More Rapid Sleep Onset with Lingual-Spray vs Oral-Tablet Delivery Zolpidem

Insomnia and related sleep disorders (somnipathies) affect a large segment of the population, and result in a significant negative impact on quality of life and reduced or lost productivity. The speed of sleep onset is a critical characteristic of successful pharmacotherapeutic intervention for insomnia. Zolpidem, a non-benzodiazepine benzodiazepine receptor agonist (nBzRA) is widely used to treat insomnia. Although not itself a benzodiazepine (BZD), zolpidem has high binding affinity for the benzodiazepine receptor, which acts as a posi-tive allosteric modulator of the GABAA receptor complex. It therefore increases the neuronal transmembrane influx of Cl − ions, thereby decreasing neuronal excitability and promoting sleep. In this four-way crossover, dose-ranging, multiple-treatment study, a lingual spray formulation of zolpidem was safe and well-tolerated and yielded more rapid pharmacokinetics (mean plasma concentration) and efficacy (visual analog scale and digit symbol substitution test) compared to oral tablets.


Treatment Recommendations
There are two widely accepted treatments for insomnia: cognitive behavioral therapy for insomnia (CBT-I) and pharmacotherapy [1] [12]. CBT-I is a structured behavioral approach typically including education and training in relaxation techniques, good sleep hygiene, stimulus control, sleep restriction, and cognitive techniques, which designed to identify and mitigate negative cognitive and behavioral influences on sleep [13].
The pharmacotherapeutic approach usually works much more rapidly than CBT-I does (minutes vs weeks), and is just as effective short-term, but it might have less carry-over effect than CBT-I [1] [13]. And of course CBT-I carries no risk of adverse effects. However, CBT-I availability is limited, time-consuming, and expensive. Less than 5% of chronic insomniacs utilize CBT-I, [14] and pharmacotherapy remains the primary treatment [1].

Pharmacologic Options
Insomnia often involves some combination of a state of hypervigilance during the day and difficulty initiating and maintaining sleep at night [15] [16] [17].
Pharmacologic treatment options include [25] short or intermediate acting BZDs, non-BZD BzRAs (such as zolpidem), melatonin agonist (e.g., ramelton), sedating antidepressant (e.g., trazodone, amitriptyline, doxepinemitazapine), sedating antiepilepsy or antipsychotic medications, or combinations of these. The therapies that traditionally have had the best therapeutic index (efficacy and safety) have been those that interact with the GABA-ergic system.

GABA and GABAA Receptor Complex
The inhibitory amino acid GABA (γ-aminobutyric acid) acts through the GABA A receptor to play an important role in sleep/wake cycles [26]  which is a ligand-gated ionotropic type receptor, increases Cl − ion influx down its concentration difference from the extracellular side to the intracellular side of neurons. Since the neuronal transmembrane resting potential difference is already negative, the influx of Cl − hyperpolarizes the neuron, i.e., increases the transmembrane potential difference, producing a post-synaptic inhibitory potential (IPSP). The resultant hyperpolarization means that the neuron is less likely to fire in response to an excitatory input, which favors sleep.

Benzodiazepines
Because of their efficacy and safety in short-term use, BZDs have been popular choices for short term treatment of insomnia. BZDs produce their effect by binding to specific sites (BzRs) on the GABA A receptor complex, producing allosteric modulation, inhibition of neuronal excitation, and an increase in speed of sleep onset and increase in total sleep time [29] [30] [31]. The BZDs represent an advance over preceding sedatives, including barbiturates, in that they are more selective and produce fewer adverse effects. However, they also have the potential for tolerance and dependence, and produce their own set of adverse effects such as disruption of psychomotor function, impairment of memory, paradoxical excitement, depression, and potential teratogenicity. [32] And they are a special problem for elderly patients, because of the potential for cognitive impairment, delirium, falls, and bone fractures [33]. In response to the problems associated with the BZDs, non-BZD BzRAs were developed to minimize adverse effects and abuse potential associated with the BZDs.

Zolpidem
Chemically, zolpidem is an imidazopyridine, not a benzodiazepine, but pharmacologically it acts the same way, that is, as a benzodiazepine receptor agonist. It displays selective binding affinity and functional efficacy at GABA A receptors that contain α1 subunits [19]. Since subunits in addition to α-1 have been associated with sedative action and sleep continuity, the molecular mechanism underlying the clinical efficacy of zolpidem's hypnotic action is likely to involve subunits other than α-1.
Zolpidem's pharmacokinetics and efficacy favor its short-term use for insomnia: it is rapidly distributed to the central nervous system [34], it does not have active metabolites, it is rapidly eliminated, and it does not accumulate after repeated administration [35]. And in most patients it reduces sleep latency [36] [37], without altering sleep stages [38], it does not cause residual morning-after effects [38] [39] [40] [41] [42], and it does not cause rebound insomnia after short-term administration [36] [43] [44].
As a result of its favorable pharmacologic properties, zolpidem is the active ingredient in several products commercially marketed to treat insomnia. The lingual spray offers a means of administration that has the advantages of easy access (favors better compliance), and distribution onto a large and highly-vascularized surface area ( Figure 1).

Oral Route
Speed of sleep onset is important for treatment of insomnia. Sleep latency (the time it takes to fall asleep) relates to sleep efficiency (the proportion of bedtime asleep), because if a person is able to fall asleep quickly, they are more likely to have an efficient sleep, and cycle normally through rapid eye movement sleep (REM) and non-rapid eye movement sleep. The oral route is relatively slow compared to other routes and subjects a drug to a first-pass metabolism effect.
Thus, bioavailability is generally low and slow compared to other routes. Additionally, this can be a problematic delivery modality for patients with dysphagia, or elderly patients that have difficulty swallowing tablets.

Dose Variance of Generics
Consistency of dose is another important characteristic that is favorable for treatment of insomnia. Although bioequivalence is defined and required by regulatory control, caution is warranted, even if in a minority of situations [45] [46].

Methods
The present study was designed in a manner to determine the pharmacokinetics, therapeutic efficacy, and safety/tolerability of two doses of zolpidem lingual spray (LS) compared to orally-administered drug in fasted (≥10-h) young healthy volunteers (N = 20 males, 23 females).

Study Design
This was a single-center, four-way crossover, open-label, dose-ranging, multiple-treatment study. There were four treatment groups: zolpidem oral tablets (AMBIEN, 5 or 10 mg) and zolpidem LS (5 or 10 mg). Zolpidem LS was admi-

Pharmacokinetic Measures
Measurements of plasma concentrations of zolpidem were made using a vali-

Efficacy Measures
Two primary measures were used.

Results
The present study was designed in a manner to determine the pharmacokinetics, efficacy, and safety/tolerability of two doses of zolpidem lingual spray (LS) compared to an orally-administered drug formulation (oral tablets) in fasted (≥10-h) young healthy volunteers (N = 20 males, 23 females).

Pharmacokinetics
An analysis of bioequivalence comparing each treatment group to each of the others when the data were normalized to a dose of 10 mg revealed: • The 5 mg AMBIEN tablet was not bioequivalent with the 10 mg AMBIEN tablet • Zolpidem LS 5 and 10 mg doses were bioequivalent to the 10 mg AMBIEN tablet • There was a gender-effect irrespective of dose normalization in which C max , AUC 0→T , and AUC 0→∞ are significantly higher in females than in males, with a significantly longer half-life and slower clearance also observed in female participants • There was no gender-treatment effect found in any of the pharmacokinetic analyses • There was no treatment-effect found in any of the pharmacokinetic analyses With regard to comparison of the two formulations (inter-formulation comparison): the plasma concentration of zolpidem rose more rapidly after 5-mg zolpidem LS compared to 5-mg AMBIEN (Figure 3), and the plasma concentration of zolpidem rose more rapidly following 10-mg zolpidem LS compared to 10-mg AMBIEN (Figure 3). In fact, the 5-mg dose of zolpidem LS formulation resulted in a faster increase in zolpidem plasma concentration than did the 10-mg dose of AMBIEN (Figure 2).

Percentage Subjects That Achieved Therapeutic Threshold
The generally-accepted therapeutic threshold for zolpidem for treatment of insomnia is a plasma concentration at and above 20 ng/mL [34] [47] [48]. Applying this criterion to the data shown in Figure 2, leads to the following determi- Comparison of the pharmacokinetic parameters that demonstrate a more rapid sleep onset with lingual-spray vs oral-tablet delivery of zolpidem are summarized in Table 1.

Efficacy
Two potential indications of therapeutic efficacy were measured in the study: a visual analog scale (VAS), and change from baseline in the Digit Symbol Substitution Test (DSST). The VAS test turned out to be an unreliable measure. It yielded only sporadic differences, and there was no apparent pattern or consistency with reference to when the differences were observed. Consequently, only the DSST is summarized below.

Onset of Sleepiness
In contrast to the VAS, which proved to be an unreliable indicator, the change from baseline in the DSST provided reliable results. The results for the mean change from baseline for all groups (zolpidem LS 5 and 10 mg and AMBIEN 5 and 10 mg) as a function of time during the first 22 minutes following administration are shown in Figure 6. This encompasses the time of onset of therapeutic effect and it allows comparison of the formulations. As expected, there is a dose-related relationship for both formulations. That is, the 10-mg dose of each formulation (zolpidem LS and AMBIEN) resulted in a more rapid increase in "sleepiness" by zolpidem than did the 5-mg dose of each formulation (intra-formulation comparison).
With regard to comparison of the two formulations (inter-dose formulation): the zolpidem-induced "sleepiness" rose more rapidly after 5-mg zolpidem LS compared to 5-mg AMBIEN (Figure 7), and zolpidem-induced sleepiness rose more rapidly following 10-mg zolpidem LS compared to 10-mg AMBIEN ( Figure  7). In fact, the 5-mg dose of zolpidem LS formulation resulted in a faster increase in zolpidem-induced sleepiness than did the 10-mg dose of AMBIEN ( Figure 6).

Comparison of Zolpidem LS vs AMBIEN
The comparison of zolpidem LS vs AMBIEN is summarized in Table 1.

Safety
The most common AEs experienced by study participants were diplopia, dizziness, euphoric mood, headache, and nausea. Only dizziness occurred in more participants after zolpidem LS (10 mg) than after AMBIEN (10 mg). In order of decreasing incidence of AEs, dizziness, diplopia, and headache were the most common among female participants, while euphoric mood, diplopia, and dizziness were the most common among male participants. No deaths or serious adverse effects (SAEs) occurred during the study.
There were no AEs indicative of local adverse reactions in the oral cavity after treatment with zolpidem LS (either 5 mg or 10 mg).

Conclusions
We report the results of a study that compared pharmacokinetic, efficacy, and safety/tolerability measures of a zolpidem lingual spray compared to zolpidem oral tablets in healthy volunteers. Greater absorption rates of zolpidem LS were also manifested in significantly earlier detectable levels up to 20 minutes following administration. The time to a zolpidem plasma concentration associated with sedation was significantly less for the zolpidem LS formulation than of the zolpidem oral tablet, which is related to a faster onset of sleepiness. Overall, zolpidem LS was safe and well-tolerated, with no signs of oral irritation on examination. There were few AEs, no SAEs either locally or systemically, and no clinically significant change in physical status. A weakness of the study is that it was only single-center and open-label.
In summary, the lingual spray formulation provided more rapid attainment of

Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this paper.