Melatonin mini-tablets and method of manufacturing the same
Inventors
Assignees
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Publication Number
US-10849856-B2
Publication Date
2020-12-01
Expiration Date
Abstract
A patient-friendly drug delivery system and method for targeted populations, such as pediatric and geriatric patients is provided, which system and method include a pharmaceutical composition in the form of mini-tablets. A method of inducing and maintaining sleep in a human in need thereof with the mini-tablets is provided. A method of manufacturing mini-tablets is provided.
Core Innovation
The invention relates to controlled-release melatonin mini-tablets for oral ingestion by a human patient. The mini-tablets contain 2 mg melatonin and one or more pharmaceutically acceptable carriers, and have a diameter of less than or equal to 4 mm. The mini-tablets are formulated to provide a release profile of less than 50% melatonin release within 1 hour and about greater than 70% melatonin release within 6 hours.
A key aspect of the controlled-release mini-tablets is the specified carrier system and weight-ratio constraint. The mini-tablets contain ammonio methacrylate copolymer, calcium hydrogen phosphate dihydrate, and lactose monohydrate, and the ratio between melatonin, ammonio methacrylate copolymer, calcium hydrogen phosphate dihydrate and lactose monohydrate by weight is 1:1.1-5.9:0.8-8.3:1.8-8.8. The release over time is structured to achieve a substantially normal endogenous melatonin plasma profile.
The invention also addresses the problem of providing controlled release performance with improved predictability, using formulation and design constraints that ensure acceptable melatonin release behavior. The disclosed methods include inducing and maintaining sleep by orally administering the controlled-release melatonin mini-tablets or a capsule containing the mini-tablets, and achieving a minimal blood level of about 60 to about 200 picograms melatonin per milliliter over at least four hours following administration without inducing unacceptable side effects.
Claims Coverage
The provided set includes four independent claims, covering the controlled-release melatonin mini-tablet formulation, a formulation designed to substantially simulate a normal endogenous melatonin plasma profile, a method of inducing and maintaining sleep, and a manufacturing method for the controlled-release mini-tablet. Across the independent claims, the inventive coverage centers on tightly defined tablet size, controlled-release performance, specified excipient components, and the by-weight ratio among melatonin and the specified carriers, with additional claim-specific performance and use elements.
Controlled-release melatonin mini-tablet with defined size and release fractions
A controlled-release melatonin mini-tablet having a diameter of less than or equal to 4 mm and a release profile of less than 50% melatonin release within 1 hour and about greater than 70% melatonin release within 6 hours of oral ingestion by a human patient.
Specific carrier components with defined by-weight ratio
The mini-tablet contains ammonio methacrylate copolymer, calcium hydrogen phosphate dihydrate, lactose monohydrate, wherein the ratio between melatonin, ammonio methacrylate copolymer, calcium hydrogen phosphate dihydrate and lactose monohydrate by weight is 1:1.1-5.9:0.8-8.3:1.8-8.8.
Plasma melatonin profile substantially simulating normal endogenous melatonin
A pharmaceutical controlled-release mini-tablet formulation releases melatonin over time such that the patient's melatonin plasma profile substantially simulates the melatonin plasma profile of a human having a normal endogenous melatonin profile.
Method of inducing and maintaining sleep with minimal blood level constraint
A method of inducing and maintaining sleep in a human comprising providing a pharmaceutical product comprising controlled-release melatonin mini-tablets capable of inducing sleep and achieving a minimal blood level of about 60 to about 200 picograms melatonin per milliliter over at least four hours following administration without inducing unacceptable side effects.
Oral administration using the specified mini-tablet product
Orally administering the controlled-release melatonin mini-tablets or the capsule to the patient, where each mini-tablet contains 2 mg melatonin and has a diameter of less than or equal to 4 mm and a release profile of less than 50% melatonin release within 1 hour and about greater than 70% melatonin release within 6 hours.
Manufacturing by combining and compressing to achieve controlled-release fractions
A method of manufacturing comprising combining melatonin and one or more pharmaceutically acceptable carriers to produce a mixture and compressing the mixture into a mini-tablet such that the mini-tablet has a controlled-release profile of less than 50% melatonin released within 1 hour of dissolution and about greater than 70% melatonin released within 6 hours of dissolution.
Taken together, the independent claims define a controlled-release melatonin mini-tablet with a diameter of ≤4 mm and specified early/late release fractions, a formulation whose plasma melatonin profile substantially simulates normal endogenous melatonin, a method of inducing and maintaining sleep using mini-tablets that additionally achieve a specified minimal blood melatonin level over at least four hours without unacceptable side effects, and manufacturing by combining and compressing a melatonin/carrier mixture to meet the same controlled-release profile, all with a specified excipient set and by-weight ratio.
Stated Advantages
Achievement of a controlled-release profile with less than 50% melatonin release within 1 hour and about greater than 70% melatonin release within 6 hours of oral ingestion.
Ability to achieve a minimal blood level of about 60 to about 200 picograms melatonin per milliliter over at least four hours following administration.
Capability to induce sleep and maintain sleep in a human without inducing unacceptable side effects.
Patient melatonin plasma profile substantially simulates the melatonin plasma profile of a human having a normal endogenous melatonin profile.
Documented Applications
Inducing and maintaining sleep in a human in need thereof by orally administering one or more controlled-release melatonin mini-tablets or a capsule.
Inducing sleep in a patient as part of a method using controlled-release melatonin mini-tablets achieving minimal blood melatonin levels over at least four hours.
Inducing and maintaining a melatonin plasma profile that substantially simulates that of a human having a normal endogenous melatonin profile.
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