Effect of HPMC and mannitol on drug release and bioadhesion behavior of buccal discs of buspirone hydrochloride: In-vitro and in-vivo pharmacokinetic studies

Delivery of orally compromised therapeutic drug molecules to the systemic circulation via buccal route has gained a significant interest in recent past. Bioadhesive polymers play a major role in designing such buccal dosage forms, as they help in adhesion of designed delivery system to mucosal membrane and also prolong release of drug from delivery system. In the present study, HPMC (release retarding polymer) and mannitol (diluent and pore former) were used to prepare bioadhesive and controlled release buccal discs of buspirone hydrochloride (BS) by direct compression method. Compatibility of BS with various excipients used during the study was assessed using DSC and FTIR techniques. Effect of mannitol and HPMC on drug release and bioadhesive strength was studied using a 3² factorial design. The drug release rate from delivery system decreased with increasing levels of HPMC in formulations. However, bioadhesive strength of formulations increased with increasing proportion of HPMC in buccal discs. Increased levels of mannitol resulted in faster rate of drug release and rapid in vitro uptake of water due to the formation of channels in the matrix. Pharmacokinetic studies of designed bioadhesive buccal discs in rabbits demonstrated a 10-fold increase in bioavailability in comparison with oral bioavailability of buspirone reported.     

Development of a buccal bioadhesive nicotine tablet formulation for smoking cessation

Bioadhesive buccal tablet formulations for delivery of nicotine into the oral cavity were developed. Carbomer (Carbopol)974P NF) (CP) and alginic acid sodium salt (NaAlg) were used as bioadhesive polymers in combination with hydroxypropyl methylcellulose (HPMC) at different ratios. Magnesium carbonate was incorporated into the formulations as a pH increasing agent. In vitro release and bioadhesion studies were performed on the developed tablets. In the formulations containing CP:HPMC, the NHT released increased with the increasing HPMC concentration whereas a decrease was observed with increasing HPMC concentration in formulations containing NaAlg:HPMC. The bioadhesive properties of the tablets containing NaAlg:HPMC was not affected by the concentration of the NaAlg (P>0.05) but increased significantly with the increasing CP concentration (P>0.05). A decrease in pH of the dissolution medium to acidic values was avoided by incorporation of magnesium hydroxide into the formulations. The developed formulations released NHT for 8h period, and remained intact except for the formulation containing CP:HPMC at 20:80 ratio.     

Polymer based solutions of bupranolol hydrochloride for intranasal systemic delivery

The present study was aimed at developing intranasal polymer based solutions as alternative route for systemic delivery of Bupranolol hydrochloride (BPH). It is a potent β-blocker drug which upon oral administration undergoes extremely high hepatic first-pass metabolism (>90% in humans). The polymeric solutions were prepared using varying concentrations of polymers like sodium alginate, chitosan, sodium carboxymethylcellulose, methylcellulose (MC), polyvinyl alcohol, carbopol, hydroxypropyl MC, and hydroxypropyl cellulose. The prepared formulations were evaluated in terms of pH of the solution, angular viscosity, drug content, gel strength, gelation temperature, in vitro drug release, in vivo pharmacodynamic studies, histopathological, and stability studies. Except MC based solutions, a biphasic pattern of drug release was obtained in all other cases. Nasal administration of selected batches of polymeric solutions were found to be nontoxic and were able to improve drug bioavailability when compared to oral, nasal, and intravenous solution administrations of BPH.     

Transbuccal permeation, anti-inflammatory activity and clinical efficacy of piroxicam formulated in different gels

In attempts to avoid the systemic side effects of piroxicam (PC) (e.g. gastrotoxicity), several buccal gel formulations containing PC were prepared and their effects on the characteristics of the drug permeation through rabbit buccal mucosa in-vitro were evaluated using a Franz-type diffusion cell. The general rank order of the total flux of 0.5% PC from gels was found to be: hydroxypropylmethylcellulose (HPMC, 2.5%) > hydroxypropylcellulose (HPC, 2.5%) >or= sodium alginate (Na alg., 7%) > methylcellulose (MC, 3%) > hydroxyethylcellulose (HEC, 1.5%) > carbopol 934 (Carb. 934, 1%) >or= sodium carboxymethylcellulose (NaCMC, 2%) > pluronic F-127 (PF-127, 20%) > polyvinyl alcohol (PVA, 10%). The effect of various penetration enhancers 1% sodium lauryl sulphate (NaLS), 3% sodium deoxycholate (NaDC), 3% sodium tauroglycocholate (NaTGC) on the rate of permeation across the excised buccal mucosa (of 0.5% PC in gels prepared using 3% MC, 2.5% HPMC or 7% Na alg. base) and histology of the buccal epithelium was also investigated. Pharmacodynamic evaluation of the anti-inflammatory activity of PC in these gel formulations (containing 3% NaDC as an enhancer) was carried out using the kaolin-induced rat paw oedema method. The results obtained indicated that PC administered in 7% Na alg. or 2.5% HPMC gel bases was significantly more effective than the 3% MC gel and oral drug solution in suppressing oedema formation in rats. Comparative clinical studies were conducted in patients with post-operative dental pain and oedema following maxillofacial operations. The results revealed that 7% Na alg. and 2.5% HPMC gel formulations applied to the buccal mucosa were slightly better than or equally effective to the orally administered commercial product (Feldene Flash) tablet) in reducing pain level, swelling and tenderness within a period of 4 days. These findings suggest that PC (0.5%) administered in the buccal gel may present a potential therapeutical use as a strong anti-inflammatory and analgesic agent.     

Development of a supersaturable SEDDS (S-SEDDS) formulation of paclitaxel with improved oral bioavailability

A new, supersaturable self-emulsifying drug delivery system (S-SEDDS) of paclitaxel was developed employing hydroxypropyl methylcellulose (HPMC) as a precipitation inhibitor with a conventional SEDDS formulation. In vitro dilution of the S-SEDDS formulation results in formation of a microemulsion, followed by slow crystallization of paclitaxel on standing. This result indicates that the system is supersaturated with respect to crystalline paclitaxel, and the supersaturated state is prolonged by HPMC in the formulation. In the absence of HPMC the SEDDS formulation undergoes rapid precipitation, yielding a low paclitaxel solution concentration. A pharmacokinetic study was conducted in male Sprague-Dawley rats to assess exposure after an oral paclitaxel dose of 10 mg/kg in the SEDDS formulations with (S-SEDDS) and without HPMC. The paclitaxel S-SEDDS formulation shows approximately 10-fold higher maximum concentration (C(max)) and five-fold higher oral bioavailability (F approximately 9.5%) compared with that of the orally dosed Taxol formulation (F approximately 2.0%) and the SEDDS formulation without HPMC (F approximately 1%). Coadministration of cyclosporin A (CsA), an inhibitor of P-glycoprotein and CYP 3A4 enzyme, at a dose of 5 mg/kg with the S-SEDDS formulation further increased the oral bioavailability (F approximately 22.6%). This assessment demonstrates that the systemic exposure of paclitaxel following oral administration can be substantially improved via the S-SEDDS approach.     

Benzydamine hydrochloride buccal bioadhesive gels designed for oral ulcers: Preparation,rheological, textural,mucoadhesive and release properties

This study developed and examined the characterization of Benzidamine hydrochloride (BNZ) bioadhesive gels as platforms for oral ulcer treatments. Bioadhesive gels were prepared with four different hydroxypropylmethylcellulose (HPMC) types (E5, E15, E50 and K100M) with different ratios. Each formulation was characterized in terms of drug release, rheological, mechanical properties and adhesion to a buccal bovine mucosa. Drug release was significantly decreased as the concentration and individual viscosity of each polymeric component increased due to improved viscosity of the gel formulations. The amount of drug released for the formulations ranged from 0.76?±?0.07 and 1.14?±?0.01 (mg/cm²?±?SD). Formulations exhibited pseudoplastic flow and all formulations, increasing the concentration of HPMC content significantly raised storage modulus (G′), loss modulus (G″), dynamic viscosity (?′) at 37°C. Increasing concentration of each polymeric component also significantly improved the hardness, compressibility, adhesiveness, cohesiveness and mucoadhesion but decreased the elasticity of the gel formulations. All formulations showed non-Fickian diffusion due to the relaxation and swelling of the polymers with water. In conclusion, the formulations studied showed a wide range of mechanical and drug diffusion characteristics. On the basis of the obtained data, the bioadhesive gel formulation which was prepared with 2.5% HPMC K 100M was determined as the most appropriate formulation for buccal application in means of possessing suitable mechanical properties, exhibiting high cohesion and bioadhesion.     

Nanotransfersomes-loaded thermosensitive in situ gel as a rectal delivery system of tizanidine HCl: preparation,in vitro and in vivo performance

The purpose of the current study was to develop tizanidine HCl (TIZ; a myotonolytic agent used for treatment of spasticity) loaded nanotransfersomes intended for rectal administration, aiming to bypass the hepatic first-pass metabolism. TIZ-loaded nanotransfersomes were prepared by thin-film hydration method followed by characterization for various parameters including entrapment efficiency, vesicle diameter, in vitro release and ex vivo permeation studies. Transfersomal formulation composed of phosphatidylcholine and Tween 80 at a weight ratio of (85:15) gave a satisfactory results. It exhibited encapsulation efficiency of 52.39%, mean diameter of 150.33?nm, controlled drug release over 8?h and good permeation characteristics. Optimum formula was then incorporated into Pluronic-based thermoreversible gel using hydroxypropyl methylcellulose (HPMC) as a mucoadhesive polymer. Pharmacokinetic study was performed by rectal administration of transfersomes-loaded in situ gel to rabbits and compared with oral drug solution and rectal TIZ in situ gel. The pharmacokinetic study revealed that the transfersomal formulation successively enhanced the bioavailability of TIZ by about 2.18-fold and increased t_1/2 to about 10?h as compared to oral solution. It can be concluded that encapsulation of TIZ into nanotransfersomes can achieve a dual purpose of prolonged TIZ release and enhanced bioavailability and so may be considered as a promising drug delivery system for the treatment of spasticity.     

Oromucosal delivery of venlafaxine by linseed mucilage based gel: in vitro and in vivo evaluation in rabbits

Linseed is the crop that is used as a foodstuff in European and Asian countries. The objective of the present work was to extract mucilage from linseed, utilize it as mucoadhesive gelling agent along with synthetic polymers and administration of venlafaxine by buccal route in the gel form. Buccal administration of venlafaxine will avoid first pass metabolism, which will increase the bioavailability of the drug. Linseed mucilage based buccal mucoadhesive gel preparations in combination with chitosan, carbopol 934P, carboxy methylcellulose and polyvinyl pyrrolidone were formulated and the viscosity, gel strength, percentage mucoadhesion and in vitro diffusion of the formulation was evaluated. Formulation (F2) was subjected to in vivo analysis in rabbits. Formulation F2, which contained linseed mucilage (2 %) and chitosan (0.5 %), showed the highest percentage of mucoadhesion, gel strength and sustained drug diffusion. The bioavailability by the oral route and buccal route were compared with that of the intravenous route. The bioavailability of venlafaxine in the formulation F2 was 63.08 ± 1.28 % by buccal route, which was higher than by the oral route (39.21 ± 6.18 %). Based on these results, the combination of linseed mucilage and chitosan can be used to form a buccal mucoadhesive gel and increase the bioavailability of venlafaxine.     

Physical characterization of HPMC and HEC and investigation of their use as pelletization aids

Pelletization of drugs with suitable excipients by extrusion/spheronization is one of the popular approaches in the development of solid dosage forms, especially for extended-release formulations. However, the choice of pelletization aids is limited to the use of microcrystalline cellulose (MCC), which is generally wet massed using water. In the formulation of water-sensitive drugs, however, pelletization excipients which may be wet massed using an organic liquid are desired. In the present study therefore, two cellulose ethers, hydroxypropyl methylcellulose (HPMC) and hydroxyethyl cellulose (HEC), were characterized for their physical properties, such as moisture content, bulk and tapped densities, median particle size and size distribution, surface area and surface morphology, in an attempt to evaluate the feasibility of their use as pelletization aids. Since HPMC and HEC are water-soluble, but insoluble in isopropyl alcohol, the latter was used as the wet massing liquid for pelletization. Microcrystalline cellulose, because of its established uniqueness as a pellet former, was used as the reference material and was also wet massed using isopropyl alcohol for consistency and comparison. Placebo pellets of the three cellulosic excipients, HPMC, HEC and MCC, were prepared by extrusion/spheronization. The placebo pellets were evaluated for their size and size distribution, hardness, friability, bulk and tapped densities and sphericity. Of the three cellulosic excipients, HPMC and MCC produced pellets with the most desirable attributes. In water as the dissolution medium, the HPMC pellets absorbed water and formed a single viscous gel matrix that slowly dissolved. HEC pellets were swollen but intact and slowly eroded, whereas MCC pellets stayed intact without dissolution or erosion. These findings indicate that HPMC will find application in pellet formulations of water-sensitive drugs, as well as in those formulations where water may not be used as wet massing liquid and an organic liquid must be used. It will also be a good choice as a pelletization excipient when complete water-solubility of all the formulation excipients is desired. It may be anticipated that modification of drug release from pelletized formulations may also be achieved by using cellulose ethers of varying viscosity grades and hydration rates.     

Nasal residence of insulin containing lyophilised nasal insert formulations, using gamma scintigraphy.

Bioadhesive dosage forms are a potential method for overcoming rapid mucociliary transport in the nose. A lyophilised nasal insert formulation previously investigated in sheep demonstrated prolonged absorption of nicotine hydrogen tartrate suggestive of extended nasal residence, and increased bioavailability. The current study was performed to quantify nasal residence of the formulations using gamma scintigraphy, and to investigate the absorption of a larger molecule, namely insulin. A four-way crossover study was conducted in six healthy male volunteers, comparing a conventional nasal spray solution with three lyophilised nasal insert formulations (1-3% hydroxypropylmethylcellulose (HPMC)). The conventional nasal spray deposited in the posterior nasal cavity in only one instance, with a rapid clearance half-life of 9.2 min. The nasal insert formulations did not enhance nasal absorption of insulin, however an extended nasal residence time of 4-5 h was observed for the 2% HPMC formulation. The 1% HPMC insert initially showed good spreading behaviour; however, clearance was faster than for the 2% formulation. The 3% HPMC nasal insert showed no spreading, and was usually cleared intact from the nasal cavity within 90 min. In conclusion, the 2% HPMC lyophilised insert formulation achieved extended nasal residence, demonstrating an optimum combination of rapid adhesion without over hydration.     

Intranasal bioavailability of buprenorphine in rabbit correlated to sheep and man

The purpose of the present study of buprenorphine is to add information about the correlation between various animal models and nasal bioavailabilities in man. PEG 300 was added to one formulation to study whether the addition of the co-solvent results in the same absorption pattern as seen for sheep. The bioavailability of intranasal buprenorphine 0.6 mg in PEG 300 and 5% dextrose was assessed in a cross-over study in six rabbits. The mean bioavailabilities, Tmax and Cmax were 46% (S.D. +/-13) and 53% (S.D. +/-17), 8 and 12 min, 28 and 27 ng/ml for 30% PEG 300 and 5% dextrose, respectively. No significant differences were found between the nasal buprenorphine formulations. The bioavailabilities in rabbit and sheep, respectively, were approximately 2.5 and four times higher than for man. The absorption rate was faster for rabbit and sheep than for man. It appears that rabbit and sheep bioavailability differ from humans, especially with respect to rate. PEG 300 do not increase the bioavailability of buprenorphine.     

Microdialysis sampling and the clinical determination of topical dermal bioequivalence

The influence of the deposition pattern and spray characteristics of nasal powder formulations on the insulin bioavailability was investigated in rabbits. The formulations were prepared by freeze drying a dispersion containing a physical mixture of drum dried waxy maize starch (DDWM)/Carbopol^® 974P (90/10, w/w) or a spray-dried mixture of Amioca^® starch/Carbopol^® 974P (25/75, w/w). The deposition in the nasal cavity of rabbits and in a silicone human nose model after actuation of three nasal delivery devices (Monopowder, Pfeiffer and experimental system) was compared and related to the insulin bioavailability. Posterior deposition of the powder formulation in the nasal cavity lowered the insulin bioavailability.

To study the spray pattern, the shape and cross-section of the emitted powder cloud were analysed. It was concluded that the powder bulk density of the formulation influenced the spray pattern. Consequently, powders of different bulk density were prepared by changing the solid fraction of the freeze dried dispersion and by changing the freezing rate during freeze drying. After nasal delivery of these powder formulations no influence of the powder bulk density and of the spray pattern on the insulin bioavailability was observed.     

Influence of multiple nasal administrations of bioadhesive powders on the insulin bioavailability

Peptides and more especially insulin are mainly used in therapies that need multiple drug administration. As peptides are highly potent, it is required that their bioavailability remains constant even during a long term administration. In this study, the bioavailability and blood glucose levels are reported after multiple nasal administration of insulin via two bioadhesive platforms consisting of a cospray dried mixture of Amioca® starch and Carbopol® 974P (1/3) and a physical mixture of drum dried waxy maize starch and Carbopol® 974P (9/1), respectively. The experiments were performed in rabbits and the formulations were administered during 8 consecutive days. The bioavailability and the maximal decrease of the blood glucose level were determined on the first and last day of the insulin administration. These two parameters were decreased on the eighth day compared with the first day of administration. When the formulations were not administered from day 2 until day 7, the bioavailability on the eighth day compared with the first day of administration was not modified. It was concluded that daily administrations of the bioadhesive formulations affected the nasal bioavailability of insulin in rabbits.     

Development and optimization of a novel oral controlled delivery system for tamsulosin hydrochloride using response surface methodology

The purpose of this study was to develop and optimize oral controlled-release formulations for tamsulosin hydrochloride using a combination of two cellulose ester derivatives, hydroxypropyl methylcellulose (HPMC) and hydroxypropyl methylcellulose phthalate (HPMCP), with Surelease as a coating material. A three-factor, three-level Box-Behnken design was used to prepare systematic model formulations, which were composed of three formulation variables, the content of HPMC (X(1)) and HPMCP (X(2)) and the coating level (X(3)), as independent variables. The response surface methodology (RSM) and multiple response optimization utilizing the polynomial equation were used to search for the optimal coating formulation with a specific release rate at different time intervals. The drug release percentages at 2, 3 and 5h were the target responses and were restricted to 15-30% (Y(1)), 50-65% (Y(2)) and 80-95% (Y(3)), respectively. The optimal coating formulation was achieved with 10% HPMC and 20% HPMCP at a coating level of 25%, and the observed responses coincided well with the predicted values from the RSM optimization technique. The drug release from pellets coated with the optimized formulation showed a controlled-release pattern (zero-order), in comparison with a commercial product (Harunal capsule). In conclusion, a novel, oral, controlled-release delivery system for tamsulosin hydrochloride was successfully developed by incorporating HPMC and HPMCP as coating additives into Surelease aqueous ethylcellulose dispersion.     

Bioavailability and in vitro oesophageal sticking tendency of hydroxypropyl methylcellulose capsule formulations and corresponding gelatine capsule formulations

The overall aim of the present study was to widen our knowledge about the biopharmaceutical behaviour of novel hydroxypropyl methylcellulose (HPMC)-based two-piece capsules by comparing them with the classic hard gelatine capsules. Firstly, the tendency of the HPMC capsules to stick to isolated porcine oesophageal preparation was evaluated. The force needed to detach the HPMC capsules from the oesophagus was significantly lower than that for the gelatine capsules (P<0.001), which is evidently an advantage of this new dosage form. The second aim was to investigate the possibility of preparing sustained-release capsules using different powdered HPMCs as diluents (K100, K4M and K15M) and the effect of the molecular weight of HPMC powder on the in vitro and in vivo behaviour of the capsules. In addition to peroral drug administration also rectal dosing was applied. Two groups of eight healthy volunteers participated in randomised, cross-over, single-dose studies. One group was administered capsules orally and the other rectally. There were no marked differences in the bioavailability properties of either the oral or rectal HPMC capsules containing ibuprofen as model drug as compared with corresponding gelatine capsule formulations. Using different viscosity grades of HPMC powders as diluents it was possible to control the absorption rate of the model drug both from gelatine and HPMC capsules as far as the oral route was concerned. After rectal administration there were no statistically significant differences between the formulations containing different grades of HPMC powder. Only partial correlation was observed between the results of the bioavailability studies and the in vitro dissolution studies. From a biopharmaceutical point of view these two shell materials can be regarded as interchangeable.     

Absorption Enhancement of Intranasally Administered Insulin by Sodium Taurodihydrofusidate (STDHF) in Rabbits and Rats

The enhancement of nasal insulin absorption by sodium taurodihydrofusidate (STDHF) was studied in rabbits and rats. Using identical nasal formulations remarkable interspecies differences were observed. The fusidate derivative at 1% (w/v) enhanced nasal insulin bioavailability from 0.9 to 5.2% and from 0.3 to 18.0% in rabbits and rats, respectively. In both species the insulin formulations with STDHF resulted in strong hypoglycemic responses. Coadministration with the trypsin inhibitor aprotinin tended further to increase insulin bioavailability in rats and decrease insulin bioavailability in rabbits; however, these aprotinin effects were not statistically significant. Addition of the aminopeptidase inhibitor bacitracin to the STDHF containing formulation did not have any effect on insulin bioavailability in rats. Hence, STDHF is a potent enhancer of nasal insulin absorption, probably both by facilitating insulin transport through the nasal mucosa and possibly also by inhibiting enzymatic degradation. Further, interspecies differences and, experimental animal conditions can greatly affect nasal drug absorption.     

Nasal administration of metoclopramide from different dosage forms: in vitro,ex vivo,and in vivo evaluation

Nasal drug delivery is an interesting route of administration for metoclopramide hydrochloride (MTC) in preventing different kind of emesis. Currently, the routes of administration of antiemetics are oral or intravenous, although patient compliance is often impaired by the difficulties associated with acute emesis or invasiveness of parenteral administration. In this perspective, nasal dosage forms (solution, gel, and lyophilized powder) of MTC were prepared by using a mucoadhesive polymer sodium carboxymethylcellulose (NaCMC). In vitro and ex vivo drug release studies were performed in a modified horizontal diffusion chamber with cellulose membrane and excised cattle nasal mucosa as diffusion barriers. The tolerance of nasal mucosa to the formulation and its components were investigated using light microscopy. In vivo studies were carried out for the optimized formulations in sheep and the pharmacokinetics parameters were compared with oral solution and IV dosage form. The release of MTC from solution and powder formulations was found to be higher than gel formulation (p?<?0.05). Histopathological examination did not detect any severe damage. Hydroxypropyl-β-cyclodextrin (HPβCD) used in powder formulations was found to be effective for enhancing the release and absorption of MTC. In contrast to in vitro and ex vivo experiments nasal bioavailability of gel is higher than those of solution and powder (p?<?0.05). In conclusion, the NaCMC gel formulation of MTC with mucoadhesive properties with increased permeation rate is promising for prolonging nasal residence time and thereby nasal absorption.     

In vitro release,rheological, and stability studies of mefenamic acid coprecipitates in topical formulations

A suitable topical formulation of mefenamic acid was developed in order to eliminate the gastrointestinal disorders associated with its oral administration. Drug coprecipitates prepared with different polymers at various drug-to-polymer ratios improved drug solubility and dissolution compared to pure drug and physical mixtures. PVP polymers (ratio 1:4) produced the best results. Aqueous ionic cream, ointments of absorption and water soluble bases and gels of methylcellulose, carboxymethylcellulose sodium, HPMC, Carbopol^® 934 and 940, and Pluronic^® F127 bases containing 1–10% drug as coprecipitates of PVP polymers (1:4) were prepared. The highest drug release was achieved at 1% drug concentration from water soluble base and methylcellulose among cream/ointment and gel bases, respectively. Gels, in general yielded better release than creams/ointments. All tested medicated creams/ointments exhibited plastic flow while all gels conformed to pseudoplasticity. Most of them showed thixotropy, a desired property of topical preparations. Stability studies revealed that HPMC and methylcellulose had the smallest changes in drug content, viscosity, and pH among the formulations. Considering drug release, rheological properties, and stability, methylcellulose gel containing 1% drug as coprecipitates of PVP K90 was the best among the studied formulations, was promising for improving bioavailability of mefenamic acid and can be used in future studies.     

Thermally reversible in situ gelling carbamazepine liquid suppository

Carbamazepine (CBZ), indicated for the control of epilepsy, undergoes extensive hepatic first-pass elimination after oral administration. A rectal dosage form of CBZ is not commercially available, although it is of particular interest when oral administration is impossible. Conventional suppositories can cause patient discomfort and may reach the end of the colon; consequently, the drug can undergo the first-pass effect. Mucoadhesive liquid suppositories of CBZ were prepared by adding carbopol to formulation of thermally gelling suppositories that contain 20% poloxamer 407 and either 15% poloxamer 188 or 1% methylcellulose. Gellan gum was also tried instead of 20% poloxamer. All formulations contained 10% CBZ. The characteristics of the suppositories differed depending on the formulation. The formula containing 20% poloxamer 407, 1% methylcellulose, and 0.5% carbopol showed reasonable gelation temperature, gel strength and bioadhesive force. The analysis of release mechanism showed that CBZ released from the suppositories by Fickian diffusion. In vivo evaluation of the same formulation showed higher peak plasma concentration of CBZ compared with the orally administered suspension containing the equivalent amount of drug. However, there was no statistical significant difference (p > 0.05) in extent of bioavailability between the liquid suppository and oral suspension as indicated by the values of AUC(0 - infinity), 17.9 and 18.8 micro g x h/ml, respectively. These results suggested that mucoadhesive in situ gelling liquid suppository could be an effective and convenient delivery system of carbamazepine.     

Transdermal administration of bromocriptine

Bromocriptine (BRC) has been mainly used for the inhibition of lactation, treatment of menstrual disorders, Parkinson disease, breast tumours, infertility and brain tumours as a dopamine agonist in clinics. But current BRC formulations have some side effects and bioavailability problems because of hepatic first pass effect. Transdermal application could be an alternative route to overcome all these problem and penetration properties of BRC has not been studied yet. Therefore, it was aimed to investigate the effectiveness of transdermal formulation of BRC which is applicable to the skin. For this purpose, a number of BRC gel formulations (Carbopol-934 (C-934), chitosan (CH) and Gantrez-SP215 (G-SP215) were developed and the effectiveness and bioavailability of the formulations were compared in rabbits. Commercial BRC tablets (Parlodel) were also given to rabbits orally and plasma levels were compared. The effects of two different penetration enhancers, sodium taurocholate (ST) and ethoxydiglycol-Transcutol) (TR) on the BRC penetration were also investigated. The skin samples from the dorsal part of the rabbit were removed after CH gel application and investigated under electron microscope to understand the effects of the gel on the penetration and the possible penetration mechanisms through skin were also discussed. In conclusion, CH gel formulation was found to be the best formulation and comparable blood BRC concentrations were obtained when applied to the rabbit skin. Higher blood levels were obtained with the use of CH. The main penetration process was found to be through transcellular route but some other mechanisms were also found to be incorporated, after microscopic investigation. CH gel was found to be a useful carrier for BRC administration through dermal route and the penetration enhancing effect and the mechanism of CH gel were first established in this study. It was concluded that transdermal delivery of BRC may be a very promising alternative route to the oral route for the treatment.