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1.
Cephalalgia ; 44(4): 3331024241230963, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38641932

RESUMO

BACKGROUND: Pediatric migraine prophylaxis is indicated when headaches are frequent and/or disabling. We aimed to conduct a study to compare the efficacy of cinnarizine and amitriptyline in pediatric migraine prophylaxis. METHODS: In a randomized, double-blind trial, patients aged 4-17 years with migraine who were eligible for prophylaxis enrolled. The primary outcome was a reduction response rate of ≥50% with p < 0.005 with respect to headache characteristics. The secondary outcome was migraine disability assessment. We evaluated patients every four weeks for three months: T1: week 4, T2: week 8 and T3: week 12. The safety profile was also assessed. RESULTS: Thirty patients were randomly assigned to each group. However, 43 patients completed the trial. Headache frequency decreased in amitriptyline group more effectively in T1 (p = 0.004). Amitriptyline was more successful in reducing the headache duration in all three periods (p < 0.005). There was no significant difference in severity improvement and reducing disability score between the two groups (p > 0.005). No serious adverse events were observed. CONCLUSIONS: Both medications are effective in ameliorating migraine headaches and related disabilities. However, amitriptyline appears be a preferable option over cinnarizine, given its faster onset of action, efficacy in reducing headache duration and longer-lasting effects.Trial Registration: The study was registered with the Iranian Registry of Clinical Trials (IRCT) under the code IRCT-20191112045413N1.


Assuntos
Cinarizina , Transtornos de Enxaqueca , Humanos , Criança , Cinarizina/uso terapêutico , Amitriptilina/uso terapêutico , Irã (Geográfico) , Resultado do Tratamento , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/prevenção & controle , Transtornos de Enxaqueca/induzido quimicamente , Cefaleia/tratamento farmacológico , Analgésicos/uso terapêutico , Método Duplo-Cego
2.
Eur J Pharm Sci ; 197: 106765, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38608735

RESUMO

Lipid-based formulations (LBFs) are an enabling-formulation approach for lipophilic poorly water-soluble compounds. In LBFs, drugs are commonly pre-dissolved in lipids, and/or surfactants/cosolvents, hereby avoiding the rate-limiting dissolution step. According to the Lipid formulation classification system, proposed by Pouton in 2006, in type II LBFs a surfactant with an HLB-value lower than 12 is added to the lipids. If high drug doses are required, e.g. for preclinical toxicity studies, supersaturated LBFs prepared at elevated temperatures may be a possibility to increase drug exposure. In the present study, the impact of digestion on drug absorption in rats was studied by pre-dosing of the lipase inhibitor orlistat. The lipid chain length of the type II LBFs was varied by administration of a medium-chain- (MC) and a long-chain (LC)-based formulation. Different drug doses, both non-supersaturated and supersaturated, were applied. Due to an inherent precipitation tendency of cinnarizine in supersaturated LBFs, the effect of the addition of the precipitation inhibitor Soluplus® was also investigated. The pharmacokinetic results were also evaluated by multiple linear regression. In most cases LC-based LBFs did not perform better in vivo, in terms of a higher area under the curve (AUC0-24 h) and maximal plasma concentration (Cmax), than MC-based LBFs. The administration of supersaturated LBFs resulted in increased AUC0-24 h (1.5 - 3.2-fold) and Cmax (1.1 - 2.6-fold)-values when compared to the non-supersaturated equivalents. Lipase inhibition led to a decreased drug exposure in most cases, especially for LC formulations (AUC0-24 h reduced to 47 - 67%, Cmax to 46 - 62%). The addition of Soluplus® showed a benefit to drug absorption from supersaturated type II LBFs (1.2 - 1.7-fold AUC0-24 h), due to an increased solubility of cinnarizine in the formulation. Upon dose-normalization of the pharmacokinetic parameters, no beneficial effect of Soluplus® could be demonstrated.


Assuntos
Cinarizina , Lipídeos , Cinarizina/química , Cinarizina/farmacocinética , Cinarizina/administração & dosagem , Animais , Masculino , Lipídeos/química , Solubilidade , Lactonas/química , Lactonas/farmacocinética , Lactonas/administração & dosagem , Ratos Wistar , Orlistate/administração & dosagem , Orlistate/farmacocinética , Absorção Intestinal , Ratos , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Lipase/antagonistas & inibidores , Polivinil/química , Precipitação Química , Tensoativos/química , Química Farmacêutica/métodos
3.
Int J Pharm ; 654: 123953, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38417725

RESUMO

A self-emulsifying drug delivery system (SEDDS) containing long chain lipid digestion products (LDP) and surfactants was developed to increase solubility of two model weakly basic drugs, cinnarizine and ritonavir, in the formulation. A 1:1.2 w/w mixture of glyceryl monooleate (Capmul GMO-50; Abitec) and oleic acid was used as the digestion product, and a 1:1 w/w mixture of Tween 80 and Cremophor EL was the surfactant used. The ratio between LDP and surfactant was 1:1 w/w. Since the commercially available Capmul GMO-50 is not pure monoglyceride and contained di-and-triglycerides, the digestion product used would provide 1:2 stoichiometric molar ratio of monoglyceride and fatty acid after complete digestion in gastrointestinal fluid. Both cinnarizine and ritonavir had much higher solubility in oleic acid (536 and 72 mg/g, respectively) than that in glyceryl monooleate and glyceryl trioleate. Therefore, by incorporating oleic acid in place of glyceryl trioleate in the formulation, the solubility of cinnarizine and ritonavir could be increased by 5-fold and 3.5-fold, respectively, as compared to a formulation without the fatty acid. The formulation dispersed readily in aqueous media, and adding 3 mM sodium taurocholate, which is generally present in GI fluid, remarkably improved the dispersibility of SEDDS and reduced particle size of dispersions. Thus, the use of digestion products of long-chain triglycerides as components of SEDDS can enhance the drug loading of weakly basic compounds and increase dispersibility in GI fluids.


Assuntos
Caprilatos , Cinarizina , Glicerídeos , Monoglicerídeos , Solubilidade , Ácido Oleico , Ritonavir , Emulsões , Química Farmacêutica , Sistemas de Liberação de Medicamentos , Tensoativos , Triglicerídeos , Ácidos Graxos , Digestão , Disponibilidade Biológica
4.
Eur J Pharm Sci ; 192: 106634, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-37951315

RESUMO

Enabling formulations, such as lipid-based formulations (LBFs), are means to deliver challenging-to-formulate, poorly soluble drugs. LBFs may be composed of lipids, surfactants and/or cosolvents and can be classified depending on the proportions of the components and the hydrophilicity of the surfactant according to the Lipid Formulations Classification System, ranging from type I (very lipophilic) to type IV (hydrophilic). In cases where drug solubility in LBFs does not suffice, e.g. for preclinical toxicity studies, supersaturated LBFs can be used in order to increase the drug load. However, the effect of digestion on drug absorption from supersaturated type I formulations (consisting exclusively of lipids) still remains relatively unexplored and unclear. In the present study, the impact of lipid digestion on absorption of cinnarizine-loaded supersaturated lipid-based formulations of type I was investigated in rats by pre-dosing of the lipase inhibitor orlistat. The lipid chain length and the drug dose were varied by testing medium-chain triglycerides (MCT) and long-chain triglycerides (LCT), both supersaturated and non-supersaturated. Due to the physical instability of supersaturated formulations of cinnarizine, i.e. a potential of precipitation of cinnarizine, the impact of the addition of the amphiphilic polymer Soluplus®, as a potential precipitation inhibitor, was also investigated. The supersaturated systems resulted in a 2.3 - 3.3-fold higher Area Under the Curve (AUC0-24 h, not dose-normalized) and 1.4 - 2.2-fold higher maximum plasma concentration (Cmax, not dose-normalized) than non-supersaturated formulations (statistically significant with p = 0.05), whereas the addition of Soluplus® did not reveal any benefit. Results indicated that lipase inhibition affected the in vivo performance of LBFs: Co-administration of the lipase inhibitor significantly reduced Cmax and AUC0-24 h (both to 33-39 %, not dose-normalized) for the LCT formulations and, though not significant, a similar trend was observed for the AUC0-24 h of the MCT formulations (to 53-87 %), suggesting a higher dependency on lipolysis for LCT. Also, tmax tended to decrease to 20-60 % when compared to the animals not dosed with orlistat but lacking statistical significance. Without lipase inhibition, the LCT in general lead to better absorption of cinnarizine as compared to MCT, with 1.2-1.7-fold higher AUC0-24 h and 1.4-1.8-fold higher Cmax, but without showing statistical significance. Overall, the study revealed that lipolysis plays a major role in drug absorption from supersaturated lipid-based formulations type I.


Assuntos
Cinarizina , Ratos , Animais , Orlistate , Preparações Farmacêuticas , Triglicerídeos , Solubilidade , Tensoativos , Lipase , Digestão , Administração Oral
5.
Int J Pharm ; 651: 123733, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38142873

RESUMO

Long-acting injectables have shown to offer a prolonged release of a drug compound up to several months, providing the opportunity to increase patient compliance for treatment of long-term and chronic conditions. Different formulation technologies have already been utilized for long-acting injectables, and especially aqueous suspensions with crystalline drug particles in the sub-micron range have sparked an interest for future development of long-acting injectables. Wet bead milling is a common top-down process used to prepare nano- and microsuspensions of crystalline drug particles with the addition of surfactants in the dispersion medium, which are working as stabilizers to prevent agglomeration or crystal growth that ultimately may influence the physical stability of nano- and microsuspensions. To examine the reproducibility of the suspensions manufactured and the behavior of their physical stability, i.e., changes in particle sizes over time, low-energy roller mill was utilized for the manufacturing of nano- and microsuspensions in the present study. Investigated formulation parameters was stabilizer type and concentration and milling parameters varied in bead size and duration of milling. The obtained results demonstrated that the physical stability of suspensions containing the two model compounds, cinnarizine and indomethacin, was highly affected by the constitution of surfactant and processing. Various size classes were obtained and accompanied by high variations between the individual samples that indicated uneven and unpredictable milling by the low-energy roller mill, limiting the possibility to prepare reproducible and physical stable suspensions. Short-term stability studies revealed clear tendencies towards reversed Ostwald ripening of suspensions stabilized with poloxamer 188 that contained cinnarizine as the drug compound, and to a smaller extent suspensions containing indomethacin. Furthermore, X-ray Powder Diffraction confirmed no alteration of the drug compounds crystal structure after roller milling for multiple days.


Assuntos
Cinarizina , Nanopartículas , Humanos , Reprodutibilidade dos Testes , Composição de Medicamentos/métodos , Excipientes/química , Tensoativos , Indometacina , Suspensões , Tamanho da Partícula , Nanopartículas/química , Solubilidade
6.
Ann N Y Acad Sci ; 1529(1): 101-108, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37715781

RESUMO

This study assessed the projected near-surface wind speed (SWS) changes and variability over the Iberian Peninsula for the 21st century. Here, we compared Coupled Model Intercomparison Project Phase 6 global climate models (GCMs) with a higher spatial resolution regional climate model (RCM; ∼20 km), known as WRF-CESM2, which was created by a dynamic downscaling of the Community Earth System Model version 2 (CESM2) using the Weather Research and Forecasting (WRF) model. Our analysis found that the GCMs tended to overestimate observed SWS for 1985-2014, while the higher spatial resolution of the WRF-CESM2 did not improve the accuracy and underestimated the SWS magnitude. GCMs project a decline of SWS under high shared socioeconomic pathways (SSPs) greenhouse concentrations, such as SSP370 and SSP585, while an interdecadal oscillation appears in SSP126 and SSP245 for the end of the century. The WRF-CESM2 under SSP585 predicts the opposite increasing SWS. Our results suggest that 21st-century projections of SWS are uncertain even for regionalized products and should be taken with caution.


Assuntos
Cinarizina , Modelos Climáticos , Humanos , Vento , Incerteza , Tempo (Meteorologia) , Mudança Climática
7.
Mol Pharm ; 20(10): 5160-5172, 2023 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-37646101

RESUMO

Organic solvent-free process or green chemistry is needed for manufacturing pharmaceutical salts to avoid various environmental, safety, and manufacturing cost issues involved. In this study, a cinnarizine (CNZ) salt with malic acid at a 1:1 molar ratio was successfully prepared by twin screw extrusion (TSE) with water assistance. The feasibility of salt formation was first evaluated by screening several carboxylic acids by neat grinding (NG) and liquid-assisted grinding (LAG) using a mortar and pestle, which indicated that malic acid and succinic acid could form salts with CNZ. Further studies on salt formation were conducted using malic acid. The examination by hot-stage microscopy revealed that the addition of water could facilitate the formation and crystallization of CNZ-malic acid salt even though CNZ is poorly water-soluble. The feasibility of salt formation was confirmed by determining the pH-solubility relationship between CNZ and malic acid, where a pHmax of 2.7 and a salt solubility of 2.47 mg/mL were observed. Authentic salt crystals were prepared by solution crystallization from organic solvents for examining crystal properties and structure by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared (FTIR) spectroscopy, solid-state 13C and 15N nuclear magnetic resonance (NMR), and single-crystal X-ray diffraction (SXD). These techniques also established that a salt, and not a cocrystal, was indeed formed. The CNZ salt crystals were then prepared by TSE of a 1:1 CNZ-malic acid mixture, where the addition of small amounts of water resulted in a complete conversion of the mixture into the salt form. The salts prepared by solvent crystallization and water-assisted TSE had identical properties, and their moisture sorption profiles were also similar, indicating that TSE is a viable method for salt preparation by green chemistry. Since TSE can be conducted in a continuous manner, the results of the present investigation, if combined with other continuous processes, suggest the possibility of continuous manufacturing of drug products from the synthesis of active pharmaceutical ingredients (APIs) to the production of final dosage forms.


Assuntos
Cinarizina , Malatos , Tecnologia Farmacêutica , Água , Varredura Diferencial de Calorimetria , Cinarizina/síntese química , Cinarizina/química , Composição de Medicamentos/métodos , Preparações Farmacêuticas , Sais/síntese química , Cloreto de Sódio , Solubilidade , Solventes/química , Espectroscopia de Infravermelho com Transformada de Fourier , Água/química , Difração de Raios X , Malatos/química , Indústria Farmacêutica , Tecnologia Farmacêutica/métodos
8.
Sci Rep ; 13(1): 13549, 2023 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-37599333

RESUMO

Orphenadrine (ORP), dimenhydrinate (DMN), and cinnarizine (CNN) were investigated using green-sensitive spectrofluorometric methods. Method, I used for determination of DMN in 0.1 M hydrochloric acid (HCl) and 1.0% sodium dodecyl sulphate (SDS) at 286 nm after λex 222 nm, while for determination of ORP in 1.0% w/v SDS involves measuring the fluorescence at 285 nm after λex 220 nm. For DMN and ORP, the detection and quantitation limits were 2.99 and 4.71 and 9.08 and 14.29 ng/mL, respectively. The ranges of DMN and ORP were 0.10-1.0 and 0.04-0.5 µg/mL, respectively, in micellar aqueous solution. Method II, the derivative intensities of DMN and CNN were measured at a fixed of different wavelength between the excitation and the emission wavelengths (Δλ) = 60 nm at 282 and 322 nm, at the zero crossing of each other, respectively. The detection and quantitation limits for DMN and CNN were 1.77 and 0.88 ng/mL and 5.36 and 2.65 ng/mL, correspondingly, through the entire range of 0.1-1.0 µg/mL for DMN and CNN. The linearity was perfectly determined through the higher values of the correlation coefficient ranging from 0.9997 to 0.9999 for both direct and synchronous methods. The precision of the proposed methods was also confirmed via the lower values of the standard deviation which ranged from 0.39 to 1.11. The technique was expanded to analyze this mixture in combined tablets and laboratory-prepared mixtures. The method validation was done depending on the international conference on harmonization (ICH) recommendations. An analysis of the statistical data revealed a high agreement between the proposed data and the comparison methodology. Three different assessment methods demonstrated the greenness of the technique.


Assuntos
Cinarizina , Dimenidrinato , Orfenadrina , Espectrometria de Fluorescência , Ácido Clorídrico , Laboratórios , Espectrometria de Fluorescência/métodos
9.
Spectrochim Acta A Mol Biomol Spectrosc ; 302: 123161, 2023 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-37478754

RESUMO

A novel diffuse reflectance fourier transform infrared spectroscopic method accompanied by chemometrics was optimized to fulfill the white analytical chemistry and green analytical chemistry principles for the quantification of cinnarizine and piracetam for the first time without any prior separation in their challenging pharmaceutical preparation, which has a pretty substantial difference in the concentration of cinnarizine/piracetam (1:16). Furthermore, the suggested method was used for cinnarizine/piracetam dissolution testing as an effective alternative to traditional methods. For the cinnarizine/piracetam dissolution tests, we used a dissolution vessel with 900 mL of phosphate buffer pH 2.5 at 37 °C ± 0.5 °C, then the sampling was carried out by frequent withdrawal of 20 µl samples from the dissolution vessel at a one-minute interval, over one hour, then representative fourier transform infrared spectra were recorded. To create a partial-least-squares regression model, a fractional factorial design with 5 different levels and 2 factors was used. This led to the creation of 25 mixtures, 15 as a calibration set and 10 as a validation set, with varying concentration ranges: 1-75 and 16-1000 µg/mL for cinnarizine/piracetam, respectively. Upon optimization of the partial-least-squares regression model, in terms of latent variables and spectral region, root mean square error of cross-validation of 0.477 and 0.270, for cinnarizine/piracetam respectively, were obtained. The optimized partial-least-squares regression model was further validated, providing good results in terms of recovery% (around 98 to 102 %), root mean square error of prediction (0.436 and 3.329), relative root mean square error of prediction (1.210 and 1.245), bias-corrected mean square error of prediction (0.059 and 0.081), and limit of detection (0.125 and 2.786) for cinnarizine/piracetam respectively. Ultimately, the developed method was assessed for whiteness, greenness, and sustainability using five assessment tools. the developed method achieved a greener national environmental method index and complementary green analytical procedure index quadrants with higher eco-scale assessment scores (91), analytical greenness metric scores (0.87), and red-greenblue 12 algorithm scores (89.7) than the reported methods, showing high practical and environmental acceptance for quality control of cinnarizine/piracetam.


Assuntos
Cinarizina , Piracetam , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Cinarizina/análise , Quimiometria , Controle de Qualidade , Análise dos Mínimos Quadrados
10.
J Clin Pharmacol ; 63(10): 1119-1125, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37491788

RESUMO

Flight simulators have an essential role in aircrew training. Occasionally, symptoms of motion sickness, defined as simulator sickness, develop during these sessions. Preventive methods for motion sickness have been investigated thoroughly; however, only a few studies have examined preventive treatments for simulator sickness. The aim of this study was to examine the efficacy of scopolamine (an anticholinergic drug) compared with cinnarizine (an antihistaminic drug) for helicopter simulator sickness prevention. A validated simulator sickness questionnaire (SSQ) score was used to determine the severity of simulator sickness symptoms in this study. Preliminary SSQ scores and SSQ scores after each sortie were calculated. Each participant was given scopolamine, cinnarizine, or a placebo in a double-blind randomized manner before the first sortie of each training day. Forty-one helicopter pilots participated in the trial. The average age was 30.5 ± 7.1 years. SSQ values significantly improved from an average of 73.30 in the preliminary SSQ questionnaire to an average of 30.92 after 2 hours following the administration of cinnarizine (P = .012, 95%CI 8.071-76.703). Scopolamine was found to be less effective than both cinnarizine and the placebo in the alleviation of simulator sickness symptoms. This study is the first to compare scopolamine with cinnarizine for simulator sickness prevention. Based on the results of this study, we recommend the use of cinnarizine over scopolamine for simulator sickness prevention.


Assuntos
Cinarizina , Enjoo devido ao Movimento , Adulto , Humanos , Adulto Jovem , Antagonistas Colinérgicos/uso terapêutico , Cinarizina/uso terapêutico , Enjoo devido ao Movimento/prevenção & controle , Enjoo devido ao Movimento/diagnóstico , Enjoo devido ao Movimento/tratamento farmacológico , Escopolamina/uso terapêutico , Inquéritos e Questionários
11.
Yakugaku Zasshi ; 143(7): 581-598, 2023.
Artigo em Japonês | MEDLINE | ID: mdl-37394454

RESUMO

In my first experience as a researcher, I isolated and performed structural predictions of the novel compounds, cis- and trans-palythenic acids, from Noctiluca milialis. I then worked for a pharmaceutical company in a research laboratory of pharmaceutics. I examined an inclusion complex of cinnarizine with ß-cyclodextrin, and found that the inclusion complex did not improve the oral bioavailability of cinnarizine. However, the bioavailability of the inclusion complex after its oral administration was improved by a competing agent. This was the first study to show the potential of a competing agent to improve bioavailability. I subsequently joined a laboratory performing drug discovery research and used experimental techniques from pre-formulation studies. A screening system of solubility for drug design and discovery was constructed to increase the solubilities of compounds synthesized in the laboratory. This screening system contributed to the discovery of a phosphodiesterase type 5 inhibitor with sufficient solubility. As a visiting lecturer at a university, I prepared amoxicillin intragastric buoyant sustained-release tablets for the eradication of Helicobacter pylori and applied cinnarizine as a competing agent. I established a laboratory of pharmaceutics at a university in Tochigi. To develop an enema with fluticasone propionate for ulcerative colitis, I investigated its physicochemical properties and methods to improve its solubility. After moving to another university in Kagawa, I developed a method to reduce the amount of drugs remaining on the surfaces of a pestle and mortar following the grinding of tablets, and new cleaning agents for an automatic dividing packaging machine were discovered.


Assuntos
Química Farmacêutica , Cinarizina , Humanos , Química Farmacêutica/métodos , Cinarizina/química , Comprimidos , Biofarmácia , Solubilidade , Descoberta de Drogas , Disponibilidade Biológica , Administração Oral
12.
J AOAC Int ; 106(5): 1154-1164, 2023 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-37279742

RESUMO

BACKGROUND: The replacement of traditional oils with a camphor and menthol-based eutectic mixture is done to prepare oil-less emulsion-like dispersions for co-delivery of cinnarizine (CNZ) and morin hydrate (MH) for managing Meniére's disease (MD). Since two drugs are loaded into the dispersions, the development of a suitable reverse phase-high performance liquid chromatography (RP-HPLC) method for their simultaneous analysis becomes inevitable. OBJECTIVE: By applying the analytical quality by design (AQbD) approach, the RP-HPLC method conditions were optimized for the concomitant determination of two drugs. METHODS: The systematic AQbD started with identifying critical method attributes (CMA) through an Ishikawa fishbone diagram, risk estimation matrix, and risk priority number-based failure mode effect analysis followed by screening using fractional factorial design and optimization by face-centered central composite design. The concomitant determination of two drugs by the optimized RP-HPLC method condition was substantiated via specificity checking using combined drug solution, drug entrapment efficiency, and in vitro release of the two drugs from emulsion-like dispersions. RESULTS: The AQbD optimized RP-HPLC method conditions revealed the retention time for CNZ and MH at 5.017 and 5.323, respectively. The studied validation parameters were found within the ICH-prescribed limits. Exposing the individual drug solutions to acidic and basic hydrolytic conditions yielded extra chromatographic peaks for MH, probably due to the degradation of MH. The DEE % values of 87.40 ± 4.70 and 74.79 ± 2.94, respectively, were noticed for CNZ and MH in emulsion-like dispersions. More than 98% CNZ and MH release was occurred from emulsion-like dispersions within 30 min post-dissolution in artificial perilymph. CONCLUSIONS: Overall, the AQbD approach could be helpful for systematic optimization of RP-HPLC method conditions to estimate concomitantly other therapeutic moieties. HIGHLIGHTS: The proposed article shows the successful application of AQbD for the optimization of RP-HPLC method conditions to concomitantly estimate CNZ and MH in combined drug solution and dual-drug-loaded emulsion-like dispersions.


Assuntos
Cinarizina , Cinarizina/química , Cromatografia Líquida de Alta Pressão/métodos , Emulsões , Composição de Medicamentos
13.
AAPS PharmSciTech ; 24(5): 121, 2023 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-37173520

RESUMO

Poorly water-soluble weak base molecules such as cinnarizine often exhibit pH-dependent solubility within the gastrointestinal tract. This means that their solubility can be influenced by the pH of the surrounding environment, and this can affect their oral absorption. The differential pH solubility between the fasted-state stomach and intestine is an important consideration when studying the oral absorption of cinnarizine. Cinnarizine has moderate permeability and is known to exhibit supersaturation and precipitation in fasted-state simulated intestinal fluid (FaSSIF), which can significantly impact its oral absorption. The present work is aimed at studying the precipitation behavior of cinnarizine in FaSSIF using biorelevant in vitro tools and GastroPlus® modeling, to identify the factors contributing to the observed variability in clinical plasma profiles. The study found that cinnarizine demonstrated variable precipitation rates under different bile salt concentrations, which could impact the concentration of the drug available for absorption. The results also showed that a precipitation-integrated modeling approach accurately predicted the mean plasma profiles from the clinical studies. The study concluded that intestinal precipitation may be one of the factors contributing to the observed variability in Cmax but not the AUC of cinnarizine. The study further suggests that the integration of experimental precipitation results representing a wider range of FaSSIF conditions would increase the probability of predicting some of the observed variability in clinical results. This is important for biopharmaceutics scientists, as it can help them evaluate the risk of in vivo precipitation impacting drug and/or drug product performance.


Assuntos
Cinarizina , Cinarizina/metabolismo , Administração Oral , Absorção Intestinal , Intestinos , Trato Gastrointestinal , Solubilidade , Modelos Biológicos
14.
Drug Dev Ind Pharm ; 49(4): 295-304, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37096982

RESUMO

OBJECTIVES: In the present study, Cinnarizine was selected as a weakly basic drug with poor aqueous solubility to investigate the supersaturation maintaining the ability of different types of anionic Eudragit polymers (Eudragits L100-55, L100 and S100). Furthermore, the interplay between polymer-mediated supersaturation maintenance and in vitro permeation enhancement was studied. METHODS: The effect of Eudragit polymers on the pH-induced supersaturation of Cinnarizine was examined under different pHs (6.4, 6.8, and 7.8). Moreover, the effect of Eudragit polymers on the permeation of Cinnarizine through the Caco-2 membrane was investigated. RESULTS: The aggregate size of Eudragit polymers in solution was determined and it was found that the size of polymer aggregate was bigger when lower pH or more hydrophobic polymer was used, which corresponded strongly with improved drug supersaturation. Based on the findings, hydrophobic Cinnarizine-polymer interactions seemed to be essential in determining the impact of Eudragit polymers on maintaining the Cinnarizine supersaturation. The permeation study demonstrated that the rate of drug permeation through the Caco-2 membrane increased in the presence of Eudragit polymers, but their effect on maintaining supersaturation was more significant than their effect on the drug permeation rate. Moreover, the highest level of Cinnarizine supersaturation observed in a non-permeation condition did not correlate with the optimal absorption in a permeation condition. CONCLUSION: This study revealed that the integration of permeation and supersaturation assays is needed to reliably predict the impact of supersaturation maintenance by polymers on the absorption of poorly soluble drugs.


Assuntos
Cinarizina , Polímeros , Humanos , Polímeros/química , Células CACO-2 , Cinarizina/química , Ácidos Polimetacrílicos , Solubilidade
15.
Eur J Pharm Sci ; 184: 106417, 2023 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-36870578

RESUMO

As numerous new drug candidates are poorly water soluble, enabling formulations are needed to increase their bioavailability for oral administration. Nanoparticles are a conceptually simple, yet resource consuming strategy for increasing drug dissolution rate, as predicting in vivo oral absorption using in vitro dissolution remains difficult. The objective of this study was to obtain insight into nanoparticle characteristics and performance utilizing an in vitro combined dissolution/permeation setup. Two examples of poorly soluble drugs were examined (cinnarizine and fenofibrate). Nanosuspensions were produced by top-down wet bead milling using dual asymmetric centrifugation, obtaining particle diameters of approx. 300 nm. DSC and XRPD studies indicated that nanocrystals of both drugs were present with retained crystallinity, however with some disturbances. Equilibrium solubility studies showed no significant increase in drug solubility over the nanoparticles, as compared to the raw APIs. Combined dissolution/permeation experiments revealed significantly increased dissolution rates for both compounds compared to the raw APIs. However, there were substantial differences between the dissolution curves of the nanoparticles as fenofibrate exhibited supersaturation followed by precipitation, whereas cinnarizine did not exhibit any supersaturation, but instead a shift towards faster dissolution rate. Permeation rates were found significantly increased for both nanosuspensions when compared to the raw APIs, indicating a direct implication that formulation strategies are needed, be it stabilization of supersaturation by precipitation inhibition and/or dissolution rate enhancement. This study indicates that in vitro dissolution/permeation studies can be employed to better understand the oral absorption enhancement of nanocrystal formulations.


Assuntos
Cinarizina , Fenofibrato , Nanopartículas , Administração Oral , Disponibilidade Biológica , Cinarizina/administração & dosagem , Cinarizina/química , Fenofibrato/administração & dosagem , Fenofibrato/química , Nanopartículas/administração & dosagem , Nanopartículas/química , Tamanho da Partícula , Preparações Farmacêuticas , Solubilidade
16.
Ann Pharm Fr ; 81(1): 74-82, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35792147

RESUMO

A highly sensitive LC-MS/MS method for the trace level determination of genotoxic impurities, Cinnamyl chloride and Benzhydryl chloride, in Cinnarizine drug substance was developed and validated. Chromatographic separation was successfully achieved on Atlantis d C18 column with dimensions 150× 4.6mm and particle size: 5µm. 0.1% Trifluoroacetic acid in water and 100% acetonitrile was used as mobile phases with gradient mode of elution at 1.0mL/min flow rate. Mass spectroscopic detection was carried out with selective ion monitoring (SIM) technique in positive mode at m/z 117 and 167 for Cinnamyl chloride and Benzhydryl chloride respectively. Developed method was proven to be selective, sensitive, and precise for the quantification of potential genotoxic impurities in Cinnarizine by validating as per the regulatory guidelines. The LOD and LOQ values observed for Cinnamyl chloride were 0.49 and 1.47ppm and for Benzhydryl chloride 0.55 and 1.67ppm respectively. Precision of the method at LOQ level was shown with good % RSD of 4.21. Method was proven linear from LOQ to 150% level with a correlation of 0.996 and accurate with a range of recovery from 86.4 to 100.8%. This highly sensitive method can be used to control both the genotoxic impurities in Cinnarizine drug substance by LC-MS/MS.


Assuntos
Cinarizina , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Cloretos
17.
J Neurol Sci ; 444: 120526, 2023 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-36584558

RESUMO

Secondary parkinsonism induced by exposure to dopamine (DA) receptor antagonists as first and second generation antipsychotics, DA storage depleters, calcium channel blockers, benzamides substituted and other classes of drugs is traditionally believed to be completely reversible in most of patients following withdrawal of the offending drug even though after a variable time delay. The lack of recovery or initial full recovery with subsequent development of progressive parkinsonism has been regarded to result from an underlying subclinical degenerative process like PD unmasked by the inducing drug. These well-recognized clinical outcomes of drug-induced parkinsonism (DIP) have disregarded the existence of another outcome, characterized by permanent non-progressive parkinsonism. This syndrome may fullfil the criteria of tardive parkinsonism, a controversial entity currently referred to as a persistent condition without indication of its long-term course and clinical features. On reviewing the published literature on DIP, we have identified two prospective long-term follow-up of elderly patients in which parkinsonism induced by the calcium channel antagonists cinnarizine and flunarizine became permanent and non-progressive following drug discontinuation in a non-negligible proportion of patients, consistent with the clinical concept of a true tardive syndrome, according to currently accepted criteria. The authors hypothesize that the development of tardive parkinsonism might be due to a neurotoxic effect of the pharmacodynamic proprieties of the calcium channel blockers and their metabolites, exerted on post-synaptic striatal neurons and/or a neurotoxic damage on presynaptic DA neurons in patients without an underlying subclinical degenerative parkinsonism, so accounting for the stable and non-progressive course over time.


Assuntos
Antipsicóticos , Cinarizina , Doença de Parkinson Secundária , Transtornos Parkinsonianos , Humanos , Idoso , Flunarizina/efeitos adversos , Cinarizina/efeitos adversos , Bloqueadores dos Canais de Cálcio/efeitos adversos , Estudos Prospectivos , Transtornos Parkinsonianos/induzido quimicamente , Doença de Parkinson Secundária/induzido quimicamente , Antagonistas de Dopamina/efeitos adversos , Antipsicóticos/efeitos adversos , Síndrome
18.
Int J Nanomedicine ; 17: 5641-5660, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36452306

RESUMO

Purpose: Cinnarizine (CIN) is a class II BSC drug, suffering from erratic bioavailability due to its pH-dependent solubility. It has preferential absorption in the stomach. In this study, new chitosan (CS) coated niosomes of CIN (CIN-loaded chitosomes) have been developed to extend the gastric retention and ameliorate CIN oral bioavailability. Methods: Various CIN-loaded niosomes were fabricated by thin-film hydration technique and fully characterized. Based on the predetermined criteria of low particle size (PS) and high entrapment efficiency percent (EE%), niosomal formulation F1 was selected and further coated with different CS concentrations. The optimized chitosomal formulation (C2) was evaluated through solid state characterization and mucoadhesive efficiency testing. It was also subjected to cytotoxicity study on Caco-2 cells; besides, in vitro drug release, stability and pharmacokinetic studies were assessed. Results: The optimized chitosomal formulation (C2) exhibited an EE% of 58.30±2.75%, PS of 440 ±13.03 nm, PDI of 0.335±0.21 and ZP of +28.1±0.10 mv. Solid state characterization results revealed the compatibility between the vesicle components and the entrapment of CIN within niosomal vesicles. C2 formulation demonstrated favorable mucoadhesive efficiency. The cytotoxicity study on Caco-2 cells manifested the safety of the optimized chitosomal formulation (C2) over the free drug. Additionally, it displayed a remarkable sustaining of CIN in vitro release up to 8 h and exhibited a good stability at the refrigerated temperature up to 3 months. In vivo pharmacokinetic assessment revealed that the CIN bioavailability from the optimized chitosomal formulation C2 was enhanced by 2.79 and 1.92 folds compared to the free drug and uncoated niosomal formulation F1, respectively. The priority of the chitosomal formulation (C2) over the niosomal one (F1) was also conferred. Conclusion: Novel formulation of chitosan coated niosomes (chitosomes) could be presented as a promising platform to improve the oral bioavailability of drugs with narrow absorption window.


Assuntos
Quitosana , Cinarizina , Humanos , Disponibilidade Biológica , Células CACO-2 , Lipossomos
19.
Cochrane Database Syst Rev ; 10: CD012715, 2022 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-36250781

RESUMO

BACKGROUND: Motion sickness is a syndrome that occurs as a result of passive body movement in response to actual motion, or the illusion of motion when exposed to virtual and moving visual environments. The most common symptoms are nausea and vomiting. Antihistamines have been used in the management of motion sickness for decades, however studies have shown conflicting results regarding their efficacy. OBJECTIVES: To assess the effectiveness of antihistamines in the prevention and treatment of motion sickness in adults and children. SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials; Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 7 December 2021. SELECTION CRITERIA: Randomised controlled trials (RCTs) in susceptible adults and children in whom motion sickness was induced under natural conditions such as air, sea and land transportation. We also included studies in which motion sickness was induced under experimental conditions (analysed separately). Antihistamines were included regardless of class, route or dosage and compared to no treatment, placebo or any other pharmacological or non-pharmacological interventions. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1) the proportion of susceptible participants who did not experience any motion sickness symptoms; 2) the proportion of susceptible participants who experienced a reduction or resolution of existing symptoms. Secondary outcomes were 1) physiological measures (heart rate, core temperature and gastric tachyarrhythmia (electrogastrography)) and 2) adverse effects (sedation, impaired cognition, blurred vision). We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included nine RCTs (658 participants). Studies were conducted across seven countries, with an overall age range of 16 to 55 years. Motion sickness was induced naturally in six studies and experimentally in four studies (rotating chair). All the naturally induced studies only evaluated first-generation antihistamines (cinnarizine and dimenhydrinate). Risk of bias across the studies varied, with mostly low risk for random sequence generation and allocation concealment, and mostly high risk for selective reporting. Only the experimentally induced studies measured physiological parameters and only the naturally induced studies evaluated adverse effects. There were no studies that clearly assessed the paediatric population. Antihistamines versus placebo or no treatment Antihistamines are probably more effective than placebo at preventing motion sickness symptoms under natural conditions (symptoms prevented: 25% placebo; 40% antihistamines) (risk ratio (RR) 1.81, 95% confidence interval (CI) 1.23 to 2.66; 3 studies; 240 participants) (moderate-certainty). The evidence is very uncertain about the effect of antihistamines on preventing motion sickness under experimental conditions (standardised mean difference (SMD) 0.32, 95% CI -0.18 to 0.83; 2 studies; 62 participants) (very low-certainty). No studies reported results on the resolution of existing motion sickness symptoms. Antihistamines may result in little or no difference in gastric tachyarrhythmia under experimental conditions (mean difference (MD) -2.2, 95% CI -11.71 to 7.31; 1 study; 42 participants) (low-certainty). No studies reported results for any other physiological measures. When compared to placebo, antihistamines may be more likely to cause sedation (sedation: 44% placebo; 66% antihistamines) (RR 1.51, 95% CI 1.12 to 2.02; 2 studies; 190 participants) (low-certainty); they may result in little or no difference in blurred vision (blurred vision: 12.5% placebo; 14% antihistamines) (RR 1.14, 95% CI 0.53 to 2.48; 2 studies; 190 participants) (low-certainty); and they may result in little or no difference in terms of impaired cognition (impaired cognition: 33% placebo; 29% antihistamines) (RR 0.89, 95% CI 0.58 to 1.38; 2 studies; 190 participants) (low-certainty). Antihistamines versus scopolamine The evidence is very uncertain about the effect of antihistamines on preventing motion sickness under natural conditions when compared to scopolamine (symptoms prevented: 81% scopolamine; 71% antihistamines) (RR 0.89, 95% CI 0.68 to 1.16; 2 studies; 71 participants) (very low-certainty). No studies were performed under experimental conditions. No studies reported results on the resolution of existing motion sickness symptoms. The evidence is very uncertain about the effect of antihistamines on heart rate under natural conditions (narrative report, 1 study; 20 participants; "No difference in pulse frequency"; very low-certainty). No studies reported results for any other physiological measures. When compared to scopolamine, the evidence is very uncertain about the effect of antihistamines on sedation (sedation: 21% scopolamine; 30% antihistamines) (RR 0.82, 95% CI 0.07 to 9.25; 2 studies; 90 participants) (very low-certainty) and on blurred vision (narrative report: not a significant difference; 1 study; 51 participants; very low-certainty). No studies evaluated impaired cognition. Antihistamines versus antiemetics Antihistamines may result in little or no difference in the prevention of motion sickness under experimental conditions (MD -0.20, 95% CI -10.91 to 10.51; 1 study; 42 participants) (low-certainty). The evidence is of low certainty due to imprecision as the sample size is small and the confidence interval crosses the line of no effect. No studies assessed the effects of antihistamines versus antiemetics under natural conditions. No studies reported results on the resolution of existing motion sickness symptoms. Antihistamines may result in little or no difference in gastric tachyarrhythmia (MD 4.56, 95% CI -3.49 to 12.61; 1 study; 42 participants) (low-certainty). No studies reported results for any other physiological measures. No studies evaluated sedation, impaired cognition or blurred vision. One study reported physiological data for this outcome, evaluating gastric tachyarrhythmia specifically. Antihistamines may result in little or no difference in gastric tachyarrhythmia (MD 4.56, 95% CI -3.49 to 12.61; 1 study; 42 participants; low-certainty evidence). This evidence is of low certainty due to imprecision as the sample size is small and the confidence interval crosses the line of no effect. Antihistamines versus acupuncture The evidence is very uncertain about the effects of antihistamines on the prevention of motion sickness under experimental conditions when compared to acupuncture (RR 1.32, 95% CI 1.12 to 1.57; 1 study; 100 participants) (very low-certainty). This study did not assess the prevention of motion sickness under natural conditions, nor the resolution of existing motion sickness symptoms. There was no study performed under natural conditions. Physiological measures and adverse effects were not reported. AUTHORS' CONCLUSIONS: There is probably a reduction in the risk of developing motion sickness symptoms under naturally occurring conditions of motion when using first-generation antihistamines, in motion sickness-susceptible adults, compared to placebo. Antihistamines may be more likely to cause sedation when compared to placebo. No studies evaluated the treatment of existing motion sickness, and there are few data on the effect of antihistamines in children. The evidence for all other outcomes and comparisons (versus scopolamine, antiemetics and acupuncture) was of low or very low certainty and we are therefore uncertain about these effects of antihistamines.


Assuntos
Antieméticos , Cinarizina , Dimenidrinato , Enjoo devido ao Movimento , Adolescente , Adulto , Criança , Antagonistas dos Receptores Histamínicos/uso terapêutico , Humanos , Pessoa de Meia-Idade , Enjoo devido ao Movimento/tratamento farmacológico , Derivados da Escopolamina , Adulto Jovem
20.
Biomed Pharmacother ; 155: 113779, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36271560

RESUMO

Microwave is commonly used in the life, manufacturing and military fields, which may induce body injuries. Brain is the major target organ of microwave radiation and microwave-induced brain injury (MIBI) can lead to insomnia, dreaminess, and a decline in learning and memory. However, there is no clinical medications are available currently. Calcium channel blockers may protect the brain tissue from microwave but most of them cannot enter the brain. Here, we selected a calcium channel blocker-cinnarizine to prepare its dissolving microneedles (MNs) for the therapy of MIBI. The cinnarizine MNs was composed of polyvinyl pyrrolidone (PVP) K90 as the tip, the photopolymerized PVP as the base and the drug, which owned high mechanical strength, leading to easily piecing the skin on the neck and high drug release in vivo. The cinnarizine MNs markedly improved the recovery of spatial memory and spontaneous exploratory behavior of the rats after microwave radiation by inhibiting the expression of calcineurin and calpain-1. The dissolving MN technique is a promising method to improve drugs into the body and perform the anti-microwave radiation action.


Assuntos
Lesões Encefálicas , Cinarizina , Ratos , Animais , Administração Cutânea , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Agulhas , Sistemas de Liberação de Medicamentos/métodos , Calcineurina , Calpaína , Polivinil , Povidona
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