John T. Fell

An in vivo investigation into the suitability of pH dependent polymers for colonic targeting.

Abstract The effect of a pH-dependent polymer coating, Eudragit S, on its ability to protect a model drug and control its release from rapidly disintegrating tablets has been examined in vitro. Conditions were chosen to mimic those likely to occur during transit from the mouth to the colon. Dissolution was affected by coating thickness and pH. At a given pH, the nature of the buffer system dramatically affected dissolution and disintegration. Profiling experiments involving pH changes and mimicking the extremes of conditions prevailing in vivo indicated that release of drug may commence in the duodenum or not at all.

An evaluation of pectin as a carrier for drug targeting to the colon

Abstract A novel colonic drug delivery system based on the polysaccharide pectin has been investigated. In vitro experiments demonstrated that high methoxy pectin (pectin USP), when applied as a compression coat, proved capable of protecting a core tablet during conditions mimicking mouth-to-colon transit and was susceptible to enzymatic attack. In vivo gamma scintigraphic studies confirmed the in vitro findings. In all the volunteers, the pectin-coated tablets disintegrated in the colon indicating that site-specificity had been achieved and illustrating the potential of a colonic drug delivery system utilising pectin.

Studies on pectin formulations for colonic drug delivery

Abstract An investigation has been undertaken to assess, in vitro, the potential of several pectin formulations as colonie drug delivery systems. Experiments were conducted on the release of model compounds from matrix tablets under conditions pertaining to those in vivo. The monitoring of release gives a sensitive indication of the behaviour of the pectin under the different conditions. The type of pectin, the presence of calcium and the solubility of the calcium salt all influence release. Additionally, pectins with a low degree of methoxylation were more susceptible to enzymic breakdown. Calcium enhanced the enzymic activity. Rheological studies indicated that gel strength was a factor in determining release. These findings suggest that either a high methoxy pectin formulation or a low methoxy pectin with a carefully controlled amount of calcium should maximise colonie specificity by providing optimal protection of a drug during its transit to the colon and a high susceptibility to enzymic attack.

The tensile strength of lactose tablets.

animals that received the monoamine oxidase inhibitor and the a-methyltyrosinecontaining diet, motor activity and brain amine levels were lower than corresponding control values. However, values for the spontaneous locomotor activity and the brain content of noradrenaline were significantly higher in the pheniprazine-a-methyltyrosine group than in saline-cr-methyltyrosine group. Although pheniprazine partially blocked the behavioural depression and noradrenaline depletion it did not alter plasma levels of a-methyltyrosine. Thus the behavioural depression after a 24 hr diet containing a-methytyrosine appears to be related to the brain levels of catecholamines. This work was supported by USPHS Grant AM-1 1083. L-a-Methyltyrosine was kindly supplied by Dr. C. A. Stone, Merck Institute for Therapeutic Research, West Point, Pa., U.S.A. Pheniprazine (JB-5 16, Catron) was supplied by Dr. R. C. Ursillo, Lakeside Laboratories, Milwaukee, Wisconsin, U S A . The technical assistance of Mrs. M. Grarnatins and Mrs. D. Simpson is gratefully acknowledged.

Hydrogel beads based on amidated pectins for colon-specific drug delivery : the role of chitosan in modifying drug release

Abstract A multiparticulate system with the potential for site-specific delivery to the colon has been investigated. Gelation of droplets of amidated pectin solutions in the presence of calcium is the basis of the method of preparation. Two drugs, indomethacin and sulphamethoxazole were successfully incorporated into the beads. Drug release from the beads was a function of media pH and drug loading. In simulated gastric and small intestinal conditions, drug release was greater with the more soluble sulphamethoxazole, but release of both drugs could be reduced to satisfactory levels by the formation of a chitosan polyelectrolyte complex around the beads. All the preparations released drug in simulated colonic conditions within 135 min.

Amoxycillin release from a floating dosage form based on alginates.

Floating alginate beads have been prepared from alginate solutions containing either dissolved or suspended amoxycillin. The beads were produced by the dropwise addition of the alginate into calcium chloride solution, followed by removal of the gel beads and freeze drying. Drug release studies showed that beads prepared with the drug in solution provided some sustained release characteristics and that these could be improved by the addition of amylose. In all cases, the drug release was consistent with release of a dissolved solute from a granular or porous matrix. The beads retained their buoyancy when amylose and amoxycillin were incorporated, exhibiting resultant weight values greater than zero after 20 h. Preparation of the beads from alginate solutions containing the drug in suspension allowed higher drug loadings, at the expense of faster release and lower buoyancy.

Pectin/chitosan mixtures as coatings for colon-specific drug delivery : an in vitro evaluation

The ability of a multiple-unit dosage form to reach the colon intact has been investigated, in vitro, using conditions chosen to simulate the pH and times likely to be encountered during transit to the colon. Small tablets were coated with either pectin USP or pectin in a 1:10 mixture with chitosan. Indomethacin and paracetamol were used as model drugs to represent poorly soluble and soluble compounds. Pectin alone was able to protect the cores from premature release, but only when a substantially thick coat was present. Pectin/chitosan mixtures achieved better protection at a lower coat weight. The use of pectinolytic enzymes to simulate breakdown in the colon showed that the pectin/chitosan mixture was susceptible to enzymic breakdown and allowed drug release to occur. The importance of pre-exposure of the tablets to conditions in the upper gastro-intestinal tract prior to exposure to the enzyme was noted.

Pectin/Ethylcellulose Film Coating Formulations for Colonic Drug Delivery

AbstractPurpose. The purpose of the study was to investigate the potential of pectin, ethylcellulose combinations as a practical film coating for colonic delivery. Methods. Combinations of pectin and ethylcellulose, in the form of an aqueous dispersion, were used as coating formulations. Paracetamol cores were used as the substrate. The coatings were assessed by a flow through dissolution system simulating in vivo conditions by changes in pH and residence time. Pectinolytic enzymes were used to simulate the bacterial flora of the colon. Results. Drug release was controlled by the ratio of ethylcellulose to pectin in the film coat. Increasing the proportion of ethylcellulose and increasing the coat weight reduced drug release in pHl and pH7.4 media. The addition of pectinolytic enzymes to pH6 media increased the release of drug. Conclusions. Combinations of ethylcellulose and pectin can provide protection to a drug in the upper g.i. tract while allowing enzymatic breakdown and drug release in the colon.

The potential use of mixed films of pectin, chitosan and HPMC for bimodal drug release.

Polyelectrolyte complex (PEC) formation between pectin USP and chitosan was investigated by examining the viscosities of supernatant solutions after removal of the precipitated complex. The amount of pectin, relative to chitosan, required for optimal PEC formation increased as the pH of the solution was reduced. At pH values of less than 1.3, there was no evidence for the formation of the PEC. Swelling studies conducted on pectin/chitosan films, showed minimal swelling occurring when the pectin:chitosan weight ratio was optimal for PEC formation, suggesting the formation of the PEC in situ. The permeability of the films to paracetamol as a model compound was dependent on film composition and was markedly increased after exposure to pectinolytic enzymes, used to mimic conditions in the colon. It may be implied from the results that similar formulations, applied as a film coat to tablets, could be used to achieve bimodal drug release with colonic conditions acting as a trigger for an increased rate of release.

Selective drug delivery to the colon using pectin:Chitosan:hydroxypropyl methylcellulose film coated tablets.

A study has been carried out to assess the potential of pectin:chitosan:hydroxypropyl methylcellulose (HPMC) (P:C:H) films for colonic drug delivery. Radiolabelled (99mTc) tablets were coated with a 3:1:1, P:C:H film and administered to human volunteers. The gastro-intestinal transit of the tablets was assessed by gamma scintigraphy. The results showed that in all cases (n=4), the tablets were able to pass through the stomach and small intestine intact. Break up of the tablets commenced once they were in the colon, due to degradation of the coat by colonic bacteria. The study has highlighted the potential of this coating system for colonic drug delivery.