Immediate Release Layer Research Articles

BILAYER TABLET OF TRAMADOL AND GABAPENTIN FOR COMBINATION PHARMACOTHERAPY OF NEUROPATHIC PAIN: DEVELOPMENT AND CHARACTERIZATION

Objective: Experiments were performed to design, develop and characterize bilayer buoyant tablets having tramadol (TH), immediate release (IR) layer and gabapentin (GBP), sustained release (SR) layer.Methods: Natural hydrophilic polysaccharide disintegrants were modified by sequential processes to obtain treated xanthan gum (TXG) and treated gellan gum (TGG), utilized for IR layer whereas carbopol and sodium carboxymethylcellulose, as sustaining polymers for SR layer and gas producing substance sodium bicarbonate which librates carbon dioxide for adequate buoyancy, was used in formulated bilayer tablet. A full two-level factorial experimental design was used for sustaining GBP release from buoyant SR layer.Results: Fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC) studies conducted, explain overall drug and excipients compatibility. More than 90% of tramadol was released from IR layer within 30 min. Diffusion exponents (0.36-0.59) and T50% (2.4-4.4h) were determined for all SR tablet formulations. Optimised (S7) formulation exhibited 95.77% GBP released over 12h.Conclusion: Developed tablet can provide excellent therapeutic result by the sequential immediate release of TH and sustained release of GBP for effective combination pharmacotherapy of neuropathic pain with once a day administration.

Development of Tizanidine HCl-Meloxicam loaded mucoadhesive buccal films: In-vitro and in-vivo evaluation.

The purpose of the study was to develop Tizanidine HCl (TZN) and Meloxicam (MLX) loaded bilayer mucoadhesive films intended for buccal administration, aiming to enhance the bioavailability. Bilayer films were prepared by solvent evaporation technique selecting arabinoxylan (ARX) as a sustained release (SR) layer forming polymer and hydroxypropyl methylcellulose (HPMC) E-15 as an immediate release (IR) layer-forming polymer. Prepared films were subjected to in-vitro drug release, surface morphology, mechanical strength, compatibility of the ingredients, drug contents, ex-vivo mucoadhesion strength and drug permeation. Crossover study design was applied to study the in-vivo pharmacokinetics by using albino rabbits. Various pharmacokinetic parameters including AUC, Cmax, tmax and t1/2 of both drugs loaded in films were compared with standard solution/dispersion administered to the rabbits at the dose of 1mg/kg. The results unveiled instant release and permeation of MLX from IR layer, while good controlled release and permeation characteristics of TZN from SR films over 8 h. films were of uniform thickness with smooth surface and satisfactory mechanical strength. Mucoadhesion strength was sufficient to provide suitable contact time with mucosal membrane. The pharmacokinetic study exhibited prompt absorption of MLX with better AUC 0-t (6655.64 ng/ml*h vs 6538.99 ng/ml*h) and Cmax (436.98 ng/ml vs 411.33 ng/ml) from oral dispersion. Similarly buccal films has shown enhanced half-life (9.91hr vs 2.51 hr), AUC 0-t (1043.4 ng/ml*h vs 149.1 ng/ml*h) and Cmax (91.92 ng/ml vs 42.29 ng/ml) from oral solution. A statistical investigation disclosed a significantly improved pharmacokinetics of TZN and MLX after their absorption across buccal route following administration of buccal film (p<0.05). ARX proved expedient and bilayer buccal films as a drug delivery system ascertained the dual effect of providing instant release of one active agent and persistent release of another one with improved pharmacokinetics.

Formulation and Evaluation of Gastroretentive Bilayered Floating Films of Famotidine: Effect of Formulation variables and in Vitro in Vivo Evaluation

The study was aimed at the formulation and evaluation of gastroretentive bilayer floating films of famotidine. A bilayer film consisting of an Immediate Release Layer (IR) and a Sustained Release Layer (SR) were prepared by solvent casting technique. The prepared films were evaluated for film thickness, percentage swelling, folding endurance, tensile strength, drug content estimation and in vitro dissolution studies. Compatibility studies using FTIR were also done for the detection of possible interaction between drug, polymer and other additives. Optimized bilayered floating films were reformulated by including barium sulphate instead of the active drug, famotidine and subjected to in vivo radiographic studies in New Zealand white rabbits in order to confirm the gastric retention.

FORMULATION AND EVALUATION OF BILAYER TABLET OF METRONIDAZOLE AND DICYCLOMINE HYDROCHLORIDE FOR TREATMENT OF IRRITABLE BOWEL DISEASE

The aim of the present study was to prepare bi-layer tablet of Metronidazole and Dicyclomine Hydrochloride for the effective treatment of Irritable Bowel Disease. Metronidazole and Dicyclomine Hydrochloride were formulated as immediate and sustained release layer respectively. The rational for formulation of bi-layer tablet of these two combinations was Metronidazole (immediate release) is strong antibiotic usually applied for antidiarrheal to treat inflammation of the large intestine and Dicyclomine Hydrochloride (Sustained release) is anticholinergic drug primarily used for irritable bowel disease. Bilayer tablet was suitable for maximizing the efficacy of drugs in irritable bowel disease.

APPLICATION OF SOLID DISPERSION TECHNIQUE IN SOLUBILITY AND DISSOLUTION RATE ENHANCEMENT OF NATEGLINIDE

Objective: Nateglinide (NTG) is a potent short-acting biopharmaceutical classification system class II antidiabetic medication. The primary objective of the present investigation was to prepare and evaluate solid dispersions of NTG to enhance the component solubility and immediate release (IR) profile. The secondary objective was to formulate sustained release (SR) matrix layer of NTG for prolonging its effect in the body and to decrease oscillations in plasma concentration level.Methods: NTG (270 mg) SR layer was formulated using release retardant polymers such as Carbopol, ethyl cellulose (EC), hydroxy EC, hydroxypropyl methylcellulose (HPMC), Kollidon, and locust bean gum at concentrations of 15% and 30%. IR layer of NTG (60 mg) was formulated using drug: Polymer inclusion complexes (1:1 and 1:2) of β-cyclodextrin (CD), HP β-CD, polyvinylpyrrolidone (PVP) K-15, and PVP K-30 by physical mixing and kneading methods (KMs).Results: Among the all the carriers tested HP β-CD at 1:2 ratio prepared by KM (I3) gave highest enhancement of dissolution rate and dissolution efficiency with acceptable f1 (10.5) and f2 (51.0) values in comparison to marketed IR tablets (Starlix-60®). The SR formulation S12 was able to show a minimum amount of drug release (15%) within 1 hr comparatively, with a complete and sustained effect on drug release.Conclusion: Thus, HPMC K-100M at a concentration of 30% in the SR layer in combination with HP β-CD (1:2) solid dispersions in the IR layer may be used in the design of oral controlled drug delivery system for NTG.

DEVELOPMENT, FORMULATION AND EVALUATION OF A BILAYER GASTRIC RETENTIVE FLOATING TABLETS OF RANITIDINE HCL AND CLARITHROMYCIN USING NATURAL POLYMERS

Objective: Bilayer gastric retentive floating tablets (BGRFT) with ranitidine HCl and clarithromycin using natural gums have been developed to prolong the gastric residence time and increase drug bioavailability. Literature review revealed no published studies on the present study.Methods: Immediate release (IR) layer prepared by using different diluents and super disintegrants like sodium starch glycolate, crosscarmellose sodium and crospovidone. Controlled released (CR) layer prepared by using neem gum, damar gum and copal gum. Prepared tablets were evaluated for in vivo and in vitro buoyancy, in vitro dissolution studies and fourier transformation-infrared spectroscopy (FTIR). Drug release was evaluated with zero and first order for release kinetics, Higuchi, Hixson-Crowell erosion models for release mechanism.Results: Prepared IR layer followed first order rate kinetics and CR layer followed zero order rate kinetics with non-Fickian diffusion mechanism. BGRFT also showed similar results as that of the individual layer. Optimized formulations were characterized by FTIR studies and found no interactions between drug and polymer.Conclusion: The results demonstrate the feasibility of the model in the development of BGRFT. BGRFT enhanced the drug release and finally the bioavailability of clarithromycin when compared with commercial tablet (Biomycin 250). The present study could establish the suitability of neem gum as CR polymer in the design of BGRFT.

Formulation development and Evaluation of immediate and sustained release Bilayer Tablets Containing Amitriptyline HCl and Pregabalin for the treatment of Neuropathic Pain

The objective of proposed study was to prepare Bilayer tablet comprising Amitriptyline HCl (AMT) and pregabalin (PGB) for effective treatment of neuropathic pain. AMT was formulated as immediate release (IR) layer using disintegrants such as starch whereas PGB was formulated as sustained release (SR) layer using polymers hydroxypropyl methyl cellulose (HPMC) K100M for increasing with a view to deliver the drug at sustained manner in gastrointestinal tract and consequently into systemic circulation. Tablet blends were evaluated through various pre-compression tests, compressed by wet granulation method and evaluated. As disintegrant, starch at 14.70% concentration produced excellent results by immediately releasing AMT to exert its anti-depression and other additional beneficial effects. K100M grade of HPMC produced excellent SR efficiency at 1: 1 drug-polymer ratio whereas extended of the dosage form for long-lasting effect of the therapeutic agent. Final formulation released 98.92% drug in 45 min and 97.27% drug in 12 h, in vitro from respective layers. Pre-compression and post-compression parameters of optimized IR layer comprising AMT and SR layer comprising PGB exhibit satisfactory results. Bilayer tablet of AMT and PGB may prove to be very effective as a combination therapy for the treatment of neuropathic pain by sequential release of the drug.

Design and evaluation of bilayer tablets of metformin hydrochloride and pioglitazone hydrochloride as combination drug therapy

The primary objective of the present investigation was to formulate and evaluate fixed dose bilayer tablet of two antihyperglycemic agents with different mechanisms of action to improve glycemic control in patients with type 2 diabetes. A secondary objective is to ensure that metformin release should be less in stomach and completely released in alkaline pH within the stipulated hours. Hence, metformin hydrochloride (500 mg) sustained release (SR) layer was formulated using various release retardant polymers such as hydroxy propyl methyl cellulose, xanthan gum and sodium carboxy methyl cellulose in three different ratios of 1:0.3, 1:0.4 and 1:0.5, such that therapeutically effective levels can be maintained. Immediate release (IR) layer of pioglitazone hydrochloride (15 mg) was formulated using super disintegrant (crosspovidone) in four different ratios of 1:0.2, 1:0.4, 1:0.6 and 1:0.8. The formulated fixed dose bilayer tablets were subjected to various physiochemical evaluations like weight variation, friability, hardness, drug content, in vitro drug release kinetics and stability studies. The optimized formulation (F8) showed the maximum drug release up to 60 min in IR layer and up to 12 h in SR layer. Formulation F8 was found to be stable at room temperature for a period of 3 months. From the study it is evident that a promising bilayer tablet of pioglitazone hydrochloride and metformin hydrochloride can be developed using crosspovidone (disintegrant) and xanthan gum (release retardant polymer).

Preparation and Optimization of Immediate Release/Sustained Release Bilayered Tablets of Loxoprofen Using Box-Behnken Design.

The aim of our current study was to characterize and optimize loxoprofen immediate release (IR)/sustained release (SR) tablet utilizing a three-factor, three-level Box-Behnken design (BBD) combined with a desirability function. The independent factors included ratio of drug in the IR layer to total drug (X 1), ratio of HPMC to drug in the SR layer (X 2), and ratio of Eudragit RL PO to drug in the SR layer (X 3). The dependent variables assessed were % drug released in distilled water at 30min (Y 1), % drug released in pH 1.2 at 2h (Y 2), and % drug released in pH 6.8 at 12h (Y 3). The responses were fitted to suitable models and statistical validation was performed using analysis of variance. In addition, response surface graphs and contour plots were constructed to determine the effects of different factor level combinations on the responses. The optimized loxoprofen IR/SR tablets were successfully prepared with the determined amounts of ingredients that showed close agreement in the predicted and experimental values of tablet characterization and drug dissolution profile. Therefore, BBD can be utilized for successful optimization of loxoprofen IR/SR tablet, which can be regarded as a suitable substitute for the current marketed formulations.

Formulation and In Vitro and In Vivo Evaluation of Lipid-Based Terbutaline Sulphate Bi-layer Tablets for Once-Daily Administration

The objective of this study was to prepare and evaluate terbutaline sulphate (TBS) bi-layer tablets for once-daily administration. The bi-layer tablets consisted of an immediate-release layer and a sustained-release layer containing 5 and 10mg TBS, respectively. The sustained-release layer was developed by using Compritol®888 ATO, Precirol® ATO 5, stearic acid, and tristearin, separately, as slowly eroding lipid matrices. A full 4 × 2(2) factorial design was employed for optimization of the sustained-release layer and to explore the effect of lipid type (X 1), drug-lipid ratio (X 2), and filler type (X 3) on the percentage drug released at 8, 12, and 24h (Y 1, Y 2, and Y 3) as dependent variables. Sixteen TBS sustained-release matrices (F1-F16) were prepared by melt solid dispersion method. None of the prepared matrices achieved the targeted release profile. However, F2 that showed a relatively promising drug release was subjected to trial and error optimization for the filler composition to develop two optimized matrices (F17 and F18). F18 which consisted of drug-Compritol®888 ATO at ratio (1:6 w/w) and Avicel PH 101/dibasic calcium phosphate mixture of 2:1 (w/w) was selected as sustained-release layer. TBS bi-layer tablets were evaluated for their physical properties, in vitro drug release, effect of storage on drug content, and in vivo performance in rabbits. The bi-layer tablets showed acceptable physical properties and release characteristics. In vivo absorption in rabbits revealed initial high TBS plasma levels followed by sustained levels over 24h compared to immediate-release tablets.

Design of bilayer tablets using modified Dioscorea starches as novel excipients for immediate and sustained release of aceclofenac sodium.

Bilayer tablets of aceclofenac sodium were developed using carboxymethylated white yam (Dioscorea rotundata) starch (CWY) for a fast release layer (2.5, 5.0, and 7.5% w/w), and acid-hydrolyzed bitter yam (Dioscorea dumetorum) starch (ABY) for a sustaining layer (27% w/w). Sodium starch glycolate (SSG) and hydroxypropyl methyl cellulose (HPMC) were used as standards. The starches were characterized using Fourier Transform Infrared spectroscopy (FT-IR), particle size, swelling power, densities and flow analyses. Mechanical properties of the tablets were evaluated using crushing strength and friability while release properties were evaluated using disintegration and dissolution times. Distinctive fingerprint differences between the native and modified starches were revealed by FT-IR. Carboxymethylation produced starches of significantly (p < 0.05) higher swelling and flow properties while acid-modification produced starches of higher compressibility. Bilayer tablets containing ABY had significantly higher crushing strength and lower friability values (p < 0.05) than those containing HPMC. Crushing strength increased while friability values decreased with increase in CWY. Generally tablets containing the modified Dioscorea starches gave faster (p < 0.05) disintegration times and produced an initial burst release to provide the loading dose of the drug from the immediate-release layer followed by sustained release (300 ± 7.56–450 ± 11.55 min). The correlation coefficient (R2) and chi-square (χ2) test were employed as error analysis methods to determine the best-fitting drug release kinetic equations. In vitro dissolution kinetics generally followed the Higuchi and Hixson-Crowell models via a non-Fickian diffusion-controlled release. Carboxymethylated white yam starch and acid-modified bitter yam starch could serve as cheaper alternative excipients in bilayer tablet formulations for immediate and sustained release of drugs respectively, particularly where high mechanical strength is required.

Formulation and Evaluation of Bilayer tablets of Metoprolol Succinate

Metoprolol is β-1 blocker drug and used in treatment of angina pectoris and hypertension. Metoprolol 100mg tablets were formulated as a modified release oral system by utilizing the concept of bilayer tablets in which 30mg drug was added as immediate release (IR) and 70 mg as extended Release (ER). The IR layer consists of lactose or microcrystalline cellulose which acts as diluents with sodium starch glycolate or crosscarmellose as superdisintegrant. The blend was evaluated for angle of repose, bulk and tapped density, Hausner's ratio, Carr's index. The bilayer tablets were prepared manually using 9 station tablet punching machine. The prepared bilayer tablets were evaluated for hardness, thickness, friability, uniformity of weight and in vitro dissolution study. The bilayer tablets were also examined for drug content, kinetic of drug release and stability study. The results showed that the immediate release layer comprising MCC and 2% SSG released 95% drug in 60mins. The sustained release layer was prepared by three polymers i.e. HPMC K 100, HPMC K 15M and HPMC K 4M. It was found that HPMC K 4M in 20% concentration sustained the release of metoprolol succinate to 12hrs. It was concluded that batch BL-3 exhibited desirable properties and optimized drug release. The in vitrodrug release of batch BL-3 was satisfactory. Hence batch BL-3 was considered as optimized batch.

Segregated Delivery of Rifampicin and Isoniazid from Fixed Dose Combination Bilayer Tablets for the Treatment of Tuberculosis

Aims: Develop an anti-tuberculosis (TB) Fixed Dose Combination (FDC) tablet containing an immediate release layer (IRL) composed of both rifampicin (RIF) and pyrazinamide (PYR) and a retarded release layer (RRL) comprised of isoniazid (INH) which would allow segregated delivery of RIF and INH. Study Design: Trials were conducted on the pre-formulations and formulations to assess the compatibility of excipients and obtain a modified release profile, for an IRL consisting of both RIF and PYR and a RRL containing INH. Place and Duration of Study: This study was performed at the Laboratory of Pharmaceutical Industrial Technology, Drug and Pharmaceutical Department, Faculty of Original Research Article British Journal of Pharmaceutical Research, 4(14): 1781-1801, 2014 1782 Pharmacy, between March 2008 and April 2010. Methodology: Preformulation studies were performed on RIF and PYR, alone and in combination with excipients. The pharmacopeic attributes of the distinct layers and the FDC tablets were evaluated for hardness, friability and disintegration time. The FDC bilayer tablets were analyzed for their drug content and cumulative dissolution of the drug. Results: Fourier transform infrared, x-ray diffraction and differential scanning calorimetry results revealed the presence of amorphous and crystalline RIF forms and no potentially relevant incompatibilities were identified in the kneaded system containing RIF, PYR and excipients. In vitro drug release from the FDC tablets revealed that the intragranular addition of croscarmellose sodium into the IRL rendered a cumulative dissolution of RIF and PYR within the limits of simulated gastric fluid. And, for RRL, the most effective retardant matrix excipient was found to be hydroxypropyl methylcellulose. Conclusion: Segregated delivery of RIF and INH from bilayer tablets is an option for the development of immediate release FDC tablets and the retarded release of INH, this strategy proved suitable for preventing contact of these two drugs under acidic conditions. This finding suggested that RIF had a high in vivo bioavailability which qualifies this FDC for future bioavailability studies.

FORMULATION AND EVALUATION OF BILAYER SUSTAINED RELEASE TABLET OF ZOLPIDEM TARTRATE

The purpose of the present study was to develop a bilayer tablet of zolpidem tartrate (ZT) using sodium starch glycolate (SSG) as superdisintegrant in the immediate release (IR) layer and hydrophilic polymers such as hydroxypropyl methylcellulose (HPMC K4M), metalose 90 SH 4000, carbapol 974 PNF in sustained release (SR) layer. Both the IR and SR granules of ZT were evaluated for bulk density, tapped density, angle of repose, Carr’s index, Hausner ratio and loss on drying. All the values were found to be satisfactoy. The prepared bilayer tablets were evaluated for weight variation, hardness, friability, drug content, in vitro drug release, FT-IR studies, similarity factor and stability studies. In vitro dissolution studies were carried out in a USP dissolution apparatus I using 500mL of 0.01N HCl as dissolution medium. The formulations gave an initial burst effect to provide the loading dose of the drug followed by sustained release for 4 h. The data obtained were fitted to Zero order, First order, Higuchi’s model and Korsmeyer-Peppas equations. The release exponent (n) values for all the formulations were less than 0.45 indicating Fickian diffusion was the drug release mechanism. FT-IR studies indicated that there are no drug-excipient interactions. The similarity factor (f2) was calculated by comparing dissolution data of all the formulations with that of marketed bilayer tablet of ZT (Ambien CR). The f2 value was highest (70) for the formulation SF8 and was selected as promising formulation among all the developed formulations. The stability study was performed on the formulation SF8 at 25oC/60% RH, 30oC/75% RH and 40oC/75% RH (accelerated condition) for 3 months. The results indicated that there were no significant changes in aforesaid tablet properties. Key words: bilayer tablets, zolpidem tartrate, sustained release, higuchi’s equation, similarity factor

Optimization and Development of a Core-in-Cup Tablet for Modulated Release of Theophylline in Simulated Gastrointestinal Fluids

A triple-layer core-in-cup tablet that can release theophylline in simulated gastrointestinal (GI) fluids at three distinct rates has been developed. The first layer is an immediate-release layer; the second layer is a sustained-release layer; and the last layer is a boost layer, which was designed to coincide with a higher nocturnal dose of theophylline. The study consisted of two stages. The first stage optimized the sustained-release layer of the tablet to release theophylline over a period of 12 hr. Results from this stage indicated that 30% w/w acacia gum was the best polymer and concentration to use when compressed to a hardness of 50 N/m2. The second stage of the study involved the investigation of the final triple-layer core-in-cup tablet to release theophylline at three different rates in simulated GI fluids. The triple-layer modulated core-in-cup tablet successfully released drug in simulated fluids at an initial rate of 40 mg/min, followed by a rate of 0.4085 mg/min, in simulated gastric fluid TS, 0.1860 mg/min in simulated intestinal fluid TS, and finally by a boosted rate of 0.6952 mg/min.