Effects of coating layer and release medium on release profile from coated capsules with Eudragit FS 30D: an in vitro and in vivo study

The aim of the present research was to evaluate the impact of coating layers on release profile from enteric coated dosage forms. Capsules were coated with Eudragit FS 30D using dipping method. The drug profile was evaluated in both phosphate buffer and Hank’s solutions. Utilization X-ray imaging, gastrointestinal transmission of enteric coated capsules was traced in rats. According to the results, no release of the drug was found at pH 1.2, and the extent of release drug in pH 6.8 medium was decreased by adding the coating layers. The results indicated single-layer coated capsules in phosphate buffer were significantly higher than that in Hank’s solution. However, no significant difference was observed from capsules with three coating layers in two different dissolution media. X-ray imaging showed that enteric coated capsules were intact in the stomach and in the small intestine, while disintegrated in the colon.     

Development and optimization of taste-masked orally disintegrating tablets (ODTs) of clindamycin hydrochloride

The purpose of this research was to develop an orally disintegrating tablet (ODT) dosage form containing taste-masked beads of clindamycin HCl. Several formulation strategies were evaluated and a taste-masked ODT of clindamycin HCl was prepared without the use of a waxy cushioning agent. Clindamycin HCl (ca. 46% w/w) was coated onto microcrystalline cellulose beads (Cellets® 200) followed by the addition of a taste-masking layer of amino methacrylate copolymer, NF (Eudragit EPO® (EPO)) coating suspension. The efficiency of both the drug coating process and the taste-masking polymer coating process, as well as the taste masking ODTs was determined using potency and drug release analysis. Magnesium stearate was found to be advantageous over talc in improving the efficiency of the EPO coating suspension. A response surface methodology using a Box–Behnken design for the tablets revealed compression force and levels of both disintegrant and talc to be the main factors influencing the ODT properties. Blending of talc to the EPO-coated beads was found to be the most critical factor in ensuring that ODTs disintegrate within 30?s. The optimized ODTs formulation also showed negligible (<0.5%) drug release in 1?min using phosphate buffer, pH 6.8 (which is analogous to the residence time and pH in the oral cavity). By carefully adjusting the levels of coating polymers, the amounts of disintegrant and talc, as well as the compression force, robust ODTs can be obtained to improve pediatric and geriatric patient compliance for clindamycin oral dosage forms.     

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.     

Preparation and evaluation of enteric coated tablets of hot-melt extruded lansoprazole

Abstract

The objective of this work was to use hot-melt extrusion (HME) technology to improve the physiochemical properties of lansoprazole (LNS) to prepare stable enteric coated LNS tablets. For the extrusion process, we chose Kollidon^® 12?PF (K12) polymeric matrix. Lutrol^® F 68 was selected as the plasticizer and magnesium oxide (MgO) as the alkalizer. With or without the alkalizer, LNS at 10% drug load was extruded with K12 and F68. LNS changed to the amorphous phase and showed better release compared to that of the pure crystalline drug. Inclusion of MgO improved LNS extrudability and release and resulted in over 80% drug release in the buffer stage. Hot-melt extruded LNS was physically and chemically stable after 12 months of storage. Both formulations were studied for compatibility with Eudragit^® L100-55. The optimized formulation was compressed into a tablet followed by coating process utilizing a pan coater using L100-55 as an enteric coating polymer. In a two-step dissolution study, the release profile of the enteric coated LNS tablets in the acidic stage was less than 10% of the LNS, while that in the buffer stage was more than 80%. Drug content analysis revealed the LNS content to be 97%, indicating the chemical stability of the enteric coated tablet after storage for six months. HME, which has not been previously used for LNS, is a valuable technique to reduce processing time in the manufacture of enteric coated formulations of an acid-sensitive active pharmaceutical ingredient as compared to the existing methods.     

Factors influencing the release kinetics of drug nanocrystal-loaded pellet formulations

Context: This article discusses the downstream processing of nanosuspensions into oral solid dosage forms. Objective: Various factors influencing the release kinetics of various pellet formulations containing drug nanocrystals have been evaluated. The effects of binder types, drug content and pellet type on the in-vitro dissolution profiles were investigated.

Materials and methods: Hydrocortisone acetate (HCA) was nanosized by using a piston gap homogenizer Micron Lab 40. The nanosuspension was admixed to various binder solutions based on chitosan chloride, polyvinyl alcohol, hydroxypropyl methylcellulose or polyvinylpyrrolidone (PVP) and sprayed on sugar beads using fluidized bed coating. For comparison, matrix cores have also been prepared using the extrusion-spheronization process. An enteric top coating was applied onto both pellet types. All pellet formulations have been tested In in-vitro dissolution studies.

Results and discussion: HCA nanosuspensions were compatible with all binders tested except for PVP. Various suspensions could be successfully transferred into spray coated pellets as well as matrix cores including a top coating. The different binder types have influenced the stability of the nanosuspensions, the zeta potential of the drug nanocrystals as well as the dissolution profiles of the final solid dosage forms.

Conclusion: Nanosuspensions can be easily processed into various pellet formulations. Spray coating with water-soluble binders is recommended for high dose drugs. This technology is also more variable with respect to the drug load In the final dosage form. Matrix cores can be beneficial for highly water-insoluble formulations, especially when only relatively low doses are needed.     

Carbamazepine Modified Release Dosage Forms

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.     

Non-coated multiparticulate matrix systems for colon targeting

Background: Colon specific drug delivery can significantly improve the efficacy of local treatments of inflammatory bowel diseases. Film coatings containing the starch derivative Nutriose have recently been reported to minimize 5-ASA release in media simulating the upper gastro intestinal tract (GIT), while releasing the drug in a time-controlled manner upon contact with feces from Crohn’s Disease and Ulcerative Colitis patients. It was the aim of this study to prepare Nutriose-containing matrix pellets and mini tablets in order to avoid a film coating step.

Methods: Highly dosed matrix pellets were prepared by extrusion-spheronization, highly dosed mini tablets by compression. Various types of lipids were added and drug release measured in 0.1 N HCl and phosphate buffer pH 6.8, optionally containing pepsin and pancreatin.

Results: The type of added lipid and the preparation technique, in particular the curing conditions, significantly affected the resulting drug release kinetics. Glyceryl palmitostearate containing pellets and mini tablets showed the most promising results upon appropriate curing, minimizing premature drug release in media simulating the upper GIT.

Conclusion: The proposed novel multiparticulates do not require a film coating step and show an interesting potential for site-specific drug delivery to the colon of inflammatory bowel disease patients.     

Development of a new esomeprazole delayed release gastro-resistant pellet formulation with improved storage stability

This study describes the development of a new esomeprazole (ESO) delayed release gastro-resistant formulation with improved storage stability. A three-step (drug-, sub(seal)- and enteric-) coating process was employed with the aid of a fluid bed coater. Several formulation factors (namely, size and quantity of starting non-pareil sugar spheres, binder quantity during drug-layering, sub(seal)-coating polymer type, and quantity and enteric coating quantity) were evaluated and the whole process was modeled with the aid of feed-forward back-propagation artificial neural networks (ANNs). Results showed that the selection of small-sized starting spheres (45/60 mesh size) leads to pellet agglomeration, while as sub(seal)-coating weight gain increases a reduction in ESO dissolution rate is observed. The enteric-coating applied (Eudragit L30D-55) showed good gastro-resistant performance in both 0.1 N HCl and pH 4.5 media, while immediate release profiles with more than 85% of ESO being released in less than 30?min were obtained. The effect of cellulose-based sub(seal)-coating polymers, (namely, hydroxypropyl cellulose and hydroxypropylmethyl cellulose) on formulation’s storage stability at 40?±?2?°C/75?±?5%RH indicated that only hydroxypropylmethyl cellulose was able to stabilize ESO delayed-release formulations in terms of assay, dissolution, impurities, and gastro-resistance performance. Finally, scanning electron microscopy (SEM) analysis revealed smooth and homogeneous external surface/coating layers in all three levels (drug-, sub(seal)-, and enteric- coating), while x-ray diffraction showed no polymorphic transformations.     

Stabilization of a new antiulcer drug (Lansoprazole) in the solid dosage forms

Abstract

In the previous study, we clarified that enteric granules were appropriate dosage forms of lansoprazole. The establishment of these formulations, however, was difficult because some of the excipients needed for these formulations are incompatible with the drug. We examined the effects of adding magnesium carbonate as an alkaline stabilizer and could get stable enteric granules. We also discuss the mechanism of stabilization.     

Manufacturing Method of Stable Enteric Granules of a New Antiulcer Drug (Lansoprazole)

Abstract

In our previous studies, we clarified that enteric granules are an appropriate dosage form for lansoprazole, and we demonstrated that enteric granules could be produced when magnesium carbonate was added as an alkaline stabilizer.

These granules however were found to be some unstable under severe conditions because some of the excipients are incompatible with lansoprazole. We therefore attempted granulation not using these incompatible excipients and could obtain more stable enteric granules using a centrifugal fluid-bed granulator instead of an extruder-spheronizer. We also compared the absorption and dissolution properties of the enteric granules manufactured by these two methods.     

Stabilization of a new antiulcer drug (Lansoprazole) in the solid dosage forms

In the previous study, we clarified that enteric granules were appropriate dosage forms of lansoprazole. The establishment of these formulations, however, was difficult because some of the excipients needed for these formulations are incompatible with the drug. We examined the effects of adding magnesium carbonate as an alkaline stabilizer and could get stable enteric granules. We also discuss the mechanism of stabilization.     

Manufacturing Method of Stable Enteric Granules of a New Antiulcer Drug (Lansoprazole)

In our previous studies, we clarified that enteric granules are an appropriate dosage form for lansoprazole, and we demonstrated that enteric granules could be produced when magnesium carbonate was added as an alkaline stabilizer.

These granules however were found to be some unstable under severe conditions because some of the excipients are incompatible with lansoprazole. We therefore attempted granulation not using these incompatible excipients and could obtain more stable enteric granules using a centrifugal fluid-bed granulator instead of an extruder-spheronizer. We also compared the absorption and dissolution properties of the enteric granules manufactured by these two methods.     

In vitro dissolution studies of sodium diclofenac granules coated with Eudragit L-30D-55 by fluidized-bed system

The objective of this work was to study the dissolution process of sodium diclofenac granules coated with a polymeric suspension of Eudragit L-30D-55® by fluidized bed. Methacrylic acid-methylmetacrylate copolymer, also known as Eudragit, has been used as a pH sensitive coating material to protect drug substances prior to delivery to the human intestines. The sodium diclofenac granules were prepared by wet granulation technology using microcrystalline cellulose (MICROCEL), sodium diclofenac, and polivinilpirrolidone K-30. The granules coating operation was carried out in a fluidized bed with top spraying by a double-fluid nozzle. The dissolutions studies of the coated granules were performed in triplicate in a dissolution test station according to USP XXIII (1995) “in vitro testing requirements” Method A (paddle method, rotation of 100 RPM and temperature fixed at 37°C). The dissolution mediums were 0.1N HCl solution and a pH 6.8 phosphate buffer solution, following the pH change dissolution procedure specified in USP for enteric-coated articles: 2 h of exposure to 750 mL of 0.1N HCl followed by testing in 1000 mL of pH 6.8 phosphate buffer, the pH being adjusted with 250 mL of 0.2 M tribasic sodium phosphate solution. The released amount of sodium diclofenac was periodically determined by UV spectrophotometry at wavelength of 276 nm, using a spectrophotometer UV-VIS HP 8453. The coated product showed gastric resistance properties confirming the feasibility of the fluidized bed for applying enteric coating in granules and pharmaceutical powders.     

In Vitro Dissolution Studies of Sodium Diclofenac Granules Coated with Eudragit L-30D-55® by Fluidized-Bed System

Abstract

The objective of this work was to study the dissolution process of sodium diclofenac granules coated with a polymeric suspension of Eudragit L-30D-55® by fluidized bed. Methacrylic acid-methylmetacrylate copolymer, also known as Eudragit, has been used as a pH sensitive coating material to protect drug substances prior to delivery to the human intestines. The sodium diclofenac granules were prepared by wet granulation technology using microcrystalline cellulose (MICROCEL), sodium diclofenac, and polivinilpirrolidone K-30. The granules coating operation was carried out in a fluidized bed with top spraying by a double-fluid nozzle. The dissolutions studies of the coated granules were performed in triplicate in a dissolution test station according to “in vitro testing requirements” Method A (paddle method, rotation of 100 RPM and temperature fixed at 37°C). The dissolution mediums were 0.1N HCl solution and a pH 6.8 phosphate buffer solution, following the pH change dissolution procedure specified in USP for enteric-coated articles: 2 h of exposure to 750 mL of 0.1N HCl followed by testing in 1000 mL of pH 6.8 phosphate buffer, the pH being adjusted with 250 mL of 0.2 M tribasic sodium phosphate solution. The released amount of sodium diclofenac was periodically determined by UV spectrophotometry at wavelength of 276 nm, using a spectrophotometer UV-VIS HP 8453. The coated product showed gastric resistance properties confirming the feasibility of the fluidized bed for applying enteric coating in granules and pharmaceutical powders.     

Enteric coating process of diclofenac sodium pellets in a fluid bed coater with a wurster insert: Influence of process variables on coating performance and release profile

The objective of this work was to study the coating process of diclofenac sodium pellets, with the commercial aqueous coating suspension for enteric release – Acryl-Eze® MP, in a fluid bed coater with a Wurster insert. Coating experiments were performed following a 2² factorial design to determine the influence of process variables on coating performance, measured by the two response variables: efficiency (η_%) and agglomeration index (m_agg%). Both response variables were found to be affected by inlet temperature and suspension flow rate with a 95% confidence level. This work also studied the release of diclofenac sodium coated and uncoated pellets in HCl 0.1 N and pH 6.8 phosphate buffer media. Results showed that the release of diclofenac sodium during the buffer stage was affected by the prior exposure to the HCl 0.1 N medium and a polymer weight gain above 9.7% (2.7 mg/cm²), was needed to modify the release in such a way that it remained below 10% for the first 120 min in HCl 0.1 N and above 75% in pH 6.8 for the next 45 min. Neither the drug content nor the release profiles were significantly affected by storage at 40 °C and 75% relative humidity.     

Modified release itraconazole amorphous solid dispersion to treat Aspergillus fumigatus: importance of the animal model selection

Previously, modified release itraconazole in the form of a melt-extruded amorphous solid dispersion based on a pH dependent enteric polymer combined with hydrophilic additives (HME-ITZ), exhibited improved in vitro dissolution properties. These properties agreed with pharmacokinetic results in rats showing high and sustained itraconazole (ITZ) systemic levels. The objective of the present study was to better understand the best choice of rodent model for evaluating the pharmacokinetic and efficacy of this orally administered modified release ITZ dosage form against invasive Aspergillus fumigatus. A mouse model and a guinea pig model were investigated and compared to results previously published. In the mouse model, despite similar levels as previously reported values, plasma and lung levels were variable and fungal burden was not statistically different for placebo controls, HME-ITZ and Sporanox^® (ITZ oral solution). This study demonstrated that the mouse model is a poor choice for studying modified release ITZ dosage forms based on pH dependent enteric polymers due to low fluid volume available for dissolution and low intestinal pH. To the contrary, guinea pig was a suitable model to evaluate modified release ITZ dosage forms. Indeed, a significant decrease in lung fungal burden as a result of high and sustained ITZ tissue levels was measured. Sufficiently high intestinal pH and fluids available for dissolution likely facilitated the dissolution process. Despite high ITZ tissue level, the primary therapeutic agent voriconazole exhibited an even more pronounced decrease in fungal burden due to its reported higher clinical efficacy specifically against Aspergillus fumigatus.     

Micropellets coated with Kollicoat® Smartseal 30D for taste masking in liquid oral dosage forms

The objective of this study was to develop delivery systems for taste masking based on multiparticulates coated with Kollicoat^® Smartseal 30D formulated as liquid oral suspensions. Coating of particles containing bitter drugs with Kollicoat^® Smartseal reduced drug leaching into aqueous medium, especially when increasing pH, therefore can be used for the formulation of liquid dosage forms. Application of an intermediate layer of ion exchange resins between drug layer and coating can further decrease drug leaching into aqueous vehicle that is beneficial in terms of taste masking. Using optimized compositions of liquid vehicles such as addition of sugar alcohols and ion exchange resin, reconstitutable or ready-to-use liquid dosage forms with micropellets can be developed with bitter taste protection after redispersion lasting longer than 3?weeks, which exceeds the usual period of application.     

Basic coating polymers for the colon-specific drug delivery in inflammatory bowel disease

During acute attacks of inflammatory bowel disease, the luminal pH of the colon decreases significantly. This drop in pH can be exploited by developing coated dosage forms with acid-soluble coating polymers to achieve topical drug delivery to the colon. Two batches of minitablets, a conventional and a swellable formulation, were prepared by direct compression and coated with different amounts of either Eudragit® E or AEA® in a small coating pan. The release of the model drug dexamethasone from the coated tablets was measured spectrophotometrically at pH 2.0, 4.0, 5.0, and 6.8 and different stirring rates (100-200 rpm) to simulate the influence of pH and hydrodynamic stress on drug release. In general, lag times of drug release, determined as the time points of a 5% drug release, were longer with AEA-coated cores compared to those coated with Eudragit E, resulting from a lower polymer dissolution rate and water permeability of this film. In low pH media, drug release was dependent on the stirring rate because the onset of drug release is determined by the time required for dissolution of the basic polymer films. At pH 6.8, lag times from nonswelling tablets coated with Eudragit E, for which drug release only begins after complete erosion of the polymer film, are not significantly affected by hydrodynamic stress. Drug release from AEA-coated cores is determined by the slow drug diffusion through the polymer film. Lag times from tablets with swelling properties, for which drug release is induced by disruption of the basic polymer films due to water penetration and subsequent core swelling, are not significantly affected by hydrodynamic stress. Additional coating layers such as an intermediate hydroxypropylcellulose (HPC) layer and an enteric outer layer do not influence the lag times of drug release, nor does a 2-hr pretreatment of the entire dosage form in acidic media.     

Basic Coating Polymers for the Colon-Specific Drug Delivery in Inflammatory Bowel Disease

During acute attacks of inflammatory bowel disease, the luminal pH of the colon decreases significantly. This drop in pH can be exploited by developing coated dosage forms with acid-soluble coating polymers to achieve topical drug delivery to the colon. Two batches of minitablets, a conventional and a swellable formulation, were prepared by direct compression and coated with different amounts of either Eudragit® E or AEA® in a small coating pan. The release of the model drug dexamethasone from the coated tablets was measured spectrophotometrically at pH 2.0, 4.0, 5.0, and 6.8 and different stirring rates (100–200 rpm) to simulate the influence of pH and hydrodynamic stress on drug release. In general, lag times of drug release, determined as the time points of a 5% drug release, were longer with AEA-coated cores compared to those coated with Eudragit E, resulting from a lower polymer dissolution rate and water permeability of this film. In low pH media, drug release was dependent on the stirring rate because the onset of drug release is determined by the time required for dissolution of the basic polymer films. At pH 6.8, lag times from nonswelling tablets coated with Eudragit E, for which drug release only begins after complete erosion of the polymer film, are not significantly affected by hydrodynamic stress. Drug release from AEA-coated cores is determined by the slow drug diffusion through the polymer film. Lag times from tablets with swelling properties, for which drug release is induced by disruption of the basic polymer films due to water penetration and subsequent core swelling, are not significantly affected by hydrodynamic stress. Additional coating layers such as an intermediate hydroxypropylcellulose (HPC) layer and an enteric outer layer do not influence the lag times of drug release, nor does a 2-hr pretreatment of the entire dosage form in acidic media.     

Pharmacokinetic evaluation of differential drug release formulations of rabeprazole in dogs

Objectives: To develop novel dual release prototype capsule formulations of rabeprazole and evaluation of pharmacokinetic properties relative to the reference product (Aciphex^®) in Beagle dogs.

Methods: The dual release prototype formulations of rabeprazole were developed by preparing optimized mini-tablets core which was subsequently coated with barrier/enteric coating using standard excipients. Both novel prototype formulations were subjected for in vitro release and assay by HPLC-UV to assess long term stability. Single dose pharmacokinetic study used a single sequence three treatments crossover design. In Periods 1 and 2, four dogs received oral 20?mg dose of two prototype formulations. In Period 3, all dogs received a 20?mg oral dose of Aciphex^® reference product. There was a 1-week washout time between two successive periods. A quantitative analysis of rabeprazole/sulfide metabolite in plasma samples was performed using a validated LC-MS/MS assay and PK parameters were estimated by non-compartmental analysis.

Results: The stability of the prototype formulations was confirmed over a period of 24 months with an acceptable assay and dissolution data. One of the novel prototype formulations showed 70% oral bioavailability relative to the reference product. Despite a 30% reduced bioavailability, this showed 1?h delay in peak concentration, longer plasma residence time of rabeprazole (up to 12?h) and longer apparent elimination half-life.

Conclusions: The use of a canine model has enabled the selection of a novel dual-release prototype formulation of rabeprazole for further clinical development.