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

• Published in: International journal of nanomedicine 2018-01, Vol.13, p.6325-6335
• Main Authors: Ahmed, Osama Aa, Badr-Eldin, Shaimaa M
• Format: Article
• Language: English
• Subjects: Administration, Intranasal; Animals; Bioavailability; Biological Availability; Biomedical materials; Bone disorder agents; Breast cancer; Cancer prevention; Cattle; Drug approval; Drug Carriers - chemistry; Drug Compounding; Drug Delivery Systems; Drugs; Electron microscopy; Emulsions; Estrogen antagonists; FDA approval; Fluorescence; fluorescence laser microscope; Fluorescence microscopy; Gels - chemistry; Glycols (Class of compounds); Health aspects; Homogenization; Lipids; Male; Metabolism; Micelles; Microscopy; mixture design; Nanoparticles - administration & dosage; Nanoparticles - chemistry; nanosized self-nanoemulsifying system; Nasal Mucosa - metabolism; Original Research; Osteoporosis; permeation; Pharmaceutical sciences; pharmacokinetics; Pharmacy; Physiological aspects; Polyethylene glycol; Polyols; Postmenopausal women; Raloxifene; Raloxifene Hydrochloride - administration & dosage; Raloxifene Hydrochloride - chemistry; Raloxifene Hydrochloride - pharmacokinetics; Rats; Rats, Wistar; Retirement benefits; Selective Estrogen Receptor Modulators - administration & dosage; Selective Estrogen Receptor Modulators - chemistry; Selective Estrogen Receptor Modulators - pharmacokinetics; Surfactants; Tissue Distribution; Vitamin E; Vitamins
• ISSN: 1178-2013; 1176-9114; 1178-2013
• DOI: 10.2147/IJN.S181587

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). 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. 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. 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.