Formulation of Risperidone as Self-Nanoemulsifying Drug Delivery System in Form of Effervescent Tablets

Risperidone is an atypical antipsychotic drug used to treat schizophrenia. This study aims to formulate risperidone as effervescent tablets to improve patient compliance. Different nanoemulsion combinations were loaded with risperidone to improve its poor water solubility then adsorbed on Aeroperl. The formula showing highest drug dissolution was formulated as effervescent tablets. Factorial design was applied for different tablet formulation variables and the prepared formulae were tested for different criteria in comparison with their corresponding formulae containing drug without nanoemulsion formulation. Statistical analysis was used to determine the most desirable tablet formula considering its Carr index, effervescence time, and drug release.     

Development and evaluation of a monolithic floating drug delivery system for acyclovir

Acyclovir (ACV), a model drug for this study, is one of the most effective drugs against viruses of the herpes group. Absorption of orally administered ACV is variable and incomplete, with a bioavailability of ca. 15-30%. The drug is absorbed in the duodenum after oral administration and hence, preparation of a floating drug delivery system (FDDS) for ACV may increase oral absorption of the drug. ACV matrix tablets (200?mg) containing an effervescent base (sodium bicarbonate and citric acid) and a binary combination of hydroxypropyl methylcellulose (HPMC) K4M with carbopol or sodium carboxymethyl cellulose (Na CMC) or polyvinylpyrrolidone (PVP) and/or sodium alginate were prepared by the direct compression method. The tablets were evaluated for physicochemical properties and in vitro floating ability (floating lag-time and duration), bioadhesiveness and drug release. The drug release studies were carried out in 0.1?N HCl (pH 1.2) at 37±0.5°C. At appropriate time intervals, samples were withdrawn and assayed spectrophotometrically at λ(max)=259?nm. The floating test showed tablets containing 15% effervescent base had a floating lag time of 10-30?s and a duration of floating time of 24?h. The formulations containing HPMC-PVP, HPMC-Na CMC, HPMC-carbopol, and HPMC-sodium alginate released about 60-90% of their drug content during a 12-h period. Increasing carbopol caused slower drug release. We concluded that the proposed tablets with 15% effervescent base, 20-30% HPMC, 30% Na CMC (and/or 20% PVP or 20% sodium alginate) showed good floating and drug release properties in vitro, and should be considered as FDDS for ACV.     

In Vitro–In Vivo Correlation of Tianeptine Sodium Sustained-Release Dual-Layer Tablets

Tianeptine tablets are currently marketed to be designed for immediate-release tablets. The tianeptine has a short half-life, making it difficult to design for sustained-release tablets and achieve bioequivalence with the tianeptine immediate-release tablet (Stablon^®). We established the in vitro–in vivo correlation (IVIVC) of three formulations of tianeptine sustained-release tablets according to their granule size. To evaluate sustained drug release, in vitro tests were performed in pH 1.2 media for 24 h. In vivo pharmacokinetic analysis was performed following oral administration of reference drug and test drug to beagle dogs. The dissolution profile revealed delayed release as the size of the granules increased. The dissolution results were confirmed in pharmacokinetic analysis, showing that the half-life was delayed as granule size increased. The final formulation and reference drug showed an equivalent area under the curve (AUC). Through this, IVIVC was established according to the size of the tianeptine sodium granules, which is the purpose of this study, and was used to predict in vivo pharmacokinetics from the formulation composition. This approach may be useful for determining optimal formulation compositions to achieve the desired pharmacokinetics when developing new formulations.     

Preparation of Losartan Potassium Controlled Release Matrices and In-Vitro Investigation Using Rate Controlling Agents

Controlled release matrices have predictable drug release kinetics, provide drugs for an extended period of time, and reduce dosing frequency with improved patient compliance as compared with conventional tablet dosage forms. In the current research work, losartan potassium controlled release matrix tablets were fabricated and prepared with rate altering agents; that is, Ethocel grade 100 combined with Carbopol 934PNF. Various drug to polymer ratios were used. HPMC, CMC, and starch were incorporated in some of the matrices by replacing some amount of filler (5%). The direct compression method was adopted for the preparation of matrices. In phosphate buffer (pH 6.8), the dissolution study was conducted by adopting the USP method-I as the specified method. Drug release kinetics was determined and dissolution profiles were also compared with the reference standard. Prolonged release was observed for all matrices, but those with Ethocel 100FP Premium showed more extended release. The co-excipient (HPMC, CMC, and starch) exhibited enhancement in the drug release rates, while all controlled release matrices released the drug by anamolous non-Fickian diffusion mechanism. This combination of polymers (Ethocel grade 100 with Carbopol 934PNF) efficiently extended the drug release rates up to 24 h. It is suggested that these matrix tablets can be given in once a day dosage, which might improve patient compliance, and the polymeric blend of Ethocel grade 100 with Carbopol 934PNF might be used in the development of prolonged release matrices of other water-soluble drugs.     

Floating and sustained-release characteristics of effervescent tablets prepared with a mixed matrix of Eudragit L-100-55 and Eudragit E PO

The aim of this study was to evaluate the influence of Na-bicarbonate as an effervescent agent on the floating and sustained-release characteristics in 0.1 M HCl of tablets made of Eudragit E PO (EE) and/or Eudragit L-100-55 (EL) as matrix formers at different EE:EL weight ratios: 0:100, 25:75, 50:50, 75:25, and 100:0. The tablets were made by direct compression utilizing metronidazole as a model drug. Effervescent tablets with 50EE/50EL (w/w) showed the best floating and sustained drug release properties in the dissolution medium. The corresponding noneffervescent tablets were nonfloating and showed significantly faster drug release. Effervescent tablets with single polymers showed an immediate drug release pattern. These results were explained by Fourier-transform infrared spectroscopy and elemental analysis, which showed strong evidence of interpolyelectrolyte complexation between EE and EL when they were exposed to 0.1 M HCl as an effervescent hybrid matrix, but not as a noneffervescent hybrid matrix. The role of Na-bicarbonate in allowing EE-EL complexation during dissolution was explained as due to raising the pH around EL particles for sufficient polymer ionization and ionic-interaction with the ionized EE.     

Anthocyanins Formulated with Carboxymethyl Starch for Gastric and Intestinal Delivery

Anthocyanins obtained from jambolan have been used as active agents in different carboxymethyl starch-based tablet formulations and their release profiles evaluated in simulated gastric fluids (SGF) and simulated intestinal (SIF) fluids. Structural analysis highlighted a strong interaction between anthocyanins and carboxymethyl starch, evidenced by scanning electron microscopy and infrared analysis. Tablet dissolution behavior varied according to the pH of the media, being controlled by the swelling and/or erosion of the polymeric matrix. Various formulations for immediate, fast, and sustained release of anthocyanins for 30 min, 2 h and 12 h of dissolution have been developed. It was found that monolithic carboxymethyl starch tablets loaded with powdered jambolan extract efficiently afforded the complete delivery (100% of anthocyanins) to different sites of the simulated gastrointestinal tract and ensured the stability of these pigments, which maintained their antioxidant activity.     

Properties of gastroretentive sustained release tablets prepared by combination of melt/sublimation actions of L-menthol and penetration of molten polymers into tablets

A novel floating sustained release tablet having a cavity in the center was developed by utilizing the physicochemical properties of L-menthol and the penetration of molten hydrophobic polymer into tablets. A dry-coated tablet containing famotidine as a model drug in outer layer was prepared with a L-menthol core by direct compression. The tablet was placed in an oven at 80°C to remove the L-menthol core from tablet. The resulting tablet was then immersed in the molten hydrophobic polymers at 90°C. The buoyancy and drug release properties of tablets were investigated using United States Pharmacopeia (USP) 32 Apparatus 2 (paddle 100 rpm) and 900 ml of 0.01 N HCl. The L-menthol core in tablets disappeared completely through pathways in the outer layer with no drug outflows when placed in an oven for 90 min, resulting in a formation of a hollow tablet. The hollow tablets floated on the dissolution media for a short time and the drug release was rapid due to the disintegration of tablet. When the hollow tablets were immersed in molten hydrophobic polymers for 1 min, the rapid drug release was drastically retarded due to a formation of wax matrices within the shell of tablets and the tablets floated on the media for at least 6 h. When Lubri wax? was used as a polymer, the tablets showed the slowest sustained release. On the other hand, faster sustained release properties were obtained by using glyceryl monostearate (GMS) due to its low hydrophobic nature. The results obtained in this study suggested that the drug release rate from floating tablets could be controlled by both the choice of hydrophobic polymer and the combined use of hydrophobic polymers.     

Zero-order release formulations using a novel cellulose ester

New carboxymethylcellulose esters were developed with useful properties for oral dosage forms in drug delivery. Normally, commercial cellulose esters are used as the major excipients in oral dosage forms as a coating or a membrane. In applications involving compression tablets, cellulose esters are usually mixed with other more hydrophilic matrix components to facilitate dissolution of the active. In the present study, novel cellulose esters were single component matrix resins. Pharmaceutical actives were cryogenically ground as a physical blend or an amorphous blend with the polymer. Subsequently, tablets were made by direct compression using a single tablet press, or capsules were made by filling them with the ground material. Dissolution tests were completed on the solid dosage forms at pH 1.2, 4.5, 6.8 or 7.4 in a United States Pharmacopeia (USP) II device to determine the release profiles for up to 24 h. Carboxymethylcellulose esters provide an excellent matrix for controlling both the rate of release and the pH at which pharmaceutical actives release into the aqueous environment. When used in suitable quantities, dictated by the active of interest, carboxymethylcellulose acetate butyrate provided zero-order release over sustained time up to 24 h.     

Bilayer tablets of atorvastatin calcium and nicotinic acid: formulation and evaluation

The objective of the study is to formulate bilayer tablets consisting of atorvastatin calcium (AT) as an immediate release layer and nicotinic acid (NA) as an extended release layer. The immediate release layer was prepared using super disintegrant croscarmellose sodium and extended release layer using hydroxypropylmethyl cellulose (HPMC K100M). Both the matrix and bilayer tablets were evaluated for hardness, friability, weight variation, thickness, and drug content uniformity and subjected to in vitro drug release studies. The amount of AT and NA released at different time intervals were estimated by HPLC method. The bilayer tablets showed no significant change either in physical appearance, drug content or in dissolution pattern after storing at 40 degrees C/75% relative humiding (RH) for 3 months. The release of the drug from the tablet was influenced by the polymer content and it was much evident from thermogravimetry/differential thermal analysis (TG/DTA) analysis. The results indicated that the bilayer tablets could be a potential dosage form for delivering AT and NA.     

Preparation and evaluation of tablets rapidly disintegrating in saliva containing bitter-taste-masked granules by the compression method.

The aim of this study was to prepare, using taste-masked granules, tablets which can rapidly disintegrate in saliva (rapidly disintegrating tablet), of drugs with bitter taste (pirenzepine HCl or oxybutynin HCl). The taste-masked granules were prepared using aminoalkyl methacrylate copolymers (Eudragit E-100) by the extrusion method. None of the drugs dissolved from the granules (% of dissolved, < 5%) even at 480 min at pH 6.8 in the dissolution test. However, the drugs dissolved rapidly in the medium at pH 1.2 in the dissolution test. Rapidly disintegrating tablets were prepared using the prepared taste-masked granules, and a mixture of excipients consisting of crystalline cellulose (Avicel PH-102) and low-substituted hydroxypropylcellulose (L-HPC, LH-11). The granules and excipients were mixed well (mixing ratio by weight, crystalline cellulose: L-HPC = 8:2) with 1% magnesium stearate, and subsequently compressed at 500-1500 kgf in a single-punch tableting machine. The prepared tablets (compressed at 500 kgf) containing the taste-masked granules have sufficient strength (the crushing strength: oxybutynin tablet, 3.5 kg; pirenzepine tablet, 2.2 kg), and a rapid disintegration time (within 20 s) was observed in the saliva of healthy volunteers. None of the volunteers felt any bitter taste after the disintegration of the tablet which contained the taste-masked granules. We confirmed that the rapidly disintegrating tablets can be prepared using these taste-masked granules and excipients which are commonly used in tablet preparation.     

A comparison of drug loading capacity of cellactose with two ad hoc processed lactose-cellulose direct compression excipients

This study compares the drug loading capacity of Cellactose and two excipients of similar composition and similar particle size, prepared by dry granulation and extrusion-spheronization respectively. The drugs evaluated were acetaminophen and furosemide. Acetaminophen did not significantly affect the flow properties of any of the excipients, whereas furosemide markedly worsened flow properties, eliminating the differences initially existing among the three excipients. For both drugs, tablet mechanical properties were clearly better with Cellactose than with the other excipients. Acetaminophen dissolution rate was very similar regardless of the excipient used, but furosemide dissolution rate was lower from Cellactose tablets than from tablets prepared with the other excipients. This important difference is discussed in terms of micropore structure, specific surface area, and wettability of tablets, and is attributable to the special structure of Cellactose particles.     

Formulation variation and in vitro-in vivo correlation for a rapidly swellable three-layered tablet of tamsulosin HCl

In order to develop a preferable once-a-day oral tablet formulation, various formulations of three-layered tablets containing tamsulosin HCl as a hydrophilic model drug were evaluated and compared with a commercial reference, tamsulosin OCAS?. When the test tablet was exposed to a release medium, the medium quickly permeated to the mid-layer and the two barrier layers swelled surrounding the mid-layer rapidly. Volume expansion showed faster and enough swelling of the three-layered tablet up to 2 h. Larger amount of barrier layers caused reduced release kinetics and a high molecular weight polymer showed more resistance against agitation force. A formulation with water-soluble mid-layer showed fast erosion decreasing its volume significantly. On the pharmacokinetic study, the mean ratio of area under the curve (AUC) and C(max) for the test formulation to the reference was 0.69 and 0.84, respectively, showing that the absorption of the drug was less complete than the reference. Plasma concentration at 24 h of the test formulation was higher than the reference. The Wagner-Nelson method showed that decreased initial dissolution rate might be the cause of the less complete absorption. On considering in vitro-in vivo correlation (IVIVC), level A, the reference (R2=0.981) showed more linear relationship than the test (R2=0.918) due to the decreased dissolution and absorption rate of the formulation. This result suggests that the in vitro dissolution profiles and release kinetics might be useful in correlating absorption kinetics as well as overall plasma drug concentration-time profiles for formulation studies.     

Spectrophotometric Determination of Esomeprazole Magnesium in Commercial Tablets Using 5‐Sulfosalicylic Acid and N‐Bromosuccinimide

Two simple, sensitive and economical spectrophotometric methods have been developed for the determination of esomeprazole magnesium in commercial dosage forms. Method A is based on the reaction of esomeprazole magnesium with 5‐sulfosalicylic acid in methanol to form a yellow product, which absorbs maximally at 365 nm. Method B utilizes the reaction of esomeprazole magnesium with N‐bromosuccinimide in acetone‐chloroform medium to form α‐bromo derivative of the drug peaking at 380 nm. Under the optimized experimental conditions, Beer's law is obeyed in the concentration ranges of 2‐48 and 10‐100 μg mL^?1 with molar absorptivity of 2.11 × 10⁴ and 4.57 × 10⁴L mol^?1 cm^?1 for methods A and B, respectively. The limits of detection for methods A and B are 0.35 and 0.46 μg mL^?1, respectively. No interference was observed from excipients commonly present in tablet formulations. Methods A and B are successfully applied to the commercial tablets for the estimation of esomeprazole magnesium with good accuracy and precision. The results compare favorably with the reference spectrophotometric method indicating no significant difference between the methods compared.     

Formulation approach for nicorandil pulsatile release tablet

The purpose of this study was to obtain a nicorandil pulsatile release tablet that has a well-regulated release lag time. When nicorandil is used as an antiangina drug, administration time control is important. A pulsatile release tablet is one of the effective approaches to modified release to reduce daily administration frequency. In this study, a pulsatile release tablet of nicorandil was formulated by fumaric acid dry coating around the core tablet including nicorandil. The model tablets, which had different content ratios of excipients in the dry-coating layer, were characterized by a dissolution test. The results showed that the release lag time was generated with fast release profiles. Various lag time controls of tablets were achieved, from 60 to 310 min on average, by variation of outer layer composition. From an analysis of the relation between lag times and outer layer composition, the key ingredient for prolongation of lag time was found to be fumaric acid. To analyze the lag time generation mechanism, water penetration for tablet was measured. The results indicated that the penetration depth was proportionate to the square root of time and the lag time formation mechanism was simple water penetration through the matrix of fumaric acid to the tablet core. The results also showed that the Washburn equation could be used to design the lag time of the pulsatile release tablet in this study. In conclusion, novel release control technology using fumaric acid was appropriate to obtain a nicorandil pulsatile release tablet that has well regulated lag time.     

Ethylcellulose, polycaprolactone, and eudragit matrices for controlled release of piroxicam from tablets and microspheres

The present paper provides details of the preparation of polymeric tablets and microspheres based on piroxicam as a therapeutic active agent and the drug release study from these formulations. Tablets composed of ethylcellulose, Eudragit? or mixtures of Eudragit? and synthesised poly(oxepan-2-one) were prepared and tested. The effect of the matrix on the drug release at 37°C was studied. The drug-loaded microparticles were prepared using solvent evaporation microencapsulation. These systems were characterised by SEM and FTIR spectroscopy and the size and size distribution were also determined. The results demonstrated that the drug release could be modified by means of these formulations. Finally, piroxicam dissolution rate constants were calculated from Higuchi??s release model.     

In vitro evaluation of mucoadhesive vaginal tablets of antifungal drugs prepared with thiolated polymer and development of a new dissolution technique for vaginal formulations

The main objective of this work was to develop antifungal matrix tablet for vaginal applications using mucoadhesive thiolated polymer. Econazole nitrate (EN) and miconazole nitrate (MN) were used as antifungal drugs to prepare the vaginal tablet formulations. Thiolated poly(acrylic acid)-cysteine (PAA-Cys) conjugate was synthesized by the covalent attachment of L-cysteine to PAA with the formation of amide bonds between the primary amino group of L-cysteine and the carboxylic acid group of the polymer. Vaginal mucoadhesive matrix tablets were prepared by direct compression technique. The investigation focused on the influence of modified polymer on water uptake behavior, mucoadhesive property and release rate of drug. Thiolated polymer increased the water uptake ratio and mucoadhesive property of the formulations. A new simple dissolution technique was developed to simulate the vaginal environment for the evaluation of release behavior of vaginal tablets. In this technique, daily production amount and rate of the vaginal fluid was used without any rotational movement. The drug release was found to be slower from PAA-Cys compared to that from PAA formulations. The similarity study results confirmed that the difference in particle size of EN and MN did not affect their release profile. The release process was described by plotting the fraction released drug versus time and n fitting data to the simple exponential model: M(t)/M(∞)=kt(n). The release kinetics were determined as Super Case II for all the formulations prepared with PAA or PAA-Cys. According to these results the mucoadhesive vaginal tablet formulations prepared with PAA-Cys represent good example for delivery systems which prolong the residence time of drugs at the vaginal mucosal surface.     

Design and in vitro evaluation of zidovudine oral controlled release tablets prepared using hydroxypropyl methylcellulose

Oral controlled release matrix tablets of zidovudine were prepared using different proportions and different viscosity grades of hydroxypropyl methylcellulose. The effect of various formulation factors like polymer proportion, polymer viscosity and compression force on the in vitro release of drug were studied. In vitro release studies were carried out using United States Pharmacopeia (USP) type 1 apparatus (basket method) in 900 ml of pH 6.8 phosphate buffer at 100 rpm. The release kinetics were analyzed using Zero-order model equation, Higuchi's square-root equation and Ritger-Peppas' empirical equation. Compatibility of drug with various formulations excipients used was studied. In vitro release studies revealed that the release rate decreased with increase in polymer proportion and viscosity grade. Increase in compression force was found to decrease the rate of drug release. Matrix tablets containing 10% hydroxypropyl methylcellulose (HPMC) 4000 cps were found to show a good initial drug release of 21% in the first hour and extended the release upto 16 h. Matrix tablets containing 20% HPMC 4000 cps and 10% HPMC 15000 cps showed a first hour release of 18% and extended the release upto 20 h. Mathematical analysis of the release kinetics indicated that the nature of drug release from the matrix tablets followed non-Fickian or anomalous release. No incompatibility was observed between the drug and excipients used in the formulation of matrix tablets. The developed controlled release matrix tablets of zidovudine, with good initial release (17-25% in first hour) and which extend the release upto 16-20 h, can overcome the disadvantages of conventional tablets of zidovudine.     

Preparation of Co-Processed Excipients for Controlled-Release of Drugs Assembled with Solid Lipid Nanoparticles and Direct Compression Materials

The purpose of the study was to develop a novel, directly compressible, co-processed excipient capable of providing a controlled-release drug system for the pharmaceutical industry. A co-processed powder was formed by adsorption of solid lipid nanoparticles (SLN) as a controlled-release film onto a functional excipient, in this case, dicalcium phosphate dihydrate (DPD), for direct compression (Di-Tab^®). The co-processed excipient has advantages: easy to implement; solvent-free; industrial scaling-up; good rheological and compressibility properties; and the capability to form an inert platform. Six different batches of Di-Tab^®:SLN weight ratios were prepared (4:0.6, 3:0.6, 2:0.6, 1:0.6, 0.5:0.6, and 0.25:0.6). BCS class III ranitidine hydrochloride was selected as a drug model to evaluate the mixture’s controlled-release capabilities. The co-processed excipients were characterized in terms of powder rheology and dissolution rate. The best Di-Tab^®:SLN ratio proved to be 2:0.6, as it showed high functionality with good flow and compressibility properties (Carr Index = 16 ± 1, Hausner Index = 1.19 ± 0.04). This ratio could control release for up to 8 h, so it fits the ideal profile calculated based on biopharmaceutical data. The compressed systems obtained using this powder mixture behave as a matrix platform in which Fickian diffusion governs the release. The Higuchi model can explain their behavior.     

The Influence of the Polymer Type on the Quality of Newly Developed Oral Immediate-Release Tablets Containing Amiodarone Solid Dispersions Obtained by Hot-Melt Extrusion

The present study aims to demonstrate the influence of the polymer-carrier type and proportion on the quality performance of newly developed oral immediate-release tablets containing amiodarone solid dispersions obtained by hot-melt extrusion. Twelve solid dispersions including amiodarone and different polymers (PEG 1500, PEG 4000; PEG 8000, Soluplus^®, and Kolliphor^® 188) were developed and prepared by hot-melt extrusion using a horizontal extruder realized by the authors in their own laboratory. Only eleven of the dispersions presented suitable physical characteristics and they were used as active ingredients in eleven tablet formulations that contain the same amounts of the same excipients, varying only in solid dispersion type. The solid dispersions’ properties were established by optical microscopy with reflected light, volumetric controls and particle size evaluation. In order to prove that the complex powders have appropriate physical characteristics for the direct compression process, they were subjected to different analyses regarding their flowability and compressibility behavior. Additionally, the Fourier transform infrared spectroscopy and X-ray diffraction analysis were performed on the obtained solid dispersions. After confirming the proper physical attributes for all blends, they were processed into the form of tablets by direct compression technology. The manufactured tablets were evaluated for pharmacotechnical (dimensions–diameter and thickness, mass uniformity, hardness and friability) and in vitro biopharmaceutical (disintegration time and drug release) performances. Furthermore, the influence of the polymer matrix on their quality was determined. The high differences in flow and compression performances of the solid dispersions prove the relevant influence of the polymer type and their concentration-dependent plasticizing properties. The increase in flowability and compressibility characteristics of the solid dispersions could be noticed after combining them with direct compression excipients owning superior mechanical qualities. The influence of the polymer type is best detected in the disintegration test, where the obtained values are quite different between the studied formulations. The use of PEG 1500 alone or combined in various proportions with Soluplus^® leads to rapid disintegration. In contrast, the mixture of PEG 4000 and Poloxamer 188 in equal proportions determined the increase in disintegration time to 120 s. The use of Poloxamer 188 alone and a 3:1 combination of PEG 4000 and Soluplus^® also generates a prolonged disintegration time for the tablets.