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1.
Food Chem ; 370: 130980, 2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-34628238

RESUMO

Low bioavailability currently limits the potential of curcumin as a health-promoting dietary compound. This study therefore explored the potential of excipient emulsions to improve curcumin bioavailability. Oil-in-water excipient emulsions were prepared using different types of oils: corn oil, olive oil, and medium chain triglycerides (MCT). The excipient emulsions increased the transportation rate of curcumin across the Caco-2 cell monolayer and showed ability to protect curcumin from metabolism in the enterocytes, with the olive oil-based systems exhibiting the highest efficacy. In addition, most of curcumin metabolites were present as hexahydro-curcumin (HHC) and its conjugates. Our results show that excipient emulsions can improve curcumin bioavailability by increasing its trans-enterocyte absorption and reducing cellular metabolism. Moreover, they show that these effects depend on the type of oil used to produce them. These findings have important implications for the rational design of lipid-based delivery systems to enhance the bioavailability of hydrophobic nutraceuticals like curcumin.


Assuntos
Curcumina , Excipientes , Disponibilidade Biológica , Células CACO-2 , Óleo de Milho , Curcumina/metabolismo , Emulsões/metabolismo , Excipientes/metabolismo , Trato Gastrointestinal/metabolismo , Humanos
2.
AAPS PharmSciTech ; 22(5): 163, 2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34031790

RESUMO

This research aimed to develop a novel drug delivery system to improve treatment of skin disorders. The system is comprised of a Carbopol 980-based nanoemulgel (NE-gel) containing a desonide (DES; 0.05%, w/w) nanoemulsion (NE), which has a small particle size, high encapsulation efficiency, good thermodynamic stability, good permeation ability, and high skin retention. DES-loaded NE (DES-NE) was prepared by high-pressure homogenization. The developed formulation was characterized by differential scanning calorimetry (DSC), X-ray diffraction, drug release, skin permeation, and drug retention. DES in vitro release and skin permeation studies with different formulations of artificial membrane and rat abdominal skin were performed with the Franz diffusion cell system. Confocal laser scanning microscopy (CLSM) was used to detect the localization and permeation pathways of drugs in the skin. Compared with commercially available gel (CA-gel) and NE, the NE-gel release process conformed to the Higuchi release model (R2 = 0.9813). NE-gel prolonged the drug release time and allowed for reduced administration dose and frequency. The unit cumulative permeation of NE and NE-gel through the skin for 12 h was 63.13 ± 2.78 and 42.53 ± 2.06 µg/cm2, respectively, values significantly higher (p < 0.01) than that of the CA-gel (30.65 ± 1.25 µg/cm2) and CA-cream (15.21 ± 0.97 µg/cm2). The DES-NE and DES NE-gel skin drug retention was significantly higher than commercially available formulations (p < 0.01). Hence, the prepared NE-gel is a potential vehicle for improved topical DES delivery for better treatment of skin disorders.


Assuntos
Desonida/administração & dosagem , Sistemas de Liberação de Medicamentos , Emulsões/química , Nanogéis/administração & dosagem , Administração Tópica , Animais , Coloides/metabolismo , Desonida/química , Excipientes/metabolismo , Microscopia Confocal , Nanogéis/química , Tamanho da Partícula , Ratos , Pele/metabolismo , Absorção Cutânea
3.
Xenobiotica ; 51(1): 95-104, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32544367

RESUMO

To date, relatively little is known about the interactions of pharmaceutical excipients with hepatic and renal drug uptake transporters. The present study was designed to systematically evaluate the effects of 16 commonly consumed excipients on human organic cation transporter 1 and 2 (hOCT1 and hOCT2), human organic anion transporter 1 and 3 (hOAT1 and hOAT3) and human organic anion transporting polypeptide 1B1 and 1B3 (hOATP1B1 and hOATP1B3). The inhibitory effects and mechanisms of excipients on transporters were investigated using in vitro uptake studies, cell viability assays, concentration-dependent studies, and the Lineweaver-Burk plot method. Triton X-100 is a non-competitive inhibitor for all six transporters. Tween 20 inhibits hOCT2, hOAT1, hOAT3, and hOATP1B3 in a mixed way, whereas it competitively inhibits hOATP1B1. The inhibition of Tween 80 is competitive for hOCT2, non-competitive for hOATP1B1 and hOATP1B3, and mixed for hOAT1 and hOAT3. Concentration-dependent studies identify Triton X-100 as a strong inhibitor of hOCT1 and hOCT2 with IC50 values of 20.1 and 4.54 µg/mL, respectively. Additionally, Triton X-100, Tween 20, and Tween 80 strongly inhibit hOAT3 with IC50 values ≤31.0 µg/mL. The present study is significant in understanding the excipient-drug interactions and provides valuable information for excipient selection in drug development.


Assuntos
Transporte Biológico/efeitos dos fármacos , Excipientes/farmacologia , Animais , Ânions/metabolismo , Cátions/metabolismo , Excipientes/metabolismo , Humanos , Rim/metabolismo , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Transportador 1 de Cátions Orgânicos/metabolismo , Transportador 2 de Cátion Orgânico/metabolismo
4.
Food Funct ; 11(12): 10655-10664, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33216090

RESUMO

The aim of the current study was to investigate the effect of an acidity regulator (SPORIX®), lactose, and vitamin D3 as excipient ingredients on digestive solubility and intestinal transport of calcium from four different calcium materials (tricalcium phosphate (TCP), fish bone (FB), nano-fish bone (NFB), and algae calcium (AC)) through an in vitro digestion model system combined with Caco-2 cells. The concentration of ionized calcium (Ca2+) in an aqueous fraction after in vitro digestion increased with the addition of SPORIX®, and it was further enhanced by adding SPORIX® + lactose + vitamin D3 into TCP, FB, NFB, and AC, respectively. In particular, FB with SPORIX® + lactose + vitamin D3 enhanced calcium ionization to 33.89 ± 0.69 mg g-1, which was about 11.76 times higher than that of FB only. In the case of intestinal cellular uptake of calcium, there was no significant difference in all the tested calcium materials with SPORIX® + lactose + vitamin D3. However, the absolute amount of intestinal transport of calcium in FB (43.95 ± 3.29 µg) was significantly higher than other calcium materials with the addition of SPORIX® + lactose + vitamin D3 (p < 0.05). This study suggests that the co-consumption of SPORIX®, lactose, and vitamin D3 with FB could enhance the calcium bioavailability by lowering pH as well as improving calcium intestinal transport by modulating the paracellular and transcellular uptake mechanism.


Assuntos
Fosfatos de Cálcio/metabolismo , Cálcio/metabolismo , Carbonatos/metabolismo , Excipientes/administração & dosagem , Mucosa Intestinal/metabolismo , Nutrientes , Animais , Transporte Biológico , Osso e Ossos , Células CACO-2 , Cálcio na Dieta/metabolismo , Colecalciferol/metabolismo , Excipientes/metabolismo , Peixes , Humanos , Intestinos , Solubilidade
5.
Eur J Pharm Biopharm ; 154: 387-396, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32717391

RESUMO

Many amorphous solid dispersions (ASDs) are thermodynamically unstable. Thus, the active pharmaceutical ingredient (API) might crystallize over time. The crystallization kinetics and therewith the long-term stability of ASDs depends on the storage conditions temperature and relative humidity (RH) as they determine the molecular mobility of the API in the polymer. To quantify the molecular mobility, the rheological behavior of two different ASDs with ibuprofen and either poly(vinyl acetate) or poly(vinylpyrrolidone-co-vinyl acetate) was analyzed as function of temperature and relative humidity by means of an oscillatory rheometer. The plasticizing effect of ibuprofen and absorbed water on the zero-shear viscosity of the polymer could be fully explained by the reduction of the glass-transition temperature of the mixture compared to the one of the pure polymer. Moreover, this work proposes an approach to predict the zero-shear viscosity of an ASD based on only the temperature dependence of the zero-shear viscosity of the pure polymer as well as the predicted water content in the ASD at certain RH using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT).


Assuntos
Umidade , Ibuprofeno/química , Polivinil/química , Pirrolidinas/química , Compostos de Vinila/química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/metabolismo , Cristalização/métodos , Excipientes/química , Excipientes/metabolismo , Ibuprofeno/metabolismo , Polivinil/metabolismo , Pirrolidinas/metabolismo , Reologia/métodos , Solubilidade , Compostos de Vinila/metabolismo , Viscosidade
6.
Mol Pharm ; 17(9): 3202-3213, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32649208

RESUMO

The scientific rationale for selection of the surfactant type during oral formulation development requires an in-depth understanding of the interplay between surfactant characteristics and biopharmaceutical factors. Currently, however, there is a lack of comprehensive knowledge of how surfactant properties, such as hydrophilic-lipophilic balance (HLB), digestibility, and fatty acid (FA) chain length, translate into in vivo performance. In the present study, the relationship between surfactant properties, in vitro characteristics, and in vivo bioavailability was systematically evaluated. An in vitro lipolysis model was used to study the digestibility of a variety of nonionic surfactants. Eight surfactants and one surfactant mixture were selected for further analysis using the model poorly water-soluble drug nilotinib. In vitro lipolysis of all nilotinib formulations was performed, followed by an in vivo pharmacokinetic evaluation in rats. The in vitro lipolysis studies showed that medium-chain FA-based surfactants were more readily digested compared to long-chain surfactants. The in vivo study demonstrated that a Tween 20 formulation significantly enhanced the absolute bioavailability of nilotinib up to 5.2-fold relative to an aqueous suspension. In general, surfactants that were highly digestible in vitro tended to display higher bioavailability of nilotinib in vivo. The bioavailability may additionally be related to the FA chain length of digestible surfactants with an improved exposure in the case of medium-chain FA-based surfactants. There was no apparent relationship between the HLB value of surfactants and the in vivo bioavailability of nilotinib. The impact of this study's findings suggests that when designing surfactant-based formulations to enhance oral bioavailability of the poorly water-soluble drug nilotinib, highly digestible, medium chain-based surfactants are preferred. Additionally, for low-permeability drugs such as nilotinib, which is subject to efflux by intestinal P-glycoprotein, the biopharmaceutical effects of surfactants merit further consideration.


Assuntos
Digestão/efeitos dos fármacos , Pirimidinas/metabolismo , Tensoativos/metabolismo , Administração Oral , Animais , Disponibilidade Biológica , Química Farmacêutica/métodos , Excipientes/metabolismo , Ácidos Graxos/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Lipólise/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Solubilidade/efeitos dos fármacos , Suspensões/metabolismo
7.
Proc Natl Acad Sci U S A ; 117(27): 16009-16018, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32571913

RESUMO

Food and drug products contain diverse and abundant small-molecule additives (excipients) with unclear impacts on human physiology, drug safety, and response. Here, we evaluate their potential impact on intestinal drug absorption. By screening 136 unique compounds for inhibition of the key intestinal transporter OATP2B1 we identified and validated 24 potent OATP2B1 inhibitors, characterized by higher molecular weight and hydrophobicity compared to poor or noninhibitors. OATP2B1 inhibitors were also enriched for dyes, including 8 azo (R-N=N-R') dyes. Pharmacokinetic studies in mice confirmed that FD&C Red No. 40, a common azo dye excipient and a potent inhibitor of OATP2B1, decreased the plasma level of the OATP2B1 substrate fexofenadine, suggesting that FD&C Red No. 40 has the potential to block drug absorption through OATP2B1 inhibition in vivo. However, the gut microbiomes of multiple unrelated healthy individuals as well as diverse human gut bacterial isolates were capable of inactivating the identified azo dye excipients, producing metabolites that no longer inhibit OATP2B1 transport. These results support a beneficial role for the microbiome in limiting the unintended effects of food and drug additives in the intestine and provide a framework for the data-driven selection of excipients. Furthermore, the ubiquity and genetic diversity of gut bacterial azoreductases coupled to experiments in conventionally raised and gnotobiotic mice suggest that variations in gut microbial community structure may be less important to consider relative to the high concentrations of azo dyes in food products, which have the potential to saturate gut bacterial enzymatic activity.


Assuntos
Bactérias/metabolismo , Excipientes/metabolismo , Aditivos Alimentares/metabolismo , Alimentos , Microbioma Gastrointestinal/fisiologia , Absorção Intestinal/fisiologia , Transportadores de Ânions Orgânicos/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Animais , Antialérgicos/metabolismo , Antialérgicos/farmacocinética , Compostos Azo , Bactérias/isolamento & purificação , Excipientes/farmacocinética , Feminino , Aditivos Alimentares/farmacocinética , Antagonistas não Sedativos dos Receptores H1 da Histamina/metabolismo , Antagonistas não Sedativos dos Receptores H1 da Histamina/farmacocinética , Humanos , Absorção Intestinal/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Terfenadina/análogos & derivados
8.
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
9.
Appl Environ Microbiol ; 86(15)2020 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-32414803

RESUMO

Androst-4-ene-3,17-dione (AD) and androst-1,4-diene-3,17-dione (ADD) are valuable steroid pharmaceutical intermediates obtained by soybean phytosterol biotransformation by Mycobacterium Cyclodextrins (CDs) are generally believed to be carriers for phytosterol delivery and can improve the production of AD and ADD due to their effects on steroid solubilization and alteration in cell wall permeability for steroids. To better understand the mechanisms of CD promotion, we performed proteomic quantification of the effects of hydroxypropyl-ß-CD (HP-ß-CD) on phytosterol metabolism in Mycobacterium neoaurum TCCC 11978 C2. Perturbations are observed in steroid catabolism and glucose metabolism by adding HP-ß-CD in a phytosterol bioconversion system. AD and ADD, as metabolic products of phytosterol, are toxic to cells, with inhibited cell growth and biocatalytic activity. Treatment of mycobacteria with HP-ß-CD relieves the inhibitory effect of AD(D) on the electron transfer chain and cell growth. These results demonstrate the positive relationship between HP-ß-CD and phytosterol metabolism and give insight into the complex functions of CDs as mediators of the regulation of sterol metabolism.IMPORTANCE Phytosterols from soybean are low-cost by-products of soybean oil production and, owing to their good bioavailability in mycobacteria, are preferred as the substrates for steroid drug production via biotransformation by Mycobacterium However, the low level of production of steroid hormone drugs due to the low aqueous solubility (below 0.1 mmol/liter) of phytosterols limits the commercial use of sterol-transformed strains. To improve the bioconversion of steroids, cyclodextrins (CDs) are generally used as an effective carrier for the delivery of hydrophobic steroids to the bacterium. CDs improve the biotransformation of steroids due to their effects on steroid solubilization and alterations in cell wall permeability for steroids. However, studies have rarely reported the effects of CDs on cell metabolic pathways related to sterols. In this study, the effects of hydroxypropyl-ß-CD (HP-ß-CD) on the expression of enzymes related to steroid catabolic pathways in Mycobacterium neoaurum were systematically investigated. These findings will improve our understanding of the complex functions of CDs in the regulation of sterol metabolism and guide the application of CDs to sterol production.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/metabolismo , Proteínas de Bactérias/metabolismo , Excipientes/metabolismo , Mycobacteriaceae/metabolismo , Fitosteróis/metabolismo , Proteômica
10.
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
11.
Int J Pharm ; 581: 119295, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32247815

RESUMO

The structuring of component particles in binary compositions affects the solid-solid interfacial properties. This work reports the effect of interparticle interactions in binary powder compositions of D-Mannitol and glass beads through the heterogeneity data obtained from Finite Dilution Inverse Gas Chromatography (FD-IGC). Three different scenarios viz. structured, random and segregated systems of the binary powder composition were considered for the analysis in the IGC column. Binary mixtures with large size disparity between the components produced structured mixtures exhibiting a guest-host type of interactions and energetic homogeneity irrespective of the energetics of the finer component. Random and segregated systems revealed a heterogeneous trend in the data indicating preferential probing of the active sites of the composition, particularly at the lower probe coverages. The results demonstrate that in the multicomponent binary systems the surface energetics is influenced by the solid-solid interfaces and structuring of the component particles within the mix i.e., the surface energy analysis could reveal a mixing behavior in powders. Furthermore, an adsorption energy distribution model based on Boltzmann statistics and simulation fitting approach was employed to deconvolute the distribution of the changing energy landscape of the binary mixtures.


Assuntos
Química Farmacêutica/métodos , Manitol/síntese química , Manitol/metabolismo , Tamanho da Partícula , Excipientes/síntese química , Excipientes/metabolismo , Pós , Propriedades de Superfície , Difração de Raios X/métodos
12.
Biomolecules ; 10(1)2020 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-31941036

RESUMO

Most of the neurological disorders in the brain are caused by the abnormal buildup of misfolded or aggregated proteins. Osmolytes are low molecular weight organic molecules usually built up in tissues at a quite high amount during stress or any pathological condition. These molecules help in providing stability to the aggregated proteins and protect these proteins from misfolding. Alzheimer's disease (AD) is the uttermost universal neurological disorder that can be described by the deposition of neurofibrillary tangles, aggregated/misfolded protein produced by the amyloid ß-protein (Aß). Osmolytes provide stability to the folded, functional form of a protein and alter the folding balance away from aggregation and/or degradation of the protein. Moreover, they are identified as chemical chaperones. Brain osmolytes enhance the pace of Aß aggregation, combine with the nearby water molecules more promptly, and avert the aggregation/misfolding of proteins by providing stability to them. Therefore, osmolytes can be employed as therapeutic targets and may assist in potential drug design for many neurodegenerative and other diseases.


Assuntos
Doenças Neurodegenerativas/metabolismo , Agregação Patológica de Proteínas/metabolismo , Dobramento de Proteína , Doença de Alzheimer/metabolismo , Aminoácidos/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Metabolismo dos Carboidratos , Descoberta de Drogas , Excipientes/metabolismo , Humanos , Metilaminas/metabolismo , Agregados Proteicos , Ureia/metabolismo
13.
Mol Pharm ; 17(3): 748-756, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-31990564

RESUMO

Mechanistic-understanding-based selection of excipients may improve formulation development strategies for generic drug products and potentially accelerate their approval. Our study aimed at investigating the effects of molecular excipients present in orally administered FDA-approved drug products on the intestinal efflux transporter, BCRP (ABCG2), which plays a critical role in drug absorption with potential implications on drug safety and efficacy. We determined the interactions of 136 oral molecular excipients with BCRP in isolated membrane vesicles and identified 26 excipients as BCRP inhibitors with IC50 values less than 5 µM using 3H-cholecystokinin octapeptide (3H-CCK8). These BCRP inhibitors belonged to three functional categories of excipients: dyes, surfactants, and flavoring agents. Compared with noninhibitors, BCRP inhibitors had significantly higher molecular weights and SLogP values. The inhibitory effects of excipients identified in membrane vesicles were also evaluated in BCRP-overexpressing HEK293 cells at similar concentrations. Only 1 of the 26 inhibitors of BCRP identified in vesicles inhibited BCRP-mediated 3H-oxypurinol uptake by more than 50%, consistent with the notion that BCRP inhibition depends on transmembrane or intracellular availability of the inhibitors. Collectively, the results of this study provide new information on excipient selection during the development of drug products with active pharmaceutical ingredients that are BCRP substrates.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Corantes/metabolismo , Excipientes/metabolismo , Aromatizantes/metabolismo , Proteínas de Neoplasias/metabolismo , Tensoativos/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Administração Oral , Corantes/química , Corantes/farmacologia , Composição de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Excipientes/química , Excipientes/farmacologia , Feminino , Aromatizantes/química , Aromatizantes/farmacologia , Células HEK293 , Humanos , Concentração Inibidora 50 , Absorção Intestinal/efeitos dos fármacos , Peso Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Transdução de Sinais/genética , Tensoativos/química , Tensoativos/farmacologia , Transfecção
14.
J Pharm Sci ; 109(1): 44-61, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31705870

RESUMO

Although many biotech products are successfully stored in the frozen state, there are cases of degradation of biologicals during freeze storage. These examples are discussed in the Perspective to emphasize the fact that stability of frozen biologicals should not be taken for granted. Frozen-state degradation (predominantly, aggregation) has been linked to crystallization of a cryoprotector in many cases. Other factors, for example, protein unfolding (either due to cold denaturation or interaction of protein molecules with ice crystals), could also contribute to the instability. As a hypothesis, additional freezing-related destabilization pathways are introduced in the paper, that is, air bubbles formed on the ice crystallization front, and local pressure and mechanical stresses due to volume expansion during water-to-ice transformation. Furthermore, stability of frozen biologicals can depend on the sample size, via its impact on the freezing kinetics (i.e., cooling rates and freezing time) and cryoconcentration effects, as well as on the mechanical stresses associated with freezing. We conclude that, although fundamentals of freezing processes are fairly well described in the current literature, there are important gaps to be addressed in both scientific foundations of the freezing-related manufacturing processes and implementation of the available knowledge in practice.


Assuntos
Produtos Biológicos/química , Excipientes/química , Congelamento/efeitos adversos , Proteólise , Produtos Biológicos/metabolismo , Cristalização/métodos , Estabilidade de Medicamentos , Excipientes/metabolismo , Humanos
15.
J Pharm Sci ; 109(1): 211-215, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31655034

RESUMO

Lyophilization of protein formulations is an essential tool for stabilization and is becoming increasingly important for pharmaceutical development. Reconstitution of the lyophilized cakes is crucial to obtain an applicable product. Nowadays, manual reconstitution by patients or medical staff is the common method defined in instructions for marketed lyophilized drug products. Even though this step is influencing the quality of the final solution, it can represent a challenge to develop a standardized manual protocol and the performance is highly dependent on human factors. This study summarizes the implementation and performance of controlled reconstitution studies for protein lyophilizates applying a mechanical reconstitution device. Using automated and standardized protocols, reconstitution time of a bispecific antibody lyophilizate could be reduced effectively from 25 to below 5 min compared to the predeveloped manual protocol. It was shown that the reconstitution protocol is influencing the stability of sensitive proteins. Monomer content as well as formation of subvisible particles differed considerably between the tested protocols emphasizing the relevance of standardized procedures.


Assuntos
Anticorpos Monoclonais/metabolismo , Química Farmacêutica/normas , Composição de Medicamentos/normas , Agregados Proteicos/fisiologia , Anticorpos Monoclonais/química , Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Estabilidade de Medicamentos , Excipientes/química , Excipientes/metabolismo , Excipientes/normas , Liofilização/métodos , Liofilização/normas , Humanos , Estabilidade Proteica , Padrões de Referência
16.
Food Funct ; 10(9): 5302-5311, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31432852

RESUMO

Many of the carotenoids found naturally in fruits and vegetables are beneficial to human health, but they often have low oral bioavailability because of their high hydrophobicity. In this study, the effects of varying the composition of the oil phase of excipient nanoemulsions on carotenoid bioaccessibility from spinach were investigated using a simulated gastrointestinal tract. Nanoemulsions containing different ratios of medium chain triglycerides (MCT) and long chain triglycerides (LCT) were prepared: (i) mixing MCT and LCT oils before homogenization and (ii) mixing MCT droplets with LCT droplets after homogenization. The release of carotenoids from spinach and their solubilization within the mixed micelles formed after lipid digestion depended strongly on the oil phase composition. As expected, carotenoid bioaccessibility was always higher in the presence of excipient nanoemulsions than in their absence. The total free fatty acids released in the small intestine increased as the MCT/LCT ratio increased, which can be attributed to the faster release of shorter chain fatty acids from the oil droplet surfaces during lipid digestion. As the MCT ratio increased, lutein bioaccessibility increased but ß-carotene bioaccessibility decreased. This difference was attributed to the ability of the formed mixed micelles to accommodate the two different kinds of carotenoids in their hydrophobic domains. Interestingly, carotenoid bioaccessibility was significantly lower (P < 0.05) when the oil droplets were mixed after homogenization than when the oils were mixed before homogenization. These results have important implications for the design of excipient foods to improve the bioavailability of hydrophobic nutraceuticals in fruits and vegetables.


Assuntos
Carotenoides/metabolismo , Trato Gastrointestinal/metabolismo , Extratos Vegetais/metabolismo , Spinacia oleracea/metabolismo , Triglicerídeos/metabolismo , Disponibilidade Biológica , Carotenoides/química , Digestão , Emulsões/química , Emulsões/metabolismo , Excipientes/química , Excipientes/metabolismo , Trato Gastrointestinal/química , Humanos , Modelos Biológicos , Extratos Vegetais/química , Spinacia oleracea/química , Triglicerídeos/química
17.
Food Funct ; 10(6): 3344-3355, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31095149

RESUMO

The impact of phytic acid on lipid digestion and curcumin bioaccessibility in oil-in-water nanoemulsions was investigated using a simulated gastrointestinal tract (GIT). The size, charge, and structural organization of the colloidal particles in the system were measured as the curcumin-loaded emulsions (7 mg curcumin per g lipid) were passed through simulated mouth (pH 6.8, 2 min), stomach (pH 2.5, 2 hours), and small intestine (pH 7.0, 2 hours) stages. After the small intestine stage, the level of free fatty acids (FFAs) generated and the bioaccessibility of curcumin were measured. The total amount of FFAs released significantly decreased with increasing phytic acid level, from 105.7 ± 5.9% (control) to 78.4 ± 6.4% (0.5% phytic acid). Conversely, curcumin bioaccessibility significantly increased from 39.4 ± 3.5% (control) to 74.7 ± 2.6% (0.5% phytic acid). The inverse relationship between lipolysis and curcumin bioaccessibility was ascribed to the impact of phytic acid on droplet flocculation and the level of free calcium ions present, which affected the production of mixed micelles capable of solubilizing the nutraceutical. The knowledge obtained here might prove beneficial for the employment of phytic acid as a multifunctional ingredient that inhibits lipid digestion while boosting nutraceutical bioavailability.


Assuntos
Curcumina/metabolismo , Trato Gastrointestinal/metabolismo , Gotículas Lipídicas/química , Gotículas Lipídicas/metabolismo , Ácido Fítico/química , Extratos Vegetais/metabolismo , Disponibilidade Biológica , Curcumina/química , Emulsões/química , Emulsões/metabolismo , Excipientes/química , Excipientes/metabolismo , Humanos , Modelos Biológicos , Tamanho da Partícula , Ácido Fítico/metabolismo , Extratos Vegetais/química
18.
Mol Pharm ; 16(7): 3100-3108, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31088082

RESUMO

Colloidal stability is among the key challenges the pharmaceutical industry faces during the production and manufacturing of protein therapeutics. Self-association and aggregation processes can not only impair therapeutic efficacy but also induce immunogenic responses in patients. Aggregation-prone regions (APRs) consisting of hydrophobic patches are commonly identified as the source for colloidal instability, and rational strategies to mitigate aggregation propensity often require genetic engineering to eliminate hydrophobic amino acid residues. Here, we investigate cucurbit[7]uril (CB[7]), a water-soluble macrocycle able to form host-guest complexes with aromatic amino acid residues, as a potential excipient to mitigate protein aggregation propensity. Two monoclonal antibodies (mAbs), one harboring an APR and one lacking an APR, were first assessed for their colloidal stability (measured as the translational diffusion coefficient) in the presence and absence of CB[7] using dynamic light scattering. Due to the presence of a tryptophan residue within the APR, we were able to monitor changes in intrinsic fluorescence in response to increasing concentrations of CB[7]. Isothermal titration calorimetry and NMR spectroscopy were then used to characterize the putative host-guest interaction. Our results suggest a stabilizing effect of CB[7] on the aggregation-prone mAb, due to the specific interaction of CB[7] with aromatic amino acid residues located within the APR. This provides a starting point for exploring CB[7] as a candidate excipient for the formulation of aggregation-prone mAbs.


Assuntos
Anticorpos Monoclonais/química , Anticorpos Monoclonais/metabolismo , Excipientes/química , Excipientes/metabolismo , Compostos Macrocíclicos/química , Compostos Macrocíclicos/metabolismo , Aminoácidos/metabolismo , Sítios de Ligação de Anticorpos , Calorimetria , Coloides/química , Composição de Medicamentos , Estabilidade de Medicamentos , Difusão Dinâmica da Luz , Interações Hidrofóbicas e Hidrofílicas , Espectroscopia de Ressonância Magnética , Ligação Proteica , Solubilidade , Água/química
19.
J Cosmet Dermatol ; 18(6): 1947-1954, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30932314

RESUMO

BACKGROUND: Laser scanning confocal microscopy (LSCM) is a nondestructive method for observing the samples in three dimensions as well in their natural environment. Therefore, it is well suited for studying human hair. This investigation is focused on evaluating the comparative penetration ability of vegetable vs mineral oils and their formulations with excipient, in human hair. AIMS: Laser scanning confocal microscopy was employed to assess thin cross sections of human hair, treated with oils and their formulations, to comprehend their penetration capability and pattern. METHODS: Hair incubated with individual oils or their formulations were labeled with the fluorescent dye was cross-sectioned into thin fragments and visualized under the LSCM. RESULTS: The mineral oil demonstrated better penetration through the hair than the vegetable oils. Combination of these oils with excipient, in an appropriate ratio, had a substantial influence on oil penetration in terms of the depth of penetration. CONCLUSIONS: Our investigation proved the suitability of fluorescent-based imaging for studying the penetration of oils across human hair. This method can be employed as a potential analytical tool to study the penetration of various hair-care formulations and/or their additives, to estimate their effects on human hair.


Assuntos
Cabelo/diagnóstico por imagem , Cabelo/metabolismo , Microscopia Confocal , Óleos/metabolismo , Excipientes/metabolismo , Humanos , Óleos Vegetais/metabolismo
20.
Biotechnol Bioeng ; 116(6): 1537-1555, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30793282

RESUMO

Nowadays, chemically defined cell culture media (CCM) have replaced serum- and hydrolysate-based media that rely on complex ingredients, such as yeast extracts or peptones. Benefits include a significantly lower lot-to-lot variability, more efficient manufacturing by reduction to essential components, and the ability to exclude components that may negatively influence growth, viability, or productivity. Even though current chemically defined CCMs provide an excellent basis for various mammalian biotechnological processes, vitamin instabilities are known to be a key factor contributing to the variabilities still present in liquid CCM as well as to short storage times. In this review, the chemical degradation pathways and products for the most relevant vitamins for CCM will be discussed, with a focus on the effects of light, oxygen, heat, and other CCM compounds. Different approaches to stabilize vitamins in solution, such as replacement with analogs, encapsulation, or the addition of stabilizing compounds will also be reviewed. While these vitamins and vitamin stabilization approaches are presented here as particular for CCM, the application of these concepts can also be considered relevant for pharmaceutical, medical, and food supplement purposes. More precise knowledge regarding vitamin instabilities will contribute to stabilize future formulations and thus decrease residual lot-to-lot variability.


Assuntos
Meios de Cultura/química , Vitaminas/química , Animais , Biotecnologia/métodos , Técnicas de Cultura de Células/métodos , Meios de Cultura/metabolismo , Estabilidade de Medicamentos , Excipientes/química , Excipientes/metabolismo , Temperatura Alta , Humanos , Luz , Oxigênio/metabolismo , Vitaminas/metabolismo
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