Formulation design and in vitro ex vivo evaluation of transdermal patches of Cinnarizine.

The aim of this study was to develop a Transdermal patch containing Cinnarizine using different ratios of hydrophilic and hydrophobic polymeric systems by solvent evaporation technique employing Polyethylene glycol (PEG 400) as plasticizer. The physicochemical compatibility of the drug and the polymers were studied by performing FT-IR spectroscopic analysis. Formulated patches were evaluated for physicochemical properties, skin irritation, in vitro drug release, ex-vivo permeation studies across rat abdominal skin and stability studies. The results of FT-IR studies revealed that there were no interactions between drug and polymers used. All the formulations exhibited uniformity in physicochemical properties. In vitro permeation studies of the formulations were performed by using Franz diffusion cells. Formulation F3 showed better permeation through rat skin (i.e., 8527.5±1.25µ/cm2 /hr) compared to rest of formulations and followed Fick's diffusion mechanism. On the basis of in-vitro drug release and ex-vivo skin permeation performance, Formulation F3 containing the polymeric blend 19:1 Hydroxypropylmethyl Cellulose (HPMC E 50cps: Eudragit RL 100) has shown optimum release in comparison to other formulations and indicated good physical stability. So it has been demonstrated that Cinnarizine can be designed as matrix type transdermal drug delivery system (TDDS) and further in-vivo evaluations were required.

Role of cyclodextrin complexation in felodipine-sustained release matrix tablets intended for oral transmucosal delivery: in vitro and ex vivo characterization.

The objective of the present research was two-fold: To characterize the produced inclusion complex of felodipine (FDP)-hydroxypropyl-ß-cyclodextrin (HPßCD) utilizing lyophilization, and to develop and characterize a complexed sustained-release polymeric matrix tablets intended for buccal delivery. The phase-solubility diagram suggested an A(L) type system with 1:1 stoichiometry. Solid complexes prepared by physical mixing and lyophilization were characterized by thermal and non-thermal analytical techniques to corroborate the fact of complex formation. The sustained-release FDP tablets were produced by direct compression, and these drug or complex-loaded hydrophilic matrices were assessed for in vitro bioadhesion and release modulation, ex vivo permeation, and in vivo residence time. The in vitro drug release and ex vivo permeation across the porcine buccal membrane demonstrated that the matrix tablets containing FDP-HPßCD (FH5) solid complex exhibited a complete and sustained drug release pattern, and a significantly higher drug permeation (p < 0.05) compared to all of the other formulations tested. This could be attributed to both, the FDP-HPßCD complexation phenomenon, and the presence of hydrophilic polymer in the formulation. All of the formulations tested, demonstrated good stability in human saliva. Additionally, in vivo mucoadhesive behavior of the optimized formulations was studied in healthy human volunteers and subjective parameters were evaluated.

Development of a high-performance liquid chromatography method for simultaneous determination of pioglitazone and felodipine in pig serum: application to pharmacokinetic study.

A simple and sensitive high-performance liquid chromatographic method was developed and validated for simultaneous estimation of pioglitazone and felodipine in pig serum. The present method consists of protein precipitation, extraction of analytes from pig serum into dichloromethane and separation using reversed-phase C(18) column. Nitrendipine was used as an internal standard and the eluent was monitored by UV detector at 240 nm. The mobile phase used was acetonitrile and 50 mm ammonium acetate buffer at a flow rate of 1 mL/min. The retention times for pioglitazone, felodipine and nitrendipine were found to be 5.12, 10.53 and 7.14 min, respectively. The intraday and inter-day coefficient of variation and percent error values of assay method were less than 7% and mean recovery was more than 94% for each analyte, and the method was found to be precise, accurate and specific during study. The method was successfully applied for pharmacokinetic study of pioglitazone and felodipine from bioadhesive buccal tablet after buccal administration to pigs. The C(Max) , T(Max) , and AUC(0-24) of pioglitazone and felodipine from buccal tablet were found to be 394.6 ng/mL, 5.6 h, 2624.2 ng h/mL and 44.4 ng/mL, 5.5 h, 275.8 ng h/mL, respectively.

Iontophoretic delivery of lisinopril: Optimization of process variables by Box-Behnken statistical design.

The objective of the investigation was to optimize the iontophoresis process parameters of lisinopril (LSP) by 3 x 3 factorial design, Box-Behnken statistical design. LSP is an ideal candidate for iontophoretic delivery to avoid the incomplete absorption problem associated after its oral administration. Independent variables selected were current (X(1)), salt (sodium chloride) concentration (X(2)) and medium/pH (X(3)). The dependent variables studied were amount of LSP permeated in 4 h (Y(1): Q(4)), 24 h (Y(2): Q(24)) and lag time (Y(3)). Mathematical equations and response surface plots were used to relate the dependent and independent variables. The regression equation generated for the iontophoretic permeation was Y(1) = 1.98 + 1.23X(1) - 0.49X(2) + 0.025X(3) - 0.49X(1)X(2) + 0.040X(1)X(3) - 0.010X(2)X(3) + 0.58X(1)(2) - 0.17X(2)(2) - 0.18X(3)(2); Y(2) = 7.28 + 3.32X(1) - 1.52X(2) + 0.22X(3) - 1.30X(1)X(2) + 0.49X(1)X(3) - 0.090X(2)X(3) + 0.79X(1)(2) - 0.62X(2)(2) - 0.33X(3)(2) and Y(3) = 0.60 + 0.0038X(1) + 0.12X(2) - 0.011X(3) + 0.005X(1)X(2) - 0.018X(1)X(3) - 0.015X(2)X(3) - 0.00075X(1)(2) + 0.017X(2)(2) - 0.11X(3)(2). The statistical validity of the polynomials was established and optimized process parameters were selected by feasibility and grid search. Validation of the optimization study with 8 confirmatory runs indicated high degree of prognostic ability of response surface methodology. The use of Box-Behnken design approach helped in identifying the critical process parameters in the iontophoretic delivery of lisinopril.

Enhanced bioavailability of buspirone from reservoir-based transdermal therapeutic system, optimization of formulation employing Box-Behnken statistical design.

The purpose of the present study was to develop and optimize reservoir-based transdermal therapeutic system (TTS) for buspirone (BUSP), a low bioavailable drug. A three-factor, three-level Box-Behnken design was employed to optimize the TTS. Hydroxypropyl methylcellulose, D: -limonene and propylene glycol were varied as independent variables; cumulative amount permeated across rat abdominal skin in 24 h, flux and lag time were selected as dependent variables. Mathematical equations and response surface plots were used to relate the dependent and independent variables. The statistical validity of polynomials was established, and optimized formulation factors were selected by feasibility and grid search. Validation of the optimization study with seven confirmatory runs indicated high degree of prognostic ability of response surface methodology. BUSP-OPT (optimized formulation) showed a flux 104.6 microg cm(-2) h(-1), which could meet target flux. The bioavailability studies in rabbits showed that about 2.65 times improvement (p < 0.05) in bioavailability, after transdermal administration of BUSP-OPT compared to oral solution. The ex vivo-in vivo correlation was found to have biphasic pattern and followed type A correlation. Reservoir-based TTS for BUSP was developed and optimized using Box-Behnken statistical design and could provide an effective treatment in the management of anxiety.

Optimization of hydrogels for transdermal delivery of lisinopril by Box-Behnken statistical design.

The aim of this study was to investigate the combined influence of three independent variables on the permeation kinetics of lisinopril from hydrogels for transdermal delivery. A three-factor, three-level Box-Behnken design was used to optimize the independent variables, Carbopol 971 P (X(1)), menthol (X(2)), and propylene glycol (X(3)). Fifteen batches were prepared and evaluated for responses as dependent variables. The dependent variables selected were cumulative amount permeated across rat abdominal skin in 24 h (Q (24); Y(1)), flux (Y(2)), and lag time (Y(3)). Aloe juice has been first time investigated as vehicle for hydrogel preparation. The ex vivo permeation study was conducted using Franz diffusion cells. Mathematical equations and response surface plots were used to relate the dependent and independent variables. The regression equation generated for the cumulative permeation of LSP in 24 h (Q(24)) was Y(1) = 1,443.3-602.59X(1) + 93.24X(2) + 91.75X(3) - 18.95X(1)X(2) - 140.93X(1)X(3) - 4.43X(2)X(3) - 152.63X(1)(2) - 150.03X(2)(2) - 213.9X(3)(2). The statistical validity of the polynomials was established, and optimized formulation factors were selected by feasibility and grid search. Validation of the optimization study with 15 confirmatory runs indicated high degree of prognostic ability of response surface methodology. The use of Box-Behnken design approach helped in identifying the critical formulation parameters in the transdermal delivery of lisinopril from hydrogels.

Development and in vitro evaluation of buccoadhesive carvedilol tablets.

Buccoadhesive tablets of carvedilol were prepared using HPMC K4M, HPMC K15M and Carbopol 934 as mucoadhesive polymers. Fifteen formulations were developed with varying concentrations of polymers. Formulations of the BC or BD series were composed of HPMC K4M or HPMC K15M in ratios of 1:1 to 1:5 whereas in the BE series Carbopol 934 was used (1:0.25 to 1:1.50). The formulations were tested for in vitro drug release, in vitro bioadhesion, moisture absorption and in vitro drug permeation through porcine buccal mucosa. Formulation BC3 showed maximum release of the drug (88.7 +/- 0.4%) with the Higuchi model release profile and permeated 21.5 +/- 2.9% of the drug (flux 8.35 +/- 0.291 microg h(-1)cm(-2)) permeation coefficient 1.34 +/- 0.05 cm h(-1)) through porcine buccal membrane. BC3 formulation showed 1.62 +/- 0.15 N of peak detachment force and 0.24 +/- 0.11 mJ of work of adhesion. FTIR results showed no evidence of interaction between the drug and polymers. XRD study revealed that the drug is in crystalline form in the polymer matrix. The results indicate that suitable bioadhesive buccal tablets with desired permeability could be prepared.

Transmucosal delivery of domperidone from bilayered buccal patches: in vitro, ex vivo and in vivo characterization.

Bilayered mucoadhesive buccal patches for systemic administration of domperidone (DOM), a dopamine-receptor (D(2)) antagonist, were developed using hydroxy propyl methyl cellulose and PVPK30 as a primary layer and Eudragit RLPO and PEO as a secondary layer. Ex vivo drug permeation through porcine buccal membrane was performed. Bilayered buccal patches were developed by solvent casting technique and evaluated for in vitro drug release, moisture absorption, mechanical properties, surface pH, in vitro bioadhesion, in vivo residence time and ex vivo permeation of DOM through porcine buccal membrane from a bilayered buccal patch. Formulation DB4 was associated with 99.5% drug release with a higuchi model release profile and 53.9% of the drug had permeated in 6 h, with a flux of 0.492 mg/h/cm(2) through porcine buccal membrane. DB4 showed 5.58 N and 3.28 mJ peak detachment force and work of adhesion, respectively. The physicochemical interactions between DOM and the polymer were investigated by differential scanning calorimetry (DSC) and fourier transform infrared (FTIR) Spectroscopy. DSC and FTIR studies revealed no interaction between drug and polymer. Stability studies for optimized patch DB4 was carried out at 40°C/75% relative humidity. The formulations were found to be stable over a period of 3 months with respect to drug content, in vitro release and ex vivo permeation through porcine buccal membrane. The results indicate that suitable bilayered mucoadhesive buccal patches with desired permeability could be prepared.

Development of bioadhesive buccal tablets for felodipine and pioglitazone in combined dosage form: in vitro, ex vivo, and in vivo characterization.

The purpose of the present research was to develop bioadhesive buccal tablets for Felodipine (FDP) and Pioglitazone (PIO), low bioavailability drugs, in a combined dosage form for the management of diabetes and hypertension. Buccal tablets were prepared by direct compression method using bioadhesive polymers hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and carbopol, alone or in combination of two polymers, and were evaluated for physicochemical properties, swelling index, in vitro bioadhesion, in vivo residence time, in vitro drug release, and ex vivo permeation through porcine buccal membrane. Formulation (PF6) showed peak detachment force (3.12 N), work of adhesion (0.72 mJ), swelling index (196%), erosion (10.8%), in vivo residence time of 280 min, in vitro drug release (99.65% and 98.96% in 6 h for FDP and PIO, respectively) with higuchi model release profile and permeated 66.1 and 64.6 % with a flux of 0.118 and 0.331 mg/h/cm(2) of FDP and PIO through porcine buccal membrane. The bioavailability study for optimized formulation (PF6) in pigs showed 2.05- and 2.13-times statistically significant (p < 0.05) improvement in bioavailability for FDP and PIO, respectively, after administration of buccal tablets compared to oral suspension. The ex vivo-in vivo correlation was found to have a biphasic pattern and followed type A correlation. The stability of the PF6 was studied and no significant changes were detected in drug content and in vitro release and ex vivo permeation through porcine buccal membrane after 6 months.

High-performance liquid chromatography determination of carvedilol in pig serum.

A simple and sensitive analytical method for quantification of carvedilol in pig serum was developed and validated. Carvedilol and internal standard (IS) were extracted into n-hexane-dichloromethane solvent system and separated using an isocratic mobile phase on a Phenomenex C(18) column. The eluent was monitored by spectroflourimetric detector at a flow rate of 1.0 mL/min. The linearity range of proposed method was 1-1000 ng/mL. The intra-day and inter-day coefficient of variation and percent error values of the assay method were less than 15%, and mean recovery was more than 89.95 and 94.27 for carvedilol and IS, respectively. The method is applicable for use in the pharmacokinetic characterization of carvedilol after administration of buccal patch (6.25 mg) in pigs.

Enhanced bioavailability of lacidipine via microemulsion based transdermal gels: formulation optimization, ex vivo and in vivo characterization.

The purpose of the present study was to develop and optimize the microemulsion based transdermal therapeutic system for lacidipine (LCDP), a poorly water soluble and low bioavailable drug. The pseudo-ternary phase diagrams were developed for various microemulsion formulations composed of isopropyl myristate, Tween 80 and Labrasol. The microemulsion was optimized using a three-factor, three-level Box-Behnken design, the independent variables selected were isopropyl myristate, surfactant mixture (Tween 80 and Labrasol) and water; dependent variables (responses) were cumulative amount permeated across rat abdominal skin in 24h (Q(24); Y(1)), flux (Y(2)), and lag time (Y(3)). Mathematical equations and response surface plots were used to relate the dependent and independent variables. The regression equations were generated for responses Y(1), Y(2) and Y(3). The statistical validity of the polynomials was established, and optimized formulation factors were selected by feasibility and grid search. Validation of the optimization study with 10 confirmatory runs indicated high degree of prognostic ability of response surface methodology. The gel of optimized formulation (ME-OPT) showed a flux of 43.7microgcm(-2)h(-1), which could meet the target flux (12.16microgcm(-2)h(-1)). The bioavailability studies in rabbits showed that about 3.5 times statistically significant (p<0.05) improvement in bioavailability, after transdermal administration of microemulsion gel compared to oral suspension. The ex vivo-in vivo correlation was found to have biphasic pattern and followed type A correlation. Microemulsion based transdermal therapeutic system of LCDP was developed and optimized using Box-Behnken statistical design and could provide an effective treatment in the management of hypertension.

Development of ultra fast liquid chromatographic method for simultaneous determination of nitrendipine and carvone in skin diffusate samples.

A simple and sensitive reverse phase ultra fast liquid chromatographic (UFLC) method for simultaneous determination of nitrendipine and carvone in skin diffusate samples and microemulsions was developed and validated. The separation was achieved using a gradient mobile phase, on an Onyx column. The eluents were monitored by photodiode array detection. The linearity ranges of proposed method were 0.125-50 microg mL(-1) and 0.125-30 microg mL(-1) for nitrendipine and carvone respectively. The intra-day and inter-day coefficient of variation and percent error values of the assay method were less than 10%. The method was found to be precise, accurate, and specific during the study. The method was successfully applied for simultaneous estimation of nitrendipine and carvone in ex vivo skin diffusate samples and microemulsions.

Development of high performance liquid chromatography method for buspirone in rabbit serum: Application to pharmacokinetic study.

A simple and sensitive high performance liquid chromatographic (HPLC) method for quantification of buspirone (BUSP) in rabbit serum was developed and validated. BUSP and internal standard (IS), diltiazem hydrochloride were extracted into dichloromethane and separated using an isocratic mobile phase, on a Kromasil C(8) column. The eluent was monitored by UV detector at 235 nm and at a flow rate of 1.0 mL min(-1). The linearity range of proposed method was 1-3000 ng mL(-1). The intra-day and inter-day coefficient of variation and percent error values of the assay method were less than 15% and mean recovery was more than 97 and 96% for BUSP and IS, respectively. The method was found to be precise, accurate, and specific during the study. The method was successfully applied for pharmacokinetic study of buspirone after application of reservoir based transdermal therapeutic system of BUSP to rabbits.