Alistair C. Ross

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.

Erosion Characteristics of an Erodible Tablet Incorporated in a Time-Delayed Capsule Device

A time-delayed oral drug delivery device was investigated in which an erodible tablet (ET), sealing the mouth of an insoluble capsule, controlled the lag-time prior to drug release. The time-delayed capsule (TDC) lag-time may be altered by manipulation of the excipients used in the preparation of the ET. Erosion rates and drug release profiles from TDCs were investigated with four different excipient admixtures with lactose: calcium sulphate dihydrate (CSD), dicalcium phosphate (DCP), hydroxypropylmethyl cellulose (HPMC; Methocel® K100LV grade) and silicified microcrystalline cellulose (SMCC; Prosolv® 90 grade). Additionally, the compressibility of different insoluble coated capsules was tested at different moisture levels to determine their overall integrity and suitability for oral delivery. Erosion rates of CSD, DCP, and SMCC displayed a nonlinear relationship to their concentration, while HPMC indicated rapid first-order erosion followed by zero-order erosion, the onset of which was dependent on the HPMC concentration. Capsule integrity was confirmed to be most suitable for oral delivery when the insoluble ethyl cellulose coat was applied to a hard gelatin capsule using an organic spray coating process. T50% drug release times varied between 245 (± 33.4) and 393 (± 40.8) minutes for 8% and 20% DCP, respectively, T50% release times of 91 (± 22.1) and 167 (± 34.6) were observed for 8% and 20% CSD; both formulations showed incidence of premature drug release. The SMCC formulations showed high variability due to lamination effects. The HPMC formulations had T50% release times of 69 (± 13.9), 213 (± 25.4), and 325 (± 30.3) minutes for 15%, 24%, and 30% HPMC concentrations respectively, with no premature drug release. In conclusion, HPMC showed the highest reproducibility for a range of time-delayed drug release from the assembled capsule formulation. The method of capsule coating was confirmed to be important by investigation of the overall capsule integrity at elevated humidity levels. The erosion characteristics of ETs containing HPMC may be described by gravimetric loss. The novel time-delayed capsule device presented in this study may be assembled to include an erodible tablet with a known concentration of HPMC. A variety of suitable drugs for targeted chronopharmaceutical therapy can beincorporated into such a device, ultimately improving drug efficacy and patient compliance, and reducing harmful side effects.

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.

Organic solvent functional group effect on enzyme inactivation by the interfacial mechanism

Abstract We have used a bubble column apparatus to study interfacial inactivation of enzymes. The amount of enzyme inactivated was proportional to the area of organic solvent exposed, as is characteristic of the interfacial mechanism. Tests were made with a series of 12 solvents of log P close to 4.0, but with different functional groups. With α- and β-chymotrypsin, inactivation was much less severe with amphiphilic molecules like decyl alcohol, than with less polar compounds (heptane as the extreme case). This corresponds to a correlation with aqueous–organic interfacial tension, and presumably reflects a more polar interface as seen by the enzyme adsorbing from the aqueous phase. A 50% mixture of decyl alcohol and heptane behaved similarly to pure decyl alcohol, which would be expected to accumulate at the interface. With pig liver esterase, the correlation was rather weak, however. Accumulated data for interfacial inactivation by alkanes was examined for the above enzymes, and also papain, trypsin, urease and ribonuclease. The differing sensitivities did not show a clear correlation with any enzyme property, although there was some relationship to adiabatic compressibility, thermal denaturation temperature and mean hydrophobicity.

A design of experiments to optimize a new manufacturing process for high activity protein-containing submicron particles

A novel method for the manufacture of protein/peptide-containing submicron particles was developed in an attempt to provide particles with increased activity while using high energy input technologies. The method consists of antisolvent co-precipitation from an aqueous solution containing both an amino acid core material (e.g. D,L-valine), and either bovine serum albumin (BSA) or lysozyme (Lys) as model proteins. The aqueous solution was added to the organic phase by means of a nebulizer to increase the total surface area of interaction for the precipitation process. Sonication proved to be an effective method to produce small particle sizes while maintaining high activity of Lys. The use of a polysorbate or sorbitan ester derivatives as stabilizers proved to be necessary to yield submicron particles. Particles with very high yields (approximately 100%) and very high activity after manufacture (approximately 100%) could be obtained. A particle size of 439.0 nm, with a yield of 48.8% and with final remaining activity of98.7% was obtained. By studying various factors using a design of experiments strategy (DoE) we were able to establish the critical controlling factors for this new method of manufacture.

A pharmacoscintigraphic study of three time‐delayed capsule formulations in healthy male volunteers

Three time-delayed capsule (TDC) formulations were investigated in a pharmacoscintigraphic study, using a three-way crossover design in eight healthy male volunteers. Additionally, the pulsed release of a TDC was investigated with time-lapse photography, using a nondisintegrating riboflavin tablet. The photographic study indicated how the release characteristics of the TDC relied on the erosion of a tablet containing hypromellose (HPMC). Each TDC was duel radio labelled with indium-111 and technetium-99 m DTPA complexes, to observe drug release scintigraphically (theophylline was a marker compound). Three formulations, having in vitro dissolution release times of 1.8, 2.9 or 4.0 h were shown to compare favourably with mean in vivo scintigraphic release times of 2.7, 3.0 and 4.0 h for each formulation containing 20, 24 or 35% (w/w) HPMC concentrations respectively. An increase in HPMC concentration was associated with a delayed technetium release time, and followed the same rank order as the in vitro dissolution study. Observed radiolabel dispersion always occurred in the small intestine. In conclusion, the study established that the TDC performs and demonstrates an in vitro-in vivo correlation. Additionally, time and site of release were accurately visualized by gamma scintigraphy, and confirmed with determination of theophylline absorption.

Inactivation of enzymes at the aqueous-organic interface

Abstract A liquid-liquid bubble column can be used to quantify interfacial inactivation of enzymes by organic liquids. Extent of inactivation per unit area can be greater for more hydrophobic solvents, particularly those with no polar groups. Inactivation rates can differ considerably even between similar enzymes, and do not show a maximum at the isoelectric point (unlike adsorption).