In situ misemgel as a multifunctional dual-absorption platform for nasal delivery of raloxifene hydrochloride: formulation, characterization, and in vivo performance

Abstract

Background: Raloxifene hydrochloride (RLX) is approved by the US Food and Drug Administration for the treatment and prevention of osteoporosis, in addition to reducing the risk of breast cancer in postmenopausal women. RLX has the disadvantages of low aqueous solubility, extensive presystemic intestinal glucuronidation, and first-pass metabolism, resulting in a limited bio-availability of only 2%. The aim of this work was to enhance the bioavailability of RLX via the formulation of an in situ nasal matrix (misemgel) comprising micelles made of vitamin E and D-α-tocopheryl polyethylene glycol 1000 succinate and nanosized self-emulsifying systems (NSEMS).

Materials and methods: Optimization of the RLX-loaded NSEMS was performed using a mixture design. The formulations were characterized by particle size and then incorporated into an in situ nasal gel. Transmission electron microscopy, bovine nasal mucosa ex vivo permeation, and visualization using a fluorescence laser microscope were carried out on the RLX in situ misemgel comparing with raw RLX in situ gel. In addition, the in vivo performance was studied in rats.

Results: The results revealed improved permeation parameters for RLX misemgel compared with control gel, with an enhancement factor of 2.4. In vivo studies revealed a 4.79- and 13.42-fold increased bioavailability for RLX in situ misemgel compared with control RLX in situ gel and commercially available tablets, respectively. The obtained results highlighted the efficacy of combining two different formulations to enhance drug delivery and the benefits of utilizing different possible paths for drug absorption.

Conclusion: The developed in situ misemgel matrix could be considered as a promising multifunctional platform for nasal delivery which works based on a dual-absorption mechanism.

Keywords: fluorescence laser microscope; micelles; mixture design; nanosized self-emulsifying systems; permeation; pharmacokinetics.

Figure 1

Two-dimensional contour plot showing the effect of mixture components on the globule size of RLX-loaded NSEMS (Y₁). Abbreviations: NSEMS, nanosized self-emulsifying systems; RLX, raloxifene hydrochloride.

Figure 2

TEM photomicrographs of optimized RLX-loaded NSEMS (A), RLX-loaded TPGS micelles (B), raw RLX in situ gel (C), and RLX in situ misemgel (D). Abbreviations: NSEMS, nanosized self-emulsifying systems; RLX, raloxifene hydrochloride; TEM, transmission electron microscopy; TPGS, D-α-tocopheryl polyethylene glycol 1000 succinate.

Figure 3

Mean cumulative percentage of the RLX that permeated (mean ± SD, n=3) across the freshly excised bovine nasal mucosa from the RLX in situ misemgel and the raw RLX in situ gel. Permeation parameters for both formulations are indicated in the inset table. Abbreviations: D, diffusion coefficients; D_max, maximum RLX amount permeated; J_ss, steady-state flux; Pc, permeability coefficients; RLX, raloxifene hydrochloride.

Figure 4

Fluorescence laser microscopy images of permeation from rhodamine-labeled in situ misemgel and raw rhodamine gel through the bovine nasal mucosa after 0.5 and 5 hours. Magnification 400×.

Figure 5

Mean RLX plasma concentration-time profiles and in vivo pharmacokinetic parameters (inset) following nasal administration of RLX in situ misemgel, nasal administration of control raw RLX in situ gel, and oral administration of RLX commercially available tablets at a dose of 5 mg/kg. Notes: P<0.05: ^#control RLX gel vs RLX tablets, ^$RLX nano-misemgel vs raw RLX gel, and ^*RLX nano-misemgel gel vs RLX tablets. ^aResults are presented as median (n=12). ^bResults are presented as mean ± SD (n=12). Abbreviations: AUC, area under the plasma concentration-time curve; AUMC, area under the first-moment curve; C_max, maximum plasma concentration; RLX, raloxifene hydrochloride; T_max, time to maximum plasma concentration.