Rainer H. Müller

Efficient dermal delivery of poorly soluble actives is still a challenge. For compounds that are poorly soluble in both water and oils (e.g., rutin with 125 μg/mL in water and 1.3 μg/mL in oleic acid), there is a very low concentration gradient between the dermal formulation and the skin, which consequently results in a low diffusional flux (see 

). A general basic approach is to increase this concentration gradient by increasing the saturation solubility (Cs) of the actives. Methods include the admixture of water-miscible organic solvents (e.g., alcohols), the use of co-solvents such as polyethylene glycol (PEG), or complexation with cyclodextrins. There are, however, problems with these approaches that can limit their effect. In the case of volatile solvents such as alcohol, the solubility of the active decreases with application time, because of the fast evaporation of the alcohol, leading to precipitation of the active on the skin in the form of large crystals that have low penetration through the skin. With the co-solvents approach, crystallization can also happen when the solvent penetrates into the skin faster than the active itself. Penetration from cyclodextrin complexes is low if the binding constant of the cyclodextrin complex is high. In this case, only little active is released to the skin.
	

	Other approaches to increase the saturation solubility of an active are by nanonization of the active crystal to nanocrystals (which increases the dissolution rate), or to use the amorphous form of the active. The NanoMorph technology (Abbott GmbH and Co. KG, Germany) combines both of these approaches to create amorphous nanoparticles (1). The amorphous state, however, is physically unstable and tends to recrystallize spontaneously during the shelf life of a product. A novel delivery system, known as smartPearls (PharmaSol GmbH, Germany), has been developed to address these challenges. smartPearls are porous particles, with the active loaded inside the pores. Being in the so-called mesopores means that the amorphous active has a nanodimension (2–50 nm), but it is not a nanoparticle. In other words, smartPearls combine the solubility increases (âCs) from both the amorphous state and the nanodimension, further increasing the saturation solubility and providing an efficient dermal delivery system.

	smartPearls are micron-sized porous particles, which are typically silica particles (e.g., Syloid silica, W. R. Grace, Columbia, MD, US). There are also various other materials that can be used, such as porous calcium carbonate or polymeric particles. Silica particles are commercially available as regulatorily accepted excipients with different pore sizes. Mesopores with a diameter between 2 nm and 50 nm are preferable, although larger pores can also be used, such as macropores in the range of more than 50 nm up to a few 100 nm. The pores are filled with the active drug in the amorphous state. Silica particle sizes range from 2 µm to a few hundred µm, and are, therefore, considered as microparticles. To avoid the sedimentation effects in dermal formulations, sizes of a few µm are preferred.

	Loading of the pearls is performed by the impregnation method. An alternative solvent-free method is by co-extrusion of silica and the melted active. In the impregnation method, the active is dissolved in a regulatorily accepted solvent. The silica particles are then soaked with this solution, so that the pores are filled. After evaporating the solvent, the active precipitates within the pores. The advantage of this approach is that the active is unable to crystallize because there is not enough space in the mesopores for crystallization (known as the “space restriction effect”). It has been shown that actives can remain in the amorphous state in silica powders for up to seven years (2).

The skin delivery mechanism of smartPearls

	The loaded smartPearls can be incorporated into the water phase of gels or oil-in-water (o/w) creams. They can be mixed into the finished product, such as with the o/w creams. Alternatively, in the case of gels, they can be added to the water phase before gelation. The particles are then evenly distributed in the gel. After admixture, a part of the amorphous active dissolves and generates a supersaturated solution (Css) in the water phase (see 

). In the case of creams, the dissolved actives will also partition into the oil phase. Following application on the skin, a high concentration gradient (Css-Cskin) is generated, leading to high passive diffusion. The amount of active diffused into the skin is immediately replaced by active dissolving out quickly from the pores (see 

). This concentration gradient is maintained until all the active have been released from the mesopores (see 

). For dermal fluid formulations, the preferable particle sizes are of a few µm (e.g., 2 µm), because they are more adhesive compared to larger ones and thus can provide prolonged delivery when applied onto the skin.
	

Assessing penetration enhancement on skin

	Nanocrystals can be considered as the gold standard in penetration enhancement of poorly soluble actives (3). For rutin, a flavonoid with anti-oxidative properties, an increase in activity in the skin by a factor 1000 was shown, compared to a formulation with a water-soluble rutin derivative. At 1/500

the concentration of rutin dissolved from nanocrystals, a two-fold increase in sun protection factor (SPF) was observed in a human study with irradiated volunteers (4). 

	The authors compared the performance of amorphous rutin in smartPearls with rutin nanocrystals and rutin microcrystals. To avoid animal studies, penetration was assessed using skin from porcine ears, and a tape stripping test was performed as a predictive test for skin penetration. 

	All the particle types were incorporated into hydroxypropyl cellulose (HPC) gels. The gels contained 5% rutin in form of micro- and nanocrystals, but only 1% amorphous rutin in the smartPearls gel. 

shows the amount of rutin found in the respective tape strips (5). Performance of the smartPearls was comparable to the nanocrystals at only 1/5th of the rutin concentration (1% amorphous rutin vs. 5% nanocrystals).
	

	Drug developers of dermal formulations are becoming more reluctant to use nanoparticles in their products because of the increasingly stringent regulatory safety requirements for nanoparticle-containing products. According to the EU cosmetic regulation (6), for example, nanoparticulate ingredients must be declared, such as the case of titanium dioxide used in sunscreens. Because smartPearls are microparticles, no “nano” declaration is necessary for the final product. In addition, silica particles are already used and well established in dermal products, such as gels and transdermal patches. In the case of smartPearls, these silica particles are loaded with actives or drugs. In contrast to synthetic polymeric porous particles, they are a natural material-an aspect of increasing importance for dermal products. 

	The smartPearls approach provides an enabling technology for delivering molecules to the skin, especially for new chemical entities that cannot be efficiently delivered into the skin with traditional dermal formulations. It also may be used as a lifecycle management/extension strategy for pharmaceutical products when a patent protection expires. 

	1 I. Martin, et al., “Nanoparticulate Active Ingredient Formulations,” US patent 20080227646, 2008.2. Q. Wei, C. M. Keck, and R. H. Müller, 

. 113, 97–107 (2017).
	3. L. Gao, D. Zhang, and M. Chen, 

10 (5) 845–862 (2008).
	4. R. Petersen, “Nanocrystals for use in topical cosmetic formulations and method of production thereof,” patent WO 2008058755, 2008.
	5. N. Jin, PhD Thesis: Nanocrystals & loaded porous silica for increased dermal bioavailability, Freie Universität Berlin, Germany, 2017.
	6. Regulation (EC) No 1223/2009 of the European Parliament and of the Council of 30 November 2009 on Cosmetic Products, 2009. 


	Vol. 42, No. 6
	June 2018
	Pages: 25–27

	When referring to this article, please cite it as R. H. Müller, B. Herziger, F. Monsuur, and S. M. Pyo, " A Novel Amorphous Delivery System to the Skin for Poorly Soluble Actives," 

is a professor in pharmaceutical technology at Freie Universität Berlin, Institute of Pharmacy, Department of Pharmaceutics, Biopharmaceutics, and NutriCosmetics, Kelchstr. 31, 12169 Berlin, Germany, and PharmaSol GmbH, Stubenrauchstr. 66, 12161 Berlin, Germany; 

is a PhD student at Freie Universität Berlin; 

is excipient development manager, at Grace Materials Technologies, Germany; and *

is a post-doctoral research scientist, at Freie Universität Berlin, Tel.: +49 30 838 507 03; pyo.sungmin@fu-berlin.de.

To whom all correspondence should be addressed.

Articles

Drugs in the amorphous form are loaded into porous silica particles, which provide a maintained concentration gradient for skin delivery.

A Novel Amorphous Delivery System to the Skin for Poorly Soluble Actives

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.

  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.

  The physiochemical characterization of these oil-loaded solid lipid nanoparticles (SLNs) revealed that the oil is encapsulated and partially segregated within the nanoparticles,

  although some controversial results have also been published.

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)],

  and nanostructured lipid carriers (NLCs) [Figure 1(b)].

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.

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

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 

, 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.

  Figure 2 shows the effect of particle size on skin hydration. 

Figure 2 Microparticles and nanoparticles: effects on skin hydration (modified after MÃ¼ller et al.1). 

Moisture barrier properties have been experimentally demonstrated by the different degree of occlusion that lipid particles exhibit according to their size.

  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.

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 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.

  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. 

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.

  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.

  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.

Other possible applications for these systems would be their ultraviolet (UV) blocking effects, which is also dependent on lipid composition and the particle size.

  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 

 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.

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

  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.

  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.

The ability to retain loaded oil droplets inside SLPs depends on the particle size (micro 

 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). 

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

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

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

., 'Fest-flüssig (halbfeste) Lipidpartikel und Verfahren zur Herstellung hochkonzentrierter Lipidpartikeldispersionen", PCT/EP00/04565 (1998). 

8. R.H. Müller and J.S. Lucks, "Azneistoffträger aus festen Lipidteilchen — feste Lipid Nanosphären (SLN)", European Patent 0605497 (1996). 

., "Effect of surfactant on the physical and chemical stability of ascorbyl palmitate-loaded NLC system", AAPS Annual Meeting and Exposition (Nashville, USA) #M1256 (2005). 

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.

Topical delivery of oily actives using solid lipid particles

The free radical theory of ageing, first postulated by Harman, is the most popular and widely tested.

  This theory is based on the chemical nature and ubiquitous presence of free radicals.

  In the cosmetic industry, the antioxidant coenzyme Q10 is widely used in anti-ageing products.

  Coenzyme Q10 is a lipid-soluble compound composed of a redox-active quinoid nucleus and a hydrophobic side chain containing 10 monounsaturated 

-isoprenoid units (Figure 1). The main biological function of coenzyme Q10 is to act as a redox component of transmembrane electron transport systems, such as the respiratory chain of mitochondria.

For the topical application of coenzyme Q10 a system that can deliver the antioxidant most efficiently into the skin is required. Therefore, investigations with different topical applied formulations, composed of NLCs, emulsion and liquid paraffin were performed for this study. 

NLCs are used as carrier systems for cosmetic ingredients and pharmaceutical drugs.

  They were developed following the success of solid lipid nanoparticles (SLNs). In contrast to emulsions, the solid particle matrix is composed of a blend of solid lipid and liquid lipid. The particle matrix is solid at body temperature, which protects the incorporated active ingredients against chemical degradation and allows the release of incorporated molecules to be modified.

  NLCs were developed in 1999/2000 and the first two cosmetic dermal products were introduced to the market at the end of 2005 (Nanorepair Q10 Cream and Nanorepair Q10 Serum [Dr Rimpler GmbH, Germany]). In 2006, more products were introduced to the market, for example, the day cream NanoVital (Dr Rimpler GmbH) and in the pipeline, IOPE the SuperVital products (cream, serum, eye cream [Amore Parcific/South Korea]). 

In this study, NLCs were investigated to compare possible advantages with a conventional oil/water (o/w) emulsion or liquid paraffin. The occlusion properties, as well as the penetration behaviour of incorporated coenzyme Q10 into the stratum corneum (SC), were analysed. 

NLCs were produced from the solid lipid cetylpalmitate (Henkel KGaA, Germany) and liquid lipid Miglyol 812 (Cognis Deutschland GmbH & Co. KG, Germany). The lipid blend was heated 5 °C above the melting point of the solid lipid and dispersed in an aqueous Tego Care 450 (Goldschmidt GmbH, Germany) solution at identical temperature (65 °C) by high-speed stirring. The pre-emulsion obtained was homogenized using a Micron LAB 40 (APV Homogeniser Systems, Germany). Cooling of the hot o/w nanoemulsion obtained led to the solidification of the lipid and the formation of NLCs. The reference emulsion was produced by substituting the cetylpalmitate with Miglyol 812 using the same high pressure homogenizer. Both formulations contained 25% (mass/mass [m/m]) coenzyme Q10 (BKI Internationaler Handel GmbH, Germany) calculated on the basis of the particle mass (i.e., 5% m/m in the total formulation). For the investigations, the formulations were diluted 1:10 with water to obtain a final coenzyme Q10 concentration of 0.5% m/m. As a second reference, a solution of 0.5% m/m coenzyme Q10 in liquid paraffin was used. 

The determination of the particle size of NLCs and the emulsion was performed by photon correlation spectroscopy (PCS) using a Zetasizer Nano ZS (Malvern Instruments, UK). Further investigations on particle size were performed by laser diffractometry (LD) using a Coulter LS 230 (Beckman-Coulter, Germany). PCS yields the mean particle size and the polydispersity index (PI) as a measure of the width of the particle size distribution. The LD data were evaluated using the diameter 50% (LD 50) and 95% (LD 95), which means that either 50% or 95% (volume distribution) of the measured particles are below this size.  

The particle charge was quantified as zeta potential using the Zetasizer Nano ZS. Measurements were performed in distilled water adjusted with sodium chloride to a conductivity of 50 μS/cm.

The occlusive effect of NLCs, emulsion and liquid paraffin was investigated using an 

  Water evaporation through a cellulose acetate membrane was measured and the occlusion factor (

) was calculated using the following equation:  

 is the amount of water evaporated through the cellulose acetate membrane without applying a formulation and 

 is the amount of water evaporated through the cellulose acetate membrane after applying a sample. For the evaluation of the occlusion factor, each sample was applied five times with a final amount of 10.2 mg/cm

 . The samples were stored at 32±1 °C and 60±5% relative humidity (RH). Water evaporation was investigated by weighing after 6, 24 and 48 h. If the applied formulation had no occlusive properties an occlusion factor of 0% would be obtained and for maximum occlusion an occlusion factor of 100% would be obtained.  

The penetration of coenzyme Q10 into the SC was studied using a  tape-stripping test. At the beginning all volunteers were asked to wash their arms and dry them afterwards. After an incubation time of 30 min at 20±1 °C and 45±5% RH, 150 mg of NLCs, emulsion and liquid paraffin containing 0.5% m/m coenzyme Q10 were applied to a 10.4 cm

  testing area on the volar forearm of five female volunteers with healthy skin in the testing areas. Thirty minutes after application the samples were washed off and the SC was removed with nine strips of Scotch Tape No. 90 (3M, MN, USA). Each tape was taken in a controlled way; that is, a 1 kg rubber weight was rolled over it 10 times. The coenzyme Q10 was extracted from the tape strips with 2 mL of acetone. The concentration of coenzyme Q10 was determined using HPLC. Strip 4 and 5, 6 and 7, 8 and 9 were analysed together. 

The NLCs and the emulsion had the same lipid content, were produced under the same conditions using the high pressure homogenization and possessed identical particle sizes (Figures 2 and 3). Figure 2 shows the PSC mean diameter and the polydispersity index of NLCs, and emulsion measured at six different time points during 1 month. The LD mean diameters (LD 50 and LD 95) for the formulations measured at the same time points as the PCS values are displayed in Figure 2. Both figures show that the particle size of NLCs and the emulsion are identical and remain constant during 1 month. Additionally, zeta potential measurements were performed. The zeta potential right after production was –54 mV for the NLCs and –57 mV for the emulsion. Zeta potentials in this range are related to no aggregation or to only little aggregation. 

Figure 4 shows the F values for NLCs, emulsion and liquid paraffin. The occlusion factor of the NLCs was much higher than the occlusion factor of the emulsion, although they had the same lipid content and particle size. This effect can be explained by the film formation of NLCs. NLCs showed a tendency to fuse, forming a dense film after application.

  NLC used for these investigations had a melting point of 47.5 °C, therefore, they are still solid at both room and skin temperature. After the water is evaporated from the NLC dispersion, only the solid NLC particles stay on the skin. The capillary force of the nanometer pores between the NLC particles are contractive, which promotes fusion and dense film formation.

  Thereby, the NLCs show the same occlusion properties as the highly occlusive liquid paraffin. It should be noted that the lipid content of the NLC dispersion was only 2%. The emulsion had relatively low occlusive properties although it had the same lipid content as the NLCs. 

With the tape stripping test it can be shown that the penetration of coenzyme Q10 from the NLCs and emulsion was much higher than from liquid paraffin (Figure 5). The NLCs showed the highest penetration of coenzyme Q10 into the SC. 

The shape of the curves obtained indicates a logarithmic relationship between the cumulative values of coenzyme Q10 and the tape strip numbers. Functions of the type can fit the data if a regression analysis is performed, where 

 is the cumulative percentage of the applied coenzyme Q10 found inside the SC, 

 the estimate equilibration coefficients (Table 1). 

Table 1 Parameters describing the logarithmic relation between the cumulative amount of coenzyme Q10 and the tape number for NLC, emulsion and liquid paraffin (p,

Coenzyme Q10-loaded NLCs: preparation, occlusive properties and penetration enhancement

Nanostructured lipid carriers are a new type of delivery system offering improved performance in terms of drug loading and long-term stability with the ability to form highly concentrated dispersions...