A recent update of water-soluble polymers in cyclodextrin-based formulations for mucosal drug delivery

Abstract

Cyclodextrins (CDs) play a crucial role in pharmaceutical formulations due to their unique ability to form inclusion complexes with a wide range of lipophilic drugs. Ternary complexes comprising CD, water-soluble polymer, and drug molecule have emerged as promising multicomponent to the challenges associated with poorly water-soluble drugs. The addition of water-soluble polymer as a ternary component often reduces the amount of CD required to form an inclusion complex thereby decreasing formulation bulk and toxicity. This review outlines the physicochemical properties of CDs and the formation of their inclusion complexes, as well as methods to enhance the complexation efficiency of drug/CD complexes. Additionally, it explores the classification and mucoadhesive properties of water-soluble polymers, and their mechanisms of mucoadhesion on mucosal membranes. The presence of small amounts of water-soluble polymers has been demonstrated to synergistically improve the complexation efficiency of drug/CD complexes. Recent advancements in modified CD-polymer conjugates and the use of water-soluble polymers in CD-based formulations, and their applications across various routes of administration are discussed, highlighting the potential of these ternary complexes as innovative platforms for drug delivery and therapeutic applications.

Introduction

In recent years, mucosal drug delivery systems have emerged as an innovative drug delivery approach for delivering systemically acting drugs. The mucosal layer lines several key regions of the body, including the eye, nose, vaginal cavity, gastrointestinal tract, buccal cavity, and rectum (Wu et al., 2018). Many systemic diseases manifest in the mucosal membranes, often involving infections, inflammation, or disruption of the mucosal barrier. Such diseases include respiratory disorders (e.g., allergic rhinitis, sinusitis), gastrointestinal conditions (e.g., ulcerative colitis, Crohn’s disease), rectal issues (e.g., hemorrhoids, ulcerative proctitis), ocular diseases (e.g., conjunctivitis, dry eye syndrome), oral conditions (e.g., oral ulcers, periodontitis), and vaginal disorders (e.g., bacterial vaginosis, vaginal candidiasis). In these conditions, transmucosal drug delivery offers several advantages, such as noninvasive administration, ease of use, rapid onset of action, and avoidance of hepatic first-pass metabolism (Senel & Hincal, 2001; (Takeuchi et al., 2001).

The mucus layer represents a major barrier to drug penetration in mucosal drug delivery. Effective drug delivery through mucosal surfaces remains challenging due to poor absorption across the mucosal epithelium (Ensign et al., 2012). The extent and rate of drug absorption depend on the physicochemical properties of the drug, the design of the delivery system, and the pathological state of the mucosa. Nanoparticulate delivery systems have shown promise in overcoming this barrier (Prego et al., 2005), often achieving faster permeation through the mucosal layer compared to free drug molecules (Lai et al., 2009; Liu et al., 2015). Nonetheless, drug permeation through mucosa is frequently inadequate, resulting in subtherapeutic plasma concentrations. One promising strategy to enhance mucosal permeability is the incorporation of cyclodextrins (CDs), which have demonstrated potential to improve drug permeation through the biological barrier (Jansook et al., 2011; Song et al., 2004).

CDs are widely recognized in the pharmaceutical industry for their ability to enhance the solubility of poorly water-soluble drugs. Interest in CDs has grown significantly since 1953, following the release of the first patent for their pharmaceutical applications (Freudenberg et al., 1953). CDs typically form water-soluble inclusion complexes with lipophilic drugs through host-guest interactions. Besides, CDs can form non-inclusion complexes, where the hydroxyl groups on their outer surface form hydrogen bonds with drugs (Loftsson & Másson, 2004). CDs are able to not only increase the drug solubility but also enhance the permeability and chemical stability, offer controlled drug release profiles and reduce local irritation (Jansook, Ogawa, et al., 2018). However, the amount of CDs used in formulation is often limited by their high cost, potential toxicity, and formulation bulk. In solid dosage forms, CDs can only be used as solubilizers for potent drugs and those with medium potency.

Several approaches have been explored to address these limitations. One promising approach involves adding small amounts of water-soluble polymers to form ternary drug/CD/polymer complexes (Kurkov & Loftsson, 2013; Loftsson & Brewster, 2012). Water-soluble polymers effectively improve the solubility and dissolution rate of poorly water-soluble drugs. Incorporating these polymers into drug/CD complexes reduces drug crystallinity and provides a synergistic effect on CD solubilization of drugs (Kurkov & Loftsson, 2013). Consequently, a smaller amount of CD is required to dissolve a given amount of drug, thereby overcoming these limitations (Kurkov & Loftsson, 2013; Loftsson, 1998). It has been reported that adding water-soluble polymers can improve drug bioavailability by reducing up to 80 % of the total CD requirement (Loftsson & Friðriksdóttir, 1998; Mura et al., 2001). In addition, the presence of hydroxyl, carboxyl, or amine functional groups on water-soluble polymers enhances their interaction with mucus, primarily through hydrogen bonding and electrostatic interactions. Thus, the mucoadhesive properties of water-soluble polymers present significant potential for CD-based formulations in mucosal drug delivery systems (Jansook et al., 2019).

Despite the acknowledged advantages of ternary drug/CD/polymer complex systems, there is currently no comprehensive review addressing the applications of water-soluble polymers in CD-based formulations. This review aims to present the impact of water-soluble polymers as a third component in ternary drug/CD/polymer complexes, focusing on their role in enhancing CD solubilization of drugs and their substantial benefits in CD-based formulations for mucosal drug delivery.

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