NZ782840B2 - Melatonin mini-tablets and method of manufacturing the same - Google Patents

Melatonin mini-tablets and method of manufacturing the same

Info

Publication number
NZ782840B2
NZ782840B2 NZ782840A NZ78284016A NZ782840B2 NZ 782840 B2 NZ782840 B2 NZ 782840B2 NZ 782840 A NZ782840 A NZ 782840A NZ 78284016 A NZ78284016 A NZ 78284016A NZ 782840 B2 NZ782840 B2 NZ 782840B2
Authority
NZ
New Zealand
Prior art keywords
melatonin
mini
release
tablet
controlled
Prior art date
Application number
NZ782840A
Other versions
NZ782840A (en
Inventor
Moshe Laudon
Nava Zisapel
Original Assignee
Neurim Pharmaceuticals Ltd
Filing date
Publication date
Application filed by Neurim Pharmaceuticals Ltd filed Critical Neurim Pharmaceuticals Ltd
Priority claimed from NZ747702A external-priority patent/NZ747702A/en
Publication of NZ782840A publication Critical patent/NZ782840A/en
Publication of NZ782840B2 publication Critical patent/NZ782840B2/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives

Abstract

The instant invention is generally directed to a patient-friendly drug delivery system for targeted populations, such as pediatric and geriatric patients. Specifically, the present invention relates to a pharmaceutical composition in the form of mini-tablets. Even more specifically, the present invention relates to a controlled-release matrix formulation comprising a therapeutically-effective amount of melatonin of between 1-10mg in the form of mini-tablets, further comprising pharmaceutically acceptable carriers within the matrix formulation comprising at least one release controlling agent, at least one water soluble compound, and at least one diluent or filler for control of the flowability and compaction properties of the matrix for tableting, wherein the mini-tablet 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.

Claims (24)

1. A controlled-release matrix formulation melatonin mini-tablet comprising: a therapeutically effective amount of melatonin of between 1 – 10 mg; and pharmaceutically acceptable carriers within the matrix formulation comprising at least a release controlling agent, a water soluble compound, and a diluent or filler for control of the flowability and compaction properties of the matrix for tableting; wherein the mini-tablet has a diameter of less than or equal to 4 mm and has a release profile of less than 50% melatonin release within 1 hour, and about greater than 70% melatonin release within 6 hours measured by in vitro dissolution of melatonin therefrom in distilled water at 37° C.
2. The controlled-release melatonin mini-tablet of claim 1, wherein the mini-tablet is formulated such that it produces a minimal blood level of about 60 to about 200 picograms melatonin per milliliter over at least four hours after oral ingestion of the controlled-release melatonin mini-tablet by a human patient.
3. The controlled-release melatonin mini-tablet of claim 1, wherein the mini-tablet is formulated such that it produces a minimal blood level of about 100 to about 200 picograms melatonin per milliliter over at least four hours after oral ingestion of the controlled-release melatonin mini-tablet by a human patient.
4. The controlled-release melatonin mini-tablet of claims 1 to 3, wherein the mini-tablet contains one or more of ammonio methacrylate copolymer, calcium hydrogen phosphate dihydrate, lactose monohydrate.
5. The controlled-release melatonin mini-tablet of claim 4, wherein the ammonio methacrylate copolymer is ammonio methacrylate copolymer type A or ammonio methacrylate copolymer type B.
6. The controlled-release melatonin mini-tablet of claim 4 or claim 5, 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.
7. The controlled-release melatonin mini-tablet of any one of claims 1 to 6, wherein the mini-tablet comprises a fast dissolving sugar or alcohol that is not lactose.
8. The controlled-release melatonin mini-tablet of any one of claims 1 to 7, wherein the mini-tablet is coated with a pharmaceutically acceptable coating.
9. A method of manufacturing a controlled-release matrix formulation melatonin mini-tablet, the method comprising: combining a therapeutically effective amount of melatonin of between 1 – 10 mg and pharmaceutically acceptable carriers within the matrix formulation comprising at least a release controlling agent, a water soluble compound, and a diluent or filler for control of the flowability and compaction properties of the matrix for tableting, to produce a mixture; and compressing the mixture into mini-tablets that each have a diameter of less than or equal to 4 mm such that the mini-tablet has a controlled-release profile of less than 50% melatonin released within 1 hour, and about greater than 70% melatonin released within 6 hours measured by in vitro dissolution of melatonin therefrom in distilled water at 37°
10. The method of claim 9, further comprising a step of coating the tablets with a pharmaceutically acceptable coating.
11. The method of claim 9 or claim 10, wherein the combining step comprises dry blending the therapeutically effective amount of melatonin and the one or more pharmaceutically acceptable carriers.
12. The method of any one of claims 9 to 11, wherein the one or more pharmaceutically acceptable carriers comprise a fast dissolving sugar or alcohol that is not lactose.
13. The method of any one of claims 9 to 12, wherein the pharmaceutically acceptable carriers comprise one or more of calcium hydrogen phosphate dihydrate, ammonio methacrylate copolymer, and lactose monohydrate.
14. Use of a controlled release matrix formulation melatonin mini-tablet comprising a therapeutically effective amount of melatonin; and pharmaceutically acceptable carriers within the matrix formulation comprising at least a release controlling agent, a water soluble compound, and a diluent or filler for control of the flowability and compaction properties of the matrix for tableting; wherein the mini-tablet has a diameter of less than or equal to 4 mm and has a release profile of less than 50% melatonin release within 1 hour, and about greater than 70% melatonin release within 6 hours measured by in vitro dissolution of melatonin therefrom in distilled water at 37° C, in the manufacture of a medicament for safely inducing sleep in a patient who has trouble sleeping, or who suffers from a melatonin deficiency or distortion in comparison to a person with a normal endogenous plasma melatonin profile.
15. The use of claim 14, wherein the patient is a pediatric patient.
16. The use of claim 14, wherein the patient is a geriatric patient.
17. The use of any one of claims 14 to 16, wherein the patient has difficulty swallowing tablets or capsules.
18. The use of any one of claims 14 to 17 wherein the patient is one or more of: a) a disabled patient, b) a patient who has an autism spectrum disorder, and c) a patient who has a neurogenetic disease.
19. The use of any one of claims 14 to 18, wherein the therapeutically effective amount is between1- 10 mg.
20. The use of any one of claims 14 to 19, wherein the mini-tablet comprises one or more of calcium hydrogen phosphate dihydrate, ammonia methacrylate copolymer, and lactose monohydrate.
21. The use of any one of claims 14 to 20, wherein the mini-tablet is to be administered before sleep.
22. The use of any one of claims 14 to 20, wherein the mini-tablet is to be administered between a first sleep period and a second sleep period.
23. Use of one or more controlled-release matrix formulation melatonin mini-tablets as claimed in any one of claims 1 to 8 in the manufacture of a medicament for safely inducing and maintaining sleep in a patient in need thereof wherein said one or more controlled-release matrix formulation melatonin mini- tablets are formulated to achieve 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 in a human, and wherein said medicament is manufactured by combining a therapeutically effective amount of melatonin and pharmaceutically acceptable carriers to produce a mixture, compressing the mixture into one or more mini-tablets that each have a diameter of less than or equal to 4 mm such that each mini-tablet has a release profile of less than 50% melatonin release within 1 hour, and about greater than 70% melatonin release within 6 hours measured by in vitro dissolution of melatonin therefrom in distilled water at 37° C, and optionally filling a plurality of the mini-tablets into a capsule.
24. The controlled release matrix formulation melatonin mini-tablet of any one of claims 1 to 8 wherein, upon administration to a patient, the 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.
NZ782840A 2016-11-29 Melatonin mini-tablets and method of manufacturing the same NZ782840B2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201662415014P 2016-10-31 2016-10-31
NZ747702A NZ747702A (en) 2016-10-31 2016-11-29 Melatonin mini-tablets and method of manufacturing the same

Publications (2)

Publication Number Publication Date
NZ782840A NZ782840A (en) 2025-02-28
NZ782840B2 true NZ782840B2 (en) 2025-06-04

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