCG in vitro and in vivo, indicating their potential in anti-bone resorption treatment strategy.


Assuntos
Catequina/análogos & derivados , Ouro/farmacologia , Nanopartículas Metálicas/química , Osteogênese/efeitos dos fármacos , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Reabsorção Óssea/patologia , Catequina/farmacologia , Morte Celular/efeitos dos fármacos , Teoria da Densidade Funcional , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Ligantes , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Nanopartículas Metálicas/ultraestrutura , Camundongos Endogâmicos BALB C , Modelos Biológicos , Ligante RANK/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Crânio/patologia , Transcrição Genética/efeitos dos fármacos
13.
Int J Nanomedicine ; 14: 5435-5448, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409997

RESUMO

Background: Ramipril (RMP) suffers from poor aqueous solubility along with sensitivity to mechanical stress, heat, and moisture. The aim of the current study is to improve RMP solubility and stability by designing solid self-nanoemulsifying drug delivery system (S-SNEDDS) as tablet. Methods: The drug was initially incorporated in different liquid formulations (L-SNEDDS) which were evaluated by equilibrium solubility, droplet size, and zeta potential studies. The optimized formulation was solidified into S-SNEDDS powder by the adsorbent Syloid® and compressed into a self-nanoemulsifying tablet (T-SNEDDS). The optimized tablet was evaluated by drug content uniformity, hardness, friability, disintegration, and dissolution tests. Furthermore, pure RMP, optimized L-SNEDDS, and T-SNEDDS were enrolled in accelerated and long-term stability studies. Results: Among various liquid formulations, F5 L-SNEDDS [capmul MCM/transcutol/HCO-30 (25/25/50%w/w)] showed relatively high drug solubility, nano-scaled droplet size, and high negative zeta potential value. The optimized SNEDDS solidification with Syloid® at ratio (1:1) resulted in a compressible powder with an excellent flowability. The optimized tablet (T-SNEDDS) showed accepted content uniformity, hardness, friability, and disintegration time (<15 minutes). The optimized L-SNEDDS, S-SNEDDS, and T-SNEDDS showed superior enhancement of RMP dissolution compared to the pure drug. Most importantly, T-SNEDDS showed significant (P<0.05) improvement of RMP stability compared to the pure drug and L-SNEDDS in both accelerated and long-term stability studies. Conclusion: RMP-loaded T-SNEDDS offers a potential oral dosage form that provides combined improvement of RMP dissolution and chemical stability.


Assuntos
Sistemas de Liberação de Medicamentos , Emulsões/química , Nanopartículas/química , Ramipril/farmacologia , Administração Oral , Adsorção , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Dureza , Nanopartículas/ultraestrutura , Tamanho da Partícula , Controle de Qualidade , Solubilidade , Eletricidade Estática , Comprimidos/química , Fatores de Tempo , Difração de Raios X
14.
Food Chem ; 299: 125118, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31288160

RESUMO

The aim of this study was to extract benzyl isothiocyanate (BITC) from green papaya by distillation apparatus without using organic solvents, and to improve the stability of BITC in aqueous solution. The distillation of mashed green papaya successfully yielded BITC as a water solution with more than 80% purity with good reproducibility. The amount of BITC in the distilled water gradually decreased during its storage at 4 °C, whereas it was not significantly changed at -20 °C for a few months. Moreover, the addition of l-cysteine ameliorated the BITC decomposition by the 4 °C-storage, but not affected by N-acetyl-cysteine and glutathione. These results suggested that the combination of BITC extraction by distillation and cysteine supplementation as well as frozen storage might be a useful method for the preparation and storage of the safer grade of BITC-containing extract.


Assuntos
Carica/química , Cisteína/química , Isotiocianatos/isolamento & purificação , Extratos Vegetais/isolamento & purificação , Acetilcisteína/química , Destilação , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Excipientes/química , Congelamento , Glutationa/química , Isotiocianatos/química , Extratos Vegetais/química , Reprodutibilidade dos Testes
15.
Cancer Sci ; 110(9): 2933-2940, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31278877

RESUMO

Chemotherapy has been the treatment of choice for unresectable peritoneal dissemination; however, it is difficult to eradicate such tumors because of poor drug delivery. To solve this issue, we developed FF-10832 as liposome-encapsulated gemcitabine to maintain a high concentration of gemcitabine in peritoneal tumors from the circulation and ascites. A syngeneic mouse model of peritoneal dissemination using murine Colon26 cell line was selected to compare the drug efficacy and pharmacokinetics of FF-10832 with those of gemcitabine. Despite the single intravenous administration, FF-10832 treatment enabled long-term survival of the lethal model mice as compared with those treated with gemcitabine. Pharmacokinetic analysis clarified that FF-10832 could achieve a more effective gemcitabine delivery to peritoneal tumors owing to better stability in the circulation and ascites. The novel liposome-encapsulated gemcitabine FF-10832 may be a curative therapeutic tool for cancer patients with unresectable peritoneal dissemination via the effective delivery of gemcitabine to target tumors.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Ascite/metabolismo , Desoxicitidina/análogos & derivados , Neoplasias Peritoneais/tratamento farmacológico , Peritônio/patologia , Animais , Antimetabólitos Antineoplásicos/farmacocinética , Ascite/etiologia , Linhagem Celular Tumoral/transplante , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacocinética , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Feminino , Humanos , Injeções Intravenosas , Estimativa de Kaplan-Meier , Lipossomos , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Peritoneais/complicações , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/patologia , Distribuição Tecidual , Resultado do Tratamento
16.
Int J Nanomedicine ; 14: 4461-4474, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31296986

RESUMO

Background: Vincristine is a potent therapeutic agent with well-defined activity against hematologic malignancies and solid tumors. It is a cell-cycle specific drug with concentration and exposure duration dependent activity. When used by liposomal delivery, it exhibits enhanced anti-tumor activity. However, vincristine liposome formulation in the clinic is supplied as a 3-vial-kit due to lacking sufficient stability. So it has to be prepared in situ prior to use through a multi-step process. Purpose: The purpose here is to develop a more stable and ready-to-use liposomal formulation for vincritstine in one vial. Patients and methods: A series of preparations were investigated based on sphingomyelin/cholesterol/PEG2000-DSPE lipid composition, with different drug/lipid (D/L) ratios (1/10, 1/5, 1/2), using an active sucrose octasulfate triethylamine salt gradient loading method. In this work, compared to generic vincristine sulfate liposome injection (GVM), the stability both in vivo and in vitro and efficacy in vivo of novel vincristine liposomes were investigated. Results: It was shown that the degradation of vincristine during 2-8°C storage was significantly decreased from 8.2% in 1 month (GVM) to 2.9% in 12 months (D/L ratio 1/5). The half-time for sphingomyelin/cholesterol/PEG2000-DSPE liposomes in vivo could be adjusted from 17.4 h (D/L ratio 1/10) to 22.7 h (D/L ratio 1/2) in rats, while the half-time for GVM was only 11.1 h. The increase in drug retention contributed to the lower in vivo toxicity. The antitumor efficacy was evaluated using a human melanoma tumor model and showed remarkable improvement compared to GVM. Conclusion: The study demonstrates that the new formulation with the drug/lipid ratio of 1/5 owns a higher encapsulation efficiency, better stability, lower toxicity and superior antitumor efficacy, which is screened out for further development.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Lipossomos/química , Vincristina/química , Vincristina/farmacologia , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Colesterol/química , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Ratos Wistar , Esfingomielinas/química , Vincristina/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Int J Nanomedicine ; 14: 4625-4636, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31303752

RESUMO

Purpose: Rosuvastatin calcium (ROSCa) nanoparticles were fabricated by planetary ball mill to enhance ROSCa dissolution rate and bioavailability. Methods: Milling time factors (milling cycle time and number as well as pause time) were explored. The effect of different milling ball size, speed, and solid-to-solvent ratio were also studied using Box-Behnken factorial design. The fabricated nanoparticles were evaluated in term of physicochemical properties and long-term stability. Results: The obtained data revealed that the integrated formulation and process factors should be monitored to obtain desirable nanoparticle attributes in terms of particle size, zeta potential, dissolution rate, and bioavailability. The optimized ROSCa nanoparticles prepared by milling technique showed a significant enhancement in the dissolution rate by 1.3-fold and the plasma concentration increased by 2-fold (P<0.05). Moreover, stability study showed that the optimized formula of ROSCa nanoparticles exhibits higher stability in long-term stability conditions at 30°C with humidity of 60%. Conclusion: Formulation of ROSCa as nanoparticles using milling technique showed a significant enhancement in both dissolution rate and plasma concentration as well as stability compared with untreated drug.


Assuntos
Nanopartículas/química , Nanotecnologia/métodos , Rosuvastatina Cálcica/química , Animais , Estabilidade de Medicamentos , Nanopartículas/ultraestrutura , Tamanho da Partícula , Coelhos , Rosuvastatina Cálcica/sangue , Rosuvastatina Cálcica/farmacocinética , Eletricidade Estática , Fatores de Tempo
18.
Soft Matter ; 15(27): 5375-5379, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31259985

RESUMO

Herein, a novel photothermal agent based on polyoxometalate clusters and food-borne antioxidant peptides was exploited to overcome the inherent problems of poor photothermal stability of polyoxometalate photothermal materials, which commonly appear in the current stage of development, and the inevitable simultaneous inflammatory responses during the therapeutic process.


Assuntos
Antibacterianos/química , Antioxidantes/química , Materiais Biocompatíveis/química , Nanopartículas/química , Oligopeptídeos/química , Compostos de Tungstênio/química , Antibacterianos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Estabilidade de Medicamentos , Escherichia coli/efeitos dos fármacos , Células Hep G2 , Humanos , Hipertermia Induzida , Raios Infravermelhos , Fototerapia/métodos , Temperatura Ambiente
19.
Chem Soc Rev ; 48(16): 4361-4374, 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31294429

RESUMO

Antibody-Drug Conjugates (ADCs) are now established as a major class of therapeutics for the clinical treatment of cancer. The properties of the linker between the antibody and the payload are proven to be critical to the success of an ADC. Although ADC linkers can be 'non-cleavable', the vast majority of ADCs in clinical development have specific release mechanisms to allow controlled linker cleavage at the target site and are thus termed 'cleavable'. In recent years, the development of new methods of drug release from ADCs has continued in parallel to the deepening understanding of the biological processes underlying the mechanisms of action of pre-existing technologies. This review summarises the advances in the field of cleavable linker technologies for ADCs.


Assuntos
Anticorpos Monoclonais/química , Imunoconjugados/química , Ácidos/química , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Catepsina B/metabolismo , Dissulfetos/química , Estabilidade de Medicamentos , Humanos , Imunoconjugados/sangue , Imunoconjugados/metabolismo
20.
Pharm Res ; 36(10): 138, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31350675

RESUMO

PURPOSE: This study aimed to incorporate ondansetron hydrochloride (ODS), a water-soluble drug into nanostructured lipid carriers (NLCs) to improve the pharmacokinetic properties of the drug. METHODS: NLCs were produced by solvent injection method. Various parameters of formulation and process were assessed to enhance the drug incorporation into NLCs. Physicochemical analyses, in vitro drug release, and pharmacokinetic studies were performed. RESULTS: Entrapment efficiency (EE) of ODS was considerably improved (>90%) by increasing pH of the aqueous phase. The use of an appropriate level of liquid lipid resulted in small, monodispersed NLCs with the enhanced EE and drug loading (DL). The optimized NLCs formulation exhibited particle size of 185.2 ± 1.9 nm, polydispersity index of 0.214 ± 0.006, EE of 93.2 ± 0.5%, and DL of 10.43 ± 0.05% as well as an in vitro sustained-release profile of ODS. Differential scanning calorimetry and X-ray powder diffraction suggested the amorphous state of ODS in the NLCs. The pharmacokinetic study in rats exhibited the sustained-release characteristic of the optimized ODS-loaded NLCs following subcutaneous administration with an extended Tmax and mean residence time as well as the enhanced systemic exposure compared to the ODS solution. CONCLUSIONS: The ODS-loaded NLCs appear potential for prolongation of drug action and reduction in dosing frequency.


Assuntos
Antieméticos/farmacocinética , Lipídeos/química , Nanocápsulas/química , Ondansetron/farmacocinética , Solventes/química , Administração Cutânea , Animais , Antieméticos/administração & dosagem , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Masculino , Ondansetron/administração & dosagem , Tamanho da Partícula , Ratos Sprague-Dawley , Resultado do Tratamento
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