Formulation and optimization of mucoadhesive buccal patches of losartan potassium by using response surface methodology.

BACKGROUND: This study was undertaken with an aim to systematically design a model of factors that would yield an optimized sustained release dosage form of an anti-hypertensive agent, losartan potassium, using response surface methodology (RSM) by employing 3(2) full factorial design. MATERIALS AND METHODS: Mucoadhesive buccal patches were prepared using different grades of hydroxypropyl methylcellulose (HPMC) (K4M and K100M) and polyvinylpyrrolidone-K30 by solvent casting method. The amount of the release retardant polymers - HPMC K4M (X1) and HPMC K100M (X2) was taken as an independent variable. The dependent variables were the burst release in 30 min (Y1), cumulative percentage release of drug after 8 h (Y2) and swelling index (Y3) of the patches. In vitro release and swelling studies were carried out and the data were fitted to kinetic equations. RESULTS: The physicochemical, bioadhesive, and swelling properties of patches were found to vary significantly depending on the viscosity of the polymers and their combination. Patches showed an initial burst release preceding a more gradual sustained release phase following a nonfickian diffusion process. DISCUSSION: The results indicate that suitable bioadhesive buccal patches with desired permeability could be prepared, facilitated with the RSM.

Possible involvement of GABAergic and nitriergic systems for antianxiety-like activity of piperine in unstressed and stressed mice.

BACKGROUND: An investigation was made to explore the possibility of anxiolytic activity of piperine in unstressed and stressed mice along with the underlying role of nitriergic and GABAergic modulation for the noted activity of piperine. METHODS: Piperine (5, 10 and 20mg/kg, ip) was administered to unstressed mice. In another groups of animals, piperine was administered 30 min before subjecting them to immobilization stress for 6h. Antianxiety activity was evaluated by employing elevated plus maze, light-dark box and social interaction test. Diazepam was employed as standard anxiolytic drug. RESULTS: Piperine produced significant antianxiety-like activity in unstressed and stressed mice. The anxiolytic-like activity of piperine was comparable to diazepam. In unstressed mice, piperine significantly increased brain GABA levels, but could not produce any change in plasma nitrite levels. Meanwhile, in stressed mice, piperine did not produce any significant change in GABA levels, but significantly decreased nitrite levels. Pre-treatment with aminoguanidine (50mg/kg, ip), an inducible nitric oxide synthase (NOS) inhibitor, significantly potentiated the anxiolytic-like activity of piperine, as compared to piperine and aminoguanidine alone in stressed mice. On the other hand, pretreatment with 7-nitroindazole (20mg/kg, ip), a neuronal NOS inhibitor significantly potentiated the antianxiety-like activity of piperine, as compared to piperine and 7-nitroindazole alone in unstressed mice. CONCLUSION: These data suggest that the piperine produced significant anxiolytic activity in unstressed mice possibly through increase in GABA levels and inhibition of neuronal NOS. On the other hand, antianxiety activity in stressed mice might be through inhibition of inducible NOS.

A clinical perspective on mucoadhesive buccal drug delivery systems.

Mucoadhesion can be defined as a state in which two components, of which one is of biological origin, are held together for extended periods of time by the help of interfacial forces. Among the various transmucosal routes, buccal mucosa has excellent accessibility and relatively immobile mucosa, hence suitable for administration of retentive dosage form. The objective of this paper is to review the works done so far in the field of mucoadhesive buccal drug delivery systems (MBDDS), with a clinical perspective. Starting with a brief introduction of the mucoadhesive drug delivery systems, oral mucosa, and the theories of mucoadhesion, this article then proceeds to cover the works done so far in the field of MBDDS, categorizing them on the basis of ailments they are meant to cure. Additionally, we focus on the various patents, recent advancements, and challenges as well as the future prospects for mucoadhesive buccal drug delivery systems.

Thymoquinone produced antianxiety-like effects in mice through modulation of GABA and NO levels.

The aim of the present study was to investigate the role of GABAergic and nitriergic modulation in the antianxiety effect of thymoquinone, a major constituent of Nigella sativa, in mice under unstressed and stressed conditions. Thymoquinone (10 and 20 mg/kg), methylene blue (1 mg/kg) and diazepam (2 mg/kg) were administered followed by behavioral testing using an elevated plus maze, the light/dark test and the social interaction test in both unstressed and stressed mice (mice subjected to 6 h immobilization). The effects of the above-mentioned drugs on plasma nitrite, a stable metabolite of nitric oxide (NO) and brain GABA content were also studied. Diazepam (2 mg/kg) produced significant anxiolytic-like effects only in unstressed mice. However, diazepam significantly increased the GABA content in both unstressed and stressed mice as compared with their respective control groups. Thymoquinone (10 and 20 mg/kg) produced significant antianxiety effects in unstressed mice without altering nitrite levels, but only the higher dose (20 mg/kg) of thymoquinone increased the GABA content in unstressed mice. In stressed mice, thymoquinone (20 mg/kg) showed anxiolytic effects, with a significant decrease in plasma nitrite and reversal of the decreased brain GABA content. Pre-treatment with methylene blue enhanced the antianxiety effect of thymoquinone in both unstressed and stressed mice. Therefore, the present study suggests an involvement of NO-cGMP and GABAergic pathways in the anxiolytic-like activity of thymoquinone.

Possible underlying influence of p38MAPK and NF-κB in the diminished anti-anxiety effect of diazepam in stressed mice.

The present study was designed to explore the possible nitriergic influence and role of p38MAPK and NF-κB in the diminished anti-anxiety effect of diazepam in stressed mice, using the elevated plus maze and light/dark box to assess anxiety. Immobilization stress for 6 h enhanced an anxiety-like behavior and increased plasma nitrite levels in mice. Diazepam (2 mg/kg, i.p.) produced an anti-anxiety effect in unstressed mice, but could not produce any change in anxiety levels of stressed mice. SB-203580 (2 mg/kg, i.p.), a specific inhibitor of p38MAPK, per se produced a significant antianxiety-like activity in stressed mice. Administration of a combination of SB-203580 (2 mg/kg, i.p.) and diazepam (2 mg/kg) in stressed mice produced a significantly higher antianxiety-like activity than that produced by SB-203580 alone. Pyrrolidine dithiocarbamate (PDTC), an inhibitor of the activation of NF-κB, per se produced a significant antianxiety-like activity in stressed mice. Combination of PDTC and diazepam also served to produce a higher significant antianxiety-like activity in stressed mice than that produced by PDTC alone. Diazepam could not produce any change in plasma nitrite levels in both unstressed and stressed mice. Both SB-203580 (2 mg/kg, i.p.) and PDTC (100 mg/kg, i.p.) significantly decreased plasma nitrite levels in stressed mice. The observations indicate that the diminished anti-anxiety effect of diazepam in stressed mice may involve strong nitriergic influence and may further be p38MAPK- and NF-κB-dependent.

Differential effects of nitric oxide synthase inhibitors on anxiety in unstressed and stressed mice.

Effects of selective nitric oxide synthase (NOS) inhibitors, 7-nitroindazole (7-NI), a selective inhibitor of neuronal nitric oxide synthase (nNOS) and aminoguanidine (AG), a selective inhibitor of inducible nitric oxide synthase (iNOS) on anxiety in unstressed and stressed mice were investigated using elevated plus maze (EPM) test and light-dark test (LDT). 7-NI (20 and 40 mg/kg, ip) produced anti-anxiety effect in unstressed mice but not in stressed mice. AG (50 and 100 mg/kg, ip) produced anxiolytic effect in stressed mice and failed to produce the similar effect in unstressed mice. Nitrite levels were increased in stressed mice, but not in unstressed mice, exposed to EPM and LDT for 5 min. Increased nitrite levels in stressed mice were attenuated by AG, but not by 7-NI. The effects of AG were enhanced by pyrrolidine-dithio-carbamate (PDTC), an inhibitor of NF-kappaB induction, in stressed mice. The results suggest the possible role of inducible nitric oxide synthase in stress-induced anxiogenesis as compared to unstressed mice, where neuronal form of NOS may plays predominant role.

GABAergic and nitriergic modulation by curcumin for its antianxiety-like activity in mice.

In the present study, effect of curcumin (10 and 20mg/kg), an active constituent of Curcuma longa was evaluated for its antianxiety-like activity in mice subjected to immobilization-induced restraint stress for 6h. The effect on anxiety was assessed by employing elevated plus maze, open field test, light/dark test and social interaction test. Only the higher dose (20mg/kg, i.p.) of curcumin produced significant antianxiety-like effect in stressed mice. Pre-treatment with aminoguanidine (50mg/kg; i.p.), an inducible nitric oxide synthase inhibitor significantly enhanced the anxiolytic-like effect of curcumin in stressed mice as compared to curcumin and aminoguanidine per se in stressed mice. Pretreatment with 7-nitroindazole (20mg/kg), a neuronal nitric oxide synthase inhibitor did not significantly affect the antianxiety-like response of curcumin in stressed mice as compared to curcumin per se. Restraint stress significantly increased plasma nitrite levels in mice. Curcumin (20mg/kg, i.p.) and aminoguanidine significantly decreased plasma nitrite levels in stressed mice. The combination of aminoguanidine and curcumin significantly decreased the plasma nitrite levels as compared to curcumin and aminoguanidine per se in stressed mice. Curcumin and aminoguanidine did not produce any significant change in brain GABA contents of the animals. Diazepam (2mg/kg) produced significant anxiolytic-like effect only in unstressed mice, but could not exert significant anxiolysis in stressed mice. However, diazepam significantly increased GABA contents in both unstressed and stressed mice as compared to respective control groups. These findings suggest the possible involvement of only inducible NOS and not neuronal NOS in antianxiety-like effect of curcumin.

Piroxicam bioadhesive ocular inserts: physicochemical characterization and evaluation in prostaglandin-induced inflammation.

PURPOSE: An attempt has been made in the present research to formulate piroxicam into bioadhesive ocular inserts with an objective to sustain drug release, reduce frequency of dosing, and enhance ocular bioavailability of piroxicam. MATERIAL AND METHODS: Drug matrices were prepared using film forming polymer, PVP and bioadhesive polymers, HPMC, CMC, and carbopol. Ocular inserts were prepared by film casting method and prepared films were subjected to investigations for their physical and mechanical properties, swelling behaviors, ex vivo bioadhesion, and in vitro drug release. The optimized formulation was tested and compared with eye drops of piroxicam for ocular anti-inflammatory activity in rabbits against PGE(2)-induced inflammation. RESULTS: The physicochemical, bioadhesive, and swelling properties of films were found to vary significantly depending on the type of the polymers and their combination. The above properties were found to be optimum for all films; however, formulation containing carbopol 0.5% and HPMC 1% was found to be the best film as it shows good adhesion, acceptable pH, and gives a reasonable drug release (99% at 12 hr). Kinetic studies indicated both diffusion and swelling as mechanism of drug release from this matrix. Further in vivo studies with this formulation indicated a significant inhibition of PGE(2)-induced lid closure and PMN migration as compared to eye drops formulation. CONCLUSION: Formulation was found promising, as it sustained the drug release and enhanced the ocular bioavailability of piroxicam as compared to piroxicam eye drops.

Involvement of NO-cGMP pathway in anti-anxiety effect of aminoguanidine in stressed mice.

In the present study, effect of aminoguanidine (12.5, 25 and 50mg/kg, i.p.), a selective inhibitor of inducible nitric oxide synthase, was evaluated for its anti-anxiety activity in stressed mice employing elevated plus maze, open field test, light/dark test and social interaction test. Restraint stress induced by immobilizing for 6h enhanced an anxiety-like behavior and increased plasma nitrite levels in mice. Only the highest dose (50mg/kg) employed of aminoguanidine attenuated the stress-induced anxiety-like behavior and decreased plasma nitrite levels. There was no significant anxiolytic effect of aminoguanidine in unstressed mice. Sildenafil (1mg/kg i.p.), was used to explore the probable mechanism of anti-anxiety activity of aminoguanidine through NO-cGMP signaling. Aminoguanidine (50mg/kg) attenuated the anxiogenic effect of sildenafil. Aminoguanidine and sildenafil per se and in combination did not affect the locomotor activity of stressed and unstressed mice as compared to their respective control groups. Thus, aminoguanidine produced anti-anxiety activity in stressed mice through iNOS-NO-cGMP pathway.

Involvement of p38 Mapkinase in attenuation of antinociceptive effect of morphine in diabetic mice.

Experimental diabetes induced by streptozotocin (200 mg/kg, ip) markedly decreased the antinociceptive effect of morphine and significantly increased the urinary nitrite concentration. Administration of FR-167653 (a selective p38MAPKinase inhibitor) in a dose of 4 mg/kg improved the antinociceptive effect of morphine and attenuated the increase in urinary nitrite concentration in diabetic mice. It may be concluded that diabetes-induced decrease in antinociceptive effect of morphine may be due to induction of p38 MAPKinase activity.