Title : The importance of invitro discriminatory tests in the development of a sublingual dosage form of TNX102 SL(Cyclobenzaprine HCl) tablets
Abstract:
The formulation of cyclobenzaprine HCl contained in TNX-102 SL has been designed specifically for sublingual administration. Earlier clinical studies indicated that the addition of a basifying agent was necessary for optimal transmucosal absorption. The TNX-102 SL formulation with added dibasic potassium phosphate resulted in higher levels of exposure during the first 2 hours after dosing and less exposure 8 to 24 hours after dosing. Sublingual TNX-102 also reduces exposure to an active, long half-life, main metabolite of cyclobenzaprine (ie, norcyclobenzaprine) as a result of bypassing first-pass hepatic metabolism. The PK profile of TNX-102 SL is optimal for bedtime dosing to improve sleep quality while minimizing daytime somnolence. (see companion abstracts, Daugherty/Nebuloni et al), The formulation development of a sublingual dosage form of Cyclobenzaprine HCl highlighted the necessity for local absorption and the importance of a local pH effect. The local pH effect was enabled by the development of a eutectic of Cyclobenzaprine HCl and Mannitol. This presentation will describe the formulation development pathway with specific emphasis on the invitro techniques used to assess and control the absorption. It will demonstrate the discriminatory behaviours of typical monograph tests such as;-dissolution and disintegration, and the development and implementation of a specific/unique test;- wetting with a direct correlation to residence of the dosage form at the site of administration. These invitro tests with emphasis on sublingual absorption will challenge the discriminatory behaviour and assess impact of particle size, excipient variation and compression force.
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Invitro test selection specific to the route of absorption and the associated critical characteristics required
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Reduce the reliance on the usual monograph invitro test methods and the need for more
specific invitro testing to accelerate formulation and process development -
This could be applied directly to other local absorption developments such as transdermal,
sublingual, buccal, films etc -
It provides a practical, easy to use invitro discriminatory test method and makes
formulation and process development simpler -
It will aid in scale-up and the development of continuous manufacturing techniques
