Taste Masking by Spray-Drying Technique

The purpose of this research was to develop the taste-masked microspheres of intensely bitter drug ondansetron hydrochloride (OSH) by spray-drying technique. The bitter taste threshold value of OSH was determined. Three different polymers viz. Chitosan, Methocel E15 LV, and Eudragit E100 were used for microsphere formation, and the effect of different polymers and drug–polymer ratios on the taste masking and release properties of microspheres was investigated. The microspheres were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, Drug loading, in vitro bitter taste evaluation, and drug-release properties. The taste masking was absent in methocel microspheres at all the drug–polymer ratios. The Eudragit microspheres depicted taste masking at 1:2 drug–polymer ratio whereas with Chitosan microspheres the taste masking was achieved at 1:1 drug–polymer ratio. The drug release was about 96.85% for eudragit microspheres and 40.07% for Chitosan microspheres in 15 min.     

General analysis of competitive binding in drug–interceptor–DNA systems

A general model of competitive binding in drug–interceptor–DNA systems has been developed in order to quantify both the interceptor and protector mechanisms. The model involves full parameterization of the basic equations governing the mutual competition between drugs binding to DNA and incorporates as partial cases various similar models existing in the literature. The generality of the model results from strict accounting of the statistical effects of the binding of the drug and interceptor with DNA according to the McGhee-von Hippel formalism, and to the strict treatment of hetero-association between the drug and interceptor, which includes formation of all possible types of self- and hetero-complexes in solution. Indirect experimental evidence is provided for the importance of the protector mechanism in drug–caffeine–DNA systems, which is sometimes ignored in the literature because of the small magnitude of the CAF-DNA binding constant.     

Isavuconazole: A Comprehensive Review of Spectrum of Activity of a New Triazole

Isavuconazole is a new triazole currently undergoing phase III clinical trials. This compound has shown in vitro activity against a large number of clinically important yeasts and moulds including Aspergillus spp., Fusarium spp., Scedosporium spp., Candida spp., the Zygomycetes and Cryptococcus spp. Similar to voriconazole, reduced in vitro activity is seen against Histoplasma capsulatum. In vivo efficacy has been demonstrated in murine models of invasive aspergillosis and candidiasis. Additionally, there are several potential pharmacokinetic and drug–drug interaction advantages of this compound over existing antifungal agents. This review summarizes existing data that has been either published or presented at international symposia.     

Preparation and Evaluation of Taste Masked Famotidine Formulation Using Drug/β-cyclodextrin/Polymer Ternary Complexation Approach

The main aim of the present study was to evaluate potential of ternary complexation (comprising of drug, cyclodextrin and polymer) as an approach for taste masking. For this purpose famotidine with property of bitter taste was selected as a model drug. Improvement in taste masking capability of cyclodextrin towards famotidine was evaluated by formulating a ternary complex including hydrophilic polymer hydroxyl propyl methyl cellulose (HPMC 5 cps) as the third component. Phase solubility analysis at 25 °C was carried out for both the binary systems (viz. drug–cyclodextrin and drug–polymer) and the ternary system (drug–cyclodextrin–polymer). Ternary complex was prepared using solution method and was further characterized using XRD, DSC, FT-IR and microscopic studies. In vitro dissolution study was carried out to see the effect of ternary complexation on drug release. Taste perception study was carried out on human volunteers to evaluate the taste masking ability of ternary complexation. Results obtained from phase solubility analysis showed that the combined use of polymer and cyclodextrin effectively increased the stability constant of the complex [from 538 M⁻¹ for binary system to 15,096 M⁻¹ for ternary system]. Ternary system showed effective taste masking as compared to binary complex and at the same time showed no limiting effect on the drug release (D.E_15min = 90%). The effective taste masking was attributed to the enhanced complexation of famotidine in ternary system compared to binary system and the same was confirmed from the characterization studies. In conclusion, the study confirmed that ternary complexation can be utilized as an alternative approach for effective taste masking.     

Current Approaches in Antifungal Prophylaxis in High Risk Hematologic Malignancy and Hematopoietic Stem Cell Transplant Patients

Invasive fungal infections (IFIs) pose the most serious infectious risk to patients with hematologic malignancies and in those undergoing hematopoietic stem cell transplantation (HSCT). Invasive candidiasis has an incidence of 8–18% and a mortality of 30–40% in various reports. Invasive aspergillosis has an incidence of 4–15% and an even higher mortality of 60–85% cited in the published literature. IFIs have remained difficult to diagnose in a timely way in neutropenic and immunocompromised patients. A timely diagnosis is essential in promptly initiating antifungal therapy in order to optimize clinical outcomes. Thus, antifungal prophylaxis has an enormous appeal to minimize the threat from IFIs. In this article, the epidemiology and risk factors for IFIs as well as evidence from antifungal prophylaxis clinical trials in certain patient groups with hematologic malignancies are reviewed. Antifungal prophylaxis has been shown to be effective in certain settings. However, concerns about shifts in fungal epidemiology, emergence of resistance, drug toxicities, and drug interactions must be considered in deciding how and in whom to use antifungal prophylaxis.     

Advanced Technologies for Oral Controlled Release: Cyclodextrins for Oral Controlled Release

Cyclodextrins (CDs) are used in oral pharmaceutical formulations, by means of inclusion complexes formation, with the following advantages for the drugs: (1) solubility, dissolution rate, stability, and bioavailability enhancement; (2) to modify the drug release site and/or time profile; and (3) to reduce or prevent gastrointestinal side effects and unpleasant smell or taste, to prevent drug–drug or drug–additive interactions, or even to convert oil and liquid drugs into microcrystalline or amorphous powders. A more recent trend focuses on the use of CDs as nanocarriers, a strategy that aims to design versatile delivery systems that can encapsulate drugs with better physicochemical properties for oral delivery. Thus, the aim of this work was to review the applications of the CDs and their hydrophilic derivatives on the solubility enhancement of poorly water-soluble drugs in order to increase their dissolution rate and get immediate release, as well as their ability to control (to prolong or to delay) the release of drugs from solid dosage forms, either as complexes with the hydrophilic (e.g., as osmotic pumps) and/or hydrophobic CDs. New controlled delivery systems based on nanotechnology carriers (nanoparticles and conjugates) have also been reviewed.     

Dissolution and Solid-State Characterization of Poorly Water-Soluble Drugs in the Presence of a Hydrophilic Carrier

The aim of this study was to investigate the effects of a hydrophilic carrier on the solid-state and dissolution characteristics of poorly water-soluble drugs. Three poorly water-soluble drugs, ibuprofen, carbamazepine, and nifedipine, were studied in combination with hydroxypropyl cellulose (HPC), a low molecular weight hydrophilic polymer, without the use of solvent. A 1:1 drug–polymer ratio was used to evaluate the percent drug release, crystallinity, and wettability. A drug–polymer ratio of 1:4 was also used in co-grinding process to evaluate the effect of polymer levels on drug release. Dissolution studies were carried out in deionized water. Mean dissolution time (MDT) was calculated, and statistical analysis of MDTs was done following a single factor one-way analysis of variance. The dissolution rate of the drugs was enhanced by several folds by the simple process of co-grinding with HPC. X-ray diffraction studies were done to investigate the effects of physical and co-ground mix with HPC on the crystallinity of the drugs, which indicated a partial loss in crystallinity upon grinding. Differential scanning calorimetry studies were performed in order to identify possible solid-state interactions between the respective drugs and HPC. Wettability of the drugs by a 0.5% aqueous HPC solution was compared with that of water and n-hexane using the “Washburn method.” Increased wetting and hydrophilization of the drugs by HPC, enlarged surface area due to particle size reduction, and a decrease in the degree of crystallinity were identified as the likely contributors to dissolution rate enhancement.     

Optimization Studies on Gastroretentive Floating System Using Response Surface Methodology

The aim of the present investigation was to develop and optimize gastroretentive floating system of amoxicillin for the efficient treatment of peptic ulcer induced by Helicobacter pylori infection. Floating microballoons were developed using central composite design (CCD), and optimization was done by employing response surface methodology. The selected independent variables were cellulose acetate phthalate, drug–Eudragit S100 ratio, and the ratio of dichloromethane/ethanol/isopropyl alcohol. The selected dependent variables were yield, mean particle size, buoyancy, encapsulation efficiency, and drug release within 8 h. A quadratic polynomial model was generated which had linear, interaction, and quadratic terms to predict and evaluate the independent variables with respect to the dependent variables. Results showed that selected independent variables significantly affect the yield (30.53–82.71%), particle size (31.62–47.03 μm), buoyancy (42.68–95.75%), encapsulation efficiency (56.96–93.13%), and cumulative drug release from the microballoons (34.01–74.65%). The interaction and quadratic terms were also found to affect the process variables. An excellent agreement was found between the actual value and predicted value. In conclusion, it can be said that CCD is a valuable second-degree design to develop and optimize GFS of amoxicillin which in turn provides a basis to localize the drug release in the gastric region for effective treatment of H. pylori-mediated infection.     

Efficacy of voriconazole in experimental Cryptococcus neoformans infection

Voriconazole is a third generation triazole with improved activity against many fungal pathogens. We examined the efficacy of voriconazole in a murine infection model and evaluated the drug’s effect on cellular characteristics and serum polysaccharide levels. The antifungal reduced serum polysaccharide and significantly prolonged the survival of lethally infected animals.     

Evaluation of Ionotropic Cross-Linked Chitosan/Gelatin B Microspheres of Tramadol Hydrochloride

Microspheres of tramadol hydrochloride (TM) for oral delivery were prepared by complex coacervation method without the use of chemical cross-linking agents such as glutaraldehyde to avoid the toxic reactions and other undesirable effects of the chemical cross-linking agents. Alternatively, ionotropic gelation was employed by using sodium-tripolyphosphate as cross-linking agent. Chitosan and gelatin B were used as polymer and copolymer, respectively. All the prepared microspheres were subjected to various physicochemical studies, such as drug–polymer compatibility by thin layer chromatography (TLC) and Fourier transform infrared (FTIR) spectroscopy, surface morphology by scanning electron microscopy, frequency distribution, drug entrapment efficiency, in vitro drug release characteristics and release kinetics. The physical state of drug in the microspheres was determined by differential scanning calorimetry (DSC) and X-ray diffractometry (XRD). TLC and FTIR studies indicated no drug–polymer incompatibility. All the microspheres showed initial burst release followed by a fickian diffusion mechanism. DSC and XRD analysis indicated that the TM trapped in the microspheres existed in an amorphous or disordered-crystalline status in the polymer matrix. From the preliminary trials, it was observed that it may be possible to formulate TM microspheres by using biodegradable natural polymers such as chitosan and gelatin B to overcome the drawbacks of TM and to increase the patient compliance.     

Antifungal Therapy for Invasive Fungal Diseases in Allogeneic Stem Cell Transplant Recipients: An Update

Invasive fungal diseases (IFDs) remain a major cause of morbidity and mortality in allogeneic stem cell transplant (SCT) recipients. While the most common pathogens are Candida spp. and Aspergillus spp., the incidence of infections caused by non-albicans Candida species as well as molds such as Zygomycetes has increased. For many years, amphotericin B deoxycholate (AMB-D) was the only available antifungal for the treatment of IFDs. Within the past decade, there has been a surge of new antifungal agents developed and added to the therapeutic armamentarium. Lipid-based formulations of amphotericin B provide an effective and less nephrotoxic alternative to AMB-D. Voriconazole has now replaced AMB-D as first choice for primary therapy of invasive aspergillosis (IA). Another extended-spectrum triazole, posaconazole, also appears to be a promising agent in the management of zygomycosis, refractory aspergillosis, and for prophylaxis. Members of the newest antifungal class, the echinocandins, are attractive agents in select infections due to their safety profile, and are a more attractive option compared to AMB-D as initial treatment for invasive candidiasis and (based on one study) challenge fluconazole for superiority in management with this mycoses. However, challenges do exist among these newer agents in very high-risk individuals like allogeneic SCT recipients, which may include adverse drug events, drug–drug interactions, variability in oral absorption, and availability of alternative formulations. The addition of newer agents has also stimulated interest in the potential application of combination therapy in serious, life-threatening infections. However, adequate studies are not available for most IFDs; thus, the clinical use of combination therapy is not evidenced based on most cases and preciseness in its use is uncertain. Finally, therapeutic drug monitoring of select antifungals (notably posaconazole and voriconazole) may play an increasing role due to significant interpatient variability in serum concentrations after standard doses.     

Oxycellulose Beads with Drug Exhibiting pH-Dependent Solubility

The aim of this study was to develop novel hydrogel-based beads and characterize their potential to deliver and release a drug exhibiting pH-dependent solubility into distal parts of gastrointestinal (GI) tract. Oxycellulose beads containing diclofenac sodium as a model drug were prepared by the ionotropic external gelation technique using calcium chloride solution as the cross-linking medium. Resulting beads were characterized in terms of particle shape and size, encapsulation efficacy, swelling ability and in vitro drug release. Also, potential drug–polymer interactions were evaluated using Fourier transform infrared spectroscopy. The particle size was found to be 0.92–0.96 mm for inactive (oxycellulose only) and 1.47–1.60 mm for active (oxycellulose–diclofenac sodium) beads, respectively. In all cases, the sphericity factor was between 0.70 and 0.81 with higher values observed for samples containing higher polymer and drug concentrations. The swelling of inactive beads was found to be strongly influenced by the pH and composition (i.e. Na⁺ concentration) of the selected media (simulated gastric fluid vs. phosphate buffer pH 6.8). The encapsulation efficiency of the prepared particles ranged from 58% to 65%. Results of dissolution tests showed that the drug loading inside of the particles influenced the rate of its release. In general, prepared particles were able to release the drug within 12–16 h after a lag time of 4 h. Fickian diffusion was found as the predominant drug release mechanism. Thus, this novel particulate system showed a good potential to deliver drugs specifically to the distal parts of the human GI tract.     

Atomic force microscopy study of DNA conformation in the presence of drugs

Binding of ligands to DNA gives rise to several relevant biological and biomedical effects. Here, through the use of atomic force microscopy (AFM), we studied the consequences of drug binding on the morphology of single DNA molecules. In particular, we quantitatively analyzed the effects of three different DNA-binding molecules (doxorubicin, ethidium bromide, and netropsin) that exert various pharmacologic and therapeutic effects. The results of this study show the consequences of intercalation and groove molecular binding on DNA conformation. These single-molecule measurements demonstrate morphological features that reflect the specific modes of drug–DNA interaction. This experimental approach may have implications in the design of therapeutically effective agents.     

Development and Evaluation of Ethyl Cellulose-Based Transdermal Films of Furosemide for Improved In Vitro Skin Permeation

Transdermal films of the furosemide were developed employing ethyl cellulose and hydroxypropyl methylcellulose as film formers. The effect of binary mixture of polymers and penetration enhancers on physicochemical parameters including thickness, moisture content, moisture uptake, drug content, drug–polymer interaction, and in vitro permeation was evaluated. In vitro permeation study was conducted using human cadaver skin as penetration barrier in modified Keshary–Chein diffusion cell. In vitro skin permeation study showed that binary mixture, ethyl cellulose (EC)/hydroxypropyl methylcellulose (HPMC), at 8.5:1.5 ratio provided highest flux and also penetration enhancers further enhanced the permeation of drug, while propylene glycol showing higher enhancing effect compared to dimethyl sulfoxide and isopropyl myristate. Different kinetic models, used to interpret the release kinetics and mechanism, indicated that release from all formulations followed apparent zero-order kinetics and non-Fickian diffusion transport except formulation without HPMC which followed Fickian diffusion transport. Stability studies conducted as per International Conference on Harmonization guidelines did not show any degradation of drug. Based on the above observations, it can be reasonably concluded that blend of EC–HPMC polymers and propylene glycol are better suited for the development of transdermal delivery system of furosemide.     

Reactive Impurities in Excipients: Profiling,Identification and Mitigation of Drug–Excipient Incompatibility

Reactive impurities in pharmaceutical excipients could cause drug product instability, leading to decreased product performance, loss in potency, and/or formation of potentially toxic degradants. The levels of reactive impurities in excipients may vary between lots and vendors. Screening of excipients for these impurities and a thorough understanding of their potential interaction with drug candidates during early formulation development ensure robust drug product development. In this review paper, excipient impurities are categorized into six major classes, including reducing sugars, aldehydes, peroxides, metals, nitrate/nitrite, and organic acids. The sources of generation, the analytical method for detection, the stability of impurities upon storage and processing, and the potential reactions with drug candidates of these impurities are reviewed. Specific examples of drug–excipient impurity interaction from internal research and literature are provided. Mitigation strategies and corrective measures are also discussed.     

Adsorption of meloxicam on porous calcium silicate: Characterization and tablet formulation

The purpose of the present study was characterization of microparticles obtained by adsorption of poorly water soluble drug, meloxicam, on a porous silicate carrier Florite RE (FLR) and development of a tablet formulation using these microparticles, with improved drug dissolution properties. The study also reveals the use of FLR as a pharmaceutical excipient. Meloxicam was adsorbed on the FLR in 2 proportions (1∶1 and 1∶3), by fast evaporation of solvent from drug solution containing dispersed FLR. Drug adsorbed FLR microparticles were evaluated for surface topography, thermal analysis, X-ray diffraction properties, infrared spectrum, residual solvent, micromeritic properties, drug content, solubility, and dissolution studies. Microparticles showed bulk density in the range of 0.10 to 0.12 g/cm³. Dissolution of drug from microparticles containing 1∶3, drug∶FLR ratio was faster than microparticles containing 1∶1, drug∶FLR ratio. These microparticles were used for formulating directly compressible tablets. Prepared tablets were compared with a commercial tablet. All the prepared tablets showed acceptable mechanical properties. Disintegration time of prepared tablets was in the range of 18 to 38 seconds, and drug dissolution was much faster in both acidic and basic medium from prepared tablets as compared with commercial tablet. The results suggest that FLR provides a large surface area for drug adsorption and also that a reduction in crystallinity of drug occurs. Increase in surface area and reduction in drug crystallinity result in improved drug dissolution from microparticles. Published: December 7, 2005     

In vitro antifungal activity of allicin alone and in combination with two medications against <Emphasis Type="Italic">Trichophyton rubrum</Emphasis>

Dermatophytes are a group of fungi able to invade keratinized tissues of humans and animals, causing dermatomycosis. Azole antifungal drugs are commonly used in the treatment of dermatomycosis. However, this group of chemicals is known to cause side effects in patients and due to increased use of these medications, azoles are known to cause drug resistance. Having said this, the purpose of the present study was to investigate an alternative anti dermatophyte which is plant based. In this study, allicin, which is a pure bioactive compound isolated from garlic, was tested for its potential as a treatment of dermatomycosis. The study evaluated the in vitro efficacy of pure allicin used alone against ten isolates of Trichophyton rubrum and it was found that the MIC₅₀ and MIC₉₀ ranged from 0.78–25.0 μg/ml, whereas the MIC values for ketoconazole and fluconazole ranged from 0.25–8.0 and 1.0–32.0 μg/ml, respectively, at 28°C for both 7 and 10 days incubation. On the other hand, time–kill studies revealed that the antifungicidal effect of allicin became active within 12–24 h of management in vitro and that it was as good as that of ketoconazole. Finally, most of the tested drug combinations demonstrated synergistic or additive interactions for all isolates for both 7 and 10 days incubation at 28°C. In conclusion, when used alone, allicin showed very good potential as an antifungal compound against mycoses-causing dermatophytes, performing better than the synthetic drug fluconazole and almost as good as ketoconazole. Furthermore, allicin in combination with ketoconazole or with fluconazole frequently showed synergistic or additive interactions against dermatomycosis.     

Antifungal Therapy in Pregnancy and Breastfeeding

Antifungal therapy during pregnancy and lactation is challenging because of a lack of data on efficacy and safety, coupled with reports of teratogenicity. Although the Food and Drug Administration pregnancy category provides guidance regarding a drug’s potential fetal risks, limitations such as lack of a specific toxic dose or predisposing pregnancy trimester thwart its application. Central to the selection of optimal antifungal therapy are exploration of the literature and assessment of patient-specific factors, including awareness of effects on the pharmacokinetics of antifungal agents that result from physiologic changes during pregnancy. Topical azoles are favored for superficial fungal infections during pregnancy and lactation, whereas amphotericin B is preferred for invasive fungal infections. Data regarding the use of antifungal agents by breastfeeding women are lacking. More studies are needed, particularly with newer antifungals, to better guide clinicians in selecting optimal antifungal therapy that will provide benefit to the mother without harm to the fetus.     

5-Fluorouracil-Loaded BSA Nanoparticles: Formulation Optimization and In Vitro Release Study

Over the past few decades, there has been considerable interest in developing protein nanoparticles as drug delivery devices. The underlying rationale is their exceptional characteristics, namely biodegradability and nonantigenicity. Herein, phase separation method was used to prepare 5-fluorouracil-loaded bovine serum albumin (BSA) nanoparticles. Drug release was tracked by continuous flow dialysis technique. Effect of process variables on loading efficiency of 5-fluorouracil was investigated and optimized through Taguchi’s M16 design with the amount of entrapped drug as response. Optimum condition was found to be 2 mg/mL of 5-fluorouracil, 3.7 mL of added ethanol, 176 μL of glutaraldehyde, drug–protein incubation time of 30 min, and pH of 8.4 for 200 mg of BSA in 2 mL drug solution. pH had the most noticeable effect on the amount of entrapped drug, but glutaraldehyde had the least. Mean diameter and zeta potential of fabricated nanoparticles under these conditions were 210 nm and −31.7 mV, respectively. Drug-loaded BSA nanoparticles suspension maintained constant release of drug for 20 h under experimental conditions, so this colloidal drug carrier is capable of releasing drug in a sustained manner.