Topical delivery of oily actives using solid lipid particles

Lipid-based drug delivery systems — such as liposomes, micro-and nanoemulsions, self-emulsified drug delivery systems, and solid lipid micro-and nanoparticles — are becoming more popular because lipid materials are easily characterized, contain a high range of well-defined/tolerated surfactant molecules and can be developed for several administration routes.

These systems are particularly suitable for topical delivery of oily substances, and are already common in a variety of topical pharmaceutical and cosmetic applications. This is because many suitable compounds are soluble in these materials, they do not irritate the skin and they have extremely low acute and chronic toxicities. The majority of existing topical formulations are applied to achieve a protective effect. Although the skin is widely recognized as a barrier against permeability for topically applied compounds, these formulations cannot be considered safe — even when used solely for protective purposes. For such purposes, well-tolerated and biocompatible materials are also required.

Additionally, for several physiological conditions, the pharmacological activity of the applied drug is required to achieve the treatment, penetration and/or absorption of a particular active ingredient. To achieve topical/dermatological drug delivery, it is necessary to develop systems that enhance drug penetration and have a high encapsulation efficiency for the APIs.

Lipid particles (LPs) can be used as penetration enhancers of encapsulated drugs through the skin because of their excellent occlusive and hydrating properties.

The LPs have been developed by exchanging the liquid lipid (oil) of the oil-in-water emulsions (o/w) by a lipid that is solid at both room temperature and body temperature.¹ The presence of a solid core has many advantages compared with a liquid core, including enhanced protection for chemically labile drugs/actives, less chance of an emulsion forming and a relatively fast release rate from liposomes.

Depending on the matrix size, particles can be below (nano) or above (micro) the nanometre range. Both are composed of a matrix that is in a solid state; that is, the melting temperature should be above 40 °C to remain solid after topical administration. Thus, the melting point of the systems can be adjusted by the choice of the lipid materials used to produce them.

Several lipid compounds from animal and vegetable sources, such as mono-, di-and tri-acylglycerols and waxes, can be used to produce LPs. When very pure lipids (e.g., tristearin and tripalmitin) are used to produce these systems, a highly ordered matrix with a low encapsulation efficiency for incorporated drug molecules is obtained. Alternatively, less-defined mixtures of acylglycerols, such as glycerol behenate and glycerol palmitostearate, can create voids and vacancies within the lipid matrix of the particles, resulting in higher encapsulation efficiencies.

Incorporating liquid lipids (oils) within the solid matrix of LPs has many advantages. In fact, many drugs/APIs are more soluble in liquid lipids than solid lipids, which increases the loading of the systems. In addition, when mixing solid lipids with sufficient amounts of oils an imperfect crystal matrix can be obtained.² The physiochemical characterization of these oil-loaded solid lipid nanoparticles (SLNs) revealed that the oil is encapsulated and partially segregated within the nanoparticles,^3–5 although some controversial results have also been published.^6,7

To produce SLNs, the lipid phase is melted and then immediately emulsified in a hot surfactant aqueous solution to prepare an emulsion. The obtained emulsion is then cooled from the molten state to room temperature to crystallize and form solid particles.

At high oil concentrations, a miscibility gap of the two lipids (i.e., the solid lipid and oil) occurs during the cooling phase, leading to phase separation, which creates tiny oily nanocompartments. As a result of the different chain lengths of the fatty acids and the mixture of mono-, di-and tri-acylglycerols, the particle matrix cannot form a highly ordered structure, creating available spaces for the drug. Figure 1 shows the morphological differences between SLPs and oil-loaded particles.

Figure 1 Morphological difference between SLPs and oil-loaded LPs.

Both systems are of solid character, therefore, these particles immobilize the incorporated drugs/APIs, preventing their leakage and protecting sensitive drugs from the external environmental. When obtaining systems below the nanometre size range they are called, respectively, SLPs [Figure 1(a)],⁸ and nanostructured lipid carriers (NLCs) [Figure 1(b)].²

As lipids are polymorphic, they can be transformed through a series of successive crystalline forms without a change in chemical structure. These polymorphic transitions depend on the matrix composition (i.e., they are influenced by the presence of one or more substances or other fats in the matrix). This is not desirable because the change in lipid structure is responsible for drug expulsion during storage, changes in the release profile of the incorporated drug/active, as well as changes in particle size parameters. Consequently, certain properties (e.g., drug retention or physiochemical stability) essential for improved drug delivery performance may be influenced. When using complex acylglycerols, such as mixed acid acylglycerols or partial acylglycerols present in oils, a less ordered structure is obtained. The drug/active can be dissolved in the oily phase or be present in the form of amorphous clusters, mainly localized in the imperfections of the crystal. In such cases, drug/active accommodation is improved when the lipid crystal has more imperfections. Thus, loading capacity can be increased by using rather crude lipid mixtures or by controlled nanostructuring of the lipid matrix; that is, creating as many imperfections as possible. Table 1 summarizes some examples of oil-loaded LPs for administration of topical drugs/APIs.^9–22

Table 1 Incorporation of oils into LPs: composition of formulations (solid lipid and surfactant), and entrapped model drugs/active ingredients.

Microparticles versus nanoparticles

The skin's low permeability makes it a widely recognized barrier compared with other biomembranes. Thus, the therapeutic efficacy of a topically applied drug depends on its ability to penetrate the skin and be accumulated in the deeper layers of the skin. Smaller particles ensure closer contact with the stratum corneum, thus nanoparticles should increase the amount of encapsulated agents penetrating into viable skin compared with microparticles.

When topically applied, nanoparticles create a monolayered lipid film of smaller interparticle pores, which are associated with higher occlusiveness and, therefore, higher hydration and skin emolliency. When composed of solid and hydrophobic nanoparticles, this film has occlusive properties on the skin retarding the loss of moisture as a result of evaporation.²³ Figure 2 shows the effect of particle size on skin hydration.

Figure 2 Microparticles and nanoparticles: effects on skin hydration (modified after Müller et al.1).

Moisture barrier properties have been experimentally demonstrated by the different degree of occlusion that lipid particles exhibit according to their size.²⁴ Better hydration properties can be achieved using nanoparticles compared with microparticles. Lipid nanoparticle (LN) dispersions are suitable to increase skin hydration because, when applied onto the skin, the pressure leads to fusion of the particles forming a dense film. This fusion is promoted by capillary forces involved during water evaporation.²⁵

The increased surface area of nanoparticles compared with microparticles is another advantage to enhance the penetration of APIs, depending on the release profile of the developed systems. The release profile depends on:

• The method used to produce the LPs.

• The composition of the formulation (i.e., the composition and concentration of surfactant).

• The solubility (and concentration) of the drug in the lipid matrix (oil/water partition coefficient).

These factors influence the inner structure of the particle and, thus, the release rate of the incorporated drug/API.^1,26–28 The drug/active release profile can vary from very fast, medium to extremely prolonged, depending on the size and on the matrix structure of LPs.

Topical administration

As previously mentioned, LPs can be used for controlled-release purposes because of their solid character. This property can be explored for developing delivery systems for essential oils or fragrances. Essential oils are volatile lipid-soluble compounds used in the pharmaceutical, cosmetic and food industries for their odourous properties, as well as some pharmacological, physiological and antimicrobial effects. They are usually originated from vegetables and can be obtained from several techniques, including expression, steam and water distillation, solvent extraction, enfleurage and carbon dioxide extraction. After extraction, most essential oils have to be diluted in ethanol for perfumery, food additives and flavourings.²⁹ To hinder their rapid evaporation, these oils can be incorporated within the solid matrix of LPs to create a once-a-day application with a prolonged effect over several hours. Comparison studies have been performed between LNs compared with o/w nanoemulsions. The fragrance/perfume release could be slowed down by oil incorporation in a SLN instead of being delivered as oil droplets.^16,17 This property can also be advantageous for the delivery of lemon oil, which acts as an insect repellent. Lemon oil evaporation was significantly reduced by being incorporated into SLNs, when compared with a conventional emulsion formulation applied onto the skin after entrapment.^18,30,31

Other possible applications for these systems would be their ultraviolet (UV) blocking effects, which is also dependent on lipid composition and the particle size.³² The smaller the particle size, the higher the sunscreen activity. SLPs can act as sunscreen carriers and increase the sun protection factor (SPF) obtained after topical application of UV absorbers incorporated within these carriers. The in vitro SPF obtained with carnauba wax/decyloleate particles revealed that the tested pigments (BaSO4, SrCO3, TiO2) showed higher values after being incorporated within the lipid matrix.³³

Lipid matrices produce a better SPF because they provide a fixation medium for the pigments. The increase observed in the SPF was explained by the applied lipid layers covering the surface of pigments fully or partially. When incorporating these pigments within the lipid matrices, the enhanced UV scattering effect was shown to be related to the SPF at different grades (i.e., the higher the reflection the higher the SPF).

Oil-loaded LPs have also been explored to deliver other APIs, such as ascorbyl palmitate^9,10 and coenzyme Q10.¹¹ These actives are well known in the cosmetic anti-ageing products because of their ability to reduce photo-oxidation and wrinkle depth. One of the main problems regarding these formulations for aqueous dispersion is their chemical instability. The production of oil-loaded LNs has been proposed to overcome such a problem.^10,11 The lipophilic nature of these actives means they can be solubilized, which will be entrapped within the solid matrix. Enhanced chemical stability, as well as the normal benefits of LPs for topical applications such as hydration, occlusiveness, and controlled release, has been reported.³⁴

Conclusions

The ability to retain loaded oil droplets inside SLPs depends on the particle size (micro versus nano) and the lipid composition. Furthermore, although nanoparticles have a higher surface area compared with microparticles, they show a higher ability to retain volatile compounds. Advantages of such systems are related to their lipid nature (biodegradability, biocompatibility, low toxicity), their small particle size (hydration, occlusiveness) and their solid character (controlled/prolonged release).

Eliana B. Souto is assistant professor of pharmaceutical technology in the department of pharmaceutical technology at Fernando Pessoa University, Porto (Portugal).

Rainer H. Müller is professor of pharmaceutics in the Department of Pharmaceutics, Biopharmaceutics & Quality Management, Free University of Berlin, Berlin (Germany).

Antonio .J. Almeida is associate professor, iMed.UL,, Faculty of Pharmacy, University of Lisbon (Portugal).

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