AU2015101196A4 - Delivery of phytomelatonin and associated methods and uses - Google Patents

Abstract

Described herein are uses of phytomelatonin derived from cherries via sublingual pathways to treat, ameliorate or treat the symptoms of a sleep disorder in a patient and unexpectedly allow for a significant reduction in dose needed to achieve a desired efficacy.

Description

DELIVERY OF PHYTOMELATONIN AND ASSOCIATED METHODS AND USES TECHNICAL FIELD Described herein are improvements in medicament delivery and use. More specifically, alternative 5 means of delivery of medicaments based on naturally derived extracts containing phytomelatonin are described, along with their methods of use. BACKGROUND ART Melatonin is the hormone we produce when we go to sleep - it helps us to wind down ready for sleep, 10 and also to get into a deep sleep state and stay there. Most people who are having trouble sleeping are short on melatonin - this is commonly the result of stress, hormonal imbalance and bad habits, but has many other causes as well. A supplement of melatonin 30-60 minutes before bed boosts melatonin levels, making it easier to go to sleep, and easier to reach a deep sleep. 15 Regular supplementation for as little as 1-3 months has been shown to reset bad habits, as well as balancing hormonal systems, and leave clients with a regular pattern of quality sleep. Melatonin is widely produced in a synthetic form, and is sold over the counter in many countries (not including New Zealand) or available on prescription. The most recognised natural plant sourced melatonin (phytomelatonin) comes from Montmorency 20 tart cherries, most commonly available in the form of a juice concentrate or a dried powder of the skins and pulp. There are many uses for these products, including as a melatonin supplement which (in the applicant's experience) is highly useful and efficacious in addressing sleep issues. Other natural sources of melatonin also exist, including some Sweet Cherry varieties grown in New Zealand, and much lower levels of melatonin may be found in foods such as walnuts, mustard seed 25 and corn. There may of course be as yet undiscovered sources which may be used with the present invention. Synthetic melatonin supplements are most often sold in dosages of 1-5mg, whereas phytomelatonin is, in the applicants' experience, often effective in doses of 30pg or less. As is the case with many natural supplements, it is safe to assume that the plant extract is more bioavailable than the synthetic 30 form, because it is still associated with its natural co-factors. Bioactive compound delivery methods are a well described field of literature. Many different delivery methods exist. As should be appreciated though, different methods of administration can produce varying medical results. 1 Tablets, liquids or other oral modes of delivery may be appropriate for some medicaments but the speed of action can be delayed via oral administration versus other methods such as parenteral delivery options. Medicaments taken orally may also be partially or substantially digested or absorbed by solids in the digestion system, requiring a larger dose in order to be effective. 5 In addition, some patients find taking oral medicaments difficult by preference or physical inability. Oral delivery may also be simply impossible such as for an incapacitated or unconscious patient. It may be useful to provide an alternative means of delivery that minimises patient discomfort, reduces the quantity of active ingredient required, eases the delivery process and allows delivery to difficult patients such as children, those with disabilities, those with taste or texture sensitivities, and 10 those otherwise unable or unwilling to take traditional oral supplements. A further issue may be the comparatively long time melatonin supplementation requires before the desired effects become noticeable. As noted above, traditional supplements take approximately 30 60 minutes to take effect. It may be desirable to reduce this time period. In addition to the above, providing a sufficiently large dose to the subject may also be difficult. In the 15 case of phytomelatonin, the extract may not be particularly rich in bioactive leading to a large volume of extract being needed to achieve the desired dose. Alternatively, considerable cost and care may be needed during the extraction process to sufficiently concentrate the extract. It should be appreciated that it would be useful to address one or more of the above difficulties or at least provide the public with a choice. 20 Further aspects and advantages of the process and product will become apparent from the ensuing description that is given by way of example only. SUMMARY Alternative means of delivery of medicaments based on phytomelatonin are described herein, along 25 with their methods of use. In a first aspect, there is provided the use of a phytomelatonin containing extract from the skin of Montmorency tart cherries or the skin of sweet cherries formulated for sublingual delivery as a solid form dose, or a dropper or spray form dose, in the manufacture of a medicament for the treatment, amelioration or treatment of the symptoms of a sleep disorder in a patient in need thereof; 30 wherein: (a) the medicament contains <2pg phytomelatonin per kilogram of patient bodyweight; and (b) the medicament dissolves under the tongue of the patient within 5 minutes. 2 The applicant has identified that sublingual delivery of a phytomelatonin active offers considerable and unexpected advantages over other modes of delivery, particularly in terms of providing a simple delivery mode, greater speed of reaction and a reduced dose for a similar effect. 5 DETAILED DESCRIPTION As noted above, described herein are alternative means of delivery of medicaments based on phytomelatonin along with their methods of use. For the purposes of this specification, the term 'about' or 'approximately' and grammatical variations thereof mean a quantity, level, degree, value, number, frequency, percentage, dimension, size, 10 amount, weight or length that varies by as much as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% to a reference quantity, level, degree, value, number, frequency, percentage, dimension, size, amount, weight or length. The term 'substantially' or grammatical variations thereof refers to at least about 50%, for example 75%, 85%, 95% or 98%. 15 The term 'comprise' and grammatical variations thereof shall have an inclusive meaning - i.e. that it will be taken to mean an inclusion of not only the listed components it directly references, but also other non-specified components or elements. In a first aspect, there is provided the use of a phytomelatonin containing extract from the skin of Montmorency tart cherries or the skin of sweet cherries formulated for sublingual delivery as a solid 20 form dose, or a dropper or spray form dose, in the manufacture of a medicament for the treatment, amelioration or treatment of the symptoms of a sleep disorder in a patient in need thereof; wherein: (a) the medicament contains <2pg phytomelatonin per kilogram of patient bodyweight; and (b) the medicament dissolves under the tongue of the patient within 5 minutes. 25 The applicant has identified that sublingual delivery of a phytomelatonin active offers considerable and unexpected advantages over other modes of delivery, particularly in terms of providing a simple delivery mode, greater speed of reaction and a reduced dose for a similar effect. The phytomelatonin may be extracted from a wide range of sources. Reducing the size of the dose required by using sublingual delivery opens up a wide range of alternative sources, which would 30 otherwise not have been considered due to the low levels of bioactive. The phytomelatonin may be extracted from cherries. The phytomelatonin may be extracted from the juice of cherries. The phytomelatonin may be extracted from the skin of cherries. In one embodiment, the cherries may be Montmorency tart cherries. The applicant's understanding is that levels of melatonin in the freeze dried skins of tart cherries is higher than the juice concentrate, so a 3 preparation of the tart cherry skins which has had the solids (e.g. fibres and cellulose) removed, or a water extraction of the skins, may provide a very concentrated dose of phytomelatonin, well suited to sublingual delivery. Sweet cherries, at least of some varieties may also provide a phytomelatonin source. As noted above, sweet cherries are largely ignored as a phytomelatonin source given the 5 relatively low concentration in sweet cherry. Since administration via the use described above dramatically reduces the dose needed, sweet cherries as a source become viable commercially. As noted herein, the applicant has found that via sublingual delivery, the dose of melatonin needed is dramatically decreased. By way of example, in the applicant's own experimental work using a phytomelatonin extract, a dose of 1-2 lozenges held under the tongue to dissolve were sufficient to 10 address sleep disorders. By contrast, the anticipated dose of lozenges based on melatonin levels and previous dose information from juice extracts was 10 lozenges to achieve the desired effects. This 5 to 10 fold reduction in dose clearly shows the potency of sublingual delivery. As should be appreciated, reduced dose allows the ability to produce smaller formulations such as lozenges and wafers. Smaller doses also ease the process of delivery and open up the product to consumers not 15 normally able to take juices or tablets and so on since all the patient does is hold the dose under their tongue until dissolved. The medicament may include approximately 0.5, or 1.0, or 1.5, or 2, or 2.5, or 3, or 3.5, or 4, or 4.5 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15pg phytomelatonin. Each single dose may only contain less than or equal to 2 pg phytomelatonin. 20 The medicament may be formulated as a water soluble dissolving lozenge, wafer or other suitable shaped form. The lozenge or wafer may be suitably sized for sublingual delivery for example being shaped to fit under the tongue of the patient. Alternatively, the medicament may be formulated as a spray or in dropper form. Where the medicament is in solid form, the medicament may be formulated to dissolve sublingually 25 under the tongue of the patient in less than 5 minutes. Dissolution may occur in less than approximately 4, or 3, or 2, or 1 minute. Note that sublingual delivery for the purposes of this specification differs to holding in the wider mouth area generally and refers to delivery under the tongue. Optionally, where the formulation is made using a phytomelatonin extract, the medicament may be 30 processed to concentrate the phytomelatonin active. The extract may be processed by one or more extraction steps of: (a) reducing the saccharine content in the extract; (b) reducing the fibre content in the extract; (c) reducing the cellulose content in the extract. 4 As an example, reducing the sugar/saccharide content in the extract may increase the phytomelatonin concentration. Montmorency tart cherry juice concentrate is approximately 68% sugar (68 brix). By removing some or all of the sugar content, the bulk of a serving of an extract therefrom may be significantly reduced and the phytomelatonin concentration increased. 5 The patient may be a human. The patient may be a child. Children inherently are more difficult to administer oral medicaments to - they often either cannot or will not swallow oral medicaments such as tablets or capsules. A typical method of administrating via an oral route to children is using syrups and liquids. These modes of administration are often more expensive to produce and not always as effective as other delivery options. Sublingual delivery presents a viable alternative means of delivery 10 to children, particularly where the composition dissolves rapidly and provides a fast reaction. The patient may be on the autism spectrum. The formulation may be particularly beneficial for children on the autism spectrum. Calming children on the autism spectrum such as around bedtime presents a significant challenge. The applicant undertook a trial with a group of strongly autistic children. Only three of those offered the opportunity would drink a juice form of Montmorency tart 15 cherry juice with most refusing to drink the juice. Of the children that did drink the juice a marked improvement in settling around bedtime was noted after two weeks of administration, the change being a reduction in the time taken by the children to settle to sleep from an average of three hours to just half an hour. For the parents of the children, this result was a dramatic life changing improvement and very welcome. The low uptake rate was however disappointing which in part 20 reflects the volume and form of the dose needed. Those on the autistic spectrum are often very sensitive to taste and texture - a sublingual delivery with little or no taste is anticipated to dramatically increase the number of "patients" including children who would be willing to ingest the serving. The patient may alternatively be a non-human animal. For example, the medicaments described 25 herein may be used in veterinary applications to calm and soothe an animal. As noted above, delivery of phytomelatonin extract sublingually may provide various unexpected benefits over art methods of administration. In the applicant's experience, a 3 to 10 fold reduction in dose may be possible. A further major advantage of sublingual delivery is the reduction in the amount of raw material required to produce a standard serving. Importing tart cherry juice 30 concentrate is very expensive - ingredient costs currently comprise 70-80% of production costs for existing juice products. Reducing the raw material requirement by up to 90% (possible based on current findings) should dramatically improve the profitability of the product, and allow for a much lower retail price per serve. A smaller raw material requirement would also lessen the impact of price increases in the raw materials as have occurred in the past. The reduced raw material needed also 35 lowers environmental impacts since fewer trees and less intense plantings are needed in the case of cherry extracts. 5 The embodiments described above may also be said broadly to consist in the parts, elements and features referred to or indicated in the specification of the application, individually or collectively, and any or all combinations of any two or more said parts, elements or features, and where specific integers are mentioned herein which have known equivalents in the art to which the embodiments 5 relates, such known equivalents are deemed to be incorporated herein as of individually set forth. Where specific integers are mentioned herein which have known equivalents in the art to which this invention relates, such known equivalents are deemed to be incorporated herein as if individually set forth. 10 WORKING EXAMPLES The above described medicaments, methods and uses are now described by reference to specific examples. 15 EXAMPLE 1 An example of a formulation for sublingual delivery is a freeze dried powder of Montmorency tart cherry juice, which may or may not have had the bulk removed, and which is formed into a lozenge with high pressure. The lozenge is then held under the tongue whilst it dissolves. 20 EXAMPLE 2 An in-house trial was conducted to assess the potential for smaller dose requirements with sublingual delivery. Adults who had regularly used a supplement of Montmorency tart cherry juice concentrate as a sleep aid, and hence who were familiar with it's action in their bodies, were recruited to the trial. 25 Based on the melatonin content of the lozenges used in the trial, when compared to a Montmorency tart cherry juice drink, the participants should on average have been required to consume 8-10 lozenges to achieve the desired result. By contrast, it was found that only 1-2 lozenges were required when the lozenges were held under the tongue to dissolve sublingually 30 6 EXAMPLE 3 A small trial was organised with members of the Otago Autism Society who experienced difficulty sleeping. Six volunteers were recruited, ranging in age from 8 years to 23 years old, each of whom had difficulty 5 sleeping. Whilst all the volunteers were originally willing and keen, only three of the six volunteers were able/willing to drink the Montmorency tart cherry drink provided. This is not unusual amongst those on the autism spectrum, as it is common to experience extreme sensitivity to taste and texture, and the Montmorency tart cherry drink has a relatively strong taste. 10 For those who actually participated, prior to the trial the average time taken to settle and go to sleep was three hours. Within two weeks of the trial commencing the average time taken to settle was reduced to just half an hour. For both the participants and their parents, this was a dramatically positive result. 15 Aspects of the above described medicaments, methods and uses have been described by way of example only and it should be appreciated that modifications and additions may be made thereto without departing from the scope of the claims herein 7

Claims (7)

1. Use of a phytomelatonin containing extract from the skin of Montmorency tart cherries or the skin of sweet cherries formulated for sublingual delivery as a solid form dose, or a dropper or spray form dose, in the manufacture of a medicament for the treatment, amelioration or treatment of the symptoms of a sleep disorder in a patient in need thereof; wherein: (a) the medicament contains <2pg phytomelatonin per kilogram of patient bodyweight; and (b) the medicament dissolves under the tongue of the patient within 5 minutes.

2. The use as claimed in claim 1 wherein the extract is processed by one or more extraction steps of: (a) reducing the saccharine content in the extract; (b) reducing the fibre content in the extract; (c) reducing the cellulose content in the extract.

3. The use as claimed in claim 1 or claim 2 wherein the medicament is formulated as a lozenge or wafer.

4. The use as claimed in any one of the above claims wherein the patient is a human.

5. The use as claimed in any one of the above claims wherein the patient is a child.

6. The use as claimed in claim 5 wherein the patient is on the autism spectrum.

7. The use as claimed in any one of the above claims wherein the extract is dried and pressed to produce the solid form dose. 8