Steven H. Neau

The use of spray-drying to enhance celecoxib solubility

The present research investigates the enhancement of the dissolution rate of celecoxib by using spray-drying to prepare a solid dispersion with various polymers, namely Kollicoat IR® (Kollicoat), polyvinyl alcohol (PVA) 22000, or polyethylene glycol 6000 (PEG). The investigated drug-to-polymer mass ratios were 1:1, 1:2, and 1:4 by weight. Hydroalcoholic or methylene chloride solvent systems were used. The obtained yields ranged from 65% to 78%, whereas the entrapment efficiencies were between 68% and 82%. The results revealed an increase in the dissolution rate of the prepared particles up to 200% within 20u2009min. The prepared particles were investigated using differential scanning calorimetry, scanning electron microscopy, X-ray diffraction, and Fourier transform infrared spectroscopy. The increased dissolution rate was attributed to hydrogen bond formation between celecoxib and each polymer together with the reduced size of the formed particles offering a greater overall surface area. It was concluded that spray-drying may be considered a successful one-step technique to improve the dissolution rate of celecoxib when using Kollicoat, PVA, or PEG as the carrier polymer.

Guar Gum, Xanthan Gum, and HPMC Can Define Release Mechanisms and Sustain Release of Propranolol Hydrochloride

The objectives were to characterize propranolol hydrochloride-loaded matrix tablets using guar gum, xanthan gum, and hydroxypropylmethylcellulose (HPMC) as rate-retarding polymers. Tablets were prepared by wet granulation using these polymers alone and in combination, and physical properties of the granules and tablets were studied. Drug release was evaluated in simulated gastric and intestinal media. Rugged tablets with appropriate physical properties were obtained. Empirical and semi-empirical models were fit to release data to elucidate release mechanisms. Guar gum alone was unable to control drug release until a 1:3 drug/gum ratio, where the release pattern matched a Higuchi profile. Matrix tablets incorporating HPMC provided near zero-order release over 12xa0h and erosion was a contributing mechanism. Combinations of HPMC with guar or xanthan gum resulted in a Higuchi release profile, revealing the dominance of the high viscosity gel formed by HPMC. As the single rate-retarding polymer, xanthan gum retarded release over 24xa0h and the Higuchi model best fit the data. When mixed with guar gum, at 10% or 20% xanthan levels, xanthan gum was unable to control release. However, tablets containing 30% guar gum and 30% xanthan gum behaved as if xanthan gum was the sole rate-retarding gum and drug was released by Fickian diffusion. Release profiles from certain tablets match 12-h literature profiles and the 24-h profile of Inderal® LA. The results confirm that guar gum, xanthan gum, and HPMC can be used for the successful preparation of sustained release oral propranolol hydrochoride tablets.

Use of coarse ethylcellulose and PEO in beads produced by extrusion-spheronization.

This study evaluated the potential of coarse ethylcellulose (CPEC) and high molecular weight polyethylene oxide (PEO) as excipients in the production of beads by extrusion-spheronization. CPEC was investigated as a diluent and PEO as an extrusion aid and a binder. Beads were manufactured with caffeine as a model drug. Release studies were conducted, and the bead size, shape, yield, and friability were determined. The effects of formulation and process variables and their interactions were studied by a sequential experimental design based on a response surface method. In the initial stage, a two level half fractional factorial design was employed as a screening design, which was subsequently augmented to a central composite design. Statistical analysis indicated that formulation variables including PEO content, microcrystalline cellulose (MCC) content, and water content, and two process variables, namely spheronizer speed and spheronization time, significantly affected the properties of the beads. Interactions between two factors have significant effects on several of the measured responses. Simultaneous optimization of the responses was conducted and validated by performing experiments at the optimal conditions. Overall, the results confirmed that immediate release, spherical beads with low friability and narrow size distribution could be produced with minimal amounts of MCC.

Biochemically altered human erythrocytes as a carrier for targeted delivery of primaquine: an In Vitro study

The aim of this study was to investigate human erythrocytes as a carrier for targeted drug delivery of primaquine (PQ). The process of PQ loading in human erythrocytes, as well as the effect of PQ loading on the oxidative status of erythrocytes, was also studied. At PQ concentrations of 2, 4, 6, and 8 mg/mL and an incubation time of 2 h, the ratios of the concentrations of PQ entrapped in erythrocytes to that in the incubation medium were 0.515, 0.688, 0.697 and 0.788, respectively. The maximal decline of erythrocyte reduced glutathione content was observed at 8 mg/mL of PQ compared with native erythrocytes p < 0.001. In contrast, malondialdehyde and protein carbonyl were significantly increased in cells loaded with PQ (p < 0.001). Furthermore, osmotic fragility of PQ carrier erythrocytes was increased in comparison with unloaded cells. Electron microscopy revealed spherocyte formation with PQ carrier erythrocytes. PQ-loaded cells showed sustained drug release over a 48 h period. Erythrocytes were loaded with PQ successfully, but there were some biochemical as well as physiological changes that resulted from the effect of PQ on the oxidative status of drug-loaded erythrocytes. These changes may result in favorable targeting of PQ-loaded cells to reticulo-endothelial organs. The relative impact of these changes remains to be explored in ongoing animal studies.

Rheological and mucoadhesive characterization of poly(vinylpyrrolidone) hydrogels designed for nasal mucosal drug delivery

Poly(vinylpyrrolidone) (PVP) hydrogels were crosslinked by gamma irradiation to add structure and rigidity, and then rheological and mucoadhesive properties were evaluated. The effects of PVP concentration, radiation dose, and additives, such as poly(ethylene glycol) (PEG) and glycerol, on rheological properties were investigated. In an oscillatory analysis, an increase in polymer concentrations increased the storage modulus (G′) and the loss modulus (G″) but decreased the loss tangent (tan δ < 1). The relationships between G′or G″ and the frequency levelled off at higher frequencies, which is indicative of polymer chain entanglement and network formation. Each of the 6% PVP hydrogels exhibited plastic flow with rheopectic behavior. PVP concentration, radiation dose, and the presence of PEG or glycerol influenced the rheological and mucoadhesive properties of the hydrogels. However, adding acyclovir to the formulation did not have a profound effect on the rheological behavior of the hydrogels. The results suggest that a 3% PVP hydrogel with 1% PEG crosslinked with 20 kGy is the most appropriate hydrogel. The results demonstrated the successful complementary application of oscillatory and flow rheometry to characterize and develop a hydrogel for mucosal drug administration.

Chitosan as a pore former in coated beads for colon specific drug delivery of 5-ASA

A multiparticulate product for colon-specific delivery of a small molecule drug has been developed and characterized. Microcrystalline cellulose core beads containing 5-aminosalicylic acid produced by extrusion-spheronization were coated with chitosan and Aquacoat(®) ECD mixtures according to a factorial design. Coated beads were characterized in terms of drug release, shape, and friability. The optimum formulation was enteric coated and exposed to media simulating conditions in the stomach, small intestine, and colon. Release studies in simulated intestinal fluid revealed that the drug release rate from the coated beads, which were spherical and rugged, depended on the level of chitosan in the coat and the coat thickness. Enlarged pores observed on the surface of the coated beads exposed to the medium containing rat cecal and colonic enzymes are believed to have caused a significant enhancement of the drug release rate compared to the control exposed only to simulated gastric and intestinal fluids. The release mechanisms involved polymer relaxation and dissolved drug diffusion for simulated intestinal fluid and simulated colonic fluid, respectively. From the facilitated drug release in a colonic environment and the inhibition of drug release under gastric and intestinal conditions, it can be concluded that this multiparticulate system demonstrates the potential for colon-specific drug delivery.

Colon-specific drug delivery using ethylcellulose and chitosan in the coat of compression-coated tablets

Background: This study investigates a new means to achieve colon-specific drug delivery. Objective: This study assesses the use of chitosan and ethylcellulose in the coat of a compression-coated tablet to achieve colon-specific drug delivery. The effects of chitosan type and its level as well as the coat thickness were evaluated. Materials and methods: Caffeine-containing core tablets were prepared by direct compression. Three chitosan samples with different molecular weight and degree of deacetylation were used. Direct compression produced the finished coated tablet. The product was tested for its potential in colon-specific drug delivery by conducting release studies in simulated gastric and intestinal fluids. Enzymes harvested from rat cecal and colonic contents contributed to a medium to study drug release under colonic conditions. Results: Essentially no drug was released until action on the tablet by either the acidic pH or the presence of enzymes in the release medium. Chitosan type had no effect on drug release as long as the coating level was the same. Lowering the chitosan level in the coat or increasing the coat thickness increased the lag time. Discussion: The type of chitosan can be changed and yet the product is still susceptible to enzyme or pH effects. This indicates that chitosan present in the coat is still available for such action by the release medium. One can control the chitosan level or the thickness of the coat to achieve a desired delivery profile. Conclusion: As colonic media can dramatically promote drug release, the potential for colon-specific drug delivery is confirmed.

Pellet characteristics and drug release when the form of propranolol is fixed as moles or mass in formulations for extruded and spheronized Carbopol-containing pellets

Characteristics of Carbopol-containing pellets have been shown to be dependent on the form of the weakly basic drug, propranolol, when the drug forms are fixed as masses in the formulations. To further investigate the effect of the drug forms on pellet and drug release characteristics, the drug forms were incorporated as a fixed number of moles in the formulation. Forms of propranolol, viz. the free base and the hydrochloride and maleate salt forms, resulted in different yield, roundness, smoothness, and friability, but the average pellet diameter was not affected. The free base form was released more slowly than the other two forms. Mathematical analysis of the release data revealed that Fickian diffusion and polymer relaxation contributed to the release mechanism in each case, although polymer relaxation was more influential with the free base form.

Propranolol forms affect properties of Carbopol-containing extruded-spheronized beads.

Drug release rates from extruded-spheronized beads containing Carbopol have been shown to be dependent on the chemical nature of different types of drugs. To further clarify solubility, salt counterion, pH, and ionic strength effects on Carbopol bead characteristics, including but not limited to the drug release profile, the present study utilizes propranolol in its free base, hydrochloride, and maleate forms. Different forms of propranolol resulted in different bead average diameter, roundness, and smoothness, but the ruggedness was not affected. Release profiles for the two salt forms were nearly superimposable, but the free base form was released more slowly. Mathematical analysis of the release data revealed that Fickian diffusion and polymer relaxation were contributing factors to the release mechanism in each case, although polymer relaxation was more influential with the free base form. In light of these results, the choice of the form of a drug should be considered carefully when preparing Carbopol-containing beads produced by extrusion-spheronization.

Use of the Flory–Huggins theory to predict the solubility of nifedipine and sulfamethoxazole in the triblock, graft copolymer Soluplus

Abstract Context: Drug dispersed in a polymer can improve bioavailability; dispersed amorphous drug undergoes recrystallization. Solid solutions eliminate amorphous regions, but require a measure of the solubility. Objective: Use the Flory–Huggins Theory to predict crystalline drugs solubility in the triblock, graft copolymer Soluplus® to provide a solid solution. Materials and methods: Physical mixtures of the two drugs with similar melting points but different glass forming ability, sulfamethoxazole and nifedipine, were prepared with Soluplus® using a quick technique. Drug melting point depression (MPD) was measured using differential scanning calorimetry. The Flory–Huggins Theory allowed: (1) interaction parameter, χ, calculation using MPD data to provide a measure of drug–polymer interaction strength and (2) estimation of the free energy of mixing. A phase diagram was constructed with the MPD data and glass transition temperature (Tg) curves. Results: The interaction parameters with Soluplus® and the free energy of mixing were estimated. Drug solubility was calculated by the intersection of solubility equations and that of MPD and Tg curves in the phase diagram. Discussion: Negative interaction parameters indicated strong drug–polymer interactions. The phase diagram and solubility equations provided comparable solubility estimates for each drug in Soluplus®. Results using the onset of melting rather than the end of melting support the use of the onset of melting. Conclusion: The Flory–Huggins Theory indicates that Soluplus® interacts effectively with each drug, making solid solution formation feasible. The predicted solubility of the drugs in Soluplus® compared favorably across the methods and supports the use of the onset of melting.