Preparation and evaluation of dual-mode floating gastroretentive tablets containing itraconazole

Abstract

The aims of the present study were to prepare new dual-mode floating gastroretentive tablets (DF-GRT) containing itraconazole (ITR) and to evaluate influence of the dosage forms on pharmacokinetic parameters of ITR. The solubility of ITR was enhanced around 200 times (from 1.54 to 248.38?µg/mL) by preparing solid dispersion (SD) with hydroxypropylmethyl cellulose. Buoyancy of DF-GRT containing ITR-SD was established by both camphor sublimation and gas generation. Camphor sublimation decreased density of DF-GRT by making pores in tablet matrix, which led to elimination of lag time for floating. Carbon dioxide generated by sodium bicarbonate and citric acid helped to maintain buoyancy of DF-GRT. Therefore DF-GRT floated on the medium without lag time until disintegrated entirely during in vitro release study. They released 89.11% of the drug at 2?h. Residual camphor was <0.5?wt% after sublimation. The pharmacokinetics of DF-GRT was evaluated in six miniature pigs and compared to immediate release tablets (IRT). Mean AUC ratio of GRT/IRT was 1.36 but there was no statistical difference between AUC values. However delayed t_max, increased MRT and equivalent C_max of DF-GRT supposed it could be a promising tool for gastroretentive drug delivery system containing ITR.     

Linseed hydrogel based floating drug delivery system for fluoroquinolone antibiotics: Design,in vitro drug release and in vivo real-time floating detection

Herein, we designed a novel gastroretentive drug delivery system as floating matrix tablets based on a polysaccharide material from linseeds (Linum usitatissimum L.) for fluoroquinolone antibiotics. A number of formulations were designed with a combination of linseed hydrogel (LSH) and different excipients to obtain a desired sustained release profile of moxifloxacin. The drug release study was performed basically at pH 1.2. However, the tablet may pass through the stomach to intestine due to certain reasons then it also offered sustained drug release at intestinal pH 4.5, 6.8 and 7.4, as well. Results indicated that sustained moxifloxacin release was directly proportional to the concentration of LSH and the release of drug followed non-Fickian diffusion. SEM of the tablets indicated porous nature of LSH with elongated channels which contributed to the swelling of the tablet and then facilitated the discharge of moxifloxacin from the core of the tablet. In vivo X-ray study was performed to assess disintegration and real-time floating of tablet that confirmed its presence for 6 h in the stomach. These findings indicated that LSH can be used to develop novel gastroretentive sustained release drug delivery systems with the double advantage of sustained drug release at all pH of GIT.     

Design and evaluation of floating multi-layer coated tablets based on gas formation

Floating multi-layer coated tablets were designed based on gas formation. The system consists of a drug-containing core tablet coated with a protective layer (hydroxypropyl methylcellulose), a gas forming layer (sodium bicarbonate) and a gas-entrapped membrane, respectively. The mechanical properties of acrylic polymers (Eudragit^® RL 30D, RS 30D, NE 30D) and ethylcellulose were characterized by the puncture test in order to screen a suitable film for the system. Eudragit^® RL 30D was chosen as a gas-entrapped membrane due to its high flexibility and high water permeability. The obtained tablets enabled to float due to the CO₂-gas formation and the gas entrapment by polymeric membrane. The effect of formulation variables on floating properties and drug release was investigated. The floating tablets using direct-compressed cores had shorter time to float and faster drug release than those using wet-granulated cores. The increased amount of a gas forming agent did not affect time to float but increased the drug release from the floating tablets while increasing coating level of gas-entrapped membrane increased time to float and slightly retarded drug release. Good floating properties and sustained drug release were achieved. These floating tablets seem to be a promising gastroretentive drug delivery system.     

Comparative evaluation of drug release from aged prolonged polyethylene oxide tablet matrices: effect of excipient and drug type

Polyethylene oxide (PEO) undergoes structural adjustments caused by elevated temperatures, which results in loss of its stability within direct compression tablets. The aim of this study was to evaluate the influence of filler solubility on the drug delivery process of matrix tablets containing drugs with different water-solubility properties and stored at elevated temperature. The results demonstrated that in the case of propranolol HCl (highly water-soluble) tablet matrices, soluble lactose promoted drug release, whereas, a stable release of drug was observed with insoluble DCP. A drug release pattern similar to the propranolol HCl formulation containing DCP was obtained for hydrophilic matrix tablets containing either lactose or DCP for the less water-soluble drug, zonisamide. In the case of the partially water-soluble drug, theophylline, formulated with lower molecular weight PEO 750, drug release increased considerably in the presence of both fillers with increasing storage time, however a stable release rate (similar to fresh samples) was observed in the case of higher molecular weight PEO 303 tablet matrices containing theophylline with either lactose or DCP. The hydration properties (e.g. solubility) of the diluents had a considerable effect on drug release behavior from various model matrices; this effect was dependent on both molecular weight of PEO and solubility of drug.     

Carboxymethyl high amylose starch for F4 fimbriae gastro-resistant oral formulation

Texture analysis is a new approach in pharmaceutical research and development; this study evaluated the correlation between drug dissolution and polymer hydration from a modified release matrix tablet of pseudoephedrine hydrochloride using a texture analyzer. A series of matrix tablets of pseudoephedrine was designed and prepared. Modified drug release was achieved by combined use of matrix excipients Polyox WSR301 (PEO) and Compritol 888ATO (GB). Dissolution profiles of the tablets were assessed using USP Method II. Polymer swelling behaviors during dissolution were measured using a texture analyzer. Increase in proportion of PEO and GB in the formulation reduced drug dissolution within the first 90 min. However, drug release was complete in 6h due to high aqueous solubility of pseudoephedrine. Linear correlations were observed among drug dissolution, polymer content and parameters of texture analysis including hydrogel thickness and AUC(TA) for formulations that contained hydrophilic PEO. The study demonstrated a unique application of a texture analyzer in characterization of modified release matrix tablets.     

Floating matrix tablets based on low density foam powder: effects of formulation and processing parameters on drug release.

The aim of this study was to develop and physicochemically characterize single unit, floating controlled drug delivery systems consisting of (i). polypropylene foam powder, (ii). matrix-forming polymer(s), (iii). drug, and (iv). filler (optional). The highly porous foam powder provided low density and, thus, excellent in vitro floating behavior of the tablets. All foam powder-containing tablets remained floating for at least 8 h in 0.1 N HCl at 37 degrees C. Different types of matrix-forming polymers were studied: hydroxypropyl methylcellulose (HPMC), polyacrylates, sodium alginate, corn starch, carrageenan, gum guar and gum arabic. The tablets eroded upon contact with the release medium, and the relative importance of drug diffusion, polymer swelling and tablet erosion for the resulting release patterns varied significantly with the type of matrix former. The release rate could effectively be modified by varying the "matrix-forming polymer/foam powder" ratio, the initial drug loading, the tablet geometry (radius and height), the type of matrix-forming polymer, the use of polymer blends and the addition of water-soluble or water-insoluble fillers (such as lactose or microcrystalline cellulose). The floating behavior of the low density drug delivery systems could successfully be combined with accurate control of the drug release patterns.     

Development and optimization of metoprolol succinate gastroretentive drug delivery system

Metoprolol succinate (MS) gastroretentive (GR) controlled release system was formulated to increase gastric residence time leading to improved drug bioavailability. Box-Behnken model was followed using novel combinations of sodium alginate (SA), sodium carboxymethylcellulose (NaCMC), magnesium alumino metasilicate (MAS) as independent variables. Floating lag time (Flag), t25, t50, t75, diffusion exponent as dependent variables revealed that the amount of SA, NaCMC and MAS have a significant effect (p < 0.05) on t25, t50, t75 and Flag. MSGR tablets were prepared and evaluated for mass, thickness, hardness, friability, drug content and floating property. Tablets were studied for dissolution for 24 h and exhibited controlled release of MS with floating for 16 h. The release profile of the optimized batch MS01 fitted first-order kinetics (R2 = 0.9868, n = 0.543), indicating non-Fickian diffusion or anomalous transport by diffusion and swelling.     

Design,Development and Optimization of S (-) Atenolol Floating Sustained Release Matrix Tablets Using Surface Response Methodology

The objective of this present investigation was to develop and formulate floating sustained release matrix tablets of s (-) atenolol, by using different polymer combinations and filler, to optimize by using surface response methodology for different drug release variables and to evaluate the drug release pattern of the optimized product. Floating sustained release matrix tablets of various combinations were prepared with cellulose-based polymers: Hydroxypropyl methylcellulose, sodium bicarbonate as a gas generating agent, polyvinyl pyrrolidone as a binder and lactose monohydrate as filler. The 3² full factorial design was employed to investigate the effect of formulation variables on different properties of tablets applicable to floating lag time, buoyancy time, % drug release in 1 and 6 h (D_{1 h,}D_{6 h}) and time required to 90% drug release (t_90%). Significance of result was analyzed using analysis of non variance and P < 0.05 was considered statistically significant. S (-) atenolol floating sustained release matrix tablets followed the Higuchi drug release kinetics that indicates the release of drug follows anomalous (non-Fickian) diffusion mechanism. The developed floating sustained release matrix tablet of improved efficacy can perform therapeutically better than a conventional tablet.     

Formulation design and optimization of fast dissolving clonazepam tablets by sublimation method

Fast dissolving tablets of clonazepam were prepared by sublimation method with a view to enhance patient compliance. A 3(2) full factorial design was applied to investigate the combined effect of two formulation variables: amount of croscarmellose sodium and camphor. Croscarmellose sodium (2-8% w/w) was used as superdisintegrant and camphor (20-40% w/w) was used as subliming agent, to increase the porosity of the tablets, since it helps water to penetrate into the tablets, along with directly compressible mannitol to enhance mouth feel. The tablets were evaluated for hardness, friability, thickness, drug content uniformity, in vitro dispersion time, wetting time and water absorption ratio. Based on in vitro dispersion time (approximately 11 s); the formulation containing 5% w/w croscarmellose sodium and 40% w/w camphor was found to be promising and tested for in vitro drug release pattern (in pH 6.8 phosphate buffer). Short-term stability (at 40°/75% relative humidity for 3 mo) and drug-excipient interaction. Surface response plots are presented to graphically represent the effect of independent variables on the in vitro dispersion time. The validity of the generated mathematical model was tested by preparing two extra-design checkpoints. The optimized tablet formulation was compared with conventional commercial tablet formulation for drug release profiles. This formulation showed nearly nine-fold faster drug release (t(50%) 1.8 min) compared to the conventional commercial tablet formulation (t(50%) 16.4 min). Short-term stability studies on the formulation indicated that there are no significant changes in drug content and in vitro dispersion time (P<0.05).     

Formulation Design and Optimization of Orodispersible Tablets of Quetiapine Fumarate by Sublimation Method

The objective of present study was to formulate directly compressible orodispersible tablets of quetiapine fumarate by sublimation method with a view to enhance patient compliance. A full 3² factorial design was used to investigate the effect of two variables viz., concentration of Indion 414 and camphor. Indion 414 (3-5 % w/w) was used as superdisintegrant and camphor (5-15 % w/w) as subliming agent. The tablets were evaluated for thickness, weight variation, hardness, friability, content uniformity, wetting time, porosity, in vitro disintegration time and in vitro drug release. The formulation containing 5% w/w of Indion 414 and 5% w/w camphor was emerged as promising based on evaluation parameters. The disintegration time for optimized formulation was 18.66 s. The tablet surface was evaluated for presence of pores by scanning electron microscopy before and after sublimation. Differential scanning colorimetric study did not indicate any drug excipient incompatibility, either during mixing or after compression. The effect of independent variables on disintegration time, % drug release and friability is presented graphically by surface response plots. Short-term stability studies on the optimized formulation indicated no significant changes in drug content and in vitro disintegration time. The directly compressible orodispersible tablets of quetiapine fumarate with lower friability, greater drug release and shorter disintegration times were obtained using Indion 414 and camphor at optimum concentrations.     

Properties of sustained-release tablets prepared by hot-melt extrusion

The objectives of the present study were to investigate the properties of polyethylene oxide (PEO) as a drug carrier and to study the release mechanism of chlorpheniramine maleate (CPM) from matrix tablets prepared by hot-melt extrusion. During the hot-melt extrusion process, a dry powder blend of drug, polymer, and other adjuvants was fed into the extruder and melted inside the barrel of the machine. The molten mass was extruded through a rod-shaped die and then cut manually into 400-mg tablets. CPM and PEO were shown to be stable under the processing conditions. The molecular weight of the PEO, the drug loading percentage, and the inclusion of polyethylene glycol as a processing aid, were all found to influence the processing conditions and the drug release properties of the extruded tablets. Faster release of CPM from the matrix tablets was observed in acidic medium than in purified water and phosphate buffer (pH 7.4). Drug release from the matrix tablet was controlled by erosion of the PEO matrix and the diffusion of the drug through the swollen gel layer at the surface of the tablets. CPM was dispersed at the molecular level in the PEO matrix at low drug loading level and recrystallization of CPM was observed at high drug loading levels. Hot-melt extrusion was demonstrated to be a viable novel method to prepare sustained-release tablets. PEO was shown to be a suitable polymeric carrier for this process.     

Freeze-Dried Highly Porous Matrix as a New Gastroretentive Dosage Form for Ecabet Sodium: In Vitro and In Vivo Characterizations

The aims of the present study were to prepare hydroxypropylmethyl cellulose-based matrix tablets prepared using the freeze-drying method for gastroretentive delivery of ecabet sodium (ECS), a locally acting antigastric ulcer drug, and to perform in vitro/in vivo characterizations.The freeze-dried gastroretentive tablets (FD-GRTs) had porous structures, while they had good friability as a pharmaceutical dosage form. The porous structures lowered the tablet density, allowing the tablet to float without any lag time. Buoyancy of FD-GRT was maintained until they were entirely disintegrated during an in vitro release study. Release rate of ECS could be controlled by the amount of ethylcellulose (EC) in FD-GRT. As amount of EC in the composition was increased, there was a decrease in both release rate and erosion rate of FD-GRT. When administered to a miniature pig, FD-GRT remained in the stomach for more than 12 h, which was significantly longer than a conventional sustained release tablet. The new FD-GRT do not contain any excipients for buoyancy and do not require any lag time for buoyancy, consequently it could be considered to be safer and more effective than conventional floating-type GRT.     

Design and in vitro testing of a floatable gastroretentive tablet of metformin hydrochloride

Metformin hydrochloride, which is better absorbed in the upper intestine, was formulated as a floating (buoyant) matrix tablet using a gas generating agent (sodium bicarbonate) and a gel forming hydrophilic polymer (hydroxypropyl methylcellulose). The formulation was optimized on the basis of floating ability and in vitro drug release. The resulting formulation produced robust tablets with optimum hardness, consistent weight uniformity and low tablet friability. All tablets but one exhibited satisfactory (gradual and near complete) drug release and buoyancy. In vitro drug release tests of these tablets indicated controlled sustained release of metformin hydrochloride and 96-99% released at the end of 8 h. Two formulations of fabricated tablets containing metformin hydrochloride (500 mg), sodium bicarbonate (75 mg), hydroxypropyl methylcellulose-K 4M (170-180 mg), citric acid (between 15 and 20 mg) and polyvinyl pyrrolidone K90 (32-40 mg) with hardness between 6.8 to 7.5 kg/cm2 showed a floating time of more than 8 h and promising drug release results. The release followed the Higuchi kinetic model, indicating diffusion dominated drug release.     

Modulation of drug release kinetics of shellac-based matrix tablets by in-situ polymerization through annealing process.

A new oral-controlled release matrix tablet based on shellac polymer was designed and developed, using metronidazole (MZ) as a model drug. The shellac-based matrix tablets were prepared by wet granulation using different amounts of shellac and lactose. The effect of annealing temperature and pH of medium on drug release from matrix tablets was investigated. The increased amount of shellac and increased annealing temperature significantly affected the physical properties (i.e., tablet hardness and tablet disintegration) and MZ release from the matrix tablets. The in-situ polymerization played a major role on the changes in shellac properties during annealing process. Though the shellac did not dissolve in acid medium, the MZ release in 0.1N HCl was faster than in pH 7.3 buffer, resulting from a higher solubility of MZ in acid medium. The modulation of MZ release kinetics from shellac-based matrix tablets could be accomplished by varying the amount of shellac or annealing temperature. The release kinetics was shifted from relaxation-controlled release to diffusion-controlled release when the amount of shellac or the annealing temperature was increased.     

Formulation and evaluation of famotidine floating tablets

The purpose of this investigation was to prepare a gastroretentive drug delivery system of famotidine. Floating tablets of famotidine were prepared employing two different grades of methocel K100 and methocel K15M by effervescent technique; these grades of methocel were evaluated for their gel forming properties. Sodium bicarbonate was incorporated as a gas-generating agent. The floating tablets were evaluated for uniformity of weight, hardness, friability, drug content, in vitro buoyancy and dissolution studies. The effect of citric acid on drug release profile and floating properties was investigated. The prepared tablets exhibited satisfactory physico-chemical characteristics. All the prepared batches showed good in vitro buoyancy. The tablet swelled radially and axially during in vitro buoyancy studies. It was observed that the tablet remained buoyant for 6-10 hours. Decrease in the citric acid level increased the floating lag time but tablets floated for longer duration. A combination of sodium bicarbonate (130mg) and citric acid (10mg) was found to achieve optimum in vitro buoyancy. The tablets with methocel K100 were found to float for longer duration as compared with formulations containing methocel K15M. The drug release from the tablets was sufficiently sustained and non-Fickian transport of the drug from tablets was confirmed.     

Cyclodextrin-containing poly(ethyleneoxide) tablets for the delivery of poorly soluble drugs: potential as buccal delivery system

The aim of this work was to develop a tablet for the buccal delivery of the poorly soluble drug carvedilol (CAR), based on poly(ethyleneoxide) (PEO) as bioadhesive sustained-release platform and hydroxypropyl-beta-cyclodextrin (HPbetaCD) as modulator of drug release. As first, PEO tablets loaded with CAR/HPbetaCD binary systems with different dissolution properties were tested for CAR and HPbetaCD release features and compared to PEO tablets containing only CAR. When the drug was incorporated as CAR/HPbetaCD freeze-dried product, all CAR content was released from the tablet in about 10 h, displaying a constant release regimen after a transient. The effect of HPbetaCD incorporation on the release mechanism, was rationalized on the basis of the interplay of different physical phenomena: erosion and swelling of the tablet, drug dissolution, drug counter-diffusion and complex formation. In the second part of the study, the potential of HPbetaCD-containing PEO tablets as buccal delivery system for CAR was tested. It was found that the incorporation of HPbetaCD in the tablet did not alter significantly its good adhesion properties. The feasibility of buccal administration of CAR was assessed by permeation experiments on pig excised mucosa. The amount of CAR permeated from PEO tablet was higher in the case of HPbetaCD-containing tablets, the maximum value being obtained for CAR/HPbetaCD freeze-dried system. Our results demonstrate that, when the tablet is employed as transmucosal system, the role of drug dissolution enhancement in the hydrated tablet is much more relevant than in solution for increasing the delivery rate.     

The physicodynamic properties of mucoadhesive polymeric films developed as female controlled drug delivery system

Phenoporlamine hydrochloride is a novel compound that is used for the treatment of hypertension. The purpose of this study was to develop a sustained release tablet for phenoporlamine hydrochloride because of its short biological half-life. Three floating matrix formulations of phenoporlamine hydrochloride based on gas forming agent were prepared. Hydroxypropyl methylcellulose K4M and Carbopol 971P NF were used in formulating the hydrogel drug delivery system. Incorporation sodium bicarbonate into matrix resulted in the tablet floating over simulated gastric fluid for more than 6 h. The dissolution profiles of all tablets showed non-Fickian diffusion in simulated gastric fluid. Moreover, release of the drug from these tablets was pH-dependent. In vivo evaluations of these formulations of phenoporlamine hydrochloride were conducted in six healthy male human volunteers to compare the sustained release tablets with immediate release tablets. Data obtained in these studies demonstrated that the floating matrix tablet containing more Carbopol was capable of sustained delivery of the drug for longer periods with increased bioavailability and the relative bioavailability of formulation (containing 25% Carbopol 971P NF, 8.3% HPMC K4M) showed the best bioequivalency to the reference tablet (the relative bioavailability was 1.11 ± 0.19).     

Novel sustained release, swellable and bioadhesive gastroretentive drug delivery system for ofloxacin

Oral sustained release gastroretentive dosage forms offer many advantages for drugs having absorption from upper gastrointestinal tract and improve the bioavailability of medications that are characterized by a narrow absorption window. A new gastroretentive sustained release delivery system was developed with floating, swellable and bioadhesive properties. All these properties were optimized and evaluated. Various release retarding polymers like psyllium husk, HPMC K100M and a swelling agent, crosspovidone in combinations were tried and optimized to get the release profile for 24 h. Formulations were evaluated for in vitro drug release profile, swelling characteristics and in vitro bioadhesion property. The in vitro drug release followed Higuchi kinetics and the drug release mechanism was found to be of anomalous or non-Fickian type. For the developed formulation, the value of n was found to be 0.5766 while for the marketed formulation the value was 0.5718 indicating the anomalous transport. The high water uptake leading to higher swelling of the tablet supported the anomalous release mechanism of ofloxacin. The similarity factor f2 was found to be 91.12 for the developed formulation indicating the release was similar to that of the marketed formulation (Zanocin OD). The swelling properties were increased with increasing crosspovidone concentration and contributed significantly in drug release from the tablet matrix. The bioadhesive property of the developed formulation was found to be significant (P < 0.005) in combination as compared to HPMC K100M and psyllium husk alone.     

Sustained-release effervescent floating matrix tablets of baclofen: development, optimization and in vitro-in vivo evaluation in healthy human volunteers

Background and the purpose of the study

Baclofen, a centrally acting skeletal muscle relaxant, is indicated in the long-term treatment of spasticity. It is difficult to formulate baclofen sustained release dosage forms because its absorption on arrival to colon (or even before) is low or nonexistent. In the present investigation efforts were made to improve the bioavailability of baclofen by increasing the residence time of the drug through sustained-release matrix tablet formulation via gastroretentive mechanism.

Methods

Tablets were prepared by wet granulation technique. The influence of gas generating and gel forming agents, amount of baclofen and total weight of tablet on physical properties, in vitro buoyancy, floating lag time, drug release, DSC, X-ray studies were investigated. The release mechanisms were explored and explained by applying zero order, first order, Higuchi and Korsmeyer equations. The selected formulations were subjected to stability study for the period of three months.

Results

For all formulations, kinetics of drug release from tablet followed Higuchi''s square root of time kinetic treatment heralding diffusion as predominant mechanism of drug release. Formulations containing 20 mg and 40 mg (F-1 and F-7) showed similar release profiles. There was no significant change in the selected formulations, when subjected to accelerated stability conditions over a period of three months. X-ray imaging in six healthy human volunteers revealed a mean gastric retention period of 5.50±0.7 hrs for the selected formulation.

Conclusion

Stable, sustained release effervescent floating matrix tablets of baclofen could be prepared by wet granulation technique.     

Formulation development of gastroretentive tablets of lamivudine using the floating-bioadhesive potential of optimized polymer blends

Objectives The current studies entail successful formulation of optimized gastroretentive tablets of lamivudine using the floating‐bioadhesive potential of carbomers and cellulosic polymers, and their subsequent in‐vitro and in‐vivo evaluation in animals and humans. Methods Effervescent floating‐bioadhesive hydrophilic matrices were prepared and evaluated for in‐vitro drug release, floatation and ex‐vivo bioadhesive strength. The optimal composition of polymer blends was systematically chosen using central composite design and overlay plots. Pharmacokinetic studies were carried out in rabbits, and various levels of in‐vitro/in‐vivo correlation (IVIVC) were established. In‐vivo gamma scintigraphic studies were performed in human volunteers using ^99mTc to evaluate formulation retention in the gastric milieu. Key findings The optimized formulation exhibited excellent bioadhesive and floatational characteristics besides possessing adequate drug‐release control and pharmacokinetic extension of plasma levels. The successful establishment of various levels of IVIVC substantiated the judicious choice of in‐vitro dissolution media for simulating the in‐vivo conditions. In‐vivo gamma scintigraphic studies ratified the gastroretentive characteristics of the optimized formulation with a retention time of 5 h or more. Conclusions Besides unravelling the polymer synergism, the study helped in developing an optimal once‐a‐day gastroretentive drug delivery system with improved bioavailability potential exhibiting excellent swelling, floating and bioadhesive characteristics.