Pharmacaeutical Nanotechnology
Production of hybrid lipid-based particles loaded with inorganic nanoparticles and active compounds for prolonged topical release

https://doi.org/10.1016/j.ijpharm.2009.08.033Get rights and content

Abstract

The production of particulate hybrid carriers containing a glyceryl monostearate (Lumulse® GMS-K), a waxy triglyceride (Cutina® HR), silanized TiO2 and caffeine were investigated with the aim of producing sunscreens with UV-radiation protection properties. Particles were obtained using the supercritical PGSS® (Particles from Gas Saturated Solutions) technique. This method takes advantages of the lower melting temperatures of the lipids obtained from the dissolution of CO2 in the bulk mixture. Experiments were performed at 13 MPa and 345 K, according to previous melting point measurements. Blends containing Lumulse® GMS-K and Cutina® HR lipids (50 wt%) were loaded with silanized TiO2 and caffeine in percentile proportions of 6 and 4 wt%, respectively. The particles produced were characterized using several analytical techniques as follows: system crystallinity was checked by X-ray diffraction and differential scanning calorimetry, thermal stability by thermogravimetric analysis, and morphology by scanning and transmission electron microscopy. Further, the UV-shielding ability of TiO2 after its dispersion in the lipidic matrix was assessed by solid UV–vis spectroscopy. Preliminary results indicated that caffeine-loaded solid lipid particles presented a two-step dissolution profile, with an initial burst of 60 wt% of the loaded active agent. Lipid blends loaded with TiO2 and caffeine encompassed the UV-filter behavior of TiO2 and the photoaging prevention properties of caffeine.

Introduction

The use of complex lipids composed by different molecules is currently a common choice in terms of preparation of novel controlled release systems with excellent pharmacological and therapeutic properties (Savolainen et al., 2002, Davis, 2004, Ljusberg-Wahren et al., 2005). For both pharmaceutical and cosmetic applications, solid lipid particles have advantages over other carriers, such as liposomes or emulsions, in terms of stability and protection of the incorporated active compounds (Müller et al., 2000). The research activity on solid lipid particles has gradually focused on cosmetic and topical products (Müller et al., 2002, Puglia et al., 2008, Pardeike et al., 2009). At the same time, the development of dermal formulations for protection from UV-radiation, incorporating organic UV-absorbers and inorganic UV-blockers, has become a topic of increasing concern in human life. Among the used inorganic UV-blockers, nanoparticulate titanium dioxide (TiO2) is widely employed in creams containing lipids, because of the broad UV-spectrum coverage of TiO2 (Lowe et al., 1997, Hexsel et al., 2008), and because solid lipids can also act as UV sunscreen systems (Yener et al., 2003, Villalobos-Hernández and Müller-Goymann, 2005, Pardeike et al., 2009). However, one of the major challenges for preparing homogeneous creams involving dispersed inorganic phases is to avoid the segregation of the mineral component from the oil phase (Chen et al., 2006, Pardeike et al., 2009). Further, life cycle impact assessment studies of nanometric materials intended for dermal use give advice of encapsulating the nanoparticles into larger particles to minimize the potential negative environmental and health impacts (Klöpffer, 2007, Grobe et al., 2008). In this context, the use of solid lipid microparticles entrapping TiO2 nanoparticles could accomplish both tasks: to reduce the risk of nanoparticles toxicity and to help dispersing the nanoparticles into the organic phase; while, simultaneously, contribute to optimize the UV-filter ability of the mixture. Hence, this work is primarily focused on the preparation of a composite comprising solid lipid particles and dispersed TiO2 with applications in sunscreens free of organic absorbers. Moreover, solid lipid particles have a great potential as vehicles for topical administration of active substances, principally owing to the possible targeting effect and controlled release in different skin strata (Müller et al., 2000, Müller et al., 2002). In the present study, advantageous solid lipid particles features for topical administration of caffeine were also considered in a preliminary study. Caffeine was selected as a model hydrophilic active drug because of its protective effects against UV-B radiation (Staniforth et al., 2006), anticellulite activity (Bertin et al., 2001) and photoaging prevention capacity (González et al., 2008), all useful features in dermal applications. The long-term aim of our work is to explore novel lipid formulations with skin targeting effect for the treatment of skin diseases (e.g., delivery of caffeine for the treatment of psoriasis (Vali et al., 2005)) or skin cancer prevention (Staniforth et al., 2006) that might benefit from topical administration, obtaining a substantial reduction of the systemic side effects.

For pharmaceutical and cosmetic products, there is an increased interest in developing technologies that allow the production of particles with controlled particle-size distribution and product quality (crystallinity, purity, morphology, etc.) under mild and clean conditions. Current methods of making solid lipid particles for pharmaceutical applications include fusion processes, cold or hot high-pressure homogenization and multi-step solvent processes, such as emulsification and ultrasonication (Gasco, 1997, Müller et al., 2000, Sethia and Squillante, 2004, Chattopadhyay et al., 2007). Technologies based on supercritical carbon dioxide (scCO2), and in particular the PGSS® (Particles from Gas Saturated Solutions) (Weidner et al., 1995) process, have emerged as alternative one-step methods to obtain solvent-free solid lipid particles at low processing temperatures (Weidner et al., 1995, Rodrigues et al., 2004, Calderone et al., 2007, Sampaio de Sousa et al., 2007, Sampaio de Sousa et al., 2009, Temelli, 2009). In this study, the PGSS® process was first used to disperse TiO2 nanoparticles into solid lipid microparticles. The technique consisted in dissolving scCO2 in the bulk of a melted lipid mixture with dispersed TiO2 nanoparticles, and the subsequent quick expansion through a nozzle, causing the complete evaporation of the gas and the solidification of the liquid suspension. A silane adhesion promoter was previously deposited as a primer on the hydrophilic surface of TiO2 to enhance its dispersion capacity (Plueddemann, 1991). The lipids selected for study were Lumulse® GMS-K and Cutina® HR. Lumulse® GMS-K is a glyceryl monostearate with a C18 alkyl chain. It is used in cosmetics and pharmaceutical dermal products as a lipophilic surfactant, emulsifier and humectant agent (Gopala Krishna, 1993). Cutina® HR (hydrogenated castor oil) is a highly hydrophobic waxy triglyceride sterified with three C18 fatty acids, which is often used as a drug carrier for topical applications (Ogunniyi, 2006, Jannin et al., 2008). Progressing on the complexity of the designed system, solid lipid particles loaded with caffeine and silanized TiO2 were also processed using the PGSS® technique.

Section snippets

Materials

Lumulse® GMS-K (GMS) and Cutina® HR (HCO) were kindly provided by Lambent Technologies and José M. Vaz Pereira S.A., respectively. TiO2 nanometric particles (∼20 nm in diameter) were supplied by Degussa (TiO2 P25). Octyltriethoxysilane (TiC8) and octadecyltrimethoxysilane (TiC18) coated TiO2 nanoparticles were prepared in our laboratory following a scCO2 reported procedure (García-González et al., 2009a, García-González et al., 2009b). Caffeine (Caff, >98 wt% purity) was purchased from Sigma

Results and discussion

In this work, we have first evaluated the optimal operating conditions to produce solid lipid particles of HCO and GMS and their mixtures using the PGSS® method by studying their melting point variations in the presence of CO2 (Fig. 2). For all the studied systems, the melting point first decreased as the pressure increased due to the incorporation of gas into the bulk of the substances (Spilimbergo et al., 2006, Calderone et al., 2007, Sampaio de Sousa et al., 2007). After a certain pressure

Conclusions

Lipidic mixtures of HCO and GMS (50 wt%) were used to obtain composite powders of lipids, active agents (caffeine) and/or mineral fillers (silanized TiO2) in presence of scCO2. The mixed lipidic matrix crystallized into the β stable modification, but the decrease of the intensity of the reflection peaks indicated the formation of a relatively low ordered matrix. The reduction in crystallinity of the solid mixture of lipids can be strongly correlated with the ability of incorporating inorganic

Acknowledgements

The financial support of the Spanish projects MAT-2007-63355-E and CTQ2008-05370/PPQ are greatly acknowledged. C.A. García-González gives acknowledgment to CSIC for its funding support through I3P program.

References (59)

  • S. González et al.

    The latest on skin photoprotection

    Clin. Dermatol.

    (2008)
  • H. Hammam et al.

    Phase behavior of some pure lipids in supercritical carbon dioxide

    J. Supercrit. Fluids

    (1993)
  • C.L. Hexsel et al.

    Current sunscreen issues: 2007 Food and Drug Administration sunscreen labelling recommendations and combination sunscreen/insect repellent products

    J. Am. Acad. Dermatol.

    (2008)
  • C. Himawan et al.

    Thermodynamic and kinetic aspects of fat crystallization

    Adv. Colloid Interface Sci.

    (2006)
  • H. Iwai et al.

    Formation of stable lamellar structures with pseudo-ceramide

    J. Colloid Interface Sci.

    (1996)
  • V. Jannin et al.

    Approaches for the development of solid and semi-solid lipid-based formulations

    Adv. Drug Deliv. Rev.

    (2008)
  • V.V. Kumar et al.

    Development and evaluation of nitrendipine loaded solid lipid nanoparticles: Influence of wax and glycerid lipids on plasma pharmacokinetics

    Int. J. Pharm.

    (2007)
  • H. Ljusberg-Wahren et al.

    Enzymatic characterization of lipid-based drug delivery systems

    Int. J. Pharm.

    (2005)
  • R.H. Müller et al.

    Solid lipid nanoparticles (SLN) for controlled drug delivery—a review of the state of the art

    Eur. J. Pharm. Biopharm.

    (2000)
  • R.H. Müller et al.

    Solid lipid nanoparticles and nanostructure lipid carriers in cosmetic and dermatological preparations

    Adv. Drug. Deliv. Rev.

    (2002)
  • P. Münüklü et al.

    The phase behavior of systems of supercritical CO2 or propane with edible fats and a wax

    J. Supercrit. Fluids

    (2006)
  • R. Neubert et al.

    Structure of stratum corneum lipids characterized by FT-Raman spectroscopy and DSC. II. Mixtures of ceramides and saturated fatty acids

    Chem. Phys. Lipids

    (1997)
  • D.S. Ogunniyi

    Castor oil: a vital industrial raw material

    Bioresour. Technol.

    (2006)
  • N. Ohta et al.

    Interaction among molecules in mixtures of ceramide/stearic acid, ceramide/cholesterol and ceramide/stearic acid/cholesterol

    Chem. Phys. Lipids

    (2002)
  • J. Pardeike et al.

    Lipid nanoparticles (SLN, NLC) in cosmetic and pharmaceutical dermal products

    Int. J. Pharm.

    (2009)
  • C. Puglia et al.

    Lipid nanoparticles for prolonged topical delivery: an in vitro and in vivo investigation

    Int. J. Pharm.

    (2008)
  • M. Rodrigues et al.

    Microcomposites theophylline/hydrogenated palm oil from a PGSS process for controlled drug delivery systems

    J. Supercrit. Fluids

    (2004)
  • A.R. Sampaio de Sousa et al.

    Solubility enhancement of trans-chalcone using lipid carriers and supercritical CO2 processing

    J. Supercrit. Fluids

    (2009)
  • A.R. Sampaio de Sousa et al.

    Preparation of glyceryl monostearate-based particles by PGSS®—application to caffeine

    J. Supercrit. Fluids

    (2007)
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