Saleh M. Al-Saidan

In vitro and in vivo evaluation of guar gum matrix tablets for oral controlled release of water-soluble diltiazem hydrochloride

The objective of the study was to develop guar gum matrix tablets for oral controlled release of water-soluble diltiazem hydrochloride. Matrix tablets of diltiazem hydrochloride, using various viscosity grades of guar gum in 2 proportions, were prepared by wet granulation method and subjected to in vitro drug release studies. Diltiazem hydrochloride matrix tablets containing either 30% wt/wt lowviscosity (LM1), 40% wt/wt medium-viscosity (MM2), or 50% wt/wt high-viscosity (HM2) guar gum showed controlled release. The drug release from all guar gum matrix tablets followed first-order kinetics via Fickian-diffusion. Further, the results of in vitro drug release studies in simulated gastrointestinal and colonic fluids showed that HM2 tablets provided controlled release comparable with marketed sustained release diltiazem hydrochloride tablets (D-SR tablets). Guar gum matrix tablets HM2 showed no change in physical appearance, drug content, or in dissolution pattern after storage at 40°C/relative humidity 75% for 6 months. When subjectd to in vivo pharmacokinetic evaluation in healthy volunteers, the HM2 tablets provided a slow and prolonged drug release when compared with D-SR tablets. Based on the results of in vitro and in vivo studies it was concluded that that guar gum matrix tablets provided oral controlled release of water-soluble diltiazem hydrochloride.

In Vitro and In Vivo Evaluation of Guar Gum-Based Matrix Tablets of Rofecoxib for Colonic Drug Delivery

The present study was carried out to develop and evaluate guar gum-based matrix tablets of rofecoxib for their intended use in the chemoprevention of colorectal cancer. Matrix tablets containing 40% (RXL-40), 50% (RXL-50), 60% (RXL-60) or 70% (RXL-70) of guar gum were prepared by wet granulation technique, and were subjected to in vitro drug release studies. Guar gum matrix tablets released only 5 to 12% of rofecoxib in the physiological environment of stomach and small intestine. The matrix tablets RXL-40 disintegrated completely within 10 h in a dissolution medium without rat caecal contents (control study), and hence not studied further. When the dissolution study was continued in simulated colonic fluids (rat caecal content medium), the matrix tablets RXL-50 were acted upon by colonic bacterial enzymes releasing the entire quantity of drug wherein there was no appreciable difference when compared to that released in control study. The matrix tablets RXL-60 released another 88% of rofecoxib whereas matrix tablets RXL-70 released only 57% of rofecoxib in simulated colonic fluids indicating the susceptibility of the guar gum formulations to the rat caecal contents. The guar gum matrix tablets RXL-70 were subjected to in vivo evaluation in human volunteers to find their ability of targeting rofecoxib to colon. The delayed Tmax, prolonged absorption time (ta), decreased Cmax and decreased ka indicated that rofecoxib was not released significantly in stomach and small intestine, but was delivered to colon resulting in a slow absorption of the drug and making it available for local action in human colon.

Effect of Nerodilol and Carvone on in vitro Permeation of Nicorandil Across Rat Epidermal Membrane

ABSTRACT The objective of the study was to investigate the effect of nerodilol and carvone on the in vitro transdermal delivery of nicorandil so as to fabricate a membrane-moderated transdermal therapeutic system. The in vitro permeation studies were carried across the rat epidermal membrane from the hydroxypropyl methylcellulose (HPMC) gels (prepared with 70:30 v/v ethanol–water) containing selected concentrations of a terpene such as nerodilol (0% w/w, 4% w/w, 8% w/w, 10% w/w, or 12% w/w) or carvone (0% w/w, 4% w/w, 8% w/w, 12% w/w, or 16% w/w). The amount of nicorandil permeated (Q24) from HPMC gel drug reservoir without a terpene was 3424.6 ± 51.4 μg/cm2, and the corresponding flux of the drug was 145.5 ± 2.2 μg/cm2· h. The flux of nicorandil increased with an increase in terpene concentration in HPMC gel. It was increased ranging from 254.9 ± 3.1 to 375.7 ± 3.2 μg/cm2·h or 207.6 ± 4.7 to 356.7 ± 15.3 μg/cm2· h from HPMC gels containing nerodilol (4% w/w to 12% w/w) or carvone (4% w/w to 16% w/w), respectively. Nerodilol increased the flux of nicorandil by about 2.62-folds whereas carvone increased the flux of the drug by about 2.49-folds across the rat epidermal membrane. The results of the Fourier Transform Infrared (FT-IR) study indicated that the enhanced in vitro transdermal delivery of nicorandil might be due to the partial extraction of stratum corneum lipids by nerodilol or carvone. It was concluded that the terpenes, nerodilol and carvone, produced a marked penetration enhancing effect on the transdermal delivery of nicorandil that could be used in the fabrication of membrane-moderated transdermal therapeutic systems.

Controlled in vivo release of nicorandil from a carvone-based transdermal therapeutic system in human volunteers.

The aim of our present study was to prepare and evaluate a carvone-based transdermal therapeutic system (TTS) of nicorandil to find its ability in providing the desired in vivo controlled release profile on dermal application to human volunteers. The effect of EVA 2825, and adhesive-coated EVA 2825, and adhesive-coated EVA 2825-rat skin composite on the in vitro permeation of nicorandil from a carvone-based HPMC gel drug reservoir was studied against a control (rat abdominal skin alone). The carvone-based drug reservoir system was sandwiched between adhesive-coated EVA 2825-release liner composite and a backing membrane. The resultant drug reservoir sandwich was heat-sealed to produce a circle-shaped TTS (20 cm2) that was subjected to in vivo evaluation on dermal application to human volunteers against oral administration of immediate-release tablets of nicorandil. The carvone-based TTS provided a steady-state plasma concentration of 20.5 ng/ml for ∼24 hr in human volunteers. We concluded that the carvone-based TTS of nicorandil provided the desired in vivo controlled-release profile of the drug for the predetermined period of time.

In vivo evaluation of limonene-based transdermal therapeutic system of nicorandil in healthy human volunteers.

Hydroxypropyl methylcellulose (HPMC) gel drug reservoir system prepared with 70:30 v/v ethanol-water solvent system containing 6% w/w of limonene was effective in promoting the in vitro transdermal delivery of nicorandil. The objective of the present study was to fabricate and evaluate a limonene-based transdermal therapeutic system (TTS) for its ability to provide the desired steady-state plasma concentration of nicorandil in human volunteers. The in vitro permeation of nicorandil from a limonene-based HPMC gel drug reservoir was studied across excised rat skin (control), EVA2825 membrane, adhesive-coated EVA2825 membrane and adhesive-coated EVA2825 membrane-excised rat skin composite to account for their effect on the desired flux of nicorandil. The flux of nicorandil from the limonene-based HMPC drug reservoir across EVA2825 membrane decreased to 215.8 ± 9.7µg/cm2·h when compared to that obtained from control, indicating that EVA2825 was effective as a rate-controlling membrane. The further decrease in nicorandil flux across adhesive-coated EVA2825 membrane and adhesive-coated EVA2825 membrane-excised rat skin composite showed that the adhesive coat and skin also controlled the in vitro transdermal delivery. The limonene-based drug reservoir was sandwiched between adhesive-coated EVA2825-release liner composite and a backing membrane. The resultant sandwich was heat-sealed as circle-shaped patch (20 cm2), trimmed and subjected to in vivo evaluation in human volunteers against immediate-release tablets of nicorandil (reference formulation). The fabricated limonene-based TTS of nicorandil provided a steady-state plasma concentration of 21.3 ng/ml up to 24 h in healthy human volunteers. It was concluded that the limonene-based TTS of nicorandil provided the desired plasma concentration of the drug for the predetermined period of time with minimal fluctuations and improved bioavailability.

Limonene enhances the in vitro and in vivo permeation of trimetazidine across a membrane-controlled transdermal therapeutic system.

The objective of the study was to design membrane-controlled transdermal therapeutic system (TTS) for trimetazidine. The optimization of (i) concentration of ethanol-water solvent system, (ii) HPMC concentration of drug reservoir and (iii) limonene concentration in 2% w/v HPMC gel was done based on the in vitro permeation of trimetazidine across excised rat epidermis. A limonene-based membrane-controlled TTS of trimetazidine was fabricated and evaluated for its in vivo drug release in rabbit model. The in vitro permeation of trimetazidine from water, ethanol and selected concentrations (25, 50 and 75% v/v) of ethanol-water co-solvent systems showed that 50% v/v of ethanol-water solvent system provided an optimal transdermal flux of 233.1+/-3.8 microg/cm(2.)h. The flux of the drug decreased to 194.1+/-7.4 microg/cm(2.)h on adding 2% w/v of HPMC to ethanolic (50% v/v ethanol-water) solution of trimetazidine. However, on adding selected concentrations of limonene (0, 2, 4, 6 and 8% w/v) to 2% w/v HPMC gel drug reservoir, the flux of the drug increased to 365.5+/-7.1 microg/cm(2.)h. Based on these results, 2% w/v HPMC gel drug reservoir containing 6% w/v of limonene was chosen as an optimal formulation for studying the influence of rate-controlling EVA2825 membrane and adhesive-coated EVA2825 membrane. The flux of the drug across EVA2825 membrane (mean thickness 31.2 microm) decreased to 285.8+/-2.2 microg/cm(2.)h indicating that the chosen membrane was effective as rate-controlling membrane. On applying an adhesive coat (mean thickness 10.2 microm) to EVA2825 membrane, the drug flux further decreased to 212.4+/-2.6 microg/cm(2.)h. However, the flux of the drug across adhesive-coated EVA2825 membrane-rat epidermis composite was 185.9+/-2.9 microg/cm(2.)h, which is about 2-times higher than the desired flux. The fabricated limonene-based TTS patch of trimetazidine showed a mean steady state plasma concentration of 71.5 ng/mL for about 14 h with minimal fluctuation when tested in rabbits. It was concluded from the investigation that the limonene-based TTS patch of trimetazidine provided constant drug delivery across the skin in rabbit model.

Transdermal Permeation of Trimetazidine from Nerodilol-Based HPMC Gel Drug Reservoir System across Rat Epidermis

Objective: To study the in vitro transdermal permeation of trimetazidine from hydroxypropylmethyl cellulose (HPMC) gel drug reservoir system using nerodilol as a penetration enhancer. Materials and Methods: An HPMC gel containing selected concentrations of nerodilol (0, 2, 4 or 5% w/v) and 2.5% w/v of trimetazidine was prepared, and subjected to in vitro permeation studies across rat epidermis. The amount of trimetazidine permeated at different time intervals (1, 2, 4, 8, 12, 18 and 24 h) was estimated, and the data were analyzed to calculate various permeation parameters. Results: There was an increase in the amount of trimetazidine (8,719.7 ± 153.3 µg/cm2)permeated across the rat epidermis up to 24 h (Q24) with an increase in nerodilol concentration (5% w/v) in HPMC gel drug reservoir. However, no significant difference (p > 0.05) was observed in the amount of drug permeated (Q24) with 5% w/v of nerodilol when compared to that obtained with 4% w/v of nerodilol (8,484.5 ± 165.8 µg/cm2). Nerodilol, at a concentration of 4% w/v enhanced the flux of trimetazidine across rat epidermis by about 1.96 times when compared to control. Conclusion: The HPMC gel drug reservoir containing 4% w/v of nerodilol showed optimal transdermal permeation of trimetazidine.