Ana Cristina Calpena Campmany

Design and optimization of self-nanoemulsifying drug delivery systems (SNEDDS) for enhanced dissolution of gemfibrozil.

Self-nanoemulsifying drug delivery systems of gemfibrozil were developed under Quality by Design approach for improvement of dissolution and oral absorption. Preliminary screening was performed to select proper components combination. Box-Behnken experimental design was employed as statistical tool to optimize the formulation variables, X(1) (Cremophor(®) EL), X(2) (Capmul(®) MCM-C8), and X(3) (lemon essential oil). Systems were assessed for visual characteristics (emulsification efficacy), turbidity, droplet size, polydispersity index and drug release. Different pH media were also assayed for optimization. Following optimization, the values of formulation components (X(1), X(2), and X(3)) were 32.43%, 29.73% and 21.62%, respectively (16.22% of gemfibrozil). Transmission electron microscopy demonstrated spherical droplet morphology. SNEEDS release study was compared to commercial tablets. Optimized SNEDDS formulation of gemfibrozil showed a significant increase in dissolution rate compared to conventional tablets. Both formulations followed Weibull mathematical model release with a significant difference in t(d) parameter in favor of the SNEDDS. Equally amodelistic parameters were calculated being the dissolution efficiency significantly higher for SNEDDS, confirming that the developed SNEDDS formulation was superior to commercial formulation with respect to in vitro dissolution profile. This paper provides an overview of the SNEDDS of the gemfibrozil as a promising alternative to improve oral absorption.

Development and Characterization of a Novel Nystatin‐Loaded Nanoemulsion for the Buccal Treatment of Candidosis: Ultrastructural Effects and Release Studies

Oral candidosis is a common opportunistic infection in patients suffering from mucositis (after chemotherapy and radiotherapy administration) and must be treated to prevent infecting other tissue. Nystatin (Nys) is one of the most prescribed drugs to treat this pathology, but because of its physicochemical properties, its pharmaceutical-technological requirements make it a challenge. The purpose of this work was the development and characterization of an optimal Nys delivery system for the potential treatment of oral candidosis avoiding undesirable side effects and toxicity of potential systemic absorption. A nanoemulsion was developed, evaluated, and characterized. It has been formulated successfully as a stable nanoemulsion with a droplet size of 138 nm. Release parameters were estimated using different mathematical approaches, and from the results of ex vivo permeation study of Nys through porcine buccal mucosa, it could be hypothesized that no systemic effects would happen. Microbiologic studies performed revealed an enhanced antifungal effect of the Nys-loaded nanoemulsion. Also, the evaluation of the treated buccal mucosa ultrastructure by transmission electron microscopy revealed a harmless effect. Thus, it could be inferred that the developed formulation could be potentially utilized for candidosis infection under mucositis conditions.

In vivo and in vitro evaluation of the use of a newly developed melatonin loaded emulsion combined with UV filters as a protective agent against skin irradiation

BACKGROUND Melatonin has attracted attention because of their high antioxidant and anticarcinogenic activity. Otherwise, the use of sunscreens is recommended for patients after chemotherapy and radiotherapy treatments or to prevent UV radiation-induced skin damages that may result in pre-cancerous and cancerous skin lesions. OBJECTIVE To evaluate the beneficial influence of melatonin in topical sunscreen emulsions combined with three common ultraviolet filters. METHODS After the formulation characterization in terms of rheology, stability studies were performed. Release studies let us to evaluate its mechanism of delivery and ex vivo permeation study through human skin, the amount of melatonin retained. The antioxidant activity assay was also carried out, and finally the in vivo photoprotective effect in rats was tested as transepidermal water loss and erythema formation. RESULTS The rheological behaviour of formulations was pseudoplastic fluid, all emulsions had good physical stability. Release studies showed a trend of enhancement in melatonin release from emulsions incorporating UV filters and followed a Weibull model. Melatonin permeation was higher from the emulsion containing melatonin combined with a mixture of three ultraviolet filters (MMIX) formulation. Equally this formulation exhibited the highest radical scavenging activity. Finally the photoprotective assay showed that only skin areas treated with this formulation were statistically equivalent to the unirradiated control area. CONCLUSION MMIX formulation would be a promising formulation for preventing the undesirable adverse effects of UV skin irradiation because melatonin not only acts as a potent antioxidant itself, but also is capable of activating an endogenous enzymatic protective system against oxidative stress.

Freeze drying optimization of polymeric nanoparticles for ocular flurbiprofen delivery: effect of protectant agents and critical process parameters on long-term stability

Abstract Context: The stabilization of flurbiprofen loaded poly-ɛ-caprolactone nanoparticles (FB-PɛCL-NPs) for ocular delivery under accurate freeze-drying (FD) process provides the basis for a large-scale production and its commercial development. Objective: Optimization of the FD to improve long-term stability of ocular administration’s FB-PɛCL-NPs. Methods: FB-PɛCL-NPs were prepared by solvent displacement method with poloxamer 188 (P188) as stabilizer. Freezing and primary drying (PD) were studied and optimized through freeze-thawing test and FD microscopy. Design of experiments was used to accurate secondary drying (SD) conditions and components concentration. Formulations were selected according to desired physicochemical properties. Furthermore, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were used to study interactions components. Results: Optimized FB-PɛCL-NPs, stabilized with 3.5% (w/w) P188 and protected with 8% (w/w) poly(ethylene glycol), was submitted to precooling at +10 °C for 1 h, freezing at −50 °C for 4 h, PD at +5 °C and 0.140 mbar for 24 h and a SD at +45 °C during 10 h. These conditions showed 188.4 ± 1.3 nm, 0.087 ± 0.014, 85.5 ± 1.4%, 0.61 ± 0.12%, −16.4 ± 0.1 mV and 325 ± 7 mOsm/kg of average size, polydispersity index, entrapment efficiency, residual moisture, surface charge and osmolality, respectively. It performed a long-term stability >12 months. DSC and XRD spectra confirmed adequate chemical interaction between formulation components and showed a semi-crystalline state after FD. Conclusions: An optimal freeze dried ocular formulation was achieved. Evidently, the successful design of this promising colloidal system resulted from rational cooperation between a good formulation and the right conditions in the FD process.AbstractContext: The stabilization of flurbiprofen loaded poly-ɛ-caprolactone nanoparticles (FB-PɛCL-NPs) for ocular delivery under accurate freeze-drying (FD) process provides the basis for a large-scale production and its commercial development.Objective: Optimization of the FD to improve long-term stability of ocular administration’s FB-PɛCL-NPs.Methods: FB-PɛCL-NPs were prepared by solvent displacement method with poloxamer 188 (P188) as stabilizer. Freezing and primary drying (PD) were studied and optimized through freeze-thawing test and FD microscopy. Design of experiments was used to accurate secondary drying (SD) conditions and components concentration. Formulations were selected according to desired physicochemical properties. Furthermore, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were used to study interactions components.Results: Optimized FB-PɛCL-NPs, stabilized with 3.5% (w/w) P188 and protected with 8% (w/w) poly(ethylene glycol), was submitted to precooling at +10...

Influence of freeze-drying and γ-irradiation in preclinical studies of flurbiprofen polymeric nanoparticles for ocular delivery using d-(+)-trehalose and polyethylene glycol.

This study investigated the suspension of poly(e-caprolactone) nanoparticles as an ocular delivery system for flurbiprofen (FB-PeCL-NPs) in order to overcome the associated problems, such as stability, sterility, tolerance, and efficacy, with two different FB-PeCL-NP formulations. The formulations were stabilized with poloxamer 188 (1.66% and 3.5%) and submitted individually for freeze-drying and γ-irradiation with polyethylene glycol 3350 (PEG3350) and d-(+)-trehalose (TRE). Both formulations satisfied criteria according to all physicochemical parameters required for ocular pharmaceuticals. The FB-PeCL-NP formulations showed non-Newtonian behavior and sustained drug release. Ex vivo permeation analysis using isolated ocular pig tissues suggested that the presence of PEG3350 results in a reduction of FB transcorneal permeation. Moreover, TRE improved the penetration of FB across the cornea, especially after γ-irradiation. In addition, both formulations did not show a significant affinity in increasing FB transscleral permeation. Both formulations were classified as nonirritating, safe products for ophthalmic administration according to hen’s egg test-chorioallantoic membrane and Draize eye test. Furthermore, an in vivo anti-inflammatory efficacy test showed that irradiated FB-PeCL-NPs prepared with PEG3350 (IR-NPsPEG) have longer anti-inflammatory effects than those presented with irradiated FB-PeCL-NPs prepared with TRE (IR-NPsTRE). IR-NPsPEG showed a suitable physical stability after an aqueous reconstitution over >30 days. This study concludes that both formulations meet the Goldman’s criteria and demonstrate how irradiated nanoparticles, with innovative permeation characteristics, could be used as a feasible alternative to a flurbiprofen solution for ocular application in clinical trials.This study investigated the suspension of poly(ε-caprolactone) nanoparticles as an ocular delivery system for flurbiprofen (FB-PεCL-NPs) in order to overcome the associated problems, such as stability, sterility, tolerance, and efficacy, with two different FB-PεCL-NP formulations. The formulations were stabilized with poloxamer 188 (1.66% and 3.5%) and submitted individually for freeze-drying and γ-irradiation with polyethylene glycol 3350 (PEG3350) and d-(+)-trehalose (TRE). Both formulations satisfied criteria according to all physicochemical parameters required for ocular pharmaceuticals. The FB-PεCL-NP formulations showed non-Newtonian behavior and sustained drug release. Ex vivo permeation analysis using isolated ocular pig tissues suggested that the presence of PEG3350 results in a reduction of FB transcorneal permeation. Moreover, TRE improved the penetration of FB across the cornea, especially after γ-irradiation. In addition, both formulations did not show a significant affinity in increasing FB transscleral permeation. Both formulations were classified as nonirritating, safe products for ophthalmic administration according to hen’s egg test-chorioallantoic membrane and Draize eye test. Furthermore, an in vivo anti-inflammatory efficacy test showed that irradiated FB-PεCL-NPs prepared with PEG3350 (IR-NPsPEG) have longer anti-inflammatory effects than those presented with irradiated FB-PεCL-NPs prepared with TRE (IR-NPsTRE). IR-NPsPEG showed a suitable physical stability after an aqueous reconstitution over >30 days. This study concludes that both formulations meet the Goldman’s criteria and demonstrate how irradiated nanoparticles, with innovative permeation characteristics, could be used as a feasible alternative to a flurbiprofen solution for ocular application in clinical trials.

Development, physical-chemical stability and release studies of four alcohol-free spironolactone suspensions for use in pediatrics

Dissolution studies have become of great significance because, in most cases, drug dissolution is the rate-limiting step in the absorption process. As occurs with solid oral dosage forms, heterogeneous dispersed systems (suspensions) could also have some problems with their in vitro dissolution. The objective of this study was to evaluate the influence of excipients on the release of spironolactone from four alcohol-free suspensions (pharmaceutical compounding) of spironolactone 5 mg/mL suitable for pediatric use. In addition, the comparison of the physical and chemical stability of the suspensions stored at 4, 25, and 40 °C over a 60-day period has been studied. Rheological behavior, particle size, a prediction of long-term physical stability, pH, and assay of spironolactone by HPLC were assessed at preset times. The dissolution profile of each suspension was determined and compared with that of the commercial tablets. A microbiological study of the best formula was also performed. Chemically, the four spironolactone suspensions were stable for 60 days stored at three temperatures; Suspension IV had optimum pH values and the highest recovery percentage. In terms of physical stability, sedimentation occurred in Suspension IV, and flotation of spironolactone occurred in Suspensions I, II, and III. Suspension III had the highest viscosity and the slowest drug release. Suspension IV was also microbiologically stable for 60 days. In conclusion, Suspension IV had the best properties. The least suitable form was Suspension III, as its high viscosity made it difficult to achieve homogeneous redispersion and it had the slowest dissolution profile.

Pharmaceutical design of a new lactose-free coprocessed excipient: application of hydrochlorothiazide as a low solubility drug model

Most co-processed excipients used in direct-compression tablets contain lactose, which prevents lactose-intolerant patients from taking such tablets. Therefore, a novel lactose-free co-processed excipient for direct compression tablets has been prepared. Microcrystalline cellulose and dicalcium phosphate dehydrate were used as primary excipients which underwent a wet granulation process and factorial experiment in order to ascertain the best prototype. Finally, the best two prototypes were added to hydrochlorothiazide, which has chosen as the model drug because of its low solubility. An extensive characterization of the new excipient as well as the drug loaded tablets is reported. Our results show adequate parameters (rheological and compression behavior, uniformity of weight, disintegration, friability, crushing force and cohesion index). Moreover, the biopharmaceutical profile was evaluated; the tablets exhibits a Weibull kinetic function and fast drug release.Most co-processed excipients used in direct-compression tablets contain lactose, which prevents lactose-intolerant patients from taking such tablets. Therefore, a novel lactose-free co-processed excipient for direct compression tablets has been prepared. Microcrystalline cellulose and dicalcium phosphate dehydrate were used as primary excipients which underwent a wet granulation process and factorial experiment in order to ascertain the best prototype. Finally, the best two prototypes were added to hydrochlorothiazide, which has chosen as the model drug because of its low solubility. An extensive characterization of the new excipient as well as the drug loaded tablets is reported. Our results show adequate parameters (rheological and compression behavior, uniformity of weight, disintegration, friability, crushing force and cohesion index). Moreover, the biopharmaceutical profile was evaluated; the tablets exhibits a Weibull kinetic function and fast drug release.

Antioxidant Nanoplatforms for Dermal Delivery: Melatonin

BACKGROUND Melatonin is emerging as a promising therapeutic agent, mainly due to its role as antioxidant. Substantial evidences show that melatonin is potentially effective in a variety of diseases as cancer, inflammation and neurodegenerative diseases. The excellent antioxidant capacity with pharmacokinetics characteristics and the emerging search for new pharmaceutical nanotechnology based systems, make it particularly attractive to elaborate nanoplatforms based on melatonin for biomedical or cosmetic dermal applications. Different nanosystems for dermal delivery have been investigated. OBJECTIVE This review focuses on nanocarrier production strategies, dermal melatonin application and delivery advances in vivo and in vitro. Equally, future perspectives of this assisted melatonin delivery have also been discussed. METHOD In the current review, we have revised relevant articles of the available literature using the major scientific databases. RESULTS One hundred and thirteen papers were included in the review, the majority of which represent latest researches in nanosized platforms for the dermal delivery of melatonin including liposomes, ethosomes, niosomes, polymeric nanoparticles, solid lipid nanoparticles and cyclodextrins. Furthermore, relevant papers reporting in vitro and in vivo application studies of these nano-based melatonin platforms were also discussed. CONCLUSION The use of nanoplatforms for the dermal melatonin delivery as antioxidant agent could improve the efficacy of conventional melatonin administration due to the preservation of the drug from premature oxidation and the enhancement of drug permeation through the skin providing greater exposure times.

Validated spectrofluorometric method for determination of gemfibrozil in self nanoemulsifying drug delivery systems (SNEDDS)

A spectrofluorometric method has been developed and validated for the determination of gemfibrozil. The method is based on the excitation and emission capacities of gemfibrozil with excitation and emission wavelengths of 276 and 304 nm respectively. This method allows de determination of the drug in a self-nanoemulsifying drug delivery system (SNEDDS) for improve its intestinal absorption. Results obtained showed linear relationships with good correlation coefficients (r(2)>0.999) and low limits of detection and quantification (LOD of 0.075 μg mL(-1) and LOQ of 0.226 μg mL(-1)) in the range of 0.2-5 μg mL(-1), equally this method showed a good robustness and stability. Thus the amounts of gemfibrozil released from SNEDDS contained in gastro resistant hard gelatine capsules were analysed, and release studies could be performed satisfactorily.