Co-Processed Excipients for Dispersible Tablets–Part 1: Manufacturability

Co-processed excipients may enhance functionality and reduce drawbacks of traditional excipients for the manufacture of tablets on a commercial scale. The following study aimed to characterise a range of co-processed excipients that may prove suitable for dispersible tablet formulations prepared by direct compression. Co-processed excipients were lubricated and compressed into 10.5-mm convex tablets using a Phoenix compaction simulator. Compression profiles were generated by varying the compression force applied to the formulation and the prepared tablets were characterised for hardness, friability, disintegration and fineness of dispersion. Our data indicates that CombiLac, F-Melt type C and SmartEx QD100 were the top 3 most suitable out of 16 co-processed excipients under the conditions evaluated. They exhibited good flow properties (Carr’s index ? 20), excellent tabletability (tensile strength >?3.0 MPa at 0.85 solid fraction), very low friability (<?1% after 15 min), rapid disintegration times (27–49 s) and produced dispersions of ideal fineness (<?250 μm). Other co-processed excipients (including F-Melt type M, Ludiflash, MicroceLac, Pharmaburst 500 and Avicel HFE-102) may be appropriate for dispersible tablets produced by direct compression providing the identified disintegration and dispersion risks were mitigated prior to commercialisation. This indicates that robust dispersible tablets which disintegrate rapidly could be manufactured from a range of co-processed excipients.     

Preparation and Evaluation of Orally Disintegrating Tablets Containing Taste-Masked Microcapsules of Berberine Hydrochloride

The purpose of this study was to prepare and evaluate a taste-masked berberine hydrochloride orally disintegrating tablet for enhanced patient compliance. Taste masking was performed by coating berberine hydrochloride with Eudragit E100 using a fluidized bed. It was found that microcapsules with a drug–polymer ratio of 1:0.8 masked the bitter taste obviously. The microcapsules were formulated to orally disintegrating tablets and the optimized tablets containing 6% (w/w) crospovidone XL and 15% (w/w) microcrystalline cellulose showed the fastest disintegration, within 25.5 s, and had a pleasant taste. The dissolution profiles revealed that the taste-masked orally disintegrating tablets released the drug faster than commercial tablets in the first 10 min. However, their dissolution profiles were very similar after 10 min. The prepared taste-masked tablets remained stable after 6 months of storage. The pharmacokinetics of the taste-masked and commercial tablets was evaluated in rabbits. The C_max, T_max, and AUC₀₋₂₄ values were not significantly different from each other, suggesting that the taste-masked orally disintegrating tablets are bioequivalent to commercial tablets in rabbits. These tablets will enhance patient compliance by masking taste and improve patients’ quality of life.KEY WORDS: berberine hydrochloride, microcapsule, orally disintegrating tablet, taste masking     

Formulation of a Novel Tianeptine Sodium Orodispersible Film

The present investigation was undertaken with the objective of formulating orodispersible film(s) of the antidepressant drug tianeptine sodium to enhance the convenience and compliance by the elderly and pediatric patients. The novel film former, lycoat NG73 (granular hydroxypropyl starch), along with different film-forming agents (hydroxypropyl methyl cellulose, hydroxyethyl cellulose, and polyvinyl alcohol), in addition to three film modifiers; namely, maltodextrin, polyvinyl pyrrolidone K90 and lycoat RS780 (pregelatinized hydroxypropyl starch) were evaluated. Eight formulae were prepared by the solvent-casting method; and were evaluated for their in vitro dissolution characteristics, in vitro disintegration time, and their physico-mechanical properties. The promising orodispersible film based on lycoat NG73 (F1); showing the greatest drug dissolution, satisfactory in vitro disintegration time and physico-mechanical properties that are suitable for orodispersible films, was evaluated for its bioavailability compared with a reference marketed product (Stablon® tablets) in rabbits. Statistical analysis revealed no significant difference between the bioavailability parameters (C_max (ng/ml), t_max (h), AUC_0–t (ng h ml⁻¹), and AUC_0–∞ (ng h ml⁻¹)] of the test film (F1) and the reference product. The mean ratio values (test/reference) of C_max (89.74%), AUC_0–t (110.9%), and AUC_0–∞ (109.21%) indicated that the two formulae exhibited comparable plasma level-time profiles. These findings suggest that the fast orodispersible film containing tianeptine is likely to become one of choices for acute treatment of depression.Key words: bioavailability from orodispersible films and tablets, fast-dissolving films, orodispersible films, solvent-casting method, tianeptine sodium     

Co-Processed Excipients for Dispersible Tablets—Part 2: Patient Acceptability

Palatability and patient acceptability are critical attributes of dispersible tablet formulation. Co-processed excipients could provide improved organoleptic profile due to rational choice of excipients and manufacturing techniques. The aim of this study was to identify the most suitable co-processed excipient to use within directly compressible dispersible tablet formulations. Nine excipients, selected based on successful manufacturability, were investigated in a randomised, preference and acceptability testing in 24 healthy adult volunteers. Excipients were classified in order of preference as follows (from most preferred): SmartEx QD100?>?F-Melt Type C?>?F-Melt Type M?>?MicroceLac?>?Ludiflash?>?CombiLac?>?Pharmaburst 500?>?Avicel HFE-102?>?Avicel PH-102. Broad differences were identified in terms of acceptability, with SmartEx QD100 being ‘very acceptable’, F-Melt Type C, F-Melt Type M and MicroceLac being ‘acceptable’, Ludiflash, CombiLac and Pharmaburst 500 being ‘neutral’ and Avicel products being ‘very unacceptable’ based on ratings using five-point hedonic scales. Organoleptic differences were ascribed to different composition and physical properties of excipients, resulting in dissimilar taste and mouth-feel. Excipients with particle size in water larger than 200–250 μm were considered poorly acceptable, which supports the use of this value as a threshold for maximum particle size of dispersible formulation. The most promising co-processed excipients for directly compressible dispersible tablets were successfully identified.     

The Influence of Sodium Carboxymethylcellulose on Drug Release from Polyethylene Oxide Extended Release Matrices

Anionic polymer sodium carboxymethylcellulose (CELLOGEN® HP-HS and/or HP-12HS) was investigated for its ability to influence the release of three model drugs propranolol hydrochloride, theophylline and ibuprofen from polyethylene oxide (POLYOX™ WSR 1105 and/or Coagulant) hydrophilic matrices. For anionic ibuprofen and non-ionic theophylline, no unusual/unexpected release profiles were obtained from tablets containing a mixture of two polymers. However, for cationic propranolol HCl, a combination of polyethylene oxide (PEO) with sodium carboxymethylcellulose (NaCMC) produced a significantly slower drug release compared to the matrices with single polymers. The potential use of this synergistic interaction can be a design of new extended release pharmaceutical dosage forms with a more prolonged release (beyond 12 h) using lower polymer amount, which could be particularly beneficial for freely water-soluble drugs, preferably for once daily oral administration. In order to explain changes in the obtained drug release profiles, Fourier transform infrared absorption spectroscopy was performed. A possible explanation for the more prolonged propranolol HCl release from matrices based on both PEO and NaCMC may be due to a chemical bond (i.e. ionic/electrostatic intermolecular interaction) between amine group of the cationic drug and carboxyl group of the anionic polymer, leading to a formation of a new type/form of the active (i.e. salt) with sustained release pattern.Key words: extended release, FT-IR, ibuprofen, matrix tablet, polyethylene oxide, polymer combination, propranolol hydrochloride, sodium carboxymethylcellulose, theophylline     

Preparation and Characterization of a Novel Co-processed Excipient of Chitin and Crystalline Mannitol

A co-processed excipient was prepared from commercially available crystalline mannitol and α-chitin using direct compression as well as spray, wet, and dry granulation. The effect of the ratio of the two components, percentage of lubricant and particle size, on the properties of the prepared co-processed excipient has been investigated. α-Chitin forms non-hygroscopic, highly compactable, disintegrable compacts when co-processed with crystalline mannitol. The compaction properties of the co-processed mannitol–chitin mixture were found to be dependent upon the quantity of mannitol added to chitin, in addition to the granulation procedure used. Optimal physicochemical properties of the excipient, from a manufacturing perspective, were obtained using a co-processed mannitol–chitin (2:8, w/w) mixture prepared by wet granulation (Cop-MC). Disintegration time, crushing strength, and friability of tablets, produced from Cop-MC using magnesium stearate as a lubricant, were found to be independent of the particle size of the prepared granules. The inherent binding and disintegration properties of the compressed Cop-MC are useful for the formulation of poorly compressible, high-strength, and low-strength active pharmaceutical ingredients. The ability to co-process α-chitin with crystalline mannitol allows chitin to be used as a valuable industrial pharmaceutical excipient.     

Meloxicam Taste-Masked Oral Disintegrating Tablet with Dissolution Enhanced by Ion Exchange Resins and Cyclodextrin

The purpose of this study was to develop taste-masked oral disintegrating tablets (ODTs) using the combination of ion exchange resin and cyclodextrin, to mask the bitter taste and enhance drug dissolution. Meloxicam (MX) was selected as a model drug with poor water solubility and a bitter taste. Formulations containing various forms of MX (free drug, MX-loaded resin or resinate, complexes of MX and 2-hydroxypropyl-β-cyclodextrin (HPβCD) or MX/HPβCD complexes, and a mixture of resinate and MX/HPβCD complexes) were made and tablets were prepared by direct compression. The ODTs were evaluated for weight variation, thickness, diameter, hardness, friability, disintegration time, wetting time, MX content, MX release, degree of bitter taste, and stability. The results showed that thickness, diameter, weight, and friability did not differ significantly for all of these formulations. The tablet hardness was approximately 3 kg/in.², and the friability was less than 1%. Tablets formulated with resinate and the mixture of resinate and MX/HPβCD complexes disintegrated rapidly within 60 s, which is the acceptable limit for ODTs. These results corresponded to the in vivo disintegration and wetting times. However, only tablets containing the mixture of resinate and MX/HPβCD complexes provided complete MX dissolution and successfully masked the bitter taste of MX. In addition, this tablet was stable at least 6 months. The results from this study suggest that the appropriate combination of ion exchange resin and cyclodextrin could be used in ODTs to mask the bitter taste of drug and enhance the dissolution of drugs that are weakly soluble in water.     

Miconazole Nitrate Oral Disintegrating Tablets: In Vivo Performance and Stability Study

The interest in and need for formulating miconazole nitrate (MN), a broad-spectrum antifungal, as an oral disintegrating tablet for treatment of some forms of candidiasis have increased. Formulation of MN in this dosage form will be more advantageous, producing dual effect: local in the buccal cavity and systemic with rapid absorption. Four formulations were prepared utilizing the foam granulation technique. The prepared tablets were characterized by measuring the weight uniformity, thickness, tensile strength, friability, and drug content. In addition, tablet disintegration time, in vitro dissolution, and in vivo disintegration time were also evaluated. Stability testing for the prepared tablets under stress and accelerated conditions in two different packs were investigated. Each pack was incubated at two different elevated temperature and relative humidity (RH), namely 40 ± 2°C/75 ± 5% RH and 50 ± 2°C/75 ± 5% RH. The purpose of the study is to monitor any degradation reactions which will help to predict the shelf life of the product under the defined storage conditions. Finally, in vivo study was performed on the most stable formula to determine its pharmacokinetic parameters. The results revealed that all the prepared tablets showed acceptable tablet characteristics and were stable under the tested conditions. The most stable formula was that containing magnesium stearate as lubricant, hydrophobic Aerosil R972 as glidant, low urea content, mannitol/microcrystalline cellulose ratio 2:1, and 9% Plasdone XL100 as superdisintegrant. The in vivo results revealed that the tested formula showed rapid absorption compared to the physical blend (t_max were 1 and 4 h, respectively), while the extent of absorption was almost the same.KEY WORDS: accelerated stability testing, bioavailability, foam granulation technique, miconazole nitrate, oral disintegrating tablet     

Sustained Release of a Water-Soluble Drug from Alginate Matrix Tablets Prepared by Wet Granulation Method

Alginate matrix tablet of diltiazem hydrochloride (DTZ), a water-soluble drug, was prepared using sodium alginate (SAL) and calcium gluconate (CG) by the conventional wet granulation method for sustained release of the drug. The effect of formulation variables like SAL/CG ratio, drug load, microenvironmental pH modulator, and processing variable like compression force on the extent of drug release was examined. The tablets prepared with 1:2 w/w ratio of SAL/CG produced the most sustained release of the drug extending up to 13.5 h. Above and below this ratio, the drug release was faster. The drug load and the hardness of the tablets produced minimal variation in drug release. The addition of alkaline or acidic microenvironmental modulators did not extend the release; instead, these excipients produced somewhat faster release of diltiazem. This study revealed that proper selection of SAL/CG ratio is important to produce alginate matrix tablet by wet granulation method for sustained release of DTZ.     

Enhanced Bioavailability of Atorvastatin Calcium from Stabilized Gastric Resident Formulation

Oral bioavailability of atorvastatin calcium (ATC) is very low (only 14%) due to instability and incomplete intestinal absorption and/or extensive gut wall extraction. When ATC is packed in the form of tablets, powders, etc., it gets destabilized as it is exposed to the oxidative environment, which is usually present during the production process, the storage of the substance, and the pharmaceutical formulation. Therefore, stabilized gastro-retentive floating tablets of ATC were prepared to enhance bioavailability. Water sorption and viscosity measurement studies are performed to get the best polymer matrix for gastro-retention. A 3² factorial design used to prepare optimized formulation of ATC. The selected excipients such as docusate sodium enhanced the stability and solubility of ATC in gastric media and tablet dosage form. The best formulation (F4) consisting of hypromellose, sodium bicarbonate, polyethylene oxide, docusate sodium, mannitol, crosscarmellose sodium, and magnesium stearate, gave floating lag time of 56 ± 4.16 s and good matrix integrity with in vitro dissolution of 98.2% in 12 h. After stability studies, no significant change was observed in stability, solubility, floating lag time, total floating duration, matrix integrity, and sustained drug release rates, as confirmed by DSC and powder X-ray diffraction studies. In vivo pharmacokinetic study performed in rabbits revealed enhanced bioavailability of F4 floating tablets, about 1.6 times compared with that of the conventional tablet (Storvas® 80 mg tablet). These results suggest that the gastric resident formulation is a promising approach for the oral delivery of ATC for improving bioavailability.Key words: atorvastatin calcium, bioavailibility, floating tablets, gastro-retention, stabilization     

Formulation and Optimization of Orodispersible Tablets of Diazepam

Diazepam is one of the most prescribed benzodiazepines. The purpose of the present research was to optimize the formulation of orodispersible tablets of diazepam. Orodispersible tablets of diazepam were prepared using different types of superdisintegrants (Ac-Di-Sol, sodium starch glycolate, and crospovidone (CP)) and different types of subliming agents (camphor and ammonium bicarbonate (AB)) at different concentrations and two methods of tablets preparations (wet granulation and direct compression methods). The formulations were evaluated for flow properties, wetting time, hardness, friability, content uniformity, in vivo disintegration time (DT), release profiles, and buccal absorption tests. All formulations showed satisfactory mechanical strength except formula F5 which contains camphor and formula F9 which is prepared by direct compression method. The results revealed that the tablets containing CP as a superdisintegrant have good dissolution profile with shortest DT. The optimized formula F7 is prepared using 10% CP as a superdisintegrant and 20% AB as a subliming agent by wet granulation method which shows the shortest DT and good dissolution profile with acceptable stability. This study helps in revealing the effect of formulation processing variables on tablet properties. It can be concluded that the orodispersible tablets of diazepam with better biopharmaceutical properties than conventional tablets could be obtained using formula F7.     

New Direct Compression Excipient from Tigernut Starch: Physicochemical and Functional Properties

Tigernut starch has been isolated and modified by forced retrogradation of the acidic gel by freezing and thawing processes. Relevant physicochemical and functional properties of the new excipient (tigernut starch modified by acid gelation and accelerated (forced) retrogradation (ST_AM)) were evaluated as a direct compression excipient in relation to the native tigernut starch (ST_NA), intermediate product (tigernut starch modified by acid gelation (ST_A)), and microcrystalline cellulose (MCC). The particle morphology, swelling capacity, moisture sorption, differential scanning calorimeter (DSC) thermographs and X-ray powder diffraction (XRD) patterns, flow, dilution capacity, and tablet disintegration efficiency were evaluated. The particles of ST_NA were either round or oval in shape, ST_A were smooth with thick round edges and hollowed center while ST_AM were long, smooth, and irregularly shaped typically resembling MCC. The DSC thermographs of ST_NA and MCC showed two endothermic transitions as compared with ST_A and ST_AM which showed an endothermic and an exothermic. The moisture uptake, swelling, flow, and dilution capacity of ST_AM were higher than those of MCC, ST_A, and ST_NA. The XRD pattern and moisture sorption profile of ST_AM showed similarities and differences with ST_NA, ST_A, and MCC that relate the modification. Acetylsalicylic acid (ASA) tablets containing ST_AM disintegrated at 3 ± 0.5 min as compared with the tablets containing ST_NA, ST_A, and MCC which disintegrated at 8.5 ± 0.5, 10 ± 0.5, and 58 ± 0.8 min, respectively. The study shows the physicochemical properties of tigernut starch modified by forced retrogradation as well as its potential as an efficient direct compression excipient with enhanced flow and disintegration abilities for tablets production.Key words: direct compression excipient, forced retrogradation, functional properties, physicochemical properties, tigernut starch     

Development and Evaluation of Cetirizine HCl Taste-Masked Oral Disintegrating Tablets

The purpose of the current study was to mask the taste of cetirizine HCl and to incorporate the granules produced in oral disintegrating tablets (ODT). The bitter, active substance was coated by fluidized bed coating using Eudragit® RL30-D at levels between 15% and 40% w/w. The ODTs were developed by varying the ratio of superdisintegrants such as sodium croscarmellose, crospovidone grades and low substituted hydroxypropyl cellulose (L-HPC). A direct compression process was used to compress the ODTs under various compaction forces to optimize tablet robustness. The properties of the compressed tablets including porosity, hardness, friability and dissolution profiles were further investigated. The in vitro and in vivo evaluation of the tablet disintegration times showed almost identical rapid disintegration below 10 s at the optimal levels of each superdisintegrant. Finally, the taste and sensory evaluation in human volunteers demonstrated excellence in masking the bitter active and tablet palatability.     

Disintegration of Highly Soluble Immediate Release Tablets: A Surrogate for Dissolution

The purpose of the work was to investigate correlation between disintegration and dissolution for immediate release tablets containing a high solubility drug and to identify formulations where disintegration test, instead of the dissolution test, may be used as the acceptance criteria based on International Conference on Harmonization Q6A guidelines. A statistical design of experiments was used to study the effect of filler, binder, disintegrating agent, and tablet hardness on the disintegration and dissolution of verapamil hydrochloride tablets. All formulation variables, i.e., filler, binder, and disintegrating agent, were found to influence tablet dissolution and disintegration, with the filler and disintegrating agent exerting the most significant influence. Slower dissolution was observed with increasing disintegration time when either the filler or the disintegrating agent was kept constant. However, no direct corelationship was observed between the disintegration and dissolution across all formulations due to the interactions between different formulation components. Although all tablets containing sodium carboxymethyl cellulose as the disintegrating agent, disintegrated in less than 3 min, half of them failed to meet the US Pharmacopeia 30 dissolution criteria for the verapamil hydrochloride tablets highlighting the dependence of dissolution process on the formulation components other than the disintegrating agent. The results identified only one formulation as suitable for using the disintegration test, instead of the dissolution test, as drug product acceptance criteria and highlight the need for systematic studies before using the disintegration test, instead of the dissolution test as the drug acceptance criteria. The opinions expressed in this work are only of authors and do not necessarily reflect the policy and statements of the FDA.     

Development,Characterization and Permeability Assessment Based on Caco-2 Monolayers of Self-Microemulsifying Floating Tablets of Tetrahydrocurcumin

Novel self-microemulsifying floating tablets were developed to enhance the dissolution and oral absorption of the poorly water-soluble tetrahydrocurcumin (THC). Their physicochemical properties and THC permeability across Caco-2 cell monolayers were assessed. The self-microemulsifying liquid containing THC was adsorbed onto colloidal silicon dioxide, mixed with HPMC, gas-generating agents (sodium bicarbonate and tartaric acid), lactose and silicified-microcrystalline cellulose and transformed into tablets by direct compression. The use of different types/concentrations of HPMC and sodium bicarbonate in tablet formulations had different effects on the floating characteristics and in vitro THC release. The optimum tablet formulation (F2) provided a short floating lag time (∼23 s) together with a prolonged buoyancy (>12 h). About 72% of THC was released in 12 h with an emulsion droplet size in aqueous media of 33.9 ± 1.0 nm while that of a self-microemulsifying liquid was 29.9 ± 0.3 nm. The tablet formulation was stable under intermediate and accelerated storage conditions for up to 6 months. The THC released from the self-microemulsifying liquid and tablet formulations provided an approximately three- to fivefold greater permeability across the Caco-2 cell monolayers than the unformulated THC and indicated an enhanced absorption of THC by the formulations. The self-microemulsifying floating tablet could provide a dosage form with the potential to improve the oral bioavailability of THC and other hydrophobic compounds.KEY WORDS: Caco-2 cells, controlled release, permeability, self-microemulsifying floating tablets, tetrahydrocurcumin     

Development and Optimization of Gastro-Retentive Controlled-Release Tablet of Calcium-Disodium Edentate and its In Vivo Gamma Scintigraphic Evaluation

Medical management of heavy metal toxicity, including radioactive ones, is a cause for concern because of their increased use in energy production, healthcare, and mining. Though chelating agents like EDTA and DTPA in parenteral form are available, no suitable oral formulation is there that can trap ingested heavy metal toxicants in the stomach itself, preventing their systemic absorption. The objective of the present study was to develop and optimize gastro-retentive controlled-release tablets of calcium-disodium edentate (Ca-Na₂EDTA). Gastro-retentive tablet of Ca-Na₂EDTA was prepared by direct compression method. Thirteen tablet formulations were designed using HPMC-K4M, sodium chloride, and carbopol-934 along with effervescing agents sodium bicarbonate and citric acid. Tablet swelling ability, in vitro buoyancy, and drug dissolution studies were conducted in 0.1 N HCl at 37 ± 0.5°C. Ca-Na₂EDTA was radiolabeled with technetium-99m for scintigraphy-based in vivo evaluation. Formula F8 (Ca-Na₂EDTA 200 mg, carbopol 100 mg, avicel 55 mg, citric acid 30 mg, NaHCO₃ 70 mg, NaCl 100 mg, and HPMC 95 mg) was found to be optimum in terms of excellent floating properties and sustained drug release. F8 fitted best for Korsmeyer–Peppas equation with an R² value of 0.993. Gamma scintigraphy in humans showed mean gastric retention period of 6 h. Stability studies carried out in accordance with ICH guidelines and analyzed at time intervals of 0, 1, 2, 4, and 6 months have indicated insignificant difference in tablet hardness, drug content, total floating duration, or matrix integrity of the optimized formulation. Gastro-retentive, controlled-release tablet of Ca-Na₂EDTA was successfully developed using effervescent technique as a potential oral antidote for neutralizing ingested heavy metal toxicity.KEY WORDS: calcium disodium EDTA, controlled-release tablet, gamma scintigraphy, heavy metal decorporation     

Controlled Release Matrix Tablets of Olanzapine: Influence of Polymers on the <Emphasis Type="Italic">In Vitro</Emphasis> Release and Bioavailability

Controlled-release (CR) tablet formulation of olanzapine was developed using a binary mixture of Methocel® K100 LV-CR and Ethocel® standard 7FP premium by the dry granulation slugging method. Drug release kinetics of CR tablet formulations F1, F2, and F3, each one suitably compressed for 9-, 12-, and 15-kg hardness, were determined in a dissolution media of 0.1 N HCl (pH 1.5) and phosphate buffer (pH 6.8) using type II dissolution apparatus with paddles run at 50 rpm. Ethocel® was found to be distinctly controlling drug release, whereas the hardness of tablets and pH of the dissolution media did not significantly affect release kinetics. The CR test tablets containing 30% Methocel® and 60% Ethocel® (F3) with 12-kg hardness exhibited pH-independent zero-order release kinetics for 24 h. In vivo performance of the CR test tablet and conventional reference tablet were determined in rabbit serum using high-performance liquid chromatography coupled with electrochemical detector. Bioavailability parameters including C_max, T_max, and AUC_0–48 h of both tablets were compared. The CR test tablets produced optimized C_max and extended T_max (P < 0.05). A good correlation of drug absorption in vivo and drug release in vitro (R² = 0.9082) was observed. Relative bioavailability of the test tablet was calculated as 94%. The manufacturing process employed was reproducible and the CR test tablets were stable for 6 months at 40 ± 2°C/75 ± 5% relative humidity. It was concluded that the CR test tablet formulation successfully developed may improve tolerability and patient adherence by reducing adverse effects.Key words: bioavailability, controlled release, Ethocel®, olanzapine     

Valsartan Orodispersible Tablets: Formulation, <Emphasis Type="Italic">In vitro</Emphasis>/<Emphasis Type="Italic">In vivo</Emphasis> Characterization

Valsartan orodispersible tablets have been developed at 40-mg dose, with the intention of facilitating administration to patients experiencing problems with swallowing and hopefully, improving its poor oral bioavailability. Work started with selecting drug compatible excipients depending on differential scanning calorimetric analysis. A 3³ full factorial design was adopted for the optimization of the tablets prepared by freeze-drying technique. The effects of the filler type, the binder type, and the binder concentration were studied. The different tablet formulas were characterized for their physical properties, weight variation, disintegration time, surface properties, wetting properties, and in vitro dissolution. Amongst the prepared 27 tablet formulas, formula number 6 (consisting of 4:6 valsartan:mannitol and 2% pectin) was selected to be tested in vivo. Oral bioavailability of two 40 mg valsartan orodispersible tablets was compared to the conventional commercial tablets after administration of a single dose to four healthy volunteers. Valsartan was monitored in plasma by high-performance liquid chromatography. The apparent rate of absorption of valsartan from the prepared tablets (C _max = 2.879 μg/ml, t _max = 1.08 h) was significantly higher than that of the conventional tablets (C _max = 1.471 μg/ml, t _max = 2.17 h), P ≤ 0.05. The relative bioavailability calculated as the ratio of mean total area under the plasma concentration–time curve for the orodispersible tablets relative to the conventional ones was 135%. The results of the in vivo study revealed that valsartan orodispersible tablets would be advantageous with regards to improved patient compliance, rapid onset of action, and increase in bioavailability.     

An Investigation into the Stabilization of Diltiazem HCl Release from Matrices Made from Aged Polyox Powders

Matrices containing PEO fail to provide stable drug release profiles when stored at elevated temperatures for a period of time. The present study aims to stabilize diltiazem HCl release from matrices made from various molecular weights of polyox powders. To this end, various molecular weights of polyox with and without vitamin E (0.25, 0.5 and 1% w/w) were stored at 40°C for 0, 2, 4 and 8 weeks. The aged polyox powders were then mixed with the model drug at a ratio of 1:1 and compressed into tablets. At different time intervals, the aged polyox with vitamin E were taken out of oven and mixed with the drug (1:1 ratio) and compressed into tablets. Dissolution studies showed a significant increase in diltiazem HCl release rate to occur with increased storage time at 40°C ± 1 from tablets made from the aged polyox (no vitamin E). This was as a result of depolymerization of the aged polyox powders as compared to the fresh polyox samples. This was confirmed by differential scanning calorimetry (DSC) which showed a reduction in the melting point of the aged samples. Concentrations of vitamin E as low as 0.25% w/w was able to overcome the quick release of drug from the matrices made from aged polyox powders. DSC traces showed that the melting point of aged polyox samples containing vitamin E remained the same as that of the fresh samples. The presence of vitamin E is essential to stabilize the drug release from polyox matrices containing diltiazem HCl.Key words: depolymerization, drug release kinetics, molecular weight, polyox matrices, thermal behaviour     

Formulation of Ketotifen Fumarate Fast-Melt Granulation Sublingual Tablet

The purpose of this study was to prepare sublingual tablets, containing the antiasthmatic drug ketotifen fumarate which suffers an extensive first-pass effect, using the fast-melt granulation technique. The powder mixtures containing the drug were agglomerated using a blend of polyethylene glycol 400 and 6000 as meltable hydrophilic binders. Granular mannitol or granular mannitol/sucrose mixture were used as fillers. A mechanical mixer was used to prepare the granules at 40°C. The method involved no water or organic solvents, which are used in conventional granulation, and hence no drying step was included, which saved time. Twelve formulations were prepared and characterized using official and non official tests. Three formulations showed the best results and were subjected to an ex vivo permeation study using excised chicken cheek pouches. The formulation F4I possessed the highest permeation coefficient due to the presence of the permeation enhancer (polyethylene glycol) in an amount which allowed maximum drug permeation, and was subjected to a pharmacokinetic study using rabbits as an animal model. The bioavailability of F4I was significantly higher than that of a commercially available dosage form (Zaditen® solution-Novartis Pharma-Egypt) (p > 0.05). Thus, fast-melt granulation allowed for rapid tablet disintegration and an enhanced permeation of the drug through the sublingual mucosa, resulting in increased bioavailabililty.Key words: chicken pouches, fast-melt granulation, ketotifen fumarate, permeation, sublingual tablet, Zaditen®