Clinical Pharmacokinetics of Buffered Propranolol Sublingual Tablet (Promptol™)—Application of a New “Physiologically Based” Model to Assess Absorption and Disposition

Abstract

Abstract. Sublingual administration of certain buffered propranolol may improve the rate and extent of absorption compared to oral administration. The main objectives of this study were to (1) compare the plasma propranolol concentrations (Cp-prop) following sublingual administration of a specially buffered formulation (Promptol™) to that following oral administration of Inderal ® and (2) evaluate the utility of a special pharmacokinetic model in describing the Cp-prop following sublingual administration. Eighteen healthy volunteers received 10 mg sublingual Promptol™ or oral Inderal ® . Multiple Cp-prop were determined and their pharmacokinetics compared. Additional data following sublingual 40 mg Promptol™ or Inderal ® were utilized for evaluation of a special advanced compartmental absorption and transit (ACAT) model. For model simulation, the physicochemical parameters were imported from AMET predictor, whereas the pharmacokinetic parameters were calculated and optimized by Gastroplus ® . Based on this model, the quantity of drug absorbed via buccal/sublingual mucosa was estimated. Cp-prop was higher at earlier times with 3-fold greater relative bioavailability following sublingual Promptol™ compared to that from oral Inderal ® . The special ACAT model provided excellent goodness of fit of Cp-prop-time curve and estimated a 56.6% increase in absorption rate from Promptol™ and higher initial Cp-prop compared to the regular formulation. The modified ACAT model provided a useful approach to describe sublingual absorption of propranolol and clearly demonstrated an improvement of absorption of Promptol™. The sublingual 10 mg Promptol™ achieved not only a similar systemic exposure as 30 mg oral Inderal ® but an earlier effective Cp-prop which may be advantageous for certain clinical conditions.

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“…This drug can also be absorbed mucosally, as demonstrated by sublingual delivery [12], and its bioavailability is higher when absorbed by this route rather than orally [13,14]. Propranolol has been delivered sublingually at 10 and 40 mg per dose [12,13], although this can produce mouth paresthesia, an undesirable effect. Also, propranolol has been delivered by rectal administration in mammals [15].…”

<p>Bucco-Adhesive Film as a Pediatric Proper Dosage Form for Systemic Delivery of Propranolol Hydrochloride: In-vitro and in-vivo Evaluation</p>

“…It worth knowing that it has been reported that propranolol causes inconsiderable irritation that can be accepted. Wang et al, 63 have reported that sublingual Promptol TM tablets might trigger slight local irritation. 63 Comparable insignificant irritation has been also detected in other studies for sublingual propranolol.…”

“…Wang et al, 63 have reported that sublingual Promptol TM tablets might trigger slight local irritation. 63 Comparable insignificant irritation has been also detected in other studies for sublingual propranolol. 64,65 Thus, according to these studies, short-term use of buccal propranolol is thought to be reasonably safe for children.…”

Development of a Novel Oral Cavity Compartmental Absorption and Transit Model for Sublingual Administration: Illustration with Zolpidem

“…The accuracy of simulation on the key PK parameters (C max , T max , and AUC) was evaluated by deviation (%) between simulated and observed values. For comparison, a simple one-compartment oral cavity model linked to the GastroPlus ACAT model was used to attempt to simulate the Cp-time profile using the default oral-cavity absorption scaling factor (ASF) value as described previously [8]. The new IO and simple oral cavity model predicted F a_IO values for the IO dosage forms, depicted on a regional absorption plot.…”

“…modeling was used to analyze absorption kinetics from the oral cavity to the systemic circulation [6,7]. More recently, the GastroPlus™ (Simulation Plus, Lancaster, CA) Advanced Compartmental Absorption and Transit (ACAT™) model and acslX (Aegis Technologies, Huntsville, AL) models were used to simulate the clinical pharmacokinetics of propranolol and fentanyl sublingual tablets, respectively [8,9]. However, all previously reported IO PK models used a simple firstorder absorption rate process without sufficiently linking oral cavity physiology and drug physicochemical properties.…”