Avinash Nangia

The use of bioadhesive polymers as a means of delivering therapeutic agents to the gastrointestinal tract (GIT) has been a focus of attention during the past two decades (1, 2). Bioadhesive oral drug delivery systems exploit the interaction between the mucus and bioadhesive polymers and thus offer significant advantages (3, 4) (see sidebar). Oral delivery systems formulated with bioadhesive polymers may increase GIT residence time, thereby improving oral bioavailability as the formulation achieves greater opportunity to interact closely with the absorption site (5, 6). Bioadhesive polymeric systems may also be useful for coating damaged esophageal and intestinal wall tissues, thus providing defense against various irritants (7). The ability to maintain an oral delivery system at the target location for an extended period of time has great appeal for the treatment of both local conditions and sustained systemic absorption (8–10). 

Despite significant research on bioadhesive polymers, the phenomenon of bioadhesion is not yet fully understood. Adhesion of bioadhesive polymers to mucus is a complex interaction and is regulated to a great extent by the intrinsic properties of the polymer, the biological substrate, and the surrounding environment (11). The term 

 is defined as adhesion to a biological surface (i.e., mucus and/or mucosal surface). Instances in which the polymeric system interacts with the mucus coating only are referred to as 

 (12). To develop an ideal oral bioadhesive system, one must have a thorough understanding of mucosa, bioadhesive polymers, and mucous-polymer interactions in the physiological environment.  

GI mucosa is composed of high molecular weight glycoproteins that are hydrated with a continuous adherent blanket of mucin. Mucin glycoproteins are rich with fucose and sialic acid groups at the terminal ends that provide a net negative charge in the acidic environment. The thickness of the mucin gel layer varies in various regions of the GIT, with thickness ranging between 50 and 500 μm in the stomach to 15–150 μm in the colon. The thickness of the mucus gel that covers the GI epithelium is attributed to the steady state between the mucus secretions and its erosion 

 enzymatic and mechanical degradation. Cohesion of the mucin gel depends on the glycoprotein concentration. 

Major attributes of oral bioadhesive based systems (ALL FIGURES AND TABLES ARE COURTESY OF THE AUTHOR.) 

The mucus layer is created biologically to protect the underlying tissues from diffusing or corrosive elements such as enzymes, acids, and other toxic molecules. As a viscoelastic gel, it helps in the transport of food over the epithelium, thereby minimizing potential erosive damage. The mucus layer, in addition to providing protection, imparts a barrier to drug absorption. The following mucin–polymer interactions have been proposed:  

Wetting and swelling of the polymer to permit intimate contact with the biological tissue

 Interpenetration of bioadhesive polymer chains and entanglement of polymer and mucin chains

Water transport followed by mucosal dehydration.  

As the bioadhesive delivery system comes into contact with the mucus layer, various nonspecific (van der Waals, hydrogen bonding, and hydrophobic interactions) or specific interactions occur between the complimentary structures (see Figure 1). However, these interactions are of limited duration because of the turnover process of mucin. Although this phenomenon is favorable from the toxicological perspective of keeping unwanted materials from gaining access to the body, it is not optimal for maintaining the bioadhesive delivery system at the mucosal surface. Hence, for a bioadhesive delivery system to be successful, it should release drug contents during the limited adhesion time (13). 

Figure 1: Schematic representation of interactions between bioadhesive and mucus polymer chains. (ALL FIGURES AND TABLES ARE COURTESY OF THE AUTHOR.) 

Prerequisites for successful bioadhesive oral dosage form

The promise of bioadhesive-based oral delivery systems has fostered numerous investigations with limited success. Different types of transmucosal oral systems have been explored using various bioadhesive polymers. A majority of these systems are based on hydrophilic hydrogel polymers and are designed primarily for buccal or sublingual applications. When these hydrophilic polymers are used for oral bioadhesive systems for drug delivery in the GIT, they typically hydrate prematurely upon contact with the stomach contents before developing interactions with the mucosal surface. In the event that some weak interactions do occur, these systems cannot withstand the high turbulence of the stomach environment, and the result is premature emptying. Therefore, although the range of hydrophilic bioadhesive polymers and their application in various low-turbulence conditions is quite broad, their usefulness in oral dosage forms, especially in designing of systems for systemic delivery, is generally limited.  

An ideal bioadhesive oral dosage form must meet several prerequisites to be successful. The first prerequisite to target a gastrointestinal site is that the behavior of the dosage form must be reproducible. Although many bioadhesive polymers have exhibited promising results 

 in animals, few benefits have been shown in human trials. The results of human clinical trials with bioadhesive oral dosage forms are summarized in Table I. Recently, Säkkinen evaluated the passage and retention of chitosan granules in the small intestine by gamma-scintigraphy in fasted human volunteers (14). Although chitosan showed marked bioadhesive capabilities 

 retention of the chitosan formulation in the upper small intestine was not sufficiently reproducible, and the duration of retention was similar to lactose granules used as a control. In developing a site-specific bioadhesive system for furosemide, a model drug with a narrow absorption window in the upper GIT, administration of furosemide in chitosan granules resulted in bioavailability lower than that from a conventional immediate-release formulation, thereby indicating that the bioadhesive formulation could not be retained long enough in the upper GIT in humans (15). 

Table I: Bioadhesive oral drug delivery systems used in various human trials. (ALL FIGURES AND TABLES ARE COURTESY OF THE AUTHOR.) 

The second prerequisite for a bioadhesive system is that it should rapidly attach to the mucosal surface and maintain a strong interaction to prevent displacement. Spontaneous adhesion of the system at the target site is critical and can be achieved through bioadhesion promoters that use tethered polymers (16). Contact time should also be sufficiently long at the target site, normally longer than that needed for complete drug release. As hydrophilic bioadhesive polymers tend to lose adhesiveness upon hydration, restricted hydration and formation of a rigid gel network would be desirable for prolonged adhesion (17). A short retention time, in relation to the drug release rate, will compromise bioavailability.  

The third prerequisite for a successful and effective bioadhesive system is that the bioadhesion performance should not be impacted by surrounding environmental pH. Studies have shown that the bioadhesiveness of polymers with ionizable groups are affected by surrounding pH. For example, polyacrylic acid is more bioadhesive when the majority of the carboxylic acid groups are in the ionized state. Polyanhydride-based hydrophobic bioadhesive polymers (e.g., Spheromers, Spherics, Mansfield, MA) undergo erosion that is mainly affected by the aqueous environment and not by pH of the surrounding medium. Studies have shown that as anhydride-based polymers degrade at the mucus surface, carboxylic acid groups are formed at the transected polymer chain ends, which generate a new polymer surface rich in carboxylic acid end groups (18). These hydrophilic functional groups then form hydrogen bonds with surrounding mucin strands that in turn penetrate the newly created surfaces. The result is the formation of both chemical and mechanical bonds. As the degradation process proceeds, a more porous surface rich with carboxyl groups is created, allowing for even greater adhesion that is essential to the success of an oral bioadhesive system. In earlier studies, one family of rapidly degradable polyanhydrides [poly (FA:SA)] produced bioadhesive interactions with rat small intestine tissue that were substantially stronger than all other polymers in this class (18). The fact that these bioadhesive polymers are stable in the acidic environment of the stomach and eventually degrade at pH ≥7.4, make them ideal for targeted delivery to the stomach and small intestine (19). 

Another prerequisite for an ideal bioadhesive delivery system is that the bioadhesive and drug-release functions are independent of each other. Often, the bioadhesive polymer used in the dosage form is also used to regulate the release of drug. Generally, these formulations are made by mixing bioadhesive polymer and drug or by coating drug-loaded beads or tablets with the bioadhesive polymer. These approaches of using bioadhesive polymers to achieve both bioadhesion and drug-release functions have compromised results. 

An effective bioadhesive formulation must not cause local tissue irritation or long-term tissue toxicity as a result of the bioadhesive polymer or other absorption enhancers used to promote drug absorption. Also, if encapsulated bioadhesive nanoparticles or multiparticulates beads are used as the delivery system, the particles may have a tendency to form agglomerates because of the charge or hydration within the capsule. Accordingly, measures should be taken to keep these structures monodisperse to allow maximum interaction with the mucosal surface upon release from the capsule. Other desirable characteristics of a bioadhesive dosage include high drug loading, complete drug release, and convenient administration.  

Although the prerequisites described above apply to bioadhesive dosage forms, the potential impact of formulation excipients on the adhesive behavior of bioadhesive drug delivery systems and mucosal surfaces also should be carefully taken into account. For example, excipients containing hydroxyl groups could form hydrogen bonds with the hydrophilic functional group of bioadhesive polymers and, as a result, prevent their interaction with the mucosal surface (20). In addition, hydrophobic lubricants (e.g., magnesium stearate and talc) tend to hinder the formation of strong bioadhesive bonds and thus reduce the bioadhesive strength significantly (21). Structural breakdown of mucin has been observed by the addition of surfactants. A number of agents (e.g., tetracycline and progesterone) may alter the viscosity of mucus by altering its molecular composition. Integrity of mucin layers is also disrupted in some disease states (e.g., inflammation and ulceration). Therefore, in developing a bioadhesive dosage form, drug and excipient characteristics as well as the presence of disease states need to be taken into account. 

Oral bioadhesive dosage forms targeting the GIT

Bioadhesive systems have been targeted to many sites within the GIT to increase the residence time available for absorption and thereby increase the overall bioavailability. Although bioadhesive polymers have been successfully used for oromucosal (buccal and sublingual) drug delivery (22), delivery to other GI sites has been a challenging task. The following sections review the drug delivery to various GI sites using bioadhesive formulations and discuss the degree of success.  

 The esophagus is lined with stratified squamous epithelium and is continuously lubricated and coated by the swallowed saliva containing mucin. Bioadhesive materials have been used in various liquid dosage forms to specifically target the esophageal mucosa (23, 24). However, because the esophagus is associated with poor blood supply, drug delivery for systemic absorption through this site is not feasible.  

Because of a relatively short esophageal transit time of dosage forms in supine subjects (10–15 s), liquid bioadhesive formulations have been explored as a vehicle for localized delivery to the esophageal mucosa or to provide a protective bandage for the underlying esophageal lining from gastric reflux (25). One study investigated the incorporation of antifungal agents into an oral formulation that coated the esophagus and provided drugs at the target site for localized delivery to treat esophageal candidiasis (26). Drug delivery to the esophagus was achieved in rabbits using magnetic particles in conjunction with hydroxypropyl cellulose and carboxyvinyl polymer as bioadhesive excipients. However, retention of the formulation (using bleomycin in hydroxypropyl cellulose:Carbopol) was insufficient for effective therapy. It was concluded that a stronger bioadhesive may help retain particles at the desired site of action (27). 

Sodium alginate in a range of water-miscible vehicles was evaluated as a bioadhesive liquid for targeting the esophageal mucosa for the treatment of gastro-esophageal reflux disease (GERD). The study showed that vehicle composition had a considerable impact on the initial contact and retention of suspended alginate; however, the rate of detachment of the adhered layer was similar for each vehicle. Thus, the ability to modulate the mucosal retention of an alginate suspension as a function of hydration offers a novel strategy for the future development of formulations with tailored bioadhesive properties (28). 

Localized delivery of hexylaminolevulinate to the Barrett's esophagus was achieved in human volunteers using poloxamer, chitosan, and sodium carboxymethylcellulose polymers as bioadhesive excipients. This study measured the esophageal transit time by endoscopic examination and suggested that a topical formulation delivered orally to treat adenocarcinoma of esophagus is feasible (29). 

Strategies for successful drug delivery to the esophagus should involve drugs that are readily soluble in bioadhesive polymers, rapidly smear the esophageal epithelium, and are not washed away by the flow of saliva and other liquids. The risk of bioadhesive dosage forms getting dislodged in the esophagus when taken with little or no water could also pose problems and should be considered as part of the formulation design (30). These problems, attributed to esophageal blockage or drug-induced injuries resulting from a high concentration of drag at the epithelium layer corrosive to the local tissue, may have serious clinical implications. 

Targeting to the stomach and small intestine. 

 One of the feasible approaches for achieving a prolonged and predictable release profile in the GIT is to maintain the dosage form in the stomach over an extended duration. This is of great importance for drugs in which the absorption site is restricted to the stomach or the proximal small intestine. Specifically, it is important for controlled-release dosage forms designed to deliver drugs to narrow absorption windows (e.g., levodopa, metformin, furosemide, gabapentin, and amoxicillin). A bioadhesive dosage form for gastric delivery should achieve a rapid interaction with the mucosal surface and be sufficiently strong to resist the propulsion forces of the stomach wall. The effectiveness of the system also should be maintained irrespective of continuous production of mucus by the gastric mucosa to replenish the mucus that is lost through peristaltic contractions, as well as dilution of the stomach contents.  

Few studies have been conducted to specifically investigate the transit time of oral bioadhesive tablet formulations containing hydrophilic polymers in animals and humans. An increase in transit time and improved absorption of griseofulvin, by three- to four-fold was observed from a bioadhesive oral dosage form containing a cross-linked acrylic acid polymer as the bioadhesive material (31). In a radioscintigraphic study (32), two different capsule formulations, based on the hydrophilic bioadhesive polymers polycarbophil and Carbopol, were evaluated for gastric emptying and small intestine transit time. Results indicated that both bioadhesive formulations were not dramatically different from the nonadhesive controlled formulation in terms of stomach emptying, small intestinal transit time, and time to reach the colon. Similar results were obtained with an oral bioadhesive controlled-release formulation of furosemide (33). A bioadhesive formulation containing Carbopol 934 and furosemide, a model drug with erratic absorption and a narrow absorption window, was evaluated in a radioscintigraphy transit time study in humans. The extent of absorption from the bioadhesive formulation was less than the control non-bioadhesive formulation. The reasons suggested for this poor performance were that 

 adhesive properties were insufficient to overcome the powerful gastric contractions during Phase III of the housekeeping motor migrating complex waves in the fasted state. Clearly, the applications of hydrophilic polymers in designing oral dosage forms, in particular, controlled-release dosage forms, has been limited.  

Figure 2: X-ray images of barium sulfate spheres (bioadhesive and control non-bioadhesive) taken at different time intervals in fasted beagles (34). At 1.5 h: bioadhesive spheres retained in the stomach while control spheres are entering the intestine; at 4.5 h: bioadhesive spheres in the stomach while control spheres entering ascending colon; at 8.5 h: bioadhesive spheres scattered evenly in stomach, small and large intestine, while control spheres are in distal descending colon; at 24 h: bioadhesive spheres still present in the intestine and no control spheres in the intestine. (ALL FIGURES AND TABLES ARE COURTESY OF THE AUTHOR.)

Based on the poor performance of hydrophilic polymer-based bioadhesive systems in humans, interest has been focused in using hydrophobic polymers. It is perceived that nonswellable polymers, with a hydrophobic polymeric backbone and various hydrophilic functional groups, may improve bioadhesiveness to mucosa. Extensive progress has been made at Spherics, Inc. into the research and development of proprietary hydrophobic polymers (Spheromers), in which oral bioadhesive dosage form approaches have been explored for sustained and targeted delivery, including the following:  

The mechanisms of Spheromer interactions with mucosal surfaces as well as the design of novel targeting strategies 

The development of novel bioadhesive controlled release formulations of challenging drugs with improved and reproducible performance in humans. 

Figure 3: Mean itraconazole plasma concentration versus time following a single dose of itraconazole bioadhesive extended release (XR) tablet, 100 mg, or  Sporanox capsule, 100 mg, in healthy volunteers, n = 8. (ALL FIGURES AND TABLES ARE COURTESY OF THE AUTHOR.)  

Animal studies have been performed with bioadhesive oral delivery systems based on bioerodible Spheromers of the polyanhydride type (34). Among the various thermoplastic polymers studied, poly(fumaric-co-sebacic) (p[FA:SA] in a 20:80 ratio) had the most bioadhesive characteristics. 

radiographic transit studies in fasted beagle dogs on bioadhesive-coated, barium sulfate–loaded microspheres showed that the microspheres remained in the stomach and intestine longer than microspheres made of non-bioadhesive polymers (Eudragit RS 100), clearly demonstrating that strong adhesive interactions delayed the passage of microspheres through the GIT (see Figure 2). 

Figure 4: Percent coefficient of variation (%CV) of Cmax and AUCo-t for itraconazole bioadhesive extended release tablet, 100 mg, compared with Sporanox capsule, 100 mg, in healthy volunteers, n = 8. (ALL FIGURES AND TABLES ARE COURTESY OF THE AUTHOR.) 

Bioadhesive extended-release formulation of drugs with narrow absorption windows and erratic absorption behavior have been developed using Spheromers to increase the residence time in the stomach and to allow drug release downstream in the small intestine in a controlled manner. Using itraconazole as a model drug, bioadhesive extended-release formulations were assessed for their pharmacokinetic performance in healthy volunteers (see Figure 3). Bioadhesive extended-release formulations provided an improved bioavailability compared with the immediate-release Sporanox capsule, while maintaining effective itraconazole plasma levels for more than 24 h and reducing intersubject variability (see Figure 4). A reduction in C

 is critical to product performance because side effects are associated with peak itraconazole plasma levels (68). These results may help prevent the risk of developing a fungal infection, especially in immunosuppressed patients. 

Figure 5: Plasma levodopa profiles following a single dose administration of levodopa-carbidopa bioadhesive extended-release (XR) tablets and Sinemet CR tablet in fed beagles (n = 6). Both tablets contain 200 mg levodopa and 50 mg carbidopa (35). (ALL FIGURES AND TABLES ARE COURTESY OF THE AUTHOR.) 

Levodopa-carbidopa was also explored in a bioadhesive oral drug delivery system as an oral dopaminergic treatment strategy to maintain the system at the target site over an extended duration and provide stable blood levels of drug in advanced Parkinson's Disease. Figure 5 shows the pharmacokinetic performance of levodopa–carbidopa administered as a bioadhesive, multilayer tablet to beagle dogs. In comparison with Sinemet controlled-release tablets, this novel bioadhesive extended-release dosage form resulted in an extended plasma levodopa profile for as long as 12 h and improved bioavailability both in fasting and fed animals as a result of prolonged residence time (see Tables II and III) (35). By providing a continuous delivery of levodopa at a constant rate, the system should not only reduce the motor complications related to abnormal intermittent pulsatile dopaminergic stimulation but also improve patient compliance and quality of life. Figure 6 shows the levodopa profile of bioadhesive extended release tablets and Sinemet  controlled-release tablets in young healthy volunteers. Because the gastroretentive systems are highly dependent on the calorie content of the meal, both formulations were administered following a light breakfast (approximately 380 calories). The bioadhesive system provides a rapid and reliable levodopa level that is needed to achieve the "morning kick," followed by a smooth delivery of levodopa over an extended duration. Reduced intersubject variability data showed superior reproducibility in the 

 performance compared with the marketed product, Sinemet controlled-release tablets (36).  

Table II: Pharmacokinetic data for levodopa-carbidopa bioadhesive extended release (XR) tablets and Sinemet CR tablets in fasted beagles (n = 6).  (ALL FIGURES AND TABLES ARE COURTESY OF THE AUTHOR.) 

Figure 7 shows the pharmacokinetic profile of a delayed-release bioadhesive capsule formulation containing 0.375 mg pramipexole (a dopamine receptor agonist) administered once daily compared with immediate-release Mirapex tablets, 0.125mg, given three times daily in healthy human volunteers. By allowing the drug to be released in the small intestine, the novel bioadhesive dosage form extended drug release to 22 h with a similar extent of exposure compared with Mirapax tablets given three times daily. Also, the bioadhesive formulation showed reduced fluctuations in pramipexole levels and eliminated nausea and vomiting (37). 

Table III: Pharmacokinetic data for levodopa-carbidopa bioadhesive extended Release (XR) tablets and Sinemet CR tablets in fed beagles (n = 6). (ALL FIGURES AND TABLES ARE COURTESY OF THE AUTHOR.) 

These examples cited demonstrate that systems based on hydrophobic bioadhesive polymers are likely to show great promise in terms of extended residence time and bring new possibilities for controlled delivery of drugs with narrow absorption windows. 

Figure 6: Plasma levodopa profiles following a single dose administration of levodopa-carbidopa bioadhesive extended release (XR) tablets and Sinemet CR tablets in healthy volunteers. Both tablets contain 200 mg levodopa and 50 mg carbidopa, n = 12 (36). (ALL FIGURES AND TABLES ARE COURTESY OF THE AUTHOR.) 

 The need to target drugs to the colon is well recognized and considered to be an effective approach in the treatment of local disorders such as irritable bowl syndrome and inflammatory bowl diseases such as Crohn's disease and ulcerative colitis. It is also a preferred absorption site for oral administration of protein and peptide drugs because of relatively low proteolytic enzyme activity (38). 

Figure 7: Plasma pramipexole profile following administration of pramipexole bioadhesive extended release (XR) capsules, 0.375 mg, given once daily versus Mirapex tablets, 0.125 mg given three times daily to health volunteers, n = 12 (37). (ALL FIGURES AND TABLES ARE COURTESY OF THE AUTHOR.) 

Because of its lower mucin turnover and lower sensitivity to mucus secretory stimulus, the colon is a suitable location for bioadhesion in the GIT (13). Slow transit of dosage forms through the colon will prolong contact time between the formulation and the absorptive surface, thereby enhancing drug exposure. This has led to the development of oral dosage forms for selective drug delivery for various colonic conditions. Typically, systems have been designed to release drugs rapidly in the upper portion of the colon. However, this may result in unnecessary exposure of drug to noninflamed tissues, thereby reducing the efficiency at the desired site of inflammation and increasing adverse effects. Therefore, a colon-specific bioadhesive multiparticulate delivery system that remains at the inflamed target site for a prolonged period of time will provide drug exposure in the local mucosa and reduce the potential for side effects (39). Achieving desired levels of drug exposure at the inflammatory target site requires careful considerations in terms of the intersubject variabilities in intestinal transit time, intraluminal pH profile, disease pattern, and drug disposition (40).  

At Spherics, an effort of exploiting Spheromer bioadhesive polymers to target delivery to distal parts of the GIT has been conducted. Proof-of-concept studies have been completed with promising results. In fluoroscopic studies in beagle dogs, bioadhesive beads coated with Spheromer bioadhesive polymers uniformly lined the ascending large bowel and remained in close apposition to colonic mucosa without mixing with digested food contents (see Figure 8). In contrast, beads coated with non-bioadhesive cellulose acetate polymer were evenly distributed in the lower small bowel, mixed with food, moved freely with the peristaltic movements, and did not attach to the intestinal mucosa. 

Figure 8: Spheromer-coated multiparticulate beads lining the large colon 8 h postdosing (top) and control non-bioadhesive multiparticulate beads 8 h postdosing (bottom). (ALL FIGURES AND TABLES ARE COURTESY OF THE AUTHOR.) 

A colonic-specific bioadhesive system should prevent drug release in the stomach and small intestine and provide rapid adhesion and drug release upon reaching the colon. The selection of triggering mechanisms (e.g., prodrug, pH, or microflora activated) that respond to the physiological conditions in the colon should be carefully selected such that the bioadhesive performance of the system remains unaffected. 

 Although peroral administration is the most common route for targeting drugs, oral administration may not be feasible. Use of a bioadhesive liquid suppository, based on 

 gelling phenomenon, has been explored as an option for the local treatment of diseases of the anorectal area as well as for systemic drug delivery (41–44). Choi examined a bioadhesive liquid suppository that combined a bioadhesive polymer with a thermal gelling polymer. With acetaminophen as a model compound, a bioadhesive system that gelled strongly at physiological temperature gave the most prolonged plasma level of acetaminophen 

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