Active pharmaceutical ingredient-ionic liquids assisted follicular co-delivery of ferulic acid and finasteride for enhancing targeted anti-alopecia.

Androgenetic alopecia (AGA) is the primary hair loss with impairing patients' quality of life. Finasteride (FIN) is an SRD5A2 inhibitor for AGA treatment, but oral FIN causes systemic adverse effects. Topical FIN delivery is anticipated to overcome this problem. Ferulic acid (FA) is a natural phenolic acid with vascular remodeling and anti-inflammatory effects. Herein, an active pharmaceutical ingredient ionic liquid (API IL) based on choline and FA (CF-IL) is for the first time constructed to load FIN for fabricating FIN CF-IL. CF-IL aims to act as carriers and cargos and enhance hair follicle (HF) co-delivery of FA and FIN for synergistic anti-alopecia. Thermal and spectroscopic analysis combined with quantum chemistry calculations and molecular dynamics confirm the formation of CF-IL. The CF-IL simultaneously increases the solubility of FA (∼648-fold) and FIN (∼686-fold), enhances the permeation and retention of FIN and FA through the follicular pathway, and promotes cellular uptake. FIN CFIL regulates the abnormal mRNA expressions in dihydrotestosterone-irritated hDPCs, and promotes hair regrowth in AGA mice in a combined manner with FIN and FA. These findings suggest that FA-based API IL is a promising approach for percutaneously co-delivering FA and FIN to HF, providing an enhanced targeting treatment for AGA.

Isotretinoin-Delonix polymeric nanoparticles: Potentials for skin follicular targeting in acne treatment.

In acne management, oral isotretinoin (IST) is associated with various untoward systemic effects, while its topical formulation has irritation side effects. Delonix (DLX) is a natural galactomannan derived from Delonix regia seed that can fabricate nanoparticles for topical skin delivery. This study aims to develop IST-DLX nanoparticles and assess their prospects for acne treatment. Fluorescent-DLX nanoparticles (made with a lipophilic BODIPY dye) or IST-DLX nanoparticles were prepared and characterized. BODIPY-DLX nanoparticles' skin distribution and IST-DLX nanoparticles' in-vitro targeting were assessed in pig ear skin, inflammatory modulation was assessed in AMJ-2 macrophage cells, while skin penetration and irritation were assessed in Wistar rats. IST-DLX nanoparticles had ≈230 nm, negative zeta potential, and ≈30% encapsulation efficiency. Confocal showed BODIPY in DLX nanoparticles accumulated in hair follicles as compared to BODIPY solution. IST-DLX nanoparticles released ≈37% IST over 48 h and increased IST 3-fold in hair follicles compared to IST solution. IST-DLX nanoparticles suppressed IL-6 expression in cells and reduced photo-irritation in Wistar rats compared to IST solution. In conclusion, IST-DLX nanoparticles may target and deliver adequate IST to skin layers associated with acne, avoid systemic penetration, modulate inflammatory pathogenic acne stage and prevent IST topical photo-irritation.

Dexamethasone-Loaded Lipomers: Development, Characterization, and Skin Biodistribution Studies.

Follicular targeting has gained more attention in recent decades, due to the possibility of obtaining a depot effect in topical administration and its potential as a tool to treat hair follicle-related diseases. Lipid core ethyl cellulose lipomers were developed and optimized, following which characterization of their physicochemical properties was carried out. Dexamethasone was encapsulated in the lipomers (size, 115 nm; polydispersity, 0.24; zeta-potential (Z-potential), +30 mV) and their in vitro release profiles against dexamethasone in solution were investigated by vertical diffusion Franz cells. The skin biodistribution of the fluorescent-loaded lipomers was observed using confocal microscopy, demonstrating the accumulation of both lipomers and fluorochromes in the hair follicles of pig skin. To confirm this fact, immunofluorescence of the dexamethasone-loaded lipomers was carried out in pig hair follicles. The anti-inflammatory (via TNFα) efficacy of the dexamethasone-loaded lipomers was demonstrated in vitro in an HEK001 human keratinocytes cell culture and the in vitro cytotoxicity of the nanoformulation was investigated.

Dermal delivery and follicular targeting of adapalene using PAMAM dendrimers.

Acne is a chronic dermatological disease of pilosebaceous units existing in the form of hair follicles (HFs) and accompanying sebaceous glands. In topical acne treatment, localisation of drug substance at the target site, in pilosebaceous units, especially in HFs is essential. The aims of this study were to develop and optimise adapalene (ADA)-loaded PAMAM dendrimer-based nanocarriers for topical acne treatment and to prepare gel formulations of the selected nanocarriers and to characterise their rheological properties and spreadability. ADA accumulation in HFs and in the skin from PAMAM dendrimers' aqueous colloidal formulations and their gel formulations were quantitatively determined using punch biopsy technique. Follicular targeting efficiency from PAMAM dendrimers and their gel formulation was compared with the commercial gel product, Differin® Gel. The localisation of fluorescently labelled PAMAM dendrimers was visualised using a confocal microscope, which confirmed a successful delivery of the carrier system to the HFs. It was also quantified that PAMAM dendrimers improved follicular localisation and skin deposition of ADA. PAMAM dendrimers' gel formulation including lower ADA doses compared with the commercial product exhibited efficient performance in terms of drug accumulation in HFs. In vitro cell viability studies showed the relative safety of G2-PAMAM dendrimers which could be considered to possibly be well tolerated by the skin. Overall, PAMAM dendrimers' potential to selectively target drugs to the site of action, reduce dose administrated, therefore minimise side effects and provide efficiency in topical treatment of dermatological diseases such as acne was shown.

Nanostructured lipid carriers for hair follicle-targeted delivery of clindamycin and rifampicin to hidradenitis suppurativa treatment.

Hidradenitis suppurativa is a chronic and debilitating inflammatory condition related to a permanent obstruction of the pilosebaceous units. Until nowadays, therapeutic options are unsatisfactory. Here, we propose nanostructured lipid carriers (NLC) entrapping an association of clindamycin phosphate (CDM) and rifampicin (RIF) as a topical alternative for the treatment of the disease. Chemical compatibility between the drugs was demonstrated using thermal analysis combined with ATR-FTIR and X-ray powder diffraction assays. Nanocarriers' diameter was narrowly distributed (polydispersity index = 0.2) around 400 ± 14 nm, they possess a negative surface charge (-48.9 ± 0.7 mV) and high drug entrapment efficiencies (80.2 ± 0.4 % and 93.4 ± 0.7 % for CDM and RIF, respectively). The formulation proved to be safe for the topical application, as it was non-irritant on both HET-CAM and reconstructed human epidermis (RHE) assays. Spin-label EPR indicated an NLC affinity for the lipidic domains of stratum corneum, which could benefit the targeting of the sebaceous units. Indeed, when applied on the skin in vitro, even when mimicking the sebaceous condition, NLC accumulated into the hair follicles openings, not altering the amount of accumulated CDM and significantly increasing by 12-fold the uptake of RIF in these structures. In conclusion, developed NLC formulation incorporating the antibiotics CDM and RIF is a promising strategy for the topical treatment of hidradenitis suppurativa or other infections that may affect the pilosebaceous units.

Thiolated and PEGylated silica nanoparticle delivery to hair follicles.

Targeting drug delivery to hair follicles is valuable to treat conditions such as alopecia's and acne, and this shunt route may also allow drug delivery to deeper skin layers and the systemic circulation by avoiding the intact stratum corneum. Here, we investigated the effects of nanoparticle surface chemistry on their delivery into hair follicles by synthesizing fluorescent thiolated silica nanoparticles and functionalizing with 750 Da and 5000 Da methoxypolyethylene glycol maleimide (PEG). The stability of the nanoparticles in skin homogenate was verified before tape stripping of porcine-dosed tissue showed the distribution of the free fluorescent dye and different nanoparticles in the skin. Analysis of microscopic images of the skin sections revealed penetration of nanoparticles functionalized with PEG into the appendages whereas thiolated nanoparticles stayed on the surface of the skin and were removed by tape stripping. Nanoparticles functionalized with PEG 5000 Da penetrated deeper into the hair follicles compared to counterparts functionalized with PEG 750 Da. PEGylation can thus enhance targeted delivery of nanoparticulates into hair follicles.

Nanocarriers as versatile delivery systems for effective management of acne.

Acne vulgaris is a chronic inflammatory skin disorder affecting mostly females. It has a negative impact on the social life and psychological well-being of the individual. Its pathogenesis involves an exaggerated secretion of sebum, hyperkeratinisation of hair follicles, colonization of anaerobic microbes in the hair follicles, and inflammation. Conventional therapy for acne utilizes antibacterial and anti-inflammatory drugs. Systemic use of these drugs is associated with undesirable toxicities. Hence, topical delivery of anti-acne drugs is desired. However, topical delivery is hindered by poor aqueous solubility of drug and inadequate penetration across stratum corneum. Nanocarriers are endowed with immense potential to facilitate topical delivery of anti-acne drugs as monotherapy or in combination by a myriad of mechanisms including occlusive nature promoting skin hydration, providing sustained drug release thereby decreasing dosing frequency, follicular targeting, and protecting the labile active from degradation. Further, smart nanocarriers can deliver the anti-acne cargo in response to some stimulus present at the disease site precluding undesirable effects at non target sites. Nanocarriers have also been explored in photothermal and photodynamic therapy of acne for destruction of antibiotic resistant bacteria implicated in acne. This review focuses on the potential of a variety of nanocarriers for treatment of acne.

Cyproterone acetate-loaded nanostructured lipid carriers: effect of particle size on skin penetration and follicular targeting.

Cyproterone acetate (CPA) is used to treat various skin disorders such as acne, hirsutism, and alopecia. Due to the limited skin penetration of CPA, nanostructured lipid carriers (NLCs) with different size ranges were considered in this study in order to enhance skin penetration and to target hair follicles. Drug loading, drug release and morphological assessment were evaluated for each targeted size (100, 300, and 600 nm). Ex vivo skin penetration was also investigated using Franz diffusion cells. Finally, in vivo follicular targeting was evaluated using rhodamine B-loaded micro and nanoparticles. Results revealed that 60-85% of drug was slowly released from lipid nanoparticles within 72 h. CPA-NLC with average diameter of 600 nm had better penetration and deposition in dermis-epidermis layer, also CPA-NLC 100 and 300 nm significantly increased drug penetration in dermis-epidermis in comparison to free CPA. Follicular targeting results revealed that NLC 300 nm had the best accumulation capacity in hair follicles. CPA-NLC with average diameter of 300 nm could be a promising topical novel drug delivery system for specific targeting of hair follicles and sebaceous glands to treat androgenic skin disorders such as acne, hirsutism, and alopecia.

Flutamide-Loaded Zein Nanocapsule Hydrogel, a Promising Dermal Delivery System for Pilosebaceous Unit Disorders.

Zein is a naturally occurring corn protein having similarity to skin keratin. Owing to its hydrophobicity and biodegradability, zein nanocarriers are promising drug delivery vehicles for hydrophobic dermatological drugs. In this study, zein-based nanocapsules (ZNCs) were exploited for the first time as dermal delivery carriers for flutamide (FLT), an antiandrogen used for the management of pilosebasceous unit disorders. FLT-loaded ZNC of appropriate particle size and negative surface charge were prepared by nanoprecipitation method. The dermal permeation and skin retention of FLT from ZNCs were studied in comparison to corresponding nanoemulsion (NE) and hydroalcoholic drug solution (HA). ZNCs showed a significantly lower permeation flux compared to NE and HA while increasing the skin retention of FLT. Confocal laser scanning microscopy (CLSM) demonstrated the follicular localization of the fluorescently labeled NCs. The incorporation of NCs in chitosan gel or Carbomer® 934 gel was studied. Carbomer® gel increased the skin retention of FLT compared to chitosan gel. Accordingly, Carbomer® hydrogel embedding FLT-loaded ZNCs is a promising inexpensive, biocompatible dermal delivery nanocarrier for localized therapy of PSU disorders suitable for application on oily skin.

Potential enhancement and targeting strategies of polymeric and lipid-based nanocarriers in dermal drug delivery.

Nanocarriers used for alternative drug-delivery strategies have gained interest due to improved penetration and delivery of drugs into specific regions of the skin in recent years. Dermal drug delivery via polymeric-based nanocarriers (polymeric nanoparticles, micelles, dendrimers) and lipid-based nanocarriers (solid-lipid nanoparticles and nanostructured lipid carriers, vesicular nanocarriers including liposomes, niosomes, transfersomes and ethosomes) has been widely investigated. Although penetration of nanocarriers through the intact skin could be restricted, these carriers are particularly considered as feasible for the treatment of dermatological diseases in which the skin barrier is disrupted and also for follicular delivery of drugs for management of skin disorders such as acne. This review mainly highlights the recent approaches on potential penetration enhancement and targeting mechanisms of these nanocarriers.

Nile red nanosuspensions as investigative model to study the follicular targeting of drug nanocrystals.

The strategy of formulating poorly soluble actives as nanosuspension has been explored by more than a thousand research papers, with some medicinal products for oral and intravenous use having reached the market or advanced clinical trials. Interestingly, there is a limited number of reports of nanosuspensions formulated for dermal and transdermal drug delivery. In the present work, a nanocrystals suspension of the fluorescent, water-insoluble dye Nile Red, is prepared through a media milling technique and exploited to characterize the fate of the nanosuspended drug when applied on the skin. More in detail, the accumulation of Nile Red nanocrystals inside the hair follicles is evidenced by scanning electron microscopy, and the diffusion of drug molecules in the different skin layers is evaluated by confocal microscopy and skin permeation studies. Overall, the combination of the analytical techniques provide a description of the mechanisms underlying dermal accumulation, and transdermal penetration of a drug formulated as a nanosuspension.

Polymeric micellar nanocarriers of benzoyl peroxide as potential follicular targeting approach for acne treatment.

The aim of this work was to optimize polymeric nano-sized micellar carriers of the anti-acne compound benzoyl peroxide (BPO) and to examine the ability of these carriers to deposit into hair follicles with the objective of improving skin delivery of BPO. BPO loaded polymeric micelles composed of Pluronic(®) F127 were prepared by the thin film hydration method and characterized in terms of size, loading capacity, morphology and physical stability. The optimized micelle formulation was then selected for skin delivery studies. The penetration of BPO loaded micellar carriers into skin and skin appendages across full thickness porcine skin was examined in vitro. Confocal microscopy images confirmed the penetration of Nile Red into hair follicles, which was loaded into micellar carriers as a model fluorescent compound. The relative safety of the polymeric micelles was evaluated with the MTT viability test using mouse embryonic fibroblasts. The results indicated that nano-sized polymeric micelles of BPO composed of Pluronic(®) F127 offer a potential approach to enhance skin delivery of BPO and that targeting of micelles into hair follicles may be an effective and safe acne treatment.

Intradermal and follicular delivery of adapalene liposomes.

BACKGROUND: Adapalene is a widely used topical anti-acne drug; however, it has many side effects. Liposomal drug delivery can play a major role by targeting delivery to pilosebaceous units, reducing side effects and offering better patient compliance. OBJECTIVE: To prepare and evaluate adapalene-encapsulated liposomes for their physiochemical and skin permeation properties. METHODS: A liposomal formulation of adapalene was prepared by the film hydration method and characterized for shape, size, polydispersity index (PDI), encapsulation efficiency and thermal behavior by techniques such as Zetasizer®, differential scanning calorimetry and transmission electron microscopy. Stability of the liposomes was evaluated for three months at different storage conditions. In vitro skin permeation studies and confocal laser microscopy were performed to evaluate adapalene permeation in pig ear skin and hair follicles. RESULTS: The optimized process and formulation parameters resulted in homogeneous population of liposomes with a diameter of 86.66 ± 3.5 nm in diameter and encapsulation efficiency of 97.01 ± 1.84% w/w. In vitro permeation studies indicated liposomal formulation delivered more drug (6.72 ± 0.83 µg/cm(2)) in hair follicles than gel (3.33 ± 0.26 µg/cm(2)) and drug solution (1.62 ± 0.054 µg/cm(2)). Drug concentration delivered to the skin layers was also enhanced compared to other two formulations. Confocal microscopy images confirmed drug penetration in the hair follicles when delivered using the liposomal formulation. CONCLUSION: Adapalene was efficiently encapsulated in liposomes and led to enhanced delivery in hair follicles, the desired target site for acne.

Follicular delivery of spironolactone via nanostructured lipid carriers for management of alopecia.

Spironolactone (SL) is a US Food and Drug Administration-approved drug for the treatment of hypertension and various edematous conditions. SL has gained a lot of attention for treating androgenic alopecia due to its potent antiandrogenic properties. Recently, there has been growing interest for follicular targeting of drug molecules for treatment of hair and scalp disorders using nanocolloidal lipid-based delivery systems to minimize unnecessary systemic side effects associated with oral drug administration. Accordingly, the objective of this study is to improve SL efficiency and safety in treating alopecia through the preparation of colloidal nanostructured lipid carriers (NLCs) for follicular drug delivery. SL-loaded NLCs were prepared by an emulsion solvent diffusion and evaporation method using 23 full factorial design. All of the prepared formulations were spherical in shape with nanometric size range (215.6-834.3 nm) and entrapment efficiency >74%. Differential scanning calorimetry thermograms and X-ray diffractograms revealed that SL exists in amorphous form within the NLC matrices. The drug release behavior from the NLCs displayed an initial burst release phase followed by sustained release of SL. Confocal laser scanning microscopy confirmed the potential of delivering the fluorolabeled NLCs within the follicles, suggesting the possibility of using SL-loaded NLCs for localized delivery of SL into the scalp hair follicles.

Nanoparticles and their interactions with the dermal barrier.

The dermal application of drugs is promising due to the ease of application. In this context nano-scale carrier systems were already evaluated in several studies with respect to the skin interaction and the impact on drug penetration. At the same time the upcoming production of engineered nano-scale materials requires a thorough safety evaluation. Drug delivery as well as risk assessment depends crucially on the ability of such carriers to overcome the skin barrier and reach deeper tissue layers. Therefore, the interaction of nanoparticles with skin and especially skin models is an intriguing field. However, the data obtained do not show a clear image on the effect of nano-carriers. Especially the penetration of such particles is an open and controversially discussed topic. The literature reports different results mainly on pig or murine skin showing strong penetration (pig and mouse) or the opposite. Looking only at the sizes of the particles also no conclusive picture can be obtained. Nevertheless, size is regarded to play an important role for skin penetration. Furthermore, the state of the skin influences penetration (hydration) and the mechanical stress is of outmost importance.