Slow release melatonin compositions

Abstract

The present invention relates to a composition comprising melatonin encapsulated within a calcium alginate hydrogel. The invention also provides an orally administrable dosage form comprising the composition retained within a gel wherein the gel is formed using starch as a gelling agent. Methods of making these compositions and their use in therapy are also disclosed.

Description

Technical Field

[0001] The present invention relates to a melatonin composition which can be used to prepare an orally administrable colloidal dosage form that provides sustained release of melatonin after administration. Background Art

[0002] Melatonin (N-acetyl-5-methoxytryptamine; CAS No.: 73-31-4; C 13 H 16 N 2 O 2 ; molecular weight: 232.3) is the main hormone secreted by the pineal gland of vertebrates. Endogenous melatonin is known to play a role in regulating the sleep-wake cycle (circadian rhythm), pubertal development, and seasonal adaptation, and its mechanism of action has been well understood. The physiological level of melatonin is about 10 pg / ml during the day and increases to about 100 pg / ml at night. It has also been found that the level of melatonin varies with age. The peak secretion of melatonin occurs at about 2 AM.

[0003] The therapeutic uses of exogenous melatonin have also been studied in depth. R.J. Reiter et al., Curr. Med. Chem. 2010, 17(19), 2070-2095 reviewed the clinical applications of melatonin in human trials. Specifically, melatonin has been found to be used as an adjuvant therapy for macular degeneration, glaucoma, gastric mucosal protection, irritable bowel syndrome, arterial hypertension, diabetes, side effects of chemotherapy and radiotherapy in cancer patients, or hemodialysis in patients with renal insufficiency, and particularly for sleep disorders caused by circadian rhythm etiologies (jet lag, delayed sleep phase syndrome, age-related sleep deterioration, etc.) and sleep disorders associated with neurodegenerative diseases (Alzheimer's disease, etc.) or Smith-Magenis syndrome. The dosage range of melatonin used is 0.1 mg to 300 mg, and it has been observed to have low toxicity and no addiction.

[0004] The most significant therapeutic use of melatonin is for the treatment of sleep disorders. Melatonin has become one of the most commonly requested over-the-counter sleep aids, helping to increase the duration of sleep and fall asleep faster. N. Covasin et al., JAMA. 2022, 327(5), 483-485 and their colleagues reported that in US adults (n = 55021, mean age 47.5 [SD 17.1] years; 52% female), the use of melatonin supplements has increased 5-fold from 1999-2000 (0.4%) to 2017-2018 (2.1%).

[0005] As proof of its widespread use, a range of melatonin dosage forms are commercially available, including liquid, tablets, capsules, and gummy preparations. Exemplary gummy preparations include 10mg melatonin gummies, a nutraceutical that helps you fall asleep faster and stay asleep longer. Melatonin gummies are non-GMO, vegan, and gluten-free, gelatin-free, artificial color-free, flavor-free, sweetener-free, and preservative-free. Similarly, Nature's fast-release melatonin products include sleep gummies that contain 3mg of melatonin and 200mg of L-theanine per serving. Other ingredients include corn syrup, sugar, gelatin, citric acid, fractionated coconut oil (with carnauba wax), natural flavors, pectin, and fruit juice (for coloring).

[0006] However, despite the large number of existing compositions, there are still many challenges in the administration of exogenous melatonin. First, melatonin has been shown to have poor and highly variable bioavailability. This is due to its short half-life, only 20 minutes - 50 minutes, and high first-pass metabolism in the liver and / or poor intestinal absorption. In addition, after ingestion, it may take more than 30 minutes for the plasma concentration of melatonin to reach its peak. In some cases, melatonin must be administered at least 2 hours before bedtime. Therefore, the effectiveness of low doses of 0.1mg - 1mg, which correspond to physiological plasma levels, is much lower than that of high doses. However, high doses are also less desirable, at least because after waking up, melatonin remains in the blood when physiological levels should be very low.

[0007] To this end, solutions to the above problems have focused on innovative methods for the sustained release of melatonin throughout the night. This would maintain the peak plasma concentration for a longer period of time and thus would improve sleep quality (such as reducing the chance of waking up). Therefore, sustained-release melatonin supplements are considered superior to fast-release supplements.

[0008] produced by Neurim Pharmaceuticals (disclosed in US 6,469,044) is a 2mg extended-release melatonin tablet for the treatment of insomnia in patients over 55 years old. The component responsible for the slow-release characteristic is an acrylic resin carrier ( RS100, ammonium methacrylate copolymer type B), which reduces the dissolution rate of melatonin. However, WO2018 / 078429 discloses compliance problems of patients with due to the difficulty of swallowing large tablets (8.1mm in diameter and 3mm - 5mm thick). When tablets are broken, crushed, or chewed by patients, they exhibit release characteristics similar to fast-release melatonin.

[0009] It is applicable to treat insomnia in children and adolescents aged 2 - 18 years suffering from autism spectrum disorder (ASD) and / or Smith - Maginness syndrome. The tablets contain 1 mg or 5 mg of melatonin, and the sustained - release property is also achieved using an acrylic resin carrier (type A / B ammonium methacrylate copolymer).

[0010] WO2020 / 150605 discloses tablet and capsule dosage forms containing a solid micro - pulverized melatonin composition. The particulate melatonin contains carboxylic acid and a hydrogel - forming polymer, which confers a sustained - release property after ingestion. However, the inventors reported that this dosage form must be prepared by dry granulation, and wet methods should be avoided. This is because water can cause deamination of melatonin, which reduces the content uniformity of the dosage form.

[0011] WO2012 / 103411 describes multilayer sustained - release melatonin tablets, where the sustained - release layer contains a material capable of forming a hydrogel.

[0012] Although gummy formulations are a popular dosage form of exogenous melatonin, the research on sustained - release gummies is limited. The main reason is that there are many greater challenges in developing sustained - release gummies compared to the corresponding tablets. For example, existing sustained - release melatonin tablet technologies rely on a layered structure. However, this method is not suitable for gummies. In addition, gummies are prepared at high temperatures using high shear forces, and these harsh conditions are adverse to the stability of melatonin in its sustained - release form.

[0013] To our knowledge, there are only two previously published literatures on sustained - release melatonin gummies. WO2021 / 144403 discloses a hydroxypropyl methylcellulose (HPMC) gummy formulation containing melatonin pellets formed by spraying micro - pulverized melatonin dispersed in a 10% aqueous HPMC solution onto microcrystalline cellulose (MCC) spheres. One limitation of this method is that HPMC is a cellulose - based coating known to dissolve at approximately 65°C. Therefore, considering that the heating step in gummy preparation may exceed 90°C, these sustained - release melatonin pellets are restricted to a narrow set of gummy manufacturing methods. Produced by Stride Consumer LLC The two - stage release gummy contains 6 mg of melatonin in two forms: one is an immediate - release preparation, and there is also an encapsulated sustained - release melatonin. Other ingredients include corn syrup, sucrose, stevia, purified water, pectin, carrageenan, gellan gum, citric acid, sodium citrate, strawberry flavor, natural pigment (E–163), carnauba wax, microcrystalline cellulose, polyvinyl acetate, basic methacrylate copolymer, and stearic acid. However, consumers are increasingly concerned that carrageenan present in some gummy compositions is harmful to human health.

[0014] Accordingly, there is still a need to provide an improved melatonin gummy to maintain the peak plasma concentration of melatonin for a longer period of time and thus improve the quality of restful sleep. Summary of the Invention

[0015] In a first embodiment, the present invention provides a composition comprising melatonin encapsulated within a calcium alginate hydrogel.

[0016] In a second embodiment, the present invention provides an orally administrable dosage form comprising the composition according to the first embodiment retained within a gel, wherein the gel is formed using starch as a gelling agent.

[0017] In a third embodiment, the present invention provides a method for preparing a composition comprising melatonin encapsulated within a calcium alginate hydrogel.

[0018] In a fourth embodiment, the present invention provides a method for preparing one or more orally administrable dosage forms comprising the composition according to the first embodiment retained within a gel, wherein the gel is formed using starch as a gelling agent.

[0019] In a fifth embodiment, the present invention provides a composition according to the first embodiment or an orally administrable dosage form according to the second embodiment for treating sleep disorders.

[0020] In a sixth embodiment, the present invention provides the use of the composition according to the first embodiment in the manufacture of a medicament for treating sleep disorders, such as an orally administrable dosage form according to the second embodiment.

[0021] In a seventh embodiment, the present invention provides a method for treating sleep disorders in an individual in need thereof, the method comprising administering to the individual the composition according to the first embodiment, or an orally administrable dosage form according to the second embodiment. Brief Description of the Drawings

[0022] Embodiments of the present invention will now be described in detail with reference to the accompanying drawings, in which:

[0023] Figure 1 A schematic diagram of a composition comprising melatonin encapsulated within a calcium alginate hydrogel is shown.

[0024] Figure 2 Shows in comparison with and the % melatonin released over time in a gastric medium by the composition of the present invention compared to prior art products. Detailed implementation manners

[0025] In a first embodiment, the present invention provides a composition comprising melatonin encapsulated within a calcium alginate hydrogel. The inventors have found that this composition provides a sustained release of melatonin upon administration and also tolerates the harsh conditions for manufacturing gummy formulations as a preferred administration form for this particular active ingredient. Preferably, the weight ratio of melatonin to the calcium alginate hydrogel within the composition is from 5:95 to 15:85, more preferably about 10:90. Based on the total weight of the composition, the composition preferably comprises 4 wt% to 10 wt% water, more preferably 6 wt% to 8 wt% water. The composition may also comprise sodium ions and lactate ions.

[0026] In a second embodiment, the present invention provides an orally administrable dosage form comprising the composition according to the first embodiment retained within a gel, wherein the gel is formed using starch as a gelling agent. The gummy dosage form is commonly referred to as a gummy formulation, and the inventors have found that using starch as a gelling agent is essential for the successful preparation of a gummy formulation using a composition comprising melatonin encapsulated within a calcium alginate hydrogel as a sustained release component.

[0027] Preferably, based on the total weight of the dosage form, the dosage form comprises 1 wt% to 3 wt% of the composition according to the first embodiment. In a further preferred embodiment, the dosage form comprises melatonin not encapsulated within the calcium alginate hydrogel. Inclusion of this melatonin is for providing an immediate release of the active ingredient upon administration, while inclusion of melatonin encapsulated within the calcium alginate hydrogel is for providing a sustained release of the active ingredient throughout the night. Preferably, based on the total weight of the dosage form, the dosage form comprises 0.01 wt% to 0.03 wt% of melatonin not encapsulated within the calcium alginate hydrogel.

[0028] Although different forms of starch can be used, it is preferred to use potato starch as the gelling agent to form the gel. A suitable commercially available potato starch is Perfectamyl Gel NF. Preferably, based on the total weight of the final dosage form, the final dosage form comprises 7 wt% to 17 wt% starch. Additionally, based on the total weight of the dosage form, the dosage form may comprise 8 wt% to 18 wt% water.

[0029] In a preferred embodiment, the dosage form further comprises one or more sweeteners, preferably in an amount of 52 wt% to 82 wt% based on the total weight of the dosage form. The one or more sweeteners are preferably selected from the group consisting of sucrose and corn syrup, and are preferably sucrose, 53DE to 73DE corn syrup, and 32DE to 52DE corn syrup. In a more preferred embodiment, based on the total weight of the dosage form, the dosage form comprises 26 wt% to 36 wt% of sucrose, 18 wt% to 28 wt% of 53DE to 73DE corn syrup, and 8 wt% to 18 wt% of 32DE to 52DE corn syrup. The 53DE to 73DE corn syrup is preferably about 63DE corn syrup (such as Globe 63DE corn syrup). The 32DE to 42DE corn syrup is preferably about 42DE corn syrup (such as Globe 42DE corn syrup).

[0030] The dosage form preferably further comprises one or more acidulants, preferably in an amount of 0.6 wt% to 1.2 wt% based on the total weight of the dosage form. The preferred acidulant is citric acid. The dosage form preferably further comprises L-theanine, preferably in an amount of 2 wt% to 4 wt% based on the total weight of the dosage form. The dosage form preferably further comprises one or more natural flavorants (such as natural blueberry flavorant WONF (WS-320-249-8) and / or natural bitter masking binder flavorant (TV-785-446-1)) and / or natural pigments (such as fruit juice, such as grape juice, where FruitMax Purple 1302WS is a commercially available example). The dosage form preferably further comprises a glazing agent (such as vegetable oil and / or carnauba wax, where Capol 42-3073A MB is a commercially available example).

[0031] The orally administrable dosage form of the present invention provides sustained release of melatonin over an extended period of time and optionally also provides immediate release of melatonin. The combination of immediate release and sustained release of melatonin provides exposure throughout the night, providing a more effective treatment for sleep disorders.

[0032] In a third embodiment, the present invention provides a method for preparing a composition comprising melatonin encapsulated within a calcium alginate hydrogel, the method comprising the steps of:

[0033] i) forming a premix of melatonin, a calcium ion source, and an alginate source;

[0034] ii) granulating the premix by wet granulation to form granules of a composition comprising melatonin encapsulated within a calcium alginate hydrogel; and

[0035] iii) drying the granules to a water content of less than 15 wt% based on the total weight of the granules.

[0036] Preferably, the calcium ion source is calcium lactate and / or the alginate source is sodium alginate. Preferably, the wet granulation step ii) includes spraying water at a rate of 500 ml / min - 1000 ml / min. Preferably, the drying step iii) includes drying the granules to a water content of 6 wt% to 8 wt% based on the total weight of the granules.

[0037] In a fourth embodiment, the present invention provides a method for preparing one or more orally administrable dosage forms, the orally administrable dosage forms comprising a composition containing melatonin encapsulated within a calcium alginate hydrogel, the method comprising the steps of:

[0038] i) providing a mixture comprising starch and water;

[0039] ii) heating the mixture from step i) under high shear mixing to prepare starch for gelation;

[0040] iii) cooling the mixture from step ii);

[0041] iv) combining the product of step iii) with a composition containing melatonin encapsulated within a calcium alginate hydrogel;

[0042] v) transferring the product of step iv) into one or more molds having a size and shape suitable for an orally administrable dosage form; and

[0043] vi) curing and drying the transferred product of step iv) to provide one or more orally administrable dosage forms comprising the composition (e.g., any composition disclosed herein) retained within the gel.

[0044] Preferably, the mixture of step i) comprises starch and water in a weight ratio of 35:65 to 55:45, preferably 40:60 to 50:50, more preferably about 45:55. Preferably, the mixture of step i) further comprises one or more sweeteners. Preferably, the heating of step ii) is carried out at a temperature of 140°C to 160°C and a pressure of 1 bar to 5 bar. Preferably, the heating of step ii) is carried out by direct steam injection. Preferably, during step iv), the product of step iii) is further combined with an acidifying agent and / or melatonin not encapsulated within the calcium alginate hydrogel and / or L-theanine and / or natural flavoring agent and / or natural pigment.

[0045] Preferably, the one or more products of step vi) are coated with a glazing agent.

[0046] As described above, the therapeutic use of melatonin for treating sleep disorders is well known. Thus, in a fifth embodiment, the present invention also provides a composition comprising melatonin encapsulated within a calcium alginate hydrogel, or an orally administrable dosage form comprising a composition containing melatonin encapsulated within a calcium alginate hydrogel, for treating sleep disorders.

[0047] In a sixth embodiment, the present invention provides the use of a composition according to the first embodiment in the manufacture of a medicament for treating sleep disorders, such as an orally administrable dosage form according to the second embodiment.

[0048] In a seventh embodiment, the present invention provides a method of treating sleep disorders in an individual in need thereof, the method comprising administering to the individual a composition according to the first embodiment, or an orally administrable dosage form according to the second embodiment.

[0049] "Sustained-release" melatonin is also referred to by those skilled in the art as slow-release melatonin, continuous-release melatonin, timed-release melatonin, extended-release melatonin, and controlled-release melatonin. The sustained-release melatonin in the various embodiments disclosed herein is melatonin encapsulated within a calcium alginate hydrogel. "Immediate-release" melatonin is also referred to by those skilled in the art as "rapid-release" melatonin, which is optionally present in any of the embodiments disclosed herein and is not encapsulated within a calcium alginate hydrogel and preferably not encapsulated within any form of alginate.

[0050] In a particularly preferred embodiment of the first through seventh embodiments described above, oral administration of any of the orally administrable dosage forms disclosed herein provides all three of the following effects: (i) faster onset of sleep (i.e., less sleep latency), (ii) longer sleep duration (i.e., longer latency to wakefulness from sleep), and (iii) enhanced relaxation, soothing, and / or sedation, all relative to an individual taking a comparative product that is otherwise formulated the same but in which melatonin and optionally L-theanine are absent.

[0051] In some embodiments, a single nightly dose of any of the orally administrable dosage forms disclosed herein is administered. In such embodiments, the single nightly dose can be administered as a single unit dosage form or multiple unit dosage forms, preferably administered about 30 minutes before bedtime (e.g., 15 minutes - 45 minutes before bedtime). As a specific non-limiting example, two units of the orally administrable dosage form (e.g., two gummies) can be administered as a single serving containing a predetermined amount of melatonin, such as about 10 mg total melatonin / serving (e.g., 5 mg - 15 mg total melatonin / serving). Preferably, the single nightly dose is administered to an individual (e.g., an individual with occasional insomnia) as a single serving that contains (i) an amount of immediate-release melatonin effective to cause the individual to fall asleep faster, (ii) an amount of sustained-release melatonin effective to cause the individual to stay asleep longer, and (iii) optionally, an amount of L-theanine effective to cause the individual to achieve at least one of relaxation, soothing, or sedation (e.g., about 100 mg L-theanine / serving, e.g., 50 mg - 150 mg L-theanine / serving).

[0052] In some embodiments, the orally administrable dosage form has one or more characteristics selected from the group consisting of: suitable for vegetarians, no artificial flavors, no artificial sweeteners, dairy-free, lactose-free, soy-free, gluten-free, wheat-free, fish-free, and no more than 10 mg of sodium (e.g., sodium-free). Preferably, the orally administrable dosage form has all of these characteristics.

[0053] Example

[0054] Example 1 - Preparation of Sustained Release Melatonin Granules :

[0055] Exemplary compositions and methods for preparing sustained-release melatonin granules on an industrial scale are as follows:

[0056] Method :

[0057] The raw materials calcium lactate, melatonin, and sodium alginate are sieved online and combined in a slowly rotating blender until homogeneous. The resulting pre-blend is transferred to a fluid bed dryer, and the following amounts of purified water are charged into a dissolver. Then melatonin granules are formed by a wet granulation method, wherein water is sprayed at a rate of 500 ml / min - 2000 ml / min while agitating the pre-blend. Then a drying process is carried out by setting the inlet air temperature within 60°C - 80°C to obtain granules with a water content within 6% - 8%. Then a cooling process is carried out by setting the inlet temperature to 20°C so as to bring the product to a temperature below 35°C.

[0058] Composition of Sustained Release Melatonin Premix :

[0059] Ingredient Unit (mg) Standard Batch (kg) Melatonin 12.120 25.000 Sodium Alginate 54.540 112.500 <![CDATA[Calcium lactate.5H 2 O]]> 54.540 112.500 Total 121.200 250.000

[0060] Composition of Sustained Release Melatonin Granules :

[0061] Ingredient Unit (mg) Standard Batch (kg) Melatonin Premix 121.200 250.000 Purified Water (evaporated after drying) 48.500 100.041 Total 121.200 250.000

[0062] Example 2 - Preparation of Sustained Release Melatonin Gummies

[0063] Exemplary compositions and methods for preparing sustained-release gummies on an industrial scale are as follows:

[0064] Method :

[0065] Load preheated water (120°F, 153 lb) and potato starch (perfectamyl gel, 185 lb) into a premix scale and stir at 50% mixing speed until homogeneous. Subsequently, add 42DE corn syrup (205 lb) and increase the stirring to 60% mixing speed until homogeneous. Then, add 63DE corn syrup (267 lb) and increase the stirring to 70% mixing speed until homogeneous. Finally, add granulated sugar (490 lb) and maintain stirring at 70% mixing speed until homogeneous.

[0066] Then, vacuum transfer the resulting premix slurry to a buffer vessel and then pump it through an injection cooker (149°C, back pressure 3.5 bar). Use a pressure dissolver with direct steam injection and high-shear mixing functions to disperse the starch granules for gelatinization.

[0067] After the injection cooker treatment, place the cooked material in a holding tank (190°F - 210°F, pH = 5.5 - 6.5), and then pump it back to the buffer vessel, which is used to rapidly cool the material and reduce the water content by evaporation.

[0068] In a separate tank, combine cold water (3.3 lb) with 63DE corn syrup (9 lb) while stirring at 50% mixing speed for 45 seconds. Subsequently, add 50% w / w aqueous citric acid solution (2.7 lb) and stir for another 30 seconds at the same speed. Then, add melatonin (3.03 lb) and stir at 50% mixing speed for 60 seconds. Add the sustained-release melatonin granules of Example 1 (0.03 lb) and stir at 60% mixing speed for 2 to 3 minutes. Finally, add L-theanine (4.68 lb) and stir at 60% mixing speed for 30 seconds.

[0069] Then, pump the cooked material into an additive mixing system and mix a portion of it (124.34 lb) with a mixture containing melatonin (22.74 lb), natural blueberry flavor (1.13 lb), natural bitterness masking agent (0.30 lb), and purple mixture (1.50 lb).

[0070] After this final mixing step, the material is transferred to a storage hopper and metered into starch-filled trays for molding into gummies (wet weight 3.75 g, pH 3.7 - 3.9). The gummies are then placed in a curing / drying chamber at a temperature between 125°F - 145°F and 8% - 20% RH for 20 hours - 60 hours to obtain a dry gum weight of 3.45 g. They are then manually demolded and coated with a glazing agent (Capol 42 - 3073A MB).

[0071] Composition of Sustained Release Melatonin Gummies (finished product) :

[0072] The dry gum weight of the finished product is 3.45 g (the range can be from 2 g to 5 g).

[0073]

[0074] Example 3 - Bioavailability Study of Sustained Release Melatonin Gummies

[0075] Method

[0076] In an improved analytical method based on the USP <2040> method, three melatonin gummy formulations (which have been processed for repeated chewing) are dissolved in vitro in a simulated gastric medium (0.1N HCl at 37°C). The formulations are commercially available 10 mg and products as well as the gummy formulation according to the present invention (labeled #1Sleep3 gummy (without plant ingredients)).

[0077] Results

[0078] The melatonin dissolution curves of these three formulations are shown below Figure 2 in. It can be seen that the 10 mg product provides a rapid release of melatonin, but not a sustained release, while the product and the formulation according to the present invention provide a sustained release curve.

[0079] Example 4 - Non - limiting Example of Melatonin Gummies

[0080]

[0081] Other ingredients: glucose syrup, sugar, modified food starch. Contains <2% of: citric acid, natural flavoring, fruit and vegetable juice (color), vegetable oil (containing carnauba wax).

[0082] Those skilled in the art can understand and implement other variations of the disclosed embodiments by studying the drawings, the present disclosure, and the appended claims when implementing the claimed invention. In the claims, the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used advantageously.

Claims

1. A composition, the composition comprising melatonin encapsulated within a calcium alginate hydrogel, and optionally further comprising additional melatonin not encapsulated by the calcium.

2. The composition according to claim 1, wherein the weight ratio of melatonin to the calcium alginate hydrogel is from 5:95 to 15:

85.

3. The composition according to claim 2, wherein the weight ratio of melatonin to the calcium alginate hydrogel is about 10:

90.

4. The composition according to any one of claims 1 to 3, based on the total weight of the composition, the composition comprises 4 wt% to 10 wt% water.

5. The composition according to claim 4, based on the total weight of the composition, the composition comprises 6 wt% to 8 wt% water.

6. The composition according to any one of claims 1 to 5, the composition further comprises sodium ions and lactate ions.

7. An orally administrable dosage form, the orally administrable dosage form comprising the composition according to any one of claims 1 to 6 retained within a gel, wherein the gel is formed using starch as a gelling agent.

8. The dosage form according to claim 7, based on the total weight of the dosage form, the dosage form comprises 1 wt% to 3 wt% of the composition according to any one of claims 1 to 6.

9. The dosage form according to claim 7 or claim 8, the dosage form further comprises melatonin not encapsulated within the calcium alginate hydrogel.

10. The dosage form according to claim 9, based on the total weight of the dosage form, the dosage form comprises 0.01 wt% to 0.03 wt% of melatonin not encapsulated within the calcium alginate hydrogel.

11. The dosage form according to any one of claims 7 to 10, wherein the gel is formed using potato starch as a gelling agent.

12. The dosage form according to any one of claims 7 to 11, based on the total weight of the dosage form, the dosage form comprises 7 wt% to 17 wt% starch.

13. The dosage form according to any one of claims 7 to 12, based on the total weight of the dosage form, the dosage form comprises 8 wt% to 18 wt% water.

14. The dosage form according to any one of claims 7 to 13, the dosage form further comprises one or more sweeteners.

15. The dosage form according to claim 14, based on the total weight of the dosage form, the dosage form comprises 52 wt% to 82 wt% of the one or more sweeteners.

16. The dosage form according to claim 14 or claim 15, wherein the one or more sweeteners are selected from the group consisting of sucrose and corn syrup.

17. The dosage form according to claim 16, wherein the sweeteners are sucrose, 53 DE to 73 DE corn syrup, and 32 DE to 52 DE corn syrup.

18. The dosage form according to claim 17, based on the total weight of the dosage form, the dosage form comprises 26 wt% to 36 wt% sucrose, 18 wt% to 28 wt% 53 DE to 73 DE corn syrup, and 8 wt% to 18 wt% 32 DE to 52 DE corn syrup.

19. The dosage form according to any one of claims 7 to 18, wherein the dosage form further comprises one or more acidifying agents.

20. The dosage form according to claim 19, wherein, based on the total weight of the dosage form, the dosage form comprises 0.6 wt% to 1.2 wt% of the one or more acidifying agents.

21. The dosage form according to claim 19 or claim 20, wherein the one or more acidifying agents comprise citric acid.

22. The dosage form according to any one of claims 7 to 21, wherein the dosage form further comprises L-theanine.

23. The dosage form according to claim 22, wherein, based on the total weight of the dosage form, the dosage form comprises 2 wt% to 4 wt% of L-theanine.

24. The dosage form according to any one of claims 7 to 23, wherein the dosage form further comprises one or more natural flavoring agents and / or natural pigments.

25. The dosage form according to any one of claims 7 to 24, wherein the dosage form further comprises a glazing agent.

26. A method for preparing a composition comprising melatonin encapsulated within a calcium alginate hydrogel, the method comprising the steps of: iv) forming a premix of melatonin, a calcium ion source, and an alginate source; v) granulating the premix by wet granulation to form granules of a composition comprising melatonin encapsulated within a calcium alginate hydrogel; and vi) drying the granules to a water content of less than 15 wt% based on the total weight of the granules.

27. The method according to claim 26, wherein the calcium ion source is calcium lactate and / or the alginate source is sodium alginate.

28. The method according to claim 26 or claim 27, wherein the wet granulation comprises spraying water at a rate of 500 ml / min - 2000 ml / min.

29. The method according to any one of claims 26 to 28, wherein the granules are dried to a water content of 6 wt% to 8 wt% based on the total weight of the granules.

30. A method for preparing one or more orally administrable dosage forms, the orally administrable dosage forms comprising a composition according to any one of claims 1 to 6 retained within a gel, the method comprising the steps of: vii) providing a mixture comprising starch and water; viii) heating the mixture from step i) under high-shear mixing to prepare the starch for gelation; ix) cooling the mixture from step ii); x) combining the product of step iii) with a composition according to any one of claims 1 to 6; xi) transferring the product of step iv) to one or more molds having a size and shape suitable for an orally administrable dosage form; and xii) curing and drying the transferred product of step iv) to provide one or more orally administrable dosage forms, the dosage forms comprising a composition according to any one of claims 1 to 6 retained within a gel.

31. The method according to claim 30, wherein the mixture of step i) comprises starch and water in a weight ratio of 35:65 to 55:45, preferably 40:60 to 50:50, more preferably about 45:

55.

32. The method according to claim 30 or claim 31, wherein the mixture in step i) further comprises one or more sweeteners.

33. The method according to any one of claims 30 to 32, wherein the heating in step ii) is carried out at a temperature of 140 °C to 160 °C and a pressure of 1 bar to 5 bar.

34. The method according to any one of claims 30 to 33, wherein the heating in step ii) is carried out by direct steam injection.

35. The method according to any one of claims 30 to 34, wherein during step iv), the product of step iii) is further combined with an acidifying agent and / or melatonin and / or L-theanine and / or natural flavoring agent and / or natural pigment not encapsulated within the calcium alginate hydrogel.

36. The method according to any one of claims 30 to 34, wherein one or more products of step vi) are coated with a glazing agent.

37. The composition according to any one of claims 1 to 6, or the orally administrable dosage form according to any one of claims 7 to 35, wherein the composition or the orally administrable dosage form is for the treatment of sleep disorders.

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