Evaluation of hydrophilic,hydrophobic and waxy matrix excipients for sustained release tablets of Venlafaxine hydrochloride

Objective: Venlafaxine is freely soluble In water and administered orally as hydrochloride salt In two to three divided doses. In the present investigation different release retarding matrices have been evaluated for sustained release of venlafaxine hydrochloride (VH) from the formulated tablets.

Materials and methods: Sustained release matrix tablets were formulated using different hydrophilic, hydrophobic and waxy materials as matrix formers. Tableting was done by pre-compression, direct compression and hot melt granulation depending on the type of matrix material used and evaluated for different tests. The formulated tablets were compared with commercial venlafaxine products. In vitro drug dissolution profiles were fitted In different mathematical models to elucidate the release mechanism.

Results: Dissolution data showed that commercial formulations Venlor XR^® and Venfax PR^® released the entire drug withIn 8?h where as the formulated tablets with hydroxypropylmethylcellulose (HPMC) and cetyl alcohol as matrix formers provided sustained release of drug for 14–15?h. The release was found to follow Hixson Crowel and Higuchi kinetics for HPMC and cetyl alcohol tablets, respectively.

Conclusion: The developed matrix tablet formulations with HPMC and cetyl alcohol provided sustained release profiles for prolonged periods than commercial formulations.     

Formulation and Release Characteristics of Hydroxypropyl Methylcellulose Matrix Tablet Containing Melatonin

A hydroxypropyl methylcellulose (HPMC) matrix tablet containing melatonin (MT) was formulated as a function of HPMC viscosity, drug loading, type and amount of disintegrant, lubricant and glidant, and aqueous polymeric coating level and was compared with two commercial products. The release characteristics of the HPMC matrix tablet were investigated in the gastric fluid for 2 hr followed by study in intestinal fluid. The surface morphology of an uncoated HPMC matrix tablet using scanning electron microscopy (SEM) was crude, showing aggregated particles and rough crystals or pores, but it became smoother as the coating levels increased. As the HPMC polymer viscosity increased, the release rate had a tendency to decrease. As the drug loadings increased, the release rate slightly decreased. When Polyplasdone®XL, Primojel®, and Ac-Di-Sol®, except Avicel®, were incorporated in the HPMC matrix tablet, the release rate was markedly increased. There was no significant difference in release profiles when a mixture of lubricants and glidants (magnesium stearate, talc, and Cab-O-Sil®), except for magnesium stearate alone, was incorporated into low and high viscosity grade HPMC matrix tablets. As the coating level increased, the release rate gradually decreased, giving an increased lag time. The sustained-release HPMC matrix tablet with optimizing formulations may provide an alternative for oral controlled delivery of MT and be helpful in the future treatment of circadian rhythmic disorders.     

Formulation and release characteristics of hydroxypropyl methylcellulose matrix tablet containing melatonin

A hydroxypropyl methylcellulose (HPMC) matrix tablet containing melatonin (MT) was formulated as a function of HPMC viscosity, drug loading, type and amount of disintegrant, lubricant and glidant, and aqueous polymeric coating level and was compared with two commercial products. The release characteristics of the HPMC matrix tablet were investigated in the gastric fluid for 2 hr followed by study in intestinal fluid. The surface morphology of an uncoated HPMC matrix tablet using scanning electron microscopy (SEM) was crude, showing aggregated particles and rough crystals or pores, but it became smoother as the coating levels increased. As the HPMC polymer viscosity increased, the release rate had a tendency to decrease. As the drug loadings increased, the release rate slightly decreased. When Polyplasdone®XL, Primojel®, and Ac-Di-Sol®, except Avicel®, were incorporated in the HPMC matrix tablet, the release rate was markedly increased. There was no significant difference in release profiles when a mixture of lubricants and glidants (magnesium stearate, talc, and Cab-O-Sil®), except for magnesium stearate alone, was incorporated into low and high viscosity grade HPMC matrix tablets. As the coating level increased, the release rate gradually decreased, giving an increased lag time. The sustained-release HPMC matrix tablet with optimizing formulations may provide an alternative for oral controlled delivery of MT and be helpful in the future treatment of circadian rhythmic disorders.     

Development of terfenadine-pseudoephedrine double-layer tablet dissolution-equivalent to core tablet

The terfenadine-pseudoephedrine dosage form discussed here is the sustained-release core tablet composed of outer (fast-release) and inner (sustained-release) layers. To develop the double-layer tablet dissolution-equivalent to a core tablet, the fast-release and sustained-release layers were prepared using various disintegrants and polymers, respectively. The layer composed of terfenadine/pseudoephedrine/lactose/cornstarch/sodium bicarbonate/hydroxypropylcellulose (HPC)/sodium lauryl sulfate/microcrystalline cellulose (60/10/90/30/20/1/40/1/293 mg), which gave the fast disintegration time and high dissolved amounts of drugs, was selected as the fast-release layer. The dissolved amounts of pseudoephedrine from sustained-release layers increased more with a smaller ratio of ethylcellulose and hydroxypropylmethylcellulose (HPMC). Dissolution mechanism analysis showed the release of pseudoephedrine was proportional to the square root of time, indicating that drug might be released from the layers by Fickian diffusion. The layer composed of pseudoephedrine/ethylcellulose/HPMC (110/30/155 mg), which had similar dissolution amounts of pseudoephedrine as the inner layer of a core tablet, was selected as the sustained-release layer. Furthermore, the dissolved amounts of drugs from the core and double-layer tablets had deviations of less than 5% against the average dissolved amounts of drugs at each time. There was no significant difference between the dissolved amounts of drugs from these tablets at each time in pH 1.2, 4.0, and 6.8 (P > .05). Our results suggest that this double-layer tablet was a dissolution equivalent to the core tablet.     

A formulation approach for development of HPMC-based sustained release tablets for tolterodine tartrate with a low release variation

Objective: The purpose of this study was to develop hydroxypropylmethylcellulose (HPMC)-based sustained release (SR) tablets for tolterodine tartrate with a low drug release variation.

Methods: The SR tablets were prepared by formulating a combination of different grades of HPMC as the gelling agents. The comparative dissolution study for the HPMC-based SR tablet as a test and Detrusitol^® SR capsule as a reference was carried out, and the bioequivalence study of the two products was also conducted in human volunteers.

Results: The amount of HPMC, the grade of HPMC and the combination ratio of different grades of HPMC had remarkable effects on drug release from the SR tablets. Both the test and reference products had no significant difference in terms of comparative dissolution patterns in four different media (f₂ > 50). Furthermore, the dissolution method and rotation speed showed no effects on the drug release from the two products. The 90% confidence intervals of the AUC_0–36 and C_max ratios for the test and reference products were within the acceptable bioequivalence intervals of log0.8–log1.25.

Conclusions: A HPMC-based SR tablet for tolterodine tartrate with a low release variation was successfully developed, which was bioequivalent to Detrusitol^® SR capsule.     

Effect of crospovidone and hydroxypropyl cellulose on carbamazepine in high-dose tablet formulation

The aim of this study was to develop a high-dose tablet formulation of the poorly soluble carbamazepine (CBZ) with sufficient tablet hardness and immediate drug release. A further aim was to investigate the influence of various commercial CBZ raw materials on the optimized tablet formulation.

Materials and methods: Hydroxypropyl cellulose (HPC-SL) was selected as a dry binder and crospovidone (CrosPVP) as a superdisintegrant. A direct compacted tablet formulation of 70% CBZ was optimized by a 3² full factorial design with two input variables, HPC (0–10%) and CrosPVP (0–5%). Response variables included disintegration time, amount of drug released at 15 and 60?min, and tablet hardness, all analyzed according to USP 31.

Results and discussion: Increasing HPC-SL together with CrosPVP not only increased tablet hardness but also reduced disintegration time. Optimal condition was achieved in the range of 5–9% HPC and 3–5% CrosPVP, where tablet properties were at least 70 N tablet hardness, less than 1?min disintegration, and within the USP requirements for drug release. Testing the optimized formulation with four different commercial CBZ samples, their variability was still observed. Nonetheless, all formulations conformed to the USP specifications.

Conclusions: With the excipients CrosPVP and HPC-SL an immediate release tablet formulation was successfully formulated for high-dose CBZ of various commercial sources.     

Study of controlled-release floating tablets of dipyridamole using the dry-coated method

Dipyridamole (DIP), having a short biological half-life, has a narrow absorption window and is primarily absorbed in the stomach. So, the purpose of this study was to prepare controlled-release floating (CRF) tablets of dipyridamole by the dry-coated method. The influence of agents with different viscosity, hydroxypropylmethylcellulose (HPMC) and polyvinylpyrollidon K30 (PVP K30) in the core tablet and low-viscosity HPMC and PVP K30 in the coating layer on drug release, were investigated. Then, a study with a three-factor, three-level orthogonal experimental design was used to optimize the formulation of the CRF tablets. After data processing, the optimized formulation was found to be: 80?mg HPMC K4M in the core tablet, 80?mg HPMC E15 in core tablet and 40?mg PVP K30 in the coating layer. Moreover, an in vitro buoyancy study showed that the optimized formulation had an excellent floating ability and could immediately float without a lag time and this lasted more than 12?h. Furthermore, an in vivo gamma scintigraphic study showed that the gastric residence time of the CRF tablet was about 8?h.     

Vitamin B12 buccoadhesive tablets: auspicious non-invasive substitute for intra muscular injection: formulation,in vitro and in vivo appraisal

Attempting to prepare a convenient bioavailable formulation of vitamin B₁₂ (cyanocobalamin), 17 tablet formulations were prepared by direct compression. Different concentrations of hydroxypropyl methyl cellulose (HPMC), carbopol 971p (CP971p), and chitosan (Cs) were used. The tablets were characterized for thickness, weight, drug content, hardness, friability, surface pH, in vitro drug release, and mucoadhesion. Kinetic analysis of the release data was conducted. Vitamin B₁₂ bioavailability from the optimized formulations was studied on rabbits by the aid of enzyme-linked immunosorbent assay. Neurotone^® I.M. injection was used for comparison. HPMC (F1-F4), CP971p (F5-F8), and HPMC/CP971p (F12-F15)-based formulations showed acceptable mechanical properties. The formulated tablets showed maximum swelling indices of 232?±?0.13. The surface pH values ranged from 5.3?±?0.03 to 6.6?±?0.02. Bioadhesive force ranged from 66?±?0.6 to 150?±?0.5?mN. Results showed that CP971p-based tablets had superior in vitro drug release, mechanical, and mucoadhesive properties. In vitro release date of selected formulations were fitted well to Peppas model. HPMC/CP971p-based formulations showed bioavailability up to 2.7-folds that of Neurotone^® I.M. injection.     

Development of novel amisulpride-loaded solid self-nanoemulsifying tablets: preparation and pharmacokinetic evaluation in rabbits

Objective: The current investigation is focused on the formulation and in vivo evaluation of optimized solid self-nanoemulsifying drug delivery systems (S-SNEDDS) of amisulpride (AMS) for improving its oral dissolution and bioavailability.

Methods: Liquid SNEDDS (L-SNEDDS) composed of Capryol? 90 (oil), Cremophor^® RH40 (surfactant), and Transcutol^® HP (co-surfactant) were transformed to solid systems via physical adsorption onto magnesium aluminometasilicate (Neusilin US2). Micromeretic studies and solid-state characterization of formulated S-SNEDDS were carried out, followed by tableting, tablet evaluation, and pharmacokinetic studies in rabbits.

Results: Micromeretic properties and solid-state characterization proved satisfactory flow properties with AMS present in a completely amorphous state. Formulated self-nanoemulsifying tablets revealed significant improvement in AMS dissolution compared with either directly compressed or commercial AMS tablets. In vivo pharmacokinetic study in rabbits emphasized significant improvements in t_max, AUC_(0–12), and AUC_(0–∞) at p?<?.05 with 1.26-folds improvement in relative bioavailability from the optimized self-nanoemulsifying tablets compared with the commercial product.

Conclusions: S-SNEDDS can be a very useful approach for providing patient acceptable dosage forms with improved oral dissolution and biovailability.     

Development of Terfenadine-Pseudoephedrine Double-Layer Tablet Dissolution-Equivalent to Core Tablet

The terfenadine-pseudoephedrine dosage form discussed here is the sustained-release core tablet composed of outer (fast-release) and inner (sustained-release) layers. To develop the double-layer tablet dissolution-equivalent to a core tablet, the fast-release and sustained-release layers were prepared using various disintegrants and polymers, respectively. The layer composed of terfenadine/pseudoephedrine/lactose/cornstarch/sodium bicarbonate/hydroxypropylcellulose (HPC)/sodium lauryl sulfate/microcrystalline cellulose (60/10/90/30/20/1/40/1/293 mg), which gave the fast disintegration time and high dissolved amounts of drugs, was selected as the fast-release layer. The dissolved amounts of pseudoephedrine from sustained-release layers increased more with a smaller ratio of ethylcellulose and hydroxypropylmethylcellulose (HPMC). Dissolution mechanism analysis showed the release of pseudoephedrine was proportional to the square root of time, indicating that drug might be released from the layers by Fickian diffusion. The layer composed of pseudoephedrine/ethylcellulose/HPMC (110/30/155 mg), which had similar dissolution amounts of pseudoephedrine as the inner layer of a core tablet, was selected as the sustained-release layer. Furthermore, the dissolved amounts of drugs from the core and double-layer tablets had deviations of less than 5% against the average dissolved amounts of drugs at each time. There was no significant difference between the dissolved amounts of drugs from these tablets at each time in pH 1.2, 4.0, and 6.8 (P >. 05). Our results suggest that this double-layer tablet was a dissolution equivalent to the core tablet.     

New sustained release of Zidovudine Matrix tablets − cytotoxicity toward Caco-2 cells

Objective: The aim of this study was to adjust the zidovudine (AZT) release from solid tablets to an ideal profile, by developing matrices comprising swellable polymers with nonswellable ones.

Methods: Directly compressed matrices comprised different ratios of hydroxypropylmethylcellulose K15M and K100M, ethylcellulose, and methacrylic acid (Eudragit^® RS PO and Eudragit^® RL PO) were prepared. Technological characterization and evaluation of the in vitro release behavior were carried out. Cell density and viability following drug exposure were evaluated by the SRB method, for the Caco-2 line, while cell morphology was assessed upon Trypan blue staining.

Results: A specific formulation containing 5% of each excipient ? HPMC K15M, HPMC K100M, Eudragit^® RS PO, and Eudragit^® RL PO ? was found to yield the best release profile. Application of the Korsmeyer–Peppas model to the dissolution profile evidenced that a non-Fickian (anomalous) transport is involved in the drug release. Regarding the influence of the tablets’ composition on the drug’s cytotoxic effect toward the Caco-2 cell line, a reduction of cell biomass (0–15%) was verified for the distinct AZT formulations tested, F19 having displayed the highest cytotoxicity, after 24 and 48?h of incubation. Additionally, a high reversibility of the AZT effect was observed.

Conclusions: The results showed that the simultaneous application of both hydrophilic and hydrophobic polymers can modulate the drug release process, leading to an improved efficacy and patient compliance. All AZT formulations studied were found to be cytotoxic against Caco-2 cells, F19 being the most effective one.     

Development of stabilized tenofovir disoproxil tablet: degradation profile,stabilization, and bioequivalence in beagle dogs

The purpose of this study was to develop a hydrolysis-resistant optimized oral formulation of tenofovir disoproxil (TD) using a stabilizer. To develop a stabilized TD tablet bioequivalent to the commercial TD fumarate (TDF, Viread^®) tablet, TD free base was prepared and its degradation profile and stability were investigated. The TD tablet showed antiviral activity, but its absorption was limited in the intestinal tract because of premature degradation. The drug subjected to severe conditions for the stress test was catalyzed under neutral, basic, oxidative, and thermolytic conditions, whereas it was comparatively stable under acidic, photolytic, and humid states. The compatibility study showed that sodium bisulfite (SB) stabilized TD by preventing its degradation in aqueous and 3% peroxide solutions compared with the unstabilized TD. According to the stability analysis and degradation profile, four TD tablet formulations were prepared. The selected TD tablets were composed of non-hygroscopic excipients (lipophilic-fumed silica, anhydrous lactose, and microcrystalline cellulose [MCC]), SB, croscarmellose sodium (CCS), and hydrogenated castor oil (HCO), and were manufactured using a dry granulation method because of their hydrolytic properties. The stabilized TD tablet showed similar dissolution properties as the TDF (Viread^®) reference tablet in pH 1.2, 4.0, and 6.8 and water. Moreover, the lower degradation rate of the tablet in simulated gastrointestinal fluid demonstrated that its intestinal absorption might have improved owing to prevention of its enzymatic hydrolysis and the pH effect. Finally, the formulated TD tablet was bioequivalent to the TDF (Viread^®) reference tablet in beagle dogs.     

The effect of pH,buffer capacity and ionic strength on quetiapine fumarate release from matrix tablets prepared using two different polymeric blends

The objective of this study was to investigate the effect of the different physiological parameters of the gastrointestinal (GI) fluid (pH, buffer capacity, and ionic strength) on the in vitro release of the weakly basic BCS class II drug quetiapine fumarate (QF) from two once-a-day matrix tablet formulations (F1 and F2) developed as potential generic equivalents to Seroquel^® XR. F1 tablets were prepared using blends of high and low viscosity grades of hydroxypropyl methylcellulose (HPMC K4M and K100LV, respectively), while F2 tablets were prepared from HPMC K4M and PEGylated glyceryl behenate (Compritol^® HD5 ATO). The two formulations attained release profiles of QF over 24?h similar to that of Seroquel^® XR using the dissolution medium published by the Food and Drug Administration (FDA). A series of solubility and in vitro dissolution studies was then carried out using media that simulate the gastric and intestinal fluids and cover the physiological pH, buffer capacity and ionic strength range of the GIT. Solubility studies revealed that QF exhibits a typical weak base pH-dependent solubility profile and that the solubility of QF increases with increasing the buffer capacity and ionic strength of the media. The release profiles of QF from F1, F2 and Seroquel^® XR tablets were found to be influenced by the pH, buffer capacity and ionic strength of the dissolution media to varying degrees. Results highlight the importance of studying the physiological variables along the GIT in designing controlled release formulations for more predictive in vitro–in vivo correlations.     

Non-invasive and rapid analysis for observation of internal structure of press-coated tablet using X-ray computed tomography

Background: Since the internal structure of a tablet can be measured without destruction of the sample by X‐ray computed tomography (CT), it could be applied to quality control of tablets during the manufacturing process. Aim: A novel, fast, noninvasive tablet observation method was developed to evaluate the internal structure of commercial press-coated tablets by using X-ray CT. Method: Thirty-two CT image slices of four kinds of commercial press-coated tablets (tablets A, B, C, and D) were measured 300 m interval between edges of the tablet by using an X-ray CT. The thinnest layer thickness of the tablets and distance between centers of gravity (DCG) of tables were calculated. Results: The order of the TLT of the tablets was tablet B > tablet C > tablet D > tablet A. The result indicated that the order of DCG was tablet A > tablet D > tablet C > tablet B. Noninvasive observation of the internal structure of commercial, press-coated tablets by X-ray CT has been demonstrated to be useful in quality control of production. Conclusion: The internal structure of press-coated tablets could be observed without pretreatment, without destruction, and very rapidly by X‐ray CT.     

Pharmaceutical and pharmacokinetic characterization of a novel sublingual buprenorphine/naloxone tablet formulation in healthy volunteers

Context: Bitter taste, as well as dissolve time, presents a significant challenge for the acceptability of formulations for oral transmucosal drug delivery.

Objective: To characterize a novel sublingual tablet formulation of buprenorphine/naloxone with regards to pharmacokinetics, dissolve time and formulation acceptability.

Methods: Dry mixing techniques were employed to produce a small and fast dissolving buprenorphine/naloxone sublingual tablet formulation, OX219 (Zubsolv®), using sucralose and menthol as sweetener and flavor to mask the bitter taste of the active ingredients. Two cross-over studies were performed in healthy volunteers to evaluate pharmacokinetics, dissolve time and acceptability of OX219 5.7/1.4?mg tablets compared to the commercially available buprenorphine/naloxone formulations Suboxone® tablets and films (8/2?mg).

Results: Buprenorphine exposure was equivalent in OX219 and Suboxone tablets. Sublingual dissolve times were significantly shorter for OX219 than for Suboxone tablets and were similar to Suboxone films. The OX219 formulation received significantly higher subjective ratings for taste and overall acceptability than both Suboxone formulations. OX219 was preferred over Suboxone tablet and film formulations by 77.4% and 88.9% of subjects, respectively.

Conclusions: A sublingual tablet formulation with an improved acceptability has been successfully developed.     

Preliminary evaluation of the in vitro release and in vivo absorption in rabbits of the modified-release dosage forms

Objective: The suitability of the rabbit as an animal model for the primary screening and selection of the pilot scale batches during the early stages of the formulation development was studied.

Materials and methods: Three modified-release formulations of aminophylline consisted of Carbopol® 971P/HPMC K4M (F-I), and HPMC K100M (F-II) or HPMC K4M (F-III) were used. Commercial products were Aminofilin retard 350?mg tablets, Srbolek, Serbia (R-I) and Phyllocontin^® 350, tablets Purdue Frederic, Canada (R-II).

Results: Calculated release rate constants and the ?2 values between R-I/F-I (84.1) and R-II/F-III (83.4) indicated similar in vitro release while the coefficient n showed presence of different mechanisms of release from Anomalous transport, Fickian diffusion to Case-II transport. Higher T_max, was found in the rabbits, dosed with F-II (12.00?h), F-III (10.50?h), and R-II (15.00?h) formulation. The highest C_max (9.22?mg/L) was obtained with F-II, similar lower values was seen for F-I and F-III, while commercial products showed the lowest values R-I (5.58?mg/L) and R-II (4.18?mg/L). Higher AUC values were detected for all three formulations (from 115.90 to 204.06 mgh/L) in relation to commercial products (105.33 and 113.25 mgh/L).

Discussion and conclusion: The results demonstrated a good correlation of Level A (r² = 0.97) for the two formulations (F-I, F-III) and commercial product (R-I) indicates that there is a reasonable assumption that the rabbit might be use as a model for the preliminary comparison of scale up formulations in the early stages of the product development.     

Quality-by-design approach for the development of telmisartan potassium tablets

A quality-by-design approach was adopted to develop telmisartan potassium (TP) tablets, which were bioequivalent with the commercially available Micardis^® (telmisartan free base) tablets. The dissolution pattern and impurity profile of TP tablets differed from those of Micardis^® tablets because telmisartan free base is poorly soluble in water. After identifying the quality target product profile and critical quality attributes (CQAs), drug dissolution, and impurities were predicted to be risky CQAs. To determine the exact range and cause of risks, we used the risk assessment (RA) tools, preliminary hazard analysis and failure mode and effect analysis to determine the parameters affecting drug dissolution, impurities, and formulation. The range of the design space was optimized using the face-centered central composite design among the design of experiment (DOE) methods. The binder, disintegrant, and kneading time in the wet granulation were identified as X values affecting Y values (disintegration, hardness, friability, dissolution, and impurities). After determining the design space with the desired Y values, the TP tablets were formulated and their dissolution pattern was compared with that of the reference tablet. The selected TP tablet formulated using design space showed a similar dissolution to that of Micardis^® tablets at pH 7.5. The QbD approach TP tablet was bioequivalent to Micardis^® tablets in beagle dogs.     

Effect of Kollidon VA®64 particle size and morphology as directly compressible excipient on tablet compression properties

The study evaluates use of Kollidon VA^®64 and a combination of Kollidon VA^®64 with Kollidon VA^®64 Fine as excipient in direct compression process of tablets. The combination of the two grades of material is evaluated for capping, lamination and excessive friability. Inter particulate void space is higher for such excipient due to the hollow structure of the Kollidon VA^®64 particles. During tablet compression air remains trapped in the blend exhibiting poor compression with compromised physical properties of the tablets. Composition of Kollidon VA^®64 and Kollidon VA^®64 Fine is evaluated by design of experiment (DoE). A scanning electron microscopy (SEM) of two grades of Kollidon VA^®64 exhibits morphological differences between coarse and fine grade. The tablet compression process is evaluated with a mix consisting of entirely Kollidon VA^®64 and two mixes containing Kollidon VA^®64 and Kollidon VA^®64 Fine in ratio of 77:23 and 65:35. A statistical modeling on the results from the DoE trials resulted in the optimum composition for direct tablet compression as combination of Kollidon VA^®64 and Kollidon VA^®64 Fine in ratio of 77:23. This combination compressed with the predicted parameters based on the statistical modeling and applying main compression force between 5 and 15?kN, pre-compression force between 2 and 3?kN, feeder speed fixed at 25?rpm and compression range of 45–49?rpm produced tablets with hardness ranging between 19 and 21?kp, with no friability, capping, or lamination issue.     

The influence of tablet density on the human oral absorption of sustained release acetaminophen matrix tablets

Abstract

Low density bilayer compressed matrix tablets of acetaminophen were tested for in vitro dissolution and in vivo oral absorption. The upper layer contained a carbon dioxide-generating blend and the lower layer contained hydroxypropyl methylcellulose (HPMC) and acetaminophen. Carbon dioxide liberated by the action of the acidic dissolution medium on the upper layer is entrapped in the gelled hydrocolloid, providing buoyancy of the tablet and sustained release of the drug. For comparative purposes, similar but non-gas generating bilayer compressed matrix tablets were formulated and tested in vitro under the same conditions. These high density tablets were found to yield similar dissolution profiles as the low density tablets. The absorption characteristics of the bilayer compressed matrix tablets were compared with those of rapidly disintegrating acetaminophen tablets (TYLENOL® tablets, 500 mg) under fasted and fed conditions in six healthy subjects. Under fasted conditions, saliva profiles showed a rapid absorption for TYLENOL tablets but slower absorption for both compressed matrix tablets. Saliva profiles of TYLENOL® tablets under fed conditions were similar to those for the fasted case. In contrast, the peak saliva levels of acetaminophen for both compressed matrix tablets were significantly increased under fed conditions. The time to maximum saliva concentrations (Tmax) of all three dosage forms was not significantly affected by food intake. The relative bioavailability of the low density tablets under fasted and fed conditions was not significantly different from those of TYLENOL tablets, but vas significantly greater than that of high density tablets under fasted and fed conditions. A possibility exists that the buoyancy mechanism enabled the tablet to maintain more prolonged residence time in the gastrointestinal tract.     

Development and optimization of press coated tablets of release engineered valsartan for pulsatile delivery

The present work is aimed to develop and optimize pulsatile delivery during dissolution of an improved formulation of valsartan to coordinate the drug release with circadian rhythm. Preliminary studies suggested that β cyclodextrin could improve the solubility of valsartan and showed A_L type solubility curve. A 1:1 stoichiometric ratio of valsartan to β cyclodextrin was revealed from phase solubility studies and Job’s plot. The prepared complex showed significantly better dissolution efficiency (p?<?0.05) compared to pure drug, which could be due to the formation of inclusion complex as revealed from FTIR and DSC studies. Continuous dissolution-absorption studies revealed that absorption of drug from valsartan β cyclodextrin complex was significantly higher (p?2 full factorial design was used to measure the response of HPMC K4M and EC on lag time and time taken for 90% drug release (T90). The optimized batch prepared according to the levels obtained from the desirability function had a lag time of 6?h and consisted of HPMC K4M:ethylcellulose in a 1:1.5 ratio with 180?mg of coating and revealed a close agreement between observed and predicted value (R^2?=?0.9694).