Antifungal Activity of Undecylenic Acid Emulsions by Microbiological Methods

Abstract

Two nonionic surfactants (Simulsol 98 and Simulsol OL 50) alone and I:I mixtures, corn oil-undecylenic acid and water formed emulsions, oily isotropic liquid phases, lamellar and hexagonal liquid crystal phases. The optimum release of undecylenic acid from these phases were controlled microbiologically. The active ingredient undecylenic acid, is released more from emulsion systems containing liquid crystals than only liquid crystalline and oily isotropic liquid phases.     

Preparation and characterization of bioadhesive systems containing propolis or sildenafil for dental pulp protection

Purpose: Binary polymeric systems containing poloxamer 407 (P407) and Carbopol 934P (C934P) were designed to deliver propolis extract (PE) or sildenafil citrate for the endodontic treatment (pulp protection).

Methods: Gelation temperature, rheology (flow), bioadhesion, and in vitro drug release of formulations were determined.

Results: Formulations showed thermoresponsive behavior, existing as a liquid at room temperature and gel at 34–37°C. In addition, they exhibited pseudoplastic flow and low degrees of thixotropy or rheopexy. The greatest bioadhesion was noted in the formulation containing 20% P407 (w/w) and 0.10% C934P (w/w). PE release from formulation containing 15% P407 (w/w) and 0.25% C934P (w/w) was controlled by the phenomenon of relaxation of polymer chains. Moreover, sildenafil release from formulation containing 20% P407 (w/w) and 0.10% C934P (w/w) was controlled by Fickian diffusion.

Conclusion: The data obtained on these formulations indicate a potentially useful role in the endodontic treatment (pulp protection) and suggest they are worthy of clinical evaluation.     

Antifungal Activity of Undecylenic Acid Emulsions by Microbiological Methods

Two nonionic surfactants (Simulsol 98 and Simulsol OL 50) alone and I:I mixtures, corn oil-undecylenic acid and water formed emulsions, oily isotropic liquid phases, lamellar and hexagonal liquid crystal phases. The optimum release of undecylenic acid from these phases were controlled microbiologically. The active ingredient undecylenic acid, is released more from emulsion systems containing liquid crystals than only liquid crystalline and oily isotropic liquid phases.     

Drug release from lipid liquid crystalline phases: relation with phase behavior

Introduction: We studied the release of propranolol hydrochloride (PHCl), a water-soluble amphiphilic drug, from monoolein (MO)/water and phytantriol/water systems. Methods: We related the dissolution profiles with phase behavior and viscosity of the different liquid crystalline phases. Diolein has been added aiming to stabilize the cubic phases and thus preventing formation of less viscous (lamellar) phases. Results: Formulations display first-order release rates and diffusion release mechanism. Some formulations (mostly MO) were close to zero-order release in the first 120 minutes. Discussion: Release mechanism can be influenced by phase changes during dissolution. Conclusions: Both MO and phytantriol show good potential to be used for propranolol hydrochloride sustained drug release.     

The preparation of silver sulfide nanoparticles in lamellar liquid crystal and application to lubrication

The silver sulfide (Ag₂S) nanoparticles were prepared by the reaction of AgNO₃ and Na₂S in the lamellar liquid crystal (LLC) formed by Triton X-100, n-C₁₀H₂₁OH and H₂O. The size of the particles is about 2-3 nm. The existence of Ag₂S nanoparticles can improve the lubrication of the lamellar liquid crystal.     

Prolonged Release of Tegafur from S/O/W Multiple Emulsion

Abstract

To develop a prolonged and sustained release preparation, we prepared an albumin microsphere-in-oil-in-water emulsion (S/O/W) and examined sustained release from it in comparison with other control preparations such as water-in-oil (W/O) emulsions and microspheres in vitro and in vivo, respectively. Tegafur was used as a model drug. A microsphere-in-oil emulsion was prepared by adding albumin microspheres to soybean oil containing 20% Span 80. To prepare an S/O/W emulsion, the microsphere-in-oil emulsion was added into an aqueous solution of hydroxypropyl methylcellulose containing Pluronic F68. The mean particle size of the albumin microspheres was 3 µm, and the ratio of entrapment of tegafur into albumin microspheres was about 25%. In an in vitro release test, the t₇₅ of the S/O/W emulsion was fourfold greater and in an in vivo release test the mean residence time of tegafur from the S/O/W emulsion was more than twofold that from a W/O emulsion or microsphere system. The mean residence time of 5-fluorouracil (5-FU) from an S/O/W emulsion was also greater than with other dosage forms. These results suggest the possible usefulness of an S/O/W emulsion for the sustained and prolonged release of tegafur.     

Synthesis of polyaniline nanostructures in different lamellar liquid crystals and application to lubrication

Polyaniline (PANI) nanostructures were synthesized in lamellar liquid crystal (LLC) formed by different surfactants. It was found that PANI presented lamellar nanostructures by using the template of LLC formed by ionic surfactant of sodium dodecyl sulfonate (SDS) or hexadecyltrimethylammonium bromide (CTAB), whereas PANI spheric nanostructures were obtained within the LLC template formed by the nonionic surfactant of Triton X-100. The formation mechanisms of PANI nanostructures were discussed. Besides, the lubricating effect of PANI in LLC template was also investigated, and the results showed that spheric PANI had better lubricative performance than lamellar PANI.     

Formulation studies of benzydamine mucoadhesive formulations for vaginal administration

Background: Vaginal cavity represents a good site for drug administration and delivery. Aim: The aim of this work was the design of new mucoadhesive semisolid dosage forms for vaginal delivery of benzydamine. Method: Simple gels, obtained by using sodium carboxymethylcellulose (NaCMC) and hydroxyethylcellulose (HEC), were employed as water phase of an oil-in-water emulsion (O/W cream) to obtain emulgels, more stable and manageable than gels. Successively, in order to modify the emulgel consistency, the ingredient cetostearylic alcohol was replaced by the same amount of gel or vaseline. All the preparations were submitted to mucoadhesion and rheological, extrusion, and release studies and compared to market vaginal cream Tantum Rosa®. Results: HEC formulations showed good drug release profiles and good rheological behavior but low mucoadhesion strength, whereas NaCMC (4%?gel) formulations had better drug release and very high mucoadhesive strength. However, the presence of NaCMC 4%?conferred too much viscosity to the preparation. Taking into consideration all performances, the most suitable formulations for vaginal applications resulted in those containing NaCMC (3%?gel) and with gel replacing cetostearylic alcohol as they showed good ex vivo performances in terms of manageability and high bioadhesion to vaginal mucosa.     

Development and In Vitro Characterization of Chitosan-based Microspheres for Nasal Delivery of Promethazine

ABSTRACT

Conventional and composed promethazine-loaded microspheres were prepared by spray drying of chitosan solution systems and double water-in-oil-in-water (W/O/W) emulsion systems, respectively. Double emulsions were prepared in two different feed concentrations, with chitosan dissolved in both water phases, and ethylcellulose dissolved in oil phase. Swelling and bioadhesive properties of the microspheres depended on the chitosan content, type and the feed concentration of spray-dried system. Results obtained suggested that better ethylcellulose microcapsules with promethazine in the chitosan matrix were formed when less concentrated emulsion systems were spray-dried. Thus, in case of such a system, with ethylcellulose/chitosan weight ratio of 1:2, prolonged promethazine release was obtained.     

Oral liquid in situ gelling methylcellulose/alginate formulations for sustained drug delivery to dysphagic patients

Background: Elderly patients with swallowing dysfunction may benefit from the oral administration of liquid dosage forms with in situ gelling properties.

Aim: We have designed in situ gelling liquid dosage formulations composed of mixtures of methylcellulose, which has thermally reversible gelation properties and sodium alginate, the gelation of which is ion-responsive, with suitable rheological characteristics for ease of administration to dysphagic patients and suitable integrity in the stomach to achieve a sustained release of drug.

Method: The rheological and gelation characteristics of solutions containing methylcellulose (2.0%) and sodium alginate (0.25–1.0%) were assessed for their suitability for administration to dysphagic patients. The gel strength and in vitro and in vivo release characteristics of gels formed by selected formulations were compared using paracetamol as a model drug.

Results: Mixtures of 2.0% methylcellulose and 0.5% alginate containing 20% d-sorbitol were of suitable viscosity for ease of swallowing by dysphagic patients and formed gels at temperatures between ambient and body temperature allowing administration in liquid form and in situ gelation in the stomach. In vitro release of paracetamol from 2.0% methylcellulose/0.5% alginate gels was diffusion-controlled at pH 1.2 and 6.8. Measurement of plasma levels of paracetamol after oral administration to rats of a 2.0% methylcellulose/0.5% alginate formulation showed improved sustained release compared to that from 2.0% methylcellulose and 0.5% alginate solutions and from an aqueous solution of paracetamol.

Conclusions: Solutions of mixtures of methylcellulose and alginate in appropriate proportions are of suitable consistency for administration to dysphagic patients and form gels in situ with sustained release characteristics.     

Lyotropic liquid crystal directed synthesis of nanostructured materials

Abstract

This review introduces and summarizes lyotropic liquid crystal (LLC) directed syntheses of nanostructured materials consisting of porous nanostructures and zero-dimensional (0-D), one-dimensional (1-D) and two-dimensional (2-D) nanostructures. After a brief introduction to the liquid crystals, the LLCs used to prepare mesoporous materials are discussed; in particular, recent advances in controlling mesostructures are summarized. The LLC templates directing the syntheses of nanoparticles, nanorods, nanowires and nanoplates are also presented. Finally, future development in this field is discussed.     

Prolonged Tissue Levels of Pentazocine from Multiple W/O/W EMULSIONS IN MICE

Abstract

Multiple W/O/W emulsions containing pentazocine were prepared and tested in virto and in viro. The in viro results indicated a well controlled and higher drug release from teh W/O/W emulsions than the W/O emulsion. The in vivo data showed prolonged tissue levels of pentazocine after oral administration of W/O/W emulsions than the W/O emulsion to mice in comparison to acquenous drug solution and W/O emulsion.     

Preparation,characterization, sterility validation,and in vitro cell toxicity studies of microemulsions possessing potential parenteral applications

Context: Water-in-oil microemulsions (w/o ME) are ideal for parenteral drug delivery. However, no such formulations have been tested for biocompatibility in in vitro cell cultures. Furthermore, sterilization of w/o MEs is a challenging process that has not been previously developed and validated.

Purpose: To formulate pharmaceutically relevant water-in-oil (w/o) microemulsion’s systems suitable for use as a parenteral formulation.

Methods: w/o MEs were prepared using dioctyl sodium sulfosuccinate (DOSS), ethyl oleate (EO), and water. Formulations were characterized using polarized light microscopy, electrical conductivity, rheology, and dynamic light scattering. An aseptic filtration method for sterilization was developed using membrane filtration. The biocompatibility of selected MEs were evaluated in NIH3T3 cell cultures. Dissolution studies were performed on microemulsions containing methylene blue to evaluate the drug release profile.

Results: The maximum amount of water incorporated in the formulations was 14% w/w. DOSS/EO/water microemulsions exhibited Newtonian flow. Particle sizes for these MEs were less than 30 nm in size. Formulations filtered aseptically were free of bacteria when gram-stained and visualized under a microscope. All MEs showed no toxicity to NIH 3T3 cells.

Discussion: The absence of birefringence and low conductivity values indicated that the formulations were w/o microemulsions. The filtration method of sterilization was validated by the absence of microbial growth on blood agar plates over a 14-day period. In vitro dye release studies demonstrate sustained release of the model drug over a 72-h time period.

Conclusion: Characteristics delineated in this study demonstrate the potential for these formulations to be used as parenteral preparations.     

High drug loading self-microemulsifying/micelle formulation: design by high-throughput formulation screening system and in vivo evaluation

Purpose: To design a high drug loading formulation of self-microemulsifying/micelle system.

Methods: A poorly-soluble model drug (CH5137291), 8 hydrophilic surfactants (HS), 10 lipophilic surfactants (LS), 5 oils, and PEG400 were used. A high loading formulation was designed by a following stepwise approach using a high-throughput formulation screening (HTFS) system: (1) an oil/solvent was selected by solubility of the drug; (2) a suitable HS for highly loading was selected by the screenings of emulsion/micelle size and phase stability in binary systems (HS, oil/solvent) with increasing loading levels; (3) a LS that formed a broad SMEDDS/micelle area on a phase diagram containing the HS and oil/solvent was selected by the same screenings; (4) an optimized formulation was selected by evaluating the loading capacity of the crystalline drug. Aqueous solubility behavior and oral absorption (Beagle dog) of the optimized formulation were compared with conventional formulations (jet-milled, PEG400).

Results: As an optimized formulation, d-α-tocopheryl polyoxyethylene 1000 succinic ester: PEG400?=?8:2 was selected, and achieved the target loading level (200?mg/mL). The formulation formed fine emulsion/micelle (49.1?nm), and generated and maintained a supersaturated state at a higher level compared with the conventional formulations. In the oral absorption test, the area under the plasma concentration-time curve of the optimized formulation was 16.5-fold higher than that of the jet-milled formulation.

Conclusions: The high loading formulation designed by the stepwise approach using the HTFS system improved the oral absorption of the poorly-soluble model drug.     

Practical Considerations for Compendial Method Selection

Abstract

The objective of this study was to develop and validate an in vitro test method that can be used as a tool for accessing batch-to-batch uniformity of finished topical products. The studies were performed by utilizing topical creams containing the 13-cis isomer of retinoic acid. Various physicochemical factors which may affect drug release from topical cream formulations were evaluated including drug concentration, internal phase droplet size distribution, viscosity and the composition of the emulsion internal and external phases. Utilizing a modified Franz diffusion cell with a cellulose membrane, the in vitro drug release profile from various cream formulations was established

The effect of varying the concentrations of various key ingredients by 30% does affect the viscosities and release rates compared to a standard formulation. However, there is no correlation between the viscosities and the release rates. No significant differences in pH and droplet size distribution were observed in these cream formulations compared to a standard formulation. The oil phase volume ratio appears to have the largest influence on the in vitro release of the drug. Intra- and inter-batch comparisons of the finished cream products show reproducible release profiles. Based on the results obtained in this study, when used together, both in vitro release and viscosity measurements may be useful as tools to assess batch-to-batch uniformity and consistent manufacturing of the finished cream product     

Alginate-Based In Situ Gelling Suspensions and Emulsions Comprising N4-Alkyloxycarbonyl Derivatives of Cytosine: Zero-Order Release and Effect of Physicochemical Properties

As an alternative to incorporation of various excipients, N⁴-alkyloxycarbonyl-cytosine derivatives possessing various physicochemical properties and cytosine regeneration rates have been examined to modify release rate and kinetics from in situ gelling alginate formulations, e.g., liquid formulations that gel in acidic gastric juice and release the entrapped derivative or parent cytosine. Linear relationships were obtained between the release rate constants and the square root of the solubility for suspension formulations. Calculated diffusion coefficients were observed to be similar for suspension and solution formulations; however, for in situ gelling emulsion formulations, diffusivity correlated linearly to log P. Zero-order release of parent cytosine was observed from in situ gelling suspensions of the poorly soluble acid-labile N⁴-adamantyloxycarbonyl-cytosine prodrug.     

Characterizing Colloidal Structures of Pseudoternary Phase Diagrams Formed by Oil/Water/Amphiphile Systems

Two pseudoternary phase diagrams were constructed using ethyl oleate, water, and a surfactant blend containing poly (oxyethylene 20) sorbitan monooleate and sorbitan monolaurate with or without the cosurfactant 1-butanol. Two colloidal regions were identified in the cosurfactant-free phase diagram; a microemulsion (ME) and a region containing lamellar liquid crystals (LC). The addition of 1-butanol increased the area in which systems formed microemulsions and eliminated the formation of any liquid crystalline phases. Samples that form the colloidal regions of both systems were investigated by freeze-fracture transmission electron microscopy and by viscosity and conductivity measurements. The three techniques were compared and evaluated as characterisation tools for such colloidal systems and also to identify transitions between the colloidal systems formed. A droplet ME was present at a low water volume fraction (?_w) in both systems (?_w <0.15) as revealed by electron microscopy. At higher ?_w values, LC structures were observed in micrographs of samples taken from the cosurfactant-free system while the structure of samples from the cosurfactant-containing system was that of a bicontinuous ME. The viscosity of both systems increased with increasing ?_w to 0.15 and flow was Newtonian. However, formation of LC in the cosurfactant-free system resulted in a dramatic increase in viscosity that was dependent on ?_w and a change to pseudoplastic flow. In contrast, the viscosity of the bicontinuous ME was independent of ?_w. Three different methods were used to estimate the percolation threshold from the conductivity data for the cosurfactant-containing system. The use of nonlinear curve fitting was found to be most useful yielding a value close to 0.15 for the ?_w.     

Injectable hydrogels with two different rates of drug release based on pluronic/water system filled with poly(ε-caprolactone) microcapsules

The present paper regards the preparation and characterization of Pluronic F127?+?F68/water/poly (ε-caprolactone) microcapsules (MCs) composite systems for tissue repair. The first part of the work relates to the production of poly(ε-caprolactone) (PCL) MCs via water-in-oil-in-water (W/O/W) double emulsion system combined with solvent evaporation method. The study of different process parameters in the final MCs characteristics and their drug release profile is herein reported. Different percentages of PCL, emulsion stabilizer, and volume proportions of the emulsion constituents have been tested, leading to considerable differences in the MCs size distributions. The selected MCs, containing an aqueous solution of methylene blue (MB) as a model drug, were then used to fill a Pluronic F127?+?F68/water system leading to the final composite system (5 and 10 wt % MB loaded PCL MCs). The composite systems were characterised in the second part of the work in terms of its rheological behaviour and drug release performance. They were found to gellify at 30 °C, and present an extended drug release to a total of 18 days. The models that best define the release profiles were also studied, with the release of MB occurring mostly by Fick diffusion and polymer chain relaxation. Pluronic F127?+?F68/water/poly (ε-caprolactone) MCs composite system is shown to be a promising injectable system, with two different drug release rates, for tissue repair.

     

Development and characterization of new and scalable topical formulations containing N-acetyl-d-glucosamine-loaded solid lipid nanoparticles

N-Acetyl-d-glucosamine (NAG) has been recently considered for topical treatment of hyperpigmentation disorders due to its inhibitory effect on thyrosinase enzymes in melanocytes. NAG is a precursor of hyaluronic acid, increasing its amount in skin, and consequently, preserving the skin hydration and elasticity. It may also act as an emulsion stabilizer.

Solid lipid nanoparticles (SLN) are advanced delivery systems successfully used in pharmaceutical and cosmetic formulations for the improvement of active molecules penetration into the skin. Therefore, this work aimed to develop and characterize stable and scalable topical formulations containing NAG-loaded SLN.

NAG was incorporated in SLN which were prepared by two high shear homogenizers and characterized regarding its morphology and particle size by transmission electron microscopy and photon correlation spectroscopy, respectively. Oil emulgel and hydrogel were used as carriers of NAG-loaded SLN. Several parameters were evaluated, including the droplet size distribution, rheology, pH and topical delivery by different techniques.

It was observed that SLN size was significantly dependent on NAG incorporation and homogenization process. Most tested SLN parameters appeared to be quite suitable, that is, spherical and well-defined SLN with approximately 258?nm and ?30?mV. Hereafter, both gels containing SLN presented a pseudoplastic flow. Emulgel formulation containing NAG-loaded SLN allowed a higher NAG permeation through the SC compared to the respective control (about 0.8 μgcm^?2?h^?1).

According to the results obtained, it can be suggested that NAG acts as an emulsion stabilizer. This stabilization was also particularly dependent on the homogenizer type which is quite important for scale-up process. This study demonstrated the potential of scalable SLN formulations to improve NAG topical delivery contributing to the improvement of skin properties on several skin disorders.     

Preparation,characterization and pharmacokinetic evaluation of rosuvastatin calcium incorporated cyclodextrin-polyanhydride nanoparticles

Abstract

Objective: The aim of the study was to formulate, cyclodextrin (CD)-polyanhydride (PA) nanoparticles (CPNs) with rosuvastatin calcium (RCa) in order to enhance the poor oral bioavailability.

Methods: CPNs containing RCa/CD complexes were prepared by a modified solvent displacement method and morphological analyses, particle size (PS), polydispersity index (PDI), zeta potential (ZP), encapsulation efficiency (EE), DSC, FT-IR, XRD, ¹H-NMR analyses were performed. In vitro release properties, release kinetics, cytotoxicity, in vitro permeability and pharmacokinetic studies were also studied. The stability of the formulations were evaluated during the storage period of 3?months.

Results: The physicochemical studies showed that the RCa/CD complexes were well incorporated into CPNs resulted in nanosized particles (215.22 and 189.13?nm) with homogenous size distribution (PDI: 0.203 and 0.182) with relatively high incorporation capacity (76.11 and 68.18%) for the CPN1 and CPN2 formulations respectively. Sustained release of RCa from CPNs were achieved. The cytotoxicity values showed that the safety of the formulations. According to permeability studies, pure RCa had lowest permeability data (3.08?×?10^?7?cm?s^?1 P_app value) while CPNs gained higher permeability data (1.36?×?10^?5 and 1.12?×?10^?5?cm?s^?1 P_app values) for the CPN1 and CPN2 formulations respectively. CPN2 formulation was selected for pharmacokinetic studies and analyses results demonstrated that approximately 8-fold relative oral bioavailability enhancement compared to the pure RCa was achieved.

Conclusion: Considering the analyses results of the study, CPNs can be regarded as suitable, safe, functional oral delivery systems for RCa with enhanced oral bioavailability.