Multiparticulate Dosage Form Research Articles

Optimisation and scale-up of a highly-loaded 5-ASA multi-particulate dosage form using a factorial approach

Pellets with high loading of 5-aminosalicylic acid (5-ASA, mesalamine) are desired to reduce the number of tablets required to deliver the daily dosing regimen. Recently, we reported an extrusion–spheronisation route for the development of a 90 wt% 5-ASA/microcrystalline cellulose formulation based on milled 5-ASA which gave good yields of pellets at the lab scale. In the present work, such formulation was optimised further by preliminary studies using a lab-scale ram extruder, and then scaled up to the pilot plant scale on a Nica screen extruder using a mixed fractional factorial approach. The final formulation featured 95 wt% 5-ASA and 5 wt% Avicel RC591 (all dry basis) and yielded spherical pellets suitable for use as the drug core of a multi-particulate DDS.

PH-responsive dual pulse multiparticulate dosage form for treatment of rheumatoid arthritis

Background: Dual pulse multiparticulate systems may provide relief from circadian disorder rheumatoid arthritis. Aim: The aim of this study was to develop a pH-responsive dual pulse multiparticulate dosage form containing a model drug ketoprofen, a nonsteroidal anti-inflammatory drug used for rheumatoid arthritis. Method: The pellets were prepared by using extrusion–spheronization method and the core pellets were coated with a pH-sensitive poly(methyl) acrylate copolymer (Eudragit® L100-55, Eudragit® S100) to achieve site-specific drug release with a lag time. The formulated pellets were characterized for shape and size uniformity, friability, surface morphology studies, coating uniformity, and drug–excipient compatibility studies. In vitro dissolution test was used for comparison of drug release profiles of various coated pellets. Results: The particle size of core and polymer-coated pellets was found to be in the range of 0.95–1.3 and 1.42–1.61 mm, respectively. The pellets were spherical in shape with smooth texture and uniformity in size. The dual pulse was aimed at release after a lag time of 2 and 5 hours. In vitro dissolution tests were carried out for the first and second dose pellets in a USP type II dissolution apparatus in media-simulating pH conditions of the gastrointestinal tract. The first dose release of the ketoprofen from the formulated pellets was established in pH 1.2 for a period of 2 hours, followed by pH 6.8. The second dose pellets were passed through pH 1.2, pH 6.8 followed by pH 7.5 for the rest of the study. Conclusion: The study concluded that the formulated multiparticulate dosage form of ketoprofen was able to relieve circadian symptoms of rheumatoid arthritis during midnight and early morning.

Formulation and Evaluation of Novel Enteric Coated Extended Release Multiparticulates of Model NSAID Ketoprofen

The aim of this study was to develop a pH responsive enteric coated extended release multiparticulate dosage form containing a model drug ketoprofen, a nonsteroidal anti-inflammatory drug used for rheumatoid arthritis. The drug loaded pellets in matrix form were prepared by using extrusion/spheronization method. The optimized pelletization method revealed that extrusion using 1 mm sieve plate and spheronization friction disc of 2mm carried out at 700 rpm for 5-10 minutes resulted in good spherical pellets and uniformity in size. Evaluated core pellets were coated with polymer Eudragit® RS 30D on Fluid bed coater to achieve a sustainable release for 12 hours. Ketoprofen as like other NSAID have been reported for gastric mucosal irritation so a pH responsive barrier coat of Eudragit L®100-55 was employed on a pan coater for abstaining release in acidic media. The formulated pellets were characterized for shape and size uniformity, friability, surface morphology studies. The particle size of core and polymer coated pellets were found to be in the range of 0.95-1.2 mm and 1.32-1.51 mm respectively. The pellets were spherical in shape with smooth texture and uniformity in size. In-vitro dissolution tests were carried out for pellets in a USP type II dissolution apparatus in media-simulating pH conditions of the gastrointestinal tract. The release of the ketoprofen from formulated pellets was established in pH 1.2 for a period of 2 h, followed by pH 7.5 for rest of the study. The study concluded that the formulated multiparticulate dosage form of ketoprofen was able to relieve symptoms of rheumatoid arthritis.

AC Biosusceptometry Technique to Evaluate the Gastrointestinal Transit of Pellets under Influence of Prandial State

Multiparticulate dosage forms have been proposed when distal regions of gastrointestinal tract are desirable as target of drugs. It is known that physiological parameters might interfere with the processes related to the drug delivery and absorption and therefore, it is essential to evaluate the behavior of such delivery systems in vivo. The aim of this study was to propose the AC Biosusceptometry technique as a noninvasive and radiation free device to evaluate the gastrointestinal transit of a magnetic multiparticulate dosage form in healthy volunteers under fasting and fed conditions. Magnetic pellets were prepared by the powder layering method of ferrite on nonpareils sugar beads and coated by using Eudragit®. Our data showed that the AC Biosusceptometry technique was able to monitoring the gastrointestinal transit of pellets presenting similar profiles as demonstrated by standard techniques. Food intake has markedly influenced the gastric emptying as well as the colon arrival and the small intestine transit of magnetic pellets. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:317–324, 2010

Design and Optimization of Famotidine Multiparticulate System through Mixture Experimental Design - a Novel Approach

The objective of this study was to develop a multiparticulate dosage form and optimise its release profile through a novel approach employing simplex mixture design. Microparticles of Famotidine were prepared with Eudragitâ RS100, RL100 and Ethyl cellulose separately using 1:4 drug polymer ratios by emulsification solvent evaporation technique. The three master formulations were characterised for different physicochemical properties and their release profile was studied. Statistical modelling and numerical optimisation was done to predict blends of component microparticles of three polymers, which gave the desired release profile. Experimental validation of the response parameters showed only around 5% error in prediction. Thus, an accurate, economical and time saving methodology could be devised for easy and reproducible development and optimisation of multiparticulate sustained release product.

Salting-out taste-masking system generates lag time with subsequent immediate release

Salting-out effects were utilized for developing a multiparticulate system balancing numbness masking and high bioavailability. A “salting-out taste-masking system” consisting of a drug core containing acetaminophen as a model drug, a salting-out layer containing sodium carbonate (Na 2CO 3) and hydroxypropylmethylcellulose (HPMC), and a water-penetration-control layer consisting of cetanol was designed and prepared. The system successfully generated a long lag time while achieving immediate drug release. In the system, the Na 2CO 3 release rate was slower and the lag time was longer than when the water-penetration-control layer was not present. During the release of Na 2CO 3 from the system, the release of HPMC and drug was suppressed. These results indicated that the water-penetration-control layer maintained a high concentration of Na 2CO 3, prevented HPMC's dissolution, and generated a long lag time of drug release. The system generated longer lag time and released drug more immediately than formulation containing the water-penetration-control layer of same thickness without the salting-out layers. These results indicated the salting-out layers were necessary for obtain a long lag time and subsequent immediate drug release. This novel taste-masking system has the potential to be a useful multiparticulate dosage form for effective, safe, and user-friendly drug therapy.

Release Kinetics of a Controlled-Release Multiparticulate Dosage Form Prepared Using a Hot-Melt Fluid Bed Coating Method

ABSTRACTDissolution profiles of various multiparticulate controlled-release dosage forms prepared by applying lipophilic materials using a hot-melt coating technique were analyzed to determine release kinetics. The dosage forms were prepared using a novel solid dispersion hot-melt fluid bed coating method. Various lipophilic materials were investigated and those showing promise as potential controlled-release coating agents were analyzed further. Dissolution data were used as the primary basis of comparison. A dual equation combining first-order and square-root-of-time release kinetics was used to fit data. The statistical output from nonlinear regression software suggests that this equation describes the data better than the individual equations alone. Particular parameters used to compare the various models include R2, the model selection criteria, and the coefficient of determination. The high degree of fit offered by the dual equation implies that two distinct kinetic processes may be involved in the release of drug from the dosage forms. A possible release mechanism based on this information is offered. The dual equation was shown to be a superior model for the controlled-release system chosen for study. The equation also appears to be applicable to a variety of other controlled-release systems reported in the literature.

Release Kinetics of a Controlled-Release Multiparticulate Dosage Form Prepared Using a Hot-Melt Fluid Bed Coating Method

Release Kinetics of a Controlled-Release Multiparticulate Dosage Form Prepared Using a Hot-Melt Fluid Bed Coating Method

Design of a new multiparticulate system for potential site-specific and controlled drug delivery to the colonic region

A multiparticulate dosage form consisting of a hydrophobic core coated with a pH-dependent polymer is proposed for colonic specific delivery of drugs. Different approaches for colon-specific drug delivery have been studied over the last decade, including prodrugs, polymeric coating using pH-sensitive or bacterial degradable polymers and matrices. In this work, we present a new multiparticulate system to deliver active molecules to the colonic region, which combines pH-dependent and controlled drug release properties. This system was constituted by drug loaded cellulose acetate butyrate (CAB) microspheres coated by an enteric polymer (Eudragit ® S). Both, CAB cores and pH-sensitive microcapsules, were prepared by the emulsion–solvent evaporation technique in an oily phase. Ondansetron (OS) and budesonide (BDS), two interesting drugs with a potentially new application for the local treatment of intestinal disorders, were efficiently microencapsulated in CAB microspheres at different polymer concentrations (6 and 8%). These hydrophobic cores (about 60 and 110 μm in size, respectively) were then microencapsulated with Eudragit ® S, resulting in multinucleated structures, except in the case of BDS–CAB microspheres prepared at 8% CAB concentration, in which more mononucleated microcapsules were obtained. The in vitro drug release studies of pH-sensitive microcapsules containing the hydrophobic cores showed that no drug was released below pH 7. After that, CAB microspheres efficiently controlled the release of BDS, the release behavior being affected by the different polymer concentration used in their preparation. However, OS–CAB microspheres did not maintain their controlled-release properties once the enteric polymer dissolved. The extraction of the drug by the Eudragit ® solvent during the second microencapsulation process was in this case the cause for the failure of the controlling release mechanism.