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1.
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
2.
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
3.
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
4.
Nat Protoc ; 16(7): 3492-3521, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34089023

RESUMO

Solid-state milling has emerged as an alternative, sustainable approach for preparing virtually all classes of compounds and materials. In situ reaction monitoring is essential to understanding the kinetics and mechanisms of these reactions, but it has proved difficult to use standard analytical techniques to analyze the contents of the closed, rapidly moving reaction chamber (jar). Monitoring by Raman spectroscopy is an attractive choice, because it allows uninterrupted data collection from the outside of a translucent milling jar. It complements the already established in situ monitoring based on powder X-ray diffraction, which has limited accessibility to the wider research community, because it requires a synchrotron X-ray source. The Raman spectroscopy monitoring setup used in this protocol consists of an affordable, small portable spectrometer, a laser source and a Raman probe. Translucent reaction jars, most commonly made from a plastic material, enable interaction of the laser beam with the solid sample residing inside the closed reaction jar and collection of Raman-scattered photons while the ball mill is in operation. Acquired Raman spectra are analyzed using commercial or open-source software for data analysis (e.g., MATLAB, Octave, Python, R). Plotting the Raman spectra versus time enables qualitative analysis of reaction paths. This is demonstrated for an example reaction: the formation in the solid state of a cocrystal between nicotinamide and salicylic acid. A more rigorous data analysis can be achieved using multivariate analysis.


Assuntos
Química Farmacêutica/métodos , Análise Espectral Raman/métodos , Algoritmos , Calibragem , Análise de Dados , Polimetil Metacrilato/química , Silício/química , Software
5.
Molecules ; 26(9)2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-34066433

RESUMO

Candida albicans, an opportunistic fungal pathogen, frequently colonizes immune-compromised patients and causes mild to severe systemic reactions. Only few antifungal drugs are currently in use for therapeutic treatment. However, evolution of a drug-resistant C. albicans fungal pathogen is of major concern in the treatment of patients, hence the clinical need for novel drug design and development. In this study, in vitro screening of novel putative pyrrolo[1,2-a]quinoline derivatives as the lead drug targets and in silico prediction of the binding potential of these lead molecules against C. albicans pathogenic proteins, such as secreted aspartic protease 3 (SAP3; 2H6T), surface protein ß-glucanase (3N9K) and sterol 14-alpha demethylase (5TZ1), were carried out by molecular docking analyses. Further, biological activity-based QSAR and theoretical pharmacokinetic analysis were analyzed. Here, in vitro screening of novel analogue derivatives as drug targets against C. albicans showed inhibitory potential in the concentration of 0.4 µg for BQ-06, 07 and 08, 0.8 µg for BQ-01, 03, and 05, 1.6 µg for BQ-04 and 12.5 µg for BQ-02 in comparison to the standard antifungal drug fluconazole in the concentration of 30 µg. Further, in silico analysis of BQ-01, 03, 05 and 07 analogues docked on chimeric 2H6T, 3N9K and 5TZ1 revealed that these analogues show potential binding affinity, which is different from the therapeutic antifungal drug fluconazole. In addition, these molecules possess good drug-like properties based on the determination of conceptual Density Functional Theory (DFT)-based descriptors, QSAR and pharmacokinetics. Thus, the study offers significant insight into employing pyrrolo[1,2-a]quinoline analogues as novel antifungal agents against C. albicans that warrants further investigation.


Assuntos
Antifúngicos/síntese química , Ácidos Carboxílicos/síntese química , Teoria da Densidade Funcional , Simulação de Acoplamento Molecular , Antifúngicos/farmacocinética , Candida albicans , Ácidos Carboxílicos/farmacocinética , Química Farmacêutica/métodos , Desenho de Fármacos , Fluconazol/farmacologia , Ligação de Hidrogênio , Indolizinas/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Conformação Proteica , Relação Quantitativa Estrutura-Atividade , Quinolinas/síntese química , Quinolinas/farmacocinética , Termodinâmica
6.
Molecules ; 26(11)2021 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-34067434

RESUMO

The flexibility of dose and dosage forms makes 3D printing a very interesting tool for personalized medicine, with fused deposition modeling being the most promising and intensively developed method. In our research, we analyzed how various types of disintegrants and drug loading in poly(vinyl alcohol)-based filaments affect their mechanical properties and printability. We also assessed the effect of drug dosage and tablet spatial structure on the dissolution profiles. Given that the development of a method that allows the production of dosage forms with different properties from a single drug-loaded filament is desirable, we developed a method of printing ketoprofen tablets with different dose and dissolution profiles from a single feedstock filament. We optimized the filament preparation by hot-melt extrusion and characterized them. Then, we printed single, bi-, and tri-layer tablets varying with dose, infill density, internal structure, and composition. We analyzed the reproducibility of a spatial structure, phase, and degree of molecular order of ketoprofen in the tablets, and the dissolution profiles. We have printed tablets with immediate- and sustained-release characteristics using one drug-loaded filament, which demonstrates that a single filament can serve as a versatile source for the manufacturing of tablets exhibiting various release characteristics.


Assuntos
Química Farmacêutica/métodos , Cetoprofeno/química , Cetoprofeno/síntese química , Impressão Tridimensional , Comprimidos , Varredura Diferencial de Calorimetria , Preparações de Ação Retardada , Composição de Medicamentos/métodos , Desenho de Fármacos , Liberação Controlada de Fármacos , Elasticidade , Excipientes/química , Álcool de Polivinil , Medicina de Precisão , Reprodutibilidade dos Testes , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura , Difração de Raios X , Microtomografia por Raio-X
7.
Molecules ; 26(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073305

RESUMO

Human skin aging is affected by various biological signaling pathways, microenvironment factors and epigenetic regulations. With the increasing demand for cosmetics and pharmaceuticals to prevent or reverse skin aging year by year, designing multiple-molecule drugs for mitigating skin aging is indispensable. In this study, we developed strategies for systems medicine design based on systems biology methods and deep neural networks. We constructed the candidate genomewide genetic and epigenetic network (GWGEN) via big database mining. After doing systems modeling and applying system identification, system order detection and principle network projection methods with real time-profile microarray data, we could obtain core signaling pathways and identify essential biomarkers based on the skin aging molecular progression mechanisms. Afterwards, we trained a deep neural network of drug-target interaction in advance and applied it to predict the potential candidate drugs based on our identified biomarkers. To narrow down the candidate drugs, we designed two filters considering drug regulation ability and drug sensitivity. With the proposed systems medicine design procedure, we not only shed the light on the skin aging molecular progression mechanisms but also suggested two multiple-molecule drugs for mitigating human skin aging from young adulthood to middle age and middle age to old age, respectively.


Assuntos
Química Farmacêutica/métodos , Desenho de Fármacos , Envelhecimento da Pele/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Biomarcadores/metabolismo , Metilação de DNA , Mineração de Dados , Epigênese Genética , Feminino , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Redes Neurais de Computação , Análise de Sequência com Séries de Oligonucleotídeos , Estresse Oxidativo , Transdução de Sinais , Pele/metabolismo , Biologia de Sistemas , Adulto Jovem
8.
Molecules ; 26(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073527

RESUMO

This article studies the solubility, Hansen solubility parameters (HSPs), and thermodynamic behavior of a naturally-derived bioactive thymoquinone (TQ) in different binary combinations of isopropanol (IPA) and water (H2O). The mole fraction solubilities (x3) of TQ in various (IPA + H2O) compositions are measured at 298.2-318.2 K and 0.1 MPa. The HSPs of TQ, neat IPA, neat H2O, and binary (IPA + H2O) compositions free of TQ are also determined. The x3 data of TQ are regressed by van't Hoff, Apelblat, Yalkowsky-Roseman, Buchowski-Ksiazczak λh, Jouyban-Acree, and Jouyban-Acree-van't Hoff models. The maximum and minimum x3 values of TQ are recorded in neat IPA (7.63 × 10-2 at 318.2 K) and neat H2O (8.25 × 10-5 at 298.2 K), respectively. The solubility of TQ is recorded as increasing with the rise in temperature and IPA mass fraction in all (IPA + H2O) mixtures, including pure IPA and pure H2O. The HSP of TQ is similar to that of pure IPA, suggesting the great potential of IPA in TQ solubilization. The maximum molecular solute-solvent interactions are found in TQ-IPA compared to TQ-H2O. A thermodynamic study indicates an endothermic and entropy-driven dissolution of TQ in all (IPA + H2O) mixtures, including pure IPA and pure H2O.


Assuntos
2-Propanol/química , Benzoquinonas/química , Química Farmacêutica/métodos , Água/química , Técnicas de Química Analítica , Desenho de Fármacos , Análise de Regressão , Reprodutibilidade dos Testes , Solubilidade , Solventes , Temperatura , Termodinâmica
9.
AAPS PharmSciTech ; 22(5): 168, 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34080070

RESUMO

Formulation development of KO-947-K mesylate injectable drug products was described. Solution formulations were initially attempted, and key parameters such as drug concentration, buffer, pH, complexing agent, and tonicity modifying agent were carefully evaluated in the lab setting, mainly focusing on solubility and chemical stability. A lead solution formulation was advanced to a scaleup campaign. An unexpected stability issue was encountered, and the root cause was attributed to the heterogeneous liquid freezing process of the formulated solution at -20°C, which had not been captured in the lab setting. A lyophilized product was then designed to overcome the issue and supplied to the phase I clinical trial.


Assuntos
Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Desenvolvimento de Medicamentos/métodos , Inibidores Enzimáticos/síntese química , Estabilidade de Medicamentos , Inibidores Enzimáticos/administração & dosagem , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Liofilização , Congelamento , Injeções , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/síntese química , Solubilidade
10.
AAPS PharmSciTech ; 22(5): 167, 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34080078

RESUMO

In developing countries, populations have employed herbal medicines for primary health care because they are believed to be more appropriate to the human body and have less side effects than chemically synthesized drugs. The present study aimed to develop and evaluate herbal tablets incorporated with a Thai traditional medicinal extract, U-pa-ri-waat (URW), using microwave-assisted extraction (MAE). The extraction efficiency for URW using MAE and traditional solvent extraction was compared based on the percent yield after spray drying. URW tablets were prepared using the dry granulation method. The optimized products were assessed using standard characterization methods based on the United States and British Pharmacopeias. DPPH and ABTS radical scavenging assays were performed to analyze the antioxidant capacity of the microwave-assisted extracts. The results revealed that the flowability of the dry granule with added maltodextrin was improved compared to a granule without additives, as indicated by an angle of repose of 33.69 ± 2.0°, a compressibility index of 15.38 ± 0.66, and a Hausner's ratio of 1.18 ± 0.06. The resulting formulation produced flat tablets with uniform weight variation, hardness, thickness, friability, and optimum disintegration time. The URW extracts showed antioxidant activity and MAE with maltodextrin carrier displayed the strongest DPPH and ABTS radical activities with IC50 values of 1.60 ± 0.02 µg/mL and 4.02 ± 0.24 µg/mL, respectively. The URW tablet formulation passed the quality control tests. Storage of the formulation tablets for 90 days under accelerated conditions had minimal effects on tablet characteristics.


Assuntos
Química Farmacêutica/métodos , Micro-Ondas , Compostos Fitoquímicos/síntese química , Preparações de Plantas/síntese química , Administração Oral , Antioxidantes/administração & dosagem , Antioxidantes/síntese química , Antioxidantes/farmacocinética , Avaliação Pré-Clínica de Medicamentos/métodos , Sequestradores de Radicais Livres/administração & dosagem , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/farmacocinética , Medicina Herbária/métodos , Humanos , Compostos Fitoquímicos/administração & dosagem , Compostos Fitoquímicos/farmacocinética , Preparações de Plantas/administração & dosagem , Preparações de Plantas/farmacocinética , Comprimidos , Tailândia
11.
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
12.
AAPS PharmSciTech ; 22(5): 178, 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34128124

RESUMO

Pharmaceutical tablets can be susceptible to damage such as edge chipping or erosion of the core during the tablet coating process. The intersection of certain process parameters, equipment design, and tablet properties may induce more significant tablet damage such as complete tablet fracture. In this work, a hybrid predictive approach was developed using discrete element method (DEM) modeling and lab-based tablet impact experiments to identify conditions that may lead to tablet breakage events. The approach was extended to examine potential modifications to the coating equipment and process conditions in silico to mitigate the likelihood of tablet breakage during future batches. The approach is shown to enhance process understanding, identify optimal process conditions within development constraints, and de-risk the manufacture of future tablet coating batches.


Assuntos
Química Farmacêutica/métodos , Comprimidos/síntese química , Simulação por Computador , Previsões , Comprimidos/normas
13.
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
14.
AAPS PharmSciTech ; 22(5): 183, 2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34132921

RESUMO

The current study evaluated the effect of location and amount of various superdisintegrants on the properties of tablets made by twin-screw melt granulation (TSMG). Sodium-croscarmellose (CCS), crospovidone (CPV), and sodium starch glycolate (SSG) were used in various proportions intra- and extra-granular. Tabletability, compactibility, compressibility as well as friability, disintegration, and dissolution performance were assessed. The extra-granular addition resulted in the fasted disintegration and dissolution. CPV performed superior to CCS and SSG. Even if the solid fraction (SF) of the granules was lower for CPV, only a minor decrease in tabletability was observed, due to the high plastic deformation of the melt granules. The intra-granular addition of CPV resulted in a more prolonged dissolution profile, which could be correlated to a loss in porosity during tableting. The 100% intra-granular addition of the CPV resulted in a distinct decrease of the disintegration efficiency, whereas the performance of SSG was unaffected by the granulation process. CCS was not suitable to be used for the production of an immediate-release formulation, when added in total proportion into the granulation phase, but its efficiency was less impaired compared to CPV. Shortest disintegration (78 s) and dissolution (Q80: 4.2 min) was achieved with CPV extra-granular. Using CPV and CCS intra-granular resulted in increased disintegration time and Q80. However, at a higher level of appx. 500 s and appx. 15 min, only SSG showed a process and location independent disintegration and dissolution performance.


Assuntos
Carboximetilcelulose Sódica/síntese química , Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Povidona/síntese química , Carboximetilcelulose Sódica/farmacocinética , Avaliação Pré-Clínica de Medicamentos/métodos , Excipientes/síntese química , Excipientes/farmacocinética , Excipientes Farmacêuticos/síntese química , Excipientes Farmacêuticos/farmacocinética , Porosidade , Povidona/farmacocinética , Solubilidade , Comprimidos , Resistência à Tração
15.
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
16.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069489

RESUMO

In this pilot study, ethosomes and transethosomes were investigated as potential delivery systems for cholecalciferol (vitamin D3), whose deficiency has been correlated to many disorders such as dermatological diseases, systemic infections, cancer and sarcopenia. A formulative study on the influence of pharmaceutically acceptable ionic and non-ionic surfactants allowed the preparation of different transethosomes. In vitro cytotoxicity was evaluated in different cell types representative of epithelial, connective and muscle tissue. Then, the selected nanocarriers were further investigated at light and transmission electron microscopy to evaluate their uptake and intracellular fate. Both ethosomes and transethosomes proven to have physicochemical properties optimal for transdermal penetration and efficient vitamin D3 loading; moreover, nanocarriers were easily internalized by all cell types, although they followed distinct intracellular fates: ethosomes persisted for long times inside the cytoplasm, without inducing subcellular alteration, while transethosomes underwent rapid degradation giving rise to an intracellular accumulation of lipids. These basic results provide a solid scientific background to in vivo investigations aimed at exploring the efficacy of vitamin D3 transdermal administration in different experimental and pathological conditions.


Assuntos
Colecalciferol/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanocápsulas/química , Linhagem Celular , Química Farmacêutica/métodos , Colecalciferol/metabolismo , Colecalciferol/farmacologia , Portadores de Fármacos/química , Fibroblastos/efeitos dos fármacos , Humanos , Queratinócitos/efeitos dos fármacos , Lipídeos/química , Lipossomos/química , Mioblastos/efeitos dos fármacos , Projetos Piloto , Pele/metabolismo , Absorção Cutânea , Tensoativos/metabolismo
17.
Nat Commun ; 12(1): 2964, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34016980

RESUMO

Knowledge of the structure of amorphous solids can direct, for example, the optimization of pharmaceutical formulations, but atomic-level structure determination in amorphous molecular solids has so far not been possible. Solid-state nuclear magnetic resonance (NMR) is among the most popular methods to characterize amorphous materials, and molecular dynamics (MD) simulations can help describe the structure of disordered materials. However, directly relating MD to NMR experiments in molecular solids has been out of reach until now because of the large size of these simulations. Here, using a machine learning model of chemical shifts, we determine the atomic-level structure of the hydrated amorphous drug AZD5718 by combining dynamic nuclear polarization-enhanced solid-state NMR experiments with predicted chemical shifts for MD simulations of large systems. From these amorphous structures we then identify H-bonding motifs and relate them to local intermolecular complex formation energies.


Assuntos
Química Farmacêutica/métodos , Espectroscopia de Ressonância Magnética , Pirazóis/química , Cristalografia/métodos , Ligação de Hidrogênio , Simulação de Dinâmica Molecular , Estrutura Molecular
18.
Nat Commun ; 12(1): 2988, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34016986

RESUMO

Heterocycles 2-pyridone and uracil are privileged pharmacophores. Diversity-oriented synthesis of their derivatives is in urgent need in medicinal chemistry. Herein, we report a palladium/norbornene cooperative catalysis enabled dual-functionalization of iodinated 2-pyridones and uracils. The success of this research depends on the use of two unique norbornene derivatives as the mediator. Readily available alkyl halides/tosylates and aryl bromides are utilized as ortho-alkylating and -arylating reagents, respectively. Widely accessible ipso-terminating reagents, including H/DCO2Na, boronic acid/ester, terminal alkene and alkyne are compatible with this protocol. Thus, a large number of valuable 2-pyridone derivatives, including deuterium/CD3-labeled 2-pyridones, bicyclic 2-pyridones, 2-pyridone-fenofibrate conjugate, axially chiral 2-pyridone (97% ee), as well as uracil and thymine derivatives, can be quickly prepared in a predictable manner (79 examples reported), which will be very useful in new drug discovery.


Assuntos
Química Farmacêutica/métodos , Descoberta de Drogas/métodos , Preparações Farmacêuticas/química , Alquilação , Catálise , Estudos de Viabilidade , Norbornanos/química , Paládio/química , Piridonas/química , Uracila/química
19.
AAPS PharmSciTech ; 22(4): 148, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33954856

RESUMO

A practice-based approach for the scale-up of fluid bed granulation in the context of drug product development is presented and evaluated in this work in the context of clinical drug product manufacturing development. The approach is based on the use of a scale-independent parameter, the evaporation energy to drying capacity ratio (EE/DC), and a process model. The EE/DC ratio is used to quantify, in one scale-independent parameter, the combined effect of the most impacting process parameters and to identify the spray rates to be used at different scales to achieve similar granule moisture rate of change. The process model is used to de-risk scale-up, by allowing the consideration of equipment differences across scales and process dynamics, which are aspects not accounted for by the EE/DC ratio. This approach was tested by scaling up the fluid bed granulation process of two formulations, one placebo and one active, from laboratory to pilot scales. This work showed how it was possible to use a simple scale-up approach coupled with a process model to achieve right first-time scale-up of a fluid bed granulation process and show how a placebo formulation could be used instead of active material, first to define the process at laboratory scale and then to de-risk the scale-up, by identifying scale-dependent differences.


Assuntos
Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Tamanho da Partícula , Tecnologia Farmacêutica/métodos , Dessecação/métodos
20.
AAPS PharmSciTech ; 22(4): 151, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33977355

RESUMO

As commonly known, the product development stage is quite complex, requires intensive knowledge, and is time-consuming. The selection of the excipients with the proper functionality and their corresponding levels is critical to drug product performance. The objective of this study was to apply quality by design (QbD) principles for formulation development and to define the desired product quality profile (QTPP) and critical quality attributes (CQA) of a product. QbD is a risk- and science-based holistic approach for upgraded pharmaceutical development. In this study, Ibuprofen DC 85W was used as a model drug, Cellactose® 80 along with MicroceLac® 100 as a filler, and magnesium stearate, stearic acid, and sodium stearyl fumarate as lubricants. By applying different formulation parameters to the filler and lubricants, the QbD approach furthers the understanding of the effect of critical formulation and process parameters on CQAs and the contribution to the overall quality of the drug product. An experimental design study was conducted to determine the changes of the obtained outputs of the formulations, which were evaluated using the Modde Pro 12.1 statistical computer program that enables optimization by modeling complex relationships. The results of the optimum formulation revealed that MicroceLac® 100 was the superior filler, while magnesium stearate at 1% was the optimum lubricant. A design space that indicates the safety operation limits for the process and formulation variables was also created. This study enriches the understanding of the effect of excipients in formulation and assists in enhancing formulation design using experimental design and mathematical modeling methods in the frame of the QbD approach.


Assuntos
Química Farmacêutica/métodos , Força Compressiva , Desenvolvimento de Medicamentos/métodos , Lubrificantes/síntese química , Química Farmacêutica/normas , Composição de Medicamentos/métodos , Desenvolvimento de Medicamentos/normas , Ibuprofeno/síntese química , Ibuprofeno/normas , Lubrificantes/normas , Ácidos Esteáricos/síntese química , Ácidos Esteáricos/normas , Tensoativos/síntese química , Tensoativos/normas , Comprimidos , Resistência à Tração
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