Optimization of the emulsification and solvent displacement method for the preparation of solid lipid nanoparticles.

OBJECTIVE: The essential aim of this article is to prepare solid lipid nanoparticles (SLNs) by emulsification and solvent displacement method and to determine the best process conditions to obtain submicron particles. METHODS: The emulsification and solvent displacement method is a modification of the well-known emulsification-diffusion method, but without dilution of the system. The extraction of the partially water-miscible solvent from the emulsion globules is carried out under reduced pressure, which causes the diffusion of the solvent toward the external phase, with subsequent lipid aggregation in particles whose size will depend on the process conditions. The critical variables affecting the process, such as stirring rate, the proportion of phases in the emulsion, and the amount of stabilizer and lipid, were evaluated and optimized. RESULTS: By this method, it was possible to obtain a high yield of solids in the dispersion for the lipids evaluated (Compritol(®) ATO 888, Geleol(®), Gelucire(®) 44/14, and stearic acid). SLNs of up to ∼20 mg/mL were obtained for all lipids evaluated. A marked reduction in size, between 500 and 2500 rpm, was seen, and a transition from micro- to nanometric size was observed. The smaller particle sizes obtained were 113 nm for Compritol(®) ATO 888, 70 nm for Gelucire(®) 44/14, 210 nm for Geleol(®), and 527 nm for stearic acid, using a rotor-stator homogenizer (Ultra-Turrax(®)) at 16,000 rpm. The best phase ratio (organic/aqueous) was 1 : 2. CONCLUSIONS: The process proposed in this study is a new alternative to prepare SLNs with technological potential.

Transdermal nortriptyline hydrocloride patch formulated within a chitosan matrix intended to be used for smoking cessation.

OBJECTIVE: The aim of this study was to prepare and characterize both physically and biopharmaceutically, a nortriptyline hydrochloride (NTP-HCl) patch formulated in chitosan. METHODS: 16 g of each chitosan patch formulation (I, II and III, see Table 1 ) was poured onto rectangular glass plates (64 cm²) at a height of 1 mm and dried for 24 h at room temperature. In order to characterize the chitosan patches, polarized microscopy, in vitro skin permeation studies by passive diffusion and iontophoresis and rheological and bioadhesion studies were performed. RESULTS: Polarized microscopy revealed the absence of aggregates and crystal forms of NTP-HCl in all transdermal patches after 30 days of storage. The rheological behavior of Patches I, II and III was predominantly elastic. The low level of adhesion of Patch III (containing PF-127 + 1-dodecanol) could be a result of the interactions between chitosan and PF-127 in the presence of 1-dodecanol. Patches I and II had approximately the same value of adhesion (≈ 60 mN.mm). The transdermal patch with chitosan, PF-127 and 1-dodecanol (Patch III) provided a reasonable flux of NTP-HCl across the skin compared with Patches I and II. Iontophoresis applied to the patches did not increase the penetration of NTP-HCl across the skin. CONCLUSIONS: The data suggest that Patch III is suitable for use in clinical practice pending further studies.

Development and characterization of a transdermal patch and an emulgel containing kanamycin intended to be used in the treatment of mycetoma caused by Actinomadura madurae.

BACKGROUND: Mycetoma is a chronic, degenerative, and incapacitating infection of the skin and subcutaneous tissue. AIM: This study focuses on developing a kanamycin-based auxiliary system intended to be used in the treatment of mycetoma caused by Actinomadura madurae. METHODS: Transdermal patches (with two different formulations: one with free kanamycin [K] and the other one with kanamycin adsorbed in silica [K-SG]) and an emulgel were developed. Both patches were prepared by the casting-evaporation technique. To characterize them, differential scanning calorimetry, bioadhesion, post-moisture detachment, strength and rupture distance, gas exchange, water uptake, and dissolution studies were carried out. The emulgel (containing 0.57% of kanamycin) was prepared from an oil-in-water emulsion, which was then incorporated to a gel. RESULTS: the patches with the best characteristics contained 22.9% of silica and 14.6% of kanamycin. Dissolution studies indicated that 8.8% of kanamycin released from K and 3.2% from K-SG at 24h. The emulgel containing 0.57% of kanamycin showed good technological characteristics for its application to the skin (viscosity, 44.9 +/- 1.4 poises; pH, 6.9 +/- 0.4; and penetrability, 52.7 +/- 5.1). CONCLUSIONS: The optimal patches were those containing 15.9% of freely dispersed kanamycin (K) and 14.6% of kanamycin adsorbed in silica (K-SG), which corresponds to the batch 2-0.8. The assessments performed to both pharmaceutical forms (patches and emulgel) show that they have the adequate technological characteristics for being used as an auxiliary in the treatment of actinomycetoma caused by A. madurae.

The use of iontophoresis in the administration of nicotine and new non-nicotine drugs through the skin for smoking cessation.

Cigarette smoking is the primary cause of lung cancer, cardiovascular diseases, reproductive disorders and delayed wound healing all over the world; as such, the goals of smoking cessation are both to reduce health risks and to improve quality of life. The development of novel and more effective medications for smoking cessation is crucial in the treatment of nicotine dependence. Currently, first-line smoking cessation therapies include nicotine replacement products and bupropion. The partial nicotinic receptor agonist, varenicline, has recently been approved by the FDA for smoking cessation. A newer product seeking approval by the FDA is nicotine vaccine. Clonidine and nortriptyline have demonstrated some efficacy, but side effects may limit their use to second-line treatment products. Other therapeutic drugs that are under development include rimonabant, mecamylamine, monoamine oxidase inhibitors, and dopamine D3 receptor antagonists. In order to increase the range of drugs available for transdermal delivery a number of chemical and physical enhancement techniques have been developed in an attempt to compromise skin barrier function in a reversible manner without concomitant skin irritation. The controlled delivery afforded by constant current iontophoresis, which involves the application of a small electrical potential sets it apart from other technologies. The amount of compound delivered is directly proportional to the quantity of charge passed; it depends on the applied current, the duration of current application and the area of the skin surface in contact with the active electrode compartment. For these reasons, iontophoresis will provide smokers with an additional option to assist in achieving smoking cessation.

Silica xerogels as pharmaceutical drug carriers.

This review focuses on silica xerogels obtained by the sol-gel method and their application as drug delivery systems. SiO(2) xerogels are potential biomaterials to be used as matrix materials for the extended and controlled release of different kinds of biologically active agents administered by various routes. The article includes some representative examples that describe the encapsulation of bioactive molecules and model compounds inside a silica matrix produced by the conventional sol-gel method or by ultrasound hydrolysis. The drug release rate from xerogels could be modified by adjusting several parameters, such as the type of precursor, the concentration of the catalyst and drying temperature. In vitro and in vivo studies have shown the efficacy and biodegradability of these composites. The potential application of silica xerogels as drug carrier systems is critically analyzed and discussed.

Nanoparticle infiltration to prepare solvent-free controlled drug delivery systems.

The purpose of this work was to propose a drug delivery system based on a biodegradable porous membrane, whose surface is covered by a nanoparticle film, thus achieving a controlled drug release rate. Furthermore, due to the fact that the assembly of the system is performed in aqueous medium, contact with organic solvents is avoided. The method is performed in two steps: (i) preparation of biodegradable porous membranes (by a solvent casting and particulate leaching technique) and biodegradable nanoparticles (by the emulsification-diffusion method), extensively eliminating the solvent in both of them; (ii) infiltration into membranes of an aqueous solution of a model drug (carbamazepine) and a nanoparticle dispersion. In both cases, poly(DL-lactic-co-glycolic acid) (PLGA 50:50) was used as a biodegradable polymer. Carbamazepine adsorbed onto biodegradable porous membranes shows an immediate release behavior (95% released in <15 min). Infiltration of different amounts of nanoparticles (50, 100, 400 and 600 mg of nanoparticles/0.625 g of membrane) into biodegradable porous membranes shows a Fickian diffusion according to Peppas model, and fits Higuchi's model. This behavior was attributed to the diffusional barrier constituted by the nanoparticle film. As expected, the carbamazepine release rate was dependent on the amount of infiltrated/adsorbed nanoparticles into biodegradable porous membrane. DSC studies show molecular dispersion of the drug throughout the membrane.

Evaluation of SiO2 sonogels, prepared by a new catalyst-free method, as drug delivery system.

Recently, we reported on the synthesis of catalyst-free SiO(2) sonogels prepared by the sonication of a neutral distilled water/ tetraethyl ortosilicate mixture. The purpose of the present study was to evaluate the feasibility of using these sonogels as pharmaceutical delivery systems. A certified color additive (sunset yellow, SY) was used as a model compound for the release experiments. Different amounts of dye were incorporated into the gels before drying. Sonogels were characterized by scanning electron microscopy and differential scanning calorimetry. The effect of three drying temperatures (25 degrees C, 40 degrees C and 80 degrees C) and two mean grain sizes (1125 and 630 microm) on release behavior was analyzed. The analysis of variance showed no significant differences between the Higuchi's constants (K(H)) obtained for SY-loaded sonogels dried at 80 degrees C with different SY loads, irrespective of the mean grain size. In contrast, for SY-loaded sonogels dried at 40 degrees C, differences were found between sonogels loaded with 2.7, 7.7, 12.2, and 18.2% of SY, and no significant differences were detected between the mean grain sizes analyzed. Considering that the preparation of sonogels by the catalyst-free method allows an easy encapsulation, sonogels may offer an interesting alternative for drug release in the pharmaceutical field.

Preparation of nanoparticles by solvent displacement using a novel recirculation system.

Submicron colloidal suspensions of poly(epsilon-caprolactone) (PCL) were prepared by the solvent displacement method, using either the conventional form or a new recirculation device. In the latter case, a process that allows the recirculation of the aqueous phase into a device, providing a continuous flow, is proposed. The influence of the organic solution injection rate and polymer concentration on mean particle size and process yield were studied for both methods. The recirculation rate was also analyzed for the recirculation system. Nanoparticles (NPs) showed mean sizes that ranged from 156 to 381. The smallest particles were obtained when recirculation rate, injection rate and polymer concentration were maximized but at the expense of the yield. The only acceptable yields (83-96%) were obtained at the lowest PCL concentration (2.5% w/v). ANOVA tests (alpha = 0.05) showed that the variables implicated in the recirculation system significantly affected the mean particle size and the process yield. The entrapment efficiencies of NPs prepared by the conventional method were not significantly different (alpha = 0.05) from those obtained by the recirculation system.

Design and evaluation of a self-adhesive naproxen-loaded film prepared from a nanoparticle dispersion.

Naproxen-loaded nanoparticles were used to prepare, in a one-step process, unilaminar films of Eudragit E-100 (EE-100), avoiding the use of organic solvents and assuring the homogeneity and molecular dispersion of the drug. Nanoparticle films (NP-F) and conventional films (CV-F, prepared by casting of methanolic solutions onto a Teflon disc) were assayed by their mechanical properties, skin adhesivity, and calorimetric studies to compare their behavior. Different proportions of plasticizer (triacetin) were included to evaluate the quality of the films. Film characterization included in vitro drug release studies through a cellulose membrane using Franz-type cells, and in vivo stratum corneum penetration experiments by the tape stripping technique. The results showed that NP-F were semi-transparent to transparent, suggesting a good compatibility between naproxen and EE-100. Differential calorimetric studies (DSC) confirmed a molecular dispersion of naproxen in the EE-100 matrix. Taking into account the mechanical properties of the films, a 20% triacetin concentration can be considered as optimal for both types of films. The in vitro release data obtained from both systems (NP-F and CV-F) followed the Higuchi's model for matrix systems, with the Fickian diffusion (t(0.5)) being the main release mechanism. Concerning the in vivo penetration studies, no statistical differences were found for the penetrated amount of naproxen across the stratum corneum and the depth of penetration for the two films and between the three contact times (2, 4, and 6 h). The films formulated from nanoparticle dispersions (NP-F) were shown to be effective for the transdermal administration of naproxen, and can be considered as an interesting alternative for the preparation of films with several technological advantages.

Chemical enhancers for the absorption of substances through the skin: Laurocapram and its derivatives.

Absorption enhancers are substances used for temporarily increasing a membrane's permeability (e.g., the skin and mucosa), either by interacting with its components (lipids or proteins) or by increasing the membrane/vehicle partition coefficient. This article presents the results of biophysical and permeability studies performed with Laurocapram and its analogues. As shown, Laurocapram and its analogues present different enhancing efficacies, for most of both hydrophilic and lipophilic substances. The enhancing effect of Laurocapram (Azone) is attributed to different mechanisms, such as insertion of its dodecyl group into the intercellular lipidic bilayer, increase of the motion of the alkylic chains of lipids, and fluidization of the hydrophobic regions of the lamellate structure. Toxicological studies reveal a low toxicity for Laurocapram, and for some derivatives, a relationship exists between toxicity and the number of carbons in the alkylic chain. Very important, when applied to human skin, Laurocapram shows a minimal absorption, being quickly eliminated from circulation. However, although Laurocapram and its derivatives have been shown to provide enhancement, they have not been widely accepted because of their suspected pharmacological activity or questions about their safety.

In vivo skin permeation of sodium naproxen formulated in pluronic F-127 gels: effect of Azone and Transcutol.

The objective of this study was to determine the penetration of sodium naproxen, formulated in Pluronic F-127 (PF-127) gels containing Azone and Transcutol as penetration enhancers, through human skin in vivo. It was found that the combination of Azone and Transcutol in PF-127 gels enhanced sodium naproxen penetration, with enhancement ratios of up to two fold compared with the formulation containing only Transcutol. These results were confirmed by TEWL and ATR-FTIR spectroscopy, suggesting a synergic action for Azone and Transcutol. Because of the thermo-reversible behavior of Pluronic gels, the influence of the components added to the gel formulations on viscosity, as a function of temperature, was also studied.

Adaptation and optimization of the emulsification-diffusion technique to prepare lipidic nanospheres.

In this study, the emulsification-diffusion method traditionally used to prepare polymeric nanoparticles was adapted to obtain lipidic nanospheres (LN) using four model lipids. The method consists of dissolving the lipid in a partially water-miscible solvent (previously saturated with water) at room temperature or at controlled temperature depending on lipid solubility. This organic phase is emulsified in an aqueous solution of a stabilizing agent (saturated with solvent) by conventional stirring at the same temperature used to dissolve the lipid. This oil-in-water emulsion is then diluted with an excess of water at controlled temperature in order to provoke the diffusion from the internal phase into the external phase thereby causing lipid aggregation in the form of LN. This new approach for the preparation of LN has clear advantages over the existing methods, namely: (i) it is efficient and versatile; (ii) easy implementation and scaling up (with no need of high energy sources); (iii) high reproducibility and narrow size distribution; (iv) less physical stress (i.e., long exposure to high temperatures and to mechanical dispersion); (v) it is not necessary to dissolve the drug in the melted lipid. The selection of the water-miscible solvent and the stabilizers are critical parameters to obtain lipidic particles in the nanometric range. In general, solvents with high water miscibility and stabilizers able to form stable emulsions are preferred. The results demonstrated that it was possible to reduce the particle size by increasing the process temperature, the stirring rate, the amount of stabilizer, and by lowering the amount of lipid. Control of the preparative variables allowed to obtain LN with diameters under 100 nm. It was found that the influence of preparative parameters was associated with a mechanism based on a physicochemical instability. In this sense, it is suggested that the rapid solvent diffusion produces regions of local supersaturation near the interface, and LN are formed due to the ensuing interfacial phase transformations and lipid aggregation that occur in these interfacial domains. In terms of stability, only poly(vinyl alcohol) (PVAL) was able to preserve the physical stability of the dispersion for long periods after preparation. This effect was attributed to the ability of PVAL chains to form a strongly attached layer on the nanoparticle surface with an excellent repulsion effect.

Preparation of polymeric nanocapsules containing octyl methoxycinnamate by the emulsification-diffusion technique: penetration across the stratum corneum.

Polymeric nanocapsules (NCs) containing octyl methoxycinnamate (OMC) as lipophilic molecule were prepared, and their in vivo distribution profile through the stratum corneum (SC) was determined by the tape-stripping technique. Penetration degree of OMC formulated in NCs was compared with that obtained for a nanoemulsion (NE), and a conventional oil-in-water (o/w) emulsion (EM). To produce stable cellulose acetate phthalate (CAP) nanocapsules containing the lipophilic sunscreen, a study was conducted to optimize the process of NC preparation based on the emulsification-diffusion technique. NC formation was verified by measuring their density using differential centrifugation. NC density revealed that an OMC (microL)/CAP (mg) ratio of 2.5:1 is optimal for encapsulation. High encapsulation entrapment (>96%) and excellent process efficiency (recovered quantity of NCs in relation with the initial amount of OMC and CAP >99%) were always achieved with this ratio or a higher one. The capsular structure of the NCs was evidenced with a direct SEM technique. NE was prepared by the emulsification-diffusion technique, dissolving a specific quantity of OMC in water-saturated 2-butanone and then, emulsifying with an aqueous solution of PVAL. In vivo percutaneous penetration, evaluated by the tape-stripping technique, demonstrated that NE increased the extent of OMC penetration relative to the penetration achieved by NCs or EM, with relative penetration depths through the SC of 0.86 +/- 0.1, 0.64 +/- 0.11, and 0.57 +/- 0.08, respectively. In the same manner, the accumulation in the skin of OMC was significantly greater with NE than with EM or NCs. OMC penetration depth was strongly dependent upon the size of the colloidal particles and their flexibility.

Effects of sucrose oleate and sucrose laureate on in vivo human stratum corneum permeability.

PURPOSE: The purpose of this work was to 1) investigate the effect of sucrose esters (sucrose oleate and sucrose laureate in water or in Transcutol, TC) on the stratum corneum (SC) barrier properties in vivo and 2) examine the impact of these surfactant-like molecules on the in vivo percutaneous penetration of a model penetrant 4-hydroxybenzonitrile (4-HB). METHODS: Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy and transepidermal water loss measurements were used to evaluate the sucrose oleate- and sucrose laureate-induced biophysical changes in SC barrier function in vivo. In addition. the effect of the enhancers on 4-HB penetration was monitored in vivo using ATR-FTIR spectroscopy in conjunction with tape-stripping of the treated site. RESULTS: Treatment of the skin with 2% sucrose laureate or sucrose oleate in TC significantly increased the extent of 4-HB penetration relative to the control. Furthermore, when skin treated with these formulations was examined spectroscopically, the C-H asymmetric and symmetric stretching bands of the lipid methylene groups were characterized by 1) decreased absorbances and 2) frequency shifts to higher wavenumbers. These effects on the SC lipids and 4-HB penetration were more pronounced for sucrose laureate when combined with TC. CONCLUSIONS: A combination of sucrose esters (oleate or laureate) and TC is able to temporally alter the stratum corneum barrier properties, thereby promoting 4-HB penetration. These molecules are worthy of further investigation as potential candidates for inclusion in transdermal formulations as penetration enhancers.