QbD based Eudragit coated Meclizine HCl immediate and extended release multiparticulates: formulation, characterization and pharmacokinetic evaluation using HPLC-Fluorescence detection method.

This study is based on the QbD development of extended-release (ER) extruded-spheronized pellets of Meclizine HCl and its comparative pharmacokinetic evaluation with immediate-release (IR) pellets. HPLC-fluorescence method was developed and validated for plasma drug analysis. IR drug cores were prepared from lactose, MCC, and PVP using water as granulating fluid. Three-level, three-factor CCRD was applied for modeling and optimization to study the influence of Eudragit (RL100-RS100), TEC, and talc on drug release and sphericity of coated pellets. HPLC-fluorescence method was sensitive with LLOQ 1 ng/ml and linearity between 10 and 200 ng/ml with R2 > 0.999. Pharmacokinetic parameters were obtained by non-compartmental analysis and results were statistically compared using logarithmically transformed data, where p > 0.05 was considered as non-significant with a 90% CI limit of 0.8-1.25. The AUC0-t and AUC0-∞ of ER pellets were not significantly different with geometric mean ratio 1.0096 and 1.0093, respectively. The Cmax of IR pellets (98.051 ng/ml) was higher than the ER pellets (84.052 ng/ml) and the Tmax of ER pellets (5.116 h) was higher than the IR pellets (3.029 h). No significant food effect was observed on key pharmacokinetic parameters of ER pellets. Eudragit RL100 (6%) coated Meclizine HCl pellets have a potential therapeutic effect for an extended time period.

Bioanalytical chiral chromatographic technique and docking studies for enantioselective separation of meclizine hydrochloride: Application to pharmacokinetic study in rabbits.

Enantiomeric resolution and molecular docking studies of meclizine hydrochloride on polysaccharide-based chiral stationary phase comprising cellulose tris(4-methylbenzoate) chiral selector (150 × 4.6 mm, 3.0 µm) were presented. The mobile phase used was acetonitrile:10mM ammonium bicarbonate (95:05, v/v). The developed technique was used to perform the enantioselective assay of meclizine hydrochloride in its marketed formulation. The elution order of meclizine hydrochloride enantiomers was determined by docking studies. Target compound was extracted from rabbit plasma using protein precipitation technique, followed by development of bioanalytical chiral separation method using the same matrix. Application of the method to determine pharmacokinetic parameters of meclizine hydrochloride enantiomers was performed using Phoenix WinNonlin 8.1 software. The results demonstrated stereoselective disposition of meclizine hydrochloride enantiomers in rabbits.

Enantiomeric Separation of Meclizine Hydrochloride in Pharmaceutical Dosage Form by HPLC Method.

OBJECTIVE: A basic, powerful and isocratic chiral fluid chromatographic technique was created and approved for the enantiomeric partition of meclizine hydrochloride in pharmaceutical dose structure. METHODS: The chromatographic partition was accomplished on Phenomenex® Lux Cellulose 1 (250 mm x 4.6 mm i.d, 5 µm molecule size) section utilizing portable stage framework containing acetonitrile: 25mM ammonium bicarbonate (75:25%v /v). The versatile stage was siphoned on the segment at the stream pace of 1.0 mL/min, and UV recognition was done at 230 nm. RESULT: The breaking points of recognition and measurement were observed to be 0.25 µg/mL and 1.00 µg/mL individually, for 20µL infusion volume. The alignment bend demonstrated phenomenal linearity over the focus scope of 1-5 µg/mL for (±) meclizine enantiomers with a relationship coefficient (r2 = 0.999). The recuperation investigation of meclizine from tablet plan was observed to be 97.33% and 98.81% separately. Meclizine standard arrangement and versatile stage were observed to be steady for in any event 32h. The meclizine enantiomers were very much settled with mean maintenance times of about (+) Meclizine at 13.14 min and (-) Meclizine at 14.33 min individually. CONCLUSION: The created technique was broadly approved and demonstrated to be hearty, exact, exact and appropriate for the examination of meclizine enantiomers in tablet measurement structure and security investigations of meclizine.

Lipids bearing extruded-spheronized pellets for extended release of poorly soluble antiemetic agent-Meclizine HCl.

BACKGROUND: Antiemetic agent Meclizine HCl, widely prescribed in vertigo, is available only in immediate release dosage forms. The approved therapeutic dose and shorter elimination half-life make Meclizine HCl a potential candidate to be formulated in extended release dosage form. This study was aimed to develop extended release Meclizine HCl pellets by extrusion spheronization using natural and synthetic lipids. Influence of lipid type, drug/lipid ratio and combinations of different lipids on drug release and sphericity of pellets were evaluated. METHODS: Thirty two formulations were prepared with four different lipids, Glyceryl monostearate (Geleol®), Glyceryl palmitostearate (Precirol®), Glyceryl behenate (Compritol®) and Carnauba wax, utilized either alone or in combinations of drug/lipid ratio of 1:0.5-1:3. Dissolution studies were performed at variable pH and release kinetics were analyzed. Fourier transform infrared spectroscopy was conducted and no drug lipid interaction was found. RESULTS: Sphericity indicated by shape factor (eR) varied with type and concentration of lipids: Geleol® (eR = 0.891-0.997), Precirol® (eR = 0.611-0.743), Compritol® (eR = 0.665-0.729) and Carnauba wax (eR = 0.499-0.551). Highly spherical pellets were obtained with Geleol® (Aspect ratio = 1.005-1.052) whereas irregularly shaped pellets were formed using Carnauba wax (Aspect ratio = 1.153-1.309). Drug release was effectively controlled by three different combinations of lipids: (i) Geleol® and Compritol®, (ii) Geleol® and Carnauba wax and (iii) Geleol®, Compritol® and Carnauba wax. Scanning electron microscopy of Compritol® pellets showed smooth surface with pores, whereas, irregular rough surface with hollow depressions was observed in Carnauba wax pellets. Energy dispersive spectroscopy indicated elemental composition of lipid matrix pellets. Kinetics of (i) Geleol® and Compritol® pellets, explained by Korsmeyer-Peppas (R2 = 0.978-0.993) indicated non-Fickian diffusion (n = 0.519-0.597). Combinations of (ii) Geleol® and Carnauba wax and (iii) Geleol®, Compritol® and Carnauba wax pellets followed Zero-order (R2 = 0.991-0.995). Similarity test was performed using combination of Geleol® and Compritol® (i) as a reference. CONCLUSIONS: Matrices for the extended release of Meclizine HCl from extruded-spheronized pellets were successfully formed by using three lipids (Geleol®, Compritol® and Carnauba wax) in different combinations. The encapsulated pellets of Meclizine HCl can be effectively used for treatment of motion sickness, nausea and vertigo for extended period of time.

Quenching of fluorescence by meclizine, a probe study for structural and conformational changes in human serum albumin.

The goal of this study was to investigate the interactions between meclizine (MEC) and human serum albumin (HSA) under physiological conditions by different spectroscopies and molecular modeling technique. The drug, MEC quenched the intrinsic fluorescence of HSA and the analysis of the results revealed that static quenching mechanism. The binding of MEC quenches the HSA fluorescence; stoichiometry was 1:1 interaction. Thermodynamic quantities were calculated at different temperatures suggested that hydrophobic and van der Waals interaction with HSA-MEC. The molecular distance, r, between donor and acceptor was estimated according to Forster's theory of non-radiation energy transfer. CD and FT-IR studies confirm changes of secondary structure of HSA. Molecular docking studies validate MEC molecule interact to HSA in sub domain IIA.

Meclizine, a pregnane X receptor agonist, is a direct inhibitor and mechanism-based inactivator of human cytochrome P450 3A.

Meclizine is an agonist of human pregnane X receptor (PXR). It increases CYP3A4 mRNA expression, but decreases CYP3A-catalyzed testosterone 6ß-hydroxylation in primary cultures of human hepatocytes, as assessed at 24h after the last dose of meclizine. Therefore, the hypothesis to be tested is that meclizine inactivates human CYP3A enzymes. Our findings indicated that meclizine directly inhibited testosterone 6ß-hydroxylation catalyzed by human liver microsomes, recombinant CYP3A4, and recombinant CYP3A5. The inhibition of human liver microsomal testosterone 6ß-hydroxylation by meclizine occurred by a mixed mode and with an apparent Ki of 31±6µM. Preincubation of meclizine with human liver microsomes and NADPH resulted in a time- and concentration-dependent decrease in testosterone 6ß-hydroxylation. The extent of inactivation required the presence of NADPH, was unaffected by nucleophilic trapping agents or reactive oxygen species scavengers, attenuated by a CYP3A substrate, and not reversed by dialysis. Meclizine selectively inactivated CYP3A4, but not CYP3A5. In contrast to meclizine, which has a di-substituted piperazine ring, norchlorcyclizine, which is a N-debenzylated meclizine metabolite with a mono-substituted piperazine ring, did not inactivate but directly inhibited hepatic microsomal CYP3A activity. In conclusion, meclizine inhibited human CYP3A enzymes by both direct inhibition and mechanism-based inactivation. In contrast, norchlorcyclizine is a direct inhibitor but not a mechanism-based inactivator. Furthermore, a PXR agonist may also be an inhibitor of a PXR-regulated enzyme, thereby giving rise to opposing effects on the functional activity of the enzyme and indicating the importance of measuring the catalytic activity of nuclear receptor-regulated enzymes.

A stability-indicating RP-HPLC method for the quantitative analysis of meclizine hydrochloride in tablet dosage form.

A specific stability-indicating reversed-phase high-performance liquid chromatographic method was developed and validated for the estimation of meclizine hydrochloride (MEC) in tablet dosage form. The HPLC method has shown adequate separation of MEC from their degradation products. The separation was achieved on a C8 (250 mm×4.6 mm×5 µm) column using a mobile phase composition of 0.2% triethylamine in water and methanol in the ratio of 65:35(pH adjusted to 3.0 with orthophosphoric acid) with a flow rate of 1 mL/min. The wavelength of a photo-diode array detector was kept at 229 nm. Stress studies were performed initially under milder conditions followed by stronger conditions so as to get sufficient degradation around 5-20%. There were six degradation products observed with adequate separation from the analyte peak. Among those detected degradation products, structures of four degradation products were verified by comparison with known impurities of meclizine analogs. The method was validated as per the International Conference on Harmonization (Q2) guidelines. The method was specific, selective, accurate and precise to quantify meclizine in the presence of degradation products.

Quantitative enantiomeric analysis of chlorcyclizine, hydroxyzine, and meclizine by capillary electrophoresis.

A simple capillary zone electrophoresis method was developed for the quantitative enantiomeric analysis of piperazine antihistamines with teratogenic suspicion in animals. Enantioseparation of chlorcyclizine, hydroxyzine, and meclizine was performed in glycine buffer (0.6 mol L(-1); pH 3.00) with sulfated beta-cyclodextrin (5 mg mL(-1)) as a chiral selector; and the separated drugs were monitored by ultra-violet detector. The lower quantitation of the individual enantiomer is attainable at 10 micro mol L(-1), using an achiral piperazine drug (cyclizine) as internal standard. The method is simple and rapid with a short run time (<5 min) for the analysis of chlorcyclizine, hydroxyzine or meclizine enantiomers.

Comparison of impact of the different hydrophilic carriers on the properties of piperazine-containing drug.

The objective of this study was to determine the impact of a series of nonionic surfactants on the solubility of piperazine-containing drug (meclizine, MZ) in comparison to that of natural cyclodextrins (alpha-CD and beta-CD) and dimethyl-beta-cyclodextrin (DM-beta-CD). The solubility of the drug was studied in either CDs solutions or nonionic surfactant solutions. Three classes of nonionic surfactants were used namely; polyoxyethylene (POE) sorbitan fatty acid esters (polysorbates), POE fatty acid esters (Myrjs) and polyethylene oxide (PEO) fatty alcohol ethers (Brijs and Eumulgins). The solubility of MZ was increased linearly with the increasing surfactant concentration, indicating that micellar solubilization follows the partition model. It was found that the longer the hydrocarbon chain in a homologous series, the more efficient is the solubilizing power of surfactant. For example, polysorbate 80 (Tween-80) is a more efficient solubilizer than polysorbate 20 (Tween-20), indicating that the drug was incorporated in the core of micelle more than the capsular region of the micelle. On the other hand, in case of POE fatty acid esters, the solubilizing power increased with decreasing polyoxyethylene chain as Myrj 53 was more efficient than Myrj 59. In class of PEO fatty alcohol ethers, the shorter the hydrophilic chain and longer lipophilic chain, the more efficient was the solubilizing capacity. Thus, Brij 58 was more efficient solubilizer than Brij 35 and Eumulgin C1000 was more active than Eumulgin C1500. Comparatively, Eumulgin C1000 had the highest solubilizing power for MZ among the studied PEO fatty alcohol ethers and other groups of surfactants. The solubility action of surfactants toward MZ was increased by raising the temperature of the surfactant solutions from 30 to 45 degrees C. Hydrophilic macromolecules (PEG 1000 and PEG 6000) or cosolvents (glycerol and propylene glycol) have a very slight effect on the solubility of MZ and confirm the predominance of hydrophobic interaction between the drug and nonionic surfactants. A(L)-type phase solubility diagrams were obtained for the drug with alpha-, beta- and DM-beta-CDs showing that the solubility of MZ was enhanced through inclusion complexation. Comparatively, DM-beta-CD had the highest solubilizing efficiency for the drug among the investigated CDs, which could be attributed to its larger hydrophobic cavity size.

Apparatus for studying in vitro drug release from medicated chewing gums.

An apparatus for in vitro drug release testing of medicated chewing gums has been developed and is described in detail. The effects on the drug release when varying critical instrumental settings such as the chewing stroke frequency, the distance between the chewing surfaces, the twisting movements of these surfaces and the temperature of the test medium have been thoroughly investigated. It has been shown that the drug release can be tuned to obtain suitable drug release profiles for a number of products: Nicorette((R)) and Nicotinell((R)) (active substance nicotine), Travvell((R)) (dimenhydrinate), V6((R)) (xylitol) and an experimental formulation containing meclizine. The main usage of the present apparatus should be within quality control but the present study has also shown that it may be employed within development pharmaceutics since useful in vivo/in vitro relationships may be obtained due to the versatile settings of the critical instrumental parameters.