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Stefanov, S. Lipid Nanoparticulate Drug Delivery Systems and Skin Disorders. Encyclopedia. Available online: (accessed on 02 December 2023).
Stefanov S. Lipid Nanoparticulate Drug Delivery Systems and Skin Disorders. Encyclopedia. Available at: Accessed December 02, 2023.
Stefanov, Stefan. "Lipid Nanoparticulate Drug Delivery Systems and Skin Disorders" Encyclopedia, (accessed December 02, 2023).
Stefanov, S.(2021, November 16). Lipid Nanoparticulate Drug Delivery Systems and Skin Disorders. In Encyclopedia.
Stefanov, Stefan. "Lipid Nanoparticulate Drug Delivery Systems and Skin Disorders." Encyclopedia. Web. 16 November, 2021.
Lipid Nanoparticulate Drug Delivery Systems and Skin Disorders

Lipid nanoparticles (LN) are recognized as promising drug delivery systems (DDS) in treating skin disorders. Solid lipid nanoparticles (SLN) together with nanostructured lipid carriers (NLC) exhibit excellent tolerability as these are produced from physiological and biodegradable lipids. Moreover, LN applied to the skin can improve stability, drug targeting, occlusion, penetration enhancement, and increased skin hydration compared with other drug nanocarriers. Furthermore, the features of LN can be enhanced by inclusion in suitable bases such as creams, ointments, gels (i.e., hydrogel, emulgel, bigel), lotions, etc. 

skin diseases lipid-based nanosystems solid lipid nanoparticles nanostructured lipid carriers

1. Introduction

1.1. Skin Disorders

The skin can be affected by various pathological changes, i.e., inflammatory, neoplastic, traumatic, hormonal, degenerative, and even hereditarily determined [1]. Infectious skin diseases such as bacterial, fungal or viral affect people and cause various dermatological problems. Chronic inflammatory skin diseases such as atopic dermatitis, allergic contact dermatitis, psoriasis, etc., are a consequence of infiltration of inflammatory T cells [2]. The schematic representation of various skin disorders is shown in Figure 1 [3][4][5][6][7][8][9][10][11][12][13][14].

Pharmaceuticals 14 01083 g003

Figure 1. Representation of the most common skin disorders [3][4][5][6][7][8][9][10][11][12][13][14].
In practice, most of the skin disorders are complicated, polygenic, and multifactorial [15]. This indicates that multiple factors, lifestyle, and the environment play a fundamental role in the clinical picture of the diseases [16].

1.2. Lipid Nanoparticulate Drug Delivery Systems

Lipid-based drug delivery systems (LBDDS) are formulations containing a dissolved or suspended drug substance in lipidic excipients [17]. LBDDS are a progressive strategy to formulate pharmaceuticals for topical delivery [18]. Liposomes, which are “pioneers” among lipid DDS, have been used to improve drug solubility and traditionally for topical and transdermal drug delivery.

Table 1 presents a brief overview of lipid-based drug delivery systems.

Table 1. Presentation of some lipid-based delivery systems.

Delivery System
Description Advantages Disadvantages
Nanovesicular carriers
Liposomes [19] Conventional single or multilayer vesicles. Formed by contact of biodegradable lipids with an aqueous medium. Widely used as drug carriers for hydrophilic and lipophilic molecules. Biocompatible and biodegradable lipids. Conventional production processes. Improved local delivery. Suitable for loading both hydrophobic and hydrophilic substances. Insufficient chemical and physical stability. Short half-life. Inadequate penetration into the viable epidermis and dermis. High production costs. Difficulties in scalability.
Highly deformable, elastic or ultra-flexible liposomes. Vesicles, similar to conventional liposomes in terms of preparation and structure. Claimed to permeate as intact vesicles through the skin layers. Functionally deformed due to the presence of an edge activator. Smaller vesicle size, higher elasticity. Compared with conventional liposomes—better penetration through the skin. High membrane hydrophilicity and elasticity allow them to avoid aggregation and fusion under osmotic stress, unlike the conventional liposomes. Elasticity of these vesicles can be compromised by hydrophobic drug loading. Occlusive application and complete skin hydration limit transdermal delivery due to inhibition of transdermal hydration. Relatively high production costs. Absence of well-established regulatory guidance for skin delivery.
Ethosomes [23][24] Lipid vesicles are composed of phospholipids, ethanol, and water. Similar to liposomes in terms of their preparation techniques and structure. Concentration of ethanol 20–45%. Their size decreases with an increase in the ethanol concentration. Exhibit high encapsulation efficiency. Appropriate for both hydrophobic and hydrophilic drug loading. Enhanced skin delivery under both occlusive and nonocclusive conditions. Higher elasticity, smaller vesicle size, and higher entrapment efficiency than conventional liposomes. High ethanol content can lead to skin irritation and toxicity. Possible structural and chemical instability during long-term storage. Need to optimize the concentration of lipids and ethanol for improved physicochemical properties and stability of ethosomes.
Lipid nanoparticulate carriers
Solid lipid nanoparticles [25][26] Colloidal lipid nanoparticles are composed of a physiological biodegradable solid lipophilic matrix (solid at room temperature and body temperature), in which the drug molecules can be incorporated. Increased drug stability. High drug payload. Incorporation of lipophilic and hydrophilic drugs. Avoidance of organic solvents. Lack of biotoxicity of the carrier. Relatively cost-effective. SLN are incorporated into semisolid carriers such as ointments and gels due to the high water content. Potential expulsion of active compounds during storage. Cost-effective manufacturing process.
Lipid Carriers [27][28]
Colloidal lipid nanoparticles composed of physiological mixing liquid lipid (oils) with the solid lipids, in which the liquid lipid is incorporated into the solid matrix or localized at the surface of solid particles Improved drug loading compared with SLN. Lower water content compared with SLN. Firmly incorporates the drug substance during storage. Biodegradable and biocompatible. Large-scale production is easily possible. Tendency to unpredictable gelation. Polymorphic transition. Low drug incorporation due to the crystalline structure of solid lipids. Lack of long-term stability data.
Microspheres, composed of solid hydrophobic lipid core and stabilized by a monolayer of a phospholipid embedded on the surface. Improved drug stability, especially for photo-labile drugs. Possibility for controlled drug release. Controlled particle size. High drug loading. Biodegradable and biocompatible. Larger particle size and poor skin permeation compared with lipid-based vesicular carriers, SLN, and NLC. Poor drug loading for hydrophilic compounds.

2. Solid Lipid Nanoparticles and Nanostructured Lipid Carriers

Solid lipid nanoparticles (SLN), as well as nanostructured lipid carriers (NLC), are extensively employed in cutaneous delivery systems. Since their creation in the nineties, lipid nanoparticles (SLN and NLC) are well known by the research and pharma technology community. Easily available raw materials, relatively simple production methods, biocompatibility, and non-toxicity as their advantages over other colloidal carriers can be mentioned as the main reasons for this [18].
Therefore, these two types of lipid nanoparticles—SLN and NLC, are classified according to their structure. First, SLN are developed with a composition of solid lipids only. Then, to upgrade to SLN, NLC were created by representing a mixture of solid and liquid lipids, with a predominant solid lipid [32].
The dermal use of SLN and NLC is proving to be one of the most convenient for therapeutic and cosmetic purposes, despite various applications to date. Lipid nanoparticles are aqueous dispersions with low viscosity for successful direct application to the skin, which implies their incorporation in semisolid systems based on SLN or NLC. One of the first successful administered and marketed products based on NLC is Cutanova® from Dr. Rimpler GmbH (Wedemark, Germany) and Nanobase® from Yamanouchi (Tokyo, Japan) [33].

2.1. Solid Lipid Nanoparticles

Generally speaking, SLN are nanometric colloidal carriers composed of a solid lipid core with an incorporated active pharmaceutical ingredient(s) (API) and a surfactant-stabilized shell [34][35][36]. SLN are composed in the 1990s and have unique properties such as biodegradability, impressive toxicity profile, protection of the API against degradation, high load capacity, sterilization ability, and scalability [37][38]. The interaction between the lipid core of SLN and the waxy lipids in SC leads to a significant permeation enhancement of the encapsulated drug into the skin, which determines their successful cutaneous application [39].

2.2. Nanostructured Lipid Carriers

The second generation of lipid nanoparticles—NLC, are composed of a mixture of solid lipids and liquid lipids in the nanocore, usually in a ratio of 7:3 to 9:1 [40]. This leads to a more significant disorder of the core of the lipid matrix, and accordingly decreases the melting point to stop the recrystallization of solid lipids [41]. NLC are considered to be an improved variety of SLN, holding the same unique properties, but with an optimized core composition, resulting in a higher drug loading capacity, better stability, and ability to act at lower temperatures. Of note is the fact that NLCs are still solid at body temperature [42].

2.3. Preparation of SLN and NLC

The literature describes a significant number of production methods and many different combinations of lipids to obtain SLN and NLC. Nevertheless, the most common technique used today is high-pressure homogenization (HPH). The procedure is divided into two stages:
  • Hot homogenization—the lipids are heated above their melting point;
  • Cold homogenization—takes place at low temperatures and is suitable for hydrophilic and temperature-sensitive API [43][44].
Other commonly used techniques are: Sonication/ultra-sonication [45][46], membrane contactor technique [47], phase inversion [48], solvent injection [49], emulsification [50], the microemulsion method [51], etc.

2.4. SLN and NLC in the Treatment of Skin Disorders

In dermal applications, SLN and NLC create a thin hydrophobic monolayer during skin contact, which has a pointed occlusive effect that settles the API penetration and prevents water loss from the skin [52].
When applied topically, the lipid nanoparticles interact with the sebum and specific skin lipids, provoking a change in the natural arrangement of corneocytes. As a result of this interaction, the encapsulated molecules are released, and their penetration into the lower layers of the epidermis and dermis is potentiated, depending on their lipophilicity, of course [53].

2.4.1. Antioxidant Effect

Okonogi and Riangjanapatee formulated NLC loaded with lycopene through a hot HPH. It has been found that the NLC with the highest concentration of lycopene had the slowest release rate and better antioxidant activity [54].
In another study, Shrotriya et al. reported the development of SLN loaded with resveratrol (entrapment efficiency of 86–89%) to treat irritant contact dermatitis (chronic skin disorder with eczematous injuries). The composition was realized by incorporation into a Carbopol gel and showed increased antioxidant activity compared with a conventional resveratrol gel [55].
Furthermore, Montenegro et al. designed a novel Idebenone (IDE)-loaded NLC containing tocopheryl acetate (VitE) as a liquid component to obtain a synergic effect between IDE and VitE [56].

2.4.2. Anti-Inflammatory Effect

Pivetta et al. formulated NLC with thymol for the local treatment of inflammatory skin diseases (entrapment efficiency of 89%). The NLC were incorporated into a gel and showed anti-inflammatory activity and healing of induced psoriasis in mice [57].
Gad et al. reported the encapsulation of chamomile oil in SLN for the local treatment of wounds. The composition contained stearic acid and chamomile oil and was prepared by the method of hot homogenization. Wound reduction was shown in the topical application in rats [58].

2.4.3. Antifungal Effect

Butani et al. developed a stable SLN system, containing amphotericin B with an enhancing antifungal activity (entrapment efficiency of 94%). The formulation indicated higher drug permeation and drug accumulation in the skin than the conventional gel in rats. A solvent diffusion technique was used for the preparation of the SLN [59].
NLC, for the treatment of candidiasis with Mediterranean essential oils and clotrimazole, were designed by Carbone et al. As a result, they are obtained as a stable NLC, without an initial burst effect and with prolonged release of clotrimazole, as well as an enhanced antifungal activity [60].

2.4.4. Anti-Acne Effect

Tretinoin-loaded NLC with anti-aging and anti-acne activities were reported by Ghate et al. The hot melt probe sonication and hot melt microemulsion methods were used to prepare the NLC. The tretinoin-loaded NLC in Carbopol gels showed no irritation or erythema after the application in rats [61].
Malik and Kaur developed the azelaic acid-loaded NLC, prepared by the melt emulsification and ultra-sonication method (entrapment efficiencies greater than 80%). NLC were incorporated into aloe-vera-based Carbopol hydrogels and demonstrated a deeper skin penetration than the commercial product (Aziderm 10%). Furthermore, the in vivo experiment in mice showed a higher effect of NLC incorporated into a gel than the plain drug suspended in the gel [62].
Table 2 presents the practical implementation of SLN and NLC in dermal drug delivery systems.
Table 2. Application of SLN and NLC DDS for the treatment of skin disorders.
LNP Type API/Drug Application Reference
SLN Doxorubicin Doxorubicin-loaded SLN for the treatment of skin cancer. [63]
SLN Adapalene Adapalene-loaded SLN in the gel for anti-acne treatment. [64]
SLN Triamcinolone acetonide Triamcinolone acetonide-loaded SLN for the topical treatment of psoriasis. [65]
SLN Resveratrol, vitamin E, and
epigallocatechin gallate
SLN containing resveratrol, vitamin E, and epigallocatechin gallate for antioxidant benefits. [66]
SLN Silybin Silybin-loaded SLN enriched gel for irritant contact dermatitis. [67]
SLN Fluconazole Fluconazole-loaded SLN topical gel for the treatment of pityriasis versicolor. [68]
SLN Tazarotene Tazarotene-loaded SLN for the treatment of psoriasis. [69]
SLN Miconazole nitrate Miconazole nitrate-loaded SLN for antifungal activity. [70]
SLN Adapalene Adapalene-loaded SLN for anti-acne therapy. [71]
SLN Isotretinoin and
SLN loaded with retinoic acid and lauric acid for the topical treatment of acne vulgaris. [72]
NLC Spironolactone Spironolactone-loaded NLC-based gel for the effective treatment of acne vulgaris. [73]
NLC Clobetasol propionate NLC-based topical gel of clobetasol propionate for the treatment of eczema. [74]
NLC Tacrolimus and tumor
necrosis factor α siRNA
NLC co-delivering tacrolimus and tumor necrosis factor α siRNA for the treatment of psoriasis. [75]
NLC Itraconazole Topical NLC containing itraconazole for the treatment of fungal infections. [76]
NLC Apremilast NLC for topical delivery of apremilast for the treatment of psoriasis. [77]
NLC Dithranol Dithranol-loaded NLC-based gel for the treatment of psoriasis. [78]
NLC Voriconazole Voriconazole-loaded NLC for antifungal applications. [79]
NLC Mometasone furoate NLC-based hydrogel of mometasone furoate for the treatment of psoriasis. [80]
NLC Antimicrobial peptide
nisin Z
Antimicrobial peptide nisin Z with conventional antibiotic-loaded NLC to enhance antimicrobial activity. [81]
NLC Adapalene and vitamin C Adapalene- and vitamin C-loaded NLC for acne treatment. [82]

3. Conclusions

Skin disorders represent a progressively emerging clinical public health problem. Treatment strategies based on conventional formulations are non-specific and can lead to considerable systemic toxicity. The progressive approach of the use of lipid nano-formulations as skin drug delivery systems can provide an incomparable prospect for the application of highly competent and safe treatments with the improved benefit-risk ratio.
The use of lipid nanoparticlulate DDS is favored recently due to the GRAS status of the excipients. Lipid nanocarriers can effectively protect the API from degradation on the skin’s surface, increase their concentration gradient in the upper skin layers, and enable gradual release. Lipid nanoparticles for topical application could be formulated with the high content of lipid matrix or dispersed in different foundations.
Lipid nanosystems provide a promising, flexible platform for the safe, effective, and biocompatible topical delivery of the API, as they do not cause cytotoxicity or morphological changes in the skin layers. The interest shown by pharmaceutical scientists, in the development of lipid nanoparticle delivery systems, may offer a future that provides sufficiently efficient lipid nanoparticle products for needy users.


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Update Date: 16 Nov 2021