Ross James Macrae

Blends of enteric and GIT-insoluble polymers used for film coating: physicochemical characterization and drug release patterns

THE OBJECTIVES OF THIS STUDY WERE: (i). to use blends of gastrointestinal tract (GIT)-insoluble and enteric polymers (ethyl cellulose and Eudragit L) as coating materials for multiparticulate controlled release dosage forms; (ii). to investigate the effects of the polymer blend ratio and coating level on the resulting drug release patterns; and (iii). to explain the observed phenomena based on the physicochemical properties of the systems. Propranolol HCl-loaded pellets were coated in a fluidized bed coater with organic polymer solutions; thin, drug-containing and drug-free, polymeric films were prepared using a casting knife. In vitro drug release, water uptake and dry weight loss studies were performed in 0.1 M HCl and phosphate buffer pH 7.4, respectively. The apparent drug diffusion coefficients within the polymeric systems were determined using different experimental and theoretical techniques (side-by-side diffusion cells, in vitro drug release from thin films; exact and approximate solutions of Ficks second law of diffusion). A broad range of drug release patterns from coated pellets could be achieved by varying the GIT-insoluble:enteric polymer blend ratio. With increasing relative amounts of Eudragit L, the release rates in both media significantly increased. The increase at low pH could be attributed to an increase in water uptake, as observed with thin films. Interestingly, only partial Eudragit L leaching occurred in phosphate buffer pH 7.4 even at high enteric polymer contents, indicating that the GIT-insoluble polymer effectively hindered the dissolution of the entrapped Eudragit L. At high pH, both polymer leaching and polymer swelling contributed to the control of drug release. The determined apparent drug diffusion coefficients take the two effects adequately into account.

Polymer Blends Used for the Coating of Multiparticulates: Comparison of Aqueous and Organic Coating Techniques

AbstractPurpose. The purpose of this study was to use polymer blends for the coating of pellets and to study the effects of the type of coating technique (aqueous vs. organic) on drug release. Methods. Propranolol HCl-loaded pellets were coated with blends of a water-insoluble and an enteric polymer (ethyl cellulose and Eudragit L). Drug release from the pellets as well as the mechanical properties, water uptake, and dry weight loss behavior of thin polymeric films were determined in 0.1 M HCl and phosphate buffer, pH 7.4. Results. Drug release strongly depended on the type of coating technique. Interestingly, not only the slope, but also the shape of the release curves was affected, indicating changes in the underlying drug release mechanisms. The observed effects could be explained by the higher mobility of the macromolecules in organic solutions compared to aqueous dispersions, resulting in higher degrees of polymer-polymer interpenetration and, thus, tougher and less permeable film coatings. The physicochemical properties of the latter were of major importance for the control of drug release, which was governed by diffusion through the intact polymeric films and/or water-filled cracks. Conclusions. The type of coating technique strongly affects the film microstructure and, thus, the release mechanism and rate from pellets coated with polymer blends.

Chronopharmaceutical drug delivery from a pulsatile capsule device based on programmable erosion.

We report the development of a chronopharmaceutical capsule drug delivery system capable of releasing drug after pre‐determined time delays.

Investigating the coating dependent release mechanism of a pulsatile capsule using NMR microscopy

Chronopharmaceutical capsules, ethylcellulose-coated to prevent water ingress, exhibited clearly different release characteristics when coated by organic or aqueous processes. Organic-coated capsules produced a delayed pulse release, whereas aqueous-coated capsules exhibited less delayed and more erratic release behaviour. Nuclear magnetic resonance microscopy was used to elucidate the internal mechanisms underlying this behaviour by studying the routes of internal water transport and the timescale and sequence of events leading to the pulse. Images showed that the seal between the shell and the tablet plug is a key route of water penetration in these dosage forms. There is evidence for a more efficient seal in the organic-coated capsule, and although some hydration of the contents was evident, erosion of the tablet plug is most probably the controlling factor in timed release. The premature failure of the aqueous-coated capsule appears to be a result of rapid influx of water between plug and capsule with hydration of the low substituted hydroxypropylcellulose expulsion agent. As a result of this, the tablet plug remains intact, but appears unable to be ejected. The resulting significant pressure build-up causes premature release by distortion and splitting of the capsule shell. These events may be aided by a weakening of the aqueous-coated gelatin shell by hydration from the inside, and at the mouth of the capsule where previous electron microscope studies have shown incomplete coating of the inside by the aqueous process.

Effect of unconventional curing conditions and storage on pellets coated with Aquacoat ECD

Purpose: Purpose of this study was to develop storage stable pellets coated with the aqueous ethylcellulose dispersion Aquacoat ECD. Methods: The influence of accelerated curing/storage conditions on the release behavior of Aquacoat/HPMC-coated drug pellets were investigated as a function of various formulations (sealing, plasticizer content, and pore-former type/amount) and process parameters (process humidity, thermal curing, and organic processing). Results: Conventionally cured Aquacoat/hydroxypropyl methylcellulose-coated pellets were storage stable at ambient conditions and 25°C/60% relative humidity (RH) but showed a decreasing drug release at 40°C/75% RH, which is a required test condition according to ICH guidelines. Conclusion: Only organic processing of dried Aquacoat or unconventionally harsh curing conditions (60°C/75% RH or 80°C) improved the storage stability of Aquacoat-coated pellets at accelerated conditions.

Enteric polymers as acidifiers for the pH-independent sustained delivery of a weakly basic drug salt from coated pellets

Weakly basic drugs and their salts exhibit a decrease in aqueous solubility at higher pH, which can result in pH-dependent or even incomplete release of these drugs from extended release formulations. The objective of this study was to evaluate strategies to set-off the very strong pH-dependent solubility (solubility: 80 mg/ml at pH 2 and 0.02 mg/ml at pH 7.5, factor 4000) of a mesylate salt of weakly basic model drug (pK(a) 6.5), in order to obtain pH-independent extended drug release. Three approaches for pH-independent release were investigated: (1) organic acid addition in the core, (2) enteric polymer addition to the extended release coating and (3) an enteric polymer subcoating below the extended release coating. The layering of aspartic acid onto drug cores as well as the coating of drug cores with an ethylcellulose/Eudragit L (enteric polymer) blend were not effective to avoid the formation of the free base at pH 7.5 and thus failed to significantly improve the completeness of the release compared to standard ethylcellulose/hydroxypropyl cellulose (EC/HPC)-coated drug pellets. Interestingly, the incorporation of an enteric polymer layer underneath the EC/HPC coating decreased the free base formation at pH 7.5 and thus resulted in a more complete release of up to 90% of the drug loading over 18 h. The release enhancing effect was attributed to an extended acidification through the enteric polymer layer. Flexible release patterns with approximately pH-independent characteristics were successfully achieved.