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1.
Pharm Res ; 35(7): 145, 2018 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-29790010

RESUMO

PURPOSE: Bioadhesion is an important property of biological membranes, that can be utilized in pharmaceutical and biomedical applications. In this study, we have fabricated mucoadhesive drug releasing films with bio-based, non-toxic and biodegradable polymers that do not require chemical modifications. METHODS: Nanofibrillar cellulose and anionic type nanofibrillar cellulose were used as film forming materials with known mucoadhesive components mucin, pectin and chitosan as functional bioadhesion enhancers. Different polymer combinations were investigated to study the adhesiveness, solid state characteristics, film morphology, swelling, mechanical properties, drug release with the model compound metronidazole and in vitro cytotoxicity using TR146 cells to model buccal epithelium. RESULTS: SEM revealed lamellar structures within the films, which had a thickness ranging 40-240 µm depending on the film polymer composition. All bioadhesive components were non-toxic and showed high adhesiveness. Rapid drug release was observed, as 60-80% of the total amount of metronidazole was released in 30 min depending on the film formulation. CONCLUSIONS: The liquid molding used was a straightforward and simple method to produce drug releasing highly mucoadhesive films, which could be utilized in treating local oral diseases, such as periodontitis. All materials used were natural biodegradable polymers from renewable sources, which are generally regarded as safe.


Assuntos
Adesivos/metabolismo , Celulose/metabolismo , Portadores de Fármacos/metabolismo , Mucinas/metabolismo , Nanofibras , Pectinas/metabolismo , Adesivos/administração & dosagem , Adesivos/química , Animais , Células CHO , Bovinos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Celulose/administração & dosagem , Celulose/química , Cricetinae , Cricetulus , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Humanos , Mucinas/administração & dosagem , Mucinas/química , Nanofibras/administração & dosagem , Nanofibras/química , Pectinas/administração & dosagem , Pectinas/química , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Resistência à Tração
2.
Int J Pharm ; 543(1-2): 21-28, 2018 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-29567196

RESUMO

Spray-dried protein formulations commonly require stabilising excipients to prevent protein degradation during processing and storage, and trehalose has been commonly used. The purpose of this work was to evaluate melibiose in spray-dried protein formulations in comparison to trehalose. The protein-activity-preserving efficacy, process behaviour and storage stability were studied. Spray drying of ß-galactosidase was carried out using different process temperature, drying air flow and feed liquid atomisation settings. Both melibiose and trehalose reduced protein activity loss during drying. A decrease in activities was observed when the process temperature exceeded a threshold temperature. During storage (30 days at 18% RH and 20 or 40 °C), the formulations dried below this threshold temperature showed no further activity loss, and the stabilising efficacy of the two disaccharides was equal. With higher process temperatures, the remaining protein activities after storage trended higher with melibiose formulations. All formulations remained amorphous. The powder yields of melibiose formulations were similar to trehalose. There was a difference in residual moisture contents, with melibiose formulations giving drier products. In conclusion, protein formulations with melibiose could be spray dried into amorphous powders that were physically stable, contained lower moisture contents and protected protein activity at least as well as trehalose formulations.


Assuntos
Excipientes/química , Melibiose/química , Trealose/química , beta-Galactosidase/química , Química Farmacêutica , Dessecação/métodos , Estabilidade de Medicamentos , Estabilidade Enzimática , Pós , beta-Galactosidase/metabolismo
3.
Anal Chem ; 90(7): 4832-4839, 2018 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-29513001

RESUMO

Raman spectroscopy is widely used for quantitative pharmaceutical analysis, but a common obstacle to its use is sample fluorescence masking the Raman signal. Time-gating provides an instrument-based method for rejecting fluorescence through temporal resolution of the spectral signal and allows Raman spectra of fluorescent materials to be obtained. An additional practical advantage is that analysis is possible in ambient lighting. This study assesses the efficacy of time-gated Raman spectroscopy for the quantitative measurement of fluorescent pharmaceuticals. Time-gated Raman spectroscopy with a 128 × (2) × 4 CMOS SPAD detector was applied for quantitative analysis of ternary mixtures of solid-state forms of the model drug, piroxicam (PRX). Partial least-squares (PLS) regression allowed quantification, with Raman-active time domain selection (based on visual inspection) improving performance. Model performance was further improved by using kernel-based regularized least-squares (RLS) regression with greedy feature selection in which the data use in both the Raman shift and time dimensions was statistically optimized. Overall, time-gated Raman spectroscopy, especially with optimized data analysis in both the spectral and time dimensions, shows potential for sensitive and relatively routine quantitative analysis of photoluminescent pharmaceuticals during drug development and manufacturing.


Assuntos
Corantes Fluorescentes/análise , Preparações Farmacêuticas/análise , Análise dos Mínimos Quadrados , Análise Espectral Raman , Fatores de Tempo
4.
Int J Pharm ; 541(1-2): 188-197, 2018 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-29481945

RESUMO

Solid dispersions (SDs) hold a proven potential in formulating poorly water-soluble drugs. The present paper investigates the interfacial phenomena associated with the bulk powder flow, water sorption, wetting and dissolution of the SDs prepared by a modified melt and quench-cooling (QC) method. Poorly water-soluble indomethacin (IND) was QC molten with solubilizing graft copolymer (Soluplus®) or polyol sugar alcohol (xylitol, XYL). The interfacial interactions of SDs with air/water were found to be reliant on the type (amorphous/crystalline) and amount of the carrier material used. The final SDs were composed of fused agglomerates (SOL) or large jagged particles (XYL) with good wetting and powder flow properties. The initial dissolution of IND was accelerated by both carrier materials studied. The QC molten SDs with amorphous Soluplus® significantly improved the dissolution rate of IND at pH 6.8 (79.9 ±â€¯0.2% at 30 min) compared to that of pure crystalline drug. The substantial improvement in the dissolution rate of IND was in connection with the amorphous state of the drug being stabilized by Soluplus® in the QC molten SDs. However, it is evident that a strong H-bond formation between the components in some regions of the QC molten SDs can limit the dissolution of IND. The QC molten two-phase SDs with a polyol carrier (XYL) showed rapid and continuous drug release without reaching a plateau.


Assuntos
Portadores de Fármacos/química , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Indometacina/farmacocinética , Química Farmacêutica , Estabilidade de Medicamentos , Excipientes/química , Indometacina/química , Transição de Fase , Polietilenoglicóis/química , Polivinil/química , Pós , Solubilidade , Xilitol/química
5.
J Pharm Biomed Anal ; 149: 343-350, 2018 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-29136591

RESUMO

This study considers the potential of low-frequency (terahertz) Raman spectroscopy in the quantitative analysis of ternary mixtures of solid-state forms. Direct comparison between low-frequency and mid-frequency spectral regions for quantitative analysis of crystal form mixtures, without confounding sampling and instrumental variations, is reported for the first time. Piroxicam was used as a model drug, and the low-frequency spectra of piroxicam forms ß, α2 and monohydrate are presented for the first time. These forms show clear spectral differences in both the low- and mid-frequency regions. Both spectral regions provided quantitative models suitable for predicting the mixture compositions using partial least squares regression (PLSR), but the low-frequency data gave better models, based on lower errors of prediction (2.7, 3.1 and 3.2% root-mean-square errors of prediction [RMSEP] values for the ß, α2 and monohydrate forms, respectively) than the mid-frequency data (6.3, 5.4 and 4.8%, for the ß, α2 and monohydrate forms, respectively). The better performance of low-frequency Raman analysis was attributed to larger spectral differences between the solid-state forms, combined with a higher signal-to-noise ratio.


Assuntos
Química Farmacêutica/métodos , Modelos Químicos , Análise Espectral Raman/métodos , Anti-Inflamatórios não Esteroides/química , Química Farmacêutica/instrumentação , Cristalização , Análise dos Mínimos Quadrados , Piroxicam/química , Técnicas de Síntese em Fase Sólida , Análise Espectral Raman/instrumentação
6.
Int J Pharm ; 510(1): 311-22, 2016 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-27321131

RESUMO

The possibility of producing amorphous isomalt and melibiose by spray drying was studied. The impact of process parameters on yield and solid-state stability was compared to sucrose and trehalose. All powders remained amorphous during 2-3 weeks. Processing was challenging due to powder stickiness. Low-temperature and low-humidity drying processes generally performed best. Most isomalt and sucrose powder was retrieved when using 60°C inlet temperature, 800L/h atomizing rate, 1.4ml/min feed rate, 15% concentration and 100% aspirator rate, giving 42-43°C outlet temperature. Isomalt was the most problematic, because it had the lowest Tg and became sticky very easily, therefore process parameters needed to be precisely balanced. There was more freedom in designing processes for melibiose but best yields were obtained with low-temperature (50°C inlet temperature, 800L/h atomizing rate, 4.9ml/min feed rate, 10% concentration and 100% aspirator, 39°C outlet temperature). Trehalose was different in that higher temperatures resulted in better yields. Yet, trehalose generally contained the highest moisture contents. The possibility to produce amorphous isomalt and melibiose at low-temperature process conditions makes them promising considering spray drying applications for heat-sensitive proteins. Melibiose is a better candidate than isomalt because of easier processability and superior solid-state stability.


Assuntos
Dissacarídeos/química , Excipientes/química , Melibiose/química , Estabilidade Proteica , Álcoois Açúcares/química , Dissacarídeos/farmacologia , Composição de Medicamentos , Excipientes/farmacologia , Melibiose/farmacologia , Tamanho da Partícula , Estabilidade Proteica/efeitos dos fármacos , Álcoois Açúcares/farmacologia
7.
J Pharm Sci ; 104(2): 307-26, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25492409

RESUMO

Cytokines are messenger proteins that regulate the proliferation and differentiation of cells and control immune responses. Interferons, interleukins, and growth factors have applications in cancer, autoimmune, and viral disease treatment. The cytokines are susceptible to chemical and physical instability. This article reviews the structure and stability issues of clinically used cytokines, as well as formulation strategies for improved stability. Some general aspects for identifying most probable stability concerns, selecting excipients, and developing stable cytokine formulations are presented. The vast group of cytokines offers possibilities for new biopharmaceuticals. The formulation approaches of the current cytokine products could facilitate development of new biopharmaceuticals.


Assuntos
Terapia Biológica , Citocinas/metabolismo , Citocinas/uso terapêutico , Estabilidade de Medicamentos , Química Farmacêutica , Citocinas/administração & dosagem , Citocinas/imunologia , Humanos
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