Miconazole: a review of its antifungal activity and therapeutic efficacy.

Miconazole2, a synthetic imidazole derivative, is a new topical antifungal agent for use in the local treatment of vaginal, and skin and nail infections due to yeasts and dermatophytes. It is particularly active against Candida spp., Trichophyton spp., Epidermophyton spp., Microsporum spp. and Pityrosporon orbiculare (Malassezia furfur), but also possesses some activity against Gram-positive bacteria. In vaginal candidiasis, miconazole vaginal cream has produced higher cure rates than conventional nystatin vaginal tablets or amphotericin B vaginal cream. There have been no published comparisons with nystatin vaginal cream or foaming vaginal tablets - the nystatin dosage form preferred by some clinicians. The vaginal cream has also achieved a cure where previous nystatin or natamycin therapy had failed. Miconazole has proved equally effective in both Candida and dermatophyte infections of the skin, but as yet there have been no published comparisons with other antifungal agents. However, it has been successfully used in chronic skin infections which had not responded satisfactorily to other agents such as natamycin and pecilocin. Preliminary experience with oral and intravenous miconazole therapy in systemic candidiasis is promising. Miconazole preparations are well accepted and tolerated.     

A Novel Approach to the Oral Delivery of Micro- or Nanoparticles

A novel oral multiple-unit dosage form which overcame many of the problems commonly observed during the compression of microparticles into tablets was developed in this study. Micro- or nano-particles were entrapped in beads formed by ionotropic gelation of the charged polysaccharide, chitosan or sodium alginate, in solutions of the counterion, tripolyphosphate (TPP) or calcium chloride (CaCl₂), respectively. The described technique did not change the physical properties of the microparticles, and it allowed a high microparticle loading (up to 98%). The ionic character of the polymers allowed pH-dependent release of the microparticles. Chitosan beads disintegrated and released the microparticles in 0.1 N HC1, while calcium alginate beads stayed intact in 0.1 N HC1 but rapidly disintegrated in simulated intestinal fluids. Coating the calcium alginate beads with cellulose acetate phthalate resulted in an enteric drug delivery system. Scanning electron microscopy and dissolution and disintegration tests were used to characterize the microparticle-containing beads. The disintegration time of the beads was studied as a function of the solution viscosity of the polysaccharide, gelation time, counterion concentration, and method of drying.     

Release characteristics of chitosan treated alginate beads: I. Sustained release of a macromolecular drug from chitosan treated alginate beads

Alginate and chitosan treated alginate beads were prepared and compared as an oral controlled release system for macromolecular drugs. Dextran (M.W. 70,000) was used as a model substance. The beads were prepared by the ionotropic gelation method and the effect of various factors (alginate, chitosan, drug and calcium chloride concentrations, the volume of external and internal phases and drying methods) on bead properties were investigated. The addition of chitosan increased the drug loading capacity of the beads, and larger beads were obtained in the presence of chitosan. On the other hand, addition of chitosan in the gel structure reduced the drug release from beads. The erosion of the beads was suppressed by chitosan treatment. The drying method was important to the properties of the chitosan-alginate beads. It is proposed that chitosan treated alginate beads may be used as a potential controlled release system of such macromolecules.     

In vitro evaluation of chitosan coated- and uncoated-calcium alginate beads containing methyl salicylate-lactose physical mixture

Context: Methyl salicylate–lactose physical mixture (1:1 and 1:1.5 ratios) was incorporated into calcium alginate beads by a coacervation method involving an ionotropic gelation/polyelectrolyte complexation approach.

Objectives: This study aims to determine the influence of chitosan coating over the beads on drug entrapment efficiency (DEE) and release characteristics in artificial saliva compared to that of the uncoated beads.

Results and discussion: Changes in formulation parameters (gelation time, concentrations of Ca²⁺ and alginate) resulted in decrease in DEE of chitosan-uncoated beads (p?<?0.05). This is due to the combined effects of drug leach-out from the physical mixture by Ca²⁺ ions, alginate gel matrix cross-linking and free drug diffusion from chitosan-uncoated beads. However, an increment in the DEE was seen for chitosan-coated beads. A rapid drug release profile was noted for uncoated beads, but for chitosan-coated beads a sustained release profile was depicted depending upon the coating conditions. Chitosan-coated beads had reduced swelling and erosion properties and thus behaved as a physical barrier to drug release. Shifting from anomalous transport type to Fickian transport confirmed the formation of physical barrier onto chitosan-coated beads.

Conclusion: Calcium alginate beads could be used as a controlled-release system for methyl salicylate–lactose physical mixture.     

Voriconazole: new preparation. Invasive aspergillosis: benefits to be confirmed

(1) Amphotericin B is the antifungal drug of choice for the treatment of invasive aspergillosis, severe candidiasis and Fusarium infection. Voriconazole is an antifungal azole sold in France for oral and intravenous treatment of these infections. (2) In 391 patients with established or probable invasive aspergillosis, combined analysis of two trials comparing voriconazole (intravenously then orally) with conventional amphotericin (intravenously) showed that the 12-week survival rate was significantly higher with voriconazole (70.8% versus 57.9%). Unfortunately, these results are undermined by methodological flaws such as the lack of blinding, the very different intravenous treatment periods in the two groups, and subsequent oral treatment with different antifungal drugs. Voriconazole has not been compared with liposomal amphotericin B. (3) In the treatment of severe candidiasis, and severe Scedosporium and Fusarium infections, we only have the (favourable) results of non comparative trials in small numbers of patients refractory to other antifungal drugs. (4) The main adverse effects were visual disturbances, elevated hepatic enzyme levels, acute renal failure, and sometimes serious cutaneous reactions. It lengthens the QT interval and can cause torsades de pointes. It inhibits the cytochrome P450 isoenzymes CY3A4, CYP2C9 and CYP2C19, hence a high risk of potentially serious drug interactions. (5) Voriconazole can be given by mouth or by IV infusion, whereas liposomal amphotericin B must be given intravenously. (6) In practice, another more rigorous trial is needed to confirm the favourable results obtained with voriconazole in invasive aspergillosis. Voriconazole is the first-line treatment for severe Scedosporium infections, despite limited experience. It is a last resort for severe candidiasis and severe Fusarium infection.     

Formulation and evaluation of floating drug delivery system of famotidine

A multiple unit oral floating drug delivery system of famotidine was developed to prolong gastric residence time, target stomach mucosa and increase drug bioavailability. Drug and polymer compatibility was studied by subjecting physical mixtures of drug and polymers to differential scanning calorimetry. Cod liver oil entrapped calcium alginate beads containing famotidine, capable of floating in the gastric condition were formulated and evaluated. The gel beads were prepared by emulsion gelation method by employing sodium alginate alone and mixture of sodium alginate and hydrophilic copolymers such as carbopol 934P and hydroxypropylmethylcellulose K15M grade in three different ratios. The effect of selected factors, such as percentage of oil and amount of copolymers on floating properties was investigated. The beads were evaluated for percent drug loading, drug entrapment efficiency, buoyancy and in vitro drug release. The in vitro drug release study of the beads was carried out in simulated gastric media employing a modified Rosette-Rice test apparatus. Wherein, the apparatus was further modified by incorporating a water jacket to the apparatus to circulate hot water to maintain 37±2° for throughout the release study. All the oil entrapped calcium alginate beads floated if a sufficient amount of oil was used. Beads formulated employing sodium alginate alone could not sustain the drug release up to 8 h, whereas beads formulated with mixture of sodium alginate and copolymers demonstrated sustained release of famotidine up to 8 h. The results suggested that cod liver oil entrapped calcium alginate beads were promising as a carrier for intragastric floating drug delivery of famotidine.     

Preparation and in vitro characterization of glibenclamide-loaded alginate hexyl-amide beads: a novel drug delivery system to improve the dissolution rate

Abstract

Objective: This investigation aimed to synthesize amphiphilic hexyl amidic derivative of alginate to be used in the preparation of glibenclamide-loaded release system of improved dissolution rate.

Materials and methods: Hexyl amine was associated to the activated carboxylic acid moieties of alginate to synthesize alginate hexyl amide polymer (AHAP). This polymer in comparison to alginate was used in different concentrations for preparing beads containing glibenclamide by an ionic gelation using Ca⁺⁺ as gelling ion. The prepared beads were characterized by DSC, FTIR and scanning electron microscope. The swelling behavior, drug loading capacity and release behavior were studied.

Results and discussion: The results showed that the prepared AHAP beads were smaller in size and more spherical. The surface was highly corrugated with much and wider pore size. The beads showed a high drug loading capacity and efficacy that was affected by the polymer concentration. The drug release rate from AHAP beads reached 100% after 4, 8 and 12 hours in comparison to 75.3%, 73.2% and 69.2% from alginate beads at 3%, 2% and 1% polymer concentrations, respectively.

Conclusion: It can thus be concluded that the amphiphilic AHAP-based bead is a simple and efficient delivery system of promising industrial significance for the improvement of the dissolution rate.     

Stability of amphotericin B and nystatin in antifungal mouthrinses containing sodium hydrogen carbonate

Amphotericin B and nystatin are two polyene antibiotics that are potent antifungal agents. These drugs are active against most pathogenic fungi like Aspergillus and Candida. Mouthrinses containing these drugs are used for preventive and curative treatment of fungal infections like oral candidiasis, which can cause multiple diseases in cancer patients. Because there were no marketed antifungal mouthrinses available, their preparations were performed at the hospital and town pharmacies. To date, there are no data available on the stability of both these drugs in the form of mouthrinses. Therefore, each mouthrinse had to be prepared extemporaneously. The aim of this study was to investigate the stability of amphotericin B (Fungizone) and nystatin (Mycostatine) in the form of mouthrinses containing 1.4% sodium hydrogen carbonate. The stability of these solutions was tested at different temperatures (4-37 degrees C) with or without electric- or sunlight exposure and in two types of containers (glass and polypropylene) over a 15-day period. The admixtures were also monitored for colour change and pH. Amphotericin B and nystatin were quantified by high-performance liquid chromatography. At 4 degrees C, amphotericin B and nystatin were stable for 15 days in polypropylene. When stored in polypropylene at room temperature, with or without light protection, amphotericin B and nystatin were stable for 3 and 4 days, respectively.     

Review and current status of emulsion/dispersion technology using an internal gelation process for the design of alginate particles

Emulsification/internal gelation has been suggested as an alternative to extrusion/external gelation in the encapsulation of several compounds including sensitive biologicals such as protein drugs. Protein-loaded microparticles offer an inert environment within the matrix and encapsulation is conducted at room temperature in a media free of organic solvents. Recently, the concept of internal gelation has been applied to formulating nanoparticles as drug delivery systems. Emulsification/internal gelation technologies available for microparticles preparation, particularly that involving alginate polymer, are described as well as recent advances towards applications in nanotechnology. Those methods show great promise as a tool for the development of encapsulation processes, especially for the new field of nanotechnology using natural polymers.     

Adipic acid dihydrazide treated partially oxidized alginate beads for sustained oral delivery of flurbiprofen

In this study, periodate oxidation of sodium alginate was controlled such that the oxidized alginate could form isolatable beads with Ca⁺² ions. The beads of oxidized alginate having a degree of oxidation 1 mol%, entrapped 89% flurbiprofen and released almost all of its content within 1.5 h in pH 7.2 phosphate buffer solution. The beads were covalently crosslinked with adipic dihydrazide (ADH) in addition to ionic crosslinks and were characterized. Scanning electron microscopy revealed that the beads were spherical having smooth surfaces. The drug entrapment efficiency decreased (90–86%) with increasing concentration of ADH (2–6% w/v) in the gelation medium. However, the beads prolonged the drug release in alkaline dissolution medium up to 8 h depending upon the concentration of ADH. The beads prepared with 2% ADH swelled more rapidly and led to faster drug release in either pH 1.2 HCl solution or pH 7.2 phosphate buffer solution. The swelling tendencies were reduced and the drug release became slower with higher concentrations in either fluid. The drug diffusion from the beads followed super case II transport mechanism. FTIR spectroscopy indicated stable nature of flurbiprofen in the beads and therefore had potential as sustained oral delivery system for the drug.     

Controlling of systemic absorption of gliclazide through incorporation into alginate beads

This work investigates preparation of biodegradable beads with alginate polymer by ionotropic gelation method to take the advantages of the swelling and mucoadhesive properties of alginate beads for improving the oral delivery of the antidiabetic agent gliclazide. It demonstrates that the ionic gelation of alginate molecules offers a flexible and easily controllable process for manipulating the characteristics of the beads which are important in controlling the release rate and consequently the absorption of gliclazide from the gastrointestinal tract. Variations in polymer concentration, stirring speed, internal phase volume and the type of surfactant in the external phase were examined systemically for their effects on the particle size, incorporation efficiency and flow properties of the beads. The swelling behavior was strongly dependent on the polymer concentration in the formulations and the pH of the medium. The in vitro release experiments revealed that the swelling is the main parameter controlling the release rate of gliclazide from the beads. In vivo studies on diabetic rabbits showed that the hypoglycemic effect induced by the gliclazide loaded alginate beads was significantly greater and more prolonged than that induced by the marketed conventional gliclazide tablet (Gliclazide). The results clearly demonstrated the ability of the system to maintain tight blood glucose level and improved the patient compliance by enhancing, controlling and prolonging the systemic absorption of gliclazide.     

Fluconazole Review and situation among antifungal drugs in the treatment of opportunistic mycoses of human immuno-deficiency virus infections

Fluconazole is a novel triazole antifungal drug chiefly used in the treatment of opportunistic mycoses in immuno-compromised patients, particularly those with the acquired immuno-deficiency syndrome (AIDS). In comparison with other antifungal drugs, fluconazole has outstanding physical and pharmacokinetic properties, such as an excellent aqueous solubility allowing a parenteral formulation, high bioavailability by the oral route, even distribution throughout the tissues, including the central nervous system and the cerebro-spinal fluid, a long half-life (permitting once daily administration), and low binding to plasma proteins. It is excreted mainly as unchanged drug in the urine. Fluconazole is a broad-spectrum antifungal agent, especially effective againstCandida spp.,Cryptococcus neoformans and dermatophytes. Its antifungal efficacy was mainly proved by testing in animal models, since there is no relationship betweenin vitro andin vivo activities. It possesses a low toxicity and it is well-tolerated. Fluconazole is currently marketed for the treatment of oropharyngeal candidiasis in immuno-compromised patients and of atrophic oral candidiasis. Its place in the treatment of opportunistic mycoses in human immuno-deficiency virus-positive patients, in particular cryptococcal meningitis, is still under investigation but is promising.     

Sulindac loaded alginate beads for a mucoprotective and controlled drug release

Ionotropic gelation was used to entrap sulindac into calcium alginate beads as a potential drug carrier for the oral delivery of this anti-inflammatory drug. Beads were investigated in vitro for a possible sustained drug release and their use in vivo as a gastroprotective system for sulindac. Process parameters such as the polymer concentration, polymer/drug ratio, and different needle diameter were analysed for their influences on the bead properties. Size augmented with increasing needle diameter (0.9 mm needle: 1.28 to 1.44 mm; 0.45 mm needle: 1.04 to 1.07 mm) due to changes in droplet size as well as droplet viscosity. Yields varied between 87% and 98% while sulindac encapsulation efficiencies of about 88% and 94% were slightly increasing with higher alginate concentrations. Drug release profiles exhibited a complete release for all formulations within 4 hours with a faster release for smaller beads. Sulindac loaded alginate beads led to a significant reduction of macroscopic histological damage in the stomach and duodenum in mice. Similarly, microscopic analyses of the mucosal damage demonstrated a significant mucoprotective effect of all bead formulation compared to the free drug. The present alginate formulations exhibit promising properties of a controlled release form for sulindac; meanwhile they provide a distinct tissue protection in the stomach and duodenum.     

Itraconazole: pharmacology, clinical experience and future development

Itraconazole is an orally active, broad-spectrum, triazole antifungal agent which has a higher affinity for fungal cytochrome P-450 than ketoconazole but a low affinity for mammalian cytochrome P-450. Itraconazole has a broader spectrum of activity than other azole antifungals and shows interesting pharmacokinetic features in terms of its tissue distribution. These properties have resulted in reduced treatment times for a number of diseases such as vaginal candidiasis, as well as effective oral treatment of several deep mycoses, including aspergillosis and candidiasis. Currently itraconazole is registered in 42 countries for the treatment of systemic fungal infections. Further development is concentrating on antifungal prophylaxis as well as on an oral solution and an intravenous formulation.     

Release characteristics of chitosan treated alginate beads: II. Sustained release of a low molecular drug from chitosan treated alginate beads

The aim of this paper was to investigate the possible applicability of chitosan treated alginate beads as a controlled release system of small molecular drugs with high solubility. Timolol maleate (mw 432.49) was used as a model drug. The beads were prepared by the ionotropic gelation method and the effect of various factors (alginate, chitosan, drug and calcium chloride concentrations, the volume of external and internal phases and drying methods) on bead properties were also investigated. Spherical beads with 0.78-1.16 mm diameter range and 10.8-66.5% encapsulation efficiencies were produced. Higher encapsulation efficiencies and retarded drug release were obtained with chitosan treated alginate beads. Among the different factors investigated such as alginate, drug, chitosan and CaCl2 concentrations, the volumes of the external and internal phases affected bead properties. The drying technique has an importance on the bead properties also. The release data was kinetically evaluated. It appeared that chitosan treated alginate beads may be used for a potential controlled release system of small molecular drugs with high solubility, instead of alginate beads.     

Options for the Management of Mucosal Candidiasis in Patients with AIDS and HIV Infection

Oropharyngeal candidiasis may be the first manifestation of human immunodeficiency viral (HIV) infection, and more than 90% of patients with the acquired immunodeficiency syndrome (AIDS) develop the disease. Although numerous antifungal agents are available, azoles, both topical (clotrimazole) and systemic (fluconazole, itraconazole), have largely replaced older topical antifungals (gentian violet, nystatin) in the management of the disease in these patients. A concern in these patients is clinical relapse, which appears to be dependent on degree of immunosuppression and is more common with clotrimazole and ketoconazole than with fluconazole or itraconazole. Candida esophagitis is also of concern, since it occurs in more than 10% of patients with AIDS. Fluconazole is an integral part of management. A cyclodextrin oral solution formulation of itraconazole has similar clinical response rates as fluconazole and is an effective alternative. In patients with fluconazole-resistant mucocutaneous candidiasis, treatment options include itraconazole and amphotericin B oral suspension and parenteral preparation.     

Alginate coated chitosan core shell nanoparticles for oral delivery of enoxaparin: In vitro and in vivo assessment

The objective of present research work was to develop alginate coated chitosan core shell nanoparticles (Alg-CS-NPs) for oral delivery of low molecular weight heparin, enoxaparin. Chitosan nanoparticles (CS-NPs) were synthesized by ionic gelation of chitosan using sodium tripolyphosphate. Core shell nanoparticles were prepared by coating CS-NPs with alginate solution under mild agitation. The Alg-CS-NPs were characterized for surface morphology, surface coating, particle size, polydispersity index, zeta potential, drug loading and entrapment efficiency using SEM, Zeta-sizer, FTIR and DSC techniques. Alginate coating increased the size of optimized chitosan nanoparticles from around 213 nm to about 335 nm as measured by dynamic light scattering in zeta sizer and further confirmed by SEM analysis. The performance of optimized enoxaparin loaded Alg-CS-NPs was evaluated by in vitro drug release studies, in vitro permeation study across intestinal epithelium, in vivo venous thrombosis model, particulate uptake by intestinal epithelium using fluorescence microscopy and pharmacokinetic studies in rats. Coating of alginate over the CS-NPs improved the release profile of enoxaparin from the nanoparticles for successful oral delivery. In vitro permeation studies elucidated that more than 75% enoxaparin permeated across the intestinal epithelium with Alg-CS-NPs. The Alg-CS-NPs significantly increased (p < 0.05) the oral bioavailability of enoxaparin in comparison to plain enoxaparin solution as revealed by threefold increase in AUC of plasma drug concentration time curve and around 60% reduction in thrombus formation in rat venous thrombosis model. The core shell Alg-CS-NPs showed promising potential for oral delivery and significantly enhanced the in vivo oral absorption of enoxaparin.     

Voriconazole : a review of its use in the management of invasive fungal infections

Voriconazole (VFEND), a synthetic second-generation, broad-spectrum triazole derivative of fluconazole, inhibits the cytochrome P450 (CYP)-dependent enzyme 14-alpha-sterol demethylase, thereby disrupting the cell membrane and halting fungal growth. In the US, intravenous and/or oral voriconazole is recommended in adults for the treatment of invasive aspergillosis, candidaemia in non-neutropenic patients, disseminated infections caused by Candida spp., oesophageal candidiasis, and in patients with scedosporiosis and fusariosis who are refractory to or intolerant of other antifungal therapy. In Europe, intravenous and/or oral voriconazole is recommended in adults and paediatric patients of at least 2 years of age for the treatment of invasive aspergillosis, candidaemia in non-neutropenic patients, fluconazole-resistant serious invasive Candida spp. infections, scedosporiosis and fusariosis.In large randomised trials, voriconazole was an effective and generally well tolerated primary treatment for candidiasis and invasive aspergillosis in adults and adolescents. More limited data also support the use of voriconazole for the treatment of invasive fungal infections in children, in those with rare fungal infections, such as Fusarium spp. or Scedosporium spp., and in those refractory to or intolerant of other standard antifungal therapies. The availability of both parenteral and oral formulations and the almost complete absorption of the drug after oral administration provide for ease of use and potential cost savings, and ensure that therapeutic plasma concentrations are maintained when switching from intravenous to oral therapy. On the other hand, the numerous drug interactions associated with voriconazole may limit its usefulness in some patients. Further clinical experience will help to more fully determine the position of voriconazole in relation to other licensed antifungal agents. In the meantime, voriconazole is a valuable emerging option for the treatment of invasive aspergillosis and rare fungal infections, including Fusarium spp. and Scedosporium spp. infections, and provides an alternative option for the treatment of candidiasis, particularly where the causative organism is inherently resistant to other licensed antifungal agents.     

Nanoparticulate Assembly of Mannuronic Acid-and Guluronic Acid-Rich Alginate: Oral Insulin Carrier and Glucose Binder

The relationship of high and low molecular weight mannuronic acid (M)- and guluronic acid (G)-rich alginate nanoparticles as oral insulin carrier was elucidated. Nanoparticles were prepared through ionotropic gelation using Ca^2 +, and then in vitro physicochemical attributes and in vivo antidiabetic characteristics were examined. The alginate nanoparticles had insulin release retarded when the matrices had high alginate-to-insulin ratio or strong alginate–insulin interaction via O-H moiety. High molecular weight M-rich alginate nanoparticles were characterized by assemblies of long polymer chains that enabled insulin encapsulation with weaker polymer–drug interaction than nanoparticles prepared from other alginate grades. They were able to encapsulate and yet release and have insulin absorbed into systemic circulation, thereby lowering rat blood glucose. High molecular weight G- and low molecular weight M-rich alginate nanoparticles showed remarkable polymer–insulin interaction. This retarded the drug release and negated its absorption. Blood glucose lowering was, however, demonstrated in vivo with insulin-free matrices of these nanoparticles because of the strong alginate–glucose binding that led to intestinal glucose retention. Alginate nanoparticles can be used as oral insulin carrier or glucose binder in the treatment of diabetes as a function of its chemical composition. High molecular weight M-rich alginate nanoparticles are a suitable vehicle for future development into oral insulin carrier. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:4353–4363,2013     

Posaconazole: a new broad-spectrum antifungal agent

The rising incidence of invasive fungal infections and the emergence of broader fungal resistance have led to the need for novel antifungal agents. Posaconazole is a new member of the triazole class of antifungals. It is available as an oral suspension and has a favorable toxicity profile, has demonstrated clinical efficacy in the treatment of oropharyngeal candidiasis and has shown promise as salvage therapy for invasive aspergillosis, zygomycosis, cryptococcal meningitis and a variety of other fungal infections. In addition, data from randomized controlled studies support its efficacy for use in prophylaxis of invasive fungal infections in patients who are severely immunocompromised. The wide spectrum activity of posaconazole in in vitro studies, animal models and preliminary clinical studies suggest that posaconazole represents an important addition to the antifungal armamentarium.