A Quality by Experimental Design Approach to Assess the Effect of Formulation and Process Variables on the Extrusion and Spheronization of Drug-Loaded Pellets Containing Polyplasdone® XL-10.

Successful pellet production has been reported in literature with cross-linked poly(vinylpyrrolidone), Polyplasdone® XL-10 and INF-10. In the present study, a quality by experimental design approach was used to assess several formulation and process parameter effects on the characteristics of Polyplasdone® XL-10 pellets, including pellet size, shape, yield, usable yield, friability, and number of fines. The hypothesis is that design of experiments and appropriate data analysis allow optimization of the Polyplasdone product. High drug loading was achieved using caffeine, a moderately soluble drug to allow in vitro release studies. A five-factor, two-level, half-fractional factorial design (Resolution V) with center point batches allowed mathematical modeling of the influence of the factors and their two-factor interactions on five of the responses. The five factors were Polyplasdone® level in the powder blend, volume of water in the wet massing step, wet mixing time, spheronizer speed, and spheronization time. Each factor and/or its two-factor interaction with another factor influenced pellet characteristics. The behavior of these materials under various processing conditions and component levels during extrusion-spheronization have been assessed, discussed, and explained based on the results. Numerical optimization with a desirability of 0.974 was possible because curvature and lack of fit were not significant with any of the model equations. The values predicted by the optimization described well the observed responses. The hypothesis was thus supported.

Use of fine particle ethylcellulose as the diluent in the production of pellets by extrusion-spheronization.

The effect of small ethylcellulose particle size on the manufacture and properties of pellets produced by extrusion-spheronization was investigated. A factorial design revealed the effects of microcrystalline cellulose (MCC), polyethylene oxide (PEO), water, and spheronization speed and time on pellet properties. Response surface modeling allowed optimization of the responses with expansion to a central composite design. Pellet yield, size, shape, friability and drug release profile were studied, along with surface and interior morphology. Pellets were spherical irrespective of the formulation and process variables and exhibited physical and mechanical characteristics appropriate for further processing. Yield in the 12/20 mesh cut was lower with FPEC than observed with coarse particle ethylcellulose (CPEC), but FPEC-containing pellets were more rugged and the PEO to obtain optimal pellets was lower for FPEC compared to CPEC. Immediate release products were obtained and ethylcellulose particle size was of no consequence to drug release. Observed responses for the optimized product agreed with predicted values, demonstrating the success of the optimization procedure. These results suggest that FPEC is a good diluent for extrusion-spheronization.

Crospovidone interactions with water. II. Dynamic vapor sorption analysis of the effect of Polyplasdone particle size on its uptake and distribution of water.

Polyplasdone of different particle size was used to study the sorption, desorption, and distribution of water, and to seek evidence that larger particles can internalize water. The three samples were Polyplasdone® XL, XL-10, and INF-10. Moisture sorption and desorption isotherms at 25 °C at 5% intervals from 0 to 95% relative humidity (RH) were generated by dynamic vapor sorption analysis. The three products provided similar data, judged to be Type III with a small hysteresis that appears when RH is below 65%. An absent rounded knee in the sorption curve suggests that multilayers form before the monolayer is completed. The hysteresis indicates that internally absorbed moisture is trapped as the water is desorbed and the polymer sample shrinks, thus requiring a lower level of RH to continue desorption. The fit of the Guggenheim-Anderson-de Boer (GAB) and the Young and Nelson equations was accomplished in the data analysis. The W(m), C(G), and K values from GAB analysis are similar across the three samples, revealing 0.962 water molecules per repeating unit in the monolayer. A small amount of absorbed water is identified, but this is consistent across the three particle sizes.

Crospovidone interactions with water. I. Calorimetric study of the effect of Polyplasdone particle size on its uptake and distribution of water.

The ability of crospovidone to take up and distribute water in the polymer samples was studied using differential scanning calorimetry (DSC). Polyplasdone(®) is an example of crospovidone that, although insoluble in water, serves as a superdisintegrant. Three samples of Polyplasdone(®) with different mean particle size were studied to see the effect of particle size on the water uptake and distribution characteristics. Water was shown to plasticize Polyplasdone(®) samples by a reduction in the glass transition temperature as the water content was increased. Although the particle sizes covered a wide range, there was essentially no difference in the ability to take up or distribute water. Three types of water were observed, namely water closely associated with the polymer, water built up as multilayers, and bulk water. Although the water closely associated with the polymer could not be detected by DSC, it could be calculated by mass balance and by extrapolation of the data to the x-axis in a plot of freezable water content as a function of the actual water content. A split in the melting endotherm of water that freezes supported the premise of two forms of freezable water. The number of water molecules per repeating unit could be calculated.

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.

Progress in antiretroviral drug delivery using nanotechnology.

There are currently a number of antiretroviral drugs that have been approved by the Food and Drug Administration for use in the treatment of human immunodeficiency virus (HIV). More recently, antiretrovirals are being evaluated in the clinic for prevention of HIV infection. Due to the challenging nature of treatment and prevention of this disease, the use of nanocarriers to achieve more efficient delivery of antiretroviral drugs has been studied. Various forms of nanocarriers, such as nanoparticles (polymeric, inorganic, and solid lipid), liposomes, polymeric micelles, dendrimers, cyclodextrins, and cell-based nanoformulations have been studied for delivery of drugs intended for HIV prevention or therapy. The aim of this review is to provide a summary of the application of nanocarrier systems to the delivery of anti-HIV drugs, specifically antiretrovirals. For anti-HIV drugs to be effective, adequate distribution to specific sites in the body must be achieved, and effective drug concentrations must be maintained at those sites for the required period of time. Nanocarriers provide a means to overcome cellular and anatomical barriers to drug delivery. Their application in the area of HIV prevention and therapy may lead to the development of more effective drug products for combating this pandemic disease.

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.

Nanoparticle-based vaginal drug delivery systems for HIV prevention.

IMPORTANCE OF THE FIELD: Several strategies are being investigated for the prevention of heterosexual transmission of HIV. Of these, topical vaginal drug delivery systems, microbicides, are being actively pursued. HIV prevention by means of a topical microbicide has several drug delivery challenges. These challenges include the vaginal mucosal barriers and potential degradation of the drugs in the vaginal lumen due to pH and enzymes present. Also, new drugs being evaluated as microbicides have specific mechanisms of action, which in some cases require drug targeting to a specific site of action. Nanoparticles provide a delivery strategy for targeted or controlled delivery to the vagina which can be applied in the field of HIV prevention. AREAS COVERED IN THE REVIEW: This review summarizes nanoparticulate systems and their use in mucosal delivery to date. The sexual transmission of HIV along with the various targets to prevent transmission are discussed as well as the potential opportunities, challenges and advantages in using a nanoparticle-based approach for microbicidal drug delivery. WHAT THE READER WILL GAIN: This review provides a general understanding of vaginal drug delivery, its challenges, and nanoparticulate delivery systems. Additionally, insight will be gained as to the limited existing application of this technology to the field of HIV prevention. TAKE HOME MESSAGE: To date, few studies have been published that exploit nanoparticle-based microbicidal delivery to the vagina. The use of nanoparticles for vaginal drug delivery provides an approach to overcome the existing barriers to success.

The functional role of C-reactive protein in aortic wall calcification.

As an ongoing effort to elucidate the mechanisms involved in bioprosthetic heart valve (BHV) calcification, the role of C-reactive protein (CRP) in the tissue calcification process was investigated. The profile of calcium-associated proteins (CAP) on glutaraldehyde-preserved (0.6%) porcine aortic wall, which were subcutaneously implanted in rats for up to 8 weeks, showed a temporal appearance pattern. The total extracted amount of proteins from the control tissues implanted for 8 weeks was significantly greater than that from ethanol-treated tissues (1.78+/-0.2 vs. 1.27+/-0.18 microg/mg), indicating that the binding affinity of CAP for BHV pretreated with an anticalcification agent was significantly decreased (p<0.05). The dye Stains-All method showed that the dark-blue colored bands, representing high calcium binding and phosphorylated proteins, were stained from the extract of the control BHV at the molecular weight varying from 4 to 250 kDa, but rarely seen in the extract of BHV pretreated with ethanol. One of those proteins was exclusively immunoreactive with CRP antibody, while there was no immunoreaction in less calcified tissues. When aortic wall was exposed to an excess amount of CRP in an in vitro simulating model, the calcification rate of aortic wall increased as the concentration of CRP increased. The results of this work clearly revealed that CRP has indirect vascular effects, leading to an increased rate of aortic wall calcification.