The notion of controlled release has been known since the 1930s, but was not significantly develo... more The notion of controlled release has been known since the 1930s, but was not significantly developed until the 1970s. At that time, Alza introduced the concept of a "therapeutic system" and proposed new pharmaceutic formulations. Over time, the idea became one of controlled drug delivery and today concerns not only one rate of release but also the site of release of the active substance. We present here definitions, fundamentals and advantages and disadvantages of currently marketed systems and provide examples illustrating oral, transdermal and respiratory delivery systems. Current research is also examined.
A simple and sensitive HPLC method for the quantification of budesonide in skin layers was develo... more 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).
European Journal of Pharmaceutics and Biopharmaceutics, Jul 1, 2017
Nanoemulsions (NE) have attracted much attention due to their as dermal delivery systems for lipo... more Nanoemulsions (NE) have attracted much attention due to their as dermal delivery systems for lipophilic drugs such as psoralens. However, NE feature low viscosity which might be unsuitable for topical application. In this work, we produced hydrogel-thickened nanoemulsions (HTN) using chitosan as thickening polymer to overcome the low viscosity attributed to NE. The aim of this study is to develop and characterize oil-in-water (o/w) HTN based on sweet fennel and clove essential oil to transdermal delivery of 8-methoxsalen (8-MOP). NE components (oil, surfactant) were selected on the basis of solubility and droplet size and processed in a high-pressure homogenizer (HPH). Drug loaded NE and HTN were characterized for particle size, stability under storage and centrifugation, rheological behavior, transdermal permeation and skin accumulation. Transdermal permeation of 8-MOP from HTN was determined by using Franz diffusion cell. Transdermal permeation from HTN using clove essential oil showed strong dependency chitosan molecular weight. On the other hand, HTN using sweet fennel oil showed an unexpected pH-dependent behavior not fully understood at the moment. These results need further investigation, nevertheless HTN revealed to be interesting and complex dermal delivery systems for poorly soluble drugs.
International Journal of Pharmaceutics, Feb 1, 2018
The aim of this work was to characterize in vitro and ex vivo the performances of Durogesic and o... more The aim of this work was to characterize in vitro and ex vivo the performances of Durogesic and of two bioequivalent generic products, by evaluating: (a) fentanyl release; (b) fentanyl permeation across porcine skin and (c) fentanyl ease of extraction. Additional characteristics studied are the effect of temperature and skin integrity, applied individually or combined, to check a possible synergism. The two generic patches resulted equivalent to the originator according to the new Guideline. Nevertheless, the same data reported in a different way, i.e. considering the total amount of drug permeated from the whole patch over the application time, highlight differences among the patches. The additional tests performed showed that skin integrity does not represent a barrier for fentanyl permeation across the skin, regardless of the type and complexity of the patch. The effect of temperature resulted critical for two out of three patches, probably due to the different composition and to the different structure. The combination of skin damage and elevated temperature did not produce a synergistic effect. Fentanyl extraction was different for the different products and variable according to the conditions used. The results reported in the present work underline the influence of patch composition and complexity on fentanyl extraction, release and skin permeation, in particular in conditions that can be critical, such as elevated temperature. In particular, the effect of critical variables, such as skin integrity and temperature, should be addressed to in the development of a new or new generic patch and new discriminant tests should be developed.
Drug Development and Industrial Pharmacy, May 7, 2017
Mydriatics release from solid and semi-solid ophthalmic formulations using different in vitro met... more Mydriatics release from solid and semi-solid ophthalmic formulations using different in vitro methods The aim of the present paper was the development of semisolid (hydrogels) and solid (film) ophthalmic formulations for the controlled release of two mydriatics: phenylephrine and tropicamide. The formulations-based on polyvinylalchol and hyaluronic acid-were characterized, and release studies were performed with three different in vitro setups , i.e. Franz-type diffusion cell, vial method and inclined plane; for comparison, a solution and a commercial insert, both clinically used to induce mydriasis, were evaluated. Both gels and film allowed for a controlled release of drugs, appearing a useful alternative for mydriatics administration. However, the release kinetic was significantly influenced by the method used, highlighting the need for optimization and standardization of in vitro models for the evaluation of drug release from ophthalmic dosage forms.
Estradiol transdermal application still represents a relevant topic due to the recent controversi... more Estradiol transdermal application still represents a relevant topic due to the recent controversies about hormone replacement therapy, its increasing potential in the treatment of skin aging and wound healing, and the new use of its derivatives in the transdermal contraceptive treatment. The aim of our work was to verify if fresh or frozen rabbit ear skin can be a suitable skin model to study in vitro estradiol transdermal absorption. Fresh rabbit ear skin demonstrated a reasonable model of human epidermis in the investigation of estradiol permeation starting from both solutions and commercial patches.
International Journal of Pharmaceutics, Jul 1, 2018
Psoriasis is a widespread chronic disease affecting 2-4 % of the population in Western countries.... more Psoriasis is a widespread chronic disease affecting 2-4 % of the population in Western countries. Its mild-to-moderate form, representing approximately 80% of the total cases, is treated by topical application, with corticosteroid being the standard treatment. However, in case of psoriasis, no single treatment works for every patient and optimizing topical therapy is a key aspect. A possible alternative is represented by cyclosporine, an immunosuppressant cyclic peptide administered orally in the treatment of the severe form. Its topical application could avoid the problems related to systemic immunosuppression, but the unfavourable physico-chemical properties (MW:1202 Da; LogP≈3) hinder its permeation across the stratum corneum. The aim of the paper was the preparation, characterization and ex-vivo evaluation of cyclosporine loaded microemulsions using oleic acid as oil phase, either Tween® 80 or a soluble derivative of vitamin E (TPGS) as surfactants and either Transcutol®, propylene glycol or 1,3 propanediol as co-surfactants. The issue of formulation viscosity was also addressed 1) by evaluating the thickening of Tween®80-based microemulsions by direct addition of different rheological modifiers 2) by building pseudo-ternary phase diagrams using TPGS, to identify the water/oil/surfactants proportions resulting in viscous self-gelifying systems. Nine formulations (five Tween®80-based and four TPGS-based) were selected, characterized in terms of droplets size (low viscosity systems) or rheological properties (high viscosity systems), loaded with 6 mg/g cyclosporine and applied ex-vivo on porcine skin for 22 h. A relevant skin accumulation was obtained either with a low-viscosity Tween®80-based microemulsion (9.78±3.86 µg/cm 2), or with a high viscosity TPGS-based microemulsion (18.3±5.69 µg/cm 2), with an increase of about 3 and 6 times respectively for comparison with a control cyclosporine solution in propylene glycol. The role of water content, surfactant, co-surfactant and viscosity was also addressed and discussed. The kinetic of skin uptake from the best performing formulation was finally evaluated, highlighting a relatively quick skin uptake and the achievement, after 2 h of contact, of potentially therapeutic cyclosporine skin concentrations.
International Journal of Pharmaceutics, Feb 1, 2001
Triptorelin is a decapeptide analog of luteinizing hormone releasing hormone, currently used for ... more Triptorelin is a decapeptide analog of luteinizing hormone releasing hormone, currently used for the treatment of sex-hormones dependents diseases. The aim of this work was to prepare triptorelin-loaded nanospheres useful for transdermal iontophoretic administration. Nanospheres were prepared with the double emulsion/solvent evaporation technique. The effect of three parameters on the encapsulation efficiency has been determined: the role of the pH of the internal and external aqueous phases, the nature of the organic solvent and the effect of three different poly(lactide-co-glycolide) (PLGA) co-polymers. Particle size, zeta potential and release kinetics were also determined. The encapsulation efficiency varied from 4 to 83% reaching the maximum value when both the internal and the external water phases were brought to pH 7 (isoelectric point of the peptide), methylene chloride was used as solvent of the copolymers and PLGA rich in free carboxylic groups was employed. The release profiles obtained with this co-polymer were characterized by the absence of burst effect. This behavior as well as the high encapsulation efficiency was explained by an ionic interaction occurring between the peptide and the co-polymer. This supports the already expressed theory that the release of peptides and proteins from PLGA nanospheres is also governed by the affinity of the encapsulated molecule versus the polymer. The obtained nanoparticles, regarding their size, amount encapsulated and zeta potential, were shown to be suitable for transdermal iontophoretic administration.
Non-invasive drug delivery to the posterior segment of the eye represents an important unmet medi... more Non-invasive drug delivery to the posterior segment of the eye represents an important unmet medical need, and trans-scleral delivery could be an interesting solution. This review analyses the possibility of trans-scleral drug delivery for high molecular weight compounds, such as proteins and genetic material, which currently represent the most innovative and efficacious molecules for the treatment of many diseases of the posterior segment of the eye. The paper reviews all the barriers, both static and dynamic, involved in trans-scleral administration of drugs, trying to elucidate the role of each of them in the specific case of macromolecules. Delivery systems to sustain drug release and enhancing strategies to improve trans-scleral penetration are also described. Finally, the review approaches the use of computational models as a screening tool to evaluate the feasibility of trans-scleral administration for macromolecules.
Objectives Lipopeptides are compounds derived from microorganisms that exhibit pronounced surface... more Objectives Lipopeptides are compounds derived from microorganisms that exhibit pronounced surface and emulsifying activity. The ability of lipopeptides to interact with stratum corneum lipids makes them candidates as transdermal penetration enhancers. We have investigated the potential of two lipopeptides, fengycin and surfactin, to act as enhancers for the transdermal penetration and skin accumulation of aciclovir. Methods To investigate a possible synergistic effect, surfactin and fengycin were associated with anodal iontophoresis. Permeation experiments were performed using vertical diffusion cells and pig ear skin as barrier. Differential scanning calorimetry was used to study the interaction between fengycin and stratum corneum lipids. Key findings The results obtained indicated that surfactin and fengycin were not suitable to enhance aciclovir flux across the skin, not even when associated with iontophoresis. Aciclovir flux was slightly decreased in passive conditions and unchanged (fengycin) or decreased (surfactin) in anodal iontophoretic conditions. When applied in passive conditions, fengycin and surfactin increased aciclovir concentration in the epidermis by a factor of 2. Conclusions Surfactin and fengycin did not enhance aciclovir transport across the skin (not even when associated with iontophoresis) although they increased aciclovir concentration in the epidermis by a factor of 2.
Journal of the Royal Society Interface, Jan 12, 2011
The present study deals with the modification of the human skin biotribological behaviour after t... more The present study deals with the modification of the human skin biotribological behaviour after tape stripping. The tape-stripping procedure consists in the sequential application and removal of adhesive tapes on the skin surface in order to remove stratum corneum (SC) layers, which electrically charges the skin surface. The skin electric charges generated by tape stripping highly change the skin friction behaviour by increasing the adhesion component of the skin friction coefficient. It has been proposed to rewrite the friction adhesion component as the sum of two terms: the first classical adhesion term depending on the intrinsic shear strength, t 0 , and the second term depending on the electric shear strength, t elec. The experimental results allowed to estimate a numerical value of the electric shear strength t elec. Moreover, a plan capacitor model with a dielectric material inside was used to modelize the experimental system. This physical model permitted to evaluate the friction electric force and the electric shear strength values to calculate the skin friction coefficient after the tape stripping. The comparison between the experimental and the theoretical value of the skin friction coefficient after the tape stripping has shown the importance of the electric charges on skin biotribological behaviour. The static electric charges produced by tape stripping on the skin surface are probably able to highly modify the interaction of formulations with the skin surface and their spreading properties. This phenomenon, generally overlooked, should be taken into consideration as it could be involved in alteration of drug absorption.
Colloids and Surfaces B: Biointerfaces, Feb 1, 2009
In the present paper, we describe a new mechanical method characterising the physico-chemical pro... more In the present paper, we describe a new mechanical method characterising the physico-chemical properties of human skin and their variations along with liquid exposure scenario to the skin surface. A specific bio-tribometer has been developed to study the physical properties of the skin in vivo by measuring the maximum adhesion force between the skin and the bio-tribometer. We showed that the lipidic film present on skin surface was responsible for skin adhesion due to capillary phenomena. The measure of pull-off force between skin and bio-tribometer has permitted to estimate the liquid/vapour surface tension of the lipidic film (LV ≈ 6.3 mJ/m 2 in 30-year-old volunteer). The kinetic of sorption/desorption (sorption means indifferently adsorption and absorption process) of distilled water from the skin has been observed through the variation of the indenter/skin pull-off force versus time after distilled water application to the skin surface. This permits to follow in real time the variation of the skin physico-chemical properties after liquid application onto the skin surface. Finally, the increasing of skin friction coefficient after distilled water application onto skin surface was explained by the capillary adhesion force between the probe and the skin.
Corticosteroids, although highly effective for the treatment of both anterior and posterior ocula... more 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 ...
Cyclosporine is an immunomodulatory drug commonly used for the treatment of mild-to-severe dry ey... more 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
This work aims at investigating the nicotinamide (NA)-ethyl-paraben (EP) binary system both in so... more This work aims at investigating the nicotinamide (NA)-ethyl-paraben (EP) binary system both in solution and in the solid state. In particular, the apparent EP solubility in water was studied in the presence of different NA concentrations (between 0.28 and 1.64 M). It was found that the apparent EP solubility increase (nearly twofold) observed at the highest NA concentration tested can be ascribed to a change in the polarity of the solvent mixture, rather than to a direct effect of NA on EP. The effect of fusion and re-crystallization from water or ethanol solutions on EP and NA mixtures was investigated by means of differential scanning calorimetry, elemental analysis and X-ray diffraction both on powder and single crystal. It was discovered that EP and NA form a co-crystal having a 1:1 molar composition that can be easily crystallized from ethanol. Single crystal X-ray analysis of this species revealed that the NA and EP molecules form corrugated layers within which the two components are intimately associated by a dense network of hydrogen bonds. In the presence of an excess NA in solution, the EP-NA co-crystal has lower water solubility with respect to both the single co-crystal formers and precipitates in aqueous solutions at ambient temperature.
European Journal of Pharmaceutics and Biopharmaceutics, Jun 1, 2008
Nicotinamide significantly increases the solubility of MP, PP, BP. It has limited effect on EP so... more Nicotinamide significantly increases the solubility of MP, PP, BP. It has limited effect on EP solubility. • Nicotinamide reduces the IPM/water partition coefficient of all parabens. • Nicotinamide reduces by one order of magnitude paraben permeability coefficient, due to a reduction of the partitioning parameter. • The effects of nicotinamide can be due to: • Modification of the polarity of the vehicle. • Formation of a complex more hydrophilic than the paraben alone. • Formation of nicotinamide micelles able to include parabens.
The notion of controlled release has been known since the 1930s, but was not significantly develo... more The notion of controlled release has been known since the 1930s, but was not significantly developed until the 1970s. At that time, Alza introduced the concept of a "therapeutic system" and proposed new pharmaceutic formulations. Over time, the idea became one of controlled drug delivery and today concerns not only one rate of release but also the site of release of the active substance. We present here definitions, fundamentals and advantages and disadvantages of currently marketed systems and provide examples illustrating oral, transdermal and respiratory delivery systems. Current research is also examined.
A simple and sensitive HPLC method for the quantification of budesonide in skin layers was develo... more 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).
European Journal of Pharmaceutics and Biopharmaceutics, Jul 1, 2017
Nanoemulsions (NE) have attracted much attention due to their as dermal delivery systems for lipo... more Nanoemulsions (NE) have attracted much attention due to their as dermal delivery systems for lipophilic drugs such as psoralens. However, NE feature low viscosity which might be unsuitable for topical application. In this work, we produced hydrogel-thickened nanoemulsions (HTN) using chitosan as thickening polymer to overcome the low viscosity attributed to NE. The aim of this study is to develop and characterize oil-in-water (o/w) HTN based on sweet fennel and clove essential oil to transdermal delivery of 8-methoxsalen (8-MOP). NE components (oil, surfactant) were selected on the basis of solubility and droplet size and processed in a high-pressure homogenizer (HPH). Drug loaded NE and HTN were characterized for particle size, stability under storage and centrifugation, rheological behavior, transdermal permeation and skin accumulation. Transdermal permeation of 8-MOP from HTN was determined by using Franz diffusion cell. Transdermal permeation from HTN using clove essential oil showed strong dependency chitosan molecular weight. On the other hand, HTN using sweet fennel oil showed an unexpected pH-dependent behavior not fully understood at the moment. These results need further investigation, nevertheless HTN revealed to be interesting and complex dermal delivery systems for poorly soluble drugs.
International Journal of Pharmaceutics, Feb 1, 2018
The aim of this work was to characterize in vitro and ex vivo the performances of Durogesic and o... more The aim of this work was to characterize in vitro and ex vivo the performances of Durogesic and of two bioequivalent generic products, by evaluating: (a) fentanyl release; (b) fentanyl permeation across porcine skin and (c) fentanyl ease of extraction. Additional characteristics studied are the effect of temperature and skin integrity, applied individually or combined, to check a possible synergism. The two generic patches resulted equivalent to the originator according to the new Guideline. Nevertheless, the same data reported in a different way, i.e. considering the total amount of drug permeated from the whole patch over the application time, highlight differences among the patches. The additional tests performed showed that skin integrity does not represent a barrier for fentanyl permeation across the skin, regardless of the type and complexity of the patch. The effect of temperature resulted critical for two out of three patches, probably due to the different composition and to the different structure. The combination of skin damage and elevated temperature did not produce a synergistic effect. Fentanyl extraction was different for the different products and variable according to the conditions used. The results reported in the present work underline the influence of patch composition and complexity on fentanyl extraction, release and skin permeation, in particular in conditions that can be critical, such as elevated temperature. In particular, the effect of critical variables, such as skin integrity and temperature, should be addressed to in the development of a new or new generic patch and new discriminant tests should be developed.
Drug Development and Industrial Pharmacy, May 7, 2017
Mydriatics release from solid and semi-solid ophthalmic formulations using different in vitro met... more Mydriatics release from solid and semi-solid ophthalmic formulations using different in vitro methods The aim of the present paper was the development of semisolid (hydrogels) and solid (film) ophthalmic formulations for the controlled release of two mydriatics: phenylephrine and tropicamide. The formulations-based on polyvinylalchol and hyaluronic acid-were characterized, and release studies were performed with three different in vitro setups , i.e. Franz-type diffusion cell, vial method and inclined plane; for comparison, a solution and a commercial insert, both clinically used to induce mydriasis, were evaluated. Both gels and film allowed for a controlled release of drugs, appearing a useful alternative for mydriatics administration. However, the release kinetic was significantly influenced by the method used, highlighting the need for optimization and standardization of in vitro models for the evaluation of drug release from ophthalmic dosage forms.
Estradiol transdermal application still represents a relevant topic due to the recent controversi... more Estradiol transdermal application still represents a relevant topic due to the recent controversies about hormone replacement therapy, its increasing potential in the treatment of skin aging and wound healing, and the new use of its derivatives in the transdermal contraceptive treatment. The aim of our work was to verify if fresh or frozen rabbit ear skin can be a suitable skin model to study in vitro estradiol transdermal absorption. Fresh rabbit ear skin demonstrated a reasonable model of human epidermis in the investigation of estradiol permeation starting from both solutions and commercial patches.
International Journal of Pharmaceutics, Jul 1, 2018
Psoriasis is a widespread chronic disease affecting 2-4 % of the population in Western countries.... more Psoriasis is a widespread chronic disease affecting 2-4 % of the population in Western countries. Its mild-to-moderate form, representing approximately 80% of the total cases, is treated by topical application, with corticosteroid being the standard treatment. However, in case of psoriasis, no single treatment works for every patient and optimizing topical therapy is a key aspect. A possible alternative is represented by cyclosporine, an immunosuppressant cyclic peptide administered orally in the treatment of the severe form. Its topical application could avoid the problems related to systemic immunosuppression, but the unfavourable physico-chemical properties (MW:1202 Da; LogP≈3) hinder its permeation across the stratum corneum. The aim of the paper was the preparation, characterization and ex-vivo evaluation of cyclosporine loaded microemulsions using oleic acid as oil phase, either Tween® 80 or a soluble derivative of vitamin E (TPGS) as surfactants and either Transcutol®, propylene glycol or 1,3 propanediol as co-surfactants. The issue of formulation viscosity was also addressed 1) by evaluating the thickening of Tween®80-based microemulsions by direct addition of different rheological modifiers 2) by building pseudo-ternary phase diagrams using TPGS, to identify the water/oil/surfactants proportions resulting in viscous self-gelifying systems. Nine formulations (five Tween®80-based and four TPGS-based) were selected, characterized in terms of droplets size (low viscosity systems) or rheological properties (high viscosity systems), loaded with 6 mg/g cyclosporine and applied ex-vivo on porcine skin for 22 h. A relevant skin accumulation was obtained either with a low-viscosity Tween®80-based microemulsion (9.78±3.86 µg/cm 2), or with a high viscosity TPGS-based microemulsion (18.3±5.69 µg/cm 2), with an increase of about 3 and 6 times respectively for comparison with a control cyclosporine solution in propylene glycol. The role of water content, surfactant, co-surfactant and viscosity was also addressed and discussed. The kinetic of skin uptake from the best performing formulation was finally evaluated, highlighting a relatively quick skin uptake and the achievement, after 2 h of contact, of potentially therapeutic cyclosporine skin concentrations.
International Journal of Pharmaceutics, Feb 1, 2001
Triptorelin is a decapeptide analog of luteinizing hormone releasing hormone, currently used for ... more Triptorelin is a decapeptide analog of luteinizing hormone releasing hormone, currently used for the treatment of sex-hormones dependents diseases. The aim of this work was to prepare triptorelin-loaded nanospheres useful for transdermal iontophoretic administration. Nanospheres were prepared with the double emulsion/solvent evaporation technique. The effect of three parameters on the encapsulation efficiency has been determined: the role of the pH of the internal and external aqueous phases, the nature of the organic solvent and the effect of three different poly(lactide-co-glycolide) (PLGA) co-polymers. Particle size, zeta potential and release kinetics were also determined. The encapsulation efficiency varied from 4 to 83% reaching the maximum value when both the internal and the external water phases were brought to pH 7 (isoelectric point of the peptide), methylene chloride was used as solvent of the copolymers and PLGA rich in free carboxylic groups was employed. The release profiles obtained with this co-polymer were characterized by the absence of burst effect. This behavior as well as the high encapsulation efficiency was explained by an ionic interaction occurring between the peptide and the co-polymer. This supports the already expressed theory that the release of peptides and proteins from PLGA nanospheres is also governed by the affinity of the encapsulated molecule versus the polymer. The obtained nanoparticles, regarding their size, amount encapsulated and zeta potential, were shown to be suitable for transdermal iontophoretic administration.
Non-invasive drug delivery to the posterior segment of the eye represents an important unmet medi... more Non-invasive drug delivery to the posterior segment of the eye represents an important unmet medical need, and trans-scleral delivery could be an interesting solution. This review analyses the possibility of trans-scleral drug delivery for high molecular weight compounds, such as proteins and genetic material, which currently represent the most innovative and efficacious molecules for the treatment of many diseases of the posterior segment of the eye. The paper reviews all the barriers, both static and dynamic, involved in trans-scleral administration of drugs, trying to elucidate the role of each of them in the specific case of macromolecules. Delivery systems to sustain drug release and enhancing strategies to improve trans-scleral penetration are also described. Finally, the review approaches the use of computational models as a screening tool to evaluate the feasibility of trans-scleral administration for macromolecules.
Objectives Lipopeptides are compounds derived from microorganisms that exhibit pronounced surface... more Objectives Lipopeptides are compounds derived from microorganisms that exhibit pronounced surface and emulsifying activity. The ability of lipopeptides to interact with stratum corneum lipids makes them candidates as transdermal penetration enhancers. We have investigated the potential of two lipopeptides, fengycin and surfactin, to act as enhancers for the transdermal penetration and skin accumulation of aciclovir. Methods To investigate a possible synergistic effect, surfactin and fengycin were associated with anodal iontophoresis. Permeation experiments were performed using vertical diffusion cells and pig ear skin as barrier. Differential scanning calorimetry was used to study the interaction between fengycin and stratum corneum lipids. Key findings The results obtained indicated that surfactin and fengycin were not suitable to enhance aciclovir flux across the skin, not even when associated with iontophoresis. Aciclovir flux was slightly decreased in passive conditions and unchanged (fengycin) or decreased (surfactin) in anodal iontophoretic conditions. When applied in passive conditions, fengycin and surfactin increased aciclovir concentration in the epidermis by a factor of 2. Conclusions Surfactin and fengycin did not enhance aciclovir transport across the skin (not even when associated with iontophoresis) although they increased aciclovir concentration in the epidermis by a factor of 2.
Journal of the Royal Society Interface, Jan 12, 2011
The present study deals with the modification of the human skin biotribological behaviour after t... more The present study deals with the modification of the human skin biotribological behaviour after tape stripping. The tape-stripping procedure consists in the sequential application and removal of adhesive tapes on the skin surface in order to remove stratum corneum (SC) layers, which electrically charges the skin surface. The skin electric charges generated by tape stripping highly change the skin friction behaviour by increasing the adhesion component of the skin friction coefficient. It has been proposed to rewrite the friction adhesion component as the sum of two terms: the first classical adhesion term depending on the intrinsic shear strength, t 0 , and the second term depending on the electric shear strength, t elec. The experimental results allowed to estimate a numerical value of the electric shear strength t elec. Moreover, a plan capacitor model with a dielectric material inside was used to modelize the experimental system. This physical model permitted to evaluate the friction electric force and the electric shear strength values to calculate the skin friction coefficient after the tape stripping. The comparison between the experimental and the theoretical value of the skin friction coefficient after the tape stripping has shown the importance of the electric charges on skin biotribological behaviour. The static electric charges produced by tape stripping on the skin surface are probably able to highly modify the interaction of formulations with the skin surface and their spreading properties. This phenomenon, generally overlooked, should be taken into consideration as it could be involved in alteration of drug absorption.
Colloids and Surfaces B: Biointerfaces, Feb 1, 2009
In the present paper, we describe a new mechanical method characterising the physico-chemical pro... more In the present paper, we describe a new mechanical method characterising the physico-chemical properties of human skin and their variations along with liquid exposure scenario to the skin surface. A specific bio-tribometer has been developed to study the physical properties of the skin in vivo by measuring the maximum adhesion force between the skin and the bio-tribometer. We showed that the lipidic film present on skin surface was responsible for skin adhesion due to capillary phenomena. The measure of pull-off force between skin and bio-tribometer has permitted to estimate the liquid/vapour surface tension of the lipidic film (LV ≈ 6.3 mJ/m 2 in 30-year-old volunteer). The kinetic of sorption/desorption (sorption means indifferently adsorption and absorption process) of distilled water from the skin has been observed through the variation of the indenter/skin pull-off force versus time after distilled water application to the skin surface. This permits to follow in real time the variation of the skin physico-chemical properties after liquid application onto the skin surface. Finally, the increasing of skin friction coefficient after distilled water application onto skin surface was explained by the capillary adhesion force between the probe and the skin.
Corticosteroids, although highly effective for the treatment of both anterior and posterior ocula... more 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 ...
Cyclosporine is an immunomodulatory drug commonly used for the treatment of mild-to-severe dry ey... more 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
This work aims at investigating the nicotinamide (NA)-ethyl-paraben (EP) binary system both in so... more This work aims at investigating the nicotinamide (NA)-ethyl-paraben (EP) binary system both in solution and in the solid state. In particular, the apparent EP solubility in water was studied in the presence of different NA concentrations (between 0.28 and 1.64 M). It was found that the apparent EP solubility increase (nearly twofold) observed at the highest NA concentration tested can be ascribed to a change in the polarity of the solvent mixture, rather than to a direct effect of NA on EP. The effect of fusion and re-crystallization from water or ethanol solutions on EP and NA mixtures was investigated by means of differential scanning calorimetry, elemental analysis and X-ray diffraction both on powder and single crystal. It was discovered that EP and NA form a co-crystal having a 1:1 molar composition that can be easily crystallized from ethanol. Single crystal X-ray analysis of this species revealed that the NA and EP molecules form corrugated layers within which the two components are intimately associated by a dense network of hydrogen bonds. In the presence of an excess NA in solution, the EP-NA co-crystal has lower water solubility with respect to both the single co-crystal formers and precipitates in aqueous solutions at ambient temperature.
European Journal of Pharmaceutics and Biopharmaceutics, Jun 1, 2008
Nicotinamide significantly increases the solubility of MP, PP, BP. It has limited effect on EP so... more Nicotinamide significantly increases the solubility of MP, PP, BP. It has limited effect on EP solubility. • Nicotinamide reduces the IPM/water partition coefficient of all parabens. • Nicotinamide reduces by one order of magnitude paraben permeability coefficient, due to a reduction of the partitioning parameter. • The effects of nicotinamide can be due to: • Modification of the polarity of the vehicle. • Formation of a complex more hydrophilic than the paraben alone. • Formation of nicotinamide micelles able to include parabens.
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Papers by Sara Nicoli