European Journal of Pharmaceutics and Biopharmaceutics
Research paperSpray-drying of solid lipid nanoparticles (SLNTM)
Introduction
Solid lipid nanoparticles (SLNTM) [1]are interesting colloidal drug delivery systems, since they have all the advantages of fat emulsions (large scale production, no organic solvents, low systemic and cytotoxicity) and polymeric nanoparticles (controlled drug release due to a solid lipid matrix) [2]. They open a broad field of applications including i.v., oral and dermal administration.
For some of these applications, the conversion of the liquid dispersion into a dry product is useful, or often necessary. SLN granulates or powders could be put into capsules, pressed into tablets or incorporated into pellets [3]. Aqueous SLN dispersions possess a long-term stability of at least three years [4]. Nevertheless, a prolonged long-term stability especially for i.v. administered systems can be achieved when stored as a dry product. This may be of interest for SLN containing drugs that are susceptible to hydrolysis or are exposed to elevated temperatures or light in aqueous dispersion [5].
The less cost-intensive spray-drying technique was investigated for SLN as an alternative method to lyophilization. Spray-drying is widely used in the chemical, the food and the pharmaceutical industries. It is commonly used to process milk, eggs, ceramics and fertilizers [6]. It converts a liquid into a dry system in a one-step process and can produce fine, dust-free powders as well as agglomerated ones, to precise specifications.
In general, the process consists of four steps [6]: (1) atomization of the feed into a spray, (2) spray-air contact, (3) drying of the spray and (4) separation of the dried product from the drying gas.
Preparation of both polymeric as well as lipid microparticles by spray-drying or spray-congealing has been reported 7, 8. For heat sensitive materials, an organic solvent was used in most cases to achieve the required lowering in temperature 7, 8, 9.
In this study, the development of an SLN system which was still suitable for i.v. administration after spray-drying was performed. The fraction of particles >5 μm, causing a possible capillary blockade, should not increase. Furthermore, the SLN powders should be reconstitutable to the identical particle size distribution of the original dispersion. No organic solvents were used, to avoid toxic residues. The number of additives was kept as low as possible. The formulation should not be too complex with respect to the acceptance by the regulatory authorities.
Section snippets
Lipids
Cetylpalmitate (m.p. 47°C) was purchased from Caelo (Hilden, Germany). Compritol 888 ATO (glycerol behenate containing ~15% monoglyceride, m.p. 72°C) was provided by Gattefossé (Weil, Germany) and Synchrowax HRSC (glyceroltribehenate and calcium behenate, m.p. 105–115°C) by Croda (Nettetal, Germany).
Emulsifier
Pluronic F68 (poloxamer 188) was donated by BASF AG (Ludwigshafen, Germany) via the distributor Tensidchemie (Düren, Germany).
Carbohydrates and alcohols
The carbohydrates (mannitol, lactose, trehalose, sorbitol, glucose and
Influence of lipid type and concentration
Generally, SLN are prepared by high pressure homogenization of a molten lipid (hot homogenization technique) [10]. Depending on the chemical nature of the lipid matrix, the recrystallization of the lipid fraction occurs rapidly, or can be retarded over weeks or months [4]. Concerning lyophilization of SLN, formulations containing a lipid with a low recrystallization index proved to be optimal [10]. The microparticle content increased only slightly.
A general difficulty when spraying aqueous
Conclusion
Aqueous SLN dispersions can be transferred into dry, fine-grained powders by spray-drying. Many parameters influence the quality of the SLN granulate and its redispersion properties.
Destabilization of the systems during the spraying process is mainly caused by the elevated temperature and by shear forces. Both increase the kinetic energy, leading to frequent particle collision. Additionally, partial melting of the lipid phase during spraying is one of the major reasons for particle growth.
The
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