A comparative study on prophylactic efficacy of cinnarizine and amitriptyline in childhood migraine: a randomized double-blind clinical trial.

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.

Development of lipid-based SEDDS using digestion products of long-chain triglyceride for high drug solubility: Formulation and dispersion testing.

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.

Continuous Synthesis of Cinnarizine Salt with Malic Acid by Applying Green Chemistry Using Water-Assisted Twin Screw Extrusion.

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.

Environmentally sustainable DRS-FTIR probe assisted by chemometric tools for quality control analysis of cinnarizine and piracetam having diverged concentration ranges: Validation, greenness, and whiteness studies.

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.

A Combined In-Vitro and GastroPlus® Modeling to Study the Effect of Intestinal Precipitation on Cinnarizine Plasma Profile in a Fasted State.

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.

The effect of anionic Eudragit polymers on drug supersaturation and in vitro permeation improvement.

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.

A sensitive LC-MS/MS method for the determination of potential genotoxic impurities in Cinnarizine.

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.

Permanent non-progressive cinnarizine and flunarizine-induced parkinsonism: An under-recognized tardive syndrome in the elderly?

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.

Unlocking the Potential: Synergistic Effects of Solid SNEDDS and Lyophilized Solid Dispersion to Enhance Stability Attributes.

BACKGROUND: Among lipid-based formulations, self-nanoemulsifying drug delivery systems (SNEDDS) have captured a spotlight, captivating both academia and the pharmaceutical industry. These remarkable formulations offer a valuable option, yet their liquid form presents certain challenges for delivering poorly soluble drugs. Ensuring compatibility with capsule shells, maintaining physical and chemical stability, and understanding their impact on lipolysis remain vital areas of exploration. Therefore, the incorporation of this liquid formulation into a solid dosage form (S-SNEDDS) is compelling and desirable. S-SNEDDSs, prepared by adsorption, enhances formulation stability but retards drug dissolution. This study aims to design drug-free solid S-SNEDDS + solid dispersion (SD) as a novel combination to enhance cinnarizine (CN) stability upon storage while maintaining enhanced drug dissolution. METHODS: Drug-free liquid SNEDDSs were solidified using Neusilin® US2 at a 1:1 ratio. CN-SDs were prepared using freeze-drying technology. The SDs that were developed underwent characterization using various techniques, including scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). In vitro lipolysis studies were conducted to evaluate the effect of the combined system on the performance of the formulation upon exposure to enzymes within biorelevant media. RESULTS: In agreement with the DSC and XRD results, FTIR confirmed the amorphization of CN within the freeze-dried solid dispersion (FD-SD) systems. The in vitro lipolysis studies showed that the drug-free S-SNEDDS + SD combination was able to maintain a significant portion of the initial CN in solution even in the presence of lipase for up to 30 min. The accelerated stability studies showed that the drug-free S-SNEDDS + SD combination maintained 96% intact CN in an amorphous state and more than 90% release at pH 1.2 for up to 6 months, while the dissolution profile at pH 6.8 showed a significant drop in CN release upon storage. CONCLUSIONS: Overall, the developed formulation could be a potential technique to enhance the dissolution of weakly basic drugs that possess challenging stability limitations.

Novel Mucoadhesive Chitosomes as a Platform for Enhanced Oral Bioavailability of Cinnarizine.

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.

Cinnarizine dissolving microneedles against microwave-induced brain injury.

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.

Application of cinnarizine in migraine prevention: A systematic review and meta-analysis.

OBJECTIVE: To investigate and analyze the available data on the prophylactic effectiveness of cinnarizine in migraine disorder. BACKGROUND: Cinnarizine has demonstrated encouraging potential in preventing the attacks of migraine. Therefore, we opted to evaluate whether its sole administration leads to positive outcomes. METHODS: The PubMed, Scopus, Web of Science, and Embase databases were searched for English-only original interventional studies published until April 2022, then screened for relevancy and eligibility. The resulting data from the included studies, including the primary (ie, headache episode frequency, intensity, duration, monthly timing, and analgesic intake frequency) and secondary (ie, reported adverse events, quality of life, and activities of daily living) outcome changes compared to placebo and active controls (e.g., sodium valproate and propranolol) were then recorded by two independent assessors. Ultimately, these data were synthesized qualitatively and quantitatively (achieved by determining the mean difference via the random-effects model). RESULTS: A total of 10 studies comprising seven randomized controlled trials and three quasi-experimental studies were included. Compared to placebo, cinnarizine demonstrated significant improvements in migraine episode frequency (Mean difference = -3.10; Confidence interval = [-3.33, -2.88]; p-value < 0.001; I2  < 0.001%), and intensity (Mean difference = -1.54; Confidence interval = [-2.08, -0.99]; p-value < 0.001; I2  < 37.97%). Moreover, cinnarizine led to similar or better results when compared to active controls, including sodium valproate, topiramate, and propranolol. CONCLUSIONS: Cinnarizine can be considered a safe and effective medication for migraine prophylaxis. However, the relatively small sample size made reaching a definite conclusion impossible. Therefore, a higher number of randomized controlled trials are recommended to be taken place to clarify the situation further.

Physico-chemical characterization of aspirated and simulated human gastric fluids to study their influence on the intrinsic dissolution rate of cinnarizine.

To elucidate the critical parameters affecting drug dissolution in the human stomach, the intrinsic dissolution rate (IDR) of cinnarizine was determined in aspirated and simulated human gastric fluids (HGF). Fasted aspirated HGF (aspHGF) was collected from 23 healthy volunteers during a gastroscopic examination. Hydrochloric acid (HCl) pH 1.2, fasted state simulated gastric fluid (FaSSGF), and simulated human gastric fluid (simHGF) developed to have rheological, and physico-chemical properties similar to aspHGF, were used as simulated HGFs. The IDR of cinnarizine was significantly higher in HCl pH 1.2 (952 ± 27 µg/(cm2·min)) than in FaSSGF pH 1.6 (444 ± 7 µg/(cm2·min)), and simHGF pH 2.5 (49 ± 5 µg/(cm2·min)) due to the pH dependent drug solubility and viscosity differences of the three simulated HGFs. The shear thinning behavior of aspHGF had a significant impact on the IDR of cinnarizine, indicating that the use of FaSSGF, with viscosity similar to water, to evaluate gastric drug dissolution, might overestimate the IDR by a factor of 100-10.000, compared to the non-Newtonian, more viscous, fluids in the human stomach. The developed simHGF simulated the viscosity of the gastric fluids, as well as the IDR of the model drug, making it a very promising medium to study gastric drug dissolution in vitro.

An Insight into Eudragit S100 Preserving Mechanism of Cinnarizine Supersaturation.

Generally, supersaturation of weakly basic drug solution in the gastrointestinal tract can be followed by precipitation, and this can compromise the bioavailability of drugs. The purpose of this study was to evaluate the effect of Eudragit® S100 on the pH-induced supersaturation of cinnarizine and to examine the preserving mechanism of cinnarizine supersaturation by Eudragit®. Variables, including pH of media, ionic strength, and degree of supersaturation, were studied to investigate the effects of these parameters on cinnarizine supersaturation in the presence and absence of Eudragit®. The size of the Eudragit® aggregate in solution using dynamic light scattering was determined. The effect of Eudragit® on the transport of cinnarizine through the Caco-2 membrane was also investigated. The particle size study of Eudragit® aggregates showed that the size of these aggregates become large when the pH was lowered. Supersaturation experiments also demonstrated that Eudragit® preserved higher cinnarizine supersaturation with increasing ionic strength of the solution. The phase separation behavior of cinnarizine solution as a function of the degree of the supersaturation could be readily explained by considering the drug amorphous solubility. In vitro permeation studies revealed that the rate of cinnarizine permeation across Caco-2 cells increased in the presence of Eudragit®. According to the obtained results, the aggregation status of Eudragit® and nonspecific hydrophobic cinnarizine-Eudragit® interactions seemed to be essential in determining the effect of Eudragit® on cinnarizine supersaturation.

Influence of Vehicles and Penetration Enhancers on the Permeation of Cinnarizine Through the Skin

Objectives: The aim of this study was to determine the influence of vehicles and penetration enhancers on the penetration and permeation of cinnarizine (CNZ) through the skin. Materials and Methods: Topical formulations based on hydrogel, o/w emulsion and oleaginous cream were prepared. After determination of physical properties of formulations, the penetration and permeation of CNZ through the stratum corneum and full-thickness skin was investigated by an ex vivo study. Results: The cumulative amount of CNZ permeated from the base hydrogel formulation was about 5 times higher than the base o/w emulsion and base oleaginous cream formulations. The incorporation of penetration enhancers to the base hydrogel and o/w emulsion formulations generally increased CNZ penetration through the skin. Transcutol® was confirmed to provide the highest penetration in the hydrogel formulation. Propylene glycol was found to be the most suitable penetration enhancer for CNZ in the oleaginous cream. Glycerol and oleic acid displayed the highest effect in the o/w emulsion. Conclusion: It was concluded that the hydrogel containing Transcutol® provided the highest penetration through the skin among all formulations and this formulation could be an alternative to the oral route in the treatment of Ménière's disease and motion sickness. Thus, the risk of systemic side effects caused by oral medication can be reduced or eliminated.

Oral cinnarizine for the treatment of COVID-19-associated chilblain-like lesions: An old drug for a new disease?

During SARS-CoV-2 pandemic, an outbreak of chilblain-like lesions has been developed, even if the relationship with the virus infection is still debated. We report the good results obtained in 12 patients with chilblain lesions and the use of oral cinnarizine, a piperazine derivative with many pharmacological properties among whom antihistaminic and calcium channel blocking activities.

Nasal Delivery of Cinnarizine Thermo- and Ion-Sensitive In Situ Hydrogels for Treatment of Microwave-Induced Brain Injury.

(1) Background: When the body is exposed to microwave radiation, the brain is more susceptible to damage than other organs. However, few effective drugs are available for the treatment of microwave-induced brain injury (MIBI) because most drugs are difficult to cross the blood-brain barrier (BBB) to reach the brain. (2) Methods: Nasal cinnarizine inclusion complexes with thermo-and ion-sensitive hydrogels (cinnarizine ISGs) were prepared to treat MIBI and the characteristics of the inclusion complexes and their thermo-and ion-sensitive hydrogels were evaluated. (3) Results: Due to high viscosity, cinnarizine ISGs can achieve long-term retention in the nasal cavity to achieve a sustained release effect. Compared with the model, the intranasal thermo-and ion-sensitive cinnarizine ISGs significantly improved the microwave-induced spatial memory and spontaneous exploration behavior with Morris water maze and open field tests. Cinnarizine ISGs inhibited the expression of calcineurin and calpain 1 in the brain, which may be related to the inhibition of calcium overload by cinnarizine. (4) Conclusion: Intranasal thermo- and ion-sensitive cinnarizine ISGs are a promising brain-targeted pharmaceutical preparation against MIBI.

Adsorbent Precoating by Lyophilization: A Novel Green Solvent Technique to Enhance Cinnarizine Release from Solid Self-Nanoemulsifying Drug Delivery Systems (S-SNEDDS).

BACKGROUND: Solidification by high surface area adsorbents has been associated with major obstacles in drug release. Accordingly, new approaches are highly demanded to solve these limitations. The current study proposes to improve the drug release of solidified self-nanoemulsifying drug delivery systems (SNEDDS) to present dual enhancement of drug solubilization and formulation stabilization, using cinnarizine (CN) as a model drug. METHODS: The solidification process involved the precoating of adsorbent by lyophilization of the aqueous dispersion of polymer-adsorbent mixture using water as a green solvent. Then, the precoated adsorbent was mixed with drug-loaded liquid SNEDDS to prepare solid SNEDDS. The solid-state characterization of developed cured S-SNEDDS was done using X-ray powder diffraction (XRD) and differential scanning calorimetry (DSC). In vitro dissolution studies were conducted to investigate CN SNEDDS performance at pH 1.2 and 6.8. The solidified formulations were characterized by Brunauer-Emmett-Teller (BET), powder flow properties, scanning electron microscopy, and droplet size analysis. In addition, the optimized formulations were evaluated through in vitro lipolysis and stability studies. RESULTS: The cured solid SNEDDS formula by PVP k30 showed acceptable self-emulsification and powder flow properties. XRD and DSC revealed that CN was successfully amorphized into drug-loaded S-SNEDDS. The uncured solid SNEDDS experienced negligible drug release (only 5% drug release after 2 h), while the cured S-SNEDDS showed up to 12-fold enhancement of total drug release (at 2 h) compared to the uncured counterpart. However, the cured S- SNEDDS showed considerable CN degradation and decrease in drug release upon storage in accelerated conditions. CONCLUSIONS: The implemented solidification approach offers a promising technique to minimize the adverse effect of adsorbent on drug release and accomplish improved drug release from solidified SNEDDS.

Supercritical fluid chromatography tandem mass spectrometry employed with evaporation-free liquid-liquid extraction for the rapid analysis of cinnarizine in rat plasma.

Cinnarizine is a weak base, which can produce supersaturation and precipitation during gastrointestinal transit, affecting its absorption in vivo. Therefore, it is necessary to investigate whether the oral bioavailability of cinnarizine can be improved after co-administration with precipitation inhibitors or not. In order to evaluate the pharmacokinetic behavior of cinnarizine in rats, a simple, rapid, sensitive, and environmentally friendly supercritical fluid chromatography-tandem mass spectrometric method was established and validated. In this method, flunarizine, a structural analogue of cinnarizine, was selected as the internal standard, and cinnarizine was extracted from rat plasma using evaporation-free liquid-liquid extraction method. The analytes were separated on a Torus 1-AA column (3.0 mm × 100 mm, 1.7 µm) within 2.0 min, using a gradient elution procedure. The transitions of cinnarizine and flunarizine were m/z 369.1 → 167.1 and m/z 405.1 → 203.1, respectively. Cinnarizine showed good linear correlation in the range of 1-500 ng/ml with a lower limit of quantification of 1 ng/ml. The intra- and interday precision and accuracy of all quality control samples were within ±15%. This high-throughput, accurate, sensitive, and reproducible method has been successfully applied to study the effects of the precipitation inhibitor cinnarizine on the pharmacokinetics in rats.

Development of monolithic matrix type transdermal patches containing cinnarizine: Physical characterization and permeation studies

To overcome the problems associated with bioavailability and systemic side effects of the drug by oral administration, monolithic matrix type transdermal patches containing cinnarizine (CNZ) were developed. For this purpose, films based on hydroxypropyl methylcellulose and polyvinylpyrrolidone as matrix-forming polymers were designed. Physical characteristics of transdermal films and drug-excipient compatibility were investigated. Factors affecting in vitro drug release and ex vivo skin penetration and permeation of the drug were studied. It was confirmed that films displayed sufficient flexibility and mechanical strength for application onto the skin for a long time period. Ex vivo penetration experiments gave satisfactory results for transdermal drug delivery through rat skin. The parameters determining good skin penetration were also evaluated. The highest drug permeation rate was obtained with incorporation of Transcutol® (0.102 mg/cm2/h) into the base CNZ formulation, followed by propylene glycol (0.063 mg/cm2/h), menthol (0.045 mg/cm2/h), and glycerin (0.021 mg/cm2/h) as penetration enhancers (p < 0.05). As a result, the developed transdermal patches of CNZ may introduce an alternative treatment for various conditions and diseases such as idiopathic urticarial vasculitis, Ménière's disease, motion sickness, nausea, and vertigo. Thus, the risk of systemic side effects caused by the drug can be reduced or eliminated