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1.
Chem Pharm Bull (Tokyo) ; 69(8): 747-759, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34334518

RESUMO

The particles of phenytoin (Phe), a poorly water-soluble model drug, were bead-milled alone or co-milled with a hydrophilic waxy additive using an ultra cryo-milling technique in liquid nitrogen (LN2) to improve its dissolution properties. However, the micronized drug particles adhered and aggregated, resulting in poor handling in manufacturing processes such as blending or tableting. To improve the dissolution profile and powder properties of the drug simultaneously, the milled products were secondarily processed together with larger spherical particles by mechanical powder processing. These secondary products were composite particles with a core-shell structure, with fine drug particles adhered and deposited on the core, based on order mixing theory. As a core, three types/sizes of spherical pharmaceutical excipient particles were applied. The resultant composite particles produced much faster release profiles than just milled or co-milled mixtures. In addition, the composite particles showed good micromeritic properties depending on the size of the core particles. These results indicate that the ultra cryo-milling and subsequent dry composite mixing is a potential approach for developing drug particles with improved dissolution.


Assuntos
Anticonvulsivantes/química , Fenitoína/química , Química Farmacêutica , Composição de Medicamentos , Tamanho da Partícula , Pós , Solubilidade
2.
Int J Pharm ; 605: 120857, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34229072

RESUMO

There are many hurdles in the development of generic formulations. In vitro biopredictive dissolution conditions together with alternative in vitro - in vivo relationship (IVIVR) approaches can be a powerful tool to support the development of such formulations. In this study, we hypothesized that the release profile of enteric coated (EC) formulations of pantoprazole in physiologically relevant bicarbonate buffer (BCB) would detect possible performance differences between test and reference formulations resulting in more accurate IVIVR results and predictability when compared to a pharmacopeial dissolution test. We correlated the in vitro performance of test and reference formulations (both in BCB and pharmacopeial phosphate buffer) with the in vivo data from a failed bioequivalence study. Test and reference formulations of EC pantoprazole tablets passed the USP dissolution criteria. However, they failed statistical similarity in vitro both in compendial and BCB. Bicarbonate buffer was additionally more discriminative while being more physiologically relevant. Having BCB as an additional test to evaluate EC products in vitro might improve the comparison of formulations. This can de-risk the development of generic EC formulations.


Assuntos
Química Farmacêutica , Tampões (Química) , Concentração de Íons de Hidrogênio , Pantoprazol , Solubilidade , Comprimidos , Comprimidos com Revestimento Entérico
3.
AAPS PharmSciTech ; 22(6): 205, 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34286391

RESUMO

Drug-loaded electrospun fibers have attracted increasing attention as a promising wound dressing material due to their capability of preventing from infections and inflammation and maintaining an appropriate environment for wound healing. In this study, polylactic acid (PLA), which is widely used in wound management, was chosen as electrospinnable polymer. A triterpene extract (TE) from the outer bark of birch known for its anti-inflammatory, antiviral, antibacterial, and wound healing effects was chosen to produce TE-loaded PLA electrospun fibers for wound dressing. A binary solvent system of dichloromethane (DCM) and dimethyl sulfoxide (DMSO) was employed, and the ratio of the solvents was optimized for preparing smooth and uniform fibers. The morphology of TE-loaded PLA electrospun fibers was investigated by scanning electron microscopy (SEM). The entrapment of TE in PLA fibers was confirmed by confocal laser scanning microscopy (CLSM). Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were used to analyze the solid state of TE in PLA fibers. The release behavior of TE was assayed by a shaking flask method for a period of 96 h. The results revealed that TE-loaded electrospun PLA microfibers could be reliably prepared and are promising future candidates in wound therapy.


Assuntos
Bandagens , Betula/química , Nanofibras/química , Casca de Planta/química , Poliésteres/síntese química , Triterpenos/síntese química , Antibacterianos/análise , Antibacterianos/síntese química , Química Farmacêutica/métodos , Nanofibras/análise , Extratos Vegetais/análise , Extratos Vegetais/síntese química , Poliésteres/análise , Triterpenos/análise
4.
Molecules ; 26(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199610

RESUMO

During the last few decades, pyridazine derivatives have emerged as privileged structures in heterocyclic chemistry, both because of their excellent chemistry and because of their potential applications in medicinal chemistry and optoelectronics. This review is focused on the recent advances in [3 + n] cycloaddition reactions in the pyridazine series as well as their medicinal chemistry and optoelectronic applications over the last ten years. The stereochemistry and regiochemistry of the cycloaddition reactions are discussed. Applications in optoelectronics (in particular, as fluorescent materials and sensors) and medicinal chemistry (in particular, antimicrobials and anticancer) are also reviewed.


Assuntos
Reação de Cicloadição/métodos , Piridazinas/síntese química , Piridazinas/farmacologia , Química Farmacêutica , Eletrônica , Humanos , Fenômenos Ópticos , Piridazinas/química , Estereoisomerismo
5.
Nat Commun ; 12(1): 4396, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285203

RESUMO

Rapid development of antisense therapies can enable on-demand responses to new viral pathogens and make personalized medicine for genetic diseases practical. Antisense phosphorodiamidate morpholino oligomers (PMOs) are promising candidates to fill such a role, but their challenging synthesis limits their widespread application. To rapidly prototype potential PMO drug candidates, we report a fully automated flow-based oligonucleotide synthesizer. Our optimized synthesis platform reduces coupling times by up to 22-fold compared to previously reported methods. We demonstrate the power of our automated technology with the synthesis of milligram quantities of three candidate therapeutic PMO sequences for an unserved class of Duchenne muscular dystrophy (DMD). To further test our platform, we synthesize a PMO that targets the genomic mRNA of SARS-CoV-2 and demonstrate its antiviral effects. This platform could find broad application not only in designing new SARS-CoV-2 and DMD antisense therapeutics, but also for rapid development of PMO candidates to treat new and emerging diseases.


Assuntos
Técnicas de Química Sintética/instrumentação , Química Farmacêutica/instrumentação , Ensaios de Triagem em Larga Escala/instrumentação , Morfolinos/síntese química , Oligonucleotídeos Antissenso/síntese química , Animais , COVID-19/tratamento farmacológico , COVID-19/virologia , Chlorocebus aethiops , Doenças Transmissíveis Emergentes/tratamento farmacológico , Doenças Transmissíveis Emergentes/microbiologia , Modelos Animais de Doenças , Ensaios de Triagem em Larga Escala/métodos , Humanos , Morfolinos/farmacologia , Morfolinos/uso terapêutico , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/genética , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/uso terapêutico , Medicina de Precisão/métodos , RNA Mensageiro/antagonistas & inibidores , RNA Viral/antagonistas & inibidores , SARS-CoV-2/genética , Fatores de Tempo , Células Vero
6.
Int J Mol Sci ; 22(14)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34299029

RESUMO

Curcumin is a natural occurring molecule that has aroused much interest among researchers over the years due to its pleiotropic set of biological properties. In the nuclear medicine field, radiolabelled curcumin and curcumin derivatives have been studied as potential radiotracers for the early diagnosis of Alzheimer's disease and cancer. In the present review, the synthetic pathways, labelling methods and the preclinical investigations involving these radioactive compounds are treated. The studies entailed chemical modifications for enhancing curcumin stability, as well as its functionalisation for the labelling with several radiohalogens or metal radionuclides (fluorine-18, technetium-99m, gallium-68, etc.). Although some drawbacks have yet to be addressed, and none of the radiolabelled curcuminoids have so far achieved clinical application, the studies performed hitherto provide useful insights and lay the foundation for further developments.


Assuntos
Antineoplásicos/química , Química Farmacêutica , Curcumina/química , Compostos Radiofarmacêuticos/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Curcumina/administração & dosagem , Curcumina/farmacocinética , Humanos , Imagem Molecular , Distribuição Tecidual
7.
Molecules ; 26(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208180

RESUMO

The pyrazoline ring is defined as a "privileged structure" in medicinal chemistry. A variety of pharmacological properties of pyrazolines is associated with the nature and position of various substituents, which is especially evident in diarylpyrazolines. Compounds with a chalcone fragment show a wide range of biological properties as well as high reactivity which is primarily due to the presence of an α, ß-unsaturated carbonyl system. At the same time, bicyclic monoterpenoids deserve special attention as a source of a key structural block or as one of the pharmacophore components of biologically active molecules. A series of new diarylpyrazoline derivatives based on isobornylchalcones with different substitutes (MeO, Hal, NO2, N(Me)2) was synthesized. Antioxidant properties of the obtained compounds were comparatively evaluated using in vitro model Fe2+/ascorbate-initiated lipid peroxidation in the substrate containing brain lipids of laboratory mice. It was demonstrated that the combination of the electron-donating group in the para-position of ring B and OH-group in the ring A in the structure of chalcone fragment provides significant antioxidant activity of synthesized diarylpyrazoline derivatives.


Assuntos
Antioxidantes/síntese química , Antioxidantes/farmacologia , Chalconas/química , Pirazóis/síntese química , Pirazóis/farmacologia , Animais , Antioxidantes/química , Química Farmacêutica , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade
8.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299259

RESUMO

In the past few years, Bruton's tyrosine Kinase (Btk) has emerged as new target in medicinal chemistry. Since approval of ibrutinib in 2013 for treatment of different hematological cancers (as leukemias and lymphomas), two other irreversible Btk inhibitors have been launched on the market. In the attempt to overcome irreversible Btk inhibitor limitations, reversible compounds have been developed and are currently under evaluation. In recent years, many Btk inhibitors have been patented and reported in the literature. In this review, we summarized the (ir)reversible Btk inhibitors recently developed and studied clinical trials and preclinical investigations for malignancies, chronic inflammation conditions and SARS-CoV-2 infection, covering advances in the field of medicinal chemistry. Furthermore, the nanoformulations studied to increase ibrutinib bioavailability are reported.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Inibidores de Proteínas Quinases/administração & dosagem , Adenina/administração & dosagem , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia/metabolismo , COVID-19/tratamento farmacológico , Química Farmacêutica/métodos , Sistemas de Liberação de Medicamentos/métodos , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Inflamação/tratamento farmacológico , Neoplasias/tratamento farmacológico , Piperidinas/administração & dosagem , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/administração & dosagem , SARS-CoV-2/efeitos dos fármacos
9.
Molecules ; 26(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200204

RESUMO

Despite the fact that COVID-19 vaccines are already available on the market, there have not been any effective FDA-approved drugs to treat this disease. There are several already known drugs that through drug repositioning have shown an inhibitory activity against SARS-CoV-2 RNA-dependent RNA polymerase. These drugs are included in the family of nucleoside analogues. In our efforts, we synthesized a group of new nucleoside analogues, which are modified at the sugar moiety that is replaced by a quinazoline entity. Different nucleobase derivatives are used in order to increase the inhibition. Five new nucleoside analogues were evaluated with in vitro assays for targeting polymerase of SARS-CoV-2.


Assuntos
Antivirais/síntese química , RNA-Polimerase RNA-Dependente de Coronavírus/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Nucleosídeos/análogos & derivados , Nucleosídeos/síntese química , SARS-CoV-2/enzimologia , Química Farmacêutica/métodos , Técnicas In Vitro , SARS-CoV-2/efeitos dos fármacos
10.
Molecules ; 26(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200376

RESUMO

The dissolution rate is the rate-limiting step for Biopharmaceutics Classification System (BCS) class II drugs to enhance their in vivo pharmacokinetic behaviors. There are some factors affecting the dissolution rate, such as polymorphism, particle size, and crystal habit. In this study, to improve the dissolution rate and enhance the in vivo pharmacokinetics of sorafenib tosylate (Sor-Tos), a BCS class II drug, two crystal habits of Sor-Tos were prepared. A plate-shaped crystal habit (ST-A) and a needle-shaped crystal habit (ST-B) were harvested by recrystallization from acetone (ACN) and n-butanol (BuOH), respectively. The surface chemistry of the two crystal habits was determined by powder X-ray diffraction (PXRD) data, molecular modeling, and face indexation analysis, and confirmed by X-ray photoelectron spectroscopy (XPS) data. The results showed that ST-B had a larger hydrophilic surface than ST-A, and subsequently a higher dissolution rate and a substantial enhancement of the in vivo pharmacokinetic performance of ST-B.


Assuntos
Solubilidade/efeitos dos fármacos , Sorafenibe/química , Acetona/química , Biofarmácia/métodos , Química Farmacêutica/métodos , Cristalização/métodos , Interações Hidrofóbicas e Hidrofílicas , Tamanho da Partícula , Pós/química , Difração de Raios X/métodos
11.
Molecules ; 26(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200647

RESUMO

Curcuminoids are the main bioactive components of the well-known Asian spice and traditional medicine turmeric. Curcuminoids have poor chemical stability and bioavailability; in vivo they are rapidly metabolized to a set of bioreduced derivatives and/or glucuronide and sulfate conjugates. The reduced curcuminoid metabolites were also reported to exert various bioactivities in vitro and in vivo. In this work, we aimed to perform a comparative evaluation of curcuminoids and their hydrogenated metabolites from a medicinal chemistry point of view, by determining a set of key pharmacokinetic parameters and evaluating antioxidant potential in relation to such properties.Reduced metabolites were prepared from curcumin and demethoxycurcumin through continuous-flow hydrogenation. As selected pharmacokinetic parameters, kinetic solubility, chemical stability, metabolic stability in human liver microsomes, and parallel artificial membrane permeability assay (PAMPA)-based gastrointestinal and blood-brain barrier permeability were determined. Experimentally determined logP for hydrocurcumins in octanol-water and toluene-water systems provided valuable data on the tendency for intramolecular hydrogen bonding by these compounds. Drug likeness of the compounds were further evaluated by a in silico calculations. Antioxidant properties in diphenyl-2-picrylhydrazyl (DPPH) radical scavenging and oxygen radical absorbance capacity (ORAC) assays were comparatively evaluated through the determination of ligand lipophilic efficiency (LLE). Our results showed dramatically increased water solubility and chemical stability for the reduced metabolites as compared to their corresponding parent compound. Hexahydrocurcumin was found the best candidate for drug development based on a complex pharmacokinetical comparison and high LLE values for its antioxidant properties. Development of tetrahydrocurcumin and tetrahydro-demethoxycurcumin would be limited by their very poor metabolic stability, therefore such an effort would rely on formulations bypassing first-pass metabolism.


Assuntos
Antioxidantes/farmacologia , Antioxidantes/farmacocinética , Diarileptanoides/farmacologia , Diarileptanoides/farmacocinética , Disponibilidade Biológica , Compostos de Bifenilo/metabolismo , Permeabilidade da Membrana Celular/fisiologia , Química Farmacêutica , Curcuma/metabolismo , Curcumina/análogos & derivados , Curcumina/metabolismo , Glucuronídeos/metabolismo , Humanos , Hidrogenação , Microssomos Hepáticos/metabolismo , Picratos/metabolismo , Solubilidade
12.
Molecules ; 26(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200887

RESUMO

Royal jelly is a natural substance produced by worker bees that possesses a variety of biological activities, including antioxidant, anti-inflammatory, antibacterial, and protective. Although fresh royal jelly is kept at low temperatures, to increase its stability, it needs to be incorporated into pharmaceutical formulations, such as in situ gels. The aim of this study was to formulate in situ ocular gels containing Lithuanian royal jelly for topical corneal use in order to increase the retention time of the formulation on the ocular surface and bioavailability. Gels were evaluated for physicochemical characteristics (pH, rheological properties, refractive index) and in vitro drug release measuring the amount of 10-hydroxy-2-decenoic acid (10-HDA). An ocular irritation test and cell viability tests were performed using the SIRC (Statens Seruminstitut Rabbit Cornea) cell culture line. Results indicated that all the in situ gels were within an acceptable pH and refractive index range close to corneal properties. Rheology studies have shown that the gelation temperature varies between 25 and 32 °C, depending on the amount of poloxamers. The release studies have shown that the release of 10-HDA from in situ gels is more sustained than royal jelly suspension. All gel formulations were non-irritant according to the short-time exposure test (STE) using the SIRC cell culture line, and long-term cell viability studies indicated that the formulations used in small concentrations did not induce cell death. Prepared in situ gels containing royal jelly have potential for ocular drug delivery, and they may improve the bioavailability, stability of royal jelly, and formation of non-irritant ocular formulations.


Assuntos
Córnea/efeitos dos fármacos , Ácidos Graxos/química , Ácidos Graxos/farmacologia , Géis/química , Géis/farmacologia , Animais , Abelhas/metabolismo , Disponibilidade Biológica , Produtos Biológicos/química , Produtos Biológicos/farmacocinética , Produtos Biológicos/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica/métodos , Córnea/metabolismo , Ácidos Decanoicos/química , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Excipientes/química , Géis/farmacocinética , Poloxâmero/química , Coelhos , Reologia , Temperatura
13.
Int J Pharm ; 606: 120875, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34273425

RESUMO

Our objectives were to stabilize a non-clinical suspension for use in toxicological studies and to develop methods to investigate the stability of the formulation in terms of salt disproportionation. The compound under research was a hydrochloride salt of a practically insoluble discovery compound ODM-203. The first of the three formulation approaches was a suspension prepared and stored at room temperature. The second formulation was stabilized by pH adjustment. In the third approach cooling was used to prevent salt disproportionation. 5 mg/mL aqueous suspension consisting of 20 mg/mL PVP/VA and 5 mg/mL Tween 80 was prepared for each of the approaches. The polymer was used as precipitation inhibitor to provide prolonged supersaturation while Tween 80 was used to enhance dissolution and homogeneity of the suspension. The consequences of salt disproportionation were studied by a small-scale in vitro dissolution method and by an in vivo pharmacokinetic study in rats. Our results show that disproportionation was successfully suppressed by applying cooling of the suspension in an ice bath at 2-8 °C. This procedure enabled us to proceed to the toxicological studies in rats. The in vivo study results obtained for the practically insoluble compound showed adequate exposures with acceptable variation at each dose level.


Assuntos
Química Farmacêutica , Excipientes , Animais , Ácido Clorídrico , Ratos , Solubilidade , Suspensões
14.
Int J Pharm ; 606: 120912, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34298099

RESUMO

Adeno-associated viruses (AAV) are among the most actively investigated vectors for gene therapy. Supply of early clinical studies with frozen drug product (DP) can accelerate timelines and minimize degradation risks. In the long-term, logistical challenges of frozen DP may limit patient access. In this work, we developed a lyophilized (freeze-dried) formulation of AAV. The mass concentration of AAV is typically low, and AAV also requires a minimum ionic strength to inhibit aggregation. These factors result in a low collapse temperature, which is limiting to lyophilization. Mannitol crystallization was found to cause extensive degradation and potency loss of AAV during the freezing step. With further development, we determined that AAV could be lyophilized in a sucrose and citrate formulation with a more desirable high glass transition temperature of the dried cake. An optimal residual moisture range (1-3%) was found to be critical to maintaining AAV8 stability. Glycerol was found to protect AAV8 from over-drying by preventing capsid damage and genome DNA release. A lyophilized formulation was identified that maintained potency for 24 months at 2-8 °C, indicating the feasibility of a dried formulation for AAV gene therapy.


Assuntos
Química Farmacêutica , Dependovirus , Cristalização , Dependovirus/genética , Estabilidade de Medicamentos , Liofilização , Terapia Genética , Humanos
15.
Int J Pharm ; 606: 120929, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34303819

RESUMO

Lyophilization formulation and process development for lipophilic nanoparticle (NPs) products is highly challenging as the NPs have a low colloidal stability. We compared two different NP types, pure paliperidone palmitate nanocrystals and trimyristin solid lipid nanoparticles regarding formulation, process, and storage stability aspects. Freeze-thaw studies were conducted to investigate the basic formulation aspects such as buffer type, pH, and ionic strength as well as different cryoprotectants. In freeze-drying conventional ramp freezing was performed and compared to freezing with an annealing step added or with controlled ice nucleation. Different formulations were lyophilized and tested for short-term storage stability up to 6 weeks. Samples were analyzed for particle size, subvisible particle number, specific surface area, residual moisture, crystallinity, and glass transition temperature. Sucrose significantly better stabilized both NP types against freeze-thaw stress compared to mannitol demonstrating the importance of a fully amorphous matrix. While the impact of buffer type and pH was negligible, the aggregation propensity of NPs was reduced in presence of NaCl. The freezing step also impacted NP aggregation but the effect was less important than the formulation design. Surfactants did not necessarily improve the colloidal stability but resulted in a lower glass transition temperature of the lyophilizates and may cause phase separation which limits storage stability. This hurdle can be overcome by using a hydroxypropyl-ß-cyclodextrin/ sucrose mixture as cryoprotectant. In general, we could show a similar freeze-drying behavior of the two NP types. Thus, we established a formulation and process approach to achieve stable lyophilizates of lipophilic NPs based on two different types of NPs. The general rules should be transferable to other NPs facilitating lyophilization development.


Assuntos
Nanopartículas , Palmitato de Paliperidona , Química Farmacêutica , Estabilidade de Medicamentos , Liofilização , Lipídeos
16.
AAPS PharmSciTech ; 22(5): 196, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34184149

RESUMO

In a formulation, traces of peroxides in copovidone can impact the stability of drug substances that are prone to oxidation. The present study aimed to investigate the impact of peroxides in novel Plasdone™ S630 Ultra and compare it with regular Plasdone™ S630 on the oxidative degradation of quetiapine fumarate amorphous solid dispersions prepared via hot-melt extrusion technique. The miscibility of copovidones with drug was determined using the Hansen solubility parameter, and the results indicated a miscible drug-polymer system. Melt viscosity as a function of temperature was determined for the drug-polymer physical mixture to identify the suitable hot-melt extrusion processing temperature. The binary drug and polymer (30:70 weight ratio) amorphous solid dispersions were prepared at a processing temperature of 160°C. Differential scanning calorimetry and Fourier transform infrared spectroscopy studies of amorphous solid dispersions revealed the formation of a single-phase amorphous system with intermolecular hydrogen bonding between the drug and polymer. The milled extrudates were compressed into tablets by using extragranular components and evaluated for tabletability. Stability studies of the milled extrudates and tablet formulations were performed to monitor the oxidative degradation impurity (N-oxide). The N-oxide impurity levels in the quetiapine fumarate - Plasdone™ S630 Ultra milled extrudates and tablet formulations were reduced by 2- and 3-folds, respectively, compared to those in quetiapine fumarate - Plasdone™ S630. The reduced oxidative degradation and improved hot-melt extrusion processability of Plasdone™ S630 Ultra make it a better choice for oxidation-labile drugs over Plasdone™ S630 copovidone.


Assuntos
Tecnologia de Extrusão por Fusão a Quente/métodos , Excipientes Farmacêuticos/síntese química , Povidona/síntese química , Pirrolidinas/síntese química , Fumarato de Quetiapina/síntese química , Compostos de Vinila/síntese química , Varredura Diferencial de Calorimetria/métodos , Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Temperatura Alta , Oxirredução , Excipientes Farmacêuticos/farmacocinética , Povidona/farmacocinética , Pirrolidinas/farmacocinética , Fumarato de Quetiapina/farmacocinética , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Compostos de Vinila/farmacocinética
17.
J Enzyme Inhib Med Chem ; 36(1): 1115-1144, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34167422

RESUMO

Nature products have been extensively used in the discovery and development of new drugs, as the most important source of drugs. The triazole ring is one of main pharmacophore of the nitrogen-containing heterocycles. Thus, a new class of triazole-containing natural product conjugates has been synthesised. These compounds reportedly exert anticancer, anti-inflammatory, antimicrobial, antiparasitic, antiviral, antioxidant, anti-Alzheimer, and enzyme inhibitory effects. This review summarises the research progress of triazole-containing natural product derivatives involved in medicinal chemistry in the past six years. This review provides insights and perspectives that will help scientists in the fields of organic synthesis, medicinal chemistry, phytochemistry, and pharmacology.


Assuntos
Produtos Biológicos/química , Produtos Biológicos/farmacologia , Triazóis/química , Linhagem Celular Tumoral , Química Farmacêutica , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
18.
AAPS PharmSciTech ; 22(5): 184, 2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34142250

RESUMO

Hot-melt extrusion has found extensive application as a feasible pharmaceutical technological option over recent years. HME applications include solubility enhancement, taste masking, and sustained drug release. As bioavailability enhancement is a hot topic of today's science, one of the main applications of HME is centered on amorphous solid dispersions. This review describes the most significant aspects of HME technology and its use to prepare solid dispersions as a drug formulation strategy to enhance the solubility of poorly soluble drugs. It also addresses molecular and thermodynamic features critical for the physicochemical properties of these systems, mainly in what concerns miscibility and physical stability. Moreover, the importance of applying the Quality by Design philosophy in drug development is also discussed, as well as process analytical technologies in pharmaceutical HME monitoring, under the current standards of product development and regulatory guidance. Graphical Abstract.


Assuntos
Química Farmacêutica/métodos , Portadores de Fármacos/síntese química , Desenvolvimento de Medicamentos/métodos , Tecnologia de Extrusão por Fusão a Quente/métodos , Disponibilidade Biológica , Composição de Medicamentos/métodos , Composição de Medicamentos/tendências , Tecnologia de Extrusão por Fusão a Quente/tendências , Temperatura Alta , Solubilidade , Tecnologia Farmacêutica/métodos , Tecnologia Farmacêutica/tendências , Termodinâmica
19.
AAPS PharmSciTech ; 22(5): 170, 2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34085150

RESUMO

A novel nanofiber insert was prepared with a modified electrospinning method to enhance the ocular residence time of ofloxacin (OFX) and to provide a sustained release pattern by covering hydrophilic polymers, chitosan/polyvinyl alcohol (CS/PVA) nanofibers, with a hydrophobic polymer, Eudragit RL100 in layers, and by glutaraldehyde (GA) cross-linking of CS-PVA nanofibers for the treatment of infectious conjunctivitis. The morphology of the prepared nanofibers was studied using scanning electron microscopy (SEM). The average fiber diameter was found to be 123 ± 23 nm for the single electrospun nanofiber with no cross-linking (OFX-O). The single nanofibers, cross-linked for 10 h with GA (OFX-OG), had an average fiber diameter of 159 ± 30 nm. The amount of OFX released from the nanofibers was measured in vitro and in vivo using UV spectroscopy and microbial assay methods against Staphylococcus aureus, respectively. The antimicrobial efficiency of OFX formulated in cross-linked and non-cross-linked nanofibers was affirmed by observing the inhibition zones of Staphylococcus aureus and Escherichia coli. In vivo studies using the OFX nanofibrous inserts on a rabbit eye confirmed a sustained release pattern for up to 96 h. It was found that the cross-linking of the nanofibers by GA vapor could reduce the burst release of OFX from OFX-loaded CS/PVA in one layer and multi-layered nanofibers. In vivo results showed that the AUC0-96 for the nanofibers was 9-20-folds higher compared to the OFX solution. This study thus demonstrates the potential of the nanofiber technology is being utilized to sustained drug release in ocular drug delivery systems.


Assuntos
Resinas Acrílicas/química , Administração Oftálmica , Quitosana/química , Nanofibras/química , Ofloxacino/química , Álcool de Polivinil/química , Resinas Acrílicas/administração & dosagem , Resinas Acrílicas/farmacocinética , Animais , Antibacterianos/química , Química Farmacêutica/métodos , Quitosana/administração & dosagem , Quitosana/farmacocinética , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Escherichia coli/efeitos dos fármacos , Escherichia coli/fisiologia , Nanofibras/administração & dosagem , Ofloxacino/administração & dosagem , Ofloxacino/farmacocinética , Álcool de Polivinil/administração & dosagem , Álcool de Polivinil/farmacocinética , Coelhos , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia
20.
Molecules ; 26(11)2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34072467

RESUMO

In this report, we describe the structural characterization of three 2,4-disubstituted-dihydropyrimidine-5-carbonitrile derivatives, namely 2-{[(4-nitrophenyl)methyl]sulfanyl}-6-oxo-4-propyl-1,6-dihydropyrimidine-5-carbonitrile 1, 4-(2-methylpropyl)-2-{[(4-nitrophenyl)methyl]sulfanyl}-6-oxo-1,6-dihydropyrimidine-5-carbonitrile 2, and 2-[(2-ethoxyethyl)sulfanyl]-6-oxo-4-phenyl-1,6-dihydropyrimidine-5-carbonitrile monohydrate 3. An X-ray diffraction analysis revealed that these compounds were crystallized in the centrosymmetric space groups and adopt an L-shaped conformation. One of the compounds (3) crystallized with a water molecule. A cyclic motif (R22(8)) mediated by N-H···O hydrogen bond was formed in compounds 1 and 2, whereas the corresponding motif was not favorable, due to the water molecule, in compound 3. The crystal packing of these compounds was analyzed based on energy frameworks performed at the B3LYP/6-31G(d,p) level of theory. Various inter-contacts were characterized using the Hirshfeld surface and its associated 2D-fingerprint plots. Furthermore, a molecular docking simulation was carried out to assess the inhibitory potential of the title compounds against the human dihydrofolate reductase (DHFR) enzyme.


Assuntos
Carbono/química , Antagonistas do Ácido Fólico/química , Nitrilas/química , Tetra-Hidrofolato Desidrogenase/química , Motivos de Aminoácidos , Domínio Catalítico , Química Farmacêutica/métodos , Simulação por Computador , Desenho de Fármacos , Humanos , Ligação de Hidrogênio , Ligantes , Conformação Molecular , Simulação de Acoplamento Molecular , Conformação Proteica , Água/química , Difração de Raios X
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