J. H. Collett

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.

The micellar properties of the poly(oxyethylene) - poly(oxypropylene) copolymer Pluronic F127 in water and electrolyte solution

The micellar properties of the ABA poly(oxyethylene)-poly(oxypropylene) block copolymer Pluronic F127 have been examined in water and electrolyte solution by photon correlation spectroscopy, total intensity light scattering and viscometric techniques. The hydrodynamic micellar radius in water, as calculated from diffusion data at the critical micelle concentration, remained constant at 10.2 ± 0.1 nm, over the temperature range 35–45 °C. Viscometric studies, however, showed a progressive dehydration of the micelles with temperature increase and it is clear from total intensity light scattering that this dehydration is accompanied by a concomitant increase in anhydrous volume such that the overall hydrated volume is unaffected by temperature change. Increase of solution concentration above about 10 g · dl−1 over this temperature range caused a marked increase of mean micellar size and of the polydispersity of micellar sizes, indicative of the onset of gelation. The influence of temperature on micellar size and hydration was less pronounced in the presence of 0.5 mol-dm−3 sodium chloride and gelation commenced at higher solution concentrations. The relevance of these studies to the thermal gelation of this poloxamer is discussed.

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.

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.

Influence of cyclodextrin complexation on the in vitro permeation and skin metabolism of dexamethasone

The influence of complexation of a model drug, dexamethasone acetate (DMA), with beta-cyclodextrin (beta-CyD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) on the in vitro permeation through hairless mouse skin and on skin metabolism have been investigated. Complexation with CyDs increased the amount of DMA permeated in the order of 2.0 and 3.0 times for beta-CyD and HP-beta-CyD, respectively. The partition coefficient, between stratum corneum and buffer (K(SC/buffer)), for DMA decreased when the drug was an inclusion complex, being greatest for DMA/HP-beta-CyD complex. Complexation protected the drug against skin metabolism. The increase of skin permeation and stability of the model drug in the skin suggest that the complexation with beta-CyD and HP-beta-CyD is a rational way to improve the physical-chemical properties of drugs for use in transdermal delivery systems.

Characterization of the influence of some cyclodextrins on the stratum corneum from the hairless mouse.

Differential scanning calorimetry (DSC), Fourier‐transform infrared (FTIR) spectroscopy and transmission electron microscopy (TEM) have been used to determine the influence of β‐cyclodextrin (β‐CyD), hydroxypropyl‐β‐CyD (HP‐β‐CyD) and γ‐CyD on the structural properties of the stratum corneum from the hairless mouse.

Influence of lecithin on some physical chemical properties of poloxamer gels: rheological, microscopic and in vitro permeation studies

Thermoreversible gels may be used in delivery systems which require a sol-gel transition at body temperature. The influence of the addition of lecithin, a permeation enhancer, on the rheological and in vitro permeation properties of poloxamer 407 gels was investigated. Light microscopy and rheological parameters were used to characterize the microscopic structure of the formulations which showed non Newtonian behaviour, pseudoplastic flow with a yield value. Increased concentrations of lecithin increased the thixotropy, yield value, apparent viscosity, and the gelation temperature of the gels. Light microscopy showed the formation of micellar structures by the addition of lecithin, which may account for changes in rheological properties. In vitro permeation of a model drug, triamcinolone acetonide, was decreased when the lecithin concentration was increased. The presence of lecithin in the poloxamer gel improved the characteristics for topical drug delivery.

The in Vitro Release of Some Antimuscarinic Drugs from Monoolein/ Water Lyotropic Liquid Crystalline Gels

AbstractPurpose. To investigate the potential use of a monoolein/water lyotropic liquid crystalline gel for the vaginal delivery of the antimuscarinic drugs, propantheline bromide and oxybutynin hydrochloride to treat urinary incontinence, using Myverol 18-99 as a commercially available grade of monoolein. Methods. The influence of propantheline bromide and oxybutynin hydrochloride on the phase structure of Myverol 18-99/water gels was investigated using polarising microscopy. The in-vitro release of the antimuscarinic drugs from Myverol 18-99/water gels was determined and the release pattern interpreted with the aid of results from swelling studies and partition coefficient determinations. Results. Myverol 18-99 forms gels with lyotropic liquid crystalline structures in the presence of water. The addition of propantheline bromide and oxybutynin hydrochloride promoted the formation of gels with a lamellar phase structure. The gels absorbed water at a rate inversely proportional to their initial water content until they reached an equilibrium water content of ~40% w/w whilst maintaining their physical integrity. The release of the antimuscarinic drugs was sustained over a period of ~18 hours and followed square root of time kinetics indicating that the rate of release was diffusion controlled. Conclusions. The in-vitro release behaviour of Myverol 18-99/water gels suggested that they are suitable carriers to deliver propantheline bromide or oxybutynin hydrochloride. The results of swelling studies indicated that a confined area, such as the vaginal cavity, would be a suitable site of administration.

The release of drugs from monoglyceride-water liquid crystalline phases

Abstract The in vitro release of model drugs, with a wide range of aqueous solubilities, from monoolein-water liquid crystalline matrix systems has been investigated. Release of melatonin, pindolol, propranolol and pyrimethamine from individual systems with initial drug loading concentrations within the range 1–20% w/w and atenolol from systems at concentrations up to 10% w/w could be fitted to both diffusion-controlled or first-order kinetics. The release of atenolol at initial drug loading concentrations of 15 and 20% w/w could be fitted to a zero-order release model. Release rates have been related to the solubility of the drugs in the monoolein-water systems. Changes in the matrix monoolein/water weight ratio over the range 4:1-1:1 had no significant influence on drug release. Monoolein-water-drug systems prepared using drugs with either a high solubility (propranolol) or a low solubility (pyrimethamine) were stable when stored in the dark at 4°C for up to 6 months with no significant change in release characteristics. Systems incorporating propranolol were unstable when stored at 26°C for 15 days; storage of systems incorporating pyrimethamine under the same conditions were stable with no change in release characteristics.