Dosage forms containing sustained-release melatonin pellets

Abstract

To provide melatonin compositions capable of delivering sustained-release doses of melatonin in a dosage form that is easier to swallow than a pill.SOLUTION: A composition includes a therapeutically effective oral pharmaceutical dosage form. The dosage form includes an aqueous carrier material having an acidic pH and a plurality of individual pellets having a first dose of melatonin therein. The individual pellets include (i) a solid core; (ii) an active coating on the solid core, the active coating comprising melatonin and a hydrophilic binder; and (iii) an enteric coating on the active coating. A dissolution pH of the enteric coating is higher than an acidic pH of the aqueous carrier material.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 962,574, filed January 17, 2020, which is incorporated by reference in its entirety.

[0002] [Technical field]

[0002] This application relates to the field of melatonin compositions, and more particularly, to sustained-release melatonin dosage forms. [Background technology]

[0003]

[0003] Melatonin is a hormone that has been shown to be effective in treating circadian rhythm disorders, sleep disorders, jet lag, shift work syndrome, seasonal affective disorder, insomnia, melatonin deficiency in the elderly, and many other medical conditions. Melatonin is typically administered in the form of an oral tablet or liquid drop.

[0004] [Summary of the Invention]

[0004] There is a need for new melatonin compositions that can deliver sustained release doses of melatonin in a dosage form that is easier to swallow than a pill.

[0005]

[0005] An example of such a composition is a therapeutically effective oral pharmaceutical dosage form comprising an aqueous carrier material having an acidic pH and a plurality of individual pellets having a first dose of melatonin therein. The individual pellets comprise a solid core and an active coating on the solid core. The active coating comprises melatonin and a hydrophilic binder. An enteric coating is on the active coating. The dissolution pH of the enteric coating is higher than the acidic pH of the aqueous carrier material.

[0006] The composition may further include one or more of the following additional features:

[0007]

[0007] The melatonin can be a powder having a melatonin median size of 5 μm to 40 μm.

[0008]

[0008] The aqueous carrier material may contain a second dose of melatonin therein, and the dosage form releases the second dose of melatonin into the oral cavity and stomach of the subject.

[0009]

[0009] The dosage form is a beverage and the aqueous carrier material comprises water.

[0010] The dosage form may be a gummy and the aqueous carrier material may be a gummy gelling agent.

[0011]

[0011] Each individual pellet may further comprise an isolation coating on the active coating, a subcoat on and between the isolation coatings, and an enteric coating on the subcoat. The subcoat may comprise a hydrogel-forming polymer and an acid, and the acid may impart a pH of 0.1 to 4.4 to the hydrogel-forming polymer. The isolation coating may separate the acid from the melatonin.

[0012]

[0012] The aqueous carrier material may be hydroxypropyl methylcellulose. The solid core may be microcrystalline cellulose beads having a diameter of 0.1 to 2 mm. The hydrophilic binder may include hydroxypropyl methylcellulose. The melatonin may be a powder having a melatonin median diameter of 5 μm to 40 μm held in a hydrophilic binder. The separating coating may include hydroxypropyl methylcellulose, the hydrogel-forming polymer may include hydroxypropyl methylcellulose, and the acid may include citric acid. The separating coating may include hydroxypropyl methylcellulose.

[0013] The composition may include any combination of these features.

[0014] An example of a method of treatment includes administering a therapeutically effective amount of an oral pharmaceutical dosage form to a patient in need thereof. The dosage form includes an aqueous carrier material having an acidic pH and a plurality of individual pellets having a first dose of melatonin therein. The individual pellets include a solid core and an active coating on the solid core. The active coating includes melatonin and a hydrophilic binder. An enteric coating is on the active coating. The dissolution pH of the enteric coating is higher than the acidic pH of the aqueous carrier material.

[0015] The method may further include one or more of the following additional features.

[0016]

[0016] The melatonin may be a powder having a melatonin median size of 5 μm to 40 μm.

[0017]

[0017] The aqueous carrier material may contain a second dose of melatonin therein, and the dosage form releases the second dose of melatonin into the oral cavity and stomach of the subject.

[0018]

[0018] The dosage form may be a drink and the aqueous carrier material comprises water.

[0019] The dosage form may be a gummy and the aqueous carrier material may be a gummy gelling agent.

[0020]

[0020] Each pellet may further comprise an isolation coating on the active coating, a subcoat on and between the isolation coatings, and an enteric coating on the subcoat. The subcoat may comprise a hydrogel-forming polymer and an acid, and the acid may impart a pH of 0.1 to 4.4 to the hydrogel-forming polymer. The isolation coating may separate the acid from the melatonin.

[0021]

[0021] The aqueous carrier material may be hydroxypropyl methylcellulose. The solid core may be microcrystalline cellulose beads having a diameter of 0.1 to 2 mm. The hydrophilic binder may include hydroxypropyl methylcellulose. The melatonin may be a powder having a melatonin median diameter of 5 μm to 40 μm held in a hydrophilic binder. The separating coating may include hydroxypropyl methylcellulose, the hydrogel-forming polymer may include hydroxypropyl methylcellulose, and the acid may include citric acid. The separating coating may include hydroxypropyl methylcellulose.

[0022] The dosage form may be therapeutically effective to aid a patient in sleeping.

[0023]

[0023] The treatment method may include any combination of these features.

[0024] An example of a processing method includes combining an aqueous carrier material with a plurality of individual pellets to form a therapeutically effective oral pharmaceutical dosage form. The aqueous carrier material has an acidic pH. The plurality of individual pellets have a first dose of melatonin therein. The individual pellets include a solid core and an active coating on the solid core. The active coating includes melatonin and a hydrophilic binder. An enteric coating is on the active coating. The dissolution pH of the enteric coating is higher than the acidic pH of the aqueous carrier material.

[0025] The method may further include one or more of the following additional features.

[0026]

[0026] The melatonin can be a powder having a melatonin median size of 5 μm to 40 μm.

[0027]

[0027] The aqueous carrier material may contain a second dose of melatonin therein, and the dosage form releases the second dose of melatonin into the oral cavity and stomach of the subject.

[0028]

[0028] The dosage form may be a drink and the aqueous carrier material comprises water.

[0029] The dosage form may be a gummy and the aqueous carrier material may be a gummy gelling agent.

[0030]

[0030] Each pellet may further comprise an isolation coating on the active coating, a subcoat on and between the isolation coatings, and an enteric coating on the subcoat. The subcoat may comprise a hydrogel-forming polymer and an acid, and the acid may impart a pH of 0.1 to 4.4 to the hydrogel-forming polymer. The isolation coating may separate the acid from the melatonin.

[0031]

[0031] The aqueous carrier material may be hydroxypropyl methylcellulose. The solid core may be microcrystalline cellulose beads having a diameter of 0.1 to 2 mm. The hydrophilic binder may include hydroxypropyl methylcellulose. The melatonin may be a powder having a melatonin median diameter of 5 μm to 40 μm held in a hydrophilic binder. The separating coating may include hydroxypropyl methylcellulose, the hydrogel-forming polymer may include hydroxypropyl methylcellulose, and the acid may include citric acid. The separating coating may include hydroxypropyl methylcellulose.

[0032] The dosage form may be therapeutically effective to aid a patient in sleeping.

[0033]

[0033] The method may include any combination of these features.

[0034]

[0034] The processing method may include any combination of these features. DETAILED DESCRIPTION OF THE INVENTION

[0035] A first example of a melatonin composition described herein is designed to release melatonin to the gastrointestinal tract of a subject in at least one step by delivery to the intestine. The composition provides sustained release of melatonin in the intestine of a subject for several hours, helping the subject maintain a full night's sleep.

[0036] A second example of a melatonin composition described herein is designed to release melatonin to a subject's gastrointestinal tract in at least two stages. In the first stage, the composition releases some of its melatonin into the oral cavity and stomach to provide an initial burst dose of melatonin that helps the subject fall asleep. In the second stage, the composition provides a sustained release dose of melatonin in the subject's intestine over several hours, helping the subject maintain sleep throughout the night.

[0037] In these examples, the melatonin is carried by a plurality of individual pellets dispersed in an aqueous carrier material that makes the pellets easy to swallow.

[0038] Each pellet is composed, at least in part, of a solid core and an active coating on the solid core. The active coating comprises melatonin from a powder held in a hydrophilic binder, the powder having a melatonin median diameter of 5 μm to 40 μm. An enteric coating is on the active coating. The dissolution pH of the enteric coating is higher than the acidic pH of the aqueous carrier material, substantially preventing the pellet from releasing melatonin into the aqueous carrier material.

[0039] Pellets are individual monolithic bodies that behave like individual small pills in the gastrointestinal tract. Each pellet is comprised of an individual dose of melatonin and is individually enteric coated. Generally, individual pellets include, but are not limited to, a solid core, an active coating, and an enteric coating. Further details regarding exemplary pellets are provided herein.

[0040] The solid core can be an inert solid material that forms a solid mechanical base or frame onto which one or more functional and / or non-functional coatings are applied.

[0041]

[0041] One possible example of an inert solid material is nonpareil sugar beads. Nonpareil sugar beads, sometimes called sugar spheres, are pharmaceutical excipients composed primarily of one or more sugars, such as sucrose, lactose, D-mannitol, and sucrose. The sugars are pharmaceutically inert and digestible by most humans and animals. Some nonpareil sugar beads may also contain one or more auxiliary ingredients, such as corn starch, that are also inert and digestible.

[0042] Another possible example of an inert solid material is an inert excipient bead. Certain cellulosic materials are acceptable pharmaceutical excipients that can form solid cores with similar mechanical properties to nonpareil beads. For example, microcrystalline cellulose (MCC) pellets or hydroxypropyl methylcellulose (HMPC or hypromellose) are inert and substantially insoluble in water. Because some cellulosic materials, such as MCC, are insoluble in water, they do not dissolve upon ingress of water, as do many nonpareil sugar beads. Therefore, if a longer, sustained release of melatonin is preferred, a cellulosic material such as microcrystalline cellulose may be useful. Because microcrystalline cellulose is substantially insoluble in water, it can prevent the pellets from immediately releasing each dose of melatonin as rapidly as if the solid core material were soluble, provided the beads remain intact.

[0043]

[0043] The shape of the solid core is not limited to any particular shape. Most examples of solid cores can be spherical, but other shapes, including amorphous shapes, are also possible. Spherical solid cores of various materials that can be used as inert pharmaceutical carriers are commercially available.

[0044]

[0044] A solid core has a critical dimension which is the largest measurement from one end of the solid core to the other. For a spherical core, the critical dimension is the diameter.

[0045] In certain examples of solid cores, the average critical dimension of the solid core is ≦2 mm, 0.1 mm to 2 mm, 0.1 mm to 1.5 mm, 0.1 mm to 1 mm, 0.4 mm to 0.1.5 mm, 0.4 mm to 1.2 mm, 0.4 mm to 0.6 mm, or about 0.5 mm. Critical dimension measurements may be based on mesh size and / or particle size analyzer measurements.

[0046]

[0046] The size of the solid core can vary depending on the formulation. The size of the solid core defines the surface area of ​​the core. The surface area of ​​the core limits the dose of melatonin that can be held on the core. Larger core sizes can carry larger doses of melatonin, but are not ideal when the pellets are filled into liquid or gummy dosage forms. Large pellets can be difficult to swallow or can be chewed and destroyed. Smaller pellets are easier to swallow and less likely to be chewed.

[0047] The active coating is a coating on the solid core and includes melatonin as the therapeutically active ingredient. The melatonin source is a powder that is advantageously selected to be not only substantially pure (e.g., at least 99.8% pure melatonin), but also to have a very small particle size. The melatonin powder is used directly in the dosage form. In certain instances, the melatonin is not dissolved in a solvent before being placed in the active coating.

[0048]

[0048] The term "particle size," as used herein, refers to the size of the individual particles that make up the powder, which may be polycrystalline. The size of the individual particles in a powder is usually not uniform; they are distributed over a range of sizes that may vary around a median size.

[0049]

[0049] Conventional techniques for reporting particle size measurements report D values ​​for powder samples, i.e., D10, D50, and D90. D10 is the particle size at which 10% of the sample's mass is a particle with a critical dimension smaller than that value. D50 is the particle size at which 50% of the sample's mass is smaller than that value and 50% of the sample's mass is larger than that value. D90 is the particle size at which 90% of the sample's mass is smaller than that value and 10% of the sample's mass is larger than that value. Particle sizes for powder samples can be measured by sieving, laser diffraction, light scattering, and / or image analysis. Critical dimension refers to the dimension from one end of an individual particle to the other. For a sphere, for example, the critical dimension is the diameter.

[0050] In some exemplary compositions, the median size of the individual melatonin crystals in the powder ranges from 5 μm to 40 μm. In some exemplary compositions, the particle size distribution is D10≦5, D50≦20, and D90≦40.

[0051] The use of small melatonin particles is advantageous for several reasons. First, melatonin has low solubility in the intestine, so small particles increase the surface area of ​​the melatonin, making it more soluble. Second, small particles allow the melatonin to be more evenly distributed across the surface of the solid core.

[0052] The active coating also includes a hydrophilic binder that binds the melatonin particles together on the solid core. The active coating can be prepared by blending melatonin, binder, and water together to form a liquid coating having melatonin particles dispersed therein. The solid core can be coated with the active coating using conventional pellet coating mechanisms, such as fluidized bed coating.

[0053]

[0053] In certain examples, the hydrophilic binder is a hydrogel-forming polymer. Hydrogel-forming polymers are polymers that can absorb water. Hydrogel-forming polymers can act as release-controlling polymers to provide sustained release of melatonin to the gastrointestinal tract over a desired period of time. Hydrogel-forming polymers useful for binders can include, for example, cellulosic polymers such as carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose; hyaluronate; alginate; polysaccharides, heteropolysaccharides, pectin; poloxamer; poloxamine; ethylene vinyl acetate; polyethylene glycol; dextran; polyvinylpyrrolidone; chitosan; polyvinyl alcohol; propylene glycol; polyvinyl acetate; phosphatidylcholine, lecithin; miglyol; polylactic acid; polyhydroxybutyric acid; mixtures thereof, copolymers thereof, and derivatives thereof.

[0054] Hydroxypropyl methylcellulose is used in certain formulations of the dosage form because it forms a hydrogel, is safe, and works well with melatonin.

[0055] The active coating may include an acid blended with the hydrophilic binder and melatonin. When used, the acid imparts an acidic pH to the aqueous matrix formed from combining the hydrophilic binder and melatonin with water during processing.

[0056] The acid may be, for example, a low molecular weight carboxylic acid such as citric acid, succinic acid, or tartaric acid. The amount of carboxylic acid is sufficient to impart an acidic pH to the hydrogel matrix. Some suitable pH ranges provided for the hydrogel matrix by the amounts of carboxylic acid described herein include 0.1-5, 1-5, 2-5, 2-4.5, 3-5, 3-4.5, 3.3-5, or 3.4-4.5, or 4.4 or less.

[0057] The active coating can be prepared by blending the active coating ingredients together with water. The hydrophilic binder absorbs some of the water to form an aqueous matrix in which the melatonin particles are dispersed. This aqueous matrix can be applied to the solid core by pharmaceutical coating techniques such as fluidized bed coating.

[0058] Optionally, an optional subcoat may be applied over the active coating, which may be selected to perform a particular function.

[0059] The subcoat may act as a physical barrier between the active coating and the enteric coating to prevent the materials in the active coating and the enteric coating from interacting with each other.

[0060] The subcoat may act as a release-controlling coating that affects the rate of melatonin release from the pellets. Such a subcoat may be selected to provide a desired release profile in the gastrointestinal tract.

[0061] The subcoat can be tailored to provide pH control around the active coating. Because melatonin has low water solubility above pH 4.4, a subcoat can be used to impart a local pH of 4.4 or less when water from the gastrointestinal tract contacts the subcoat. In such cases, the subcoat material includes a hydrogel-forming polymer and an acid.

[0062] When the hydrogel-forming polymer in the subcoat comes into contact with water, it absorbs water and swells, forming a hydrogel matrix. The hydrogel matrix then creates an aqueous environment around the core. The acid in the hydrogel lowers the pH of the hydrogel below 4.4 or between 0.1 and 4.4. The acidic hydrogel may help keep the melatonin in a local acidic environment where it remains soluble, regardless of the pH of the region of the gastrointestinal tract in which the pellet is located.

[0063]

[0063] Hydrogel-forming polymers useful for the subcoat may include, for example, cellulosic polymers such as carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose; hyaluronate; alginate; polysaccharides, heteropolysaccharides, pectin; poloxamer; poloxamine; ethylene vinyl acetate; polyethylene glycol; dextran; polyvinylpyrrolidone; chitosan; polyvinyl alcohol; propylene glycol; polyvinyl acetate; phosphatidylcholine, lecithin; miglyol; polylactic acid; polyhydroxybutyric acid; mixtures thereof, copolymers thereof, and derivatives thereof.

[0064]

[0064] When the subcoat contains an acid, a separation coating may be disposed between the core and the subcoat. The purpose of the separation coating is to separate the melatonin in the active coating from the acid in the subcoat until after ingestion. Hydrogel-forming polymers useful for the separation coating may include, for example, cellulose-based polymers such as carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose; hyaluronate; alginate; polysaccharides, heteropolysaccharides, pectin; poloxamer; poloxamine; ethylene vinyl acetate; polyethylene glycol; dextran; polyvinylpyrrolidone; chitosan; polyvinyl alcohol; propylene glycol; polyvinyl acetate; phosphatidylcholine; lecithin; miglyol; polylactic acid; polyhydroxybutyric acid; mixtures thereof, copolymers thereof, and derivatives thereof. In a specific example, HPMC is used as the separation coating material.

[0065]

[0065] The enteric coating may be disposed on the individual pellets or on the subcoat or separator coating, if present. The enteric coating substantially prevents the melatonin from being released from the pellets in the stomach. The enteric coating material has pH-dependent solubility. At the low pH of the stomach, the enteric coating material is typically substantially insoluble. Thus, the enteric coating remains intact in the stomach, which substantially prevents the melatonin in the pellets from being released into the stomach.

[0066] The enteric coating material has a dissolution pH above which it becomes soluble. The dissolution pH is typically the pH found in the human intestine. When the pellets enter an area with a pH above the dissolution pH, the enteric coating dissolves. As the enteric coating dissolves, melatonin is released from the pellets into the intestine, where it can be absorbed systemically by the body.

[0067]

[0067] Enteric coating materials can be selected based on their dissolution pH to ensure release of melatonin from the pellets in the desired region of the gastrointestinal tract. Examples of enteric coating materials include shellac, cellulose acetate phthalate, polyvinyl acetate phthalate, ethylcellulose / sodium alginate, hypromellose acetate succinate, or methacrylic acid-based polymers or copolymers such as methacrylic acid-ethyl acrylate copolymer.

[0068] Examples of enteric coatings are reported in Table 1 along with their dissolution pH. [Table 1]

[0069]

[0069] The pellets are delivered to the stomach by an aqueous carrier, disperse in the stomach, and are adapted to pass through the stomach without substantially releasing melatonin into the stomach. In certain instances, the pellets release melatonin in a sustained manner for at least 3 hours and up to 10 hours within the pH range found in the intestine. In certain instances, the pellets may release melatonin for 3 to 10 hours after ingestion, regardless of the pH environment through which they pass. This sustained release of melatonin from the pellets may help a subject maintain a full night's sleep.

[0070] The pellets are administered to a subject as part of an oral pharmaceutical dosage form. In addition to the pellets, the dosage form includes a carrier material. The carrier material is a material in which the pellets are dispersed before ingestion.

[0071] To prevent the enteric coating from dissolving in the carrier material, the carrier material has a pH below the dissolution pH of the enteric coating. The pH may be an inherent property of the carrier material itself, or may be imparted to the carrier material by an acid in the carrier material. The amount of acid in the carrier material is sufficient to impart the desired pH to the carrier material.

[0072]

[0072] The carrier material can have many different forms, but in many examples of compositions it is an aqueous carrier material, in which water is used as part of the vehicle.

[0073]

[0073] In certain examples of compositions, the composition is designed to be ingested by drinking, giving the composition a drink or drink-like dosage form. In this manner, the pellets are swallowed along with the carrier material when the subject drinks a liquid. This dosage form can be beneficial for subjects who have difficulty swallowing pills. Herein, the pellets are added to the liquid carrier material and ingested simultaneously.

[0074] The liquid carrier material can be made in many different ways. In one particular example, the liquid carrier material is composed of water and an acid. It may also contain other beverage-making ingredients such as flavorings, sweeteners, preservatives, surfactants, emulsifiers, carbonation components, viscosity modifiers, and sequestrants, among others.

[0075] The liquid carrier material formulation may include an acid, such as those acids described above. The acid creates an acidic environment within the dosage form and substantially prevents the enteric coating on the pellets from dissolving within the carrier material or during processing. The amount of acid in the liquid carrier material is sufficient to impart a pH of 0.5 to 5, 1 to 5, 2 to 5, 3 to 5, 3 to 4.5, or 3 to 4 to the liquid carrier material solution.

[0076]

[0076] In certain examples of the composition, the dosage form is a gummy with pellets dispersed therein. In such examples, the carrier material is suitable for preparing a gummy dosage form.

[0077]

[0077] The gummy carrier material includes a gelling agent that forms the physical structure of the gummy. Examples of gelling agents include, but are not limited to, pectin, gelatin, HPMC, or another conventional gelling material.

[0078] The gummy carrier material may include an acid. The acid creates an acidic microenvironment within the gummy and substantially prevents the enteric coating on the pellets from dissolving within the gummy or during processing. The amount of acid in the gummy carrier material is sufficient to impart a pH of 0.5-5, 1-5, 2-5, 3-5, 3-4.5, or 3-4 to the gummy dosage form.

[0079] The gummy carrier material also contains water which the gelling agent absorbs, causing the gelling agent to swell and form the physical structure of the gummy. The amount of water used will vary depending on the gelling agent selected.

[0080]

[0080] The gummy dosage forms may be flavored with flavorings and / or sweeteners. A variety of conventional flavorings may be used. Similarly, a variety of natural and artificial sweeteners may be used.

[0081]

[0081] The carrier material, whether liquid, gummy, or otherwise, can contain melatonin in either solid or soluble form. By including an amount of melatonin in the carrier material, the carrier material provides an initial burst dose of melatonin to help the subject fall asleep. The remaining melatonin in the pellet then provides a sustained release of melatonin in the intestine to help the subject maintain sleep throughout the night.

[0082] The total melatonin dose in a given unit dosage form may be 100% in the pellets or may be distributed between the pellets and the carrier material. In certain examples, the composition has the following % melatonin in the pellets to % melatonin in the carrier material: 50% pellets:50% carrier material, 60% pellets:40% carrier material, 70% pellets:30% carrier material, 80% pellets:20% carrier material, 90% pellets:10% carrier material, 95% pellets:5% carrier material.

[0083] The dosage form can be orally administered to a human or animal patient in a therapeutically effective amount, which is an amount sufficient to provide a therapeutic benefit that affects a disease or condition in the body.

[0084] The therapeutically effective amount of melatonin is 0.1 to 1,000 mg / day, for example, 0.1 to 25 mg / day, 0.1 to 10 mg / day, 1 to 20 mg / day, 1 to 10 mg / day, 2 to 10 mg / day, 50 to 75 mg / day, 75 to 100 mg / day, 100 to 150 mg / day, 150 to 200 mg / day, 200 to 250 mg / day, 250 to 300 mg / day, 300 to 350 mg / day, The recommended doses are 350-400 mg / day, 400-450 mg / day, 450-500 mg / day, 500-550 mg / day, 550-600 mg / day, 600-650 mg / day, 650-700 mg / day, 700-750 mg / day, 750-800 mg / day, 800-850 mg / day, 850-900 mg / day, 900-950 mg / day, and 950-1,000 mg / day. Higher doses (1,000-3,000 mg / day) may also be effective. Because weights in mg are often corrected for the patient's weight in kg, these exemplary doses can also be described in mg per kg of body weight per day (mg / kg).

[0085]

[0085] In practice, a therapeutically effective amount may vary depending on numerous factors related to the patient, including age, weight, height, severity of the condition, the technique of administration, and other factors. The therapeutically effective amount to be administered to a patient can be determined by a medical professional taking into account the relevant circumstances.

[0086]

[0086] Therapeutically effective amounts can be determined or predicted from empirical evidence. The specific dosage may vary depending on a number of factors and may be initially determined empirically.

[0087] The compositions can be administered as a single dose or as part of a dosing regimen in which the therapeutically effective amount is a dose that can be adjusted to provide the desired therapeutic response.

[0088]

[0088] Multiple doses may be administered at predetermined time intervals, with subsequent doses being relatively lower or higher depending on the circumstances.

[0089]

[0089] When this disclosure refers to treating a medical condition, it should be understood that the terms "treat," "treatment," or other variations of the word "treat" include prevention of the condition, management of the condition, and substantial symptomatic relief from the condition.

[0090]

[0090] The composition may be prepared by making the pellets and carrier material separately and then combining them into the final dosage form. If the carrier material is a liquid, the pellets may be added directly to the liquid.

[0091]

[0091] When the carrier material is a gummy, the pellets can be combined with a gelling agent prior to gelling, and then the gelling process can be carried out with the pellets inside, positioning the pellets within the gummy so that when the gummy is placed in the mouth and the pellets are chewed or swallowed, the pellets are delivered to the mouth and gastrointestinal tract.

[0092]

[0092] Pellets can be prepared by obtaining solid cores of a desired size and applying a coating. The active coating can be applied to the solid cores by coating the solid cores with an active coating material. The active coating material can be a solution of melatonin, a binder, and water. Coating the solid cores with the active coating can be performed by fluidized bed coating or the like. The active coating can be allowed to dry on the cores.

[0093]

[0093] The enteric coating may be applied using conventional enteric coating techniques, such as fluidized bed coating. The enteric coating may be dried after application. [Example]

[0094] The following examples are provided to illustrate the aspects of certain embodiments of the compositions, and the scope of possible embodiments is not limited to the details of these examples.

[0095]

[0095] Specific examples of compositions are prepared according to the following procedures.

[0096] 200 kg of MCC inert nonpareil spheres (VIVAPUR® Grade 1000 with a diameter of 1 mm to 1.4 mm) are loaded into a Wurster Model 3200 fluid bed coater. 10 kg of micronized melatonin dispersed in a 10% aqueous solution of HPMC (PHARMACOAT® 603) is gradually spray coated onto the MCC spheres at inlet air temperatures up to 100°F.

[0097] After the micronized melatonin is sprayed onto the nonpareil spheres, 5 g of a 10% aqueous solution of HPMC (PHARMACOAT® 603) is spray coated onto the micronized melatonin layer.

[0098] 50 kg of citric acid dissolved in a 10% aqueous solution of HPMC (PHARMACOAT® 603) is spray coated onto the HPMC layer.

[0099]

[0099] 32 kg dry weight of an enteric coating suspension containing 27.7 kg KOLLICOAT® MAE 30D, 2.8 kg PLASACRYL® T20, and 1.5 kg triethyl citrate is spray coated onto the citric acid layer.

[0100]

[0100] After the coated spheres leave the coater, they are classified to remove any agglomerated spheres or fines.

[0101] The finished enteric-coated spheres are added to HPMC gummies at the beginning of the gelling / incubation / hardening period, targeting anywhere from 0.05 mg to 20 mg of melatonin per gummies. The pH of the gummies matrix is ​​kept below 4.0 using an acceptable buffer or acid. Colors or flavors may be added to the gummies as needed.

[0102]

[0102] This disclosure describes exemplary embodiments, but does not describe all possible embodiments of the compositions and methods. When a particular feature is disclosed in the context of a particular example, that feature can also be used in combination with and / or in the context of other examples, to the extent possible. The compositions and methods can be embodied in many different forms and should not be construed as limited to only the examples set forth herein.

[0103]

[0103] The compositions and methods are not limited to the details described in connection with the exemplary embodiments. There are many variations and modifications of the compositions that can be made and the methods that can be carried out without departing from the scope of what is claimed.

Claims

1. 1. A composition comprising a therapeutically effective oral pharmaceutical dosage form, comprising: (a) an aqueous carrier material having an acidic pH; and (b) a plurality of individual pellets having a first dose of melatonin therein, the individual pellets comprising: (i) a solid core; (ii) an active coating on the solid core, the active coating comprising melatonin and a hydrophilic binder; and (iii) an enteric coating on the active coating, the enteric coating having a dissolution pH greater than the acidic pH of the aqueous carrier material. A composition comprising:

2. 2. The composition of claim 1, wherein the melatonin is a powder having a median melatonin size of 5 μm to 40 μm.

3. 10. The composition of claim 1, wherein the aqueous carrier material contains a second dose of melatonin therein, and the dosage form releases the second dose of melatonin to the oral cavity and stomach of the subject.

4. 10. The composition of claim 1, wherein the dosage form is a beverage and the aqueous carrier material comprises water.

5. 10. The composition of claim 1, wherein the dosage form is a gummy and the aqueous carrier material is a gummy gelling agent.

6. the individual pellets further comprising an isolation coating on the active coating, a subcoat on and between the isolation coatings, and an enteric coating on the subcoat; the subcoat comprising a hydrogel-forming polymer and an acid, the acid imparting a pH of 0.1 to 4.4 to the hydrogel-forming polymer; 10. The composition of claim 1, wherein the separating coating separates the acid from the melatonin.

7. 7. The composition of claim 6, wherein the aqueous carrier material is hydroxypropyl methylcellulose, the solid core is a microcrystalline cellulose bead having a diameter of 0.1 to 2 mm, the hydrophilic binder comprises hydroxypropyl methylcellulose, the melatonin is a powder held by the hydrophilic binder and having a melatonin median size of 5 μm to 40 μm, the isolating coating comprises hydroxypropyl methylcellulose, the hydrogel-forming polymer comprises hydroxypropyl methylcellulose, the acid comprises citric acid, and the isolating coating comprises hydroxypropyl methylcellulose.

8. The composition of claim 1, comprising any combination of the features of any one of claims 2 to 7.

9. 1. A method comprising administering a therapeutically effective amount of an oral pharmaceutical dosage form to a patient in need thereof, said dosage form comprising: (a) an aqueous carrier material having an acidic pH; and (b) a plurality of individual pellets having a first dose of melatonin therein, the individual pellets comprising: (i) a solid core; (ii) an active coating on the solid core, the active coating comprising melatonin and a hydrophilic binder; and (iii) an enteric coating on the active coating, the enteric coating having a dissolution pH greater than the acidic pH of the aqueous carrier material. A method comprising:

10. 10. The method of claim 9, wherein the melatonin is a powder having a median melatonin size of 5 μm to 40 μm.

11. 10. The method of claim 9, wherein the aqueous carrier material comprises a second dose of melatonin therein, and the dosage form releases the second dose of melatonin to the oral cavity and stomach of the subject.

12. 10. The method of claim 9, wherein the dosage form is a beverage and the aqueous carrier material comprises water.

13. 10. The method of claim 9, wherein the dosage form is a gummy and the aqueous carrier material is a gummy gelling agent.

14. the individual pellets further comprising an isolation coating on the active coating, a subcoat on and between the isolation coatings, and an enteric coating on the subcoat; the subcoat comprising a hydrogel-forming polymer and an acid, the acid imparting a pH of 0.1 to 4.4 to the hydrogel-forming polymer; the separating coating separates the acid from the melatonin; 10. The method of claim 9.

15. 15. The method of claim 14, wherein the aqueous carrier material is hydroxypropyl methylcellulose, the solid core is a microcrystalline cellulose bead having a diameter of 0.1 to 2 mm, the hydrophilic binder comprises hydroxypropyl methylcellulose, the melatonin is a powder retained by the hydrophilic binder and having a melatonin median size of 5 μm to 40 μm, the isolating coating comprises hydroxypropyl methylcellulose, the hydrogel-forming polymer comprises hydroxypropyl methylcellulose, the acid comprises citric acid, and the isolating coating comprises hydroxypropyl methylcellulose.

16. 10. The method of claim 9, wherein the dosage form is therapeutically effective to aid sleep in the patient.

17. The method according to claim 9, comprising any combination of the features according to any one of claims 10 to 16.

18. 1. A method comprising combining an aqueous carrier material with a plurality of individual pellets to form a therapeutically effective oral pharmaceutical dosage form, comprising: the aqueous carrier material has an acidic pH; The method of claim 1, wherein the plurality of individual pellets have a first dose of melatonin therein and comprise: (i) a solid core; (ii) an active coating on the solid core, the active coating comprising melatonin and a hydrophilic binder; and (iii) an enteric coating on the active coating, the enteric coating having a dissolution pH greater than the acidic pH of the aqueous carrier material.

19. 19. The method of claim 18, wherein the melatonin is a powder having a melatonin median size of 5 μm to 40 μm.

20. 20. The method of claim 18, wherein the aqueous carrier material comprises a second dose of melatonin therein, and the dosage form releases the second dose of melatonin to the oral cavity and stomach of the subject.

21. 20. The method of claim 18, wherein the dosage form is a beverage and the aqueous carrier material comprises water.

22. 20. The method of claim 18, wherein the dosage form is a gummy and the aqueous carrier material is a gummy gelling agent.

23. the individual pellets further comprising an isolation coating on the active coating, a subcoat on and between the isolation coatings, and an enteric coating on the subcoat; the subcoat comprising a hydrogel-forming polymer and an acid, the acid imparting a pH of 0.1 to 4.4 to the hydrogel-forming polymer; 19. The method of claim 18, wherein the separating coating separates the acid from the melatonin.

24. 24. The method of claim 23, wherein the aqueous carrier material is hydroxypropyl methylcellulose, the solid core is a microcrystalline cellulose bead having a diameter of 0.1 to 2 mm, the hydrophilic binder comprises hydroxypropyl methylcellulose, the melatonin is a powder retained by the hydrophilic binder and having a melatonin median size of 5 μm to 40 μm, the isolating coating comprises hydroxypropyl methylcellulose, the hydrogel-forming polymer comprises hydroxypropyl methylcellulose, the acid comprises citric acid, and the isolating coating comprises hydroxypropyl methylcellulose.

25. The method according to claim 18, comprising any combination of the features according to any one of claims 19 to 24.

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