WO2012109695A1

WO2012109695A1 - Drug compositions for the treatment of insomnia

Info

Publication number: WO2012109695A1
Application number: PCT/AU2011/000217
Authority: WO
Inventors: Ramon Ernesto CASAL Y GALZOV
Original assignee: Casal Y Galzov Ramon Ernesto
Priority date: 2011-02-16
Filing date: 2011-02-25
Publication date: 2012-08-23

Abstract

This patent is for a kind of pharmaceutical formulation, used to treat insomnia, consisting of two compounds. The first compound is melatonin or a melatonin receptor agonist. The second is a hypnotic sedative, typically, but not necessarily, one that affects the brain's Gamma-aminobutyric acid A (GABAA) receptors. Examples include zopiclone (a cyclopyrrone), Zolpidem (an imidazopyridine), zaleplon (a pyrazolopyrimidine) and the older benzodiazepine drugs. The formulations are single-dose, meaning that both compounds are ingested at once, though depending on the individual composition, they may be designed to absorb into the bloodstream at differing rates. The melatonin acts by potentiating the second compound and reducing the quantity needed to initiate and maintain sleep. One aim of this is to minimise the dose used of the second compound, since many GABAA-receptor agonists are known to cause physical dependence, and discontinuation after long-term use often requires time-consuming dose reduction. Another aim is to reduce the time of sleep onset caused by the second compound.

Description

DRUG COMPOSITIONS FOR THE TREATMENT OF INSOMNIA

Applicant: Ramon Casal Y Glazov

DESCRIPTION:

Most hypnotic sedative formulations can be divided into three categories: those used to combat sleep-onset insomnia (or difficulty falling asleep), those used to prevent nocturnal awakenings, and less specialised drugs which can be adapted for either form of insomnia. Traditionally, the main difference between a sleep-onset insomnia drug and a nocturnal awakening drug has been biological half-life. A strong sedative with a short half-life (such as triazolam) is ideal for sleep-onset insomnia, while sedatives with intermediate half-lives (such as temazepam) are a standard treatment for the awakening kind. This situation is changing with the development of sustained-release and continuous-release formulations. In its natural state, Zolpidem has a half-life only slightly longer than drinking alcohol but its continuous-release form makes it viable for patients with difficulties maintaining sleep.

Cyclopyrrones, imidazopyridines and benzodiazepines are the current first-line treatments for both kinds of insomnia. All three groups carry a dependence liability and can produce tolerance with prolonged use. Melatonin is naturally produced in the pineal gland of humans and other mammals, and has not been proven to have as many adverse effects as most GABAA-receptor ligands. However, its standalone effectiveness against insomnia also seems lower. A Public Assessment Report by Australia's Therapeutic Goods Association (Submission No: PM^2008-2125-1) found only "modest efficacy for [prolonged-release melatonin] in improving sleep quality," though no adverse effects appeared during Australian trials. Despite this, the TGA report concluded there was "some evidence for continued efficacy" over longer periods of time (six to twelve months) and the drug did not appear to cause tolerance.

Very little research has been performed into interactions between melatonin and traditional, GABAA-ergic, hypnotic sedatives. The TGA Report cites a study ("Protocol No. NEU112001") suggesting melatonin had a potentiating effect on Zolpidem. It concluded that "Zolpidem alone but not melatonin alone impaired cognitive function up to 4 hours post dosing" and a zolpidem-melatonin combination produced more impairment than Zolpidem alone. However, we should note that the study was framed in a series of driving and motor coordination tests rather than measuring sleep onset. That is to say the "impaired cognitive function" could well have been due to drowsiness, which, for sedative hypnotics, is the desired effect. The 'impairment' lasted 4 hours in both the zolpidem-alone and zolpidem-melatonin groups. This is consistent with Zolpidem's half-life and it does not appear that melatonin prolonged its effects or clearance from the system. Curiously, the researchers reported that the difference between the Zolpidem group and the melatonin-zolpidem group was especially apparent at 1 hour post-dosing. Melatonin has a significantly shorter half life than Zolpidem, leaving a possibility that it "wore off' before the sedative. Regardless, this trial suggests that melatonin did not produce the cognitive changes in isolation but enhanced the effects of the Zolpidem. The researchers did not notice a difference between melatonin alone and a placebo.

This patent-applicant has observed similar effects after a combination of melatonin and zopiclone, which has similar effects to Zolpidem, but a 6-hour half life. The melatonin (2-4mg) seemed to halve the dose he needed during bouts of insomnia from approximately 3 tablets (22.5mg), to 1.5 (11.25mg). A single zopiclone tablet rarely helped his sleep-onset insomnia, but the addition of 2mg of melatonin seemed to have more efficacy than 2 tablets of zopiclone alone. On some occasions, he swallowed the melatonin and zopiclone simultaneously. On others, he took the melatonin afterwards. Drowsiness would still appear if he took the melatonin three or four hours from the zopiclone dose, which is unsurprising given the sedative's long half-life. The zopiclone's effects did not have to be noticeable for this to happen. On one occasion, he found himself sleepy at midday after taking 2mg of melatonin, possibly due to residual zopiclone from the night before. These observations are subjective but not untestabie, especially since melatonin's half-life is shorter than most of the sedatives it would likely be paired with.

The notion of therapeutically pairing melatonin with a sedative does not occur to the authors of the TGA report, especially not in a single-formulation dose. They suggest that the coincidental use of melatonin and Zolpidem should "possibly be contra-indicated," but give no reasons other than the driving test. Certainly, it may not be an ideal mixture to hand contestants at a Formula One rally, but this does not disqualify it as a hypnotic sedative. Combining a sedative with another CNS depressant (such as alcohol) may indeed pose dangers, but melatonin is not classed as a depressant and has no known mechanism that affects breathing or heart rate, or any verified cases of acute toxicity.

Note also that while there is at least one existing patent for controlled-release melatonin (which has already been marketed as a monotherapy), the compositions described here do not depend upon the release of the melatonin to be controlled artificially in any way. It is possible, for instance, to have a melatonin-zopiclone combination in tablet form where both compounds are immediate-release. It is also possible to have a capsule where granules of ordinary, immediate- release melatonin are mixed with other granules containing a controlled-release sedative. Therefore, embodiments of this invention do not depend on any existing patents.

In fact, a melatonin receptor agonist may enhance the safety profile of several sedatives. If, indeed, melatonin produces little or no tolerance, it may decrease the rate of dose titration in patients prescribed the sedative for prolonged periods. Zopiclone and benzodiazepines are known to cause painful and even dangerous discontinuation symptoms, and a drug capable of minimising their doses could prove invaluable. If melatonin is shown to decrease the time of sleep onset in a clinically significant population, it may also act as a preventative against the "sleep-walking" side-effects sometimes associated with Zolpidem use. A composite formulation that decreases sleep onset could also prove a dete^"frent against abuse, or at least make it undesirable for recreational abusers to consume large quantities of the sedative.

In some embodiments of this invention, the melatonin receptor agonist may be melatonin itself. In other embodiments, the compound may be another substance that binds to the brain's first or second melatonin receptors (MT1 or MT2).

In certain embodiments, the sedative may be Zolpidem or another imidazopyridine. In certain other embodiments, the sedative may be zopiclone or another cyclopyrrone. In certain other embodiments, the sedative may be a pyrazolopyrimidine, such as zaleplon. In other embodiments, it may be a benzodiazepine or any other GABAA receptor modulator. In all cases the word "sedative" refers to any chemical that initiates or maintains sleep whose ability to initiate or maintain sleep is positively enhanced by melatonin or another MT1 or MT2 receptor agonist. In this context, the melatonin receptor agonist "positively enhances" the sedative if a greater effect is produced (at any point between the formulation's administration and the clearance of both compounds from the body) than the sum of the dose of the MT1 or T2 agonist in isolation and the dose of the sedative in isolation. For example, if the studies described in the TGA report are accurate, imipramine may count as a sedative as its ability to initiate sleep is enhanced by melatonin. (However, as tricyclic antidepressants have too many side-effects to prescribe as a first-line insomnia treatment, GABAA receptor modulators remain the ideal sedative component for most versions of this invention.)

In certain embodiments, both compounds are designed for simultaneous and immediate, absorption into the bloodstream. For example, a formulation for sleep-onset insomnia containing 2mg of immediate-release melatonin and 10 miligrams of immediate-release Zolpidem, or 2mg of immediate-release melatonin and 7.5 miligrams of immediate-release zopiclone. In these examples, the melatonin receptor agonist is intended to enhance the effect of the sedative for approximately the first 1.5 or 2.5 hours after ingestion. In other embodiments, the melatonin receptor agonist's absorption may be lengthened to reduce the chance of nocturnal awakenings, if, like melatonin, it has a comparatively short half-life. Certain embodiments may have two quantities of either compound or both compounds, one for immediate release and the other for release at a slower rate. For instance, it may release 2mg of melatonin immediately and a further milligram every subsequent hour, for the duration of the sleep period, or however much is considered ideal for the maintenance of sleep. However, all embodiments require an overlap between the times that the compounds are present within the body in active amounts. In the case of melatonin, an "active amount" is an artificially elevated level within the body that is at least high enough to noticeably enhance the effects of the sedative. This point should be made because melatonin is an endogenous hormone. Furthermore, it is not absolutely necessary for any embodiment to have a single sedative or a single melatonin-like potentiator as long as there are at least two chemical agents, with one acting as a sedative and one, with MT1 or MT2 affinities, acting as the potentiator. Both chemical agents may be bonded to one molecule by the relevant manufacturer, as long as a separation occurs in vivo. That is after ingestion and before the melatonin-receptor agonist binds to its relevant sites.

Some embodiments may be tablets, pills, lozenges, syrups, capsules or other items for oral, buccal or sublingual administration. Other embodiments may be aqueous solutions for intravenous, intramuscular, subcutaneous or other injections not specified. Certain embodiments may take the form of nose drops or other intranasal preparations or suppositories or any forms not otherwise specified. The two compounds defined by this invention may be combined with any number of diluents or carriers or other non-active ingredients with any purpose other than to treat insomnia. An embodiment of this invention may be manufactured, prepared or formulated in any conventional or pre-existing ways that are appropriate for its route of administration.

EXAMPLES OF FORMULATIONS:

(All of the examples below are non-limiting and merely representative of aspects of this invention. However, given the novelty of Zolpidem and zopiclone when compared to benzodiazepines these formulations are probably the most marketable.)

1. Immediate release melatonin with immediate release Zolpidem in a single-dose tablet or capsule: The short half-lives of both drugs make this an ideal option for sleep-onset insomnia and patients with little difficulty staying asleep. Formulation may come in multiple strengths of 5mg zolpidem/lmg melatonin and lOmg zolpidem/2mg melatonin. Immediate release melatonin with immediate release zopiclone: the long half-life of the zopiclone maintains sleep while the potentiator assists sleep onset within the first hour of dosing. The 7.5mg strength used for most brands of zopiclone around the world remains sensible, along with lmg melatonin.

A possible "low abuse" Zolpidem with a higher ratio of melatonin to zopiclone, possibly 3mg zolpidem/lmg melatonin and 6mg zolpidem/2mg melatonin. May be subject to trials comparing its efficacy to the existing 5mg/10mg strengths.

A coated zopiclone tablet with an immediate release layer consisting of melatonin and zopiclone, and a further, continuous-release, layer of zopiclone, with or without melatonin.

Claims

THE CLAIMS DEFINING THIS INVENTION ARE AS FOLLOWS:

1. A formulation consisting of melatonin, or a drug (the "potentiator") that binds to the first or second melatonin receptors within the human brain and thus produces a similar action to melatonin, and a drug (the "sedative") which initiates or maintains sleep, such as Zolpidem, zopiclone, zaleplon, a benzodiazepine or any other GABAA-receptor agonist. A necessary characteristic of the sedative is that its ability to initiate or maintain sleep must be open to enhancement by melatonin or another potentiator. As stated previously, this means its efficacy, concurrent with the potentiator, must noticeably or measurably exceed the efficacy of the sum of both drugs in isolation, at least in combating insomnia. To "measurably exceed" means to be capable of doing so in a scientific trial with at least four control groups (placebo, sedative, potentiator and neither). To "noticeably exceed" means that the sedative's exact effects on sleeping patterns are distinct from the observable effects of the potentiator, but nonetheless amplified by its addition. The formulation must be ingestible by a human being in a manner that allows the potentiator and sedative to reach their sites of action within the body that are relevant to insomnia. Both active compounds in the formulation must be proffered for use alongside each other - that is, the potentiator must be taken with the intent to modify the action of the sedative and with a reasonable medical expectation of doing so. "Alongside each other" also means marketed or distributed together in any way as part of a single product, whether as two separate tablets in one container, or as two kinds of granules in one capsule, or two compounds bound within a single lozenge or any situation where there is an expectation of concurrent use.

2. A formulation as daimed in claim 1, with more than two active ingredients but at least one potentiator and at least one sedative. For instance, a triple formulation of Zolpidem, zopiclone and melatonin.

3. A formulation as claimed in claims 1 or 2, with any additional number of binders, carriers, diluents, colouring agents or any other ingredients with no effect on insomnia. Otherwise, a formulation with ingredients that are common to a range of pills or other dosage forms regardless of medical purpose (e.g. titanium oxide, microcrystalline cellulose.)

4. Any variation of the formulation in claims 1, 2, or 3 specifically for sleep-onset insomnia (for instance, one containing immediate release ingredients with short half-lives) or mixed insomnia (for instance one with extended-release ingredients or a sedative with an intermediate half-life).

5. Any formulation as claimed in claims 1, 2, 3 or 4 with a lower dose of the sedative and a compensatory amount of the potentiator, used as a "low abuse" option, or trialled as a solution to the sleepwalking side-effects sometimes reported with Zolpidem, or used to minimise a long-term or dependent patient's daily dose of the sedative or to facilitate tapering, if withdrawal symptoms are exclusively nocturnal.

6. The most viable formulations of this invention are probably the nonbenzodiazepine- melatonin composites in the "Examples" section at the end of the patent description.