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1.
Int J Nanomedicine ; 15: 5217-5226, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801687

RESUMO

Aim: Chronic use of oral nonsteroidal anti-inflammatory drugs (NSAIDs) is commonly associated with gastric irritation and gastric ulceration. Therefore, the aim of study was to develop a novel oral drug delivery system with minimum gastric effects and improved dissolution rate for aceclofenac (ACF), a model BCS class-II drug. Methods: Self-emulsifying drug delivery systems (SEDDS) were formulated to increase the solubility and ultimately the oral bioavailability of ACF. Oleic acid was used as an oil phase, Tween 80 (T80) and Kolliphor EL (KEL) were used as surfactants, whereas, polyethylene glycol 400 (PEG 400) and propylene glycol (PG) were employed as co-surfactants. Optimized formulations (F1, F2, F3 and F4) were analyzed for droplet size, poly dispersity index (PDI), cell viability studies, in vitro dissolution in both simulated gastric fluid and simulated intestinal fluid, ex vivo permeation studies and thermodynamic stability. Results: The optimized formulations showed mean droplet sizes in the range of 111.3 ± 3.2 nm and 470.9 ± 12.52 nm, PDI from 244.6 nm to 389.4 ± 6.51 and zeta-potential from -33 ± 4.86 mV to -38.5 ± 5.15 mV. Cell viability studies support the safety profile of all formulations for oral administration. The in vitro dissolution studies and ex vivo permeation analysis revealed significantly improved drug release ranging from 95.68 ± 0.02% to 98.15 ± 0.71% when compared with control. The thermodynamic stability studies confirmed that all formulations remain active and stable for a longer period. Conclusion: In conclusion, development of oral SEDDS might be a promising tool to improve the dissolution of BCS class-II drugs along with significantly reduced exposure to gastric mucosa.


Assuntos
Diclofenaco/análogos & derivados , Sistemas de Liberação de Medicamentos/métodos , Emulsões/química , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Disponibilidade Biológica , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Diclofenaco/administração & dosagem , Diclofenaco/farmacocinética , Liberação Controlada de Fármacos , Emulsões/administração & dosagem , Excipientes/química , Humanos , Masculino , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Polietilenoglicóis/química , Polissorbatos/química , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/farmacocinética , Ratos Sprague-Dawley , Solubilidade , Tensoativos/química
2.
Int J Pharm ; 588: 119689, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32717282

RESUMO

A handful of singular structures and laws can be observed in nature. They are not always evident but, once discovered, it seems obvious how to take advantage of them. In chemistry, the discovery of reproducible patterns stimulates the imagination to develop new functional materials and technological or medical applications. Two clear examples are helical structures at different levels in biological polymers as well as ring and spherical structures of different size and composition. Rings are intuitively observed as holes able to thread elongated structures. A large number of real and fictional stories have rings as inanimate protagonists. The design, development or just discovering of a special ring has often been taken as a symbol of power or success. Several examples are the Piscatory Ring wore by the Pope of the Catholic Church, the NBA Championship ring and the One Ring created by the Dark Lord Sauron in the epic story The Lord of the Rings. In this work, we reveal the power of another extremely powerful kind of rings to fight against the pandemic which is currently affecting the whole world. These rings are as small as ~1 nm of diameter and so versatile that they are able to participate in the attack of viruses, and specifically SARS-CoV-2, in a large range of different ways. This includes the encapsulation and transport of specific drugs, as adjuvants to stabilize proteins, vaccines or other molecules involved in the infection, as cholesterol trappers to destabilize the virus envelope, as carriers for RNA therapies, as direct antiviral drugs and even to rescue blood coagulation upon heparin treatment. "One ring to rule them all. One ring to find them. One ring to bring them all and in the darkness bind them." J. R. R. Tolkien.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Ciclodextrinas/química , Ciclodextrinas/farmacologia , Nanoestruturas , Pneumonia Viral/tratamento farmacológico , Betacoronavirus/metabolismo , Coagulação Sanguínea/efeitos dos fármacos , Infecções por Coronavirus/prevenção & controle , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Estabilidade de Medicamentos , Excipientes/química , Excipientes/farmacologia , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Vacinas Virais/química , Vacinas Virais/farmacologia
3.
Chemosphere ; 260: 127478, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32683022

RESUMO

Slow-releasing carbon source tablets were manufactured for an in-situ biological denitrification system. The average zero-order nitrate degradation rates seen, from highest to lowest, were in microcosms to which lactate, fumarate, propionate, and formate had been added. Fumarate was approximately 80% cheaper than lactate, and consequently was determined to be the most optimal slow-releasing carbon source in tablet form. The slow-releasing precipitating tablet (SRPT) and slow-releasing floating tablet (SRFT) were manufactured with hydroxypropyl methylcellulose (HPMC) as the agent of release control, microcrystalline cellulose pH 101 (MCC 101) as the binder, #8 sand as the precipitation agent, and calcium carbonate and citric acid as floating agents. Fourier transform infrared spectroscopy and powder X-ray diffraction indicated that the crystal arrangement in the SRPTs and SRFTs was maintained and ordered in a manner similar to raw excipients. SRFTs floated in water within 30 min and remained so for 5 d due to the buoyancy of carbon dioxide. The carbon source release rate was proportional to the quantity of HPMC added. The longevities of SRPT with 300 mg of HPMC and SRFT with 400 mg of HPMC were 25.4 d and 37.3 d, respectively. This study observed that SRPT and SRFT were manufactured effectively and are suitable for in-situ slow-releasing biological systems.


Assuntos
Desnitrificação , Água Subterrânea/química , Preparações de Ação Retardada , Excipientes/química , Derivados da Hipromelose , Nitratos , Pós , Solubilidade , Comprimidos , Água/química
4.
Food Chem ; 330: 127209, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32535314

RESUMO

Bovine ß-casein is an amphiphilic protein that exists as a monomer and self-organizes into micelles in aqueous solution. The protein has been used as natural vehicles for bioactives. Trans-resveratrol has received significant attention due to its vast health benefits and conversion to cis-isomer during processing and storage. However, cis-isomer has not yet gained as much attention as that of trans-isomer. In this study, the interaction of ß-casein with trans- and cis-resveratrol was characterized. Trans-resveratrol exhibited a higher affinity for ß-casein than cis-isomer, and ß-casein could bind two isomers simultaneously to form protein-diligand complexes. Both trans- and cis-isomers could be encapsulated into ß-casein micelles with encapsulation efficiencies of ~69% and ~57%, respectively. The ß-casein micelles could delay photo-isomerization of trans-isomer to cis-isomer, while ß-casein-ligand complex showed a better protective effect for both isomers during storage than ß-casein micelles. These results might be useful for the development of protein-based carriers for the polyphenols.


Assuntos
Caseínas/química , Excipientes/química , Resveratrol/química , Animais , Bovinos , Isomerismo , Ligantes , Micelas
5.
Food Chem ; 328: 127127, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-32473492

RESUMO

Poor stability of fish hydrolyzed collagen (HC) hampers its applications, especially as food ingredients. The use of liposome as a vesicle can be a potential means to enhance bioactivities and stability of HC. HC from defatted Asian sea bass skin at different levels (0.25%-2%, w/v) were loaded into liposomes prepared from soy phosphatidylcholine (SPC) with various stabilizers (cholesterol (CHO) or glycerol (GLY)). The highest encapsulation efficiency (EE) was found in SPC-CHO-0.5%HC (P < 0.05) (85.42%), while liposome stabilized with GLY had the highest EE (74.54%) for SPC-GLY-0.25%HC (P < 0.05). After lyophilization, SPC-CHO-0.5%HC had higher EE than SPC-GLY-0.25%HC (P < 0.05). Increasing particle size and decreasing negative surface charge were found for both lyophilized samples. Lyophilized SPC-CHO-0.5%HC exhibited higher stability than lyophilized SPC-GLY-0.25%HC during storage at 25 °C for 28 days. Also, higher antioxidant activities in gastrointestinal track model system was found for SPC-CHO-0.5%HC. Thus, SPC-CHO liposome could be used as a promising carrier of HC.


Assuntos
Antioxidantes/química , Colágeno/química , Lipossomos/química , Lipossomos/farmacologia , Animais , Antioxidantes/farmacologia , Bass , Colesterol/química , Excipientes/química , Armazenamento de Alimentos , Liofilização , Trato Gastrointestinal , Glicerol , Hidrólise , Lecitinas/química , Tamanho da Partícula , Fosfatidilcolinas/química , Pele/química , Temperatura
6.
AAPS PharmSciTech ; 21(4): 128, 2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32399597

RESUMO

Capsule-based dry powder inhaler (DPI) products can be influenced by a multitude of interacting factors, including electrostatic charging. Tribo-charging is a process of charge transfer impacted by various factors, i.e., material surface characteristics, mechanical properties, processing parameters and environmental conditions. Consequently, this work aimed to assess how the charging behavior of capsules intended for inhalation might be influenced by environmental conditions. Capsules having different chemical compositions (gelatin and hydroxypropyl methylcellulose (HPMC)) and distinct inherent characteristics from manufacturing (thermally and cold-gelled) were exposed to various environmental conditions (11%, 22% and 51% RH). Their resulting properties were characterized and tribo-charging behavior was measured against stainless steel and PVC. It was observed that all capsule materials tended to charge to a higher extent when in contact with PVC. The tribo-charging of the thermally gelled HPMC capsules (Vcaps® Plus) was more similar to the gelatin capsules (Quali-G™-I) than to their HPMC cold-gelled counterparts (Quali-V®-I). The sorption of water by the capsules at different relative humidities notably impacted their properties and tribo-charging behavior. Different interactions between the tested materials and water molecules were identified and are proposed to be the driver of distinct charging behaviors. Finally, we showed that depending on the capsule types, distinct environmental conditions are necessary to mitigate charging and assure optimal behavior of the capsules.


Assuntos
Fenômenos Químicos , Inaladores de Pó Seco/métodos , Derivados da Hipromelose/química , Eletricidade Estática , Administração por Inalação , Cápsulas , Avaliação Pré-Clínica de Medicamentos/métodos , Excipientes/química , Excipientes/metabolismo , Gelatina/química , Gelatina/metabolismo , Derivados da Hipromelose/metabolismo , Pós
7.
AAPS PharmSciTech ; 21(4): 133, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32415395

RESUMO

Phage therapy has gained prominence due to the increasing pathogenicity of "super bugs" and the rise of their multidrug resistance to conventional antibiotics. Dry state formulation of therapeutic phage is attractive to improve their "druggability" by increasing their shelf life, improving their ease of handling, and ultimately retaining their long-term potency. The use and selection of excipients are critical to stabilize phage in solid formulations and protect their viability from stresses encountered during the solidification process and long-term storage prior to use. Here, this review focuses on the current classes of excipients used to manufacture dry state phage formulations and their ability to stabilize and protect phage throughout the process, as discussed in the literature. We provide perspective of outstanding challenges involved in the formulation of dry state phage. We suggest strategies to improve excipient identification and selection, optimize the potential excipient combinations to improve phage viability during formulation, and evaluate new methodologies that can provide greater insight into phage-excipient interactions to improve design criteria to improve formulation of dry state phage therapeutics. Addressing these challenges opens up new opportunities to re-design and re-imagine phage formulations for improved efficacy as a pharmaceutical product.


Assuntos
Bacteriófagos/química , Produtos Biológicos/química , Composição de Medicamentos/métodos , Excipientes/química , Animais , Produtos Biológicos/administração & dosagem , Estabilidade de Medicamentos , Excipientes/administração & dosagem , Humanos
8.
Pharm Res ; 37(6): 92, 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32394200

RESUMO

PURPOSE: The aim of the study was to evaluate organogel nanoparticles as a lipophilic vehicle to increase the oral bioavailability of poorly soluble compounds. Efavirenz (EFV), a Biopharmaceutical Classification System (BCS) Class II, was used as drug model. METHODS: Organogel nanoparticles loaded with EFV were formulated with sunflower oil, 12-hydroxystearic acid (HSA) and polyvinyl alcohol (PVA). Various parameters have been investigated in the current study such as (i) the release profile of organogel assessed by USP 4 cell flow dialysis, (ii) the impact of organogel on intestinal absorption, using Caco-2 cells as in vitro model and jejunum segments as ex vivo assay and (iii) the bioavailability of organogel following oral pharmacokinetic study. RESULTS: 250-300 nm spherical particles with a final concentration of 4.75 mg/mL drug loading were obtained, corresponding to a thousand fold increase in EFV solubility, combined to a very high encapsulation efficiency (>99.8%). Due to rapid diffusion, drug was immediately released from the nanoparticles. The biopharmaceutical evaluation on ex vivo jejunum segments demonstrated an increased absorption of EFV from organogel nanoparticles compare to a native EFV suspension. In vitro assays combining Caco-2 cell cultures with TEM and confocal microscopy demonstrated passive diffusion, while paracellular integrity and endocytosis activity remain expelled. Oral pharmacokinetics of EFV organogel nanoparticles improve oral bioavailability (Fr: 249%) and quick absorption compared to EFV suspension. CONCLUSION: Organogel nanoparticles increase the bioavailability of BCS Class II drugs. The main phenomena is simply oil transfer from the gelled particles through the cell membrane.


Assuntos
Benzoxazinas/química , Portadores de Fármacos/química , Géis/química , Nanocápsulas/química , Álcool de Polivinil/química , Ácidos Esteáricos/química , Óleo de Girassol/química , Animais , Benzoxazinas/administração & dosagem , Benzoxazinas/farmacocinética , Disponibilidade Biológica , Células CACO-2 , Permeabilidade da Membrana Celular , Sobrevivência Celular/efeitos dos fármacos , Difusão , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Excipientes/química , Humanos , Absorção Intestinal , Masculino , Solubilidade , Suspensões/química , Distribuição Tecidual
9.
Pharm Res ; 37(6): 99, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32435855

RESUMO

PURPOSE: To evaluate the performance of artificial membranes in in vitro lipolysis-permeation assays useful for absorption studies of drugs loaded in lipid-based formulations (LBFs). METHODS: Polycarbonate as well as PVDF filters were treated with hexadecane, or lecithin in n-dodecane solution (LiDo) to form artificial membranes. They were thereafter used as absorption membranes separating two compartments mimicking the luminal and serosal side of the intestine in vitro. Membranes were subjected to dispersions of an LBF that had been digested by porcine pancreatin and spiked with the membrane integrity marker Lucifer Yellow (LY). Three fenofibrate-loaded LBFs were used to explore the in vivo relevance of the assay. RESULTS: Of the explored artificial membranes, only LiDo applied to PVDF was compatible with lipolysis by porcine pancreatin. Formulation ranking based on mass transfer in the LiDo model exposed was the same as drug release in single-compartment lipolysis. Ranking based on observed apparent permeability coefficients of fenofibrate with different LBFs were the same as those obtained in a cell-based model. CONCLUSIONS: The LiDo membrane was able to withstand lipolysis for a sufficient assay period. However, the assay with porcine pancreatin as digestive agent did not predict the in vivo ranking of the assayed formulations better than existing methods. Comparison with a Caco-2 based assay method nonetheless indicates that the in vitro in vivo relationship of this cell-free model could be improved with alternative digestive agents.


Assuntos
Portadores de Fármacos/química , Fenofibrato/química , Lipídeos/química , Lipólise , Membranas Artificiais , Administração Oral , Adsorção , Alcanos/química , Animais , Bioensaio/métodos , Células CACO-2 , Digestão , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Excipientes/química , Fenofibrato/administração & dosagem , Humanos , Lecitinas/química , Modelos Biológicos , Pancreatina/metabolismo , Permeabilidade , Solubilidade , Suínos
10.
Pharm Res ; 37(6): 100, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32436083

RESUMO

PURPOSE: We investigated the potential correlations between skin barrier integrity and hydrophilic drugs distribution in skin in the presence of different types of penetration enhancers (PEs) and their combinations. METHODS: We measured skin conductivity to evaluate skin barrier integrity before and after the topical application of different chemical PEs, physical PE, peptide PE and their combinations in vitro. We also investigated their effect on the skin distribution profiles of two hydrophilic model drugs, Fluorescein sodium (376 Da) and Fluorescein isothiocyanate-dextrans 10 (10 KDa). RESULTS: The physical PE significantly increased the skin conductivity compared to all other PEs, while the peptide PE had no effect on it. The drug deposition in different skin layers was not only dependent on PE applied but also its own molecular weight. We further found two excellent correlations: one (R2 = 0.9388) between skin barrier integrity and total skin absorption of FNa and another one(R2 = 0.9212) between skin barrier integrity and the deposition of FNa in dermis and receptor in presence of chemical or physical PEs and their combinations. CONCLUSIONS: The total skin absorption or the deposition in dermis and receptor of small hydrophilic drug in the presence of chemical and physical PEs and their combinations show a good correlation with skin barrier integrity. However, such correlations hold true neither for large hydrophilic drug nor for peptide PE. All good relationships found in this work will allow screening suitable PEs or combinations by measuring the skin conductivity induced by corresponding PEs. Graphical Abstract The total skin absorption of small hydrophilic drug shows a good correlation with skin barrier integrity in the presence of chemical and physical penetration enhancers and their combinations. However, such a correlation hold true neither for large hydrophilic drug nor for peptide penetration enhancer.


Assuntos
Melhoramento Biomédico/métodos , Portadores de Fármacos/química , Peptídeos/química , Preparações Farmacêuticas/química , Absorção Cutânea/efeitos dos fármacos , Pele/metabolismo , Administração Cutânea , Animais , Dextranos/administração & dosagem , Dextranos/química , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Excipientes/química , Fluoresceína/administração & dosagem , Fluoresceína/química , Fluoresceína-5-Isotiocianato/administração & dosagem , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/química , Cobaias , Humanos , Interações Hidrofóbicas e Hidrofílicas , Técnicas In Vitro , Conformação Molecular , Estrutura Molecular , Peso Molecular , Permeabilidade , Preparações Farmacêuticas/administração & dosagem , Solubilidade , Relação Estrutura-Atividade , Distribuição Tecidual
11.
Food Chem ; 321: 126712, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32247179

RESUMO

Zein, a class of prolamine proteins extracted from maize, is extensively used in the food and pharmaceutical industries. Characterization of its components is essential for quality control and safety evaluation. We performed in silico digestion of zein proteins using tandem combinations of different proteinases, to improve protein sequence coverage and subsequent identification by nano-LC-MS/MS analysis. Trypsin/chymotrypsin yielded the highest protein sequence coverage of up to 79.5% and increased the number of proteins from 11 to 35 compared to trypsin/Lys-C. Besides, SDS-PAGE analysis revealed 37 proteins in the zein extract, as well as the possibility of protein polymers. Also, 420 peptides originating from 71 proteins were identified, of which 116 were predicted as bioactive by in silico approach. In conclusion, in silico prediction coupled with multi-enzyme digestion can significantly improve the coverage of complex zein protein proteome, and the potential function of zein proteins and peptides need be further investigated.


Assuntos
Excipientes/química , Peptídeos/química , Zea mays/química , Zeína/química , Sequência de Aminoácidos , Cromatografia Líquida de Alta Pressão , Excipientes/metabolismo , Peptídeos/metabolismo , Proteoma/química , Proteoma/metabolismo , Espectrometria de Massas em Tandem , Zea mays/metabolismo , Zeína/metabolismo
12.
Pharm Res ; 37(4): 70, 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32185516

RESUMO

PURPOSE: While including amorphous solid dispersion (ASD) in tablet formulations is increasingly common, tablets containing high ASD loading are associated with slow disintegration, which presents a challenge to control pill burden for less potent compounds. METHODS: We use a model ASD, composed of a hydrophobic drug with copovidone and a non-ionic surfactant, to explore formulation options that can prevent slow disintegration. RESULTS: In addition to the ASD loading, the pH of the disintegration medium and the inclusion of inorganic salts in the tablet also have an impact on the tablet disintegration time. Certain kosmotropic salts, when added in the formulation, can significantly accelerate tablet disintegration, though the rank order in their effectiveness does not exactly follow the Hofmeister series at pH 1.8. The particle size and dissolution rate of the salt can contribute to its overall effectiveness. CONCLUSION: We provided a mechanistic explanation of the disintegration process: fast-dissolving kosmotropic salt results in a concentrated salt solution inside the restrained tablet matrix, thus inhibiting the dissolution of copovidone and preventing polymer gelling which is the main cause leading the slow disintegration. The outcome of this study has enabled the design of a higher ASD loading platform formulation for copovidone based ASD. Graphical Abstract MicroCT aids the mechanistic understanding of the role of inorganic salt in the tablet disintegration of amorphous solid dispersion based formulation.


Assuntos
Pirrolidinas/química , Sais/química , Comprimidos/química , Compostos de Vinila/química , Química Farmacêutica , Excipientes/química , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Concentração Osmolar , Tamanho da Partícula , Solubilidade
13.
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
14.
PLoS One ; 15(3): e0228547, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32119679

RESUMO

Some excipients are currently available for the formulation of pharmaceutical suspensions. The objective of this study is to develop cheap and effective starch-based excipient that can be used as an effective alternative for the formulation of pharmaceutical suspensions. Carboxymethylated Plectranthus edulis, Vatke (P. edulis) [fam., Lamiaceae], starch was evaluated as a suspending agent in metronidazole benzoate suspensions in comparison with sodium carboxymethyl cellulose (NaCMC) at a concentration range of 1-4% (w/v). The resulting suspensions were evaluated for their sedimentation volume (%), degree of flocculation, rheology, redispersibility, and dissolution rate. Stability studies were performed for 3 months. The apparent viscosities of the formulations prepared with carboxymethylated P. edulis starch at reaction condition E (CMPS-E) was significantly lower than that of NaCMC (p < 0.05). The flowability of the suspensions, at all concentration levels of the suspending agents, were in the order of CMPS-E > NaCMC. AT 1% concentrations, carboxymethylated P. edulis starch (76 ± 1.5%) provided significantly higher (p < 0.05) sedimentation volume than NaCMC (40 ± 1.5%). At 3% and 4%, both gave comparable sedimentation volume (100%). Potassium dihydrogen phosphate (KH2PO4) employed as a flocculating agent significantly increased (p < 0.05) the sedimentation volume of the suspensions prepared with carboxymethylated P.edulis starch and NaCMC. The redispersibilities of CMPS-E were better than those of NaCMC. All suspensions showed a release of greater than 85% of drug within 1 h. The results of stability studies showed that all suspension formulations were stable. From the foregoing, it can be concluded that carboxymethylated P. edulis starch could be used as an alternative suspending agent.


Assuntos
Benzoatos/química , Composição de Medicamentos , Excipientes/química , Metronidazol/química , Plectranthus , Amido/química , Reologia , Suspensões
15.
Int J Nanomedicine ; 15: 1073-1094, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32103956

RESUMO

Purpose: This study demonstrated improved transdermal delivery of rifampicin-loaded cationic nanoemulsion gel to treat systemic and cutaneous tuberculosis using capmul, labrasol, and acconon, which exert anti-Mycobacterium activities. This approach enhanced drug permeation across the skin, increased therapeutic efficacy, and reduced dose-related side effects. Methods: Design Expert® was used to optimize formulations (Smix ratio and capmul as independent factors), which were prepared using a slow spontaneous titration method. The optimized nanoemulsion was incorporated into carbopol gel to allow for topical application and comparative assessments. Nanoemulsions and gels were evaluated for size, size distribution, shape, zeta potential, percent spread, viscosity, in vitro hemolysis, in vitro release, and ex vivo skin permeation and deposition. A mechanistic evaluation was performed using scanning electron microscopy. Furthermore, in vivo pharmacokinetic and irritation studies were performed. Results: The optimized cationic nanoemulsion (OCNE-1) was characterized by small particle size (≤100 nm), had optimal viscosity, percent spread, zeta potential, and percent drug release, and was hemocompatible. The OCNE-1T gel exhibited higher permeation flux (51.32 ± 0.5 µg/cm2 hr), permeation coefficient (2.566 ± 0.08 cm/hr), drug deposition (994.404 µg/cm2), and enhancement ratio (7.16) than those of the OCNE-1 nanoemulsion or drug solution. Scanning electron microscopy was used to characterize the mechanism of enhanced permeation. An In vivo study showed that the Cmax and area under the curve following transdermal application were 4.34- and 4.74-fold higher than those following oral administration. Conclusion: Transdermal delivery of rifampicin could be a promising alternative to conventional approaches to treat systemic and local tuberculosis, and other bacterial infections.


Assuntos
Antituberculosos/administração & dosagem , Emulsões/administração & dosagem , Rifampina/administração & dosagem , Tuberculose/tratamento farmacológico , Resinas Acrílicas/química , Administração Cutânea , Animais , Antituberculosos/farmacocinética , Antituberculosos/farmacologia , Disponibilidade Biológica , Caprilatos/química , Cátions/química , Emulsões/farmacologia , Excipientes/química , Géis/química , Géis/farmacologia , Glicerídeos/química , Mycobacterium/efeitos dos fármacos , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Tamanho da Partícula , Ratos Sprague-Dawley , Rifampina/farmacocinética , Rifampina/farmacologia , Pele/efeitos dos fármacos , Tuberculose Cutânea/tratamento farmacológico
16.
J Chromatogr A ; 1619: 460911, 2020 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-32007219

RESUMO

High performance liquid chromatography (HPLC) methods with UV/vis detection are the most widespread analytical procedures in modern pharmaceutical applications, but reach their limitations when it comes to non-chromophore molecules. Hence, instead of using tiresome derivatization procedures, many liquid chromatography methods make use of the so-called aerosol-based universal detectors, namely the evaporative light scattering detector (ELSD), the condensation nucleation light scattering detector (CNLSD) and the charged aerosol detector (CAD). Amongst these, the CAD, being the youngest (introduced in 2005) of these three options, is often described as the most easy-to-use detector and is stated to exhibit sufficient sensitivity and good linearity of signal in a dedicated range of concentration. Therefore, this review sets its focus on the recent applications of the CAD for active pharmaceutical ingredients, excipient analysis as well as botanical applications. Alongside the post-column solvent addition techniques, the new CAD's ability to adjust the evaporation temperature and the possibility to use an integrated power function for signal linearization are reviewed as previously unavailable, new parameters for optimization.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Preparações Farmacêuticas/análise , Aerossóis/análise , Excipientes/química , Extratos Vegetais/química , Controle de Qualidade , Tecnologia Farmacêutica/métodos , Tecnologia Farmacêutica/normas , Temperatura
17.
AAPS PharmSciTech ; 21(3): 94, 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32096096

RESUMO

The aim of this study is to investigate the relationship between the structural, molecular, and particulate properties of alginic acid and its functional characteristics in direct compression (tabletability, compressibility, elasticity, deformation mechanism, and disintegration ability). Therefore, accurate characterization of two different batches of alginic acid was executed (X-ray powder diffraction, Fourier-transform infrared spectroscopy, thermogravimetric analysis, scanning electronic microscopy, 1H nuclear magnetic resonance, size exclusion chromatography - multi angle light scattering, viscosimetry, carboxylic acid titration, powder flowability, true density, laser granulometry). Results showed that molecular weight seems to affect tablet properties and that the alginic acid with the lowest molecular weight provides the hardest tablets with the lowest elastic recovery. Furthermore, these results show the potential interest of exploiting alginic acid as filler excipient in tablet formulation. Finally, disintegration properties of tested materials were found to be close to that of commercial superdisintegrants (Glycolys® and Kollidon Cl®) but not correlated to their swelling force. It can be concluded, for the first time, that the determination of alginic acid molecular weight seems key for applications in direct compression and in particular for obtaining tablets with reproducible strength.


Assuntos
Ácido Algínico/análise , Ácido Algínico/química , Avaliação Pré-Clínica de Medicamentos/métodos , Elasticidade , Excipientes/química , Dureza , Fenômenos Mecânicos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Relação Estrutura-Atividade , Comprimidos , Difração de Raios X/métodos
18.
Pharm Res ; 37(2): 23, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900680

RESUMO

Significant efforts are made to characterize molecular liabilities and degradation of the drug substance (DS) and drug product (DP) during various product life-cycle stages. The in vivo fate of a therapeutic protein is usually only considered in terms of pharmacokinetics (PKs) and pharmacodynamics (PDs). However, the environment in the human body differs substantially from that of the matrix (formulation) of the DP and may impact on the stability of an injected therapeutic protein. Stabilizing excipients used in protein formulations are expected to undergo more rapid distribution and dissociation in vivo, compared to a protein as a highly charged macromolecule. Thus, in vivo stability may significantly differ from shelf-life stability. In vivo degradation of the therapeutic protein may alter efficacy and/or safety characteristics such as immunogenicity. Studying the stability of a therapeutic protein in the intended body compartment can de-risk drug development in early stages of development by improving the selection of better clinical lead molecules. This review assesses the considerations when aiming to evaluate the in vivo fate of a therapeutic protein by comparing the physiology of relevant human body compartments and assessing their potential implications on the stability of a therapeutic protein. Moreover, we discuss the limitations of current experimental approaches mimicking physiologic conditions, depending on the desired route of administration, such as intravenous (IV), subcutaneous (SC), intravitreal (IVT), or intrathecal (IT) administration(s). New models more closely mimicking the relevant physiologic environment and updated analytical methods are required to understand the in vivo fate of therapeutic proteins.


Assuntos
Preparações Farmacêuticas/química , Proteínas/química , Animais , Química Farmacêutica/métodos , Estabilidade de Medicamentos , Excipientes/química , Humanos
19.
Eur J Pharm Biopharm ; 147: 102-110, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31899368

RESUMO

Electrospraying or electrohydrodynamic atomisation, i.e. the formation of tiny droplets from a jet of conductive liquid under the influence of an electric field, has been gaining in popularity as a particle engineering technique in recent years. In addition to general benefits for particle engineering, e.g. the ability to generate nanometre sized particles with a very narrow size distribution, electrospraying also possesses a number of characteristics, like its applicability at ambient conditions, which could make it especially interesting for formulating therapeutic proteins. However, as fully aqueous solutions of proteins tend to have relatively high electrical conductivities and surface tensions, obtaining a stable Taylor cone-jet mode for these solutions is inherently challenging. This is why in the majority of studies reporting the successful electrospraying of proteins, either emulsions, aqueous suspensions or a mixture of water and one or more organic solvents were used instead of fully aqueous solutions. Therefore, an ab initio electrospraying formulation development study was conducted, using only fully aqueous feed solutions containing protein stabilising excipients commonly used in spray- and freeze-drying of therapeutic proteins. The study included bovine serum albumin (BSA) as a model protein and consisted out of two parts: (1) a one parameter at a time screening study, designed to improve the understanding of how various formulation components influence relevant physicochemical properties and the electrospraying process and (2) two subsequent mixture design of experiments (DoE) studies, designed to aid in the statistical description and prediction of the influence of different protein-excipient combinations on the electrospraying process. Additionally, the influence of physicochemical properties relevant to the electrospraying process, i.e. the volumetric mass density, electrical conductivity, kinematic viscosity and surface tension, was assessed for all feed solutions included in the study.


Assuntos
Composição de Medicamentos/métodos , Excipientes/química , Soroalbumina Bovina/química , Tecnologia Farmacêutica/métodos , Estudos de Viabilidade , Liofilização , Hidrodinâmica , Tamanho da Partícula , Soroalbumina Bovina/administração & dosagem , Solventes/química , Tensão Superficial , Viscosidade , Água/química
20.
J Chromatogr A ; 1609: 460450, 2020 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-31443971

RESUMO

Polysorbates, a group of nonionic surfactants, are widely used as pharmaceutic excipient. Their quality and safety are closely related to their profiles, including composition, structure, proportion and polyoxyethylene (POE) polymerization degree. However, due to complex composition and similar skeletons, it is difficult and time-consuming to profile and identify them. There is no integrated strategy for routine control. In this paper, an UHPLC-HRMS method was established, and 211 components belonging to 10 species in polysorbate-80 were identified based on their MS/MS data and further confirmed by NMR. A mathematical model was then established to predict all possible components based on the good logarithmic relationship between the POE polymerization degrees and retention times (RTs) of the components for the first time. A database of 853 detected and predicted components of polysorbate-80, -60, -40 and -20 was created. A novel rapid identification strategy was established for comprehensive polysorbate profiling by comparing the exact masses and RTs of the test peaks to the database. This novel strategy was employed to profile polysorbates in 14 pharmaceutic excipients and preparations. Approximately 200 components were identified and semiquantified in each sample, and the number and content of components differed among these samples.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Excipientes/química , Polissorbatos/química , Espectrometria de Massas em Tandem/métodos , Ésteres/química , Polietilenoglicóis/química , Polimerização , Espectroscopia de Prótons por Ressonância Magnética
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