Gastric Retentive Strategies Mucoadhesion Bioadhesives

The concept of mucoadhesion is based on the formulation first making good contact with the mucus layer of the stomach, followed by its adhesion to the mucus layer. Thus the formulation remains in the stomach until the mucus layer sloughs off or the formulation no longer adheres to the mucus. There are several challenges with this approach: the first is the challenge to make good contact with the mucus layer. In the fed state, nonspecific adhesion could occur with food. In both the fed and fasted state, free mucus may also adhere to the formulation. Once good contact is made, sufficient adhesion is required to hold the formulation to the mucus.

Selection of the proper mucoadhesive polymer is often performed in-vitro prior to in-vivo evaluation. However, Laulicht et al. [17] reveal a lack of IVIVC for predicting suitable performance. Laulicht et al. also concluded that polymers that produce strong bioadhesive bonds may not achieve prolonged gastric retention in-vivo. This brings up the third challenge, even if the formulation successfully avoids nonspecific adhesion and correctly attaches to the mucus layer of the stomach, the turnover rate of the mucus will dictate the residence time in the stomach. The turnover rate for the mucus layer has not been definitively determined, but in some cases is reported to be 5 h and in others 24 or 48 h. However, it is clear that if adhesion to the uppermost layer of the mucus occurs, that mucus will be the first to slough off, limiting the duration of mucoadhesion. Based on all of the challenges encountered with this approach, there is a very low probability of success and to our knowledge no mucoadhesion techniques have been proven to be clinically successful.

17.5.2.1 Polymers for Mucoadhesion

"Mucoadhesive" materials are commonly divided into three categories: anionic, cationic, and neutral. Though many materials are claimed as mucoadhesive, only a few, such as Carbopol 934P/974P have been tested in-vivo. More recent strategies include targeting specific cross-links in the mucus layer, such as disulfide bonds using thiol-based polymers "thiomers" [18] and novel polymers "spheromers" (homo- and copolymers of fumaric, sebacic, and adipic anhydride with or without metal oxides) [19].

17.5.2.2 Maximizing the Surface for Mucoadhesion: A Potential Opportunity

One physical aspect of a mucoadhesive polymer that can influence performance is the surface area capable of interacting with the mucus layer. This is analogous to reducing drug substance particle size to increase surface area in order to have more contact with liquid to increase the rate of dissolution. To maximize the surface area for adhesion to the mucus layer, the polymer should have a high surface area to volume ratio.

Electrospinning techniques have been used to create nanofibers of polymers. The high surface area of such nanofibers and the rougher texture of a nonwoven nanofiber matrix may provide improved mucoadhesion compared to a typical cast film or tablet coat. Takeuchi et al. [20] mention that a particle less than 1 mm in size has the ability to penetrate deeper into the mucus layer, thus allowing more potential for interaction. Interactions with the deeper portions of the mucus layer would also reduce the turnover rate associated with the upper, loosely adherent layer that limits gastric residence time.

Using the Gantrez polymer ES225 (normally used for denture adhesives), an electrospun nanofiber mat was manufactured and compared to a cast film. An SEM of the nanofiber mat is shown in Fig. 17.5. The diameters of the nanofibers are estimated to be 350 nm.

When the nanofiber mat was compared to a cast film of the same material, it demonstrated improved mucoadhesion versus cast films of the same formulation during ex-vivo mucoadhesion testing with rat stomach tissue. The test was performed with freshly excised rat stomach tissue which was held in place using a studded Perspex block with a top plate. A texture analyzer (Model TAXT2i) with a 14 mm diameter stainless steel plate probe was brought in contact with the sample for a period of 5 s at a force of 0.05 N and the force and time required to detach the probe were measured. The area under the detachment force vs. time curve was

Fig. 17.5 SEM image of the Gantrez ES-225 nanofiber matrix which was electrospun from a 20% w/w polymer solution in an 85:15 mixture of ethanol and water. The technique to electrospin the polymer is described by Burke [21]
Table 17.3 Comparison of Gantrez ES225 cast films and an electrospun nanofiber matrix for mucoadhesion to excised rat stomach tissue as measured with a texture analyzer [21]

Mucoadhesiveness (ns)

"Stringiness" (mm)

Gantrez ES225 Cast Film

0.03

0.79

Gantrez ES225 Electrospun Nanofiber matrix

0.07

4.16

calculated as the mucoadhesiveness of the sample and the time to achieve complete detachment was calculated as the "stringiness." A summary of the findings are shown in Table 17.3.

Based on the significant improvement in the performance of the nanofiber presentation versus a cast film, the Gantrez electrospun nanofiber mat was dosed in mongrel dogs to determine in-vivo gastric emptying performance. The average gastric residence time was evaluated using gamma scintigraphy by tracking a poly-vinylacetate nanofiber with entrapped nanoparticles of samarium oxide. The polyvi-nylacetate nanofibers were used at a very low level and were intertwined with the Gantrez nanofiber matrix polymers. The average gastric emptying time using three mongrel dogs was an impressive 19.3 h.

This case study highlights a key parameter that formulation scientists have to improve mucoadhesive performance. However, the key challenges mentioned earlier in this section still limit the true possibility to develop a successful GRF based on mucoadhesion.

Table 17.4 Gastric residence time of floating calcium alginate beads in the fed [25] and fasted state [26] in healthy volunteers

Fed or fasted

Onset of gastric emptying

Time to completion of gastric emptying

Fed (n = 7) Fasted (n = 5)

Did not begin (still in stomach after at least 5.5 h) 20-82 min

Unknown, all subjects had retained the beads when imaging was stopped 5-55 min

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