Transdermal delivery of Risedronate and anti-osteoporosis effect in ovariectomized mice model

Abstract

Risedronate (1-hydroxy-2-(3-pyridinyl) ethylidene bisphosphonic acid) has been shown to be effective for the treatment of metabolic bone diseases such as Paget disease, multiple myeloma, and for the prevention of bone loss in early postmenopause. Risedronate was developed for the oral delivery although oral bioavailability of risedronate is about 0.5%. The reason for this is the undoubted biological efficacy of risedronate. Although risedronate has been used widely and showed its powerful pharmaceutical effects, risedronate also causes various adverse effects such as esophagitis, abdominal pain, acid reflux, acute phase reactions, atypical fragility fractures, pain in bone, muscle, and joint, and osteonecrosis of jaw. Considering the side effects, it is necessary to discover an alternative route to reduce the problems through oral delivery. Besides, strict administration guidelines of risedronate also induce inconvenience to patients. For these reasons, I considered transdermal delivery represents an attractive alternative to oral delivery of risedronate. Particularly, transdermal delivery is used when there is a significant first-pass effect of the liver that can prematurely metabolize drugs, resulting in increasing bioavailability. In addition, transdermal systems are noninvasive and can be self-administered. Therefore, transdermal delivery of risedronate can reduce adverse effects and improve patient compliance. However the greatest challenge for transdermal delivery is that only a limited number of drugs are capable to administration by this route. It has been difficult to exploit the transdermal route to deliver hydrophilic drugs such as risedronate and other bisphosphonates. The major impediment to successful delivery of risedronate is their poor lipophilicity. Risedronate is negatively charged at physiological pH and is capable of chelation of metal ions. Thus, although their molecular weights are rather small from a skin delivery point of view, the inherent hydrophilicity coupled with a pair of negative charges would practically disallow transport across the stratum corneum as well as across the follicular route. It may be possible to enhance transport across the stratum corneum with the aid of appropriately selected permeation enhancers without incurring skin irritation effects. To overcome these limitations, firstly, I created ion pairs of risedronate by combining an oppositely charged species with a charged permeant. The formation of ion pairs can increase the penetration of drugs through the skin by decreasing the charge and increasing the lipophilicity. Therefore, we considered an ion-pairing system to enhance the flux of RIS through the skin. Secondly, I searched the general penetration enhancers for risedronate, which have been unknown until now. I used the various water soluble enhancers, and found the appropriate enhancers to increase the penetration rate of risedronate through the skin layers. Lastly, I improved the therapeutic effect of risedornate by transdermal delivery in an ovariectomized mouse model using a simple aqueous formulation and without causing the skin irritation associated with topical RIS at the end of the experiment. These studies provide the way to developing a topical RIS and possibility of transdermal delivery of risedronate both in vivo and in vitro. Most of all, the development of a topical administration method of risedronate will enable better compliance in people suffering from osteoporosis and other related bone diseases.