Micelles-in-Liposome Systems Obtained by Proliposomal Approach for Cannabidiol Delivery: Structural Features and Skin Penetration.

Deformable liposomes represent valuable drug carriers for cutaneous administration. Nevertheless, the fluid lipid membrane can favor the drug leakage during storage. Proliposomes may represent a suitable strategy to solve this issue. As an alternative, a novel carrier, which encloses hydrophobic drugs in the inner core of vesicles, namely, a drug-in-micelles-in-liposome system (DiMiL), has been proposed. In this work, we investigated the possible advantages of combining these two approaches to obtain a formulation able to enhance the skin penetration of cannabidiol (CBD). Proliposomes were prepared by spray-drying or slurry method testing lactose, sucrose, and trehalose as carriers at different sugar/lipid weight ratios. The ratio between soy-phosphatidylcholine (main lipid) and Tween 80 was instead fixed at 85:15 w/w. DiMiL systems were extemporaneously obtained by the hydration of proliposomes with a Kolliphor HS 15 micellar dispersion (containing CBD, when appropriate). Based on the technological properties, sucrose and trehalose at 2:1 sugar/lipid ratio resulted in the best carriers for spray-dried and "slurried" proliposomes, respectively. Cryo-EM images clearly showed the presence of micelles in the aqueous core of lipid vesicles and the presence of sugars did not alter the structural organization of DiMiL systems, as demonstrated by SAXS analyses. All formulations were highly deformable and able to control CBD release regardless of the presence of sugar. The permeation through human epidermis of CBD carried by DiMiL systems was significantly improved compared to that obtained loading the drug in conventional deformable liposomes with the same lipid composition or in an oil solution. Furthermore, the presence of trehalose led to a further slight increase of the flux. Altogether, these results demonstrated that proliposomes may be a valuable intermediate for the preparation of deformable liposome-based cutaneous dosage forms, improving the stability without compromising the overall performances.

Caffeic Acid-Grafted PLGA as a Novel Material for the Design of Fluvastatin-Eluting Nanoparticles for the Prevention of Neointimal Hyperplasia.

Drug-eluting nanoparticles (NPs) administered by an eluting balloon represent a novel tool to prevent restenosis after angioplasty, even if the selection of the suitable drug and biodegradable material is still a matter of debate. Herein, we provide the proof of concept of the use of a novel material obtained by combining the grafting of caffeic acid or resveratrol on a poly(lactide-co-glycolide) backbone (g-CA-PLGA or g-RV-PLGA) and the pleiotropic effects of fluvastatin chosen because of its low lipophilic profile which is challenging for the encapsulation in NPs and delivery to the artery wall cells. NPs made of such materials are biocompatible with macrophages, human smooth muscle cells (SMCs), and endothelial cells (ECs). Their cellular uptake is demonstrated and quantified by confocal microscopy using fluorescent NPs, while their distribution in the cytoplasm is verified by TEM images using NPs stained with an Ag-PVP probe appositely synthetized. g-CA-PLGA assures the best control of the FLV release from NP sizing around 180 nm and the faster SMC uptake, as demonstrated by confocal analyses. Interestingly and surprisingly, g-CA-PLGA improves the FLV efficacy to inhibit the SMC migration, without altering its effects on EC proliferation and migration. The improved trophism of NPs toward SMCs, combined with the excellent biocompatibility and low modification of the microenvironment pH upon polymer degradation, makes g-CA-PLGA a suitable material for the design of drug-eluting balloons.

Rationalizing the Design of Hyaluronic Acid-Decorated Liposomes for Targeting Epidermal Layers: A Combination of Molecular Dynamics and Experimental Evidence.

This work provides information on the features of low molecular weight hyaluronic acid (HA)-decorated liposomes to target resveratrol (RSV) in the skin. Deformable liposomes were made of soy-phosphatidylcholine with Tween 80 as the fluidizing agent. For HA conjugation, three different phosphoethanolamines were tested: 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). The different phosphoethanolamine-HA conjugates were inserted into the liposome bilayer by hydration (HA on both faces of the bilayer) or by the postinsertion method (HA only on the external face of the bilayer). The effect of these variables on deformability was experimentally assessed by an in-house method (K value, the lower the value, the higher the deformability) and molecular dynamics (MD) simulations. The results showed that the K values of HA-liposomes obtained by hydration were higher than the K values of HA-liposomes prepared by postinsertion, and both were at least 10-fold higher than the K values of the corresponding plain liposomes. The nature of the lipid anchor played a key role in deformability (DMPE > DOPE > DPPE) with high variability in the case of DOPE formulations. These data were justified by the trends found in silico for the bilayer bending modulus and the HA end-to-end distance. In addition to liposome flexibility, the HA extent seems to be the key factor governing the skin penetration of RSV. When the extent is higher, the amount of the drug retained in the skin is larger. Regarding skin permeation, a parabolic trend was recorded, and the optimal amount to favor skin permeation was an approximately 30 HA/phospholipid (µg/mmol) ratio. This study reports the first piece of evidence that it is possible to control drug delivery in the skin by tuning the amount of HA on the vesicle surface.

Extemporaneous printing of diclofenac orodispersible films for pediatrics.

OBJECTIVE: The possible application of a hot-melt ram extrusion printing to the preparation of diclofenac orodispersible films (ODF) made of maltodextrin was studied focusing the attention on the effects of taste-masking agents (i.e. namely mint, licorice-mint, and sucralose) and an opacifier (titanium dioxide [TiO2]). SIGNIFICANCE: This is a proof-of-concept of the feasibility to print ODF loaded with a thermosensitive drug substance by hot-melt technologies. METHODS: Diclofenac sodium (DNa) ODF made of maltodextrin (dextrose equivalent (DE) = 6 ) plasticized with glycerol were prepared by hot-melt extrusion printing. ODF were characterized for disintegration time, drug content, and solid state, in vitro dissolution in deionized water and simulated salivary fluid at pH 5.7, tensile, and adhesive properties. Moreover, the stability of ODF was assessed in accelerated conditions over six months. RESULTS: After the preparation, no variation in drug solid state was evident and the formation of impurity A of DNa was detected, even if it remained below the Pharmacopoeia (Ph. Eur.) limits (< 0.2%). Only the addition of DNa significantly improved the ODF tensile properties: the tensile strength increased from 0.17 ± 0.03 MPa (placebo ODF) to 2.21 ± 0.54 MPa (p ≤ 0.03). All ODF disintegrated in about 1 min, and the t80% was lower than 3 min. TiO2 reduced the static and dynamic peel forces (p ≤ 0.006) favoring the ODF detachment from the primary packaging material. During the accelerated stability study, ODF were easy to handle without fracture; the drug content, impurity A, and dissolution profiles remained superimposable. CONCLUSION: Hot-melt printing can be suitable to prepare palatable ODF loaded with bitter thermosensitive drugs.

Gellan Nanohydrogels: Novel Nanodelivery Systems for Cutaneous Administration of Piroxicam.

The feasibility to use gellan nanohydrogels (Ge-NHs) as delivery system for the cutaneous administration of piroxicam (PRX) was investigated using gellan conjugated with cholesterol or riboflavin. The in vitro skin penetration studies through human epidermis were performed using a saturated aqueous drug solution, a 50% w/v Transcutol aqueous solution, and a commercially available PRX plaster as controls. Confocal microscopy, ATR-FTIR spectroscopy, circular dichroism, and a dynamometer assisted extrusion assay were performed to clarify the permeation mechanism of Ge-NHs. The skin permeation studies evidenced that Ge-NHs enhance the PRX retention in the epidermis and, at the same time, slow down the permeation process with respect to the controls. NHs can penetrate the stratum corneum, and then gradually disassemble thus diffusing in the viable epidermis reaching the spinosum layer. In conclusion, NHs represent a novel strategy to target poorly permeable compounds in the epidermis, thus improving the management of cutaneous pathologies.

Tuning the Extent and Depth of Penetration of Flexible Liposomes in Human Skin.

In this work we made an attempt to assess the effect of drug-induced changes of flexibility on the penetration of deformable vesicles into the human skin. Eight cationic liposomes with different degrees of flexibility were obtained by entrapping unfractionated heparin, enoxaparin, and nadroparin. The deformability was studied by a novel, facile, and reliable extrusion assay appositely developed and validated by means of quantitative nanoscale mechanical AFM measurements of vesicle elastic modulus (log10(YM)). The proposed extrusion assay, determining the forces involved in vesicles deformation, resulted very sensitive to evidence of minimal changes in bilayer rigidity (σ) and vesicle deformation (K). The drug loading caused a reduction of liposome flexibility with respect to the reference plain liposomes and in accordance to the heparin type, drug to cationic lipid (DOTAP) ratio, and drug distribution within the vesicles. Interestingly, the σ and log10(YM) values perfectly correlated (R2 = 0.935), demonstrating the reliability of the deformability data obtained with both approaches. The combination of TEM and LC-MS/MS spectrometry allowed the pattern of the penetration of the entire vesicles into the skin to be followed. In all cases, intact liposomes in the epidermis layers were observed and a relationship between the depth of penetration and the liposome flexibility was found, supporting the hypothesis of the whole vesicle penetration mechanism. Moreover, the results of the extent (R24) of vesicle penetration in the human skin samples showed a direct relation to the flexibility values (σ1 = 0.65 ± 0.10 MPa → R24 = 3.33 ± 0.02 µg/mg; σ2 = 0.95 ± 0.04 MPa → R24 = 1.18 ± 0.26 µg/mg; σ3 = 1.89 ± 0.30 MPa → R24 = 0.53 ± 0.33 µg/mg).

Impact of semi-solid formulations on skin penetration of iron oxide nanoparticles.

BACKGROUND: This work aimed to provide useful information on the incidence of the choice of formulation in semi-solid preparations of iron-oxide nanoparticles (IONs). The appropriate analytical methods to assess the IONs physical stability and the effect of the semi-solid preparations on IONs human skin penetration were discussed. The physical stability of IONs (Dh = 31 ± 4 nm; ζ = -65 ± 5 mV) loaded in five semi-solid preparations (0.3% w/v), namely Carbopol gel (CP), hydroxyethyl cellulose gel (HEC), carboxymethylcellulose gel (CMC), cetomacrogol cream (Cet) and cold cream was assessed by combining DLS and low-field pulsed NMR data. The in vitro penetration of IONs was studied using human epidermis or isolated stratum corneum (SC). RESULTS: Reversible and irreversible IONs aggregates were evidenced only in HEC and CMC, respectively. IONs diffused massively through SC preferentially by an intercellular pathway, as assessed by transmission electron microscopy. The semi-solid preparations differently influenced the IONs penetration as compared to the aqueous suspension. Cet cream allowed the highest permeation and the lowest retained amount, while cold cream and CP favored the accumulation into the skin membrane. CONCLUSION: Basic cutaneous semi-solid preparations could be used to administer IONs without affecting their permeation profile if they maintained their physical stability over time. This property is better discriminated by low-field pulsed NMR measurements than the commonly used DLS measurements.

A successful experimental model for intimal hyperplasia prevention using a resveratrol-delivering balloon.

OBJECTIVE: Restenosis due to intimal hyperplasia is a major clinical problem that compromises the success of angioplasty and endovascular surgery. Resveratrol (RSV) has demonstrated a beneficial effect on restenosis from angioplasty. Unfortunately, the physicochemical characteristics of RSV reduce the practicality of its immediate clinical application. This work proposes an experimental model aiming to setup an intravessel, elutable, RSV-containing compound. METHODS: A 140 µg/mL RSV sterile injectable solution with a suitable viscosity for intravascular administration by drug-delivery catheter (RSV-c) was prepared. This solution was locally administered in the common iliac artery of adult male New Zealand White rabbits using a dedicated device (Genie; Acrostak, Geneva, Switzerland) after the induction of intimal hyperplasia by traumatic angioplasty. The RSV concentrations in the wall artery were determined, and the thickness of the harvested iliac arteries was measured over a 1-month period. RESULTS: The Genie catheter was applied in rabbit vessels, and the local delivery resulted in an effective reduction in restenosis after plain angioplasty. Notably, RSV-c forced into the artery wall by balloon expansion might accumulate in the interstitial areas or within cells, avoiding the washout of solutions. Magnification micrographs showed intimal proliferation was significantly inhibited when RSV-c was applied. Moreover, no adverse events were documented in in vitro or in vivo studies. CONCLUSIONS: RSV can be advantageously administered in the arterial walls by a drug-delivery catheter to reduce the risk of restenosis.

Skin Penetrating Peptide as a Tool to Enhance the Permeation of Heparin through Human Epidermis.

This study aimed to identify a new skin penetrating peptide (SPP) able to enhance unfractionated heparin (UFH) permeation through human epidermis by screening a phage display peptide library. The effects of the synthesized heptapeptide (DRTTLTN) on human stratum corneum organization were investigated by ATR-FTIR spectroscopy and molecular dynamics simulation. The DRTTLTN penetration within the human epidermis caused both a fluidization of the stratum corneum lipids and the extension of keratins due to the increase of the contribution of α-helices. The coadministration of DRTTLTN with UFH resulted ineffective in increasing skin penetration due to UFH affinity for keratins. The conjugation of DRTTLTN to UFH by N-(3-(dimethylamino)propyl)-N'-ethylcarbodiimide hydrochloride and sodium N-hydroxysulfosuccinimide led to an increase of the flux of 24-36-fold with respect to raw UFH, depending on the adopted synthetic procedure. The new compounds showed a decrease of the antifactor Xa activity of about 4-5 times. DRTTLTN also permitted to increase the fluxes of small model molecules. In conclusion, these data support the use of SPP to enhance the skin penetration of poorly absorbed compounds even in the case of macromolecules as polysaccharides.

Nanocarriers to Enhance the Accumulation of Vitamin K1 into the Skin.

PURPOSE: Vitamin K1 (VK1) is a molecule abundant in some species of leaf vegetables with beneficial effects in humans following administration on the skin. This work investigates the possibility to use formulations based on lipid vesicles, namely liposomes, transfersomes and ethosomes, suitable to be administered on the skin by nebulization and alternative to fat semisolid preparations present on the market. METHODS: Lipid vesicles encapsulating VK1 were prepared and characterized. Ex-vivo experiments on Franz cells were carried out to study the VK1 accumulation/permeation in/through the skin. Vesicles interaction with the skin was investigated by confocal laser scanning microscopy (CLSM) and attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy. RESULTS: All developed carriers were stable following long-term storage and were not altered following nebulization. In ex-vivo experiments, vesicles with the highest deformability index, namely transfersomes and ethosomes, led to an enhanced VK1 accumulation/permeation into/through the skin. Interestingly, the nebulization of the vesicles led to a further increase of VK1 accumulation into the skin. CONCLUSIONS: In conclusion, to achieve a local effect of VK1 on the skin, the topical nebulization of VK1-containing transfersomes could offer a good compromise between a high VK1 penetration into the skin and a limited permeation through it.

On the characterization of medicated plasters containing NSAIDs according to novel indications of USP and EMA: adhesive property and in vitro skin permeation studies.

Abstract This work aims to establish if the assays recently introduced by EMA (Guideline on quality of transdermal patches-draft) and USP (Specific tests for transdermal delivery systems) to characterize transdermal patches (TP) are suitable for medicated plasters (MP). Six approved MP differing for type and characteristics of adhesive and backing layer were selected and characterized in terms of adhesive performances by tack, shear adhesion, peel adhesion and release liner removal tests and in vitro skin permeation. As far as the adhesive properties are concerned, the major drawback is related to the measurement of shear adhesion of MP made of an adhesive hydrogel and/or a stretchable backing layer which could be solved by reducing the applied load. Moreover, a concern on the mass balance prescribed by EMA draft for the acceptance of the results of in vitro penetration studies remains. Indeed, the acceptance range is narrow than that reported by Ph. Eur. requirement for uniformity of content. Finally, a novel calculation for evaluating the in vitro efficiency of MP in releasing the loaded drug through the skin was proposed.

An insight into the skin penetration enhancement mechanism of N-methylpyrrolidone.

This work aims to elucidate the mechanism by which N-methylpyrrolidone (NMP) enhances the skin permeation of a compound by combining experimental data with molecular dynamic (MD) simulations. The addition of 10% NMP significantly increased the propranolol (PR) permeation through the human epidermis (∼ 15 µg/cm(2) vs ∼ 30 µg/cm(2)) while resulting inefficacious on hydrocortisone (HC) diffusion. No significant alterations in the stratum corneum structure were found after the in vitro treatment of human epidermis with NMP dispersed in mineral oil or water by attenuated total reflectance Fourier transform infrared (ATR-FTIR) analyses. MD simulations revealed the formation of a complex by H-bonds and the π-π stacking interactions between the NMP's amido group and the drug's aromatic systems. The size of the depicted NMP/PR clusters was in line with the hydrodynamic radius derived by dynamic light scattering analyses (∼ 2.00 nm). Conversely, no interaction, and consequently cluster formation, between NMP and HC occurred. These results suggest that NMP is effective in enhancing the drug permeation through human epidermis by a cotransport mechanism when NMP/drug interaction occurs.

The role of the conformational profile of polysaccharides on skin penetration: the case of hyaluronan and its sulfates.

The literature data suggest the capacity of biomacromolecules to permeate the human skin, even though such a transdermal permeation appears to be governed by physicochemical parameters which are significantly different compared to those ruling the skin permeation of small molecules. On these grounds, the present study was undertaken to investigate the in vitro diffusion properties through the human epidermis of hyaluronic acid and their sulfates. Low- and medium-molecular-weight hyaluronic acids and the corresponding derivatives at two degrees of sulfation were then tested. In vitro studies evidenced that the sulfated polymers permeate better than the corresponding hyaluronic acid, despite their vastly greater polarity, while the observed permeation markedly decreases when increasing the polymer's molecular weight regardless of the sulfation degree. Using a fluorescent-labeled polysaccharide, it was also evidenced that hyaluronans have a great affinity for corneocytes and likely cross the stratum corneum mainly through a transcellular route. The molecular-dynamics study revealed how the observed permeations for the investigated polysaccharides can be rationalized by monitoring their conformational profiles, since the permeation was found to be directly related to their capacity to assume extended and flexible conformations.

Formulation study of a patch containing propranolol by design of experiments.

OBJECTIVE: To evaluate the feasibility of a transdermal patch containing propranolol (PR). METHOD: Skin penetration enhancers (SPEs) able to improve the skin permeability of PR were selected and a quality by design approach was applied to the development of the patch by a 2(4) full factorial design. The permeation profile of PR from the formulations was assessed in in vitro permeation studies performed by using Franz diffusion cells and human epidermis as membrane. Finally, skin irritation was evaluated by the Draize test. RESULTS: N-methyl pyrrolidone (NMP) resulted as the best SPE: in addition, the critical factors influencing the PR diffusion through the human epidermis when loaded in the patch resulted in the matrix thickness (X1, p = 0.0957) and PR content (X3, p = 0.0004) which improved the flux; conversely, NMP lacked its enhancement effect when loaded in the patch and the increase in its concentration (X4, p = 0.006) affected the drug permeation through human epidermis. The flux of optimal formulation was 12.7 µg/cm(2)/h. On the basis of the steady-state concentration and clearance of PR, the estimated patch surface was 100-120 cm(2), since the activity of PR is related to its Senantiomer and no in vivo bioconversion occurs. CONCLUSION: A patch containing (S)-PR was prepared and the (S)-PR flux (13.3 µg/cm(2)/h) permitted to confirm the suitability of a transdermal administration of PR. In particular, the use of a 50 µm thick methacrylic matrix containing 8% (S)-PR and 15% NMP can allow to develop a patch non-irritating to the skin, in order to ensure a constant permeation flux of PR over 48 h.

Equivalence assessment of creams with quali-quantitative differences in light of the EMA and FDA regulatory framework.

EMA and FDA are upgrading guidelines on assessing the quality and the equivalence of topically applied drug products for developing copies of originator products and supporting post-marketing variations. For topical products having remarkably similar composition, both EMA and FDA accept the equivalence on the bases of the comparison of rheological properties and in vitro drug release constant (k) and skin permeation flux (J) values, instead of clinical studies. This work aims to evaluate the feasibility to expand this approach to variations of the composition of complex semi-solid preparations. Ibuprofen (IB) creams at two different strengths (i.e., 1 % and 10 %) were used as a model formulation. Two formulative changes were performed: (a) the addition of the humectant to simulate a minor post-marketing variation; (b) the substitution of the emulsifying system to simulate a major one. These variations impacted only in 1 % IB formulations where both the equivalences of rheological data and J-values failed. At the highest concentration, the presence of IB crystals broke down the differences in rheological patterns and lead the IB thermodynamic activity at the maximum figuring out an overlapping of the J-values. Such data suggest the combination of these studies, which are thought mainly for the development of copies, could be also applied to the management of post-marketing variations that involve product composition.

Updating 'Data on the determination of human epidermis integrity in skin permeation experiments by electrical resistance' with Data on pig ear skin.

The data presented in this article are an update of the dataset provided by Musazzi et al. [1] and are related to the research article entitled "Equivalence assessment of creams with quali-quantitative differences in light of the EMA and FDA regulatory framework" [2]. In vitro permeation study (IVPT) is typically conducted using the method of Franz's diffusion cell for assessing the biopharmaceutical performance of topically applied products. While the human epidermis is considered the benchmark, various animal models (for instance, pig ear) have been accepted as a permeation membrane. Nonetheless, it is crucial to evaluate the integrity of the membrane to ensure the quality of the experiments. The methods employed for this assessment vary, and the outcomes are heavily reliant on the operational conditions, and the model membrane. The article contributes to the existing dataset by providing data on the electrical resistance values of pig ear skin samples and their correlation with the in vitro permeability fluxes of caffeine and benzoic acid. This data is utilized to determine a suitable cut-off for verifying the skin integrity of such an animal model. This information could be beneficial for facilitating critical or comprehensive analyses, contributing to the creation of a standard method.

Mucosa-penetrating liposomes for esophageal local drug delivery.

Local drug delivery to the esophagus is hampered by rapid transit time and poor permeability of the mucosa. If some strategies aimed to improve the residence time have been proposed, non-invasive approaches to increase the drug penetration in the mucosa have not been described so far. Herein, we designed mucosa-penetrating liposomes to favor the penetration and retention of curcumin (CURC) in the esophagus. A novel mucosa penetrating peptide (MPP), SLENKGP, was selected by Phage Display and conjugated to pegylated liposomes at different PEG and MPP's surface densities. Pegylation assured a long residence time of liposomes (at least 30 min) in the esophagus in vivo, but it did not favor the penetration of CURC in the mucosa. MPP-decorated liposomes instead delivered a significant higher amount of CURC in the mucosa compared to naked pegylated liposomes. Confocal microscopy studies showed that naked pegylated liposomes remain confined in the superficial layers of the mucosa whereas MPP-decorated liposomes penetrate the whole epithelium. In vitro, MPP reduced the interaction of PEG with mucin, meanwhile favoring the paracellular penetration of liposomes across epithelial cell multilayers. In conclusion, pegylated liposomes represent a valid approach to target the esophagus and the surface functionalization with MPP enhances their penetration in the mucosa.

3D printed mucoadhesive orodispersible films manufactured by direct powder extrusion for personalized clobetasol propionate based paediatric therapies.

The aim of this work is the development and production by Direct Powder Extrusion (DPE) 3D printing technique of novel oral mucoadhesive films delivering Clobetasol propionate (CBS), useful in paediatric treatment of Oral Lichen Planus (OLP), a rare chronic disease. The DPE 3D printing of these dosage forms can allow the reduction of frequency regimen, the therapy personalization, and reduction of oral cavity administration discomfort. To obtain suitable mucoadhesive films, different polymeric materials, namely hydroxypropylmethylcellulose or polyethylene oxide blended with chitosan (CS), were tested and hydroxypropyl-ß-cyclodextrin was added to increase the CBS solubility. The formulations were tested in terms of mechanical, physico-chemical, and in vitro biopharmaceutical properties. The film showed a tenacious structure, with drug chemical-physical characteristics enhancement due to its partial amorphization during the printing stage and owing to cyclodextrins multicomponent complex formation. The presence of CS enhanced the mucoadhesive properties leading to a significant increase of drug exposure time on the mucosa. Finally, the printed films permeation and retention studies through porcine mucosae showed a marked retention of the drug inside the epithelium, avoiding drug systemic absorption. Therefore, DPE-printed films could represent a suitable technique for the preparation of mucoadhesive film potentially usable for paediatric therapy including OLP.

The influence of the polar head and the hydrophobic chain on the skin penetration enhancement effect of poly(ethylene glycol) derivatives.

The effect of a homologue series of nonionic surfactants, namely poly(ethylene glycol) (PEG) fatty acid esters, differing in oxyethylene (PEG 8, PEG 12, and PEG 40) and fatty acid (stearate, mono and di-laurate, and mono and di-oleate) chain lengths, on in vitro skin permeability of ketoprofen (KTP) vehicled in plasters was investigated. The drug diffusion through hairless mouse skin as well as the effect of the surfactant type and strength was studied by Franz diffusion cells and ATR-FTIR spectroscopy. The use of PEG stearate series revealed that the surfactant with the largest polar head, namely PEG 40, was ineffective in enhancing the skin permeation of KTP, independently of the plaster concentrations. The effect of the hydrophobic chain was investigated only by using the shortest oxyethylene chains. The experimental results revealed that the oxyethylene chain length of surfactants appeared to be more influent than the alkyl chain. The prediction of the absorption enhancing capability of these PEG derivatives appeared related to the vehicle other than the proper combination of the number of ethylene oxide groups and alkyl groups.

Spotlight on Calcipotriol/Betamethasone Fixed-Dose Combination in Topical Formulations: Is There Still Room for Innovation?

Psoriasis is a lifelong disease which requires treatment adherence for successful management. Considering the complexity of this pathology, the combination of active pharmaceutical ingredients with a synergistic mechanism of action can improve the safety and efficacy of the treatment with respect to the conventional monotherapy. Moreover, a fixed dose of therapeutic agents in a topical formulation offers the possibility to simplify administration, reduce the doses of each active ingredient, and improve patient's compliance. Among the first-line treatments in mild to moderate psoriasis, the formulation of calcipotriol (Cal) and betamethasone dipropionate (BD) in a single vehicle is challenging due to their chemical incompatibility in an aqueous environment and the formation of degradation products. Based on these considerations, this review aims to provide an overview on the biopharmaceutical properties of Cal/BD fixed-dose combination products available on the market (namely ointment, oleogel, foam, and O/W cream), highlighting also the novel approaches under evaluation. The main differences among topical formulations are discussed considering the different features of the anatomic districts involved in psoriasis and the patient's adherence. Moreover, since in vitro experiments are fundamental to evaluate the skin permeation profile during the development of an efficacious medicinal product, special emphasis is given to models proposed to mimic psoriatic lesions.