INTRAORAL DELIVERY - Utilization of Intraoral Administration for Enablement & Enhancement of Drug Delivery – Highlights of Recent Commercial Products

INTRODUCTION

Intraoral administration of therapeutics through the mucosal linings of the oral cavity is one of the alternative delivery approaches. Alternative routes of drug delivery have enabled drugs that cannot be delivered via the oral route due to poor oral bioavailability.1 Traditionally, such drugs have been administrated through the parenteral route, which is often not a preferred approach for patient compliance. This challenge has presented an opportunity for utilizing the intraoral route as a viable option in the pharmaceutical industry. Many classes of drugs could benefit from intraoral administration by avoidance of first-pass metabolism and other unfavorable factors (eg, degradation, food/pH effect) in the GI tract. In addition, as the oral mucosa is highly vascularized, transmucosal absorption could access to systemic circulation directly and provide the potential for fast onset of action. This advantage could be a desirable development requirement for certain medical needs, such as pain management, cardiovascular treatment, insomnia, and migraine treatment. Patient adherence and preference for intraoral administration are also favored compared to other alternative routes (eg, nasal, pulmonary, transdermal) as intraoral administration shares similar dosage forms with traditional oral delivery but with a more convenient and discreet manner. There are several good recent review papers covering intraoral formulation development and therapeutic applications.2-4 The purpose of this article is to highlight several commercialized intraoral formulations from a clinical pharmacokinetic perspective and reveal its mechanism for enablement or enhancement of drug delivery via intraoral administration.

HIGHLIGHTS OF RECENT COMMERCIAL EXAMPLES

Clinical pharmacokinetics associated with intraoral delivery is intriguing, considering it combines the unique characteristics of initial intraoral absorption and subsequent intestinal absorption. Although pharmacokinetic profiles vary among different drugs via intraoral administration, three categories could be classified when compared to conventional oral delivery based on current commercial products. For the first category, intraoral formulations enable the delivery of drugs that cannot be achieved by the conventional oral route (eg, due to extensive first-passmetabolism). For the second category, enhancement of pharmacokinetic (PK) and pharmacodynamic (PD) performance is achieved by intraoral administration in comparison to the existing oral delivery formulation (eg, faster onset of action). In the last category, intraoral dosage forms are aimed to differentiate with existing oral products by further improving patient convenience and/or compliance, eg, orally disintegrating tablet (ODT) or film (ODF), for patients with difficulty in swallowing conventional tablets. Three recent approved commercial products delivered via intraoral administration are presented herein to reflect the aforementioned general categories. These examples represent three scenarios for various levels of modulation of clinical pharmacokinetics by applying the intraoral route in comparison to the conventional oral delivery. The relevant pharmacokinetic parameters are summarized in Table 1 for each case.

Enablement of Drug Delivery – Asenapine Sublingual Tablets (Saphris®)

Asenapine is indicated for the treatment of acute schizophrenia and bipolar disorder. According to Biopharmaceutics Classification System (BCS), asenapine maleate is classified as a BCS Class 2 compound (low solubility, high permeability). In early Phase I studies in healthy volunteers, asenapine was administered orally, but this route of administration was abandoned soon due to only 2% of oral bioavailability caused by extensive and rapid first-pass metabolism. Based on the human study using [14C] asenapine sublingually, >70% of circulating radioactivity was associated with conjugated metabolites, and the major metabolic routes were direct glucuronidation and Ndemethylation. 5 In addition, this study suggested that at least 50% of the dose administered sublingually was absorbed as 50% radioactivity was recovered from urine, which supported the explanation that first-pass metabolism caused the poor oral bioavailability. The sublingual tablet was subsequently developed, and the absolute bioavailability was increased to 35% at a dose of 5 mg.6 The increased bioavailability after sublingual administration of asenapine is primarily attributed to sublingual absorption as the contribution from intestinal absorption is minimal. The commercialization of Saphris clearly demonstrated the enablement of intraoral delivery for drugs that have failed in development as conventional oral dosage forms.

In addition to the relative bioavailability between the two delivery systems, several biopharmaceutical studies were performed to assess the safety and efficacy of the sublingual tablet under various dosing scenarios, including the effects of drinking water, administration sites, and food intake. Compared to a relatively longer and constant transit time in the GI tract for oral delivery, the residence time in the oral cavity is short, variable, and controlled by saliva swallowing and water intake. In general, water intake after sublingual administration is expected to reduce the residence time of the intraoral dosage form in the oral cavity. Interestingly, the clinical results showed that the exposure and Tmax of asenapine were highly independent of the residence time of the drug in the oral cavity beyond 2 minutes.6 Specifically, drinking water after 2 minutes post-sublingual administration has a minor impact on the pharmacokinetic profiles of asenapine. And, water intake at 5 minutes post-sublingual administration showed only 10% reduction of AUC, and there was no change in exposure after longer time. Furthermore, drinking water at only 2 minutes post-sublingual administration had no visible effect on Tmax.6 The possible reason for these rather unexpected observations is that fast partition was achieved between drug in solution and mucosal membrane, so no further absorption occurred even the residence time was longer. Because of these results, patients are only instructed to not eat or drink for 10 minutes after administration of asenapine sublingual tablets.

Although patients are instructed to place the tablet under the tongue when taking sublingual tablets, deviation from this instruction could occur in practice. Some patients may allow the tablet to dissolve on the top of the tongue or place the tablet buccally. Such deviations from the instruction could theoretically alter the pharmacokinetics considering different permeability and thickness across various mucosal tissues in oral cavity. Hence, it is important to understand the effect of different absorption sites (sublingual, supralingual, or buccal) on clinical pharmacokinetics of an intraoral dosage form. The in vivo results showed that asenapine exposure was the highest with buccal administration, followed by sublingual, and the lowest from the supralingual route.7 However, the differences in the pharmacokinetics between buccal and sublingual administration were minor (<20%) and were considered to be of limited clinical relevance. Similarly, supralingual administration was bioequivalent to sublingual administration based on AUC. Tolerability and safety studies were also performed and not affected by variability of placing tablet on different mucosal tissues. These results demonstrated that although sublingual administration is the recommended dosing route, administration at different intraoral sites has no clinically relevant impact on asenapine pharmacokinetics.7

The effect of food on pharmacokinetics was also assessed for the sublingual tablets of asenapine. Because asenapine is primarily absorbed in the oral cavity, food intake is not expected to affect its absorption phase when dosed sublingually. However, asenapine is a high-clearance compound, and its pharmacokinetics may be affected by elevated liver blood flow due to the intake of a high-fat meal. The clinical results showed that mean asenapine exposure was approximately 20% lower after intake of a high-fat meal prior to dosing. As the food effect on asenapine exposure was small, it was not considered as clinically relevant. Therefore, no additional food restrictions are required during asenapine dosing except for avoidance of eating and drinking for 10 minutes post-administration to ensure optimal absorption in the oral cavity.8

Enhancement of Drug Delivery – Zolpidem Sublingual Tablets (Intermezzo®)

Zolpidem is a nonbenzodiazepine hypnotic agent for the short-term treatment of insomnia. Zolpidem has rapid and good oral absorption, and the absolute oral bioavailability is 70% in human with moderate first-pass metabolism. Oral tablets of zolpidem tartrate are available on the market under the trade name of Ambien®. Considering fewer disturbances were preferred for insomnia patients when taking medicines, several intraoral dosage forms (no need to dose with water) were developed and approved in recent years. Oral spray of zolpidem tartrate, Zolpimist®, was approved by the FDA in 2008. Later, Edluar® (zolpidem tartrate sublingual tablet, 5 mg and 10 mg), received FDA approval in 2009. In 2011, lower doses of zolpidem tartrate sublingual tablets (1.75 mg and 3.5 mg), Intermezzo®, received FDA approval as well. Both Zolpimist and Edluar were developed for the treatment of insomnia with sleep initiation difficulties while Intermezzo was developed for the treatment of insomnia when middle-of-the-night awakening is followed by difficulty returning to sleep.

In addition to the advantage in patient convenience and/or minimal disturbance to sleep, intraoral dosage forms of zolpidem also provide desirable pharmacokinetic and pharmacodynamic benefits in comparison to the conventional oral tablet. The latest FDA-approved zolpidem tartrate sublingual tablets (Intermezzo) are a good example. A relative bioavailability study was conducted to compare bioperformance between the sublingual tablets and the conventional immediate-release oral tablets. Although both Cmax and AUC0-inf values were similar between the two dosage forms, a faster rise of PK profile was observed after sublingual administration compared to the normal oral dosing (Figure 1). The partial area under the curve up to 20 minutes (AUC0-20min) was three-fold greater for sublingual administration compared to oral administration (Table 1). The greater AUC0-20min value indicated the contribution from rapid transmucosal absorption in the oral cavity for the sublingual tablet compared to Ambien.9 It is worth to note that although sublingual administration provides intraoral absorption, bioequivalence is achieved between oral and sublingual administration of zolpidem. This outcome is largely due to good intestinal absorption of zolpidem and high bioavailability achieved from the oral route.

Most importantly, several PD studies demonstrated that sublingually administrated zolpidem has a significant earlier sleep initiation as compared to oral zolpidem in both healthy and insomnia patients.10,11 The sublingual formulation significantly shortened latency to persistent sleep (LPS), sleep onset latency (SOL), and latency to stage 1 (ST1L) in comparison to oral zolpidem. It indicated that transmucosal absorption of zolpidem in the oral cavity could translate into faster onset of action compared to the conventional oral tablet. Regarding next-day residual effect, sublingual administration showed similar or less side effect in the Digit-Symbol Substitution Test (DSST) compared to the oral tablet. Both favorable efficacy and safety profiles showed benefits of Intermezzo to differentiate from the previously approved oral product.9 Similarly, Zolpimist (oral spray of zolpidem), also showed faster intraoral absorption and early onset of action compared to Ambien.12

Because sublingual administration of zolpidem resulted in significant transmucosal absorption, the effect of residence time was evaluated in clinical study using different swallowing times. Patients were separated into three groups, which swallowed every 2 minutes, every 5 minutes, or swallowed once at 10 minutes post-administration. As expected, the extent of absorption from swallowing every 2 minutes appears to be less than that from swallowing every 5 minutes. Interestingly, the PK results of swallowing every 5 minutes were comparable to that of swallowing once after 10 minutes.9

Regarding food effect, food significantly lowers bioavailability of Intermezzo compared to that under fasting conditions. Cmax is decreased by approximately 38%, and AUC0-t is decreased by 19% following administration with food, while Tmax is increased from 1 hour in the fasted state to around 3 hours in the fed state.9 The observed food effect for Intermezzo is similar to oral products (Ambien). Based on this result, Intermezzo is instructed not to be administered with or immediately after a meal.9

The example of Intermezzo illustrates that intraoral delivery can enhance both pharmacokinetic and pharmacodynamics profiles of a drug, while bioequivalence is demonstrated between the conventional oral tablet and the sublingual tablet. As a matter of fact, this approach has been served as an effective way for product life cycle management.

Improvement of Patient Convenience – Vardenafil Orally Disintegrating Tablets (Staxyn®)

Vardenafil hydrochloride is a phosphodiesterase type-5 (PDE5) inhibitor for the treatment of erectile dysfunction (ED). Its oral dosage formulation, film-coated immediate-release tablets (Levitra) was approved by the FDA in 2003. Vardenafil showed rapid oral absorption with >90% drug almost entirely recovered in feces using [14C] vardenafil. Due to extensive first-pass metabolism, most radioactivity was from its metabolites, and the absolute oral bioavailability of Levitra is 15%.13 A 10-mg orally disintegrating tablet of vardenafil (Staxyn®) was developed and subsequently approved by the FDA in 2010. In general, ODTs are intended for placement on the tongue where they disintegrate and dissolve in saliva, and then swallowed. The GI tract is usually considered as the major absorption site for most ODT formulations; however, there are a few exceptions where transmucosal absorption plays a dominant role for drugs that have extensive first-pass metabolism, for instance Zelapar® ODT.14 The objective of vardenafil ODT development was to develop a formulation that allows patients to take it in a discreet manner (without water), thus potentially improving convenience to the patients.

As usual, the initial development strategy was to demonstrate bioequivalence of the ODT with the already approved film-coated tablets as this approach potentially allows the fastest regulatory approval under the 505(b)(2) application. However, compared to Levitra, the Cmax and AUC of vardenafil after administration of the ODT formulation (without water intake) increased by 15% and 44%, respectively, in healthy male volunteers (Figure 2). For ED patients, the Cmax was somewhat lower (8%), but AUC was still greater by 29% relative to Levitra.13 Possibly due to a slower intraoral absorption compared to GI absorption, the Tmax of vardenafil ODT right shifted from 0.75 hours to 1.5 hours (Table 1). The increased bioavailability of the ODT was attributed to transmucosal absorption in the oral cavity that bypasses the first-passmetabolism. In order to gain mechanistic understanding of the absorption process, a clinical study was conducted to measure the absolute amount of vardenafil absorbed in the oral cavity. Healthy subjects were asked to hold a 10-mg vardenafil solution in their mouths for 15 minutes without swallowing. Subsequently, they expelled the solution and rinsed their mouths with 20 mL of water five times. The mouth rinses were collected and analyzed to estimate intraoral absorption.15 The relative bioavailability (ratio of AUC values) after sublingual administration was 24.6% compared to the oral administration (control group) of vardenafil solution. After subtracting the amount of drug recovered in saliva and rinsing water, 8% of the 10-mg dose of vardenafil was absorbed in the oral cavity.15 Considering only 15% of vardenafil was orally bioavailable at the same dose, the amount of intraoral absorption (0.8 mg) led to an increase of bioavailability via bypassing of first-pass metabolism to some extent.15 Because Staxyn is not bioequivalent to Levitra, the two dosage forms are not interchangeable.

As the ODT formulation showed suprabioavailability, clinical studies to demonstrate its efficacy and safety were performed in two Phase III studies. Staxyn was significantly superior to placebo in all efficacy parameters assessed, and a retrospective analysis showed it has a rapid onset of action comparable with that of Levitra.16 Furthermore, the safety data were in line with that already known for Levitra, indicating a similar safety profile.

The effect of dosing with and without water was also evaluated as part of vardenafil ODT development. The results indicated that dosing without water could result in a significantly higher exposure than that of dosing with water. The systemic exposure (AUC) of vardenafil ODT formulation was decreased by 29% when the ODT was swallowed with water. This is primarily due to less intraoral absorption occurring after dosing with water, thus the labeling indicates that the dose should be administered without water. For the ODT formulation, food intake (high fat, high calorie) reduced the Cmax of vardenafil by ~ 35%, while the AUC of vardenafil was not significantly affected. Therefore, it is concluded that the ODT formulation can be administrated regardless of food intake.15

Vardenafil ODT is a unique formulation that differentiates from the existing film-coated tablet by providing a favorable PK profile (suprabioavailability), similar PD effect, and preferred patient convenience. In addition to benefit patients that have difficulty in swallowing tablets, the small ODT size and the award-winning burgopak slider pack made it discreet to carry and take vardenafil compared to the conventional oral tablet.

CONCLUSIONS

In summary, a selective review of recently approved intraoral-associated products highlighted the importance and opportunities of utilizing the intraoral route to enable or enhance drug delivery through modulation of pharmacokinetic profiles, which results in an improved efficacy or patient convenience. Increased bioavailability, faster onset of action, and improved patient convenience represented three major scenarios that intraoral delivery is superior to conventional oral delivery from a clinical pharmacokinetic perspective. Furthermore, compared to oral delivery, intraoral administration showed some unique biopharmaceutical features, such as effects of water intake and saliva swallowing, administration site within oral cavity, and food intake. The examples described in this review have showcased that intraoral delivery can be effectively used for the development of a new chemical entity (NCE), as well as be creatively applied to product life cycle management to differentiate from the existing products.

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REFERENCES

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6. Bartlett JA, van der Voort Maarschalk K. Understanding the oral mucosal absorption and resulting clinical pharmacokinetics of asenapine. AAPS PharmSciTech. 2010;13(4):1110-1115.
7. Gerrits M, de Greef R, Peeters P. Effect of absorption site on the pharmacokinetics of sublingual asenapine in healthy male subjects. Biopharmaceut & Drug Dispos. 2010;31(5-6):351-357.
8. Dogterom P. The effect of food on the high clearance drug asenapine after sublingual administration to healthy male volunteers. Eur J Clin Pharmacol.
9. FDA 2011. Intermezzo NDA file http://www.accessdata.fda.gov/drugsatfda_ docs/nda/2011/022328Orig1s000ClinPhar mR.pdf.
10. Staner L, Eriksson M, Cornette F, Santoro F, Muscat N, Luthinger R, Roth T. Sublingual zolpidem is more effective than oral zolpidem in initiating early onset of sleep in the post-nap model of transient insomnia: a polysomnographic study. Sleep Med. 2009;10(6):616-620.
11. Staner C, Joly F, Jacquot N, Vlasova ID, Nehlin M, Lundqvist T, Edenius C, Staner L. Sublingual zolpidem in early onset of sleep compared to oral zolpidem: polysomnographic study in patients with primary insomnia. Curr Med Res Opin. 2010;26(6):1423-1431.
12. FDA 2008. Zolpimist NDA file http://www.accessdata.fda.gov/drugsatfda _docs/nda/2008/022196s000_ClinPharm R_P2.pdf.
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14. FDA 2006. Zelapar NDA file http://www.accessdata.fda.gov/drugsatfda _docs/nda/2006/021479s000_ClinPharmR_P3.pdf.
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16. Debruyne FM, Gittelman M, Sperling H, Borner M, Beneke M. Time to onset of action of vardenafil: a retrospective analysis of the pivotal trials for the orodispersible and film-coated tablet formulations. J Sex Med. 2011;8(10):2912-2923.

Dr. Zhen Yang is a Senior Scientist at Merck. As a member of the Biopharmaceutics group, he supports biopharmaceutical evaluation of oral formulations at various clinical development stages. His areas of interest focus on oral, intraoral, and intranasal delivery development and pharmacokinetics. Prior to Joining Merck, Dr. Yang worked at USA Medical Toxicology as a Laboratory Supervisor. He earned his BS in Pharmaceutics from China Pharmaceutical University, his MS from Shanghai Institute of Pharmaceutical Industry, and his PhD in Pharmaceutical Science from University of Houston.

 

Dr. Yunhui (Henry) Wu is currently a Director of Biopharmaceutics in Pharmaceutical Sciences & Clinical Supply in Merck Research Laboratories (MRL). Dr. Wu’s research activities have spanned from drug discovery, preclinical and clinical formulation development, and life-cycle management. Dr. Wu joined MRL at West Point, PA, in 1996. He leads a group of scientists who evaluate biopharmaceutical performance of clinical IR/CR formulations of global development candidates using various in vivo, in vitro, and in silico models. His group also conducts rapid feasibility assessment of alternative drug delivey, including intraoral, intranasal, topical, transdermal, ocular, and injectable routes. Dr. Wu earned his BS in Chemistry from University of Science & Technology of China, his MS in Medicinal Chemistry from Shanghai Institute of Pharmaceutical Industry, and his PhD in Organic Analytical Chemistry from New York University.