The micellization of a model cationic drug, diminazene diaceturate (DIM) and a series of new diblock copolymers, carboxymethyldextranpoly(ethylene glycols) (CMD-PEG), were evaluated as a function of the ionic charge density or degree of substitution (DS) of the carboxymethyldextran block and the molar ratio, [+]/[−], of positive charges provided by the drug to negative charges provided by CMD-PEG. Micelles ([+]/[−] = 2) incorporated up to 64% (w/w) DIM and ranged in hydrodynamic radius (RH) from 36 to 50 nm, depending on the molecular weight and DS of CMD-PEG. The critical association concentration (CAC) was on the order of 15-50 mg/L for CMD-PEG of DS > 60%, and ca. 100 mg/L for CMD-PEG of DS~30%. The micelles were stable upon storage in solution for up to 2 months and after freeze-drying in the presence of trehalose. They remained intact within the 4 pH 11 range and for solutions of pH 5.3, they resisted increases in salinity up to ~0.4 M NaCl in the case of CMD-PEG of high DS. However, micelles of DIM and a CMD-PEG of low DS (30%) disintegrated in solutions containing more than 0.1 M NaCl, setting a minimum value to the DS of copolymers useful in in-vivo applications. Sustained in-vitro DIM release was observed for micelles of CMD-PEG of high DS ([+]/[−] = 2).

Omeprazole (OME) is a proto type anti-secretary agent. This compound is very unstable, especially in acidic aqueous solutions. A stability indicating HPLC assay has been developed in order to investigate the effect of different factors on the stability of omeprazole. These factors included the pH with the tested values ranging from 6-10 and the temperature by monitoring the drug stability at 25, 37 and 40ºC. The study was then extended to investigate the effect of cyclodextrins, namely beta-cyclodextrin (β-CD), dimethyl-beta-cyclodextrin (DMβ-CD), hydroxypropyl-beta-cyclodextrin (HPβ-CD) and maltosyl-beta-cyclodextrin (Mβ-CD) on the stability of omeprazole. The results showed the dependence of drug stability on the pH and temperature with the degradation being significant below pH 7 and at higher temperature. The degradation kinetics follows the first-order kinetics. The addition of different cyclodextrins accelerates the degradation of drug, and this effect was in the following manner: β-CD> DMβ-CD> Mβ-CD> HPβ-CD. The effect of different concentrations of HPβ-CD on the degradation of drug was also studied. It was noted that the degradation of drug depends on the concentration of HPβ-CD up to 1.0 mM; above this concentration the degradation was constant.

The basic objectives of this study were to prepare and characterize solid dispersions of poorly soluble drug spironolactone (SP) using gelucire carriers by spray-drying technique. The properties of the microparticles produced were studied by differential scanning calorimetry (DSC), scanning electron microscopy, saturation solubility, encapsulation efficiency, and dissolution studies. The absence of SP peaks in DSC profiles of microparticles suggests the transformation of crystalline SP into an amorphous form. The in-vitro dissolution test showed a significant increase in the dissolution rate of microparticles as compared with pure SP and physical mixtures (PMs) of drug with gelucire carriers. Therefore, the dissolution rate of poorly water-soluble drug SP can be significantly enhanced by the preparation of solid dispersion using spray-drying technique.

Chitosan (CH), partially N-deacetylated chitin, is a biodegradable and biocompatible polymer that has shown great potential in drug delivery and tissue engineering applications. Although bioadhesive, CH has limited mucoadhesion in wet conditions due to weak interactions with biological surfaces. DOPA (3,4-dihydroxy-L-phenylalanine), a catechol-containing molecule naturally present in marine mussel foot proteins, has been shown to increase the mucoadhesion of several polymers. We report here a simple and bioinspired approach to enhance CH mucoadhesion in wet conditions by preparing mixed hydrogels including CH and different catechol-containing compounds, namely DOPA, hydrocaffeic acid (HCA), and dopamine (DA). We characterized the hydrogels for their swelling, release kinetics of the catechol compounds, and mucoadhesive strength to rabbit small intestine. The swelling of the hydrogels was pH dependent with maximum swelling at pH 1. The hydrogel swelling was higher in the presence of the DOPA and DA but lower in the presence of HCA. HCA/CH hydrogel also showed the slowest catechol release, most likely due to electrostatic interactions between CH and HCA. Lower hydrogel swelling and slower HCA release resulted in increased mucoadhesion: HCA/CH showed more than 2-fold enhancement of mucoadhesion to rabbit small intestine compared to CH alone. Since it is known that catechol compounds can be oxidized, we analyzed the oxidation of DOPA, HCA, and DA at different pH values and its effect on mucoadhesion. We found that oxidation occurring before contact with the intestinal mucosa did not improve mucoadhesion, while oxidation occurring during the contact further increased the mucoadhesion of HCA/CH hydrogels. These results show that mucoadhesion of CH hydrogels can be increased with a simple bioinspired approach, which has the potential to be applied to other polymers since it does not require any chemical modification.

Omeprazole microparticles were prepared by different drying techniques using Kollicoat IR® and hydroxypropyl-β-cyclodextrin hydrophilic polymers. Physico-chemical properties were investigated using differential scanning calorimetry and powder X-ray diffractometry. Dissolution rate was determined and compared to the physical mixtures and the morphology was studied using a scanning electron microscope. Omeprazole transformed from the crystalline state to the amorphous state as confirmed by the disappearance of its melting peak and the characteristic of the crystalline peaks. Omeprazole dissolution rate was enhanced significantly from its spray- and freeze-dried microparticles as compared to the corresponding physical mixtures and drug alone (P 0.05). F3 and F5 formula possessed superior release rate over other formulations. In acidic medium, the release of drug from enteric-coated capsules was not detectable, while it is completely released within 40 min after changing dissolution medium to phosphate buffer (pH 7.4). The transformation of OME from crystalline to amorphous state by using either Kollicoat IR® or hydroxylpropyl-β-cyclodextrin is considered a promising way to improvement of drug dissolution.

Solid dispersion of a slightly water soluble drug, omeprazole (OME), was prepared using different concentrations of Kollicoat IR by a spray drying technique. The physicochemical properties of the drug alone and its microparticles were investigated using differential scanning calorimetry (DSC) and powder X-ray diffractometry (PXRD). The analyses showed that omeprazole transformed from the crystalline state to the amorphous state as confirmed by the disappearance of its melting peak and the characteristic of the crystalline peaks. Solid dispersion of the drug with this hydrophilic polymer was used in suppository formulations to investigate their role in enhancement drug release. The bases used in this study include hydrophilic base, polyethylene glycol (PEG), and lipophilic bases such as Suppocire AM and Witepsol H15. The release of omeprazole from a hydrophilic base was higher than that of a lipohilic base. Also, the release of drug from Supocire AM was superior to Witepsol H15. Incorporation of solid dispersion of drug using Kollicoat IR prepared by spray drying technique increases the release of OME from its suppository bases. The Kinetic study of the release of drug and its solid dispersion was carried out and the results indicated that the release of drug from different suppository bases is diffusion model.

An acetyl salicylic acid-caffeine complex was prepared and evaluated for the potential use in rectal administration. The results revealed the formation of a complex between acetyl salicylic acid and caffeine in a 1:1 molar ratio by a charge transfer mechanism. The effects of acetyl salicylic acid and complex on the rectal tissues showed destruction in the mucosal epithelium in case of acetyl salicylic acid; however, no change in the rectal tissues was noticed upon the administration of the complex. The effect of suppository bases on the release of the complex was studied using Witepsol H15 as fatty base and polyethylene glycols (PEG) 1000 and 4000 as a water soluble suppository base. The release profiles of acetyl salicylic acid and the complex were faster from PEG than from that of Witepsol H15. The percent release for the complex and acetyl salicylic acid from PEG base were 45.8, and 34.9%, respectively. However, it was 8.7 and 7.8%, respectively, from Witepsol H15 fatty base. The release kinetic was found to follow the non-Fickian diffusion model for complex from the suppository bases. It was concluded that acetyl salicylic acid caffeine complex can be used safely for rectal administration.

An acetyl salicylic acid-caffeine complex was prepared and evaluated for the potential use in rectal administration. The results revealed the formation of a complex between acetyl salicylic acid and caffeine in a 1:1 molar ratio by a charge transfer mechanism. The effects of acetyl salicylic acid and complex on the rectal tissues showed destruction in the mucosal epithelium in case of acetyl salicylic acid; however, no change in the rectal tissues was noticed upon the administration of the complex. The effect of suppository bases on the release of the complex was studied using Witepsol H15 as fatty base and polyethylene glycols (PEG) 1000 and 4000 as a water soluble suppository base. The release profiles of acetyl salicylic acid and the complex were faster from PEG than from that of Witepsol H15. The percent release for the complex and acetyl salicylic acid from PEG base were 45.8, and 34.9%, respectively. However, it was 8.7 and 7.8%, respectively, from Witepsol H15 fatty base. The release kinetic was found to follow the non-Fickian diffusion model for complex from the suppository bases. It was concluded that acetyl salicylic acid caffeine complex can be used safely for rectal administration.

Gastrointestinal side effects may interrupt essential therapy with indomethacin, a non-steroidal anti-inflammatory drug. Formulation of this drug into sustained release multiparticulate form may reduce some of these side effects by avoiding contact of drug crystals with gastrointestinal mucosa at high concentrations, as may happen with immediate release dosage forms. Indomethacin (IM) sustained release pellets containing 5 or 10% w/w of the drug were prepared using an extrusion-spheronization technique. Different concentrations of hydrophilic polymers, polyethylene glycol 4000 (PEG 4000), hydroxypropyl methylcellulose E5 LV premium (HPMC) and polyvinyl pyrrolidone (PVP K30), were mixed at different concentrations (5,10 and 20%) with Avicel PH 101 to prepare the sustained release formulae. Moreover, a mixer torque rheometer was used to quantitatively determine the suitable moisture content in the pastes before the extrusion process. The resulting pellets were characterized for content, particle size, shape and dissolution profile. The studies on the effect of the polymers used on Avicel rheological properties revealed that the magnitude of torque for the system was decreasing as the polymer concentration increased. The in vitro release of IM from the prepared Avicel pellets was found to be dependent upon the type and concentration of the added polymer. The rank order of IM release in the presence of the investigated polymers was as follows: PEG > HPMC > PVP. Furthermore, the magnitude of IM release rate from the pellet formulations was found to be dependent on the magnitude of the peak torque of the pellet forming paste, which in turn depends on the type and concentration of the added polymer. Increasing IM loading from 5 to 10% has led to an increase in dissolution rates. At least two of the prepared pellet formulations showed dissolution profiles similar to the commercial product Bonidon 75 SR capsules. In conclusion, the formulation of IM sustained release pellets successfully controlled the drug release which might be beneficial in lowering the risk of side effects and improving patient convenience as an advantage of the pellets as a drug delivery system.

Aminoglycoside antibiotics are effective in the treatment of infections caused by aerobic Gram negative bacilli, but their widespread use is hampered by serious side effects that may be alleviated through the use of tailored delivery systems. Robust polyion complex (PIC) micelles, incorporating up to 50 weight % drug, were prepared using two aminoglycosides: paromomycinand neomycin, and a dihydrophilic block copolymer consisting of a poly(ethyleneglycol) (PEG) chain linked to a carboxymethyldextran fragment (CMD) lightly grafted with n-dodecyl groups. The micelles were stable under physiological conditions (pH 7.4, 150 mM NaCl), in contrast to micelles formed by the unmodified CMD-PEG and the aminoglycosides or their guanidinylated derivatives. The aminoglycosides were released from the n-dodecyl-CMD-PEG micelles in a pharmacologically active form as indicated by their ability to kill test micro-organisms in culture. This study opens up new opportunities in the biomedical applications of PIC micelles with inherently enhanced stability.