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Trazodone is a triazolpyridine derivative approved for the treatment of depression, and currently marketed as oral formulations. The transdermal administration of this drug could reduce side effects, related to peak plasma concentration, and improve patient adherence due to a reduced administration frequency. The aims of this work were: (a) the evaluation of the effect of pH vehicle and permeation enhancers on trazodone permeability across porcine skin ex-vivo; (b) the development and optimization of a transdermal drug delivery system containing trazodone hydrochloride. From the results obtained, it was found that the effect of pH of the vehicle on the permeation of trazodone across the skin is quite complex, because it influences both solubility and partitioning and that the presence of fatty acids in the vehicle has a notable effect on permeation (the enhancement factor obtained was approx. 100). For both the fatty acid selected (oleic and lauric) a parabolic relationship between the transdermal flux and the concentration was found, with an optimum activity in the range 2-3 %. In the second part of the work, different patches were prepared and tested ex-vivo. Overall, the results obtained seem to highlight that drug loading, rather than the components of the adhesive matrix, plays the most relevant role for the permeation of trazodone. The addition of lauric acid, which produced a considerable enhancement in solution, was not effective when included in the patch. The obtained data are promising although probably not clinically relevant for the treatment of depression, but might be interesting for the treatment of insomnia and anxiety disorder, which require much lower doses.
Assuntos
Administração Cutânea , Absorção Cutânea , Trazodona , Trazodona/administração & dosagem , Trazodona/farmacocinética , Animais , Suínos , Absorção Cutânea/efeitos dos fármacos , Pele/metabolismo , Pele/efeitos dos fármacos , Permeabilidade , Ácido Oleico/química , Solubilidade , Concentração de Íons de Hidrogênio , Ácidos Láuricos/química , Ácidos Láuricos/administração & dosagem , Adesivo Transdérmico , Química Farmacêutica/métodos , Antidepressivos de Segunda Geração/administração & dosagem , Antidepressivos de Segunda Geração/farmacocinética , Sistemas de Liberação de Medicamentos/métodosRESUMO
TPGS (D-α-tocopheryl polyethylene glycol 1000 succinate) polymeric micelles show interesting properties for ocular administration thanks to their solubilization capability, nanometric size and tissue penetration ability. However, micelles formulations are generally characterized by low viscosity, poor adhesion and very short retention time at the administration site. Therefore, the idea behind this work is the preparation and characterization of a crosslinked film based on xanthan gum that contains TPGS micelles and is capable of controlling their release. The system was loaded with melatonin and cyclosporin A, neuroprotective compounds to be delivered to the posterior eye segment. Citric acid and heating at different times and temperatures were exploited as crosslinking approach, giving the possibility to tune swelling, micelles release and drug release. The biocompatibility of the platform was confirmed by HET-CAM assay. Ex vivo studies on isolated porcine ocular tissues, conducted using Franz cells and two-photon microscopy, demonstrated the potential of the xanthan gum-based platform and enlightened micelles penetration mechanism. Finally, the sterilization step was approached, and a process to simultaneously crosslink and sterilize the platform was developed.
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Administração Oftálmica , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Micelas , Fármacos Neuroprotetores , Polissacarídeos Bacterianos , Vitamina E , Polissacarídeos Bacterianos/química , Animais , Suínos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacocinética , Vitamina E/química , Vitamina E/administração & dosagem , Preparações de Ação Retardada/química , Ciclosporina/administração & dosagem , Ciclosporina/química , Melatonina/administração & dosagem , Melatonina/química , Melatonina/farmacologia , Melatonina/farmacocinética , Esterilização , Reagentes de Ligações Cruzadas/química , Portadores de Fármacos/química , Olho/efeitos dos fármacos , Olho/metabolismo , Sistemas de Liberação de Medicamentos/métodosRESUMO
One of the most innovative strategies for administrating bioactive molecules is the design of adequate drug delivery systems [...].
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Ocular drug delivery is challenging due to the poor drug penetration across ocular barriers and short retention time of the formulation at the application site. Films, applied as inserts or implants, can be used to increase residence time while controlling drug release. In this work, hydrophilic films made of hyaluronic acid and two kinds of PVA were loaded with dexamethasone (included as hydroxypropylcyclodextrin complex) and levofloxacin. This association represents one of the main treatments for the post cataract surgery management, and it is also promising for eye infections with pain and inflammation. Films were characterized in terms of swelling and drug release and were then applied to porcine eye bulbs and isolated ocular tissues. Film swelling leads to the formation of either a gel (3D swelling) or a larger film (2D swelling) depending on the type of PVA used. Films, prepared in an easy and scalable method, demonstrated high loading capacity, controlled drug release and the capability to deliver dexamethasone and levofloxacin to the cornea and across the sclera, to potentially target also the posterior eye segment. Overall, this device can be considered a multipurpose delivery platform intended for the concomitant release of lipophilic and hydrophilic drugs.
Assuntos
Ácido Hialurônico , Levofloxacino , Suínos , Animais , Sistemas de Liberação de Medicamentos , Córnea , DexametasonaRESUMO
Corticosteroids, although highly effective for the treatment of both anterior and posterior ocular segment inflammation, still nowadays struggle for effective drug delivery due to their poor solubilization capabilities in water. This research work aims to develop nanostructured lipid carriers (NLC) intended for periocular administration of dexamethasone acetate to the posterior segment of the eye. Pre-formulation studies were initially performed to find solid and liquid lipid mixtures for dexamethasone acetate solubilization. Pseudoternary diagrams at 65 °C were constructed to select the best surfactant based on the macroscopic transparency and microscopic isotropy of the systems. The resulting NLC, obtained following an organic solvent-free methodology, was composed of triacetin, Imwitor® 491 (glycerol monostearate >90%) and tyloxapol with Z-average = 106.9 ± 1.2 nm, PDI = 0.104 ± 0.019 and zeta potential = -6.51 ± 0.575 mV. Ex vivo porcine sclera and choroid permeation studies revealed a considerable metabolism in the sclera of dexamethasone acetate into free dexamethasone, which demonstrated higher permeation capabilities across both tissues. In addition, the NLC behavior once applied onto the sclera was further studied by means of multiphoton microscopy by loading the NLC with the fluorescent probe Nile red.
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The topical use of imiquimod (IMQ), a non-specific immune response modifier, showed to be a promising therapeutic option for the early-stage treatment of some type of oral cancer, even when performed with a formulation (Aldara®) developed and approved for skin application. The aim of this work was the development of buccal formulations for the topical administration of IMQ with improved mucosal retention and reduced trans-mucosal permeation when compared to the reference formulation. Three different hydrogels based on carboxymethyl chitosan (CMChit), sodium alginate (A), and xanthan gum (X) in different combinations were prepared, and the loading of imiquimod was successfully performed by using a micellar formulation based on d-α-tocopheril polyethylene glycol 100 succinate (TPGS). Except for CMChit formulation, in all the other cases, the performance in vitro on the mucosa resulted comparable to the commercial formulation, despite the drug loading being 50-fold lower. Converting the gels in films did not modify the IMQ accumulated with respect to the correspondent gel formulation but produced as a positive effect a significant reduction in the amount permeated. Compared to the commercial formulation, this reduction was significant (p < 0.01) in the case of X film, resulting in an improvement of the retained/permeated ratio from 1 to 5.44. Mucoadhesion evaluation showed similar behavior when comparing the developed gels and the commercial formulation, and an excellent bioadhesion was observed for the films.
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Cyclosporine is an immunomodulatory drug commonly used for the treatment of mild-to-severe dry eye syndrome as well as intermediate and posterior segment diseases as uveitis. The ocular administration is however hampered by its relatively high molecular weight and poor permeability across biological barriers. The aim of this work was to identify a micellar formulation with the ability to solubilize a considerable amount of cyclosporine and promote its transport across ocular barriers. Non-ionic amphiphilic polymers used for micelles preparation were tocopherol polyethylene glycol 1000 succinate (TPGS) and Solutol® HS15. Furthermore, the addition of alpha-linolenic acid was assessed. A second aim was to evaluate micelles fate in the ocular tissues (cornea and sclera) to shed light on penetration mechanisms. This was possible by extracting and quantifying both drug and polymer in the tissues, by studying TPGS hydrolysis in a bio-relevant environment and by following micelles penetration with two-photon microscopy. Furthermore, TPGS role as permeation enhancer on the cornea, with possible irreversible modifications of tissue permeability, was analyzed. Results showed that TPGS micelles (approx. 13 nm in size), loaded with 5 mg/ml of cyclosporine, promoted drug retention in both the cornea and the sclera. Data demonstrated that micelles behavior strictly depends on the tissue: micelles disruption occurs in contact with the cornea, while intact micelles diffuse in the interfibrillar pores of the sclera and form a reservoir that can sustain over time drug delivery to the deeper tissues. Finally, cornea quickly restore the barrier properties after TPGS removal from the tissue, demonstrating its potential good tolerability for ocular application.
Assuntos
Ciclosporina , Micelas , Córnea , Portadores de Fármacos , Polietilenoglicóis , Polímeros , Solubilidade , Succinatos , Tocoferóis , Vitamina E , Ácido alfa-LinolênicoRESUMO
An innovative and sensitive HPLC-UV method for the extraction and quantification of methotrexate (MTX) in skin layers was developed and validated. Owing to the physico-chemical characteristics of the drug and the nature of the tissue, it was necessary to use folic acid (FA) as an internal standard for MTX quantification in the dermis. MTX (and FA) analysis was performed on a Phenomenex Jupiter C18 column, using a 50 mm sodium acetate buffer (pH 3.6) and methanol mixture (87:13, v/v) as mobile phase, pumped at 1 ml/min. The absorbance was monitored at 290 nm. The method was selective, linear in the range 0.11-8.49 µg/ml for extraction solvent and 0.05-8.94 µg/ml for pH 7.4 phosphate-buffered saline, precise and accurate, with lower limits of quantitation of 0.11 µg/ml (extraction solvent) and 0.05 µg/ml (pH 7.4 phosphate-buffered saline). The method developed is suitable for the quantification of MTX in skin layers at the end of in vitro permeation experiments; the overall mass balance was 96.5 ± 1.4%, in line with the requirements of the Organisation for Economic Co-operation and Development guideline for the testing of the chemicals (Skin absorption: in vitro method).
Assuntos
Metotrexato , Fosfatos , Cromatografia Líquida de Alta Pressão/métodos , Metotrexato/análise , Reprodutibilidade dos Testes , SolventesRESUMO
The greatest achievement in the advanced drug delivery field should be the optimization of non-invasive formulations for the delivery of high molecular weight compounds. Peptides, proteins, and other macromolecules can have poor membrane permeation, principally due to their large molecular weight. The aim of this work was to explore the possibility of administering fluorescently labeled dextrans (molecular weight 4-150 kDa) across the buccal mucosa. Permeation experiments across pig esophageal mucosa were carried out using fatty acids and bile salts as penetration enhancers. The data obtained show that it is possible to increase or promote the mucosa permeation of high molecular weight dextrans by using caprylic acid or sodium taurocholate as the chemical enhancers. With these enhancers, dextrans with molecular weight of 70 and 150 kDa, that in passive conditions did not permeate, could cross the mucosa in detectable amounts. FD-70 and FD-150 showed comparable permeability values, despite the molecular weight difference. The results obtained in the present work suggest that the buccal administration of high molecular weight compounds is feasible.
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There is increasing consensus in considering statins beneficial for age-related macular degeneration and in general, for immune and inflammatory mediated diseases affecting the posterior segment of the eye. However, all available data relate to oral administration, and safety and effectiveness of statins directly administered to the eye are not yet known, despite their ophthalmic administration could be beneficial. The aim was the development and the characterization of polymeric micelles based on TPGS or TPGS/poloxamer 407 to increase simvastatin solubility and stability and to enhance the delivery of the drug to the posterior segment of the eye via trans-scleral permeation. Simvastatin was chosen as a model statin and its active hydroxy acid metabolite was investigated as well. Results demonstrated that polymeric micelles increased simvastatin solubility at least 30-fold and particularly TPGS/poloxamer 407 mixed micelles, successfully stabilized simvastatin over time, preventing the hydrolysis when stored for 1 month at 4 °C. Furthermore, both TPGS (1.3 mPas) and mixed micelles (33.2 mPas) showed low viscosity, suitable for periocular administration. TPGS micelles resulted the best performing in delivery simvastatin either across conjunctiva or sclera in ex vivo porcine models. The data pave the way for a future viable ocular administration of statins.
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A simple and sensitive HPLC method for the quantification of budesonide in skin layers was developed and validated. Budesonide was extracted from stratum corneum, epidermis and dermis by means of a mixture of acetonitrile:water (recovery > 90%). Budesonide quantification was performed with a RP-C18 column using methanol and water mixture (69:31, v/v) as mobile phase, pumped at 0.8 ml/min. The absorbance was monitored at 254 nm. The method resulted to be selective, linear in the range 0.05-5 or 10 µg/ml, precise and accurate. LLOQ resulted to be 0.05 µg/ml. The developed method appeared to be appropriate for the quantification of budesonide in skin layers at the end of in vitro permeation experiments since the recovery of the applied dose was 97 ± 1%, in line with requirement of the OECD guideline for the testing of the chemicals (Skin absorption: in vitro method).
Assuntos
Budesonida/análise , Cromatografia Líquida de Alta Pressão/métodos , Pele/química , Animais , Budesonida/química , Budesonida/metabolismo , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Pele/metabolismo , Absorção Cutânea , SuínosRESUMO
The aim of this work was to evaluate the ex vivo effect of the combination of two strategies, complexation with cyclodextrin, and poloxamer hydrogels, for improving water solubility in the dermal absorption of budesonide. Two hydrogels containing 20% poloxamer 407, alone or in combination with poloxamer 403, were prepared. Each formulation was loaded with 0.05% budesonide, using either pure budesonide or its inclusion complex with hydroxypropyl-ß-cyclodextrin, and applied in finite dose conditions on porcine skin. The obtained results showed that for all formulations, budesonide accumulated preferentially in the epidermis compared to the dermis. The quantity of budesonide recovered in the receptor compartment was, in all cases, lower than the LOQ of the analytical method, suggesting the absence of possible systemic absorption. The use of a binary poloxamer mixture reduced skin retention, in line with the lower release from the vehicle. When the hydrogels were formulated with the inclusion complex, an increase in budesonide skin retention was observed with both hydrogels. Poloxamer hydrogel proved to be a suitable vehicle for cutaneous administration of budesonide.
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Among enhancing strategies proposed in ocular drug delivery, a rising interest is directed to cell penetrating peptides (CPPs), amino acid short sequences primarily known for their intrinsic ability to cell internalization and, by extension, to cross biological barriers. In fact, CPPs may be considered as carrier for delivering therapeutic agents across biological membranes, including ocular tissues. Several CPPs have been proposed in ophthalmic delivery, and, among them, penetratin (PNT), a 16-amino acids natural peptide, stands out. Therefore, we describe the synthesis via the mimotopic approach of short fluorescently labeled analogues of both PNT and its reversed sequence PNT-R. Their ability to cross ocular membranes was checked ex vivo using freshly explanted porcine cornea. Furthermore, some sequences were studied by circular dichroism. Despite the hydrophilic nature and the relatively high molecular weight (approx. 1.6 kDa), all analogues showed a not negligible trans-corneal diffusion, indicating a partial preservation of penetration activity, even if no sequences reached the noteworthy ability of PNT. It was not possible to find a correlation between structure and corneal penetration ability, and further studies, exploring peptides distribution within corneal layers, for example using imaging techniques, deserve to be performed to figure out a possible difference in intracellular delivery.
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Crisaborole, a nonsteroidal phosphodiesterase 4 inhibitor, represents the first nonsteroidal medication approved for the treatment of atopic dermatitis in over a decade. In this work, crisaborole skin permeation and retention was studied in vitro from a 2% ointment using porcine skin as barrier. Crisaborole was also characterized in terms of thermal behavior, solubility, and logP. Control experiments were performed also on tape stripped skin to clarify the role of stratum corneum in drug partitioning and permeation across the skin. The results obtained indicate that crisaborole accumulates into the skin in considerable amounts after application of a topical lipophilic ointment. Crisaborole shows more affinity for the dermis compared to the epidermis despite its relatively high value of partition coefficient; stratum corneum analysis revealed a low affinity of the drug for this skin layer. Skin penetration across hair follicles or sebaceous glands can be a reason for the high dermis retention and is worth further investigation. The comparison with data obtained from a solution in acetonitrile suggests that the formulation plays a certain role in determining the relative distribution of crisaborole in the skin layers and in the receptor compartment.
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This paper addresses the problem of ocular delivery of lipophilic drugs. The aim of the paper is the evaluation of polymeric micelles, prepared using TPGS (d-α-Tocopheryl polyethylene glycol 1000 succinate), a water-soluble derivative of Vitamin E and/or poloxamer 407, as a vehicle for the ocular delivery of dexamethasone, cyclosporine, and econazole nitrate. The research steps were: (1) characterize polymeric micelles by dynamic light scattering (DLS) and X-ray scattering; (2) evaluate the solubility increase of the three drugs; (3) measure the in vitro transport and conjunctiva retention, in comparison to conventional vehicles; (4) investigate the mechanisms of enhancement, by studying drug release from the micelles and transconjunctival permeation of TPGS; and (5) study the effect of micelles application on the histology of conjunctiva. The data obtained demonstrate the application potential of polymeric micelles in ocular delivery, due to their ability to increase the solubility of lipophilic drugs and enhance transport in and across the conjunctival epithelium. The best-performing formulation was the one made of TPGS alone (micelles size ≈ 12 nm), probably because of the higher mobility of these micelles, an enhanced interaction with the conjunctival epithelium, and, possibly, the penetration of intact micelles.
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Crisaborole is a boron compound recently approved by the US Food and Drug Administration as a 2% ointment for the treatment of mild to moderate atopic dermatitis. This work describes a simple method for the quantification of the drug in the skin layers at the end of in-vitro permeation experiments. Chromatographic separation was carried out on a reverse-phase C18 column using a mixture of trifluoroacetic acid 0.05%-acetonitrile (55:45, v/v) as mobile phase, pumped at 1 ml/min. Column temperature was 35°C and UV detection was performed at 250 nm. The method was linear in the range of concentration from 0.06 to 6 µg/ml (R2 = 1) and was selective, precise and accurate. Depending on the solvent used, the LOQ ranged from 0.014 to 0.030 µg/ml and the LOD from 0.005 to 0.010 µg/ml. The extraction from all the skin layers was quantitative. The developed method was successfully tested in an in-vitro permeation study, proving to be an effective tool in the development of new formulations containing crisaborole.
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Compostos de Boro/análise , Compostos de Boro/isolamento & purificação , Compostos Bicíclicos Heterocíclicos com Pontes/análise , Compostos Bicíclicos Heterocíclicos com Pontes/isolamento & purificação , Pele/química , Animais , Compostos de Boro/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia de Fase Reversa/métodos , Dermatite Atópica , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Espectrofotometria Ultravioleta , SuínosRESUMO
Ucuùba fat is fat obtained from a plant found in South America, mainly in Amazonian Brazil. Due to its biocompatibility and bioactivity, Ucuùba fat was used for the production of ketoconazole-loaded nanostructured lipid carriers (NLC) in view of an application for the treatment of onychomycosis and other persistent fungal infections. The development and optimization of Ucuùba fat-based NLC were performed using a Box-Behnken design of experiments. The independent variables were surfactant concentration (% w/v), liquid lipids concentration (% w/v), solid lipids concentration (% w/v), while the outputs of interest were particle size, polydispersity index (PDI) and drug encapsulation efficiency (EE). Ucuùba fat-based NLC were produced and the process was optimized by the development of a predictive mathematical model. Applying the model, two formulations with pre-determined particle size, i.e., 30 and 85 nm, were produced for further evaluation. The optimized formulations were characterized and showed particle size in agreement to the predicted value, i.e., 33.6 nm and 74.6 nm, respectively. The optimized formulations were also characterized using multiple techniques in order to investigate the solid state of drug and excipients (DSC and XRD), particle morphology (TEM), drug release and interactions between the formulation components (FTIR). Furthermore, particle size, surface charge and drug loading efficiency of the formulations were studied during a one-month stability study and did not show evidence of significant modification.
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After application to the skin surface, a topical formulation is submitted to changes in composition produced by evaporation of volatile components, penetration of components into the skin and extraction of skin components ("vehicle metamorphosis"). The aim of this work was to study the effect of vehicle metamorphosis on skin delivery from microemulsions containing triamcinolone acetonide. The microemulsions were prepared and characterized for water evaporation kinetics, in vitro release and skin permeation and retention. Skin retention experiments were performed on full thickness pig ear skin, in both occluded infinite and un-occluded finite dose conditions. For comparison purposes, two creams, the commercial Ledercort® and a vanishing cream, were tested. With triamcinolone acetonide water evaporation does not modify skin retention, probably for the lipophilic nature of the drug. However, if water is eliminated from the microemulsions, the performance is reduced, probably because drug partitioning from vehicle to stratum corneum is disfavored. If a water-soluble drug (methyl prednisolone sodium succinate) is used, infinite dose application in occlusive conditions increases in a significant way the amount of drug retained in the skin. The involved mechanisms are probably stratum corneum swelling and increase of stratum corneum/viable epidermis partitioning.
Assuntos
Glucocorticoides/administração & dosagem , Absorção Cutânea , Triancinolona Acetonida/administração & dosagem , Animais , Liberação Controlada de Fármacos , Emulsões , Excipientes/administração & dosagem , Excipientes/química , Glucocorticoides/química , Pele/metabolismo , Suínos , Triancinolona Acetonida/químicaRESUMO
INTRODUCTION: Polymeric micelles represent nowadays an interesting formulative approach for ocular drug delivery, as they act as solubility enhancers of poorly soluble drugs and promote drug transport across cornea and sclera. In particular, in the last 5 years polymeric nanomicelles have been increasingly investigated to overcome some of the important challenges of the topical treatment of ocular diseases. AREAS COVERED: The aim of this review was to gather up-to-date information on the different roles that polymeric micelles (commonly in the nanosize scale) can play in ocular delivery. Thus, after a general description of ocular barriers and micelles features, the attention is focused on those properties that are relevant for ophthalmic application. Finally, their efficacy in improving the ocular delivery of different classes of therapeutics (anti-inflammatory, immunosuppressant, antiglaucoma, antifungal, and antiviral drugs) are reported. EXPERT OPINION: Although still a few, in vivo experiments have clearly demonstrated the capability of polymeric nanomicelles to overcome a variety of hurdles associated to ocular therapy, notably increasing drug bioavailability. However, there are still some very important issues to be solved, such as tolerability and stability; additionally, the role of micelles in drug uptake by the ocular tissues and their potential for the treatment of posterior eye diseases still need to be clarified/verified.
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Sistemas de Liberação de Medicamentos , Oftalmopatias/tratamento farmacológico , Polímeros/química , Administração Oftálmica , Animais , Disponibilidade Biológica , Córnea/metabolismo , Composição de Medicamentos , Humanos , Micelas , Esclera/metabolismo , SolubilidadeRESUMO
BACKGROUND/AIMS: Infantile hemangioma (IH), the most common benign tumor of childhood, is currently treated with propranolol. The aim of this work was to study in vitro propranolol permeation and skin retention from an original polymeric film, composed of polyvinyl alcohol and an acrylic polymer. METHODS: Propranolol polymeric films were applied in occlusive and non-occlusive conditions, on either full thickness skin or isolated epidermis. Experiments were performed also on stripped skin, to simulate the skin permeability of damaged skin. RESULTS: The results obtained underline the importance of determining skin concentration when dealing with drugs that should act on the skin. Skin permeation data are a poor predictor of skin retention data, in particular in critical conditions, such as heavily damaged skin. CONCLUSION: The film proposed for the treatment of IH (and other vascular diseases) with propranolol seems to be a good alternative to semisolid formulations, in particular if used in non-occlusive conditions, because it guarantees high proportions of drug retained in the skin, compared to permeated across the skin, reducing the risks of systemic side effect.