Development of a Phosphoric Acid-Mediated Hyaluronic Acid Gel Sheet for Efficient Transdermal Delivery of Alendronate for Anti-Osteoporotic Therapy.

Chihiro Naito,Sachi Kamei,Mayuko Nishidono,Ayaka Tamba,Hidemasa Katsumi,Akiko Tanaka,Masaki Morishita,Kunio Yoneto,Akiya Mizoguchi,Akira Yamamoto,Mao Omura

doi:10.3390/pharmaceutics11120643

Abstract

For efficient transdermal delivery of alendronate (ALN) for anti-osteoporotic therapy, we developed a hyaluronic acid (HA) gel sheet that was prepared simply by enhancing HA noncovalent interactions using phosphoric acid and polyhydric alcohol (propanediol and glycerin). HA solution viscosity increased after addition of phosphoric acid, and the HA gel sheet formed after heated drying. The HA gel sheet could be converted to high viscosity state by addition of water. These results indicate that phosphoric acid enhances the noncovalent interactions of HA molecules. The HA gel sheet elicited no skin irritation over 7 days after a 24-h application. The permeation of ALN across rat and human skin was 109 and 7.17 µg/cm2, respectively, up to 24 h after application of the ALN-loaded HA gel sheet, which is sufficient for clinical treatment of osteoporosis. The bioavailability of ALN in rats was ~20% after application of the ALN-loaded HA gel sheet, and plasma calcium levels were effectively reduced 3 days after sheet application. Furthermore, in a rat osteoporosis model, the reduction in tibial bone density was suppressed by treatment with the ALN-loaded HA gel sheet. These results indicate that our phosphoric acid-mediated HA gel sheet is a promising transdermal formulation for efficient ALN delivery.

Highlights

Alendronate (ALN) is a bisphosphonate that inhibits osteoclastic bone resorption and is widely used as a first-line treatment for postmenopausal osteoporosis [1]
It was reported that ALN increased bone mineral density in women with postmenopausal osteoporosis [2] and decreased the risk of vertebral and nonvertebral fractures, including hip fractures [3]
Alendronate sodium trihydrate was obtained from Toronto Research Chemicals, Inc. (North York, ON, Canada). [14C]ALN sodium salt was purchased from Moravek, Inc. (Brea, CA, USA)

Summary

Introduction

Alendronate (ALN) is a bisphosphonate that inhibits osteoclastic bone resorption and is widely used as a first-line treatment for postmenopausal osteoporosis [1]. It was reported that ALN increased bone mineral density in women with postmenopausal osteoporosis [2] and decreased the risk of vertebral and nonvertebral fractures, including hip fractures [3]. ALN can cause serious gastrointestinal side effects, such as diarrhea, abdominal pain, and inflammation, and erosions and ulceration of the upper gastrointestinal tract [5]. To prevent these side effects, patients should sit up for at least 30 min after the oral administration of ALN, which can be difficult for some elderly patients. The development of alternative formulations is required to improve adherence and the quality of life of patients who are being treated with ALN and to improve its therapeutic efficacy

Objectives

Methods

Conclusion