Sustained-release Tablet Formulation Research Articles

Formulation and evaluation of bilayer sustained release tablets of tramadol hydrochloride by using natural and synthetic polymers

The main objective of the present work was to develop sustained release bilayer tablets ofwater soluble drug tramadol using Guargum, HPMC, NaCMC and Xanthan gum, either alone or in combinations. Tablets were prepared by immediate release direct compression and sustained release wet granulation method and evaluated for various physical parameters. The drug release studies were performed using USP apparatus type І using 0.1N Hcl and pH 6.8 phosphate buffer as dissolution medium. The drug release was dependent on the type and concentration of the polymer. Drug release was faster from tablets prepared with Guargum, NaCMC and HPMC alone. However, in combination with HPMC, NaCMC, Guargum with Xanthan gum it sustained drug release effectively. The rate and mechanism of release of Tramadol Hcl analysed by fitting the dissolution data into the zero order, First order, Higuchi, Korsmeyer-Peppas and hexon crowel equations. All the Formulations (F1-F10) followed Zero order release Mechanism. Higuchi plots for all the formulations were linear indicating the drug release by diffusion controlled. Hixon-Crowell cube root model showed high r2 value proportionality due to erosion of hydrophilic gel layer. To explore the release pattern, results of the in-vitro dissolution data were fitted to the Korsmeyer-Peppas equation, which characterizes the transport mechanism indicates the non fickian transport it refer to combination of both diffusion and erosion rate release. It can be concluded that the optimized batch F7 by adopting biphasic drug release pattern in a single dosage could improve patient compliance and give better disease management.

Effects of Filtration on the Presence of Particulate and Oxycodone Content of Injections Prepared from Crushed OxyContin® Tablets

It is common for injecting drug users (IDU) to prepare injections by crushing tablets which are not designed for parental administration. The injection of insoluble tablet excipients can lead to serious local and systemic medical complications. The aim of the study was to investigate the effectiveness of various types of filters in removing harmful insoluble particles from the injections prepared using crushed oxycodone tablets. Injections were prepared from a sustained-release oxycodone tablet formulation. The filtration of tablet extracts was carried out following procedures used by IDU using makeshift filter and commercially available filters. Particulate contamination and oxycodone content were analysed using light microscopy and spectrophotometer. Unfiltered extracts contained hundreds of thousands of particles of sufficient size to cause harms. Cigarette filters removed large particles but failed to remove small particles. The combination of cigarette filter and syringe filter (0.45 μm or 0.22 μm) reduced the particle count by 90 - 95%. A double membrane syringe filter (0.8/0.2 μm) removed more than 99% of the particles. Recovery of oxycodone was more than 95% with the tested syringe filters. Particulate contamination in injections prepared from crushed tablets can be effectively removed using a combination process of cigarette filter and syringe filters, or a 0.8/0.2 μm syringe filter. Compared to other filters, the 0.8/0.2 μm syringe filter did not block, the filtration was quick and easy to perform, and did not retain oxycodone. The use of a 0.8/0.2 μm syringe filter can provide an important harm reduction measure for IDU.

Evaluation of Two Olibanum Resins as Rate Controlling Matrix Forming Excipients in Oral Sustained Release Tablets

Olibanum is an oleo-gum resin which is economically and culturally valuable product obtained from several species of the genus Boswellia. In this study, the resins extracted from local olibanum: Boswellia papyrifera (Tigray type) and Boswellia rivae (Ogaden type) were evaluated as matrix forming agents in sustained release tablet formulations employing diclofenac sodium as a model drug. Some physico-chemical characterization of the resins revealed low solubility, moisture content and swelling ratio. Sustained release matrix tablets containing 100 mg of diclofenac sodium were then prepared using different proportions of the olibanum resins by wet granulation and direct compression methods, and evaluated for their pharmacotechnical properties and in vitro drug release kinetics. Both resins produced matrix tablets with acceptable weight variation, hardness and friability. Dissolution studies showed that the olibanum resins sustain the drug release beyond 12 h. Drug release from the olibanum resins matrix tablets were best fitted to the Korsmeyer-Peppas model with the mechanism of drug release generally following non-Fickian diffusion process. Diclofenac release profiles from some of the formulated tablets were comparable to that of the commercial sustained release tablet Diclo-Denk® Retard.Keywords: Olibanum resin, matrix tablet, diclofenac sodium, sustained release, release kinetics

Formulation development and optimization of bilayer tablets of aceclofenac

Objective: The objective of the present study was to develop bilayer tablets of aceclofenac that are characterized by initial burst drug release followed by sustained release of drug.Methods: The fast-release layer of the bilayer tablet was formulated using microcrystaline cellulose (MCC) and HPMC K4M. The amount of HPMC E4M (X1) and MCC (X2) was used as independent variables for optimization of sustained release formulation applying 32 factorial design. Three dependent variables were considered: percentage of aceclofenac release at 1 h, percentage of aceclofenac release at 12 h, and time to release 50% of drug (t50%). The composition of optimum formulation of sustained release tablets were employed to formulate double layer tablets.Results: The results indicate that X1 and X2 significantly affected the release properties of aceclofenac from sustained release formulation. The double layer tablets containing fast-release layer showed an initial burst drug release of more than 30% of its drug content during first 1 h followed by sustained release of the drug for a period of 24 h.Conclusion: The double layer tablets for aceclofenac can be successfully employed as once-a-day oral-controlled release drug delivery system characterized by initial burst release of aceclofenac for providing the loading dose of drug.

Evaluation of Sesamum indicum gum as a binder in the formulation of paracetamol granules and tablets

Comparative evaluation of Sesamum indicum gum as a binder in the formulation of paracetamol (PCM) granules and tablets was performed using acacia, gelatin, and Sodium carboxyl methylcellulose (SCMC) as standard binders for comparison. The properties of granules and tablets such as; flow rate, angle of repose, density, weight uniformity, crushing strength, friability, disintegration rate and release profiles, were evaluated. The compact granules had good flow properties. However, binder concentration influenced flow characteristics. SIG gave the highest hardness/friability ratios. It also prolonged disintegration and dissolution time and dissolution rate. Hence, SIG may not be useful as a binder in conventional tablet formulation but may serve as a binder or hydrophilic polymer in sustained release tablet formulation. Key words: Sesamum indicum gum, binder, paracetamol tablets.

Formulation and evaluation of rifampicin sustained release tablets using juice of Citrus limetta as bio-retardant

The advantages of biopolymers over synthetic polymers are low cost, natural origin, free from side effects, biocompatible, bio-acceptable, environmental friendly processing, local availability, better patient tolerance as well as public acceptance. Sustained release tablets containing rifampicin was prepared by adding 100 mg polymer and 50 mg Drug and Granules. Same procedure was followed with 3% and 5% of polymer for preparation of sustained release tablets. Additional Tablets of 100 mg, 200 mg and 400 mg were prepared using 5% of the polymer. The results indicated that the selected biopolymer had a good release retardant property thus it can be concluded that the selected biopolymer can be utilized as low cost natural biocompatible and biodegradable agent.

Formulation and Evaluation of L-arginine Sustained Release Tablets

Formulation and Evaluation of L-arginine Sustained Release Tablets

Design, formulation, optimization and evaluation of sustained release tablets of domperidone

Domperidone is widely used in the management of gastric disorders, particularly gastro esophageal reflux disorder and peptic ulcer. But the short half-life of domperidone leads to poor compliance and adverse reactions; that is why domperidone in sustained release dosage form is needed to achieve better therapeutic effects and to improve patient compliance. For this purpose sustained release tablets of domperidone were manufactured using different polymers, including hydroxylpropylmethylcellulose (HPMC) K100LV, hydroxylpropylcellulose (HPC) K100M and ethocel (EC-22). The prepared tablets were evaluated for their physical parameters, that is, weight variation was determined with the help of electronic balance, hardness by Monsanto tester, thickness by Vernier caliper and friability of the prepared tablets were determined with the help of Erweka friabilator and drug content was determined by UV/Visible spectrophotometer. The in vitro release studies were carried out for all the formulations of the model drug in a buffer solution of pH 6.8 and 0.1 N HCl solution. The results obtained were analyzed by different pharmacokinetic models, such as zero order, first order, Higuchi model, Hixson-Crowell cube root law and Korsmeyer-Peppas model. All the materials used were available in the local market, so we could be able to minimize the per oral cast of the formulation and also improve the patient compliance by reducing the frequency of dosing, reduce relapse and improve therapeutic outcome. Key words: Domperidone, sustained release tablets, compliance, polymers.

Formulation and Evaluation of Bioadhesive Cyproheptadine Tablets

Purpose: To evaluate the effect of formulation variables on the bioadhesion and release properties of bioadhesive cyproheptadine hydrochloride tablets.Methods: Screening of polymers - hydroxypropyl methylcellulose, (HPMC), sodium carboxy methyl cellulose (CMC), and Carbopol 974p and 934p - in solution form were carried out by shear stress and detachment force measurement,based on Taguchi model, in order to determine their bioadhesion properties. Central composite design (CCD) was applied to optimize the combined effects of the polymers on release rate constant (K), diffusion coefficient (n), regression coefficient (R2) and detachment force of a sustained release tablet formulation of cyproheptadine hydrochloride containing also a prompt dose of the drug.Results: The shear stress of 3 % solution of HPMC was greater than that of an equivalent concentration of Carbopol 934P. The values of K, n, R2 and detachment force for the optimized formulation (F0) were 0.269, 0.696, 0.964 and 0.066 Newton (N), respectively, and showed good correlation with the predicted values, thus confirming the practicability and validity of the model.Conclusion: Gastric retention time can be increased for cyproheptadine hydrochloride by formulating it as a bioadhesive tablet that enhances the retention of the dosage form in the stomach and hence gastric absorption of the drug.Keywords: Cyproheptadine hydrochloride, Bioadhesive core tablet, Detachment force, Taguchi design, Central composite design

Optimization of Release Kinetics from Sustained-Release Formulations using Model-Independent Pharmacokinetic Simulation

In the present work, a single model-independent approach was developed to optimize the release kinetics of drugs from sustained-release formulations, using stavudine (d4T) as a model drug. This approach is based on the pharmacokinetic simulation of drug plasma levels through a semiparametric approach of the input function and on convolution with an empirical polyexponential unit impulse response function. Input functions were evaluated using different zero-order and first-order release constants. Optimum drug release to obtain a specific pharmacokinetic profile was approached using target model-independent pharmacokinetic parameters such as C(max)(SS), C(min)(SS), t(max)(SS), and peak-trough fluctuations. A Monte Carlo simulation was performed to estimate the fractional attainment of d4T plasma concentrations over therapeutic d4T levels. Zero-order (K(0) = 4 mg/h) and first-order (K(1) = 0.05 h(-1)) release constants were optimal for the formulation of sustained-release d4T tablets, plasma concentrations within the therapeutic range being achieved.

A bioequivalence study of two tamsulosin sustained-release tablets in Indonesian healthy volunteers

The bioavailability of two 0.4 mg tamsulosin sustained-release film-coated tablet formulations was compared; using generic tablets (Prostam(®)) as test formulation and the originator product as reference formulation. Twenty-four subjects were included in this single-dose, open-label, randomized two-way crossover design following an overnight fasting. A one-week wash-out period was applied. Blood samples were drawn up to 72 h following drug administration. Plasma concentration of tamsulosin was determined by liquid chromatography-tandem mass spectrometry method with TurboIonSpray mode. Pharmacokinetic parameters AUC(0-t,) AUC(0-∞), C (max) and t (½) were determined and used for bioequivalence evaluation after log-transformation, whereas t (max) ratios were evaluated non-parametrically. The estimated point and 90% confidence intervals (CI) for AUC(0-t,) AUC(0-∞), C (max) and t (½) were 109.55% (96.41-124.49%), 109.94% (96.85-124.81%), 105.87% (92.88-120.67%) and 100.00% (90.56-110.43%), respectively. These results indicated that the two formulations of tamsulosin were bioequivalent; therefore they may be prescribed interchangeably.

The use of response surface methodology for the formulation and optimization of salbutamol sulfate hydrophilic matrix sustained release tablets

The objective of this study was to develop a hydrophilic matrix formulation with in vitro release characteristics similar to Asthalin® tablets and that would sustain the release of salbutamol sulfate over a 12-h period. A central composite design was used as the framework for manufacturing formulations that may be used to understand the relationships between polymer levels and in vitro release characteristics. Tablets were manufactured using wet granulation with Surelease® as the granulating fluid and different levels of Methocel® K100M, xanthan gum, and Carbopol® 974P as matrix-forming materials. In vitro dissolution testing was conducted using USP Apparatus 3 and samples were analyzed using a validated reversed-phase HPLC method. The results revealed that the levels and types of polymers had a significant impact on the rate of drug release from these formulations and that it was possible to optimize the levels of matrix-forming polymers to achieve the desired release characteristics. Statistical design and response surface methodology have been successfully used to understand and optimize formulation factors and interactions that impact the in vitro release characteristics of salbutamol sulfate from a potential multisource sustained release dosage form.

Formulation and In Vitro Evaluation of Araucaria bidwilli Gum-Based Sustain Release Matrix Tablets of Diclofenae Sodium

A gel forming Polysaccharide gum obtained form the bark of Araucaria bidwilli was employed as a matrix sustained release tablet formulation of Diclofenac sodium (a non steroidal anti inflammatory agent). The effect of Araucaria bidwilli gum ( Natural ) and Synthetic polymer Hydroxypropyl methyl cellulose ( HPM C K4 M ) on the release of Diclofenac sodium was studied. The FT - IR spectroscopic studies of drug, gum and mixture indicated no chemical interaction . Six formulations were prepared by wet granulation method containing Araucaria bidwilli gum pow der concentration 10 % 20 % & 30 % w w and 10 % 20% &30% w w of HPMC K4M with sufficient volume of granulating agent Polyvinyl pyrrolene (PVP K 30) , Avicel pH101 as diluents , Magnesium stearate and Aero silis used lubricant and glidant respectively . This study was carried out to find out the difference between synthetic and natural gum and whether synthetic gum can be replaced by natural gums. Physical and techno logical studies of granules and tablets were compliance with Pharmacopoial standards . The drug release increased with Araucaria bidwilli gum when compared to synthetics polymer concentration. The value of release exponent were found to be almost straight line and regression coefficient value between 0. 9 38 and 0. 99 8 . This implies that the release mechanism is diffusion. Formulation F3 (contained 30% w w Araucaria bidwilli gum) met the desired requirements for a sustained release dosage form.

Development and characterization of gastroretentive mucoadhesive tablets of venlafaxine hydrochloride.

The present study was undertaken with an aim to formulation development and evaluation of gastroretentive mucoadhesive sustained release tablet of Venlafaxine hydrochloride which releases the drug in a sustained manner over a period of 12 hours, by using Carbopol 971P in combination with eudragit RS-PO and ethyl cellulose as a mucoadhesive and release retardant respectively. Preformulation study was done initially and results directed for the further course of formulation. Based on Preformulation studies different batches of Venlafaxine hydrochloride were prepared using Carbopol 971P, Eudragit RS-PO and ethyl cellulose chosen for their different hydrophilic properties to calculate the sustained release properties. Sustained release tablets were prepared by direct compression and were evaluated for bioadhesion time, swelling index and matrix erosion, and in vitro drug release. The tablets of batch F3 and F6 had high swelling behaviors but release of drug is very less. And batch F2 having considerable swelling index and in vitro drug release (99.85%). Batch F2 can be taken as an ideal or optimized formulation of sustained release tablets for 12 hour release as it fulfills all the requirements for sustained release tablet. From the discussion it is concluded that use of carbopol as a release retardant and adhesive polymer is very effective; and also it act as strong release retardant in combination with hydrophobic polymers. Keywords: Gastroretentive; Mucoadhesive; Venlafaxine hydrochloride; Tablet.

Development and Optimization of a Novel Sustained-release Tablet Formulation for Bupropion Hydrochloride using Box-Behnken Design

【The objectives of this study were to evaluate the effect of formulation ingredients on the drug release and to optimize the novel sustained release matrix tablet formulations of bupropion hydrochloride. A three factor, three-level Box-Behnken design was used for the optimization procedure, with the amounts of PEO ( $X_1$ ), citric acid ( $X_2$ ) and Compritol 888 ATO ( $X_3$ ) as the independent variables. The selected dependent variables were the cumulative percentage values of bupropion hydrochloride that had dissolved after 1, 4 and 8 hr. Various dissolution profiles of the drug from sustained release matrix tablets were obtained. Optimization was performed for $X_1$ , $X_2$ and $X_3$ using the following target ranges; $30%{\leq}Y_1{\leq}45%$ ; $70{\leq}Y_2{\leq}85%$ ; $85%{\leq}Y_3{\leq}100%$ . The optimized formulation for bupropion hydrochloride was achieved with 12.5% PEO ( $X_1$ ), 2.5% citric acid ( $X_2$ ) and 10% Compritol 888 ATO ( $X_3$ ). The sustained release matrix tablets with the optimized formulation provided a release profile that was close to predicted values. In addition, the dissolution profiles of the sustained release matrix tablet with the optimized formulation were similar to those of the commercial product Wellbutrin $^{(R)}$ SR tablets ( $f_2$ =79.8 79.83).】

A Comparative Study of the Pharmacokinetics of Conventional and Sustained-release Tablet Formulations of Aceclofenac in Healthy Male Subjects

Purpose: To examine the pharmacokinetics of a formulated aceclofenac sustained release tablet formulation and determine if it is bioequivalent to a commercial brand of aceclofenac immediate release tablet (Zerodol® 100 mg). Methods: Each of two groups of twelve fasting volunteers received either the reference standard (Zerodol 100 mg tablets) or the test formulation (200 mg aceclofenac) orally once, using a cross-over design with a one week wash-out period. Their blood samples were obtained at regular time intervals over 24 h and analyzed by high performance liquid chromatography (HPLC). Using the noncompartmental approach, plasma levels of aceclofenac were employed to compute their individual disposition kinetics, including peak plasma concentration (Cmax), peak time (Tmax), area under the plasma level-time curve (AUC 0-t), elimination rate constant (Kel) and elimination half life ( t1/2). Results: The Cmax values of 11043 ± 3073 ng/ml and 12301 ± 3000 ng /ml were attained in 2.58 ± 1.22h and 1.29 ± 0.75 h for the test and reference products, respectively, while AUCO-
was 45996 ± 10427 and 50253 ± 8283 ng.h/ml, respectively. At 90% confidence interval, the C max, AUC 0-t and AUC0-
values of the test preparation were 96.4 - 101.3, 100.2 -101.9 and 98.5 - 99.8%, respectively, of the values for the reference. The t1/2 values were found to be 4.50 ± 1.25 and 2.20 ± 2.59 h for the reference and test products. Conclusion: On the basis of the pharmacokinetic data, it can be said that the test aceclofenacsustained release formulation and the reference product were bioequivalent in some respects. However, the test formulation exhibited a longer elimination half-life (t1/2), thus demonstrating sustained release properties, unlike the reference.Keywords : Pharmacokinetics; Bioequivalence; Sustained release aceclofenac formulation.

The Development and In Vitro Evaluation of Sustained Release Tablet Formulations of Benzydamine Hydrochloride and its Determination

A novel oral controlled delivery system for benzydamine hydrochloride (BN) was developed and optimized. Hydrophilic matrix tablets of BN were prepared by using hydroxypropylmethylcellulose (HPMC) and chitosan as polymer substance to achieve required sustained release profile. The matrix tablets were prepared both direct compression and wet granulation method. The influence of matrix forming agents and binary mixtures of them on BN release was investigated. The formulated tablets were characterized by hardness, friability, thickness, weight variation and in vitro drug release. The formulated tablets had acceptable physicochemical characters. The quantity of BN present in the tablets and the release medium were estimated by a simple, sensitive, rapid and validated HPLC method. The dissolution results show that increased amount of polymer resulted in reduced and extended drug release. F7 formulation containing 12.5% HPMC and 12.5 % chitosan with direct compression method is the optimum formulation due to its better targeting profile in terms of release. Higuchi (diffusion) and Hixon-Crowell (erosion) kinetic profiles were achieved and this codependent mechanism of drug release was established. This formulation may provide an alternative for oral controlled delivery of BN and be helpful in the future treatment of primary normoreactive types of inflammation.

Formulation Development of Morphine Sulfate Sustained-Release Tablets and Its Bioequivalence Study in Healthy Thai Volunteers

The objectives of this study were to develop morphine sulfate sustained-release tablet formulations and to evaluate the bioequivalence compared with a commercial brand. The physicochemical properties of the formulated and commercial tablets were determined and compared. The bioequivalence investigation was carried out in 15 healthy male volunteers who received a single dose in a randomized two-way crossover design. After dosing, serial blood samples were collected for a period of 24 h. Morphine concentration was assayed by high-performance liquid chromatography with electrochemical detector. The log-transformed C(max) and AUC(s) were statistically compared by analysis of variance, and the 90% confidence intervals (CIs) of the ratio of the log-transformed C(max) and AUC(s) between the most promising developed formulation and the commercial product were determined. It was found that the dissolution rate profile of a developed formulation was similar to the commercial brand. Their similarity and difference factors were well within limits. In the bioequivalence study, the AUC(last) and AUC(inf) between the test and the reference products were not statistically different (p = 0.227 and p = 0.468, respectively), with the 90% CIs of 83.4-102.6% and 87.7-139.4%, respectively. However, the C(max) of the two formulations was significantly different (p = 0.019). The 90% CI of the developed formulation was 72.0-93.0% compared to the commercial product. In vitro dissolution of locally prepared morphine sulfate sustained-release tablets was comparable to commercial brand. However, the results justified the conclusion of lack of bioequivalence of the developed product to the commercial one.

FORMULATION AND EVALUATION OF SUSTAINED RELEASE TABLETS CONTAINING ANTIOXIDANTS

Deficiency in nutrients especially antioxidants play an important role in the pathogenesis of acquired immuno-deficiency syndrome (AIDS). Antioxidants; vitamin A, vitamin C, vitamin E, zinc and selenium are available in market as capsules. The release rate is very fast followed by fast elimination. It is necessary to prolong the residence time of antioxidants. Sustained release tablet formulation was designed and evaluated on small scale and on large scale preparations. Low attention has been discuss the use of sustained release formula in treatment of AIDS. Sustained release tablet formulation was designed and evaluated on small scale and on large scale preparations. The formulated tablets contained beta-carotene, vitamin C, tocopherol acetate, selenium, yeast and zinc pidolate. Vitamin C was chosen as tracer for detection and evaluation of tablet dosage form. Vitamin C was found to be stable in 0.1 N HCl (pH 1.2) along 8 hrs at 37°C. The formulated tablets passed the pharmacopeial requirements for all tablet tests. The formulated tablets showed sustained release characteristics of vitamin C as a tracer, within 8 hrs.

Evaluation of khaya gum as a directly compressible matrix system for controlled release

Khaya gum has been evaluated as a controlled release agent in modified release matrices in comparison with hydroxypropylmethylcellulose (HPMC) using paracetamol (water soluble) and indometacin (water insoluble) as model drugs. Tablets were produced by direct compression and the in-vitro drug release was assessed in conditions mimicking the gastrointestinal system. Khaya gum matrices provided a controlled release of paracetamol for up to 5 h. The release of paracetamol from khaya gum matrices followed time-independent kinetics (n = 1.042) and release rates were dependent on the concentration of the drug present in the matrix. The addition of tablet excipients not only improved the mechanical properties of the tablet, but also altered the dissolution profile, except for dicalcium phosphate where the profile remained unchanged. HPMC could be used to control the drug release rates from khaya gum matrices and a combination of khaya gum and HPMC gave zero-order time-independent release kinetics. Indometacin exhibited a lag time in excess of 2 h, due to its insolubility at low pH, before the zero-order release was observed. Thus khaya gum matrices could be useful in the formulation of sustained release tablets for up to 5 h and the appropriate combination of khaya gum and HPMC could be used to provide a time-independent release for longer periods.