Solid lipid nanoparticles for targeted delivery of triclosan into skin for infection prevention

Abstract

Healthcare-associated infections (HAIs) are a concern for health service providers, exacerbated by poor delivery of antimicrobials to target sites within the skin. The dermal route is attractive for local and systemic delivery of drugs, however; permeation, penetration, and access to deeper skin layers are restricted due to the barrier function of the stratum corneum (SC). Solid lipid nanoparticles present several benefits for topical delivery for therapeutic applications, especially via the follicular route. Hair follicles, surrounded by a close network of blood capillaries and dendritic cells, are an important target for delivery of antimicrobials and present a unique microbial nidus for endogenous infections in situations where the barrier is disrupted, such as after surgery, for example, triclosan, a broad-spectrum antimicrobial agent, was encapsulated into nanoparticles using glyceryl behenate and glyceryl palmitostearate (GP) solid lipids, and incorporating Transcutol P, a known permeation enhancer at different ratios. Optimised formulation was stable over 90?d and in vitro permeation studies using full thickness porcine ear skin showed that the lipid-based nanoparticles enhanced delivery of triclosan into the skin and could direct the agent towards hair follicles, indicating their potential as a carrier system for antiseptic dermal delivery.     

Nanocarrier-based topical drug delivery for the treatment of skin diseases

Introduction: Skin disorders will continue to cause complications in patients. At present, there is an expansion of research into dermatologic treatment due to a critical need for new treatment options to treat skin diseases.

Areas covered: The skin itself provides a natural barrier against particle penetration for topical delivery. However, it also offers a potential approach for the delivery of therapeutics, especially in diseased skin and via the openings of hair follicles. Recent innovation might be achieved in the field of dermatological treatment with improvement in the dermal localization of bioactives into the affected skin region, via novel nanocarriers that deliver the drugs directly to the target cells. After application, these nanocarriers can penetrate through the stratum corneum into viable skin and accumulate at the target site. However, noteworthy uptake does occur after damage and in certain diseased skin.

Expert opinion: Skin-targeted topical delivery by means of nanosystems, in order to produce sustained release and maintain a localized effect, will result in an effective treatment of various life-threatening dermatological conditions. In addition, research continues into the interactions between novel particles, skin and skin lipid, and the influence of particle composition on drug distribution within the skin strata.     

Solid lipid nanoparticles suspension versus commercial solutions for dermal delivery of minoxidil

Solid lipid nanoparticles have been reported as possible carrier for skin drug delivery. Solid lipid nanoparticles are produced from biocompatible and biodegradable lipids. Solid lipid nanoparticles made of semi-synthetic triglycerides stabilized with a mixture of polysorbate and sorbitan oleate were loaded with 5% of minoxidil. The prepared systems were characterized for particle size, pH and drug content. Ex vivo skin penetration studies were performed using Franz-type glass diffusion cells and pig ear skin. Ex vivo skin corrosion studies were realized with a method derived from the Corrositex^® test. Solid lipid nanoparticles suspensions were compared to commercial solutions in terms of skin penetration and skin corrosion. Solid lipid nanoparticles suspensions have been shown as efficient as commercial solutions for skin penetration; and were non-corrosive while commercial solutions presented a corrosive potential. Solid lipid nanoparticles suspensions would constitute a promising formulation for hair loss treatment.     

A dynamic topical hydrofluoroalkane foam to induce nanoparticle modification and drug release in situ

Topical nanoparticles are usually applied using semi-solid formulations, but the delivery process is often inefficient due to the poor drug release from the particles. The aim of this study was to investigate the capability of a dynamic foam to break open nanoparticles upon application to the skin and enhance drug delivery efficiency. Vitamin E acetate (VEAc) was selected as a model drug and loaded into lipid nanoparticles (50-60 nm) prepared by phase inversion. The highest drug loading was 18.9 ± 1.2 mg/ml and the corresponding encapsulation efficiency was 81.5 ± 4.1%. Dynamic foams were generated by emulsifying VEAc-loaded nanoparticle suspensions with hydrofluoroalkane using pluronic L62D. An in vitro permeation study demonstrated that VEAc did not release from the nanoparticles when administered as an aqueous suspension, but attained a flux of 18.0 ± 2.1 (μg cm⁻² h⁻¹) when applied using the foam. Drug release from the foam was shown to be a consequence of nanoparticle modification after dose administration and this led to the foam delivering 0.7 ± 0.3% VEAc into the stratum corneum (SC) when applied to human skin.     

Nanocarrier-based topical drug delivery for the treatment of skin diseases

INTRODUCTION: Skin disorders will continue to cause complications in patients. At present, there is an expansion of research into dermatologic treatment due to a critical need for new treatment options to treat skin diseases. AREAS COVERED: The skin itself provides a natural barrier against particle penetration for topical delivery. However, it also offers a potential approach for the delivery of therapeutics, especially in diseased skin and via the openings of hair follicles. Recent innovation might be achieved in the field of dermatological treatment with improvement in the dermal localization of bioactives into the affected skin region, via novel nanocarriers that deliver the drugs directly to the target cells. After application, these nanocarriers can penetrate through the stratum corneum into viable skin and accumulate at the target site. However, noteworthy uptake does occur after damage and in certain diseased skin. EXPERT OPINION: Skin-targeted topical delivery by means of nanosystems, in order to produce sustained release and maintain a localized effect, will result in an effective treatment of various life-threatening dermatological conditions. In addition, research continues into the interactions between novel particles, skin and skin lipid, and the influence of particle composition on drug distribution within the skin strata.     

Application of lipid nanoparticles to ocular drug delivery

ABSTRACT

Introduction: Although eye drops are widely used as drug delivery systems for the anterior segment of the eye, they are also associated with poor drug bioavailability due to transient contact time and rapid washout by tearing. Moreover, effective drug delivery to the posterior segment of the eye is challenging, and alternative routes of administration (periocular and intravitreal) are generally needed, the blood–retinal barrier being the major obstacle to systemic drug delivery.

Areas covered: Nanotechnology, and especially lipid nanoparticles, can improve the therapeutic efficiency, compliance and safety of ocular drugs, administered via different routes, to both the anterior and posterior segment of the eye. This review highlights the main ocular barriers to drug delivery, as well as the most common eye diseases suitable for pharmacological treatment in which lipid nanoparticles have proved efficacious as alternative delivery systems.

Expert opinion: Lipid-based nanocarriers are among the most biocompatible and versatile means for ocular delivery. Mucoadhesion with consequent increase in pre-corneal retention time, and enhanced permeation due to cellular uptake by corneal epithelial cells, are the essential goals for topical lipid nanoparticle delivery. Gene delivery to the retina has shown very promising results after intravitreal administration of lipid nanoparticles as non-viral vectors.     

Potential and problems of developing transdermal patches for veterinary applications

A new frontier in the administration of therapeutic drugs to veterinary species is transdermal drug delivery. The primary challenge in developing these systems is rooted in the wide differences in skin structure and function seen in species ranging from cats to cows. The efficacy of a transdermal system is primarily dependent upon the barrier properties of the targeted species skin, as well as the ratio of the area of the transdermal patch to the species total body mass needed to achieve effective systemic drug concentrations. A drug must have sufficient lipid solubility to traverse the epidermal barrier to be considered for delivery for this route. A number of insecticides have been developed in liquid ‘pour-on’ formulations that illustrate the efficacy of this route of administration for veterinary species. The human transdermal fentanyl patch has been successfully used in cats and dogs for post-operative analgesia. The future development of transdermal drug delivery systems for veterinary species will be drug and species specific. With efficient experimental designs and available transdermal patch technology, there are no obvious hurdles to the development of effective systems in many veterinary species.     

Pharmaceutical nanocrystals: A promising approach for improved topical drug delivery

The barrier function of skin and the non-optimal physicochemical properties of drugs present challenges to the skin penetration of many drugs, thus motivating the development of novel drug delivery systems. Recently, nanocrystal-based formulations have been investigated for topical drug delivery and have demonstrated improved skin penetration. This review highlights barriers in skin penetration, current techniques to improve topical delivery and application of nanocrystals in conquering obstacles for topical delivery. Nanocrystals can improve delivery through the skin by mechanisms including the creation of a higher concentration gradient across skin resulting in increased passive diffusion, hair follicle targeting, formation of diffusional corona, and adhesion to skin. The recent research would be of interest for formulation scientists seeking to develop products involving molecules that are ‘difficult-to-deliver’ topically.     

Skin penetration enhancement of core-multishell nanotransporters and invasomes measured by electron paramagnetic resonance spectroscopy

In order to cross the skin barrier several techniques and carrier systems were developed to increase skin penetration of topical dermatics and to reduce systemic adverse effects by avoiding systemic application. Ultra-flexible vesicles, e.g. invasomes and core-multishell (CMS) nanotransporters are efficient drug delivery systems for dermatological applications. Electron paramagnetic resonance (EPR) spectroscopic techniques were used for the determination of localization and distribution of the spin label 3-carboxy-2,2,5,5-tetramethyl-1-pyrrolidinyloxy (PCA; log P = −1.7) within the carrier systems and the ability of the carriers to promote penetration of PCA into the skin. The results show an exclusive localization of PCA in the hydrophilic compartments of the invasome dispersion and the CMS nanotransporter solution. PCA penetration was enhanced 2.5 fold for CMS and 1.9 fold for invasomes compared to PCA solution. Investigation of penetration depth by step-wise removal of the stratum corneum by tape stripping revealed deepest PCA penetration for invasomes. UV-irradiation of PCA-exposed skin samples revealed that the spin label is still reactive. In conclusion novel polymer-based CMS nanotransporters and invasomes can favor the penetration of PCA or hydrophilic drugs. This offers possibilities for e.g. improved photodynamic therapy.     

Site-specific drug delivery in the skin for the localized treatment of skin diseases

ABSTRACT

Introduction: Due to the well-organized structure and barrier function of the skin, it is generally difficult for drugs applied directly on the surface of skin to reach their expected site of action. Accordingly, site-specific drug delivery in the skin has been increasingly explored to facilitate the treatment of skin diseases and reduce the systemic toxicity.

Area covered: An overview of the generally used sites for drug delivery in the skin is herein presented. Different strategies including particle-based carriers, physical technologies, and chemical approaches are discussed with regards to their potential application in site-specific drug delivery in the skin.

Expert opinion: Particle-based carriers are of particular significance for the enhancement of drug delivery in the skin. Although no recommendation can be made regarding which type of carriers can provide better skin penetration, the lipid-based colloidal systems appear to be favored due to their compatibility. In addition, the physical technologies provide unique advantages in delivering hydrophilic macromolecules for the skin immunization. As a new class of permeation enhancers, skin penetrating peptides are gaining more attention in drug delivery to skin cells. For the design of robust site-specific drug delivery systems, the impacts of diseased state and drug properties should not be disregarded.     

In vitro penetration properties of solid lipid nanoparticles in intact and barrier-impaired skin

Treatment of skin diseases implies application of a drug to skin with an impaired epidermal barrier, which is likely to affect the penetration profile of the drug substance as well as the carrier into the skin. To elucidate this, the effect of skin barrier damage on the penetration profile of a corticosteroid applied in solid lipid nanoparticles (SLN) composed of different lipids, varying in polarity, was studied. The studies were carried out in vitro using impaired and intact porcine ear skin, and the SLN were compared with a conventional ointment. It was shown that a significantly higher amount of corticosteroid remained in the skin, intact as well as barrier impaired, when SLN was used as a vehicle. In general, the penetration profile of the drug substance into the skin was affected by the type of lipid used in the formulation and related to lipid polarity and drug substance solubility. When formulated in SLN and applied to intact skin, the permeation of the drug substance across the skin was significantly reduced, as compared to the ointment. Altogether, in both barrier-impaired and intact skin, a higher amount of drug substance remained in the skin during application of SLN for 6, 16, and 24 h, as compared to the ointment. These results emphasize the applicability of SLN to create a drug reservoir in skin, with the drug localized distinctively in the stratum corneum.     

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.     

Low frequency sonophoresis mediated transdermal and intradermal delivery of ketoprofen

The objective of this study was to test low frequency sonophoresis at 20 kHz for delivery of ketoprofen into and across the skin. Permeation studies were carried out in vitro on excised hairless rat skin over a period of 24 h using Franz diffusion cells after which, skin samples were subjected to skin extraction to quantify the amount of drug present in skin. Parameters like ultrasound application time, duty cycle coupling medium and distance of ultrasound horn from skin were optimized. Transepidermal water loss (TEWL) was measured to indicate the extent of barrier disruption following sonophoresis. Confocal microscopy was used to visualize dye penetration through sonophoresis treated skin. Application of ultrasound significantly enhanced permeation of ketoprofen from 74.87 ± 5.27 μg/cm² for passive delivery to 491.37 ± 48.78 μg/cm² for sonophoresis. Drug levels in skin layers increased from 34.69 ± 7.25 μg following passive permeation to 212.62 ± 45.69 μg following sonophoresis. TEWL increased from 31.6 ± 0.02 (passive) to 69.5 ± 12.60 (sonophoresis) indicating disruption of barrier properties. Confocal microscopy images depicted enhanced dye penetration through sonophoresis treated skin confirming barrier disruption. Low frequency sonophoresis with optimized ultrasound parameters can be effectively used to actively enhance transdermal and topical delivery of ketoprofen.     

纳米制剂在透皮药物递送系统中的应用研究进展

透皮药物递送系统作为一种非侵入式给药途径,与传统给药方式相比具有顺应性高、无首过效应等优势。纳米技术的应用使得透皮药物递送系统的药物选择范围进一步扩大,并提高了药物的治疗效果,形成了一种极具价值、令人期待的新型给药方式。目前常用于透皮药物递送系统的纳米制剂包括纳米乳、脂质纳米囊泡、脂质纳米粒、聚合物纳米粒、纳米晶体、溶致液晶纳米粒等。介绍了皮肤屏障和透皮递送的常用促渗方法,综述了各类应用于透皮药物递送系统的纳米制剂及其与物理促渗方法联合应用的研究进展,以期为纳米制剂在透皮递送方面的深入研究提供参考。     

Potentials of new nanocarriers for dermal and transdermal drug delivery

Nanocarriers (NCs) are colloidal systems having structures below a particle or droplet size of 500 nm. In the previous years, the focus for the application of NCs was primarily placed on the parenteral and oral application. However, NCs applied to the skin are in the center of attention and are expected to be increasingly applied as the skin offers a lot of advantages for the administration of such systems. For the use of NCs to the skin, one has to differentiate between the desired effects: the local effect within the skin (dermal drug delivery) or a systemic effect accompanied by the permeation through the skin (transdermal drug delivery).Both for dermal and transdermal drug delivery, the stratum corneum (SC), the main barrier of the skin, has to be overcome.SC is one of the tightest barriers of the human body. Therefore, it is the primary goal of new NC to overcome this protective and effective barrier. For that purpose, new NCs such as microemulsions, vesicular (liposomes) and nanoparticular NCs are developed and investigated. This article evaluates the potentials of these NCs for dermal and transdermal drug delivery.     

Drug delivery into the skin by degradable particles

Recently, it was demonstrated that particles could be utilized as carrier systems for drugs into the hair follicles. In the present study, a two-component drug delivery system is presented consisting of degradable particles loaded with fluorescein isothiocyanate and a separate protease formulation for degradation. The particles were applied alone, 30 min previous to the protease application and simultaneously with the protease onto porcine skin. Subsequently, biopsies were removed, and the penetration depths of the particles were analyzed using laser scanning microscopy.The obtained results demonstrate that the particles alone achieved a penetration depth of around 900 μm. Similar results were obtained for the successive application of particles and protease, whereas a release of the fluorescent dye was only observed in the upper 250 μm corresponding to the penetration depth of the protease. In the case of the simultaneous application, the particles were partly dissolved before application, leading to a reduced particle size and diminished penetration depth.The results revealed that degradable particles are a promising tool for drug delivery into the skin.     

Targeting of liposome-associated calcipotriol to the skin: effect of liposomal membrane fluidity and skin barrier integrity

Many dermal diseases like psoriasis are characterized by major changes in skin barrier function, which challenge the reproducible delivery of drugs into specific layers of diseased skin. The purpose of this study was to elucidate how liposomal bilayer fluidity and barrier integrity affected the delivery of liposome-associated calcipotriol to the skin. Calcipotriol-containing gel state and liquid state dipalmitoylphosphatidyl-choline:dilauroylphosphatidylcholine liposomes were prepared by extrusion. Using Langmuir monolayers, calcipotriol was shown to affect the packing of the lipid membrane. The penetration of radioactively labeled lipid and calcipotriol into pig skin was examined using the Franz diffusion cell model, and tape stripping was applied to impose an impaired barrier. Distorting the skin barrier resulted in an enhanced penetration of lipid from both gel and liquid state liposomes. In addition, increased penetration of lipid from liquid state liposomes was observed compared to gel state liposomes into barrier-impaired skin. For barrier-impaired skin, an elevated calcipotriol-to-lipid ratio was found in the receptor fluid for both liposome compositions indicating that calcipotriol is released from the vesicles. This suggests that the liposome-mediated delivery of calcipotriol to the epidermis of diseased skin is affected by the fluidity of the liposomal membrane.     

Drug delivery to hair follicles

Introduction: The optimization of drug delivery to and via the hair follicles is gaining more and more importance as it has been recognized that the hair follicles are an interesting target site for topical applications. They are closely surrounded by capillaries and antigen-presenting cells, are associated with the sebaceous glands and are the host of stem cells in the bulge region of the hair follicle.

Areas covered: The present review shortly summarizes the complexity of the structure, biology and functions of the hair follicle and presents the models and methods suitable to investigate follicular penetration. Drug delivery to hair follicles was clearly shown to be dependent on the physicochemical properties of the applied substances and vehicles as well as on the activity status, size and density of the hair follicles. Especially particulate substances were demonstrated to be proficient drug carriers into the hair follicles, whereas dependent data for transfollicular penetration into the deeper viable skin layers could only be found for non-particulate substances which then, however, received rapid access to the circulation when the follicular pathway was accessible.

Expert opinion: Promising concepts to optimize hair follicle delivery and to beneficially utilize particulate substances for efficient follicular drug delivery are the application of external or internal stimuli for controlled drug release from the particles such as the combined application with protease or the usage of gold nanoparticles in combination with near-infrared irradiation.     

Novel approaches to retinal drug delivery

The properties inherent in poly(alkylcyanoacrylate) (PACA) nanoparticles, such as biocompatibility and biodegradability of the polymer, a simple preparation process and particularly the entrapment of bioactives, specifically proteins and peptides, have sparked extensive interest in these nanoparticles as drug delivery systems. Research has focused on the oral route of administration, however ocular, transdermal and delivery across the blood–brain barrier have also been investigated. Despite numerous promising studies, no formulation with this colloidal carrier has been marketed to date. A number of factors have been identified as interfering with the reproducibility of in vitro and in vivo results, which impedes the comparison of the plethora of experiments done with PACA nanoparticles. This review will highlight the challenges and opportunities of using PACA nanoparticles as drug delivery systems, including polymerisation mechanisms and templates, entrapment, release, nanoparticle uptake and toxicity. In vitro and in vivo studies, as well as possible surface modifications for targeted delivery in the human field and veterinary applications of PACA nanoparticles are reviewed. Emphasis will be placed on microemulsions as templates for the preparation of PACA nanoparticles and oral delivery of proteins and peptides.     

New Delivery Route of Gambogic Acid Via Skin for Topical Targeted Therapy of Cutaneous Melanoma and Reduction of Systemic Toxicity

Cutaneous melanoma is the deadliest form of skin cancer, and gambogic acid (GA) exhibits potent anti-melanoma activity. However, clinical application of GA via intravenous injection and oral administration is limited by systemic toxicity and rapid metabolism in the blood. Here, we developed a new, topical route of GA delivery for anti-melanoma activity and reduction of systemic toxicity. The results indicated that the barrier of the stratum corneum (SC) and low diffusion of GA in the hydrophilic viable skin (epidermis and dermis) limited the GA penetration through intact skin. The combination of azone (AZ) and propylene glycol (PG) showed obvious synergistic effects on skin penetration by GA via improving the permeability of the SC and greatly increasing the skin accumulation of GA, thereby forming a high drug concentration in the skin and achieving a topical targeted treatment of melanoma. In addition, GA (AZ–PG) achieved the same anti-melanoma effect via topical delivery as via intravenous injection. Intravenous injection and oral administration of GA induced remarkable pathological changes in various organs in mice, whereas GA was not toxic to various organs or to the skin via topical delivery. These findings indicated that topical administration of GA is an alternative route for melanoma treatment.