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1.
AAPS PharmSciTech ; 20(7): 271, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31363868

RESUMO

Dry powder inhalers have attracted more interest over the years in every aspect related to them. Interestingly, when focusing on the effects of particle morphology of the active or carrier (excipient), it is generally regarded particle size and shape to influence drug availability of aerosolized particles. However, to date, few studies have examined the effect of texture, i.e., roughness, on this relationship. The main objective of the present work is to gain a closer understanding of the influence of carrier morphology on the aerosolization performance of dry powder inhaler formulations. Image analysis and microscopy were used to visualize the aerosolization process. It is considered that the scale of morphological features on the surface of the carrier particles is responsible for the dispersion of the powder formulation, separation of the drug/carrier, and entrainment from a dry powder inhaler. Thus, for this study, the carrier particles of different surface roughness were mixed with micronized salbutamol sulphate. Aerosolization in vitro testing was used to evaluate the performance. The results indicate a connection between the qualitative surface roughness of coarse carriers and aerosolization performance during powder dispersibility. This investigation demonstrated that indeed, powder dispersion, a dynamic process, is influenced by the scale of the carrier morphology.


Assuntos
Albuterol/química , Albuterol/farmacocinética , Broncodilatadores/química , Broncodilatadores/farmacocinética , Química Farmacêutica/métodos , Inaladores de Pó Seco/métodos , Administração por Inalação , Aerossóis/química , Aerossóis/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Inaladores de Pó Seco/instrumentação , Excipientes/química , Excipientes/farmacocinética , Tamanho da Partícula , Pós , Propriedades de Superfície
2.
AAPS PharmSciTech ; 20(5): 197, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-31123855

RESUMO

The present investigation is to study the effect of two different induction ports (IP), i.e., USP IP and USP-modified IP equipped with andersen cascade impactor on in vitro aerodynamic performance along with the impact of USP-modified glass sampling apparatus on delivered dose uniformity of fluticasone propionate (FP) dry powder inhaler (DPI). FP DPI was fabricated by spray drying technique using engineered mannitol microparticles (EMP) with different force controlling agents, i.e., leucine and magnesium stearate. Additionally, commercially available two DPI inhaler devices namely Handihaler® and Breezhaler® were used to aerosolize the FP blends. Spherical smooth surface of EMP showed good powder flow properties and acceptable percentage content uniformity (> 95%). Amounts of FP deposited in cascade assembly using USP-modified IP with the Breezhaler® device was significantly higher (1.32-fold) as compared with the Handihaler® device. Moreover, USP-modified IP showed better deposition as compared with USP IP. Additionally, both inhaler devices showed a satisfactory delivered dose (> 105%) for FP using modified glass sampling apparatus at a flow rate of 60 L/min for 2 s. It was interesting to note that not only formulation properties but also IP geometry and device resistance have significant impact on DPI deposition pattern. This study is a first detailed account of aerodynamic performance of FP using USP-modified IP and USP-modified glass sampling apparatus. Thus, it can be of potential importance for both the academic and industry perspective.


Assuntos
Broncodilatadores/química , Inaladores de Pó Seco/instrumentação , Fluticasona/química , Vidro/química , Manitol/química , Microesferas , Administração por Inalação , Broncodilatadores/farmacocinética , Engenharia Química/instrumentação , Engenharia Química/métodos , Composição de Medicamentos , Inaladores de Pó Seco/métodos , Desenho de Equipamento/instrumentação , Desenho de Equipamento/métodos , Fluticasona/farmacocinética , Manitol/farmacocinética , Tamanho da Partícula
3.
Eur J Pharm Sci ; 133: 137-144, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30946963

RESUMO

INTRODUCTION: Many factors can affect dry powder inhalers' (DPIs) aerosol emission and lung deposition. The fluctuation of environmental temperature and relative humidity (RH) that inhalers experience in realistic daily use has not been extensively evaluated. This work aimed to evaluate the delivered dose (DD) and aerodynamic particle size distribution (APSD) of tiotropium Handihaler DPI (H) after exposure to patients' real-life use environments. METHODS: Ethical approval was obtained to enrol adult patients already using H. Patients who gave written consent were given new H to use and HygroLog temperature and RH data loggers to keep in the vicinity of the given inhaler. The H and HygroLog were returned after 2 weeks. Patient recruitment was done during the summer (HS) and winter (HW). As control, other HC were stored as per the leaflet storage instructions. The Next Generation Impactor was used to evaluate the inhalers. RESULTS: The HC were stored under an average of 21.0 °C and 46.9% RH. The patients' HS and HW lived in an average (range) temperature (°C) 23.2 (18.3-38.2) and 17.8 (13.5-24.6), respectively, and RH 50.8% (24.3-65.3%) and 50.4% (30.6-72.4%), respectively. All H groups had comparable environments (p > 0.05). The HC, HS and HW gave similar tiotropium DD (µg) 7.60, 8.01 and 7.61, respectively (p > 0.05). Moreover, the fine particle dose µg (median diameter (µm)) were HC 2.41 (3.84), HS 2.55 (3.81) and HW 2.37 (3.83) (p > 0.05). CONCLUSIONS: The aerosol emission behaviour of tiotropium Handihaler was tolerant to real-life retention environments of patients in Amman, Jordan.


Assuntos
Broncodilatadores , Inaladores de Pó Seco , Umidade , Temperatura Ambiente , Brometo de Tiotrópio , Administração por Inalação , Adulto , Aerossóis , Broncodilatadores/administração & dosagem , Broncodilatadores/química , Armazenamento de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho da Partícula , Brometo de Tiotrópio/administração & dosagem , Brometo de Tiotrópio/química
4.
Int J Pharm ; 564: 153-161, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-30981874

RESUMO

It is essential to optimize a carrier of dry powder inhalation (DPI) for the aerodynamic deposition in vitro to achieve pulmonary delivery of drug molecules in vivo. In this study, neutralized nanoporous γ-cyclodextrin metal-organic framework (CD-MOF) crystals with cubic morphology and uniform inhalation size were developed and modified as a DPI carrier for budesonide (BUD). Cholesterol (CHO) and leucine (LEU)-poloxamer were used to modify the CD-MOF powder for the improvement of flowability and particle aerodynamic behaviour, for which the particle size distribution, Carr's index and in vitro pulmonary deposition were assessed. Compared to CD-MOF or LEU-CD-MOF-BUD, CHO-CD-MOF had a superior mass median aerodynamic diameter (4.35 ±â€¯0.04 µm) and inhalable performance (fine particle fraction of 30.60 ±â€¯0.76%), which were maintained after budesonide loading (4.47 ±â€¯0.30 µm, 24.95 ±â€¯4.33%). The crystallinity, cytotoxicity and in vivo deposition of drug loaded samples (CHO-CD-MOF-BUD) were then investigated by powder X-ray diffraction (PXRD), cell viability study, in vivo fluorescence imaging and pharmacokinetic studies in rats. The characteristic PXRD crystallinity peaks of budesonide disappeared after being loaded into CHO-CD-MOF, potentially indicating the molecular incorporation of budesonide into the pores of CD-MOF. The cell viability of A549 cell was more than 90% for CHO-CD-MOF-BUD as a result of the good biocompatibility of CD-MOF. When Rhodamine B was carried by the DPI particles, the fluorescence signal at the lung tissue was markedly improved after cholesterol modification compared with CD-MOF, whilst the bioavailability of CHO-CD-MOF-BUD in rat was equivalent with that of the commercial product of Pulmicort Turbuhaler. Therefore, the CD-MOF powders modified by cholesterol can be used as a promising inhalable carrier for pulmonary delivery of drugs with small dose.


Assuntos
Broncodilatadores/administração & dosagem , Budesonida/administração & dosagem , Colesterol/administração & dosagem , Ciclodextrinas/administração & dosagem , Hidróxidos/administração & dosagem , Leucina/administração & dosagem , Compostos de Potássio/administração & dosagem , Administração por Inalação , Animais , Broncodilatadores/química , Broncodilatadores/farmacocinética , Budesonida/química , Budesonida/farmacocinética , Colesterol/química , Colesterol/farmacocinética , Ciclodextrinas/química , Ciclodextrinas/farmacocinética , Hidróxidos/química , Hidróxidos/farmacocinética , Leucina/química , Leucina/farmacocinética , Masculino , Nanoporos , Compostos de Potássio/química , Compostos de Potássio/farmacocinética , Ratos Sprague-Dawley
5.
Respir Res ; 20(1): 66, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30943978

RESUMO

BACKGROUND: Interferon gamma (IFN-γ) is a clinically relevant immunomodulatory cytokine that has demonstrated significant potential in the treatment and management of respiratory diseases such as tuberculosis and pulmonary fibrosis. As with all large biomolecules, clinical translation is dependent on effective delivery to the disease site and delivery of IFN-γ as an aerosol offers a logical means of drug targeting. Effective localization is often hampered by instability and a lack of safe and efficient delivery systems. The present study sought to determine how effectively IFN-γ can be nebulized using two types of vibrating mesh nebulizer, each with differing mesh architectures, and to investigate the comparative efficiency of delivery of therapeutically active IFN-γ to the lungs. METHODS: Nebulization of IFN-γ was carried out using two different Aerogen vibrating mesh technologies with differing mesh architectures. These technologies represent both a standard commercially available mesh type (Aerogen Solo®) and a new iteration mesh (Photo-defined aperture plate (PDAP®). Extensive aerosol studies (aerosol output and droplet analysis, non-invasive and invasive aerosol therapy) were conducted in line with regulatory requirements and characterization of the stability and bioactivity of the IFN-γ post-nebulization was confirmed using SDS-PAGE and stimulation of Human C-X-C motif chemokine 10 (CXCL 10) also known as IFN-γ-induced protein 10KDa (IP 10) expression from THP-1 derived macrophages (THP-1 cells). RESULTS: Aerosol characterization studies indicated that a significant and reproducible dose of aerosolized IFN-γ can be delivered using both vibrating mesh technologies. Nebulization using both devices resulted in an emitted dose of at least 93% (100% dose minus residual volume) for IFN-γ. Characterization of aerosolized IFN-γ indicated that the PDAP was capable of generating droplets with a significantly lower mass median aerodynamic diameter (MMAD) with values of 2.79 ± 0.29 µm and 4.39 ± 0.25 µm for the PDAP and Solo respectively. The volume median diameters (VMD) of aerosolized IFN-γ corroborated this with VMDs of 2.33 ± 0.02 µm for the PDAP and 4.30 ± 0.02 µm for the Solo. SDS-PAGE gels indicated that IFN-γ remains stable after nebulization by both devices and this was confirmed by bioactivity studies using a THP-1 cell model in which an alveolar macrophage response to IFN-γ was determined. IFN-γ nebulized by the PDAP and Solo devices had no significant effect on the key inflammatory biomarker cytokine IP-10 release from this model in comparison to non-nebulized controls. Here we demonstrate that it is possible to combine IFN-γ with vibrating mesh nebulizer devices and facilitate effective aerosolisation with minimal impact on IFN-γ structure or bioactivity. CONCLUSIONS: It is possible to nebulize IFN-γ effectively with vibrating mesh nebulizer devices without compromising its stability. The PDAP allows for generation of IFN-γ aerosols with improved aerodynamic properties thereby increasing its potential efficiency for lower respiratory tract deposition over current technology, whilst maintaining the integrity and bioactivity of IFN-γ. This delivery modality therefore offers a rational means of facilitating the clinical translation of inhaled IFN-γ.


Assuntos
Broncodilatadores/administração & dosagem , Interferon gama/administração & dosagem , Nebulizadores e Vaporizadores , Telas Cirúrgicas , Tecnologia Farmacêutica/instrumentação , Vibração , Administração por Inalação , Aerossóis/administração & dosagem , Aerossóis/química , Broncodilatadores/química , Humanos , Interferon gama/química , Tecnologia Farmacêutica/métodos , Vibração/uso terapêutico
6.
AAPS PharmSciTech ; 20(3): 137, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30847607

RESUMO

Corticosteroid resistance poses a major challenge to effective treatment of chronic obstructive pulmonary diseases. However, corticosteroid resistance can be overcome by co-administration of theophylline. The aim of this study was to formulate the corticosteroid budesonide with theophylline into inhalable dry powders intended for pulmonary combination therapy. Four types of spray-dried powders were prepared: (i) budesonide and theophylline co-dissolved and processed using a 2-fluid nozzle spray drier, (ii) budesonide nanocrystals and dissolved theophylline co-dispersed and processed using a 2-fluid nozzle spray drier, (iii) dissolved budesonide and dissolved theophylline processed using a 3-fluid nozzle spray drier, and (iv) budesonide nanocrystals and dissolved theophylline processed using a 3-fluid nozzle spray drier. Spray drying from the solutions resulted in co-amorphous (i) and partially amorphous powders (iii), whereas spray drying of the nanosuspensions resulted in crystalline products (ii and iv). Even though budesonide was amorphous in (i) and (iii), it failed to exhibit any dissolution advantage over the unprocessed budesonide. In contrast, the dissolution of budesonide from its nanocrystalline formulations, i.e., (ii) and (iv), was significantly higher compared to a physical mixture or unprocessed budesonide. Furthermore, the spray-dried powders obtained from the 2-fluid nozzle spray drier, i.e., (i) and (ii), exhibited co-deposition of budesonide and theophylline at the same weight ratio in the aerodynamic assessment using the New Generation Impactor. In contrast, the depositions of budesonide and theophylline deviated from the starting weight ratio in the aerodynamic assessment of spray-dried powders obtained from the 3-fluid nozzle spray drier, i.e., (iii) and (iv). Based on these results, the powders spray-dried from the suspension by using the 2-fluid nozzle spray drier, i.e., (ii), offered the best formulation properties given the physically stable crystalline solid-state properties and the co-deposition profile.


Assuntos
Broncodilatadores/administração & dosagem , Broncodilatadores/química , Budesonida/administração & dosagem , Budesonida/química , Pós , Teofilina/administração & dosagem , Teofilina/química , Administração por Inalação , Formas de Dosagem , Combinação de Medicamentos , Quimioterapia Combinada , Inaladores de Pó Seco , Humanos , Pulmão , Tamanho da Partícula , Suspensões
7.
Int J Pharm ; 560: 35-46, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30664994

RESUMO

The evaluation of particle size recommended in the pharmacopeias requires a constant flow rate, and the method for pediatric inhaled drugs is the same as for adult drugs. In this study, the aerosol concentration and particle size distribution (PSD) were measured under a realistic breathing pattern and constant flow. Two types of nebulizer (i.e., breath-enhanced nebulizer and vibrating-mesh nebulizer) and two formulations (i.e., budesonide suspension and albuterol solution) were chosen for comparison. The aerosol concentration under the realistic pattern was not constant, which was different from the result at constant flow. The changing trend of aerosol concentration varied with the operation process of each device. The aerosol concentration profile was similar between budesonide suspension and albuterol solution. As to the PSD, as inspiratory flow increased, the X50 (50% undersize) increased with all nebulizers but Omron microAir NE-U22 nebulizer. There was good agreement between X50 obtained under the realistic inhalation patterns and their equivalent average flow rates by Bland-Altman analysis, although the X50 obtained under the realistic inhalation pattern was greater than value at constant flow. The agreement of the two breath-enhanced jet nebulizers was better than that of the vibrating-mesh nebulizers. The X50 of budesonide was not equal to that of albuterol when using the same nebulizer. Interestingly, a significant difference was observed in the X50 and Span when comparing the results of PSD under adult and child breathing patterns. Furthermore, all vibrating-mesh nebulizers produced aerosol droplets having larger mean diameter and narrower size distribution than those of the air-jet nebulizers. We conclude that it will be more conducive to the evaluation of particle size to use a laser diffractometer under a realistic pattern and make up for the shortcomings of cascade impactors. The effects of flow pattern, nebulizer and formulation should be taken into account in the evaluation of the qualities of nebulizer products in pharmaceutical practice.


Assuntos
Albuterol/administração & dosagem , Broncodilatadores/administração & dosagem , Budesonida/administração & dosagem , Nebulizadores e Vaporizadores , Administração por Inalação , Adulto , Aerossóis , Albuterol/química , Broncodilatadores/química , Budesonida/química , Criança , Desenho de Equipamento , Humanos , Lasers , Tamanho da Partícula , Vibração
8.
Eur J Pharm Sci ; 122: 64-76, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-29928985

RESUMO

Roflumilast is a selective inhibitor of phosphodiesterase-4 isoenzyme in lung cells. Having psychiatric adverse reactions when administered orally affects negatively the patients' adherence to the drug. This work aimed to prepare emulsified spray dried alginate microparticles for the pulmonary delivery of roflumilast. Sodium alginate was used as microparticle-forming material, isopropyl myristate as an oil, Tween®80 as surfactant and calcium beta-glycerophosphate as cross-linking agent to enhance the mechanical properties of the particles. The prepared particles were evaluated for their encapsulation efficiency, particle size and in-vitro drug release. From the studied carriers, beta-cyclodextrin (CD) was the best regarding giving formulation with smaller particle size and more sustained drug release. The inhalation profile of CD-based microparticles was investigated using Anderson cascade impactor. The aerosolization profile of CD-based microparticles suggested their efficiency to deliver the drug deep in the lung. The CD-based microparticles possessed more inhibitory effects on the viability of A549 cells and on the pro-inflammatory cytokines (TNF-α, IL-6 and IL-10) compared to the pure drug. Hence, CD-based microparticles could regulate the tumorigenesis besides tumor-associated inflammation. Finally, CD-based microparticles showed more sustained bronchodilatation properties in healthy human volunteers when compared to Ventolin®HFA. CD-based microparticles proved to be a promising carrier for inhaled roflumilast in human.


Assuntos
Alginatos , Aminopiridinas , Benzamidas , Broncodilatadores , Portadores de Fármacos , Inibidores da Fosfodiesterase 4 , Células A549 , Administração por Inalação , Adulto , Alginatos/administração & dosagem , Alginatos/química , Aminopiridinas/administração & dosagem , Aminopiridinas/química , Benzamidas/administração & dosagem , Benzamidas/química , Broncodilatadores/administração & dosagem , Broncodilatadores/química , Sobrevivência Celular/efeitos dos fármacos , Estudos Cross-Over , Ciclopropanos/administração & dosagem , Ciclopropanos/química , Citocinas/metabolismo , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Desenho de Drogas , Liberação Controlada de Fármacos , Feminino , Ácido Glucurônico/administração & dosagem , Ácido Glucurônico/química , Glicerofosfatos/química , Ácidos Hexurônicos/administração & dosagem , Ácidos Hexurônicos/química , Humanos , Pulmão/efeitos dos fármacos , Pulmão/fisiologia , Masculino , Pessoa de Meia-Idade , Tamanho da Partícula , Inibidores da Fosfodiesterase 4/administração & dosagem , Inibidores da Fosfodiesterase 4/química , Espirometria , beta-Ciclodextrinas/administração & dosagem , beta-Ciclodextrinas/química
9.
AAPS PharmSciTech ; 19(5): 2335-2345, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29858973

RESUMO

The performance of pressurized metered dose inhalers (MDIs) is affected by formulation and device variables that impact delivered dose, aerodynamic particle size distribution, and consequently lung deposition and therapeutic effect. Specific formulation variables of relevance to two commercially available products-Proventil® HFA [albuterol sulfate (AS) suspension] and Qvar® [beclomethasone dipropionate (BDP) solution]-were evaluated to determine their influence on key performance attributes measured experimentally with in vitro cascade impaction studies. These commercial MDIs, utilized as model systems, provided mid-points for a design of experiments (DoE) plan to manufacture multiple suspension and solution MDI formulations. The experimental results were utilized as input variables in a computational dosimetry model to predict the effects of MDI formulation variables on lung deposition. For the BDP solution DoE MDIs, increased concentrations of surfactant oleic acid (0-2% w/w) increased lung deposition from 24 to 46%, whereas changes in concentration of the cosolvent ethanol (7-9% w/w) had no effect on lung deposition. For the AS suspension DoE MDIs, changes in oleic acid concentration (0.005-0.25% w/w) did not have significant effects on lung deposition, whereas lung deposition decreased from 48 to 26% as ethanol concentration increased from 2 to 20% w/w, and changes in micronized drug volumetric median particle size distribution (X50, 1.4-2.5 µm) increased deposition in the tracheobronchial airways from 5 to 11%. A direct correlation was observed between fine particle fraction and predicted lung deposition. These results demonstrate the value of using dosimetry models to further explore relationships between performance variables and lung deposition.


Assuntos
Albuterol/química , Anti-Inflamatórios/química , Beclometasona/química , Broncodilatadores/química , Pulmão , Inaladores Dosimetrados , Administração por Inalação , Aerossóis/química , Aerossóis/metabolismo , Albuterol/metabolismo , Anti-Inflamatórios/metabolismo , Beclometasona/metabolismo , Broncodilatadores/metabolismo , Composição de Medicamentos , Tamanho da Partícula , Suspensões/química , Suspensões/metabolismo
10.
Biochim Biophys Acta Gen Subj ; 1862(8): 1781-1789, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29763642

RESUMO

BACKGROUND: Antioxidant properties have been recently suggested for caffeine that seems showing protective effects against damages caused by oxidative stress. In particular, a HO scavenging activity has been ascribed to caffeine. Even if the oxidation of caffeine has been widely studied, the antioxidant mechanism is still far to be understood. METHODS: The electrochemical behavior of caffeine, theobromine and theophylline was studied in aprotic medium by cyclic voltammetry and electrolysis in UV-vis cell; a computational analysis of the molecular structures based on the Density Functional Theory was performed; the reactivity of all substrates towards lead dioxide, superoxide and galvinoxyl radical was followed by UV-vis spectrophotometry. RESULTS: Results supported the mono-electronic oxidation of the C4C5 bond for all substrates at high oxidation potentials, the electron-transfer process leading to a radical cation or a neutral radical according to the starting methylxanthine N7-substituted (caffeine and theobromine) or N7-unsubstituted (theophylline), respectively. A different following chemical fate might be predicted for the radical cation or the neutral radical. No interaction was evidenced towards the tested reactive oxygen species. CONCLUSIONS: No reactivity via H-atom transfer was evidenced for all studied compounds, suggesting that an antiradical activity should be excluded. Some reactivity only with strong oxidants could be predicted via electron-transfer. The acclaimed HO scavenging activity should be interpreted in these terms. The study suggested that CAF might be hardly considered an antioxidant. GENERAL SIGNIFICANCE: Beyond the experimental methods used, the discussion of the present results might provide food for thought to the wide audience working on antioxidants.


Assuntos
Antioxidantes/química , Cafeína/química , Estresse Oxidativo , Espécies Reativas de Oxigênio/química , Teobromina/química , Teofilina/química , Broncodilatadores/química , Estimulantes do Sistema Nervoso Central/química , Humanos , Oxirredução , Solventes
11.
Bioelectrochemistry ; 123: 182-189, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29783192

RESUMO

The understanding of DNA-drug interaction mechanism is among the important aspects of biological studies for drug design, discovery and pharmaceutical development processes. Published rather detailed FTIR and UV-visible spectroscopic studies on the interactions of theophylline, theobromine and caffeine with calf thymus DNA have shown effective binding of these methylxanthine derivatives to DNA and RNA involving H-bonds. However, to our knowledge, there is no such investigation using electrochemical approach. As a novelty of the study, in this paper the bioelectrochemical approach has been chosen for the investigation of an interaction of low molecular salmon sperm dsDNA, ssDNA and mononucleotides with theophylline (TP) in aqueous phosphate buffered medium using DNA-based electrochemical biosensors and biosensing in solution phase. Exploitation of the electrochemical approach via changes in square wave voltammetric responses of deoxyguanosine (dGuo) and deoxyadenosine (dAdo) provided a new indication on preferential association of TP with dGuo in the case of double helical dsDNA structure which was not reported previously. Moreover, an attachment of TP molecules outside DNA was found in the presence of high concentration of 3.3 × 10-4 M TP in solution which diminishes the electron transfer and leads to the difficulties in quantitative evaluation of the TP and dGuo voltammetric responses. The changes in UV-vis and FTIR spectra obtained in the same medium confirmed the association interaction of TP with both nucleobases. Utilizing the model and the published energies of hydrogen bonding stabilization, the formation of a DNA-TP complex was predicted through the intermolecular H-bonds between TP and the NH-CO moiety of guanine and the N-NH2 moiety of adenine.


Assuntos
Técnicas Biossensoriais/métodos , Broncodilatadores/metabolismo , DNA/metabolismo , Teofilina/metabolismo , Vasodilatadores/metabolismo , Animais , Sítios de Ligação , Broncodilatadores/química , DNA/química , Técnicas Eletroquímicas/métodos , Ligações de Hidrogênio , Salmão , Teofilina/química , Vasodilatadores/química
12.
Int J Pharm ; 545(1-2): 45-50, 2018 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-29689370

RESUMO

Dissolution testing for inhalers were previously conducted either on unfractionated drug-carrier powders or drug of specific aerodynamic particle size. In this study, the collection of the full fine particle fraction (FPF) was attempted on a single stage. Capsules containing 30 mg of 2% salbutamol sulfate (SS) was tested to have a FPF of 9 ±â€¯1% using the full set of Andersen cascade impactor (ACI) and a modified Rotahaler® capable of achieving 4.0 kPa pressure drop at 60 L/min air flow rate. A truncated ACI comprising the USP throat, pre-separator, stage 0, stage 4, stage F, polytetrafluoroethylene funnel (TF) and small collection plate (sCP) was found to be capable of achieving a FPF of 9% collected on TF and sCP. An adhesive tape was used to collect the FPF from the TF and sCP and held in place by an enhancer cell in a 200 mL round bottom vessel containing 50 mL Gamble's solution with 0.2 v/v, % Tween 80. Dissolution testing of SS and Seretide® showed burst release of SS and salmeterol while sustained release of fluticasone. This study demonstrated a reproducible method which may be used for evaluation of the full FPF of orally inhaled products.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/química , Albuterol/química , Broncodilatadores/química , Combinação Fluticasona-Salmeterol/química , Glucocorticoides/química , Tecnologia Farmacêutica/instrumentação , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Aerossóis , Albuterol/administração & dosagem , Broncodilatadores/administração & dosagem , Cápsulas , Composição de Medicamentos , Liberação Controlada de Fármacos , Inaladores de Pó Seco , Desenho de Equipamento , Combinação Fluticasona-Salmeterol/administração & dosagem , Glucocorticoides/administração & dosagem , Tamanho da Partícula , Pós , Solubilidade , Tecnologia Farmacêutica/métodos
13.
Phytomedicine ; 42: 172-179, 2018 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-29655683

RESUMO

BACKGROUND: Lignosus rhinocerotis (Cooke) Ryvarden is a popular medicinal mushroom used for centuries in Southeast Asia to treat asthma and chronic cough. The present study aimed to investigate the effect of this mushroom on airways patency. MATERIALS AND METHODS: The composition of L. rhinocerotis TM02 cultivar was analyzed. Organ bath experiment was employed to study the bronchodilator effect of Lignosus rhinocerotis cold water extract (CWE) on rat isolated airways. Trachea and bronchus were removed from male Sprague-Dawley rats, cut into rings of 2 mm, pre-contracted with carbachol before adding CWE into the bath in increasing concentrations. To investigate the influence of incubation time, tissues were exposed to intervals of 5, 15 and 30 min between CWE concentrations after pre-contraction with carbachol in subsequent protocol. Next, tissues were pre-incubated with CWE before the addition of different contractile agents, carbachol and 5-hydroxytrptamine (5-HT). The bronchodilator effect of CWE was compared with salmeterol and ipratropium. In order to uncover the mechanism of action of CWE, the role of beta-adrenoceptor, potassium and calcium channels was investigated. RESULTS: Composition analysis of TM02 cultivar revealed the presence of ß-glucans and derivatives of adenosine. The extract fully relaxed the trachea at 3.75 mg/ml (p < 0.0001) and bronchus at 2.5 mg/ml (p < 0.0001). It was observed that lower concentrations of CWE were able to fully relax both trachea and bronchus but at a longer incubation interval between concentrations. CWE pre-incubation significantly reduced the maximum responses of carbachol-induced contractions (in both trachea, p = 0.0012 and bronchus, p = 0.001), and 5-HT-induced contractions (in trachea, p = 0.0048 and bronchus, p = 0.0014). Ipratropium has demonstrated a significant relaxation effect in both trachea (p = 0.0004) and bronchus (p = 0.0031), whereas salmeterol has only affected the bronchus (p = 0.0104). The involvement of ß2-adrenoceptor and potassium channel in CWE-mediated airway relaxation is ruled out, but the bronchodilator effect was unequivocally affected by influx of calcium. CONCLUSIONS: The bronchodilator effect of L. rhinocerotis on airways is mediated by calcium signalling pathway downstream of Gαq-coupled protein receptors. The airway relaxation effect is both concentration- and incubation time-dependent. Our findings provide unequivocal evidence to support its traditional use to relieve asthma and cough.


Assuntos
Brônquios/efeitos dos fármacos , Broncodilatadores/farmacologia , Cálcio/metabolismo , Polyporaceae/química , Traqueia/efeitos dos fármacos , Animais , Asma/tratamento farmacológico , Brônquios/fisiologia , Broncodilatadores/química , Carbacol/farmacologia , Masculino , Contração Muscular/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Plantas Medicinais/química , Canais de Potássio/metabolismo , Ratos Sprague-Dawley , Receptores Adrenérgicos beta 2/metabolismo , Serotonina/farmacologia , Traqueia/fisiologia
14.
J Integr Med ; 16(1): 62-70, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29397096

RESUMO

OBJECTIVE: Anacardium occidentale L. leaf is useful in the treatment of inflammation and asthma, but the bioactive constituents responsible for these activities have not been characterized. Therefore, this study was aimed at identifying the bioactive constituent(s) of A. occidentale ethanolic leaf extract (AOEL) and its solvent-soluble portions, and evaluating their effects on histamine-induced paw edema and bronchoconstriction. METHODS: The bronchodilatory effect was determined by measuring the percentage protection provided by plant extracts in the histamine-induced bronchoconstriction model in guinea pigs. The anti-inflammatory effect of the extracts on histamine-induced paw edema in rats was determined by measuring the increase in paw diameter, after which the percent edema inhibition was calculated. The extracts were analyzed using gas chromatography-mass spectrometry to identify the bioactive constituents. Column chromatography and Fourier transform infrared spectroscopy were used respectively to isolate and characterize the constituents. The bronchodilatory and anti-inflammatory activities of the isolated bioactive constituent were evaluated. RESULTS: Histamine induced bronchoconstriction in the guinea pigs and edema in the rat paw. AOEL, hexane-soluble portion of AOEL, ethyl acetate-soluble portion of AOEL, and chloroform-soluble portion of AOEL significantly increased bronchodilatory and anti-inflammatory activities (P < 0.05). Oleamide (9-octadecenamide) was identified as the most abundant compound in the extracts and was isolated. Oleamide significantly increased bronchodilatory and anti-inflammatory activities by 32.97% and 98.41%, respectively (P < 0.05). CONCLUSION: These results indicate that oleamide is one of the bioactive constituents responsible for the bronchodilatory and anti-inflammatory activity of A. occidentale leaf, and can therefore be employed in the management of bronchoconstriction and inflammation.


Assuntos
Anacardium/química , Anti-Inflamatórios/administração & dosagem , Broncodilatadores/administração & dosagem , Edema/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Animais , Anti-Inflamatórios/química , Broncoconstrição/efeitos dos fármacos , Broncodilatadores/química , Edema/fisiopatologia , Feminino , Cobaias , Humanos , Masculino , Ácidos Oleicos/administração & dosagem , Ácidos Oleicos/química , Extratos Vegetais/química , Folhas de Planta/química , Ratos , Ratos Wistar
15.
Int J Pharm ; 538(1-2): 30-39, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29289516

RESUMO

The in-vitro aerosol performance of two combination dry powder inhaler (DPI) products, Foster® NEXThaler® and Seretide® Diskus® were investigated with single particle aerosol mass spectrometry (SPAMS). The in-vitro pharmaceutical performance is markedly different for both inhalers. Foster® NEXThaler® generates a higher fine particle fraction (FPF <5 µm) and a much higher relative extra fine particle fraction (eFPF <2 µm). In terms of the composition of the aerodynamic particle size distribution (APSD), it could be verified with SPAMS that overall Foster® NEXThaler® emits a significantly higher number of fine and extra fine particles with a median aerodynamic diameter (MAD) of 2.1 µm while Seretide® Diskus® had a larger MAD of 3.1 µm. Additionally, the interactions between the two active pharmaceutical ingredients (APIs) in both products are different. While Seretide® Diskus® emits a significant (37%) number of co-associated API particles, only a negligible number of co-associated API particles were found in Foster® NEXThaler® (<1%). A major difference with Foster® NEXThaler® is that it contains magnesium stearate (MgSt) as a second excipient besides lactose in a so-called 'dual excipient' platform. The data generated using SPAMS suggested that nearly all of the beclomethasone dipropionate particles in Foster® NEXThaler® also contain MgSt and must therefore be co-associated with this additional excipient. This may help explain why beclomethasone dipropionate in Foster® NEXThaler® forms less particle co-associations with the second API, formoterol fumarate, shows a lower cohesive strength in respect to beclomethasone itself and why both APIs exhibit superior detachment from the carrier as evidenced by the increased eFPF and smaller MAD.


Assuntos
Broncodilatadores/administração & dosagem , Inaladores de Pó Seco , Excipientes/química , Aerossóis , Beclometasona/administração & dosagem , Broncodilatadores/química , Combinação de Medicamentos , Combinação Fluticasona-Salmeterol/administração & dosagem , Fumarato de Formoterol/administração & dosagem , Lactose/química , Tamanho da Partícula
17.
Pharm Dev Technol ; 23(5): 540-551, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27718780

RESUMO

The aim of this study was to prepare a highly porous multiparticulate dosage form containing cilostazol for gastroretentive drug delivery. The floating pellets were prepared with glyceryl behenate as a matrix former and camphor as a sublimating agent by extrusion/spheronization and sublimation under vacuum. Granules prepared with sublimation at 60 °C displayed a slower dissolution rate and smoother surface morphology than those prepared at lower temperatures. This was unexpected as the reported melting point of glyceryl behenate is higher than 69 °C. The DSC study revealed that melting began at a lower temperature owing to the multicomponent property of glyceryl behenate, which led to a sintering effect. The prepared pellets were spherical with unimodal size distribution. They also had porous structures with increased porosity, which led to immediate buoyancy. As cilostazol is a hydrophobic drug that has an erosion-based release mechanism, drug release profile was highly correlated with the percentage of disintegrated pellets. Various excipients were added to the glyceryl behenate-based formulation to increase the floating duration. When hydroxyethyl cellulose was added to the glyceryl behenate-based pellets, acceptable dissolution rate and buoyancy were acquired. This system could potentially be used for gastroretentive delivery of various hydrophobic drugs, which was generally considered difficult.


Assuntos
Broncodilatadores/administração & dosagem , Excipientes/química , Ácidos Graxos/química , Inibidores da Agregação de Plaquetas/administração & dosagem , Tetrazóis/administração & dosagem , Broncodilatadores/química , Cilostazol , Dessecação , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Inibidores da Agregação de Plaquetas/química , Porosidade , Solubilidade , Comprimidos , Tetrazóis/química
18.
Pharm Dev Technol ; 23(6): 655-662, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28714756

RESUMO

Different previous works have shown that various kinds of spheres can be manufactured by rotor granulation in a 'single-pot process' using a lipid base: hydrogenated castor oil. This single-pot technology is based on wet granulation where all components are placed in the powder form in the rotor bowl; then, they are continuously suspended in a fluidized air, with a tangentially sprayed liquid solution. This process allows the granulation and manufacturing of sphere during the same time. Previous experiments have studied the influence of the formulation and the manufacturing process parameters on spheres in terms of feasibility and dissolution properties. Both the spraying time and the weight of liquid sprayed were found to be the most relevant parameters that govern the final quality of the sphere. Now, in a second part of the work, a first comparison is made with two different fluid bed methods: the tangential rotor spray and the Wurster bottom spray for coating the lipid spheres previously manufactured with the rotor tangential spray. The external aspect of the coated spheres manufactured has been evaluated with an electronic microscopy analysis and a study of dissolution properties of the active ingredient has been done by USP in vitro dissolution tests.


Assuntos
Broncodilatadores/administração & dosagem , Óleo de Rícino/química , Composição de Medicamentos/métodos , Excipientes/química , Teofilina/administração & dosagem , Broncodilatadores/química , Preparações de Ação Retardada/química , Composição de Medicamentos/instrumentação , Desenho de Equipamento , Hidrogenação , Tamanho da Partícula , Propriedades de Superfície , Teofilina/química
19.
Eur J Pharm Sci ; 111: 549-555, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29056403

RESUMO

Terahertz pulsed imaging (TPI) was applied to analyse the inner structure of multiple unit pellet system (MUPS) tablets. MUPS tablets containing different amounts of theophylline pellets coated with Eudragit® NE 30 D and with microcrystalline cellulose (MCC) as cushioning agent were analysed. The tablets were imaged by TPI and the results were compared to X-ray microtomography. The terahertz pulse beam propagates through the tablets and is back-reflected at the interface between the MCC matrix and the coated pellets within the tablet causing a peak in the terahertz waveform. Cross-section images of the tablets were extracted at different depths and parallel to the tablet faces from 3D terahertz data to visualise the surface-near structure of the MUPS tablets. The images of the surface-near structure of the MUPS tablets were compared to X-ray microtomography images at the same depths. The surface-near structure could be clearly resolved by TPI at depths between 24 and 152µm below the tablet surface. An increasing amount of pellets within the MUPS tablets appears to slightly decrease the detectability of the pellets within the tablets by TPI. TPI was shown to be a non-destructive method for the detection of pellets within the tablets and could resolve structures thicker than 30µm. In conclusion, a proof-of-concept was provided for TPI as a method of quality control for MUPS tablets.


Assuntos
Broncodilatadores/química , Implantes de Medicamento/química , Imagem Terahertz , Teofilina/química , Comprimidos , Microtomografia por Raio-X
20.
Spectrochim Acta A Mol Biomol Spectrosc ; 190: 140-149, 2018 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-28922640

RESUMO

Photostability studies of drugs and drug products are an integral part of the product development process in the pharmaceutical industry. These studies are carried out to ensure quality, efficacy and safety of the formulated products during manufacture, storage and use. In this investigation, a novel spectroscopic approach has been adopted by employing the FTIR-ATR and UV/Visible techniques to detect the photochemical reactions of the drug Doxofylline, chemically designated as 7-(1, 3 dioxolane-2-yl methyl) theophylline, in its raw (pure) form. Significant changes were observed in terms of optical density of the absorption bands and a satisfactory analysis has been performed using ANOVA Statistics. It highlights the role of the photochemistry of drugs with respect to its spectral profiles and also explains photo physical processes. In addition; the drug compatibility study was also undertaken by using FTIR-ATR technique which indicated that there were no interactions occurring between the raw sample of the drug and the excipients used in the preparation of the pharmaceutical formulation. With this, UV-visible spectroscopic method was validated for the quantitative estimation of Doxofylline in pharmaceutical dosage forms and was performed with λmax at 274nm. Calibration curves were linear between the concentration range 10-50µg/ml. The various parameters such as linearity, precision, accuracy, recovery and specificity were studied according to ICH guidelines (Ahmed et al., 2016; Jain et al., 2011; ICH, 1996).


Assuntos
Broncodilatadores/química , Processos Fotoquímicos , Análise Espectral/métodos , Teofilina/análogos & derivados , Análise de Variância , Calibragem , Formas de Dosagem , Composição de Medicamentos , Excipientes/química , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman , Teofilina/química , Vibração
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