Biowaiver Monographs for Omeprazole Immediate Release Solid Oral Dosage Forms

Background: Generic versions of innovator drugs are granted marketing authorizations after demonstrating similarities in terms of safety and efficacy with their innovator counterparts. Since 1960s, bioequivalence (BE) studies have emerged as pivotal tools in proving similarity and interchangeability between innovator drugs and their generic versions. The advent of the biopharmaceutical classification system (BCS) has revolutionized the processes of drug development and approval. BCS-based biowaivers allow using in vitro dissolution testing as a surrogate to in vivo BE testing. Biowaivers simplify, accelerate and reduce the costs of drug licensing and bringing new drug products to the market place. Objectives: The objectives of this thesis were to systematically evaluate the possibility of granting biowaiver for immediate release (IR) formulations containing omeprazole (OMZ) as an active pharmaceutical ingredient (API). The release characteristics of delayed release formulations containing OMZ were also be assessed and compared because IR formulations containing OMZ were not available on the Palestinian pharmaceutical markets. Methods: Solubility investigations were conducted to determine the solubility characteristics of OMZ according to the BCS principles using a standard shake-flask method. Solubility experiments were conducted in four different aqueous buffered media with pH values of 1.2 (0.1 M HCl), 4.5, 6.8 and 7.5. Solubility of OMZ was determined using a UV spectrophotometer. Dissolution tests were performed in accordance with the USP procedure for delayed release (enteric-coated) formulations and in accordance with the recommendations in the FDA dissolution database. OMZ was determined in all samples by UV spectrophotometric analysis at 302 nm. Molecular descriptors like polar surface area (PSA), n-octanol/water partition coefficient (log P), distribution-coefficient at pH 7.4 (log D7.4), number of hydrogen bond acceptors, number of hydrogen bond donors and pKa of OMZ were calculated using ACD/Labs, ChemAxon, ALOGPS, and ChemBioDraw Ultra software packages. Literature data published in PubMed, Scopus, Micromedex, the Merck Index, Martindale, and DrugBank databases were searched. The BE and dissolution data of solid oral formulations containing OMZ as an API were searched using the above mentioned databases. Data pertaining to bioinequivalence of OMZ formulations were also searched. Results: The solubility in acidic media could not be determined using our method as OMZ rapidly underwent degradation and changed color. The dose number ranged from 1.818 to 0.664 in the pH range of 4.5 to 7.5. These results suggest that OMZ should be assigned a “low solubility class” according to the BCS guidelines. Calculated as well as in silico predicted physicochemical properties suggested that OMZ was a lipophilic compound. OMZ was shown to have higher permeability–related physicochemical properties than the high/low permeability benchmark compound “metoprolol”. These results suggest that OMZ would have higher intestinal permeability than metoprolol and therefore would be assigned to “high permeability” BCS class. However, literature reported contradictory permeability data. Therefore, the literature was deemed inconclusive on the permeability characteristics of OMZ. Consequently, unlike solubility, we are unable to unequivocally assign OMZ to either high or low permeability BCS class. More than 85% of OMZ contents were released from the different dosage forms used in this study at pH 10.4. Therefore, similarity (ƒ2) and difference (ƒ1) factors were not calculated or compared. Conclusions: OMZ is a low-solubility, high or low permeability drug, and is therefore classified as a BCS class II or IV compound. Oral dosage forms containing OMZ as an API did not perform well in BE testing and generics were deemed bioinequivalents in many occasions. Although OMZ is not highly toxic and consequences of OMZ overdose are not extremely severe, still, we believe OMZ is not a suitable candidate for biowaiver applications. Therefore, providing evidence for equivalency and interchangeability might be established through BE studies instead of in vitro dissolution testing. Granting a biowaiver for solid oral dosage forms containing OMZ would not be scientifically justified due to the following reasons. First, OMZ is not stable in acidic media and therefore need either to be formulated in some sort of enteric coating or should be accompanied with sodium bicarbonate to ensure stability in the stomach. Therefore, OMZ is not commonly formulated in IR oral dosage forms except in combination with sodium bicarbonate. OMZ does not belong to BCS class I or II drugs; neither an acidic BCS class II drug with considerable absorption from the stomach. Furthermore, it is unstable in the stomach. Consequently, many oral formulations containing OMZ as an API failed BE testing. Even incorporation of antacids like sodium bicarbonate did not improve the stability of some IR formulations in acidic media. Finally, some acidic excipients may degrade or accelerate the degradation of OMZ. Key words: absorption; bioavailability; bioequivalence; biopharmaceutical classification system (BCS); biowaiver; omeprazole; pharmacokinetics; permeability; solubility.