Pharmaceutical Nanotechnology
Human skin penetration and distribution of nimesulide from hydrophilic gels containing nanocarriers

https://doi.org/10.1016/j.ijpharm.2007.03.031Get rights and content

Abstract

The objective of this work was to study the in vitro skin penetration of a drug model (nimesulide) from semi-solid topical formulations containing nanospheres, nanocapsules or nanoemulsion. Nanoprecipitation, interfacial deposition and spontaneous emulsification methods were used to prepare the nanostructured suspension. The hydrodynamic diameters were 252 nm for the nanoemulsion, 277 nm for the nanocapsules and 202 nm for the nanospheres containing nimesulide. The different nanocarrier systems were incorporated in the hydrophilic gels and their ability of delivering the drug into the human skin were investigated using stripping technique and Franz-type diffusion cells. The amount of nimesulide released into the stratum corneum (SC) from the gel containing nanocapsules (GNM-NC) and the gel containing nanospheres (GNM-NS) was similar. On the other hand, for the gel containing nanoemulsion (GNM-NE), the nimesulide was not quantified in SC, but it has been directly permeated for the dermis. The penetration of the nimesulide using the gel containing nanocapsules (GNM-NC) was larger in the deeper skin than using the gel containing nanospheres (GNM-NS) or the one containing nanoemulsion (GNM-NE). The gels containing nanocarriers (GNM-NC, GNM-NS and GNM-NE) were able to release the drug in the viable layer of the skin, comparing to a non-particulated nimesulide-loaded formulation at the same concentration.

Introduction

Nanoparticles and microparticles have been increasingly investigated to achieve targeted and sustained release of drugs (Couvreur et al., 2002, Schaffazick et al., 2003, Jalón et al., 2001a). These systems have been extensively studied for oral and parenteral administration, and they are also useful to deliver drugs into the skin. Besides, some investigations have shown that the nanoparticles and liposomes present the tendency to interact with inflamed tissues. Additionally, nanometric systems present an enormous surface area, which makes them suitable for important pharmaceutic and cosmetic applications, such as topical formulations of lipophilic encapsulated drugs for a homogeneous release (Bouchemal et al., 2004).

These carriers present some advantages for topical application since sustained release is important to supply the skin with the drug over a prolonged period of time (Jalón et al., 2001b). The mechanism of action of nanoparticles can be attributed to their association with the skin surface. The small particle size ensures close contact with the stratum corneum. That is why the amount of encapsulated agent penetrating into the viable skin facilitates drug transport by changing the vehicle/stratum corneum partition coefficient (Jenning et al., 2000a, Alvarez-Román et al., 2004). Studies have been conducted in order to explain the mechanism in which the nanocarriers are able to increase the release of some drugs in the skin (Lopez et al., 2000). For instance, vitamin A was released from solid–lipid–nanoparticles into the upper skin layers, but did not penetrate into the deeper skin strata (Jenning et al., 2000b). Quantification of octyl methoxycinnamate (OMC) in the skin using tape-stripping technique has showed that its nanoencapsulation increased 3.4-folds of the level of OMC into the stratum corneum. The confocal images showed that the fluorescence profile observed in the skin after application of Nile Red-loaded nanoparticles was different from that visualized after application of Nile Red dissolved in propylene glycol. The modified distribution of Nile Red-loaded nanoparticles was due, at least in part, to its altered thermodynamic activity (relative to that in propylene glycol) that resulted in a partition coefficient in the SC increased (Alvarez-Román et al., 2004).

Taking into account those considerations, the objective of this work was to evaluate the ability of nanocapsules, nanospheres and nanoemulsion in modulating the skin penetration of a drug model, the nimesulide. Nimesulide (4-nitro-2-phenoxymethanesulfonamide) is an anti-inflammatory non-steroidal drug, which selectively inhibits cyclooxygenase-2. It is widely used for the treatment of rheumatoid arthritis and inflammatory conditions (Rabasseda, 1997, Bernareggi, 1998). This analgesic presents a very low solubility in water (0.01 mg/mL), an octanol–water partition (log P) of 2.60 and a pKa value of 6.46 (Gupta et al., 1996, Piel et al., 1997, Fallavena and Schapoval, 1997). Semi-solid topical formulations containing nimesulide-loaded nanocapsules, nimesulide-loaded nanospheres or nimesulide-loaded nanoemulsion were evaluated using Franz diffusion cells and a tape-stripping technique in order to investigate if these formulations would be able to modify the distribution of nimesulide in the different strata of the full-thickness human skin. The influence of the nanocarriers was compared to a similar gel formulation containing the free drug in the absence of nanocarriers. Additionally, the flux and permeability coefficient of the gel containing nimesulide-loaded nanocapsules, using heat-separated human skin membrane, were also evaluated. As far as we know, this is the first report consecrated to compare the ability of different nanocarriers in modulating the penetration of a lipophilic drug in the human skin.

Section snippets

Materials

Nimesulide was obtained from Henrifarma and poly(ɛ-caprolactone) (MW = 80,000) from Aldrich (Strasbourg, France). Caprylic/capric triglyceride, sorbitan monostearate, polysorbate 80, methylparaben, propylparaben, sorbitol and triethanolamine were supplied by Delaware (Porto Alegre, Brazil). Carbopol 940® was acquired from B.F. Goodrich (São Paulo, Brazil). All other chemicals and solvents used were of pharmaceutical grade. All reagents were used as received.

Preparation and characterization of nanocapsules, nanospheres and nanoemulsion (Alves et al., 2005)

Formulations containing nimesulide were

Results and discussion

Formulations showed pH values from 5.1 to 5.3 and diameters were 277, 202 and 253 nm for NC, NS and NE, respectively. The polydispersity values were below 0.25 indicating narrow size distributions of the particles and, consequently, good homogeneity of these systems (Guterres et al., 1995, Calvo et al., 1996, Müller et al., 2001, Milão et al., 2003, Alves et al., 2005).

Hydrogel formulations showed final nimesulide concentrations of 1300 μg/cm3 (nanocapsules: GNM-NC), 1230 μg/cm3 (nanospheres:

Conclusions

The gels containing nimesulide-loaded nanocarriers were able to promote the drug penetration in the stratum corneum and/or in the layer of viable skin compared to a nimesulide-loaded non-particulated formulation. The gel containing nimesulide-loaded nanocapsules (GNM-NC) and the gel containing nimesulide-loaded nanospheres (GNM-NS) presented significant similar drug penetration into the stratum corneum. On the other hand, the gel containing nimesulide-loaded nanoemulsion (GNM-NE) showed no drug

Acknowledgements

The authors thank FAPERGS, CNPq/Brasília and Rede de Nanobiotecnologia CNPq/MCT e Rede de Nanocosméticos CNPq/MCT.

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