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However, recent advances show that non-classical zwitterions, designed to create internal charge offset and intramolecular hydrogen bonds, can maintain high permeability and low lipophilicity suggesting innovative opportunities to improve peptide transport across the buccal barrier which non-classical zwitterions such as piroxicam an optimized molecular design featuring weak, matched pK a values acting through intramolecular stabilization allows compounds to maintain low lipophilicity in water without sacrificing passive membrane permeability [89]

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More recently, a breakthrough 2026 study utilizing both in-vitro cellular models and an in-vivo human pharmacokinetic trial further solidified these findings