Effect of preparation method on the surface properties and UV imaging of indomethacin solid dispersions.

This work explores the use of UV imaging in solid dispersion systems. Solid dispersions are one of the common strategies used in improving the dissolution of poorly soluble drugs. Three manufacturing techniques (spray drying (SD), freeze drying (FD) and homogenising (HG)) are investigated. Differential Scanning Calorimetry (DSC) and X-Ray Powder Diffraction (XRPD) was used in characterising the solid dispersions. Advanced imaging was implemented to give an insight into how these solid dispersions performed. The DSC and XRPD results showed that all three methods and the various ratios studied produced amorphous solid dispersions. Ultra-Violet (UV) imaging of the pseudo Intrinsic Dissolution Rate (IDR) deduced only two samples to have superior pseudo IDR values to the IDR of the parent drug indomethacin (INDO). The whole dose imaging of the capsule formulation however showed all the samples (SD, FD and HG) to have superior dissolution to that of INDO which was in contrast to the IDR results. The UV images obtained from the determination of the pseudo IDR also showed a phenomenon the authors are reporting for the first time where increased polymer (Soluplus) content produced "web-like" strands that migrated to the top of the quartz cell which may have been responsible for the low pseudo IDR values. The authors also report for the first time using this UV imaging technique, the tip of a capsule coming off for drug to go into solution. The area under the curve suggested the best five samples dissolution wise to be 1:3 SD > 1:1 HG > 1:1 SD > 1:3 FD > 1:3 HG meaning a ratio of INDO to SOL in these dispersion of up to 1:3 being sufficient to produce significant dissolution increases. The developed interfacial (surface) area ratio (Sdr) highlighted how the surface area of the IDR compacts varied between the batches, in particular highlighting larger surface area gains for the FD and HG compacts. A choice of instrumentation/techniques to use in making solid dispersions may well come down to cost or instrument availability for a formulator as all three techniques were successful in improving the dissolution of indomethacin. This work thus highlights the importance of having both complimentary IDR and whole dosage imaging techniques in giving a better understanding of solid dispersion systems.

Solid-state, triboelectrostatic and dissolution characteristics of spray-dried piroxicam-glucosamine solid dispersions.

This work explores the use of both spray drying and d-glucosamine HCl (GLU) as a hydrophilic carrier to improve the dissolution rate of piroxicam (PXM) whilst investigating the electrostatic charges associated with the spray drying process. Spray dried PXM:GLU solid dispersions were prepared and characterised (XRPD, DSC, SEM). Dissolution and triboelectric charging were also conducted. The results showed that the spray dried PXM alone, without GLU produced some PXM form II (DSC results) with no enhancement in solubility relative to that of the parent PXM. XRPD results also showed the spray drying process to decrease the crystallinity of GLU and solid dispersions produced. The presence of GLU improved the dissolution rate of PXM. Spray dried PXM: GLU at a ratio of 2:1 had the most improved dissolution. The spray drying process generally yielded PXM-GLU spherical particles of around 2.5µm which may have contributed to the improved dissolution. PXM showed a higher tendency for charging in comparison to the carrier GLU (-3.8 versus 0.5nC/g for untreated material and -7.5 versus 3.1nC/g for spray dried materials). Spray dried PXM and spray dried GLU demonstrated higher charge densities than untreated PXM and untreated GLU, respectively. Regardless of PXM:GLU ratio, all spray dried PXM:GLU solid dispersions showed a negligible charge density (net-CMR: 0.1-0.3nC/g). Spray drying of PXM:GLU solid dispersions can be used to produce formulation powders with practically no charge and thereby improving handling as well as dissolution behaviour of PXM.

Drug release from E chemistry hypromellose tablets using the Bio-Dis USP type III apparatus: An evaluation of the effect of systematic agitation and ionic strength.

The aim of the study was to evaluate the effect of systematic agitation, increasing ionic strength and gel strength on drug release from a gel-forming matrix (HPMC E10M, E4M and E50LV) using USP type III Bio-Dis apparatus with theophylline as a model drug. The triboelectric charging; particle sizing, water content, true density and SEM of all the hypromellose grades, theophylline and formulated blends were characterised. The results showed that balanced inter-particulate forces exist between drug particles and the excipient surface and this enabled optimum charge to mass ratio to be measured. Agitation and ionic strength affected drug release from E50LV and E4M tablet matrices in comparison to the E10M tablet matrices. Drug release increased substantially when water was used as the dissolution media relative to media at pH 1.2 (containing 0.4M NaCl). The results showed all f2 values for the E10M tablet matrices were above 50 suggesting the drug release from these tablet matrices to be similar. Rheological data also explained the different drug release behaviour with the stress required to yield/erode being 1Pa, 150Pa, and 320Pa, for the E50LV, E4M and E10M respectively. The stiffness of the gel was also found to be varied from 2.5Pa, 176.2Pa and 408.3Pa for the E50LV, E4M and E10M respectively. The lower G' value can be explained by a softer gel being formed after tablet introduction into the dissolution media thereby indicating faster drug release.

Modification of drug delivery to improve antibiotic targeting to the stomach.

The obstacles to the successful eradication of Helicobacter pylori infections include the presence of antibiotic-resistant bacteria and therapy requiring multiple drugs with complicated dosing schedules. Other obstacles include bacterial residence in an environment where high antibiotic concentrations are difficult to achieve. Biofilm production by the bacteria is an additional challenge to the effective treatment of this infection. Conventional oral formulations used in the treatment of this infection have a short gastric residence time, thus limiting the duration of exposure of drug to the bacteria. This review summarizes the current research in the development of gastroretentive formulations and the prospective future applications of this approach in the targeted delivery of drugs such as antibiotics to the stomach.

Formulation and evaluation of floating mucoadhesive alginate beads for targeting Helicobacter pylori.

OBJECTIVES: There are various obstacles in the eradication of Helicobacter pylori infections, including low antibiotic levels and poor accessibility of the drug at the site of the infection. This study describes the preparation and characterisation of novel floating mucoadhesive alginate beads loaded with clarithromycin for delivery to the gastric mucosa to improve the eradication of this microorganism. METHODS: Calcium alginate beads were prepared by ionotropic gelation. The formulation was modified through addition of oil and coating with chitosan to improve floating, mucoadhesion and modify drug release. KEY FINDINGS: Scanning electron microscopy confirmed the sphericity of the beads with X-ray microtomography showing the three-dimensional structure of the beads with the layered internal structure of the bead and the even distribution of the drug within the bead. This formulation combined two gastro-retentive strategies, and produced excellent in-vitro floating, mucoadhesive and drug release characteristics. Enhanced stability of the beads in phosphate buffer raises a potential for the modified formulations to be targeted to regions of higher pH within the gastrointestinal tract. Drug release from these beads was sustained through an unstirred mucin layer simulating in-vivo conditions under which the H. pylori resides in the gastric mucosa. CONCLUSIONS: This novel formulation will ensure retention for a longer period in the stomach than conventional formulations and control drug release, ensuring high local drug concentrations, leading to improved eradication of the bacteria.

Lectin-conjugated microspheres for eradication of Helicobacter pylori infection and interaction with mucus.

Using second generation mucoadhesives may enhance targeting antibiotics for eradication of Helicobacter pylori from the stomach for the treatment of peptic ulcer. The aim of this research was to prepare and characterise ethylcellulose/chitosan microspheres containing clarithromycin with their surfaces functionalised with concanavalin A to produce a floating-mucoadhesive formulation. The microspheres were prepared using an emulsification-solvent evaporation method. Particle size, surface morphology, in vitro buoyancy profile, zeta potential, drug entrapment efficiency, in vitro drug release and release kinetics of the particles were determined. Lectin was conjugated to the microsphere surface using two-stage carbodiimide activation and confirmed using FTIR, fluorescence studies and zeta potential measurements. Conjugation ranged from 11 to 15 µg Con A/mg microspheres which represents over 56% efficiency although there was some drug loss during the conjugation process. Conjugation did not have a significant effect on the buoyancy and release of drug from the microspheres using a mucus diffusion model with 53% and 40% of drug released from unconjugated and conjugated microspheres within 12h. Conjugation improved mucoadhesion and interaction with porcine gastric mucin compared to unconjugated microspheres. The buoyancy and improved mucoadhesion of the microspheres provides potential for delivery of clarithromycin and other drugs to the stomach.

Preparation and characterisation of gastroretentive alginate beads for targeting H. pylori.

There are various obstacles in the eradication of Helicobacter pylori (H. pylori) infections including low drug levels due to short gastric residence times and poor accessibility of the drug at the site of the infection. In this study, calcium alginate beads containing metronidazole were prepared by ionotropic gelation with diameters ranging from 2 to 3 mm and bulk densities ranging from 0.11 to 0.23 g/cm(3). These beads failed buoyancy tests and released the drug rapidly. The formulation was modified in order to improve floating and modify their drug release profile through addition of oil and coating with chitosan. Upon modification, buoyancy improved and drug release was sustained. This novel formulation will ensure retention for a longer period in the stomach and control the release of drug, ensuring high local drug concentrations, leading to improved eradication of the bacteria.