Absolute Bioavailability of Microdosed Midazolam After Buccal Administration Is Dependent on Buccal Exposure Time

Abstract

Midazolam is an established probe drug to assess cytochrome P450 3A activity (phenotyping). Microdosed midazolam is increasingly used for this purpose; a buccal formulation might be of advantage, but buccal absorption might occur. We therefore tested in a single-center, open-label clinical trial with 12 healthy volunteers the absolute bioavailability of 10 μg of midazolam after buccal administration in relation to buccal exposure time. In relation to a drinking solution, there was an increase of midazolam exposure (area under the plasma concentration-time curve from time 0 to infinity) with increasing buccal exposure time with an apparent saturation at 100-second buccal exposure. Absolute bioavailability increased from 27.8% (95% confidence interval, 23.5-32.9) for the drinking solution (0 seconds) to 66.1% (95% confidence interval, 60.0-72.8) after 100-second buccal exposure with no further increase after 150 seconds. A Hill equation described the time dependency of midazolam bioavailability with maximal bioavailability as 64.5% and buccal exposure time resulting in half maximal bioavailability increase as 16 seconds. In conclusion, midazolam bioavailability is highly dependent on buccal exposure time, and even a few seconds of buccal exposure will increase bioavailability due to buccal absorption. This needs to be taken into account for any buccal administration of midazolam.

Using intranasal dexmedetomidine with buccal midazolam for magnetic resonance imaging sedation in children: A single-arm prospective interventional study

“…Hence, intranasal midazolam is not recommended in pediatric sedation. The bioavailability of the oral midazolam is 21%, and that of buccal midazolam ranged from 43.6% to 66.1% ( 18 ). We employed buccal administration instead of intranasal or oral midazolam to avoid irritability with good bioavailability.…”

“…We employed buccal administration instead of intranasal or oral midazolam to avoid irritability with good bioavailability. Although the bioavailability of buccal midazolam is mainly dependent on buccal exposure time ( 18 ), the success rate of 97.7% was higher than that of the combination with intranasal or oral midazolam, which the efficacy was comparable to that of intravenous propofol ( 23 , 24 ).…”

“…Given that buccal midazolam formulation is currently unavailable in our country, we prepared palatable buccal midazolam by intravenous midazolam hydrochloride formulation combined with an equivalent volume of medical-grade sucrose syrup (Guangdong Bang Min Pharmaceutical Co., Ltd., Lian Yun Gang, Guangzhou, China). The bioavailability of midazolam after buccal administration is mainly dependent on buccal exposure time ( 18 ). To increase the duration of buccal exposure, the use of sticky sucrose syrup improved the bitter taste and enhanced the adhesion of the water-soluble midazolam hydrochloride injection to the buccal mucosa.…”

Bioavailability and Safety of a New Highly Concentrated Midazolam Nasal Spray Compared to Buccal and Intravenous Midazolam Treatment in Chinese Healthy Volunteers

“…Early treatments would shorten the duration and help avoid adverse effects from prolonged seizure activity [ 16 ]. Given the limitations of intravenous delivery in this specific scenario, which make it difficult for nonclinical caregivers to administer quickly and safely, alternative routes of antiepileptic drugs administration have been explored, e.g., oral [ 19 ], intranasal [ 17 , 20 ], intramuscular [ 21 ], and buccal delivery [ 4 , 22 ]. Children and adolescents with prolonged acute convulsive seizures occurring in community settings can be managed with BC-MDZ, owing to its demonstrated quicker and easier access than the intravenous route [ 23 ].…”

Oral bioavailability of microdoses and therapeutic doses of midazolam as a 2-dimensionally printed orodispersible film in healthy volunteers

“…In this manufacturing process, active pharmaceutical ingredients (API) dissolved in a carrier solution (ink) are printed on polymeric ODF [12,16]. This dosage form has several advantages: (i) different APIs can be applied onto the same ODF; (ii) it is possible to print the API on the ODF in divided, well-separated doses so that the dose can be swallowed whole or changed over a wide dose range by cutting the ODF (dosing exibility); (iii) mucosal administration can accelerate absorption and increase the bioavailability of certain drugs (including midazolam [17]), and (iv) ODF are easier to swallow and their handling is well accepted [18].…”