Background: Cinnarizine (CIN) is a poorly soluble drug used in the treatment of vestibular disorders. Its solubility can be improved by complexation with cyclodextrins (CDs). This study focused on the preparation of 1:1 CIN/CD complexes with β-cyclodextrin (βCD) and its derivatives hydroxypropyl-β-cyclodextrin (HPβCD) and sulfobutylether-β-cyclodextrin (SBEβCD) by mechanical activation. Methods: Complexes were obtained under optimized grinding conditions using a high-energy vibrational mill with ZrO2 grinding media. Solid products were characterized by DSC, TGA, XRPD, and FTIR spectroscopy. Dissolution studies were performed in phosphate buffer (pH 4.5). The effect of βCD and HPβCD on CIN stability was assessed under hydrolytic (acidic, neutral, and basic) and oxidative conditions. A stability-indicating UHPLC-DAD-HRMS method was developed and validated, enabling CIN quantification in the presence of degradation products, whose structures were proposed based on HRMS/MS data. Potential toxicity, bioaccumulation, and mutagenicity of degradation products were predicted using QSAR modeling. Accelerated stability studies (40 °C, 75% RH) were conducted to evaluate long-term stability. Results: Solid-state analyses confirmed CIN/CD interactions in the ground products. The highest dissolution efficiency was observed for CIN/HPβCD complexes, while CD complexation did not alter CIN permeability in biomimetic membrane assays. CIN and its complexes demonstrated satisfactory chemical stability, with no degradation products detected under accelerated conditions. Conclusions: Solid-state complexes of CIN with CDs enhanced dissolution without compromising stability, supporting their potential as promising candidates for novel pharmaceutical formulations.

Abstract Currently, there are no reported green “high-performance thin-layer chromatography (HPTLC)” methods for domperidone (DOM) and cinnarizine (CNZ) simultaneous detection. The objective of the present study was to design and verify a reverse-phase HPTLC method for the concurrent analysis of CNZ and DOM in commercial tablets that is fast, sensitive, and greener. As a green mobile phase, acetone and water in an 80:20 (v/v) binary ratio were used to simultaneously determine CNZ and DOM. The stationary phase was reverse-phase silica gel 60F254S plates. Concurrent measurements of CNZ and DOM were performed at 230 nm. Four different tools were used to assess the greenness of the current method: AGREE, AES, ChlorTox, and NEMI. For both medications, the current approach was linear in the 25–1,000 ng/band range. The accuracy, precision, robustness, sensitivity, and environmental friendliness of the suggested technique for the CNZ and DOM simultaneous detection were verified. The new method's profile was noticeably greener, as seen by the results of every greenness tool, including NEMI, AES (89), ChlorTox (1.08 g), and AGREE (0.83). Utilizing the current approach, the amount of CNZ and DOM in pharmaceutical tablets was found to be 99.53 and 98.87%, respectively. These findings validate the suitability of the existing method for measuring CNZ and DOM simultaneously in commercial tablets. The results of the proposed study indicated that measuring CNZ and DOM in commercial products could be done consistently with the current methodology.

Drug delivery to perilymph after crossing the round window membrane is paramount important for inner ear disease management. Intratympanic (IT) injection of emulsion-like dispersions augments cinnarizine (CNZ) and morin hydrate (MH)-Lipoid E80 complex permeation into perilymph in a healthy rabbit inner ear model. A Box-Behnken design (BBD) followed by artificial neural network (ANN)-linked Levenberg - Marquardt (LM) algorithm was used for optimizing the injection formula. Immediately after 30-120 minutes post-IT injections, the concentration levels of CNZ and MH in both perilymph and plasma were monitored. The ANN-linked LM algorithm displayed lower prediction and mean squared errors as well as higher correlation coefficient values for all responses when compared to the corresponding values shown by BBD. The IT injections possessed 156.8 ± 8.5 nm mean particle size, 42.70 ± 4.20 mV zeta potential, >98% CNZ and MH release within 10-20 minutes dissolution in pH 7.4 artificial perilymph solution, >97.26% cell viability in MTT assay and near normal histopathology. The 63.07 ± 23.62 µg/ml CNZ and 82.51 ± 8.33 µg/ml MH were attained in perilymph at 60 minutes post-IT injections. The IT-injected formulation can be used to co-deliver two drugs in perilymph for managing inner ear diseases.

Abstract Recently, microwave-based cyclodextrin nanosponges (CDNS) of domperidone (DOM) for their solubility and dissolution improvement have been studied. However, microwave-based CDNS for the dual-loading of cinnarizine (CIN) and DOM have not been documented. Therefore, this research concentrates explicitly on the concurrent loading of two drugs employing these nanocarriers, namely CIN and DOM, both categorized under Class II of the Biopharmaceutical Classification System. A green approach involving microwave synthesis was employed to fabricate these nanocarriers. Fourier transform infrared (FTIR) spectroscopy confirmed the formation of CDNS, while scanning electron microscopy scans illustrated their porous nature. X-ray diffraction studies established the crystalline structure of the nanocarriers. Differential scanning calorimetry and FTIR analyses corroborated the drugs’ loading and subsequent amorphization. In vitro drug release studies demonstrated an enhanced solubility of the drugs, suggesting a potential improvement in their bioavailability. The in vivo pharmacokinetic investigation emphatically substantiated this hypothesis, revealing a 4.54- and 2.90-fold increase in the bioavailability of CIN and DOM, respectively. This enhancement was further supported by the results of the pharmacodynamic study utilizing the gastrointestinal distress/pica model, which indicated a significantly reduced consumption of kaolin. Conclusively, this study affirms the adaptability of microwave-based CDNS for the concurrent loading of multiple drugs, leading to improved solubility and bioavailability.

Abstract E. Ng: None. A.E. Taylor: None. W.M. Drake: None. M.J. Brown: None. Introduction: The discovery of primary aldosteronism (PA) genotypes and correlating phenotypes calls for targeted and personalised therapy. PA caused by CACNA1D mutations may benefit from Cav1.3 inhibition. Cinnarizine (CIN) fits the Cav1.3 crystal structure and has similar structure to Compound B, a Cav1.3 inhibitor which suppresses aldosterone ex vivo. Hypothesis Cav1.3 blockade by CIN may achieve similar, or greater, reduction in aldosterone secretion than non-selective Cav1.2/1.3 blockade by nifedipine (NIF). Methods Ex vivo Treatment of H295R cells with CIN at varying doses (technical and biological triplicates). Culture medium was collected to measure aldosterone levels; RNA extraction and qPCR were performed to evaluate CYP11B2 expression normalised to 18S as a housekeeping gene. Relative expression of CACNA1D and CACNA1C in H295R cells were measured by RNA sequencing (RNASeq). In vivo Prospective, open-label, Latin square crossover study of 15 adults with PA, with two weeks of either CIN 30 mg three times a day or NIF extended release 60 mg daily, separated by a two week washout. Interfering medications were ceased pre-study. The hierarchical primary outcome was change in aldosterone-to-renin ratio (ARR), urinary tetrahydroaldosterone (THA) and plasma aldosterone concentration (PAC) with CIN and NIF. Blood pressure (BP) change was a secondary outcome. The study had 90% power to detect 30% reduction in PAC. Parametric analysis was undertaken on log-transformed data. Results: Both NIF and CIN showed a dose-related reduction in aldosterone levels and CYP11B2 expression ex vivo. Mean change ± SEM in fold change of aldosterone levels and CYP11B2 relative to untreated were -0.47 ± 0.04 and -0.55 ± 0.06, respectively, with CIN 10-5 M and -0.52 ± 0.06 and -0.10 ± 0.10 with NIF 10-4 M. RNASeq reads were 5.99 (0.15) (mean(SD)) for CACNA1C and 16.29 (0.47) for CACNA1D. Of the 15 subjects in the crossover trial, 13 were male, 10 Black, age 55 ± 13. NIF reduced ARR (median (IQR) 2650 (1163-4043) to 1808 (825-2946) pmol/L:nmol/L/h) but not CIN (2458 (1268-3764) to 2739 (1795-3751) pmol/L:nmol/L/h) (f=5.15, p=0.040, repeated measures ANOVA). Similar trends were seen for urinary THA (f=5.04, p=0.043) but not PAC. BP fell by 18±13 / 8±10 mmHg with NIF and 6±14 / 5±10 mmHg with CIN (p<0.01 for BP fall on NIF). Conclusion: CIN was less effective than NIF in inhibiting aldosterone production by H295R cells, despite an estimated excess of CACNA1D (encoding Cav1.3) over CACNA1C (Cav1.2). Similarly in the patients, NIF was more effective at lowering ARR. The efficacy of CIN is probably limited by solubility ex vivo, and dose in vivo, and by its mixed pharmacology including dopamine blockade. The potential for a more effective and specific Cav1.3 blocker in PA is illustrated by the <50% reduction in ARR on NIF, likely due to direct adrenal inhibition (Cav1.3) being offset by baroreceptor stimulation of renin-aldosterone. Monday, June 3, 2024

The aim of this study is to establish and test an in vitro digestion-in situ absorption model that can mimic in vivo drug flux by employing a physiologically relevant value of the membrane surface area (S)/volume (V) ratio for accurate prediction of oral drug absorption from lipid-based formulations (LBFs). Three different types of LBFs (Type IIIA-MC, Type IIIA-LC, and Type IV) loaded with cinnarizine (CNZ), a lipophilic weak base with borderline permeability, and a control suspension were prepared. Subsequently, a simultaneous in vitro digestion-permeation experiment was conducted using a side-by-side diffusion cell with a dialysis membrane having a low S/V value. During digestion, CNZ partially precipitated for Type IV, while it remained solubilized in the aqueous phase for Type IIIA-MC and Type IIIA-LC in the donor compartment. However, in vitro drug fluxes for Type IIIA-MC and Type IIIA-LC were lower than those for Type IV due to the reduced free fraction of CNZ in the donor compartment. In pharmacokinetic studies, a similar improvement in in vivo oral exposure relative to suspension was observed, regardless of the LBFs used. Consequently, a poor correlation was found between in vitro permeation and areas under the plasma concentration-time curve (AUCoral) (R2 = 0.087). A luminal concentration measurement study revealed that this discrepancy was attributed to the extremely high absorption rate of CNZ in the gastrointestinal tract compared to that across a dialysis membrane evaluated by the in vitro digestion-permeation model, i.e., the absorption of CNZ in vivo was completed regardless of the extent of the free fraction, owing to the rapid removal of CNZ from the intestine. Subsequently, we aimed to predict the oral absorption of CNZ from the same formulations using a model that demonstrated high drug flux by employing the physiologically relevant S/V value and rat jejunum segment as an absorption sink (for replicating in vivo intestinal permeability). Predigested formulations were injected into the rat intestinal loop, and AUCloop values were calculated from the plasma concentration-time profiles. A better correlation was found between AUCloop and AUCoral (R2 = 0.72), although AUCloop underestimated AUCoral for Type IV due to the precipitation of CNZ during the predigestion process. However, this result indicated the importance of mimicking the in vivo drug absorption rate in the predictive model. The method presented herein is valuable for the development of LBFs.

Green and sustainable scientific research is crucial for health and environmental improvement. Electrochemical analysis simplifies complex processes, saving time and cost. Ion selective electrode method, a key in green analytical chemistry, was utilized. A highly selective solid contact sensor was developed for two applications, detecting cinnarizine (CIN) and dimenhydrinate (DMH) in pharmaceuticals, and identifying CIN and diphenhydramine (DIP) in human plasma. Careful selection of ionophores ensured accurate detection. Multi-wall carbon-nanotubes (MWCNTs) facilitate rapid and precise measurement. The concentration range for CIN, DMH, and DIP was 1 × 10−6 M to 1 × 10−2 M, with mean recovery% of 100.07 ± 0.80, 100.12 ± 0.76, and 100.07 ± 0.53, respectively. Validation parameters exhibited accuracy and precision, with accuracy results of 100.87 ± 0.89, 99.96 ± 0.42, and 99.82 ± 0.31, and LODs of 0.5 × 10−6, 1.0 × 10−7, and 0.2 × 10−6 for CIN, DMH, and DIP, respectively. The study highlighted benefits like speed, economy, and sustainability, emphasizing the electrode’s reusability. SWOT analysis and environmental assessments further underscored its advantages, promising applications in pharmaceutical analysis and quality control.

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. 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. 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. Overall, the developed formulation could be a potential technique to enhance the dissolution of weakly basic drugs that possess challenging stability limitations.

Whiteness and greenness assessment with efficacy evaluation of two UPLC systems applied for the quantification of cinnarizine and dimenhydrinate along with their toxic impurities

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.

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.

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. By applying the analytical quality by design (AQbD) approach, the RP-HPLC method conditions were optimized for the concomitant determination of two drugs. 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. 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. Overall, the AQbD approach could be helpful for systematic optimization of RP-HPLC method conditions to estimate concomitantly other therapeutic moieties. 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.

An accurate, precise and sensitive reverse-phase high-performance liquid chromatography (RP-HPLC) bioanalytical approach was developed for the simultaneous estimation of cinnarizine (CIN) and domperidone (DOM) in rat plasma using irbesartan (IRB) as an internal standard (IS). The proposed RP-HPLC approach was validated as per the latest ICH M10 guidelines. The analytes (CIN and DOM) and IS were extracted from plasma samples using the protein precipitation strategy. Chromatographic separation is accomplished by a C18 SunfireTM (5 µm, 250 mm × 4.6 mm) analytical column, using an isocratic mobile phase consisting of acetonitrile-methanol in 30:70 proportions at a flow rate of 1 mL/min. The detection of all three constituents was recorded at a wavelength of 270 nm with a UV detector. DOM, CIN and IS were eluted at 3.2, 4.5 and 6.1 min, respectively, utilizing a total run time of 10 min. The lower limit of quantification (LLOQ) was 5 ng/mL for CIN and DOM in rat plasma. The proposed RP-HPLC approach was linear in the 5–200 ng/mL range for CIN and DOM. The recovery of the method was greater than 95%, and the relative uncertainty was less than 2%, indicating that the proposed bioanalytical approach was accurate and precise. The limit of detection was established as 1.1 ng/mL for CIN and 1.7 ng/mL for DOM. The created approach was found to be robust and passed all validation criteria; thus, the proposed RP-HPLC approach can be employed successfully for the simultaneous assessment of CIN and DOM in rat plasma.

The eco-friendly high-performance thin-layer chromatographic (HPTLC) approaches for measuring cinnarizine (CIN) are scant in reported databases. As a result, the current work has developed and validated an eco-friendly HPTLC technique for assessing CIN in commercial formulations. The proposed approach was based the use of ethyl alcohol-water (90:10 v/v) as the eco-friendly mobile phase. A wavelength of 197 nm was used to detect CIN. The greenness score of the current approach was measured using the Analytical GREENness (AGREE) approach. The current approach was linear for CIN measurement in 50–800 ng band−1 range. The current approach for CIN measurement was validated successfully using ICH guidelines and was found to be linear, accurate (% recovery = 99.07–101.29%), precise (% CV = 0.80–0.95%), robust, sensitive (LOD = 16.81 ng band−1 and LOQ = 50.43 ng band−1), specific, selective, stability-indicating, and eco-friendly. The AGREE score for the current approach was calculated to be 0.80, showing an excellent greenness characteristic of the present approach. Under forced degradation conditions, the current approach was successful in separating the CIN degradation product, demonstrating the stability-indicating qualities/selectivity of the present approach. The % assay of CIN in commercial tablet brands A and B was found to be 98.64 and 101.22%, respectively, suggesting the reliability of the present approach in the pharmaceutical analysis of CIN in commercial dosage forms. The obtained findings indicated that CIN in commercial formulations could be routinely determined using the current approach.

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.

This work targeted studying organogel as a potential floating system. Organgel has an excellent viscoelastic properties, floating system posses a depot property. Different formulations of 12-hydroxyoctadecanoic acid (HOA) in sesame oil were gelled and selecting F1, F3 and F5 HOA organogels for various examinations: tabletop rheology, optical microscopy, and oscillatory rheology studies. Also, the floating properties studies were conducted at in vitro and in-vivo levels. Lastly, the in-vitro release study using cinnarizine (CN) was to investigate the organogel depot property. Based on the results, the selected concentrations of HOA in sesame oil organogels showed temperature transitions from gel to sol higher than body temperature. These organogels scaffolds inner structures were a star-like shape. The formulation F5 HOA/SO organogels were developing higher storage modulus values, which resulted from the amplitude sweep study. Indeed, all the selected organogels were frequency sweep independent. The organogel’s in vitro floating properties were found positively proven our work’s aim and were buoyant for 24 hours as F5 HOA organogels remained for 12 hours in the rat’s stomach. The depot property showed the slow release of CN from F5 HOA/SO organogel and not more than 65% w/w of CN released after 24 hours.

In this work we investigate span 40, span 60 and SA as a gelators and olive oil (OO) as apolar liquid phase to discover the ability of organogel formed to be floating in acidic media and gain a unique gastroretentive dosage form. In addition, take advantage of the chemical
 
 and physical properties of cinnarizine (CN) as a model drug suitable for gastroretentive systems. The floating parameters were studied where the floating lag time and floating duration for organogel in both solid and liquid states. Organogels charecterization were accomplished through the folowing investigatational techniques and analytical methods: table top rheology, optical microscope, Fourier-transform infrared spectroscopy (FTIR) and in- vitro release study. The results showed that all organogels immediately floated and they were floating in both states. Moreover, table top rheology showed that the transition temperature was reversible and higher than 37 ºC except for 7% w/w and 10% w/w SA in OO organogels where, optical images of organogel showed fibrillar network. The FTIR showed peaks associated to carbonyl groups indicated to form gelator-gelator interactions. Moreover, in vitro release study of organogel system showed continuous release CN for 9-12 hours.

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. 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. 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. 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.

Between 293.2 and 313.2 K and at 0.1 MPa, the solubility of the weak base, cinnarizine (CNZ) (3), in various {Transcutol-P (TP) (1) + water (2)} combinations is reported. The Hansen solubility parameters (HSP) of CNZ and various {(TP) (1) + water (2)} mixtures free of CNZ were also predicted using HSPiP software. Five distinct cosolvency-based mathematical models were used to link the experimentally determined solubility data of CNZ. The solubility of CNZ in mole fraction was increased with elevated temperature and TP mass fraction in {(TP) (1) + water (2)} combinations. The maximum solubility of CNZ in mole fraction was achieved in neat TP (5.83 × 10−2 at 313.2 K) followed by the minimum in neat water (3.91 × 10−8 at 293.2 K). The values of mean percent deviation (MPD) were estimated as 2.27%, 5.15%, 27.76%, 1.24% and 1.52% for the “Apelblat, van’t Hoff, Yalkowsky–Roseman, Jouyban–Acree, and Jouyban–Acree–van’t Hoff models”, respectively, indicating good correlations. The HSP value of CNZ was closed with that of neat TP, suggesting the maximum solubilization of CNZ in TP compared with neat water and other aqueous mixtures of TP and water. The outcomes of the apparent thermodynamic analysis revealed that CNZ dissolution was endothermic and entropy-driven in all of the {(TP) (1) + water (2)} systems investigated. For {(TP) (1) + water (2)} mixtures, the enthalpy-driven mechanism was determined to be the driven mechanism for CNZ solvation. TP has great potential for solubilizing the weak base, CNZ, in water, as demonstrated by these results.

The study aims to design a novel combination of drug-free solid self-nanoemulsifying drug delivery systems (S-SNEDDS) + solid dispersion (SD) to enhance cinnarizine (CN) dissolution at high pH environment caused by hypochlorhydria/achlorhydria. Drug-loaded and drug-free liquid SNEDDS were solidified using Neusilin® US2 at 1:1 and 1:2 ratios. Various CN-SDs were prepared using freeze drying and microwave technologies. The developed SDs were characterized by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRD). In-vitro dissolution studies were conducted to evaluate CN formulations at pH 6.8. Drug-free S-SNEDDSs showed acceptable self-emulsification and powder flow properties. DSC and XRD showed that CN was successfully amorphized into SDs. The combination of drug-free S-SNEDDS + pure CN showed negligible drug dissolution due to poor CN migration into the formed nanoemulsion droplets. CN-SDs and drug-loaded S-SNEDDS showed only 4% and 23% dissolution efficiency (DE) while (drug-free S-SNEDDS + FD-SD) combination showed 880% and 160% enhancement of total drug release compared to uncombined SD and drug-loaded S-SNEDDS, respectively. (Drug-free S-SNEDDS + SD) combination offer a potential approach to overcome the negative impact of hypochlorhydria/achlorhydria on drug absorption by enhancing dissolution at elevated pH environments. In addition, the systems minimize the adverse effect of adsorbent on drug release.