Development, optimization and in vivo characterization of domperidone-controlled release hot-melt-extruded films for buccal delivery.

OBJECTIVE: The aim of the present investigation was the development and in vivo characterization of domperidone (DOM) hot-melt extruded (HME) controlled release films by central composite design (CCD) for buccal delivery. METHODS: Concentration of PEO N750 (X1) and HPMC E5 LV (X2) as independent variables and tensile strength (Y1), percent drug release at 6 h (Q6, Y2) and percent drug permeated at 6 h (Y3, P6) as responses. In total, 13 formulations were prepared and studied. HME films were evaluated for drug excipient compatibility, physico-mechanical properties, drug content, in vitro drug release, bioadhesion, swelling and erosion, ex vivo permeation. Furthermore, statistically optimized formulation was subjected for bioavailability studies in healthy human volunteers. RESULTS: Statistically optimized formulation exhibited a tensile strength (3.86 kg/mm(2)), 93.62 ± 2.84% of drug release and 63.36 ± 2.12% of drug permeated in 6 h. HME films demonstrated no drug excipient interaction and excellent content uniformity. Furthermore, optimized formulation exhibited elongation at break (38.6% mm(2)), peak detachment force (1.75 N), work of adhesion (3.21 mJ), swelling index (240.4%) and erosion (8.5%). Bioavailability from the statistically optimized buccal films was 3.2 times higher than the oral dosage form (p < 0.05). The ex vivo-in vivo correlation was found to have biphasic pattern and followed type A correlation. The stability of the optimized formulation was studied and no significant changes were detected in 6 months. CONCLUSION: The results indicate that hot-melt extrusion is a viable technique for the preparation of DOM buccal-adhesive controlled release films with improved bioavailability by CCD.

Oral transmucosal delivery of domperidone from immediate release films produced via hot-melt extrusion technology.

The objective of the study was to prepare and characterize the domperidone (DOM) hot-melt extruded (HME) buccal films by both in vitro and in vivo techniques. The HME film formulations contained PEO N10 and/or its combination with HPMC E5 LV or Eudragit RL100 as polymeric carriers, and PEG3350 as a plasticizer. The blends were co-processed at a screw speed of 50 rpm with the barrel temperatures ranging from 120-160°C utilizing a bench top co-rotating twin-screw hot-melt extruder using a transverse-slit die. The HME films were evaluated for drug content, drug excipient interaction, in vitro drug release, mechanical properties, in vivo residence time, in vitro bioadhesion, swelling and erosion, ex vivo permeation from HME films and the selected optimal formulation was subjected for bioavailability studies in healthy human volunteers. The extruded films demonstrated no drug excipient interaction and excellent content uniformity. The selected HME film formulation (DOM2) exhibited a tensile strength (0.72 Kg/mm(2)), elongation at break (28.4% mm(2)), in vivo residence time (120 min), peak detachment force (1.55 N), work of adhesion (1.49 mJ), swelling index (210.2%), erosion (10.5%) and in vitro drug release of 84.8% in 2 h. Bioavailability from the optimized HME buccal films was 1.5 times higher than the oral dosage form and the results showed statistically significant (p < 0.05) difference. The ex vivo-in vivo correlation was found to have biphasic pattern and followed type A correlation. The results indicate that HME is a viable technique for the preparation of DOM buccal-adhesive films with improved bioavailability characteristics.

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.

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.

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.

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.

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.

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.

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.

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.

Solubility and stability enhancement of atorvastatin by cyclodextrin complexation.

The objective of the study was to increase the solubility, stability, and dissolution rate of atorvastatin calcium (ATN Ca), a poorly water-soluble 3-hydroxy 3-methyl glutaryl CoA (HMG-CoA) reductase inhibitor through inclusion complexation with beta-cyclodextrin (beta-CD). The phase solubility profile indicated that the solubility of ATN Ca was significantly increased in the presence of beta-CD and was classified as AL-type, indicating the 1:1 stoichiometric inclusion complexes. Solid complexes prepared by physical mixing, kneading, co-evaporation, and freeze-drying methods were characterized using differential scanning calorimetry, fourier transform infrared spectroscopy, and powder X-ray diffractometry. In vitro studies showed that the solubility and dissolution rate of ATN Ca were significantly improved by complexation with beta-CD with respect to the drug alone. In contrast, freeze-dried product showed higher solubility and dissolution rates than the other complexes. ATN Ca unit dosage form was developed and evaluated for physico-chemical properties, stability, and dissolution rate. The stability of tablets was studied and no significant changes were detected in the dissolution profile of tablets after 1 month.

Development of novel bioadhesive buccal formulation of diltiazem: in vitro and in vivo characterization.

The aim of the investigation was to develop and evaluate buccoadhesive tablets of diltiazem hydrochloride (DZH) using hydroxypropyl methyl cellulose (HPMC) K4M and Carbopol 934 as mucoadhesive polymers. Formulations A1, A2, A3, A4, and B1, B2, and B3, were composed of HPMC K4M and Carbopol 934 at ratios of 1:2, 1:3, 1:4, 1:5, and 1:1, 1:2, 1:3, respectively. The developed formulations were evaluated for physicochemical, in vitro drug release, in vitro adhesion and in vivo studies in healthy human volunteers. The buccal absorption study in healthy volunteers revealed that about 36.86% of the drug was absorbed. Formulation A3 showed maximum release in 8 h. As the concentration of polymer in the formulation increased, the drug release decreased. The bioavailability of diltiazem from buccoadhesive tablets was 1.57-fold higher than oral tablets. The basic pharmacokinetic parameters, C(Max), T(Max), and the area under the curve, were calculated and showed statistically significant difference (P < 0.05) when the drug was given by the buccal route compared to that of oral tablet. The results indicate that suitable bioadhesive buccal tablets with improved bioavailability could be prepared.