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1.
Molecules ; 25(17)2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32899354

RESUMO

Peptidyl fluoromethyl ketones occupy a pivotal role in the current scenario of synthetic chemistry, thanks to their numerous applications as inhibitors of hydrolytic enzymes. The insertion of one or more fluorine atoms adjacent to a C-terminal ketone moiety greatly modifies the physicochemical properties of the overall substrate, especially by increasing the reactivity of this functionalized carbonyl group toward nucleophiles. The main application of these peptidyl α-fluorinated ketones in medicinal chemistry relies in their ability to strongly and selectively inhibit serine and cysteine proteases. These compounds can be used as probes to study the proteolytic activity of the aforementioned proteases and to elucidate their role in the insurgence and progress on several diseases. Likewise, if the fluorinated methyl ketone moiety is suitably connected to a peptidic backbone, it may confer to the resulting structure an excellent substrate peculiarity and the possibility of being recognized by a specific subclass of human or pathogenic proteases. Therefore, peptidyl fluoromethyl ketones are also currently highly exploited for the target-based design of compounds for the treatment of topical diseases such as various types of cancer and viral infections.


Assuntos
Clorometilcetonas de Aminoácidos/síntese química , Fenilalanina/análogos & derivados , Vírus da SARS/efeitos dos fármacos , Inibidores de Serino Proteinase/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Clorometilcetonas de Aminoácidos/farmacologia , Química Farmacêutica/métodos , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , HIV/efeitos dos fármacos , HIV/enzimologia , Protease de HIV/química , Protease de HIV/metabolismo , Humanos , Cinética , Fenilalanina/síntese química , Fenilalanina/farmacologia , Vírus da SARS/enzimologia , Inibidores de Serino Proteinase/farmacologia , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo
2.
Int J Mol Sci ; 21(17)2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32825444

RESUMO

At the moment, there are no U.S. Food and Drug Administration (U.S. FDA)-approved drugs for the treatment of COVID-19, although several antiviral drugs are available for repurposing. Many of these drugs suffer from polymorphic transformations with changes in the drug's safety and efficacy; many are poorly soluble, poorly bioavailable drugs. Current tools to reformulate antiviral APIs into safer and more bioavailable forms include pharmaceutical salts and cocrystals, even though it is difficult to classify solid forms into these regulatory-wise mutually exclusive categories. Pure liquid salt forms of APIs, ionic liquids that incorporate APIs into their structures (API-ILs) present all the advantages that salt forms provide from a pharmaceutical standpoint, without being subject to solid-state matter problems. In this perspective article, the myths and the most voiced concerns holding back implementation of API-ILs are examined, and two case studies of API-ILs antivirals (the amphoteric acyclovir and GSK2838232) are presented in detail, with a focus on drug property improvement. We advocate that the industry should consider the advantages of API-ILs which could be the genesis of disruptive innovation and believe that in order for the industry to grow and develop, the industry should be comfortable with a certain element of risk because progress often only comes from trying something different.


Assuntos
Aciclovir/química , Antivirais/química , Betacoronavirus/efeitos dos fármacos , Butiratos/química , Crisenos/química , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Aciclovir/farmacologia , Antivirais/farmacologia , Disponibilidade Biológica , Butiratos/farmacologia , Química Farmacêutica/métodos , Crisenos/farmacologia , Reposicionamento de Medicamentos/métodos , Humanos , Líquidos Iônicos/química , Pandemias , Solubilidade
3.
Yakugaku Zasshi ; 140(8): 1071-1080, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32741865

RESUMO

The purpose of the present study was to establish a novel method to evaluate water penetration rates by combining the local dynamic contact angle and thermographic approach to characterize water conduction properties in orally disintegrating (OD) tablets. The OD tablet tester OD-mate was used to measure the disintegration times of OD tablets. Other formulation characteristics, such as tablet hardness and friability, were evaluated. By examining three formulation characteristics, such as the disintegration time, tablet hardness, and friability, of 33 OD tablets for generic drugs, four characteristic OD tablets containing aripiprazole were selected. To quantitatively evaluate water penetration rates into the tablet interior, we measured the dynamic contact angle after dropping water locally on the tablet surface. Linearity with a high correlation coefficient was observed for each of the initial time-dependent changes in the dynamic contact angle. Water penetration rates into tablets were approximately twice as fast for Pharmaceuticals A and B than for Pharmaceuticals C and D. These rates were consistent with changes observed in tablet thermographic imaging. The relationship between the rapid disintegration of the tablet and its physical strength was discussed based on the internal structure of the tablet by X-ray CT and the additives of each OD tablet. The present results demonstrated that the water penetration rates of OD tablets, as measured by dynamic contact angle, may accurately detect differences in disintegration times in the human oral cavity.


Assuntos
Química Farmacêutica/métodos , Comprimidos , Termografia , Administração Oral , Fenômenos Químicos , Dureza , Solubilidade , Água
4.
Nat Commun ; 11(1): 3628, 2020 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-32686668

RESUMO

Triazolopyridinone derivatives are of high value in both medicinal and material chemistry. However, the chiral or hindered triazolopyridinone derivatives remain an underexplored area of chemical space because they are difficult to prepare via conventional methods. Here we report an electrochemical rearrangement for the efficient synthesis of otherwise inaccessible triazolopyridinones with diverse alkyl carboxylic acids as starting materials. This enables the efficient preparation of more than 60 functionalized triazolopyridinones under mild conditions in a sustainable manner. This method is evaluated for the late stage modification of bioactive natural products, amino acids and pharmaceuticals, and it is further applied to the decagram scale preparation of enantiopure triazolopyridinones. The control experiments support a mechanism involving an oxidative cyclization and 1,2-carbon migration. This facile and scalable rearrangement demonstrates the power of electrochemical synthesis to access otherwise-inaccessible triazolopyridinones and may find wide application in organic, material and medicinal chemistry.


Assuntos
Purinas/síntese química , Química Farmacêutica/métodos , Eletroquímica/métodos , Purinas/análise
5.
Nat Commun ; 11(1): 2890, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32513962

RESUMO

Employment of sulfoxides as electrophiles in cross-coupling reactions remains underexplored. Herein we report a transition-metal-free cross-coupling strategy utilizing aryl(heteroaryl) methyl sulfoxides and alcohols to afford alkyl aryl(heteroaryl) ethers. Two drug molecules were successfully prepared using this protocol as a key step, emphasizing its potential utility in medicinal chemistry. A DFT computational study suggests that the reaction proceeds via initial addition of the alkoxide to the sulfoxide. This adduct facilitates further intramolecular addition of the alkoxide to the aromatic ring wherein charge on the aromatic system is stabilized by the nearby potassium cation. Rate-determining fragmentation then delivers methyl sulfenate and the aryl or heteroaryl ether. This study establishes the feasibility of nucleophilic addition to an appended sulfoxide as a means to form a bond to aryl(heteroaryl) systems and this modality is expected to find use with many other electrophiles and nucleophiles leading to new cross-coupling processes.


Assuntos
Álcoois/química , Éteres/química , Hidrocarbonetos Policíclicos Aromáticos/química , Sulfóxidos/química , Elementos de Transição/química , Carbono/química , Catálise , Química Farmacêutica/métodos , Compostos Heterocíclicos/química , Hidrocarbonetos Aromáticos/química , Metais/química , Modelos Químicos , Estrutura Molecular , Hidrocarbonetos Policíclicos Aromáticos/síntese química , Enxofre/química
6.
Yakugaku Zasshi ; 140(6): 773-776, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32475926

RESUMO

The rapid increase in the use of ethical generic pharmaceutical formulations in Japan emphasizes the importance of measures to ensure the quality of pharmaceutical distribution. This short review discusses the contributions of the Japanese Pharmacopoeia (JP) to pharmaceutical quality control. Numerous monographs have defined specifications and tests for multiple active pharmaceutical ingredients and excipients. Standardized methods of performing general tests and reference standards allow efficient, reliable evaluation of pharmaceutical quality during development processes and commercial manufacturing. Some new methods of characterizing the structure and performance of nonbiological complex drugs have been included in recent editions. An introduction to general tests and general information regarding the control of impurities in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines should significantly reduce the safety risks of pharmaceuticals.


Assuntos
Medicamentos Genéricos , Farmacopeias como Assunto , Controle de Qualidade , Química Farmacêutica/métodos , Medicamentos Genéricos/análise , Medicamentos Genéricos/normas , Excipientes/análise , Japão
7.
Yakugaku Zasshi ; 140(6): 777-782, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32475927

RESUMO

Biologics listed in the Japanese Pharmacopoeia (JP) include drugs in which the active pharmaceutical ingredient is a peptide, protein, or polysaccharide. Biologics were previously manufactured by purification from biological sources, however, most recently developed products are manufactured using biotechnology such as genetic recombination and cell culture technologies. The JP provides useful information to ensure the quality of such products in the form of monographs, general test, and general information. A recent topic related to biologics is the adoption of general test 〈6.17〉 "Insoluble Particulate Matter Test for Protein Injections". Test 〈6.17〉 enables the determination of insoluble particulate matter using the light obscuration method with smaller sample volumes and indicates points to consider in handling protein samples. In addition, the draft general information "Basic Concept of Quality Assurance of Biotechnology Products (Biopharmaceuticals)" has been released for public consultation and will be listed in the 18th edition of the JP. In this review, the contents of JP monographs, general chapters, and general information on biologics are introduced, and future perspectives on the role of the JP for ensuring the quality of biologics are discussed.


Assuntos
Produtos Biológicos , Farmacopeias como Assunto , Controle de Qualidade , Produtos Biológicos/análise , Biotecnologia , Química Farmacêutica/métodos , Japão
8.
AAPS PharmSciTech ; 21(5): 170, 2020 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-32529303

RESUMO

Felodipine (FLD), a dihydropyridine calcium channel blocker with excellent antihypertensive effect, is poorly soluble and undergoes extensive hepatic metabolism, which lead to poor oral bioavailability (about 15%) and limit its clinic application. The goal of this study was to develop solid lipid nanoparticles (SLNs) loading FLD to improve the oral bioavailability. The FLD loaded solid lipid nanoparticles (FLD-SLNs) were prepared by the effervescent dispersion technique developed by our laboratory, which might have some advantages over traditional methods. The FLD-SLNs showed desired particle characteristics with particle size (198.15 ± 1.82 nm), poly dispersity index (0.26 ± 0.02), zeta-potential (- 25.53 ± 0.60 mV), entrapment efficiency (95.65 ± 0.70%), drug loading (2.33 ± 0.10%), and a spherical appearance. Pharmacokinetic results showed that the FLD-SLNs presented 3.17-fold increase in area under the curve (AUC(0-t)) compared with free FLD after oral administration in beagle dogs, which indicated that SLNs prepared using the effervescent dispersion technique can improve the bioavailability of lipophilic drugs like felodipine by enhancement of absorption and reduction first-pass metabolism.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacocinética , Química Farmacêutica/métodos , Felodipino/farmacocinética , Nanopartículas/metabolismo , Administração Oral , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacocinética , Disponibilidade Biológica , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/síntese química , Estudos Cross-Over , Cães , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Portadores de Fármacos/farmacocinética , Felodipino/administração & dosagem , Felodipino/síntese química , Lipídeos , Masculino , Nanopartículas/administração & dosagem , Nanopartículas/química , Tamanho da Partícula , Distribuição Aleatória
9.
Adv Exp Med Biol ; 1194: 115-125, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468528

RESUMO

Computer-aided drug design (CADD) is the framework in which the huge amount of data accumulated by high-throughput experimental methods used in drug design is quantitatively studied. Its objectives include pattern recognition, biomarker identification and/or classification, etc. In order to achieve these objectives, machine learning algorithms and especially artificial neural networks (ANNs) have been used over ADMET factor testing and QSAR modeling evaluation. This paper provides an overview of the current trends in CADD-applied ANNs, since their use was re-boosted over a decade ago.


Assuntos
Algoritmos , Química Farmacêutica , Desenho de Fármacos , Redes Neurais de Computação , Química Farmacêutica/métodos , Química Farmacêutica/tendências , Computadores , Aprendizado de Máquina , Relação Quantitativa Estrutura-Atividade
10.
Expert Opin Drug Deliv ; 17(7): 899-902, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32427004

RESUMO

The ongoing COVID-19 crisis has highlighted the importance of a robust drug supply chain which can be quickly and flexibly ramped up to produce life-saving drug treatments. 3D printing (3DP) of oral solid dosage forms (OSDF) could be a viable part of the emergency drug production response to support vulnerable patients in rural regions and other isolated locations. In the context of the current pandemic, the suitability of different 3DP technologies will depend on the physicochemical properties, unit dose strength and BCS classification of the repurposed drug compounds currently being trialed for COVID-19. Furthermore, the deployment strategy should focus on simplifying dosage forms and formulations, scaling down the size and complexity of the printing systems and real-time quality assurance via process analytical technologies (PAT).


Assuntos
Antivirais/uso terapêutico , Betacoronavirus , Química Farmacêutica/métodos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Impressão Tridimensional , Administração Oral , Humanos , Pandemias , Tecnologia Farmacêutica/métodos
11.
AAPS PharmSciTech ; 21(4): 126, 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32382992

RESUMO

Orally dissolving films (ODFs) have received much attention as potential oral drug delivery systems for paediatric and geriatric patients, particularly those suffering from dysphagia. With their unique properties and advantages, the technology offers improved patient compliance and wider acceptability, eliminates the fear of choking, enables ease of administration and offers dosing convenience, without the requirement of water. However, adequate drug loading remains a challenge. The aim of this study was to mechanistically design and evaluate fast and extended release ODF formulations with high drug loading capacity, displaying good physicochemical and mechanical properties, as a potential dosage form for paediatric and geriatric use employing a slightly soluble model drug-ibuprofen. Different polymers (0.6-10% HPMC, 0.6-1.5% guar gum), plasticisers (0.1-0.5% glycerine, 0.1% sorbitol) and processing conditions (40-60°C drying temperatures, 8-16 h drying times) were investigated to produce films using the solvent casting method. Molecular compatibility was assessed using TGA, XRD and FTIR whereas film topography was assessed using SEM. Maximum ibuprofen load in single films was 20.7 mg/film (54.4%) and released 100% drug content in 5 min, while triple layered ibuprofen-loaded films contained 62.2 mg/film and released 100% drug release in 1 h. The ODFs demonstrated good disintegration time using low volume artificial saliva media and high dosage from uniformity. This study provides a mechanistic insight to the design and evaluation of fast and extended release ODFs with high drug loading, suitable for administration to paediatric and geriatric patients.


Assuntos
Química Farmacêutica/métodos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Ibuprofeno/química , Ibuprofeno/metabolismo , Administração Oral , Idoso , Criança , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/metabolismo , Geriatria , Humanos , Ibuprofeno/administração & dosagem , Pediatria , Solubilidade , Difração de Raios X/métodos
12.
Life Sci ; 250: 117602, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32240677

RESUMO

AIMS: Extrinsic ageing or photoageing relates to the onset of age-linked phenotypes such as skin hyperpigmentation due to UV exposure. UV induced upregulated production of tyrosinase enzyme, which catalyses the vital biochemical reactions of melanin synthesis is responsible for the inception of skin hyperpigmentation. We aimed to generate a validated QSAR model with a dataset consisting of 69 thio-semicarbazone derivatives to elucidate the physicochemical properties of compounds essential for tyrosinase inhibition and to identify novel lead molecules with enhanced tyrosinase inhibitory activity and bioavailability. MAIN METHODS: Lead optimization and insilico approaches were employed in this research work. QSAR model was generated and validated by exploiting Multiple Linear Regression method. Prioritization of lead-like compounds was accomplished by performing multi parameter optimization depleting molecular docking, bioavailability assessments and toxicity prediction for 69 compounds Derivatives of best lead compound were retrieved from chemical spaces. KEY FINDINGS: Molecular descriptors explicated the significance of chemical properties essential for chelation of copper ions present in the active site of tyrosinase protein target. Further, derivatives which comprise of electron donating groups in their chemical structure were predicted and analysed for tyrosinase inhibitory activity by employing insilico methodologies including chemical space exploration. SIGNIFICANCE: Our research work resulted in the generation of a validated QSAR model with higher degree of external predictive ability and significance to tyrosinase inhibitory activity. We propose 11 novel derivative compounds with enhanced tyrosinase inhibitory activity and bioavailability.


Assuntos
Química Farmacêutica/métodos , Biologia Computacional/métodos , Indóis/antagonistas & inibidores , Monofenol Mono-Oxigenase/antagonistas & inibidores , Pele/efeitos dos fármacos , Agaricales/metabolismo , Domínio Catalítico , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Elétrons , Inibidores Enzimáticos/farmacologia , Humanos , Ligação de Hidrogênio , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Relação Quantitativa Estrutura-Atividade , Pigmentação da Pele/efeitos dos fármacos , Tiossemicarbazonas/química , Raios Ultravioleta
13.
Zhongguo Zhong Yao Za Zhi ; 45(5): 1082-1089, 2020 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-32237450

RESUMO

Some Chinese herbal medicine needs to be processed before it can be used as medicine, especially toxic Chinese medicine. Highly toxic Aconti Kusnezoffii Radix(Caowu in Chinese) is widely used in traditional Chinese medicine and Mongolian medicine. In traditional Chinese medicine, Caowu is usually processed by boiling with water(CW) until no white part inside and being tasted without tongue-numbing. In Mongolian medicine, it is usually soaked in Chebulae Fructus(Hezi in Chinese) decoction for several days(CH). Both methods could reduce toxicity according to reports. The biggest difference between CW and CH is that CW needs to be heated for 4-6 h, while CH needs Hezi as processing adjuvants. To explore the toxicity reduction mechanism of CW and CH, we studied the contents of various compounds in Caowu processed by two methods by UPLC-Orbitrap-MS. The results indicated that CW had 14 new ingredients, such as 14-O-anisoylneoline and dehydro-mesaconitine, while N-demethyl-mesaconitine and aconitine disappeared. At the same time, it could significantly decrease the content of diester diterpenoid alkaloids and increase the contents of monoester diterpenoid alkaloids and amine-diterpenoid alkaloids. CH had 9 new ingredients from Hezi, like gallic acid, chebulic acid and shikimic acid. Neither the kinds nor the contents of compositions from Caowu in CH changed little. This suggested that the processing mechanism of CW reduced highly toxic components(diester diterpenoid alkaloids) and increased the content of lowly toxic components(monoester diterpenoid alkaloids and amine-diterpenoid alkaloids). Attenuated principle of CH may be related to the components of Hezi. In this experiment, the conclusion shows that the chemical constituents of CW and CH are essentially different, and the two methods have different toxicity reduction principles.


Assuntos
Aconitum/química , Alcaloides/análise , Medicamentos de Ervas Chinesas/análise , Aconitina , Química Farmacêutica/métodos , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas , Medicina Tradicional Chinesa
14.
J Mycol Med ; 30(2): 100949, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32234349

RESUMO

Onychomycosis is one of the most prevalent and severe nail fungal infections, which is affecting a wide population across the globe. It leads to variations like nail thickening, disintegration and hardening. Oral and topical drug delivery systems are the most desirable in treating onychomycosis, but the efficacy of the results is low, resulting in a relapse rate of 25-30%. Due to systemic toxicity and various other disadvantages associated with oral therapy like gastrointestinal, hepatotoxicity, topical therapy is commonly used. Topical therapy improves patient compliance and reduces the cost of treatment. However, due to poor penetration of topical therapy across the nail plate, research is focused on different chemical, mechanical and physical methods to improve drug delivery. Penetration enhancers like Thioglycolic acid, Hydroxypropyl-ß-cyclodextrin (HP-ß-CD), Sodium lauryl sulfate (SLS), carbocysteine, N-acetylcysteine etc. have shown results enhancing the drug penetration across the nail plate. Results with physical techniques such as iontophoresis, laser and Photodynamic therapy are quite promising, but the long-term suitability of these devices is in need to be determined. In this article, a brief analysis of the treatment procedures, factors affecting drug permeation across nail plate, chemical, mechanical and physical devices used to increase the drug delivery through nails for the onychomycosis management has been achieved.


Assuntos
Onicomicose/terapia , Administração Oral , Administração Tópica , Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Química Farmacêutica/métodos , Terapia Combinada , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Sistemas de Liberação de Medicamentos , Humanos , Iontoforese/métodos , Iontoforese/tendências , Terapia a Laser/métodos , Terapia a Laser/tendências , Unhas/efeitos dos fármacos , Unhas/metabolismo , Unhas/efeitos da radiação , Onicomicose/tratamento farmacológico , Onicomicose/epidemiologia , Onicomicose/microbiologia , Permeabilidade/efeitos dos fármacos , Permeabilidade/efeitos da radiação , Fotoquimioterapia/métodos , Fotoquimioterapia/tendências
15.
Zhongguo Zhong Yao Za Zhi ; 45(1): 1-6, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-32237404

RESUMO

The discovery of active constituents of traditional Chinese medicine(TCM) faces multiple challenges, such as limited approaches to evaluate poly-pharmacological effects, and the lack of systematic methods to identify active constituents. Aimed at these bottleneck problems in the field, the present study intensively discussed the key scientific problems in the identification of active constituents of TCM, based on scientific methodologies including systematology, information theory, and synergetics. A comprehensive strategy is herein proposed to investigate the correlations between the chemical composition and biological activities of TCM, from macro-, meso-, and micro-scales. Moreover, in this study, we systematically proposed the methodology of the multimodal identification of TCM active constituents, and thoroughly constructed its core technologies. Its technical framework is suggested to be assessed by multimodal information acquisition, centered on multisource information fusion, and focused on interaction evaluation. Furthermore, the core technologies for the multimodal identification of active constituents of TCM were developed in this study, which is according to the characteristics of the exchanges of between TCM and biological organisms, in the aspects of material, energy and information. Finally, two examples of the application of the proposed method were briefly introduced. The proposed methodology provides a novel way to solve the bottlenecks in the study of active constituents of TCM, and lays the foundation for the multimodal study of TCM.


Assuntos
Química Farmacêutica/métodos , Medicamentos de Ervas Chinesas/química , Medicina Tradicional Chinesa , Projetos de Pesquisa
16.
Zhongguo Zhong Yao Za Zhi ; 45(1): 98-105, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-32237417

RESUMO

To improve the spray drying effect of extract of Wenjing Zhitong Prescription, this study takes the yield, hygroscopic property and the fluidity of dry powder as indexes to screen out auxiliary materials, and the proportion of the auxiliary materials was optimized based on the mixing design experiment; based on that, HPLC method was established for the determination of glycyrrhizin and 6-gingerol in spray powder, the yield of spray powder and the retention rate of the two index components were taken as indexes to further optimize the spray drying parameters. The finally selected auxiliary materials were light magnesium oxide, maltodextrin and silica, and regression equations of dry powder yield, moisture absorption rate, angle of rest with proportion of auxiliary materials were established, and the optimized proportion of auxiliary materials was dry paste-light magnesium oxide-maltodextrin-silica=0.5∶0.305∶0.145∶0.05; according to the optimized drying process parameters of Wenjing Zhitong Prescription, initial temperature was 60 ℃, air inlet temperature was 130 ℃, air flow rate was 35 m~3·h~(-1), atomizing pressure was 40 mm, and liquid inlet speed was 4.5 mL·min~(-1). Under these conditions, the dry powder yield was 90.28%, the retention rate of glycyrrhizin was 74.51%, and the retention rate of 6-gingerol was 72.10%. In this study, optimized auxiliary materials can improve the yield of spray drying and the property of spray powder, and the optimized processing conditions were good for retaining the unstable gingerol components, which can lay a foundation for the further preparation research of meridian warming and pain relieving prescriptions, and provide reference for extract of other traditional Chinese medicine extracts that are difficult to spray drying.


Assuntos
Química Farmacêutica/métodos , Dessecação/métodos , Medicamentos de Ervas Chinesas/química , Temperatura Alta , Medicina Tradicional Chinesa , Pós
17.
Int J Pharm Compd ; 24(2): 148-155, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32196477

RESUMO

Orodispersible tablets disintegrate rapidly (within 3 minutes) in the oral cavity and release the medicament before swallowing. The mode of disintegrant addition might affect the properties of orodispersible tablets. The objective of this study was to formulate and evaluate orodispersible tablets by studying different modes of disintegration addition with varying concentrations of disintegrants. The wet granulation method was used to produce the orodispersible tablets. Two methods of disintegration addition were compared (i.e., intragranular, extragranular). Three disintegrants (i.e., cornstarch, sodium starch glycolate, crospovidone) were used at three levels (5%, 10%, and 15%) in the study. The formulations were tested for the powder flowability (angle of repose) and characterized physically (hardness, weight, thickness, friability, disintegration time). The mangosteen pericarp extract was used as a model active pharmaceutical ingredient to be incorporated into the optimum formulation. It was observed that the extragranular method produced granules with better flowability compared to that of the intragranular method. Crospovidone was found as the most efficient disintegrant among the three. The optimum formulation selected was one with the highest concentration of crospovidone (15%), which showed the fastest disintegration time. The mode of disintegrant addition into the orodispersible tablets formulation was found to show a marked difference in the disintegration, as well as other physical characteristics of the orodispersible tablets where the extragranular mode of addition showed better property, which caused the orodispersible tablets to disintegrate the fastest.


Assuntos
Composição de Medicamentos/métodos , Excipientes , Comprimidos/química , Administração Oral , Química Farmacêutica/métodos , Excipientes/química , Dureza , Pós , Solubilidade
18.
Int J Nanomedicine ; 15: 1585-1594, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32210553

RESUMO

Background: Aripiprazole, which is a quinolinone derivative, has been widely used to treat schizophrenia, major depressive disorder, and bipolar disorder. Purpose: A Central Composite Rotatable Design (CCRD) of Response Surface Methodology (RSM) was used purposely to optimize process parameters conditions for formulating nanoemulsion containing aripiprazole using high emulsification methods. Methods: This design is used to investigate the influences of four independent variables (overhead stirring time (A), shear rate (B), shear time (C), and the cycle of high-pressure homogenizer (D)) on the response variable namely, a droplet size (Y) of nanoemulsion containing aripiprazole. Results: The optimum conditions suggested by the predicted model were: 120 min of overhead stirring time, 15 min of high shear homogenizer time, 4400 rpm of high shear homogenizer rate and 11 cycles of high-pressure homogenizer, giving a desirable droplet size of nanoemulsion containing aripiprazole of 64.52 nm for experimental value and 62.59 nm for predicted value. The analysis of variance (ANOVA) showed the quadratic polynomial fitted the experimental values with F-value (9.53), a low p-value (0.0003) and a non-significant lack of-fit. It proved that the models were adequate to predict the relevance response. The optimized formulation with a viscosity value of 3.72 mPa.s and pH value of 7.4 showed good osmolality value (297 mOsm/kg) and remained stable for three months in three different temperatures (4°C, 25°C, and 45°C). Conclusion: This proven that response surface methodology is an efficient tool to produce desirable droplet size of nanoemulsion containing aripiprazole for parenteral delivery application.


Assuntos
Aripiprazol/química , Emulsões/química , Nanoestruturas/química , Química Farmacêutica/métodos , Concentração Osmolar , Solubilidade , Viscosidade
19.
J Vis Exp ; (157)2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32202528

RESUMO

The presented protocol enables a high-throughput continuous preparation of low temperature-sensitive liposomes (LTSLs), which are capable of loading chemotherapeutic drugs, such as doxorubicin (DOX). To achieve this, an ethanolic lipid mixture and ammonium sulfate solution are injected into a staggered herringbone micromixer (SHM) microfluidic device. The solutions are rapidly mixed by the SHM, providing a homogeneous solvent environment for liposomes self-assembly. Collected liposomes are first annealed, then dialyzed to remove residual ethanol. An ammonium sulfate pH-gradient is established through buffer exchange of the external solution by using size exclusion chromatography. DOX is then remotely loaded into the liposomes with high encapsulation efficiency (> 80%). The liposomes obtained are homogenous in size with Z-average diameter of 100 nm. They are capable of temperature-triggered burst release of encapsulated DOX in the presence of mild hyperthermia (42 °C). Indocyanine green (ICG) can also be co-loaded into the liposomes for near-infrared laser-triggered DOX release. The microfluidic approach ensures high-throughput, reproducible and scalable preparation of LTSLs.


Assuntos
Química Farmacêutica/métodos , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Verde de Indocianina/administração & dosagem , Lipídeos/química , Lipossomos/química , Microfluídica , Sulfato de Amônio , Tampões (Química) , Cromatografia , Concentração de Íons de Hidrogênio , Dispositivos Lab-On-A-Chip , Temperatura
20.
PLoS One ; 15(2): e0223201, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32050259

RESUMO

The objective of this study was based on the formulation development of fast dispersible Aceclofenac tablets (100 mg) and to evaluate the influence of pharmaceutical mixtures of directly compressible Avicel PH102 with Mannitol and Ac-di-sol on the compressional, mechanical characteristics and drug release properties. Fast dispersible Aceclofenac formulations were developed by central composite design (CCD). Among them the best possible formulation was selected on the basis of micromeritic properties, appropriate tablet weight and disintegration time for further study. Tablets were directly compressed using manual hydraulic press with a compressional force ranging from 7.2 to 77.2 MN/m2. Pre and post compression studies were performed and the compressed formulations (FA-FF) were assessed for different quality tests. The Heckel and Kawakita equations were applied for determination of compressional behavior of formulations. The quality attributes suggested that formulation (FB) containing avicel PH 102 (20%), mannitol (25%) and ac-di-sol (3%) as best optimized formulation showing better mechanical strength i.e. hardness 35.40 ± 6.93N, tensile strength 0.963 MN/m2, and friability 0.68%. Furthermore, compressional analysis of FB showed lowest PY value 59.520 MN/m2 and Pk value 1.040 MN/m2 indicating plasticity of the material. Formulation FB disintegrated rapidly within 21 seconds and released 99.92% drug after 45 min in phosphate buffer pH 6.8. Results of drug release kinetics showed that all formulations followed Weibull and First-order models in three different dissolution media. Avicel PH102 based formulation mixture exhibit excellent compactional strength with rapid disintegration and quick drug release.


Assuntos
Química Farmacêutica/métodos , Diclofenaco/análogos & derivados , Composição de Medicamentos/métodos , Estresse Mecânico , Comprimidos/química , Anti-Inflamatórios não Esteroides/química , Força Compressiva , Diclofenaco/química , Dureza , Cinética , Solubilidade , Resistência à Tração
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