Effervescent Buccal Fentanyl Tablet for Treatment of Breakthrough Pain

Lipophilic opioids are more efficiently absorbed across the oral mucosa than hydrophilic opioids [108]. Fentanyl also enters the central nervous system (CNS) faster, rapidly crossing the blood-brain barrier once it is in the systemic circulation. The rate constant for the equilibrium of fentanyl between the blood and CNS is 6min [109], whereas the rate constant for morphine is approximately 17min [110].

The rapid onset of pain relief with oral mucosal delivery devices is attributable to the lipophilic nature of fentanyl. However, the lipophilic nature of fentanyl also makes it more difficult to dissolve in saliva, which is the first step in the buccal delivery of a solid dosage form. Fentanyl, which has a pKa of 8.4, is a weak base and, in its ionized form, is much more soluble in aqueous solutions. Therefore, dissolution is favored by a low pH, in which the ionized, less lipophilic form of fentanyl predominates. However, absorption across the buccal mucosa is favored by a high pH, in which the more lipophilic, nonionic form is more common [111].

OraVescent® technology (Cephalon Inc, Salt Lake City Utah, USA) utilizes the principles outlined above to enhance the oral transmucosal delivery of drugs such as fentanyl that are characterized as weak bases. The Fentora® buccal tablets take advantage of effervescence to bring about the pH changes necessary to optimize drug absorption.

Effervescence reactions involve the production of carbon dioxide from the combination of an acid and bicarbonate in an aqueous solution. Initially, when hydrogen ions from an acid in solution combine with bicarbonate, carbonic acid is formed. Carbonic acid rapidly dissociates into carbon dioxide and water. In open systems, carbon dioxide dissipates into the atmosphere and the equilibrium reactions favor the breakdown of the acid. The equilibrium reactions can be summarized as:

A FEET i200¡jg( ■ Nonîfforwssonnabiot (20t)(ig) • OTFC (20C(,g)

A FEET i200¡jg( ■ Nonîfforwssonnabiot (20t)(ig) • OTFC (20C(,g)

Figure IV-42. Serum fentanyl concentrations after administration of fentanyl effervescent buccal tablets (FEBT) 200 |g, fentanyl 200 |g tablets without effervescent agents, and oral transmucosal fentanyl citrate (OTFC) 200 |g. Adapted from [112]

Fentanyl effervescent buccal tablets (FEBT Fentora®) contain citric acid, sodium bicarbonate, sodium carbonate, and fentanyl citrate. As the tablets dissolve, citric acid lowers the pH. As the hydrogen ions combine with bicarbonate (and carbonate), carbon dioxide is formed. Dissipation of the carbon dioxide increases the pH. This process leaves sodium citrate and excess sodium bicarbonate in the solution.

Preliminary data suggest that use of fentanyl effervescent buccal tablets (FEBT) results in a faster onset and in plasma levels exceeding the non-effervescent tablet and those of oral transmucosal fentanyl citrate (Fig. IV-42). Due to the promising results the company is planning to market the product on a large scale.

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