Drug Incorporation in Solid Lipid Nanoparticles

The active drug may incorporate into the solid lipid nanoparticles in three major ways based on the properties of the drug and excipients and their interaction(s) with each other [58]. The three models proposed include the homogenous matrix model, the drug- enriched shell model, and the drug-enriched core model. Homogenous matrix entrapment results when using cold homogenization or hot homogenization with highly

Nanoparticulate Systems for Therapeutic and Diagnostic Applications 117

lipophilic drugs. In this model, the drug is dispersed at the molecular level in the solid lipid nanoparticle matrix, which is responsible for the prolonged release of drug over a period of time. Drug-enriched shell entrapment results when phase separation occurs between lipids and the aqueous phase during the formation of solid lipid nanoparticles from liquid drops. Drug release from this type of nanoparticles is very fast and is desirable when the formulation is intended for external application such as topical application for the skin. Drug-enriched core type of entrapment results when the drug precipitates first during the process of nanoparticle formation. The drug release process from these solid lipid nanoparticles is membrane controlled and follows the Fick’s law of diffusion. Fig. 6.8 schematically represents the above-stated models:

Several research groups have studied various drugs incorporated in solid lipid nanoparticles. Table 6.3 summarizes some examples [54].

Solid lipid nanoparticles have generated significant interest as a specialty formulation category for various anticancer drugs, for various reasons. For example, Mosallaei et al. have demonstrated the superiority ofdocetaxel-loaded solid lipid nanoparticles compared with Taxotere, the commercial docetaxel formulation that is injected intravenously. As shown in Fig. 6.9, the docetaxel-loaded solid lipid nanoparticles demonstrate higher cytotoxicity than Taxotere in both colorectal (C 26) and malignant melanoma cells (A375) [74].

In another study, Martins et al. studied the in vitro and in vivo efficacy of camptothecin-loaded solid lipid nanoparticles. The in vitro studies have shown prolonged release of drug for up to 8 h. The in vitro cell viability studies in porcine brain capillary endothelial cells with three types of camptothecin-loaded solid lipid nanoparticles prepared using three different lipids have shown similar cytotoxicity when compared with each other. All camptothecin-loaded solid lipid nanoparticle formulations show superior cytotoxicity compared with the free drug solution and blank (drug-free) nanoparticles (Fig. 6.10) [75].

In 2008, Yaping Li et al. demonstrated that the tumor growth inhibition by targeted docetaxel solid lipid nanoparticles is higher than that by nontargeted solid lipid nanoparticles and free docetaxel solution (Taxotere) in hepatocellular carcinoma-bearing nude mice. A single-dose administration of solid lipid nanoparticles has shown significant

Schematic representation of models of drug entrapment in solid lipid nanoparticles

Figure 6.8 Schematic representation of models of drug entrapment in solid lipid nanoparticles.

Table 6.3 Examples of drugs studied in solid lipid nanoparticle formulations Drug Research group

Timolol

Cavalli et al. [65]

Deoxycorticosterone

Gasco et al. [66]

Tetracaine

Zur Muhlen et al. [57]

Betamethasone valerate

Westesesn et al. [67]

Piribedil

Demirel et al. [68]

Hydrocortisone

Cavalli et al. [69]

Paclitaxel

Cavalli et al. [70]

Acyclovir

Lukowski et al. [71]

Diazepam

Gasco et al. [72]

Camptothecin

Yang et al. [73]

In vitro cell viability of docetaxel

Figure 6.9 In vitro cell viability of docetaxel (DTX)-loaded solid lipid nanoparticles (SLN) compared with the commercially available docetaxel injection Taxotere (TXT) in colorectal C-26 cells and malignant melanoma A 375 cells [74]. (Reprinted with permission.)

In vitro viability of brain capillary endothelial cells

Figure 6.10 In vitro viability of brain capillary endothelial cells (BCECs) exposed for 24 h to campto- thecin (CPT) solution, free lipids (CP5P802, D145P802, and WE855P602), drug (CPT)-free formulations, and drug (CPT)-loaded formulations at the CPT concentrations between 0.25 and 10 pM [75]. (Reprinted with permission.)

Nanoparticulate Systems for Therapeutic and Diagnostic Applications 119

Antitumor effect of targeted docetaxel-loaded solid lipid nanoparticles

Figure 6.11 Antitumor effect of targeted docetaxel-loaded solid lipid nanoparticles (tSLN), nontargeted docetaxel-loaded solid lipid nanoparticles (nSLN), Taxotere or saline in nude mice bearing hepatoma after a single dose (A) or a schedule of multiple doses (B). (Reprinted with permission.) tumor volume inhibition compared with saline-treated and Taxotere-treated mice (Fig. 6.11A). Moreover, multiple-dose administration showed complete inhibition of tumors in case of targeted docetaxel solid lipid nanoparticle compared with nontargeted docetaxel solid lipid nanoparticle and Taxotere-treated mice (Fig. 6.11B) [76].

 
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