Fortified chocolate mousse with powder and extract from Moringa oleifera leaves for nutritional value improvement.

This study focuses on the characterisation and incorporation of Moringa oleifera leaf powder (MOP) from Luanda (Angola) and its extract (MOE) in fortified chocolate mousse. Dark green (DG) leaves presented superior nutritional values compared to other leaves. DG contained a higher concentration of mineral salts (10 ± 1 mg/100 g of dry leaves), phenolic compounds (267 ± 4 mg GAE/g), vitamins (1.9 ± 0.2 mg/g of dry extract) and strong antioxidant capacity (IC50, 115 ± 8 µg/mL). Therefore, DG leaves were used to fortify the chocolate mousse. The leaves were prepared in three samples: control, 2 % MOP (w/w) and 2 % MOE (v/v). Textural and rheological analysis of chocolate mousse samples revealed a pseudoplastic profile for all samples, with decreased texture attributes and viscosity due to the incorporation. The sensory evaluation demonstrated that MOP and MOE samples presented 93 % and 88 % resemblance to the original product regarding general acceptance, respectively.

Safe-by-design development of a topical patch for drug delivery

Few topical products have been developed specifically to treat acute and chronic arthritis and inflammation, using non-steroidal anti-inflammatory drugs (NSAIDs). The lack of dosing accuracy commonly found in locally applied semisolid products for cutaneous use is a critical issue that leads to treatment failure. The aim of the present work is to develop a differentiated and innovative topical patch based on a monolithic hydrogel for ibuprofen skin delivery, in order to provide a safer and accurate way of drug administration along with improved treatment compliance. Topical patches based on hydroxypropylmethylcellulose (HPMC) were optimized in composition, in terms of enhancer and adhesive, supported on a systematic assessment of in vitro release and permeation behavior and adhesion properties. Several mathematical models were used to scrutinize the release mechanisms from the patches. In vitro release kinetics was shown to be mainly driven by diffusion. However, other mechanisms seemed to be also present, supporting the feasibility of using patches for sustained drug delivery. PEG 200 provided the best permeation rate, with a permeation enhancement ratio of ca. 3 times higher, than the commercial reference. The addition of Eudragit L30D 55 to the formulation led to the best adhesion profile, thus achieving a successful development based on a safe-by-design concept.

Development of levofloxacin-loaded PLGA microspheres of suitable properties for sustained pulmonary release.

Aerosol antibiotics are an interesting alternative to oral or intravenous therapy in Cystic Fibrosis lung infections. Levofloxacin (LVX) inhaled solution is already an effective option. In this study, the aim was the development of LVX-loaded PLGA microspheres (MS) for pulmonary administration as a dry powder. MS were prepared, for the first time, by a modified double emulsion solvent evaporation method with premix membrane homogenization. Aqueous phases were saturated with LVX and a fatty acid (lauric acid) was added to avoid the drug escaping from the organic phase. MS were characterized in terms of size, drug content, morphology and in vitro release properties. X-ray diffraction, Fourier-transform infrared spectroscopy, differential and gravimetric thermal analysis, and cytotoxicity analyses were performed. Results showed this new method increased the drug loading while maintaining an adequate (∼5 µm) particle size and controlled release. Compared to a solution for inhalation, these properties combined with the dry-powder nature of these MS will improve patient compliance. The incorporation of lauric acid was not advantageous because the particle size was higher and no improvements concerning the sustained release occurred. LVX was molecularly dispersed in the matrix, or it was in amorphous state, as confirmed by the physico-chemical analyses. Calu-3 cell viability assays demonstrated no cytotoxicity for these MS, making them a promising system for LVX pulmonary delivery.

Pulmonary pharmacokinetics of levofloxacin in rats after aerosolization of immediate-release chitosan or sustained-release PLGA microspheres.

A comparative pharmacokinetic study was conducted in rats after intratracheal aerosolization of levofloxacin, as a solution, as immediate-release chitosan microspheres or as sustained-release PLGA microspheres. A pharmacokinetic model was constructed to model levofloxacin concentrations both in plasma and in the lung epithelial lining fluid (ELF). The plasma and ELF experimental concentration profiles versus time were similar for the intravenous and intratracheal levofloxacin solutions and for the intratracheal levofloxacin-loaded chitosan microsphere dry powder, indicating that levofloxacin diffused almost instantaneously through the broncho-alveolar barrier and that the chitosan microspheres released levofloxacin very rapidly, as anticipated from in vitro release studies. The bioavailability for the intratracheal levofloxacin solution and intratracheal chitosan microspheres was estimated to be 98% and 71%, respectively, both with a direct release into the ELF compartment. The ELF-to-unbound plasma AUC ratios were slightly above 2 and may result from an efflux transport. For the intratracheal PLGA microspheres, a high ELF-to-unbound plasma AUC concentration ratio (311) was observed and high levofloxacin concentrations were maintained in ELF for at least 72h in consistency with the in vitro release studies. The bioavailability was 92%, with 19% of the dose released immediately (burst release) into the ELF and 73% released slowly into the ELF from a depot compartment, i.e. the PLGA microspheres, according to a Weibull model. These results highlight the benefit of using sustained-release microspheres administered as aerosols to provide and to maintain high pulmonary concentrations of an antibiotic characterized with a high permeability profile through the broncho-alveolar barrier. The sustained-release microsphere dry powder aerosol may therefore provide advantages over solutions or pure drug dry powders for inhalation in terms of treatment efficiency, ease of use and frequency of administration.

Optimization of levofloxacin-loaded crosslinked chitosan microspheres for inhaled aerosol therapy.

The aim of this work was the development of innovative levofloxacin-loaded swellable microspheres (MS) for the dry aerosol therapy of pulmonary chronicPseudomonas aeruginosainfections in Cystic Fibrosis patients. In a first step, a factorial design was applied to optimize formulations of chitosan-based MS with glutaraldehyde as crosslinker. After optimization, other crosslinkers (genipin, glutaric acid and glyceraldehyde) were tested. Analyses of MS included aerodynamic and swelling properties, morphology, drug loading, thermal and chemical characteristics,in vitroantibacterial activity and drug release studies. The prepared MS presented a drug content ranging from 39.8% to 50.8% of levofloxacin in an amorphous or dispersed state, antibacterial activity and fast release profiles. The highest degree of swelling was obtained for MS crosslinked with glutaric acid and genipin. These formulations also presented satisfactory aerodynamic properties, making them a promising alternative, in dry-powder inhalers, to levofloxacin solution for inhalation.

Structure activity relationships in alkylammonium C12-gemini surfactants used as dermal permeation enhancers.

The purpose of this study was to determine the ability and the safety of a series of alkylammonium C12-gemini surfactants to act as permeation enhancers for three model drugs, namely lidocaine HCl, caffeine, and ketoprofen. In vitro permeation studies across dermatomed porcine skin were performed over 24 h, after pretreating the skin for 1 h with an enhancer solution 0.16 M dissolved in propylene glycol. The highest enhancement ratio (enhancement ratio (ER)=5.1) was obtained using G12-6-12, resulting in a cumulative amount of permeated lidocaine HCl of 156.5 µg cm−2. The studies with caffeine and ketoprofen revealed that the most effective gemini surfactant was the one with the shorter spacer, G12-2-12. The use of the latter resulted in an ER of 2.4 and 2.2 in the passive permeation of caffeine and ketoprofen, respectively. However, Azone was found to be the most effective permeation enhancer for ketoprofen, attaining a total of 138.4 µg cm−2 permeated, 2.7-fold over controls. This work demonstrates that gemini surfactants are effective in terms of increasing the permeation of drugs, especially in the case of hydrophilic ionized compounds, that do not easily cross the stratum corneum. Skin integrity evaluation studies did not indicate the existence of relevant changes in the skin structure after the use of the permeation enhancers, while the cytotoxicity studies allowed establishing a relative cytotoxicity profile including this class of compounds, single chain surfactants, and Azone. A dependence of the toxicity to HEK and to HDF cell lines on the spacer length of the various gemini molecules was found.

A combination of nonionic surfactants and iontophoresis to enhance the transdermal drug delivery of ondansetron HCl and diltiazem HCl.

The present work reports the evaluation of three nonionic ether-monohydroxyl surfactants (C(12)E(1), C(12)E(5,) and C(12)E(8)) as skin permeation enhancers in the transdermal drug delivery of two drugs: ondansetron hydrochloride and diltiazem hydrochloride, formulated as hydrogels. The enhancers are used alone, or in combination with iontophoresis (0.3 mA - 8h). After 1h of pre-treatment with 0.16 M enhancer solutions in propylene glycol (PG), passive and iontophoretic 24 h in vitro studies across dermatomed porcine skin were performed using vertical Franz diffusion cells. Data obtained showed that the nonionic surfactant C(12)E(5) was the most effective permeation enhancer, both for the passive process as well as for samples subjected to iontophoresis, resulting in cumulative amounts of ondansetron HCl after 24h of approximately 93 µg/cm(2) and 336 µg/cm(2), respectively. Data obtained using diltiazem HCl showed a similar trend. The use of the nonionic surfactant C(12)E(5) resulted in higher enhancement ratios (ER) in passive studies, but C(12)E(8) yielded slightly higher values of drug permeated (2678 µg/cm(2)) than C(12)E(5) (2530 µg/cm(2)) when iontophoresis was also employed. Skin integrity studies were performed to assess potential harmful effects on the tissues resulting from the compounds applied and/or from the methodology employed. Skin samples used in permeation studies visualized by light microscopy and Scanning Electron Microscopy (SEM) at different levels of magnification did not show significant morphological and structural changes, when compared to untreated samples. Complementary studies were performed to gain information regarding the relative cytotoxicity of the penetration enhancers on skin cells. MTS assay data using human epidermal keratinocytes (HEK) and human dermal fibroblasts (HDF) indicated that HEK are more sensitive to the presence of the enhancers than HDF and that the toxicity of these compounds is enhancer molecular weight dependent.

Aggregation and gelation in hydroxypropylmethyl cellulose aqueous solutions.

In this work we present an analysis of the thermal behavior of hydroxypropylmethyl cellulose aqueous solutions, from room temperature to higher temperatures, above gelation. We focus on significant aspects, essentially overlooked in previous work, such as the correlation between polymer hydrophobicity and rheological behavior, and the shear effect on thermal gelation. Micropolarity and aggregation of the polymer chains were monitored by both UV/vis and fluorescence spectroscopic techniques, along with polarized light microscopy. Gel formation upon heating was investigated using rheological experiments, with both large strain (rotational) tests at different shear rates and small strain (oscillatory) tests. The present observations allow us to compose a picture of the evolution of the system upon heating: firstly, polymer reptation increases due to thermal motion, which leads to a weaker network. Secondly, above 55 degrees C, the polymer chains become more hydrophobic and polymer clusters start to form. Finally, the number of physical crosslinks between polymer clusters and the respective lifetimes increase and a three-dimensional network is formed. This network is drastically affected if higher shear rates, at non-Newtonian regimes, are applied to the system.

Mucoadhesion and the gastrointestinal tract.

The concept of mucoadhesion is one that has the potential to improve the highly variable residence times experienced by drugs and dosage forms at various sites in the gastrointestinal tract, and consequently, to reduce variability and improve efficacy. Intimate contact with the mucosa should enhance absorption or improve topical therapy. A variety of approaches have been investigated for mucoadhesion in the gastrointestinal tract, particularly for the stomach and small intestine. Despite interesting results in these sites, mucoadhesive approaches have not yet shown success in humans. The potential of the lower gut for these applications has been largely neglected, although the large intestine in particular may benefit, and the colon has several factors that suggest mucoadhesion could be successful there, including lower motility and the possibility of a lower mucus turnover and thicker mucus layer. In vitro studies on colonic mucoadhesion show promise, and rectal administration has shown some positive results in vivo. This review considers the background to mucoadhesion with respect to the physiological conditions of the gastrointestinal tract as well as the principles that underlie this concept. Mucoadhesive approaches to gastrointestinal drug delivery will be examined, with particular attention given to the lower gut.

Drug transport in responding lipid membranes can be regulated by an external osmotic gradient.

In this paper, we demonstrate, for the first time, how an external osmotic gradient can be used to regulate diffusion of solutes across a lipid membrane. We present experimental and theoretical studies of the transport of different solutes across a monoolein membrane in the presence of an external osmotic gradient. The osmotic gradient introduces phase transformations in the membrane, and it causes nonlinear transport behavior. The external gradient can thus act as a kind of switch for diffusive transport in the skin and in controlled release drug formulations.