Carbamazepine Modified Release Dosage Forms

Abstract

The preparation of sustained release dosage forms of Carbamazepine (anti-epileptic drug characterized by a very low water solubility and by a short half life on chronique dosing) was carried out.

These formulations were obtained in two different steps:

a) modified release granules were prepared by the loading of cross-linked sodium carboxymethylcellulose (swellable polymer), with the drug and an enteric polymer. Cellulose acetate phthalate, methacrylic acid – methacrylic acid methyl ester copolymer (usually employed as enteric coating agents) and cellulose acetate trimellitate (a new enteric polymer) were used in different weight ratios.

b) some sustained release dosage forms were prepared tabletting physical mixtures of the modified release granules with different weight ratios of hydroxypropylmethylcellulose.

In vitro dissolution tests of modified release granules in gastric fluid (USP XXI) showed a modulation of the drug release, while in intestinal fluid (USP XXI) a quick drug dissolution was observed.

In vitro dissolution tests of sustained release dosage forms, performed varying during the test, the pH of the dissolution medium, (hydrochloric acid pH 1 from 0 to 2 hours and phosphate buffer pH 6.8 from 2 to 18 hours) showed that the determining factors in the controlling release of the drug are: the type and amount of enteric polymer constituting the granules and the amount of hydroxy-propylmethylcellulose mixed with them.     

Sucralfate as a Bioadhesive Gastric Intestinal Retention system: Preliminary Evaluation

Abstract

A prototype formulation of a gastric intestinal retention system was successfully developed. A matrix tablet containing sucralfate, Methocel E4M and the appropriate type of drug powder, granules or pellets was prepared using the Carver Press. Three different formulations were evaluated using three different drug entities, namely; theophylline sustained release pellets, aspirin granules and antacid powder. Tablets of these three different formulations showed remarkable adhesive characteristics onto the glass vessel in acidic medium up to at least eight hours. In addition, all three different formulations exhibited sustained release in-vitro dissolution profiles. These data imply that this gastric intestinal retention system can be used to prepare sustained release formulations.     

Studies on Sustained release XI: Lipid Granules of Sulfamethizole

The aim of this study was to prepare a sustained release granule of sulfamethizole, employing hydrogenated castor oil (Cutina HR). After the dosage form design was made, different formulations were prepared as granules by the fusing technique. The granules manufactured were analysed with sieves between 0.5 and 1 mm openings. The fractions obtained were tested for dissolution rate for a period of seven hours with fluids of varying pHs with the continuous flow-through cell apparatus.

Upon the kinetic evaluation of dissolution data, it was seen that the target release rates were achieved. The results showed that, the drug release rates increase with increasing amounts of PEG 4000 added to the formulations; up to a certain percentage. No increase beyond this point was noticed.

The drug release rates mostly followed zero-order and modified Hixson-Crowell kinetics.     

Testing of Drug Release from Bioadhesive Vaginal Tablets

Abstract

To establish en in vitro test method that can predict the drug release and dissolution behaviour of vaginal bioadhesive controlled release tablets, a system was developed and its appropriateness to the in situ conditions was examined. For this purpose, the dissolution rates of vaginal bioadhesive tablets were measured by three different methods. These were, USP dissolution apparatus two and a new vaginal dissolution tester (NVDT) which was developed by us with some modification of the vaginal tablet desentegration apparatus of BP 1988 and, testing in cow vaginas in situ. Four different bioadhesive tablet formulations were used being composed of the drug and the anionic polymer, polyacrylic acid (PAA) and the nonionic polymers, hydroxypropylmethyl cellulose (HPMC) and ethyIcellulose (EC). The release profiles of the in vitro and in situ methods were investigated and evaluated kinetically.

It was found that NVDT could be used to investigate the drug release from vaginal tablets.     

A Mixture Experiment Approach for Controlling the Dissolution Rate of a Sustained-Release Tablet

Abstract

Several sustained-release tablet formulations with acceptable pharmacokinetic properties were found to be unstable because of the effects of lactose. Because the pharmacokinetic properties were acceptable, an attempt was made at developing stable formulations that reproduced the in vitro drug release characteristics of the unstable formulations. Through the use of a statistically designed mixture experiment, alternative formulations were generated and tested for dissolution. The dissolution data collected in the mixture experiment were used to develop a statistical regression model for identifying formulations with dissolution rates equal to those of the unstable formulations. The form of the regression model was based on the Higuchi equation. The data analysis indicated that it is possible to generate dissolution profiles that reproduce those of the original formulations by adjusting the ratios of Methocel® K4MCR Premium and Methocel KWOMCR Premium and by replacing the detrimental lactose with calcium phosphate dibasic anhydrous.     

Development of Near Zero-Order Release Dosage Forms Using Three-Dimensional Printing (3-DP™) Technology

ABSTRACT

Three near zero-order controlled-release pseudoephedrine hydrochloride (PEH) formulations demonstrating proportional release rates were developed using 3-Dimensional Printing (3-DP?) technology. Mixtures of Kollidon SR and hydroxypropylmethyl cellulose (HPMC) were used as drug carriers. The release rates were adjusted by varying the Kollidon SR-HPMC ratio while keeping fabrication parameters constant. The dosage forms were composed of an immediate release core and a release rate regulating shell, fabricated with an aqueous PEH and an ethanolic triethyl citrate (TEC) binder, respectively. The dosage form design called for the drug to be released via diffusional pathways formed by HPMC in the shell matrix. The release rate was shown to increase correspondingly with the fraction of HPMC contained in the polymer blend. The designed formulations resulted in dosage forms that were insensitive to changes in pH of the dissolution medium, paddle stirring rate, and the presence/absence of a sinker. The near zero-order release properties were unchanged regardless of the dissolution test being performed on either single cubes or on a group of eight cubes encased within a gelatin capsule shell. The chemical and dissolution properties of the three formulations remained unchanged following 1 month's exposure to 25°C/60% RH or 40°C/75% RH environment under open container condition. The in vivo performance of the three formulations was evaluated using a single-dose, randomized, open-label, four-way crossover clinical study composed of 10 fasted healthy volunteers. The pharmacokinetic parameters were analyzed using a noncompartmental model. Qualitative rank order linear correlations between in vivo absorption profiles and in vitro dissolution parameters (with slope and intercept close to unity and origin, respectively) were obtained for all three formulations, indicating good support for a Level A in vivo/in vitro correlation.     

Controlled-Release Theophylline Tablet Formulations Containing Acrylic Resins,II. Combination Resin Formulations

Abstract

Theophylline tablet formulations containing a combination of cationic and anionic acrylic resins were prepared and evaluated. Equal amounts of Eudragit RSPM (cationic resin) and Eudragit L100 (anionic resin) were included at the 15% level (total polymer content) into the tablet formulations. Pressure-hardness profiles with theophylline-resin compacts (4:1) demonstrated that compacts containing the RSPM resin were the most compressible. The dissolution profiles for theophylline in acidic media showed slower release rates from tablets containing the combined resins than from those containing each of the single resins. It was proposed that this decrease in drug release rate was a result of a solid state interaction between the oppositely charged polymers. As the amount of retardant in the matrix increased, the release rates in acidic media decreased. In pH 7.4 phosphate buffer, much faster release was seen due to the higher solubility of the Eudragit L-100 resin at this pH level. Tablet hardness between the range of 6.8 kg to 15 kg showed minimal influences on the dissolution rate. Recompression and relubrication of the tablet formulation containing both polymers, produced a decrease in release rates of theophylline from the tablet matrix.     

Xanthan Gum and Alginate Based Controlled Release Theophylline Formulations

Abstract

The oral absorption of theophylline from two sustained release formulations, formulated using xanthan gum or sodium alginate, has been investigated in the beagle dog. A commercial product was used for comparison. Dissolution tests and an in vivo dog study both indicated that the xanthan gum tablet released drug at a constant rate and performed as a pH independent zero-order controlled release formulation. With the alginate tablet, faster dissolution rates were observed when acid medium was present. The pH dependent release behavior of the alginate formulation is explained. Drug release mechanisms which are influenced by the gel behaviors in these two polymers are discussed. The relative oral bioavailabilities of these two formulations in dog were 74–84% compared to immediately releasing capsules, and three-fold that of the commercial product with an equivalent dose.     

Selection of Optimum Dissolution Test Methods in Dosage Form Design

Abstract

The rate limiting factors involved in release of a drug from a tablet are generally accepted to be the disintegration of the tablet followed by the subsequent dissolution of the drug from the dispersed granules.

The development of new potencies of an existing tabletted product by weight multiplication was found to result in non-conformance to established specifications for the product not formulation related.

In addition to a study of the rate limiting factors mentioned above compendial dissolution tests were also compared. Apparatus II was shown to produce more rapid and consistent results than Apparatus I in this investigation and this test is recommended as the one of choice where large volume compacts are involved.     

Multivariate Analysis of Variance of Dissolution Data in the Development of Oral Sustained Release Formulations

Abstract

A multivariate analysis of variance applied to polinomial interpretation of growth curves in used for the interpretation of dissolution curves of four experimental, sustained release, wax type theophylline tablets.

The factors under study were glyceril palmitic stearate, carboxypol imethylene contents and compression force. The tablets were formulated according an experimental design based on 4 × 4 Hadamard matrix. The USP type I apparatus for dissolution test and CHI 0.1 N plus O.1%. polysorbate 80 as dissolution medium was used.

The statistical interpretation of results showed: first, that dissolution rates were almost constant for the four formulations during 8 h; second, the main difference between formulation dissolution rates can be inputed to fat excipient content and in much lesser extent to carboxipolymethylene content; third, the theopylline release rate was unaffected by compression force.     

Development of an Implantable,Biodegradable, Controlled Drug Delivery System for Local Antibiotic Therapy

Abstract

A novel drug delivery system was developed using a monoglyceride (Glycerol Monostearate) and a water-soluble release rate modifier as the matrix. Cefuroxime sodium (Zinacef®) was chosen as a model drug in this study. Formulations (cylindrical implants 6 × 6 mm) were prepared by a melt-dispersion method. Dissolution studies were performed using USP paddle method. The effect of glycerol, PEG 400 and their combination on drug release profiles was studied. Two assay methods (UV and HPLC) for cefuroxime analysis were compared. Percent recovery from four formulations (A-D) was higher with UV than HPLC assay. While both UV and HPLC assay methods were developed for cefuroxime, only HPLC assay is stability indicating. Glycerol showed higher accelerating effect than PEG 400 on the drug release. All formulations exhibited extended release of cefuroxime. Degradation of cefuroxime occurred mainly during dissolution suggesting drug stability in the formulations.     

A Flow-Through Dissolution Approach to In Vivo/In Vitro Correlation of Adinazolam Release from Sustained Release Formulations

Abstract

A Copley? fraction collector and a Disotest? flow-through system were coupled to provide an automatic discrete sampling flow-through dissolution system for use both in the “open-loop” and “closed-loop” mode. The system was used to investigate the release characteristics of adinazolam in sustained release formulations using a pH 1.2 simulated gastric fluid (without enzymes) dissolution medium (USP XXI). These experimental formulations are designed to provide relatively slow to rapid drug release. The dissolution effluent was analysed off-line by reverse phase HPLC to determine the adinazolam concentration at programmed timed intervals. The differential dissolution profiles produced when the system is used in the “open-loop” configuration are more discriminating in describing the release characteristics of the formulations according to the relative release rates than the “closed-loop” cumulative profiles. Using the characteristic dissolution time parameter from the Weibull function, a better correlation with in vivo bioavailability data was achieved for the data from the system in the “open-loop” mode than when it was used in the “closed-loop” mode. In the “open-loop” mode the Weibull function characteristic dissolution time parameter yielded the best quantitative correlation with a correlation coefficient of 0.92 compared to a value of 0.85 for the “closed-loop” configuration     

Effect of Excipient and Processing Variables on Adhesive Properties and Release Profile of Pentoxifylline From Mucoadhesive Tablets

ABSTRACT

The bioavailability and onset of action of drugs with high first-pass metabolism can be significantly improved by administration via the sublingual route. The objective of this study was to evaluate the effect of polymer type and tablet compaction parameters on the adhesive properties and drug release profile from mucoadhesive sublingual tablet formulations. Pentoxifylline was selected as the model drug because it has poor oral bioavailability due to extensive first-pass metabolism. Two polymers known to possess mucoadhesive properties, carbomer and hydroxypropyl methyl cellulose (HPMC), were used to prepare the formulations. Tablets were prepared by using direct compression technique and evaluated for in vitro dissolution, drug-excipient interactions, and adhesive properties. In general, there was a decrease in the rate of drug release with an increase in the concentration of polymers. No drug-excipient interactions were evident from differential scanning calorimetry or high-performance liquid chromatography analysis. For the formulations containing HPMC, the force of mucoadhesion increased with an increase in the concentration of polymer; however, for carbomer formulations, no such correlation was observed. Force of mucoadhesion decreased as a function of hydration time in both of the polymers.     

Controlled-Release Matrix of Acetaminophen-Ethylcellulose Solid Dispersion

Abstract

In this study ethylcellulose was evaluated as a carrier for preparation of prolonged release acetaminophen tablets. Solid dispersions containing three levels of ethylcellulose and acetaminophen (1:3; 1:1; 3:1) were prepared by the solvent method. Also physical mixtures at the same level of ethylcellulose and acetaminophen were prepared. Systems composed of solid dispersion or physical mixture containing the equivalent weight of 50 mg acetaminophen, Lactose fast-flo as diluent and 1% magnesium stearate as lubricant were compressed into tablets and tested for dissolution. The dissolution data showed that the drug release decreased as the level of ethylcellulose increased in the solid dispersion formulations. The drug release from tablets prepared with solid dispersion followed the diffusion controlled model for inert porous matrix, while the drug release from tablets prepared with physical mixture followed the first-order kinetic model.     

The Effect of the Wet Granulation Process on Drug Dissolution

Abstract

Wet granulation can be an important processing step for pharmaceutical solid dosage forms. In this investigation emphasis was directed towards the influence of a “simple” wet granulation process on drug release from granules and their resulting tablets. Direct compression blends of the same materials were used as controls. Binary mixtures containing a 5% level of either theophylline, hydrochlorothiazide or chlorpheniramine maleate in microcrystalline cellulose or lactose were granulated with water. Experimentally, the powders were dry blended in a planetary mixer, wet granulated, and subsequently wet milled and dried. No dry milling step was included. Granule characterization consisted of particle size, density, porosity, compression and dissolution testing. Dissolution results varied with the drug, as expected, and dissolution at 10 minutes ranged from 35 to 95 % release. In general, however, the results indicate that dissolution from granules and the corresponding direct compression blend are similar. Although differences in compressibility were observed in the systems studied, granulation was not found to be detrimental to drug release.     

Dissolution Characteristics of Pharmaceutical Equivalents

Abstract

The in-vitro release of diltiazem from pharmaceutical equivalents of sustained release tablets, commercially available in Italy, was studied.

The in-vitro release profiles were determined by means of different methods and apparatus. Paddle, basket, Poole, Diffutest and Stricker methods were compared.

The absorption rates in artificial gastric and enteric juices by means of lipid barriers were calculated.

Some preparations showed a diffusion mechanism, some a first-order release.

The differences among the dissolution profiles of the formulations were enhanced with the Strieker method.     

Optimization of piribedil mucoadhesive tablets for efficient therapy of Parkinson’s disease: physical characterization and ex vivo drug permeation through buccal mucosa

Objective: The aim of this study was optimization of buccal piribedil (PR) mucoadhesive tablets to improve its low bioavailability and provide controlled release for the treatment of Parkinson’s disease.

Methods: Buccal tablets were prepared by direct compression method using carbomer (CP), carboxymethyl cellulose (CMC), and hydroxypropyl methylcellulose (HPMC) as mucoadhesive polymers. Physical properties of powder mixtures and buccal tablets were evaluated. Physicochemical compatibility between ingredients was investigated with infrared spectroscopy and differential scanning calorimetry analysis. In vitro dissolution profiles and drug release kinetics of buccal tablets were investigated. Mucoadhesion and ex vivo permeation studies were performed using sheep buccal mucosa.

Results: Powder mixtures demonstrated sufficient flow properties and physical characteristics of all tablet formulations were within compendia limits. Tablet ingredients were absent of any chemical interactions. CP tablets displayed slower drug release compared to HPMC tablets with zero order release, while CMC tablets lost their integrity and released entire drug after 6?h following Higuchi model. All formulations displayed adequate mucoadhesion and steady state flux of PR through buccal mucosa were higher with HPMC compared to CP-containing tablets.

Conclusion: Overall, HPMC was found to combine desired controlled release and mucoadhesion characteristics with sufficient pharmaceutical quality for optimization of buccal tablets. Piribedil mucoadhesive buccal tablets designed for the first time may introduce a new alternative for the treatment of Parkinson’s disease.     

Development of Polysaccharide-Based Colon Targeted Drug Delivery Systems for the Treatment of Amoebiasis

ABSTRACT

The main focus of this study is to develop colon targeted drug delivery systems for metronidazole (MTZ). Tablets were prepared using various polysaccharides or indigenously developed graft copolymer of methacrylic acid with guar gum (GG) as a carrier. Various polysaccharides such as GG, xanthan gum, pectin, carrageenan, β-cyclodextrin (CD) or methacrylic acid-g-guar (MAA-g-GG) gum have been selected and evaluated. The prepared tablets were tested in vitro for their suitability as colon-specific drug delivery systems. To further improve the colon specificity, some selected tablet formulations were enteric coated with Eudragit-L 100 to give protection in an acidic environment. Drug release studies were performed in simulated gastric fluid (SGF) for 2 hr followed by simulated intestinal fluid (SIF) at pH 7.4. The dissolution data demonstrate that the rate of drug release is dependent upon the nature and concentration of polysaccharide/polymer used in the formulations. Uncoated tablets containing xanthan gum or mixture of xanthan gum with graft copolymer showed 30–40% drug release during the initial 4–5 hr, whereas for tablets containing GG with the graft copolymer, it was 70%. After enteric coating, the release was drastically reduced to 18–24%. The other polysaccharides were unable to protect drug release under similar conditions. Preparations with xanthan gum as a matrix showed the time-dependent release behavior. Further, in vitro release was performed in the dissolution media with rat caecal contents. Results indicated an enhanced release when compared to formulations studied in dissolution media without rat caecal contents, because of microbial degradation or polymer solubilization. The nature of drug transport was found to be non-Fickian in case of uncoated formulations, whereas for the coated formulations, it was found to be super-Case-II. Statistical analyses of release data indicated that MTZ release is significantly affected by the nature of the polysaccharide used and enteric coating of the tablet. Differential scanning calorimetry indicated the presence of crystalline nature of drug in the formulations.     

Development of novel amisulpride-loaded liquid self-nanoemulsifying drug delivery systems via dual tackling of its solubility and intestinal permeability

Objective: The aim of the current investigation was at enhancing the oral biopharmaceutical behavior; solubility and intestinal permeability of amisulpride (AMS) via development of liquid self-nanoemulsifying drug delivery systems (L-SNEDDS) containing bioenhancing excipients.

Methods: The components of L-SNEDDS were identified via solubility studies and emulsification efficiency tests, and ternary phase diagrams were constructed to identify the efficient self-emulsification regions. The formulated systems were assessed for their thermodynamic stability, globule size, self-emulsification time, optical clarity and in vitro drug release. Ex vivo evaluation using non-everted gut sac technique was adopted for uncovering the permeability enhancing effect of the formulated systems.

Results: The optimum formulations were composed of different ratios of Capryol? 90 as an oil phase, Cremophor^® RH40 as a surfactant, and Transcutol^® HP as a co-surfactant. All tested formulations were thermodynamically stable with globule sizes ranging from 13.74 to 29.19?nm and emulsification time not exceeding 1?min, indicating the formation of homogenous stable nanoemulsions. In vitro drug release showed significant enhancement from L-SNEDDS formulations compared to aqueous drug suspension. Optimized L-SNEDDS showed significantly higher intestinal permeation compared to plain drug solution with nearly 1.6–2.9 folds increase in the apparent permeability coefficient as demonstrated by the ex vivo studies.

Conclusions: The present study proved that AMS could be successfully incorporated into L-SNEDDS for improved dissolution and intestinal permeation leading to enhanced oral delivery.     

Formulation of Nitrofurantoin Tablets Fulfilling the Pharmacopoeial Specifications

Abstract

The USP XXII specifies that the disintegration time for nitrofurantoin tablets must be not less than 30 minutes, not less than 25% of the drug is dissolved in 60 minutes and not less than 85% is dissolved in 120 minutes. These specifications were done to minimize the side effects and to achieve a proper bioavailability for the drug.

On testing the market tablet preparation (Furadantin), it was found that it does not fit to the [JSP specifications, Nine nitrofurantoin tablet formulations were then tried and each was studied for disintegration time and % dissolution in the first and second hours. The best formula was found to be consisted of adding 2% of collodion in 40% of the starting granules, coated with 4% CAP and adding another 2% of collodion to the remaining 60% of the granules.