1. INTRODUCTION:

In the past few decades, the prevalence of colonic diseases has increased worldwide, demanding the effective local treatment of colonic diseases for more efficacious and safer drug therapies. Among colonic diseases, colorectal cancer (CRC) causes the most cancer-related deaths in Europe (accounting more than 200,000 deaths annually) [1], and it is the third most commonly diagnosed cancer worldwide [1,2]. The incidence of inflammatory bowel disease (IBD) is also increasing at an alarming rate in previously low-incidence areas such as Asia [3]. Consequently, the effective treatment of colonic diseases has become an important worldwide public healthcare issue.

For the local treatment of colonic diseases, colon-targeted drug delivery systems have been actively pursued since conventional non-targeted therapy may have undesirable side-effects and low efficacy due to the systemic absorption of drug before reaching the target site [4,5]. In addition to the topical delivery, colon-targeted drug delivery systems are also applicable to improve the bioavailability of drugs particularly macromolecules such as proteins and peptides due to lower protease activity in the colon [6–8].

Colon targeted drug delivery systems are designed to selectively release a drug in response to the colonic environment without premature drug release in the upper GI tract. Therefore, it is imperative to consider the physiological properties of the colon and the microenvironment surrounding disease site (s) for the successful development of colon-targeted drug delivery systems. Patients with colonic diseases produce high levels of reactive oxygen species (ROS) and inflammatory cytokines. The pathophysiological changes in the microenvironment surrounding disease sites should be considered during formulation development, various formulation approaches have been explored to optimize the colonic drug delivery, including pH-sensitive systems, enzyme-triggered systems, and magnetically-driven systems. To enhance the specificity at disease sites, receptor-mediated systems have also been studied, which preferentially interact with specific receptors over expressed at the site (s) of the disease. This review covers recent advancements in various formulation approaches in designing colon-targeted drug delivery systems. Fig. 1 represents the drug release in colon.

Figure 1: drug release in colon by various drug delivery systems.

2. Formulation Approaches for Colon Targeted Drug Delivery:

2.1. Polymer-Based Nano-/Micro-Particles:

Many studies have demonstrated that pH-dependent polymeric nanoparticles are e_ective as colonic drug delivery systems [9,10]. Mutalik et al. [11] used novel pH-sensitive hydrolyzed polyacrylamide-grafted-xanthan gum (PAAm-g-XG) for the colon-targeted delivery of curcumin nanoparticles. The amount of drug released from the PAAm-g-XG-modified nanoparticles was minimal in acidic conditions (pH 1.2 and 4.5), while faster and higher drug release from Nanoparticles was observed at pH 7.2 [11]. Accordingly, the nanoparticles were e_ective in attenuating colonic inflammation and weight loss in IBD rat models. Furthermore, the blended mixture of two di_erent pH-sensitive polymers can be used to control the drug release rate. Sahu and Pandey [12] developed the HBsAg-loaded nanoparticles by using the combination of Eudragit® L100 and Eudragit® S100 for e_ective colonic immunization, confirming the e_ective distribution of nanoparticles at the colon along with the improved immune response [12]. To improve the site-specificity to the colon, Naeem et al. [13] fabricated budesonide-loaded pH-/time-dependent nanoparticles for the e_ective treatment of colitis. These nanoparticles were prepared with Eudragit® FS30D and Eudragit® RS100, using an oil-in-water emulsion solvent evaporation method. Eudragit® FS30D is a pH-dependent polymer that dissolves in an environment above pH 7.0, while Eudragit® RS100 is a time-dependent, controlled-release polymer having low permeability. Combining these two polymers e_ectively minimized premature drug release in the upper GI tract and achieved sustained-drug release throughout the colon. Furthermore, in colitis mice models, these pH-/time-dependent nanoparticles delivered drugs more e_ciently to the inflamed colonic sites [13].

2.2. Enzyme-Sensitive Drug Delivery Systems:

2.2.1. Polysaccharide-Based Systems:

Microbiota-activated delivery systems have shown promise in colon-targeted drug delivery due to the abrupt increase of microbiota and the associated enzymatic activities in the lower GI tract. These systems are dependent on the specific enzyme activity of the colonic bacteria and the polymers degradable by colonic microorganisms. Particularly, polysaccharides such as pectin, guar gum, inulin, and chitosan have been used in colon-targeted drug delivery systems, because they can retain their integrity in the upper GI tract but are metabolized by colonic microflora to release the entrapped drug [14]. Recently, new polysaccharides including arabinoxylans and agave fructans are also being explored for colonic drug delivery systems [15,16]. Furthermore, structural modifications or derivatives of polysaccharides can improve drug release behavior, stability, and site specificity [17]. Mucoadhesiveness of polysaccharides can be advantageous for drug uptake via the prolonged contact between the mucosal surface and drug delivery carriers. Polysaccharide-based delivery systems also have some additional advantages including availability at large scale, relatively low cost, low toxicity and immunogenicity, high biocompatibility, and biodegradability [14,18]. Consequently, the polysaccharide-based, microbiota-triggered system is promising strategy for colon-specific drug delivery. However, polysaccharides-based delivery systems also have some potential drawbacks, which include broad range of molecular weights and variable chemistry of polysaccharides [18,19]. In addition, low solubility in most organic solvents limits the chemical modification of polysaccharides, while hydrophilicity and excessive aqueous solubility of polysaccharides may cause the early and undesirable drug release in the upper GI tract [19,20].

Accordingly, cross-linking agents are often used to overcome this issue. In addition, the lack of film forming ability, along with swelling and solubility characteristics of polysaccharides limits theirapplication for colonic drug delivery.

To overcome these issues and also to avoid premature drug release in the upper GI tract, polysaccharide-based systems can be prepared by using the combination of polysaccharides and polymers.

2.2.2. Phloral® Technology:

Ibekwe et al. [21] reported a novel colonic coating technology which integrated pH-dependent and bacterially-triggered systems into a single layer matrix film. Tablets were film-coated by using a mixture of Eudragit S and biodegradable polysaccharide. Gamma scintigraphy study in human volunteers confirmed the consistent disintegration of these tablets in the colon regardless of feeding status, suggesting that this dual-mechanism coating may overcome the limitation of single trigger systems and improve the colonic drug targeting [21]. Subsequently, Phloral® (Figure 2) coating technology demonstrated the precise and fail-safe drug release in the colon in both healthy and diseased states [22]. This system consists of an enzyme-sensitive component (natural polysaccharide) and a pH-dependent polymer, where these pH and enzymatic triggers work in a complementary manner to facilitate site-specific release [22]. Even if the dissolution threshold of the pH-dependent polymer is not reached, the enzyme-sensitive component is independently digested by enzymes secreted by colonic microflora. This additional fail-safe mechanism overcomes the limitations of conventional pH-dependent systems. This innovative technology has been validated in clinical studies for consistent drug release with reduced-intra subject variability in patients and healthy subjects [22,23]. It is also applicable for the oral delivery of macromolecules such as peptides, proteins, and vaccines. Recently, Dodoo et al. [24] investigated the applicability of this technology in the colonic delivery of probiotics. The commercial products as well as in-house freeze-dried Lactobacillus acidophilus strain were encapsulated into capsules using dual-trigger coating technology to target the delivery into lower small intestines or colon. The viabilities of approximately 90% were retained after these capsules were exposed to gastric environment for 2 h while the unencapsulated probiotics showed poor tolerance to the gastric environment [24]. Based on a comparative cohort analysis in patients, Allegretti et al. [25] also demonstrated the e_ective colon-targeting of the fecal microbiota transplantation capsules coated with a blend of enzyme-triggered and pH-responsive polymers. Opticore. that stands for optimized colonic release is a novel starch-based coating technology. It has been developed based on the Phloral® technology and utilizes both pH-triggered and enzymatic-triggered release. This coating technology consists of two trigger systems in an outer coating layer and an accelerator in an inner coating layer to ensure the consistent drug release within the colon.

Figure 2: Schematic illustration of Phloral® tablet (A) and the drug release from Phloral® tablet (B).

2.3. Ligand/Receptor-Mediated Drug Delivery System:

For a more e_ective local treatment of colonic disease with reduced toxic side e_ects, ligand/receptor-mediated systems have been explored that increase target specificity via the interaction between targeting ligands on the carrier surface and specific receptors expressed at disease sites (Figure 3) [26]. Ligand/receptor-mediated system can be designed using various ligands (e.g., antibodies, peptides, folic acid, and hyaluronic acids) selected based on the functional expression profiles of specific receptors/proteins at the target cells/organs. It can be also combined with pH-dependent systems to maximize its GI stability and site specificity, if needed. Some of the ligands used in colon specific delivery are as described below.

2.3.1. Antibodies:

Harel et al. [27] prepared anti-transferrin receptor antibody-conjugated liposome’s, demonstrating better cellular internalization of the conjugated liposomes than unconjugated liposomes. Furthermore, anti-transferrin receptor antibody-conjugated liposomes exhibited preferential distribution to the inflamed mucosa rather than normal mucosa, resulting in greater accumulation at the site of inflammation (more than 4-fold higher) when compared to that of normal mucosa. Xiao et al. [28] also developed Nanoparticles fabricated with single-chain CD98 antibodies on their surface (scCD98-functionalized) for IBD therapy. CD98 is a heterodimeric neutral amino acid transporter, which is over expressed in intestinal macrophages and colonic epithelial cells in mice with colitis. scCD98-functionalized Nanoparticles exhibited a high affinity for CD98-overexpressed cells [28]. In mice with colitis, scCD98-functionalized nanoparticles containing CD98 siRNA (siCD98) reduced the expression levels of CD98 and the severity of colitis in mice.

2.3.2. Hyaluronic Acid:

Hyaluronic acid (HA) is a natural polysaccharide consisting of disaccharide units of d-glucuronic acid and N-acetyl-d-glucosamine. Since HA has a high affinity for the CD44 receptor, which is overexpressed in various cancers, HA-conjugated drug delivery systems have been examined for target-selective drug delivery [29]. For example, previous studies [29,30] have examined the effectiveness of HA-modified mesoporous silica nanoparticles targeting the CD44-overexpressing cancer cells. Vafaei et al. [31] developed self-assembled HA nanoparticles as colonic carriers of budesonide for targeting inflamed intestinal mucosa. Budesonide loaded HA nanoparticles exhibited higher uptake in inflamed cells over-expressing CD44 receptors, leading to a decrease in IL-8 and TNF-_ secretion in an inflamed cell model [31]. Accordingly, HA-conjugated nanoparticles appear to be a promising targeted drug delivery system for IBD treatment.

Xiao et al. [32] investigated an HA nanoparticle-based combination chemotherapy to create synergistic, targeted drug delivery system for colon cancer therapy. They prepared HA-functionalized camptothecin (CPT)/curcumin (CUR)-loaded polymeric NPs (HA-CPT/CUR-NPs) approximately 289 nm in size with a negative zeta potential. HA-CPT/CUR-NPs exhibited significant cancer-targeting capability against Colon-26 cells [32]. They also investigated a simultaneous delivery system of curcumin (CUR) and CD98 siRNA (siCD98), using hyaluronic acid (HA)-functionalized polymeric nanoparticles [33]. Compared to the single drug-based monotherapy, co-delivery of siCD98 and CUR by HA-functionalized nanoparticles exhibited an enhanced therapeutic e_ect against ulcerative colitis by protecting the mucosal layer and alleviating inflammation [33]. Therefore, HA-functionalized polymeric nanoparticles may be an effecient colonic delivery carrier for combination drug therapy. Recently, Prajapati et al. [34] developed HA-conjugated PEGylated multi-walled carbon nanotubes containing gemcitabine (GEM/HA-PEG-MWCNTs) for colon cancer targeting. HA was conjugated to the surface of PEGylated multi-walled carbon nanotubes (MWCNTs). This formulation showed promising results for effective colon cancer targeting including improved anti-proliferative activity and pharmacokinetic behaviors [34].

Figure 3: Schematic illustration of representative ligand/receptor-mediated drug delivery system.

2.4. Magnetically-Driven Drug Delivery System:

Magnetic microcarriers including magnetic microspheres, magnetic nanoparticles, magnetic liposomes, and magnetic emulsions are emerging novel formulations for controlled and targeted drug delivery (Figure 4). To improve the targeted treatment of colorectal cancer by mAb198.3 (a FAT1-specific monoclonal antibody), Grifantini et al. [35] developed two di_erent novel drug delivery systems having magnetic properties to improve the targeted treatment of colorectal cancer by mAb198.3 (a FAT1-specific monoclonal antibody), where mAb198.3 was directly bound to super-paramagnetic nanoparticles or embedded into human erythrocyte-based magnetized carriers. They observed that both systems were very e_ective at targeting colon cancer cells and inhibiting cancer growth at significantly lower antibody doses [35]. This study demonstrated the potential of magnetically-driven drug delivery systems at improving the bioavailability and target specificity of anti-FAT mAb198.3, opening a new avenue for colon-targeted drug delivery [35]. Another previous study improved the efficacy of hydrocortisone using a magnetic belt on rats [36]. This nanodevice consisted of magnetic mesoporous silica microparticles loaded with hydrocortisone. The outer surface of the drug-loaded nanoparticles was functionalized with a bulky azo derivative with urea moieties. The nanodevices remained capped at neutral pHs, but a noticeable payload release occurred in the presence of sodium dithionite because it reduced the azo bonds in the capping joint [36]. They also observed the improvedefficacy in rats wearing magnetic belts, particularly being more e_ective when a magnetic field was externally applied to lengthen the retention time in the areas of interest [36]. This study demonstrated that the use of a magnetic belt increased the drug e_cacy in the treatment of IBD due to enhanced retention time of the drugs in the colon. Recently, Kono et al. [37] developed magnetically-directed cell delivery systems via the incorporation of superparamagnetic iron oxide nanoparticles (SPIONs) and plasmid DNA (pDNA) into RAW264 murine macrophage-like cells. They also demonstrated that del ivery system could enhance the colonic delivery of macrophages in mice (105). Fig 4 represents the magnetically driven drug delivery system in cancer cells.

Figure 4: Schematic illustration of magnetically driven drug delivery system.

3. Complementary Tools for Designing the Effective Colonic Drug Delivery Systems:

Optimizing drug formulations using traditional approach requires many experiments including various in vitro and in vivo tests, which are often tedious, time-consuming, high-cost tasks [38]. Furthermore, many drug delivery systems are promising in vitro but often fail in vivo, which is mainly due to the lack of mechanistic insight from experiments based on trial and error [39]. The computational methods including molecular modeling and simulation, data mining, and an artificial intelligence technique are useful to expedite the rational formulation design. It can save much experimentation effort and time by identifying the critical factors for the optimization of formulations and selecting the promising candidates for further experimental confirmation. For example, Metwally and Hath out [38] have proven that the combined use of several chemo/bio informatics and statistical tools could effectively predict the loading efficiency of drugs in a carrier and also elucidate the effect of certain molecular descriptors of drugs on their docked binding energies on carriers [38]. This would allow the accurate estimation of entrapment efficiencies and loading capacity in drug delivery systems without exhaustive laboratory experiments.

3.1. Electronic Device-Assisted Formulation Design:

For the successful development of colon-specific drug delivery systems, in vivo characterization of drug absorption throughout the GI tract is essential. Accordingly, there is a strong need for a quick and simple way to precisely and reliably assess the drug release properties within the GI tract to determine whether the tested formulation is valid for modified drug release. In that sense, the use of electronics brings a new approach for integration of data from multiple sources. IntelliCap® is the world’s first intelligent electronic drug delivery and monitoring device, which combines controlled drug release, patient monitoring, and real-time wireless communication [40,41]. Since this electronic capsule features real-time wireless data recording, it can provide care givers the ability to monitor the progress of the capsule through the GI tract. Furthermore, simultaneous measurement of pH and transit, along with accurately targeting drug delivery, makes in vivo data available for a formulation design [40,41]. Consequently, IntelliCap® technology provides a fast and convenient tool for the controlled drug release to specific sites in the GI tract. By using Intellicap® system, In addition to many benefits, there are also some disadvantages associated with electronic capsules including high cost, manufacturing di_culties, biocompatibility issues, and potential risk of device failure [40,41]. Hence, there should be continuous efforts to overcome these disadvantages in order to make electronic delivery systems more widely compatible. In the long run, electronic drug delivery system is a promising new approach for the controlled drug release at the desired target sites.

4. SUMMARY:

Colon-targeted drug delivery is an essential strategy for more effective local treatment of colonic diseases such as IBD and colorectal cancers. It may offer many benefits over conventional dosage forms in terms of safety, efficacy, and patient compliance. In addition, colon-targeted delivery systems are applicable to improve the systemic exposure of acid-and/or enzyme-labile drugs including macromolecules. Although advancements in biotechnology and protein engineering have expanded the therapeutic application of proteins and peptides, most biologics on the pharmaceutical market are in parenteral formulations due to their low permeability and physicochemical and metabolic instability in the GI tract. Therefore, colon-targeted delivery systems gain great attention as an effective formulation strategy to improve the oral bioavailability of macromolecules.

In this review, various formulation approaches to develop the effective colon-targeted delivery systems were discussed with some case studies. All of these formulation strategies possess their own advantages and disadvantages, requiring continuous refinement to improve their therapeutic efficiency. For the successful development of colon-targeted drug delivery systems, it is imperative to consider the physiological and pathophysiological properties of the colon and the microenvironment surrounding disease site(s). However, the dynamic changes in the physiological conditions in GI tract and also the pathophysiological changes in the microenvironment surrounding disease sites make optimal formulation design more complicated, often leading to in vivo failure with lack of site specificity. For example, the dynamic pH change in GI tract by many internal and external factors may attenuate the efficiency of pH-dependent drug release systems, resulting in premature drug release in upper GI tract, or incomplete drug release at the target site. Accordingly, the combined systems of the different release-triggering mechanisms are actively pursued to overcome the pathophysiological variability issues. In addition, nano-/micro-particles hold great potential for enhancing drug targeting as well as drug uptake. Therefore, various formulations with particle size reduction may be beneficial for colon-targeted drug delivery. Computer-assisted and electronic device-assisted formulation design also allow more rational formulation design and optimization, reducing the time and cost for experiments. Taken together, to overcome the limitations of current formulation approaches, there should be continuous efforts to invent new formulation technologies. These efforts include the discovery of the new biocompatible functional materials, the development of more precise drug delivery devices, and utilization of big data

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Received on 22.05.2020 Revised on 15.06.2020

Asian J. Pharm. Res. 2020; 10(4):268-274.

DOI: 10.5958/2231-5691.2020.00047.7