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WO2025172348A1 - Formulation orale à double libération pulsée retardée - Google Patents

Formulation orale à double libération pulsée retardée

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Publication number
WO2025172348A1
WO2025172348A1 PCT/EP2025/053697 EP2025053697W WO2025172348A1 WO 2025172348 A1 WO2025172348 A1 WO 2025172348A1 EP 2025053697 W EP2025053697 W EP 2025053697W WO 2025172348 A1 WO2025172348 A1 WO 2025172348A1
Authority
WO
WIPO (PCT)
Prior art keywords
hpc
wax
core
formulation according
tablet formulation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/053697
Other languages
English (en)
Inventor
Muhammad Tariqul ISLAM
Kenneth Vielsted CHRISTENSEN
René HOLM
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Contera Pharma AS
Original Assignee
Contera Pharma AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Contera Pharma AS filed Critical Contera Pharma AS
Publication of WO2025172348A1 publication Critical patent/WO2025172348A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K9/2806—Coating materials
    • A61K9/288—Compounds of unknown constitution, e.g. material from plants or animals

Definitions

  • the present disclosure relates to a pulsatile release tablet formulation that enables a delayed pulse release of two or more active agents.
  • Parkinson’s disease is a progressive neurological condition with disabling symptoms of tremor, rigidity and bradykinesia or akinesia. The symptoms are related to a depletion of dopamine in the corpus striatum of the brain. Dopamine cannot be administered orally or systemically due to its inability to cross the blood brain barrier. Levodopa is an exogenous dopamine precursor which is converted to dopamine after moving across the blood brain barrier.
  • Levodopa is administered orally in the treatment of Parkinson’s disease alongside a DOPA decarboxylase inhibitor, such as Carbidopa, which prevents peripheral metabolism of Levodopa thus enhancing central nervous system bioavailability, reducing the overall dose of Levodopa required and minimising Levodopa related side effects.
  • Patients treated with Levodopa often develop motor fluctuations such as peak dose dyskinesia or end of dose akinesia. Producing a steady plasma level of Levodopa can attenuate these symptoms.
  • Mobility problems and recurring tremor early in the morning before the first intake of levodopa are early events in the development of motor complications associated with sustained oral levodopa treatment of Parkinson’s Disease, PD.
  • Recent surveys have indicated that early morning akinesia (or morning OFF episodes) are present in around 60% of PD patients across all disease stages and that a similar number of patients are affected by nocturnal immobility with difficulties turning in bed. In most patients experiencing early morning akinesia, this is associated with non-motor symptoms such as anxiety, depression, pain, and urinary urge.
  • Levodopa is routinely administered in combination with a DOPA decarboxylase inhibitor such as carbidopa that prevents the conversion of levodopa to dopamine in the peripheral circulation before it can reach the brain and take effect, thereby allowing more levodopa to cross the blood-brain barrier into the central nervous system (CNS).
  • Carbidopa enables a much lower dose of levodopa (80% less) and helps reduce the side effects of nausea and vomiting.
  • circulating levodopa is primarily metabolized by catechol-O- methyltransferase (COMT) to 3-O-methyldopa (3-OMD).
  • COMT inhibitors in combination with levodopa/DOPA decarboxylase inhibitor preparations are associated with an increase of CNS bioavailability of levodopa.
  • Carbidopa/levodopa tablets are available in immediate-release (IR) and extended- release (ER) forms as well as dissolvable tablets that are placed under the tongue.
  • IR immediate-release
  • ER extended- release
  • a small, portable infusion pump delivers carbidopa and levodopa directly into the small intestine. It has been suggested that pretreatment with carbidopa prior to levodopa in some instances increases levodopa plasma AUC compared to simultaneous administration (see e g. Leppert et al. 1988).
  • the present inventors have developed a delayed release dual pulse combined Carbidopa/Levodopa tablet formulation for improved management of nocturnal hypomobility and morning akinesia in individuals with Parkinson’s disease.
  • a combined or single-tablet formulation as provided herewith is shown to provide a clear and defined burst release.
  • the formulation can be taken at bedtime to release a first delayed pulse of Carbidopa about 4 to 6 hours after oral administration followed by release of a second delayed pulse of Levodopa which is delayed about 0.5 to 1 hr longer than the first delayed pulse.
  • therapeutically relevant plasma levels and central levels of Levodopa can be delivered prior to waking and offering potential relief from nocturnal hypomobility and morning akinesia.
  • the present disclosure provides a tablet formulation, such as a press-coated tablet, for oral administration of two or more active agents, the tablet comprising: i) A core, such as a triple-layer core, comprising or consisting of a.
  • a first core, or first core layer comprising an amount of a first active agent and one or more excipients, wherein said first active agent prevents peripheral metabolism of levodopa (L-DOPA); such as wherein said first active agent is a DOPA decarboxylase inhibitor and/or a COMT inhibitor; alternatively wherein said first active agent is selected from dopamine, a dopamine agonist, a dopamine precursor and a dopamine prodrug; and b.
  • L-DOPA levodopa
  • the release of the two or more active agents is delayed for 2 to 10 hours after placing in an aqueous solution; such as placing in 500 ml aqueous solution comprising 0.1 N HCI at 37°C +/- 0.5°C at 50 rpm.
  • the delayed release layer and the barrier layer comprises a wax and one or more low-substituted hydroxypropyl cellulose (L-HPC), and optionally further comprising a hydroxypropyl cellulose (HPC).
  • L-HPC low-substituted hydroxypropyl cellulose
  • HPC hydroxypropyl cellulose
  • the first active agent is a DOPA decarboxylase inhibitor and the second active agent is levodopa, or a pharmaceutically acceptable derivative thereof.
  • the DOPA decarboxylase inhibitor is carbidopa, or a pharmaceutically acceptable derivative thereof.
  • FIG. 1 Illustration of prototypes 1 to 5: Pulsatile release tablet formulations comprising carbidopa (CD) as a first active agent and levodopa (LD) as a second active agent.
  • the tablet formulations comprise a core comprising the first and second active agent surrounded by an outer delayed release layer (see Example 1).
  • Figure 2 Representative anterior scintigraphic images with overlaid standard stomach outline for subject dosed with Treatment A at four time points post-dose, a) 90 mins post dose, tablet located in stomach, b) 270 mins post dose, tablet located in small intestine, c) 300 mins post dose, onset of radiolabel release in small intestine, d) 330 mins post dose, released activity in small intestine (see Example 2).
  • Figure 3 Representative anterior scintigraphic images with overlaid standard stomach outline for subject dosed with Treatment B at four time points post-dose, a) 0 mins post dose, tablet located in stomach, b) 60 mins post dose, tablet located in stomach, c) 390 mins post dose, onset of radiolabel release in stomach, d) 480 mins post dose, released activity in small intestine (see Example 2).
  • Dopamine refers to a catecholamine neurotransmitter and hormone.
  • Dopamine is a precursor of adrenaline (epinephrine) and noradrenaline (norepinephrine) and activates the five types of dopamine receptors - D1 , D2, D3, D4, and D5 - and their variants.
  • L-DOPA 3-hydroxyphenylalanine
  • levodopa is a precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline). L-DOPA is able to cross the blood-brain barrier, and is used for treatment of Parkinson’s disease and dopamine-responsive dystonia.
  • pharmaceutically acceptable derivative in present context includes pharmaceutically acceptable salts, which indicate a salt which is not harmful to the patient. Such salts include pharmaceutically acceptable basic or acid addition salts as well as pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium salts.
  • a pharmaceutically acceptable derivative further includes esters, solvates and prodrugs, or other precursors of a compound which may be biologically metabolized into the active compound, and crystal and cocrystal forms of a compound.
  • a prodrug is a pharmacologically inactive compound that, after intake, is converted into a pharmacologically active drug.
  • Parkinson's disease refers to a neurological syndrome characterized by a dopamine deficiency, resulting from degenerative, vascular, or inflammatory changes in the basal ganglia of the substantia nigra. This term also refers to a syndrome which resembles Parkinson's disease, but which may or may not be caused by Parkinson's disease, such as Parkinsonian-like side effects caused by certain antipsychotic drugs and parkinsonism.
  • terapéuticaally effective amount of a compound as used herein refers to an amount sufficient to cure, alleviate, prevent, reduce the risk of, or partially arrest the clinical manifestations of a given disease or disorder and its complications.
  • treatment refers to the management and care of a patient for the purpose of combating a condition, disease or disorder.
  • the term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound for the purpose of: alleviating or relieving symptoms or complications; delaying the progression of the condition, disease or disorder; curing or eliminating the condition, disease or disorder; and/or preventing the condition, disease or disorder, wherein “preventing” or “prevention” is to be understood to refer to the management and care of a patient for the purpose of hindering the development of the condition, disease or disorder, and includes the administration of the active compounds to prevent or reduce the risk of the onset of symptoms or complications.
  • the patient to be treated is preferably a mammal, in particular a human being.
  • “approximately” and “about” as referred herein are synonymous. In some embodiments, “approximately” and “about” refer to the recited amount, value, or duration ⁇ 5%, ⁇ 4.5%, ⁇ 4%, ⁇ 3.5%, ⁇ 3%, ⁇ 2.5%, ⁇ 2%, ⁇ 1.75%, ⁇ 1.5%, ⁇ 1.25%, ⁇ 1 %, ⁇ 0.9%, ⁇ 0.8%, ⁇ 0.7%, ⁇ 0.6%, ⁇ 0.5% ⁇ 0.4%, ⁇ 0.3%, ⁇ 0.2%, ⁇ 0.1 %.
  • “approximately” and “about” refer to the listed amount, value, or duration ⁇ 2.5%, ⁇ 2%, ⁇ 1.75%, ⁇ 1.5%, ⁇ 1.25%, ⁇ 1%, ⁇ 0.9%, ⁇ 0.8%, ⁇ 0.7%, ⁇ 0.6%, ⁇ 0.5%. In some embodiments, “approximately” and “about” refer to the listed amount, value, or duration ⁇ 1%. In some embodiments, “approximately” and “about” refer to the listed amount, value, or duration ⁇ 0.5%. In some embodiments, “approximately” and “about” refer to the listed amount, value, or duration ⁇ 0.1%.
  • a tablet formulation refers to solid dosage forms designed for oral administration, and typically comprises one or more active agent(s) and other excipients that are required to enable the pharmacokinetic and mechanical properties of the final dosage form. These excipients are primarily diluents or fillers, compressing agents, binders, disintegrants and lubricants.
  • tablette formulation refers to a solid oral dosage form which is a tablet formulation comprising a core, such as a triple-layer core, and an outer delayed release layer surrounding said core.
  • triple-layer core refers to a tablet core comprising two cores or core layers (‘dosage units’), each core or core layer comprising an amount of an API, and having a barrier layer between said two cores or core layers.
  • two or more active agents herein refers to a first active agent and a second active agent as follows:
  • references to a ‘first active agent’ refers to an agent that prevents peripheral metabolism of levodopa (L-DOPA); alternatively an agent selected from dopamine, a dopamine agonist, a dopamine precursor and a dopamine prodrug;
  • L-DOPA levodopa
  • Reference to a ‘second active agent’ refers to an agent selected from dopamine, a dopamine agonist, a dopamine precursor and a dopamine prodrug.
  • a ‘binder’ (tablet binder) or binding agent is an excipient used in oral solid dosage forms that helps bind excipients together and ensuring mechanical strength and proper release (also known as an adhesive). Binders are added in a formulation to form granules either in dry or liquid form during wet granulation or in dry form during dry granulation or directly compressed tablets. Tablet binders and disintegrants have the opposite use in an oral solid formulation; binders delay tablet disintegration while disintegrants increases tablet disintegration.
  • a ‘filler’ is an excipient used in oral solid dosage forms (also known as a diluent).
  • the main function of the filler is to increase the weight or volume of the tablet to increase tablet size, facilitate compression and reduce the cost of the solid material.
  • the filler may also be added to improve the performance of the material.
  • organic, inorganic, metal or non-metal powders that do not contain water, are neutral, and do not play a negative role with the material components can be used as fillers.
  • Commonly used fillers include starches, sugars, celluloses and inorganic salts.
  • the filler can be water-soluble or water-insoluble.
  • Waxes are a diverse class of organic compounds that are lipophilic, malleable solids near ambient temperatures. They include higher alkanes and lipids, typically with melting points above about 40 °C (104 °F), melting to give low viscosity liquids. Waxes are insoluble in water but soluble in nonpolar organic solvents. Natural waxes of different types are produced by plants and animals and occur in petroleum. Natural waxes may contain unsaturated bonds and include various functional groups such as fatty acids, primary and secondary alcohols, ketones, aldehydes and fatty acid esters. Synthetic waxes often consist of homologous series of long-chain aliphatic hydrocarbons (alkanes or paraffins) that lack functional groups.
  • wax as used herein also comprises Water soluble waxes or Carbowax, which are polyethylene glycols (PEG) of varying degrees of polymerization and molecular weights, or polyethylene glycol fatty acid esters, such as polyethylene glycol monostearate.
  • PEGs differ in their physical and chemical properties depending on their molecular weight: PEGs are liquids when molecular weights are ⁇ 1000 and the molecule turns to waxy solids with increasing molecular weights.
  • Pulsatile drug delivery is defined as the rapid and transient release of an active agent within a short time period immediately after a predetermined off-released period, i.e., lag time.
  • Pulsatile drug delivery systems deliver the active agent at the right time, at the right site of action and in the right amount, and the active agent is released rapidly and completely as a pulse (or burst) after a lag time.
  • Lag time is defined as the time between when a dosage form is placed into an aqueous environment and the time at which the active agent begins to release from the dosage form.
  • the present disclosure provides a tablet formulation for oral administration that provides for a delayed, followed by a pulsed release of two or more active agents, preferably two active agents, i.e. the first and second active agent according to the present disclosure.
  • the first active agent is an agent that prevents peripheral metabolism of levodopa (L-DOPA); alternatively an agent selected from dopamine, a dopamine agonist, a dopamine precursor and a dopamine prodrug.
  • the second active agent is an agent selected from dopamine, a dopamine agonist, a dopamine precursor and a dopamine prodrug.
  • the release of the two or more active agents is delayed for about 2 to 10 hours after oral administration, whereafter the two or more active agents are pulse released to target the desired time and place of release.
  • the two or more active agents may be pulse released essentially at the same time after the delay of 2 to 10 hours.
  • the two agents are pulse released at differing times after the delay such that the first active agent is released before the second active agent is released.
  • the release of the second active agent is delayed for about 10 to 120 minutes more than the release of the first active agent, which releases after about 2 to 10 hours delay. This provides for a delayed first pulse release of first active agent, followed within 10 to 120 minutes by a delayed second pulse release of a second active agent.
  • a tablet formulation for oral administration that provides for a 2 to 10 hours delayed, followed by a pulsed release of a first active agent that prevents peripheral metabolism of levodopa; for example a DOPA decarboxylase inhibitor such as carbidopa, or a pharmaceutically acceptable derivative thereof; and a second active agent which is levodopa, or a pharmaceutically acceptable derivative thereof.
  • the pulse release of the second active agent is delayed for 10 to 120 minutes after the pulse release of the first active agent.
  • a tablet formulation for oral administration that provides for a 2 to 10 hours delayed, followed by a first pulsed release of a DOPA decarboxylase inhibitor such as carbidopa, or a pharmaceutically acceptable derivative thereof, followed by a second pulse release of levodopa, or a pharmaceutically acceptable derivative thereof; wherein the DOPA decarboxylase inhibitor is pulse released before levodopa to mimic DOPA decarboxylase inhibitor pre-treatment.
  • a DOPA decarboxylase inhibitor such as carbidopa, or a pharmaceutically acceptable derivative thereof
  • a tablet formulation for oral administration of two or more active agents comprising: i) A core, such as a triple-layer core, comprising or consisting of a.
  • a first core, or first core layer comprising an amount of a first active agent and one or more excipients, wherein said first active agent prevents peripheral metabolism of levodopa (L-DOPA); alternatively wherein said first active agent is selected from dopamine, a dopamine agonist, a dopamine precursor and a dopamine prodrug, b.
  • a barrier layer interposed between the first and the second core, or first and second core layer said barrier layer comprising or consisting of a wax and one or more binders and/or fillers, such as comprising one or more binders selected from L-HPC, HPC and other binders, and ii) A delayed release layer surrounding the core, or triple-layer core, said delayed release layer comprising or consisting of a wax and one or more binders and/or fillers, such as comprising one or more binders selected from L-HPC, HPC, and other binders, wherein the release of the two or more active agents is delayed for 2 to 10 hours and thereafter the two or more active agents are pulse released, such that at least 70% by weight of the amount of the two or more active agents in the first and second core, or core layer, is released within 5 to 80 minutes.
  • a tablet formulation for oral administration of two active agents In a preferred embodiment there is provided a tablet formulation for oral administration of exactly two active agents, or not more than two active agents.
  • the barrier layer does not comprise an active agent.
  • first core, or first core layer comprises an amount of a single or sole first active agent (i.e. does not contain further active agents).
  • second core, or second core layer comprises an amount of a single or sole second active agent (i.e. does not contain further active agents).
  • Reference to ‘the two or more active agents are pulse released’ means that the ‘the two or more active agents are pulse released from the core’, specifically from the first and second core, or first and second core layer, respectively.
  • a tablet formulation for oral administration of two or more active agents comprising: i) A core, such as a triple-layer core, according to the present disclosure, and ii) A delayed release layer surrounding the core, according to the present disclosure, wherein the delayed release layer delays the release of the two or more active agents for 2 to 10 hours and thereafter the two or more active agents are pulse released, such that at least 70% by weight of the amount of the two or more active agents is released within 5 to 80 minutes.
  • said tablet comprises: i) A triple-layer core, comprising or consisting of a.
  • a first core layer comprising an amount of a first active agent and one or more excipients, wherein said first active agent prevents peripheral metabolism of levodopa (L-DOPA); alternatively wherein said first active agent is selected from dopamine, a dopamine agonist, a dopamine precursor and a dopamine prodrug, b.
  • a second core layer comprising an amount of a second active agent and one or more excipients, wherein said second active agent is selected from dopamine, a dopamine agonist, a dopamine precursor and a dopamine prodrug, and c.
  • a barrier layer interposed between the first and the second core layer comprising or consisting of a wax and one or more binders and/or fillers, such as comprising one or more binders selected from L-HPC, HPC, and other binders, and ii) A delayed release layer surrounding the triple-layer core, said delayed release layer comprising or consisting of a wax and one or more binders and/or fillers, such as comprising one or more binders selected from L-HPC, HPC, and other binders.
  • a tablet formulation for oral administration of two or more active agents comprising: i) A core, such as a triple-layer core, comprising or consisting of a.
  • a first core, or first core layer comprising an amount of a first active agent and one or more excipients, wherein said first active agent prevents peripheral metabolism of levodopa (L-DOPA), and b.
  • a second core, or second core layer comprising an amount of a second active agent and one or more excipients, wherein said second active agent is levodopa, or a pharmaceutically acceptable derivative thereof, and c.
  • a barrier layer interposed between the first and the second core, or first and second core layer said barrier layer comprising or consisting of a wax and one or more binders and/or fillers, such as comprising one or more binders selected from L-HPC, HPC, and other binders, and ii) A delayed release layer surrounding the core, or the triple-layer core, said delayed release layer comprising or consisting of a wax and one or more binders and/or fillers, such as comprising one or more binders selected from L- HPC, HPC, and other binders, wherein the release of the two or more active agents is delayed for 2 to 10 hours and thereafter the two or more active agents are pulse released, such that at least 70% by weight of the amount of the two or more active agents is released from the first and second core, or core layer, within 5 to 80 minutes.
  • a tablet formulation for oral administration of two or more active agents comprising: i) A core, such as a triple-layer core, comprising or consisting of a.
  • a first core, or first core layer comprising an amount of a first active agent and one or more excipients, wherein said first active agent is selected from dopamine, a dopamine agonist, a dopamine precursor and a dopamine prodrug, and b.
  • a second core, or second core layer comprising an amount of a second active agent and one or more excipients, wherein said second active agent is selected from dopamine, a dopamine agonist, a dopamine precursor and a dopamine prodrug, and c.
  • the one or more excipients are one or more pharmaceutically acceptable excipients. In some embodiments the one or more excipients are one or more immediate release excipients.
  • the tablet formulation is a pulsatile release dosage form for oral administration.
  • first and second core, or first and second core layers are dosage units.
  • a tablet formulation for oral administration of two or more active agents comprising: i) A core, such as a triple-layer core, comprising or consisting of a.
  • a first core, or first core layer comprising an amount of a first active agent which is a DOPA decarboxylase inhibitor and/or a COMT inhibitor; and one or more excipients, and b.
  • a second core, or second core layer comprising an amount of a second active agent which is levodopa, or a pharmaceutically acceptable derivative thereof, and one or more excipients, and c.
  • first core and first core layer
  • second core and second core layer
  • core and ‘triple-layer core’ may be used interchangeably herein.
  • the first core, or first core layer comprises an amount of a first active agent which is a DOPA decarboxylase inhibitor; such as carbidopa or a pharmaceutically acceptable derivative thereof; and one or more excipients
  • the second core, or second core layer comprises an amount of a second active agent which is levodopa, or a pharmaceutically acceptable derivative thereof, and one or more excipients.
  • the tablet formulation is a press-coated tablet, or tablet formulation.
  • the tablet formulation is processed through direct compression and/or compression coating.
  • the tablet formulation of the present disclosure is a Tablet in Tablet dosage form (triple-layer core with outer coating).
  • the delayed release layer delays the release of the two or more active agents for 2 to 10 hours and thereafter the two or more active agents are pulse released from the core. It is understood that it is the delayed release layer that delays the release of the two or more active agents from the core.
  • the delayed release layer is a delayed release barrier layer.
  • the delayed release layer is an erodible delayed release layer. In some embodiment the delayed release layer is an erodible delayed release barrier layer. In some embodiments the delayed release layer is an erosion matrix.
  • the delayed release layer surrounding the core is an outer coating layer on the core. In some embodiment the delayed release layer surrounding the core forms a border or edging round the core.
  • the delayed release layer surrounding the core is a layer that covers the core, such as covers all sides of the core, such as covers the top, the bottom and the sides of the core. In some embodiment the delayed release layer fully surrounds the core. In some embodiment the delayed release layer surrounds all edges (or sides) of the core.
  • the core is entirely surrounded by the delayed release layer such that the core is not immediately exposed, such as exposed to the dissolution media, or to the gastroenteric environment following oral administration of the tablet formulation to a subject.
  • the release of the two or more active agents is delayed for 2 to 10 hours after (or following) oral administration of the tablet to a subject.
  • the subject is a human subject.
  • the subject is a patient.
  • the subject has Parkinson’s Disease.
  • the release of the two or more active agents is delayed for 2 to 10 hours after placing the tablet in an aqueous solution.
  • the release of the two or more active agents is delayed for 2 to 10 hours after placing the tablet in an aqueous solution comprising about 0.1 N HCI at 37°C +/- 0.5°C, optionally in about 500 ml solution at about 50 rpm.
  • the release of the two or more active agents is delayed for 2 to 10 hours after placing the tablet in an aqueous solution at pH 1.2 HCI at 37°C +/- 0.5°C, optionally in about 500 ml solution at about 50 rpm. In some embodiments the release of the two or more active agents is delayed for 2 to 10 hours after placing the tablet in an aqueous solution as measured by the USP 2 paddle method at about 50 rpm in about 500 ml of an aqueous solution at 37°C +/- 0.5°C at pH 1.2 HCI and/or comprising about 0.1 N HCI.
  • the release of the two or more active agents is delayed for about 2 hours, such as for about 2.5 hours, such as for about 3 hours, such as for about 3.5 hours, such as for about 4 hours, such as for about 4.5 hours, such as for about 5 hours, such as for about 5.5 hours, such as for about 6 hours, such as for about 6.5 hours, such as for about 7 hours, such as for about 7.5 hours, such as for about 8 hours, such as for about 8.5 hours, such as for about 9 hours, such as for about 9.5 hours, such as for about 10 hours.
  • the release of the two or more active agents is delayed for 2 to
  • 2.5 hours such as for 2.5 to 3 hours, such as for 3 to 3.5 hours, such as for 3.5 to 4 hours, such as for 4 to 4.5 hours, such as for 4.5 to 5 hours, such as for 5 to 5.5 hours, such as for 5.5 to 6 hours, such as for 6 to 6.5 hours, such as for 6.5 to 7 hours, such as for 7 to 7.5 hours, such as for 7.5 to 8 hours, such as for 8 to 8.5 hours, such as for
  • the release of the two or more active agents is delayed for 3 to 10 hours, such as for 3 to 9 hours, such as for 3 to 8 hours, such as for 3 to 7 hours. In some embodiments the release of the two or more active agents is delayed for 2 to 9 hours, such as for 2 to 8 hours, such as for 2 to 7 hours.
  • the release of the two or more active agents is delayed for at least about 3 hours, such as at least about 3.5 hours, such as at least about 4 hours.
  • the release of the two or more active agents is delayed for 3 to 5 hours, such as for 3.5 to 4.5 hours, such as for 4 hours.
  • the release of the two or more active agents is delayed for at least about 5 hours, such as at least about 5.5 hours, such as at least about 6 hours.
  • the release of the two or more active agents is delayed for 5 to 7 hours, such as for 5.5 to 6.5 hours, such as for about 6 hours.
  • the delayed release layer comprises or consists of a wax and one or more binders and/or fillers in a ratio that provides for a release that is delayed for 2 to 10 hours, such as 3 to 8 hours, such as 4 to 6 hours.
  • the delayed release layer comprises or consists of a wax and one or more binders and/or fillers in a ratio that provides for erosion of said delayed release layer to delay release for 2 to 10 hours, such as 3 to 8 hours, such as 4 to 6 hours.
  • the thickness (the proportion of the final tablet weight) of the delayed release layer provides for a release that is delayed for 2 to 10 hours, such as 3 to 8 hours, such as 4 to 6 hours.
  • the thickness of the delayed release layer is provided herein elsewhere (50 to 75% w/w of the final tablet weight).
  • the release of the two or more active agents is delayed for essentially the same period of time for both of said two or more active agents.
  • the two or more active agents are pulse released essentially at the same time.
  • the release of the first active agent is delayed for a shorter period of time, and the release of the second active agent is delayed for a longer period of time.
  • the first active agent is pulse released before the second active agent is pulse released, such as pulse released 10 to 120 minutes before the second active agent is pulse released.
  • the barrier layer delays the start of the pulse release of the second active agent.
  • pulse release of the second active agent starts after the pulse release of the first active agent starts. It is understood that pulse release of the first active agent starts after the 2 to 10 hours delay of release.
  • pulse release of the second active agent starts 10 to 120 minutes after the pulse release of the first active agent starts.
  • pulse release of the second active agent starts 15 to 90 minutes, such as 15 to 60 minutes, such as 15 to 45 minutes; such as 30 to 60 minutes after the pulse release of the first active agent starts.
  • pulse release of the second active agent starts 10 to 15 minutes, such as 15 to 20 minutes, such as 20 to 25 minutes, such as 25 to 30 minutes, such as 30 to 35 minutes, such as 35 to 40 minutes, such as 40 to 45 minutes, such as 45 to 50 minutes, such as 50 to 55 minutes, such as 55 to 60 minutes, such as 60 to 70 minutes, such as 70 to 80 minutes, such as 80 to 90 minutes, such as 90 to 100 minutes, such as 100 to 110 minutes, such as 110 to 120 minutes after the pulse release of the first active agent starts.
  • the pulse release of the second active agent is delayed for 10 to 120 minutes after the start of the pulse release of the first active agent.
  • the release of the two or more active agents is delayed for 2 to 10 hours, and the release of the second active agent is delayed 10 to 120 minutes longer than the release of the first active agent.
  • the release of the second active agent is delayed 15 to 90 minutes longer, such as 15 to 60 minutes longer, such as 15 to 45 minutes longer; such as 30 to 60 minutes longer than the release of the first active agent.
  • the release of the second active agent is delayed 10 to 15 minutes longer, such as 15 to 20 minutes longer, such as 20 to 25 minutes longer, such as 25 to 30 minutes longer, such as 30 to 35 minutes longer, such as 35 to 40 minutes longer, such as 40 to 45 minutes longer, such as 45 to 50 minutes longer, such as 50 to 55 minutes longer, such as 55 to 60 minutes longer, such as 60 to 70 minutes longer, such as 70 to 80 minutes longer, such as 80 to 90 minutes longer, such as 90 to 100 minutes longer, such as 100 to 110 minutes longer, such as 110 to 120 minutes longer than the release of the first active agent.
  • the barrier layer comprises or consists of a wax and one or more binders and/or fillers in a ratio that enables control of the release of the two or more active agents.
  • the ratio of wax to binders and/or fillers is provided herein elsewhere (>30% to ⁇ 70% w/w wax).
  • the thickness (the proportion of the combined weight of the core, or of the final tablet weight) of the barrier layer enables control of the release of the two or more active agents.
  • the thickness of the barrier layer is provided herein elsewhere (25 to 50% w/w of the combined weight of the core).
  • a pulse release is defined as wherein at least 70% by weight of the amount of an active agent is released within 5 to 80 minutes.
  • the delay of release and the subsequent pulse release occurs after oral administration of the tablet formulation to a subject, and/or after placing the tablet in a aqueous environment, according to the present disclosure.
  • At least 70% by weight of the amount of the two or more active agents in the first and the second core, or core layer is released within 5 to 80 minutes, such as within 5 to 60 minutes, such as within 5 to 45 minutes, such as within 5 to 30 minutes, such as within 5 to 15 minutes.
  • At least 80% by weight of the amount of the two or more active agents is released within 5 to 80 minutes, such as within 5 to 60 minutes, such as within 5 to 45 minutes, such as within 5 to 30 minutes, such as within 5 to 15 minutes.
  • At least 90% by weight of the amount of the two or more active agents is released within 5 to 80 minutes, such as within 5 to 60 minutes, such as within 5 to 45 minutes, such as within 5 to 30 minutes, such as within 5 to 15 minutes. In some embodiments at least 95% by weight of the amount of the two or more active agents is released within 5 to 80 minutes, such as within 5 to 60 minutes, such as within 5 to 45 minutes, such as within 5 to 30 minutes, such as within 5 to 15 minutes.
  • 70-75%, such as 75-80%, such as 80-85%, such as 85-90%, such as 90-95% by weight of the amount of the two or more active agents is released within 5 to 80 minutes, such as within 5 to 60 minutes, such as within 5 to 45 minutes, such as within 5 to 30 minutes, such as within 5 to 15 minutes.
  • At least 70%, at least 80%, at least 90%, or at least 95% by weight of the amount of the two or more active agents is released within 5 to 80 minutes, such as within 5 to 60 minutes, such as within 5 to 45 minutes, such as within 5 to 30 minutes, such as within 5 to 15 minutes.
  • At least 70%, at least 80%, at least 90%, or at least 95% by weight of the amount of the two or more active agents is released within 5 to 80 minutes, such as within 5 to 60 minutes, such as within 5 to 45 minutes, such as within 5 to 30 minutes, such as within 5 to 15 minutes, after oral administration to a subject.
  • the release of the two or more active agents is measured by the USP 2 paddle method at about 50 rpm in about 500 ml of an aqueous solution at 37°C +/- 0.5°C; at pH 1.2 HCI or in an aqueous solution comprising about 0.1 N HCI.
  • At least 70%, at least 80%, at least 90%, or at least 95% by weight of the amount of the two or more active agents is released within 5 to 80 minutes, such as within 5 to 60 minutes, such as within 5 to 45 minutes, such as within 5 to 30 minutes, such as within 5 to 15 minutes, as measured by the USP 2 paddle method at about 50 rpm in about 500 ml of an aqueous solution comprising about 0.1 N HCI at 37°C +/- 0.5°C.
  • At least 70%, at least 80%, at least 90%, or at least 95% by weight of the amount of the two or more active agents is released within 5 to 80 minutes, such as within 5 to 60 minutes, such as within 5 to 45 minutes, such as within 5 to 30 minutes, such as within 5 to 15 minutes as measured by the USP 2 paddle method at about 50 rpm in about 500 ml of an aqueous solution at pH 1.2 HCI at 37°C +/- 0.5°C.
  • the delayed release layer and the barrier layer of the present disclosure comprises a wax and one or more binders and/or fillers.
  • the delayed release layer and the barrier layer does not comprise an active agent.
  • a wax according to the present disclosure comprises a lipophilic wax, or lipophilic waxlike solid, and a water-soluble wax, or water-soluble wax-like solid.
  • the wax is a lipophilic wax.
  • a lipophilic wax may also be known as a lipid-based excipient.
  • a lipophilic wax is a fatty material that consists of a long hydrocarbon chain, with or without a functional group. Common functional groups found in waxes include alcohol, ketone, aldehyde, and ester. Petroleum-derived waxes are mixtures of long-chain hydrocarbons, but are not esters.
  • the wax comprises fatty acids and/or alcohols, such as long-chain fatty acids and/or alcohols (C16-C36).
  • the wax is a wax ester (an ester of a fatty acid and a fatty alcohol).
  • the wax consists of a single wax. In some embodiments the wax is a combination of two or more waxes, such as two waxes, such as three waxes, such as three or more waxes. In some embodiments the wax comprises two or more waxes.
  • the delayed release layer and/or the barrier layer comprises more than 30% w/w of a wax (>30% w/w), such as at least 31 % w/w of a wax, such as at least 32% w/w of a wax, such as at least 33% w/w of a wax, such as at least 34% w/w of a wax, such as at least 35% w/w of a wax, such as at least 36% w/w of a wax, such as at least 37% w/w of a wax, such as at least 38% w/w of a wax, such as at least 39% w/w of a wax, such as at least 40% w/w of a wax, such as at least 42% w/w of a wax.
  • a wax >30% w/w
  • a wax such as at least 31 % w/w of a wax, such as at least 32% w/w of a wax, such as at least 33% w/w
  • the delayed release layer and/or the barrier layer comprises less than 70% w/w of a wax ( ⁇ 70% w/w), such as 65% w/w or less of a wax, such as 60% w/w or less of a wax. In preferred embodiments the delayed release layer and/or the barrier layer comprises >30% to ⁇ 70% w/w wax. In some embodiments the delayed release layer and/or the barrier layer comprises more than 30% w/w of a wax and less than 70% w/w of a wax.
  • the delayed release layer and/or the barrier layer comprises >30% to 32% w/w of a wax, such as 32% to 35% w/w of a wax, such as 35% to 40% w/w of a wax, such as 40% to 42% w/w of a wax, such as 42% to 45% w/w of a wax, such as 45% to 50% w/w of a wax, such as 50% to 60% of a wax, such as 60 to 65% of a wax, such as 65 to 68% of a wax such as 68 to ⁇ 70% of a wax.
  • a wax such as 32% to 35% w/w of a wax, such as 35% to 40% w/w of a wax, such as 40% to 42% w/w of a wax, such as 42% to 45% w/w of a wax, such as 45% to 50% w/w of a wax, such as 50% to 60% of a wax, such as 60 to 65% of a wax, such as 65
  • the delayed release layer and/or the barrier layer comprises >30% to ⁇ 70% w/w of a wax, such as 32 to 68% w/w of a wax, such as 35 to 65% w/w of a wax, such as 35 to 60% w/w of a wax, such as 40 to 60% w/w of a wax, such as 42 to 50% w/w of a wax, such as about 42% w/w of a wax, such as about 50% w/w of a wax.
  • a wax such as 32 to 68% w/w of a wax, such as 35 to 65% w/w of a wax, such as 35 to 60% w/w of a wax, such as 40 to 60% w/w of a wax, such as 42 to 50% w/w of a wax, such as about 42% w/w of a wax, such as about 50% w/w of a wax.
  • the wax is selected from a glyceryl ester, a petroleum based wax (paraffin wax), a saturated solid triglyceride such as a hydrogenated oil, a long chain saturated carboxylic acid, saturated long chain monoglyceride, a long chain alcohol, a plant wax, an animal wax, montan wax, a PEG with a molecular weight of at least 1000, and any combination of waxes.
  • the delayed release layer and/or the barrier layer comprises a wax selected from a glyceryl ester, a petroleum based wax (paraffin wax) such as microcrystalline wax, a saturated solid triglyceride such as a hydrogenated oil such as hydrogenated castor oil and hydrogenated cottonseed oil, a long chain saturated carboxylic acid such as stearic acid and/or palmitic acid (stearic acid, palmitic acid such as palmitic acid 98%, and stearic/palmitic acid), saturated long chain monoglyceride such as glycerol monostearate, a long chain alcohol such as stearyl alcohol, a plant wax such as carnauba wax, candelilla wax, jojoba oil and ouricury wax, an animal wax such as beeswax, spermaceti and lanolin, montan wax, a PEG with a molecular weight of at least 1000, and any combination of waxes.
  • a wax selected from a gly
  • the delayed release layer and/or the barrier layer comprises a wax which is a glyceryl ester. In some embodiments the delayed release layer and/or the barrier layer comprises a wax which is a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof.
  • Glyceryl behenate is an ester of behenic acid and glycerol (glyceride). Glyceryl behenate is a mixture of mono-, di- and tri-esters of behenic acid (C22) and glycerol, the diester fraction being predominant.
  • the wax is a glyceryl ester.
  • the delayed release layer and/or the barrier layer comprises a wax which is a glyceryl behenate; such as a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, and glyceryl tribehenate, and any mixture thereof; such as a glyceryl behenate comprising a mixture of glyceryl behenate, glyceryl dibehenate and glyceryl tribehenate.
  • said wax consists of a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, and glyceryl tribehenate, and any mixture thereof. In some embodiments said wax consist of 100% w/w of a glyceryl ester such as a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, and glyceryl tribehenate, and any mixture thereof.
  • said wax is a glyceryl ester such as a glyceryl behenate in combination with one or more other waxes or wax-like solids.
  • said wax comprises 25 to 75% w/w of a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, and glyceryl tribehenate, and any mixture thereof. In some embodiments said wax comprises 25 to 75% w/w of said glyceryl ester and 25 to 75% w/w of one or more other waxes or wax-like solids. In some embodiments said wax comprises about 50% w/w of said glyceryl ester and about 50% w/w of one or more other waxes or wax-like solids.
  • the delayed release layer and/or the barrier layer comprises a wax which is a petroleum based wax, such as microcrystalline wax.
  • the wax consists of a petroleum based wax such as microcrystalline wax.
  • the wax is a combination of a glyceryl ester and a petroleum wax.
  • the wax is a combination of a glyceryl ester and a petroleum wax in a 25:75 to a 75:25 ratio, such as about a 50:50 ratio.
  • the wax is a combination of a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof, and microcrystalline wax; in some embodiments in a 25:75 to a 75:25 ratio, such as about a 50:50 ratio.
  • the delayed release layer and/or the barrier layer comprises a wax which is v.
  • the wax consists of a hydrogenated oil.
  • the delayed release layer and/or the barrier layer comprises a wax which is a hydrogenated oil, such as selected from hydrogenated castor oil and hydrogenated cottonseed oil.
  • a wax which is a hydrogenated oil, such as selected from hydrogenated castor oil and hydrogenated cottonseed oil.
  • said wax is Kolliwax ®.
  • the wax is a combination of a glyceryl ester and a hydrogenated oil. In some embodiments the wax is a combination of a glyceryl ester and a hydrogenated oil in a 25:75 to a 75:25 ratio, such as about a 50:50 ratio.
  • the wax is a combination of a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof, and hydrogenated castor oil or hydrogenated cottonseed oil; preferably hydrogenated castor oil; in some embodiments in a 25:75 to a 75:25 ratio, such as about a 50:50 ratio.
  • the delayed release layer and/or the barrier layer comprises a wax which is a plant wax, such as a plant wax selected from carnauba wax, candelilla wax, jojoba oil and ouricury wax.
  • the wax consists of a plant wax, such as carnauba wax or candelilla wax.
  • the wax is a combination of a glyceryl ester and a plant wax. In some embodiments the wax is a combination of a glyceryl ester and a plant wax in a 25:75 to a 75:25 ratio, such as about a 50:50 ratio. In some embodiments the wax is a combination of a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof, and carnauba wax or candelilla wax; in some embodiments in a 25:75 to a 75:25 ratio, such as about a 50:50 ratio.
  • the delayed release layer and/or the barrier layer comprises a wax which is an animal wax, such as an animal wax selected from bees wax, spermaceti and lanolin.
  • the wax consists of an animal wax, such as bees wax.
  • the wax is a combination of a glyceryl ester and an animal wax. In some embodiments the wax is a combination of a glyceryl ester and an animal wax in a 25:75 to a 75:25 ratio, such as about a 50:50 ratio.
  • the wax is a combination of a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof, and bees wax; in some embodiments in a 25:75 to a 75:25 ratio, such as about a 50:50 ratio; in other embodiments in a 95:5 to 50:50 ratio (95-50% w/w glyceryl ester, 50-5% w/w bees wax).
  • a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof, and bees wax
  • bees wax in some embodiments in a 25:75 to a 75:25 ratio, such as about a 50:50 ratio
  • a 95:5 to 50:50 ratio 95-50% w/w glyceryl ester, 50-5% w/w bees wax
  • the delayed release layer and/or the barrier layer comprises a wax which is montan wax, such as Montan SX Wax.
  • the wax is a combination of a glyceryl ester and montan wax.
  • the wax is a combination of a glyceryl ester and montan wax in a 25:75 to a 75:25 ratio, such as about a 50:50 ratio.
  • the wax is a combination of a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof, and montan wax; in some embodiments in a 25:75 to a 75:25 ratio, such as about a 50:50 ratio; in other embodiments in a 95:5 to 50:50 ratio (95-50% w/w glyceryl ester, 50-5% w/w montan wax).
  • a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof
  • montan wax in some embodiments in a 25:75 to a 75:25 ratio, such as about a 50:50 ratio; in other embodiments in a 95:5 to 50:50 ratio (95-50% w/w glyceryl ester, 50-5% w/w montan wax).
  • the delayed release layer and/or the barrier layer comprises a wax which is a long chain saturated carboxylic acid.
  • a long chain saturated carboxylic acid is a fatty acids with 14 or more carbon atoms (>C12), with no double bonds.
  • the wax consists of a long chain saturated carboxylic acid.
  • said wax comprises a long chain saturated carboxylic acid selected from stearic acid (C18:0), palmitic acid (C16:0), and stearic/palmitic acid (C16/C18).
  • said wax comprises palmitic acid, such as palmitic acid 98%.
  • said wax comprises Kolliwax S.
  • the wax is a combination of a glyceryl ester and a long chain saturated carboxylic acid. In some embodiments the wax is a combination of a glyceryl ester and a long chain saturated carboxylic acid in a 25:75 to a 75:25 ratio, such as about a 50:50 ratio.
  • the wax is a combination of a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof, and a long chain saturated carboxylic acid selected from stearic acid, palmitic acid and stearic/palmitic acid; in some embodiments in a 25:75 to a 75:25 ratio, such as about a 50:50 ratio.
  • the delayed release layer and/or the barrier layer comprises a wax which is a saturated long chain (>C12) monoglyceride.
  • said saturated long chain monoglyceride is glycerol monostearate.
  • said wax comprises Kolliwax GMS II.
  • the wax consists of a saturated long chain monoglyceride.
  • the wax is a combination of a glyceryl ester and a saturated long chain monoglyceride. In some embodiments the wax is a combination of a glyceryl ester and a saturated long chain monoglyceride in a 25:75 to a 75:25 ratio, such as about a 50:50 ratio.
  • the wax is a combination of a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof, and a saturated long chain monoglyceride which is glycerol monostearate; in some embodiments in a 25:75 to a 75:25 ratio, such as about a 50:50 ratio; in other embodiments in a 95:5 to 50:50 ratio.
  • the delayed release layer comprises a wax which is a long chain alcohol.
  • said long chain alcohol is stearyl alcohol.
  • said wax comprises Kolliwax SA.
  • the wax consists of a long chain alcohol.
  • the barrier layer does not comprise a wax comprising or consisting of a long chain alcohol, such as stearyl alcohol.
  • the wax is a combination of a glyceryl ester and a long chain alcohol. In some embodiments the wax is a combination of a glyceryl ester and a long chain alcohol in a 25:75 to a 75:25 ratio, such as about a 50:50 ratio.
  • the wax is a combination of a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof, and a long chain alcohol which is stearyl alcohol; in some embodiments in a 25:75 to a 75:25 ratio, such as about a 50:50 ratio.
  • the delayed release layer and/or the barrier layer comprises a water soluble wax.
  • Water soluble wax, Carbowax and polyethylene glycol (PEG) are terms used to describe the same material.
  • Pharmaceutical-grade PEG is used as an excipient in many pharmaceutical products. PEGs are prepared by polymerization of ethylene oxide molecules to make joining units of ethylene glycol by an ether linkage, and are commercially available over a wide range of molecular weights (Mw). PEGs differ in their physical and chemical properties depending on their molecular weight: PEGs are liquids when molecular weights are ⁇ 1000 and the molecule turns to waxy solids with increasing molecular weights. Pharmaceutical-grade PEG usually has a molecular weight of 20,000 or less. The molecular weight of a PEG is an average or mean molecular weight.
  • said wax is a PEG. In some embodiments said wax consists of a PEG (100% w/w). In some embodiments said wax comprises a PEG. In some embodiments said wax comprises or consist of a PEG with a molecular weight of at least 1000 (PEG1000), such as a PEG with a molecular weight of at least 1,450 (PEG1450), such as a PEG with a molecular weight of at least 1,500 (PEG1500), such as a PEG with a molecular weight of at least 3,000 (PEG3000). In some embodiments said PEG has molecular weight of 1000 to 20,000, such as 1 ,450 to 20,000, such as 3,000 to 20,000.
  • said PEG has a molecular weight of 1000 to 1 ,450, such as 1 ,450 to 3,000, such as 3,000 to 5,000, such as 5,000 to 7,500, such as 7,500 to 10,000, such as 10,000 to 15,000, such as 15,000 to 20,000, such as 20,000 to 25,000, such as 25,000 to 50,000, such as 50,000 to 75,000, such as 75,000 to 100,000.
  • said PEG has a molecular weight of about 3,000 (PEG3000). In some embodiments said PEG has a molecular weight of about 20,000 (PEG20,000).
  • said wax is a combination of a glyceryl ester and a water soluble wax such as a PEG with a molecular weight of at least 1000. In some embodiments the wax is a combination of a glyceryl ester and said PEG in a 25:75 to a 75:25 ratio, such as about a 50:50 ratio.
  • the wax is a combination of a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof, and a PEG of the present disclosure; in some embodiments a PEG with a molecular weight of at least 1000, at least 1 ,450, at least 3,000, such as a PEG with a molecular weight of 1 ,450 to 20,000 or 3,000 to 20,000; in some embodiments in a 25:75 to a 75:25 ratio, such as about a 50:50 ratio.
  • the delayed release layer and the barrier layer according to the present disclosure comprises or consist of a wax and one or more binders and/or fillers.
  • the delayed release layer and the barrier layer comprises or consist of a wax, one or more binders and one or more fillers. In some embodiments the delayed release layer and the barrier layer comprises a wax, a binder and a filler.
  • the delayed release layer and the barrier layer comprises or consist of a wax and one or more binders selected from L-HPC, HPC, isomalt, microcrystalline cellulose (MCC), hydroxypropyl methylcellulose (HPMC), cellulose, methylcellulose, polymethacrylates, sodium carboxymethyl cellulose (sodium CMC), polyvinyl pyrrolidone (PVP), starch, pregelatinized starch, sodium alginate and gelatin.
  • binders selected from L-HPC, HPC, isomalt, microcrystalline cellulose (MCC), hydroxypropyl methylcellulose (HPMC), cellulose, methylcellulose, polymethacrylates, sodium carboxymethyl cellulose (sodium CMC), polyvinyl pyrrolidone (PVP), starch, pregelatinized starch, sodium alginate and gelatin.
  • the delayed release layer comprises a wax and two L-HPC and a HPC. In some embodiments the delayed release layer comprises a wax and pregelatinized starch. In some embodiments the delayed release layer comprises a wax and starch. In some embodiments the delayed release layer comprises a wax and isomalt. In some embodiments the delayed release layer comprises a wax and isomalt and MCC. In some embodiments the barrier layer comprises or consist of a wax and one or more binders selected from L-HPC, HPC, isomalt, MCC, and pregelatinized starch.
  • the barrier layer comprises a wax and two L-HPC and a HPC.
  • the barrier layer comprises a wax and pregelatinized starch.
  • the barrier layer comprises a wax and isomalt.
  • the barrier layer comprises a wax and isomalt and MCC.
  • the binder is a dry binder.
  • a dry binder can be added to a powder is a dry powder which is mixed with the other ingredients before compaction.
  • Notable dry binders are microcrystalline cellulose and (MCC) and polyvinyl pyrrolidone (PVP).
  • the delayed release layer and/or the barrier layer comprises a wax and one or more fillers.
  • the delayed release layer comprises a wax, one or more binders and one or more fillers.
  • the delayed release layer and the barrier layer comprises a wax and one or more water-soluble fillers and/or water-insoluble fillers.
  • the delayed release layer and the barrier layer comprises a wax and one or more fillers selected from mannitol, sorbitol, xylitol, lactose, sucrose, cellulose, glucose, calcium carbonate, calcium phosphate and calcium hydrogen phosphate dihydrate.
  • the barrier layer comprises or consists of a wax and one or more binders, and no fillers. In some embodiments the barrier layer consists of a wax and one or more binders. In some embodiments the barrier layer does not comprise any fillers, such as does not comprise a filler selected from mannitol, sorbitol and lactose.
  • the delayed release layer comprises a wax and one or more water-soluble fillers, such as a water-soluble filler selected from mannitol, sorbitol and lactose. In some embodiments the delayed release layer comprises a wax and one or more water-soluble fillers selected from mannitol, sorbitol and lactose. In some embodiments the delayed release layer comprises a wax, one or more binders, and one or more water-soluble fillers selected from mannitol, sorbitol and lactose.
  • the wax and the one or more binders and/or fillers are provided in a weight ratio of wax to binder and/or fillers of about 40:60 w/w, such as about 41 :59, such as about 42:58, such as about 43:57, such as about 44:56, such as about 45:55, such as about 46:54, such as about 47:53, such as about 48:52, such as about 49:51 , such as about 50:50, such as of about 51:49, about 52:48, about 53:47, about 54:46, about 55:45 w/w.
  • the delayed release layer comprises or consist of more than 30% w/w and less than 70% w/w of a wax, and more than 30% w/w and less than 70% w/w of one or more binders and/or fillers. In some embodiments the delayed release layer consist of more than 30% w/w and less than 70% w/w of a wax, and more than 30% w/w and less than 70% w/w of one or more binders and/or fillers, wherein the wax and the one or more binders/fillers together make up 100% w/w of the delayed release layer.
  • the barrier layer comprises or consist of more than 30% w/w and less than 70% w/w of a wax, and more than 30% w/w and less than 70% w/w of one or more binders. In some embodiments the barrier layer consist of more than 30% w/w and less than 70% w/w of a wax, and more than 30% w/w and less than 70% w/w of one or more binders, wherein the wax and the one or more binders together make up 100% w/w of the barrier layer.
  • a tablet formulation for oral administration of two or more active agents such as two active agents
  • the tablet comprising: i) A core, such as a triple-layer core, comprising or consisting of a.
  • a first core, or first core layer comprising an amount of a first active agent and one or more excipients, wherein said first active agent prevents peripheral metabolism of levodopa (L-DOPA); alternatively wherein said first active agent is selected from dopamine, a dopamine agonist, a dopamine precursor and a dopamine prodrug, b.
  • L-DOPA levodopa
  • the delayed release layer and the barrier layer comprises a wax and one or more binders, wherein said one or more binder is L-HPC.
  • the delayed release layer of the present disclosure surrounding the core comprises a wax and one or more L-HPC. In some embodiments the delayed release layer comprises a wax and two L-HPC.
  • the barrier layer interposed between the first and the second core, or first and second core layers comprises a wax and one or more L-HPC. In some embodiments the barrier layer comprises a wax and two L-HPC.
  • the wax and the one or more, such as two, L-HPC in the delayed release layer and/or in the barrier layer are provided in a weight ratio of wax to L-HPC of 30:70 to 70:30 w/w, such as of 35:65 to 65:35 w/w, such as of 40:60 to 60:40 w/w, such as of 45:55 to 55:45 w/w; such as a weight ratio of wax to L-HPC of about 35:65 to 55:45 w/w; such as of about 40:60 to 50:50 w/w; such as of about 60:40 to 50:50 w/w; such as a weight ratio of wax to L-HPC of about 30:70; such as of about 35:65, such as of about 40:60, such as of about 41:59 w/w, such as of about 42:58 w/w, such as of about 43:57 w/w, such as of about 44:56 w/w, such as of about 45:55 w
  • the delayed release layer and/or the barrier layer comprises 30 to 70% w/w of one or more L-HPC, such as of two L-HPC, such as 35 to 65% w/w, such as 40 to 60% w/w, such as 45 to 60% w/w, such as 45 to 55% w/w, such as 42 to 62% w/w, such as 47 to 57% w/w, such as about 52% w/w.
  • L-HPC such as of two L-HPC, such as 35 to 65% w/w, such as 40 to 60% w/w, such as 45 to 60% w/w, such as 45 to 55% w/w, such as 42 to 62% w/w, such as 47 to 57% w/w, such as about 52% w/w.
  • the one or more L-HPC has a hydroxypropyl content of about 11% (10.0-12.9%) and a molecular weight of about 120,000, and optionally a mean particle size of 45 urn (35-55 urn); such as wherein said one or more L-HPC is LH-21.
  • L-HPC with a hydroxypropyl content of about 11% (10.0-12.9%)
  • L-HPC with a hydroxypropyl content of about 11 weight% or 11% by weight (10.0-12.9 weight% or % by weight). This applies equally to any other L-HPC % hydroxypropyl content (i.e. weight%) as referred to herein throughout.
  • the one or more L-HPC has a hydroxypropyl content of about 8% (7.0-9.9%), a molecular weight of about 115,000, and optionally a mean particle size of 20 urn (17-23 urn); such as wherein said one or more L-HPC is LH-32.
  • the one or more L-HPC has a hydroxypropyl content of about 11% (10.0-12.9%), a molecular weight of about 130,000, and optionally a mean particle size of 55 urn (45-65 urn),; such as wherein said one or more L-HPC is LH-11.
  • the one or more L-HPC has a hydroxypropyl content of about 8% (7.0-9.9%), a molecular weight of about 135,000, and optionally a mean particle size of 45 urn (35-55 urn); such as wherein said one or more L-HPC is LH-22.
  • the one or more L-HPC has a hydroxypropyl content of about 11% (10.0-12.9%), a molecular weight of about 140,000, and optionally a mean particle size of 55 urn (45-65 urn); such as wherein said one or more L-HPC is LH-B1
  • the one or more L-HPC has a hydroxypropyl content of about 11% (10.0-12.9%), a molecular weight of about 100,000, and optionally a mean particle size of 20 urn (17-23 urn); such as wherein said one or more L-HPC is LH-31.
  • the one or more L-HPC has a mean particle size of 45 urn (35- 55 urn), a 90% cumulative particle size of 70-130 urn, and a hydroxypropyl content of about 14% (13-15.9%); such as wherein said one or more L-HPC is NBD-020.
  • the one or more L-HPC has a mean particle size of 45 urn (35- 55 urn), a 90% cumulative particle size of 70-130 urn, and a hydroxypropyl content of about 11 % (10-12.9%); such as wherein said one or more L-HPC is NBD-021.
  • the one or more L-HPC has a mean particle size of 45 urn (35- 55 urn), a 90% cumulative particle size of 70-130 urn, and a hydroxypropyl content of about 8% (7-9.9%); such as wherein said one or more L-HPC is NBD-022.
  • the one or more L-HPC is selected from LH-11 , LH-21 , LH-22, LH-B1 , LH-31 , LH-32, NBD-022, NBD-021 and NBD-020.
  • the one or more L-HPC has a hydroxypropyl content of about 11% (10.0-12.9%) and a molecular weight of about 120,000, and optionally a mean particle size of 45 urn (35-55 urn). In a particular embodiment said one or more L-HPC is LH-21.
  • the one or more L-HPC has a hydroxypropyl content of about 8% (7.0-9.9%), a molecular weight of about 115,000, and optionally a mean particle size of 20 urn (17-23 urn). In a particular embodiment said one or more L-HPC is LH-32.
  • the delayed release layer and/or the barrier layer comprises a wax and two or more L-HPC, such as comprises a wax and two L-HPC.
  • the delayed release layer and/or the barrier layer comprises a wax and two or more grades of L-HPC, such as comprises a wax and two grades of L- HPC.
  • the delayed release layer and the barrier layer comprises a wax and two L-HPC.
  • the two or more L-HPC in the delayed release layer and/or the barrier layer are individually selected from: a. an L-HPC with a hydroxypropyl content of about 11% (10.0-12.9%), a molecular weight of about 120,000, and optionally a mean particle size of 45 urn (35-55 urn); such as wherein said one or more L-HPC is LH- 21; b.
  • the two or more grades of L-HPC include a coarse particle L- HPC and a medium particle L-HPC; such as a coarse particle L-HPC and a medium particle L-HPC selected from any one of the following combinations: LH-11 and LH-21, LH-11 and LH-22, LH-11 and NBD-022, LH-11 and NBD-021 , LH-11 and NBD-020, LH-B1 and LH-21, LH-B1 and LH-22, LH-B1 and NBD-022, LH-B1 and NBD-021 , and LH-B1 and NBD-020.
  • a coarse particle L-HPC and a medium particle L-HPC selected from any one of the following combinations: LH-11 and LH-21, LH-11 and LH-22, LH-11 and NBD-022, LH-11 and NBD-021 , LH-11 and NBD-020, LH-B1 and LH-21, LH-B1 and LH-22,
  • the two or more grades of L-HPC include a coarse particle L- HPC and a micronized particle L-HPC; such as a coarse particle L-HPC and a micronized particle L-HPC selected from any one of the following combinations: LH-11 and LH-31, LH-11 and LH-32, LH-B1 and LH-31, LH-B1 and LH-32, NBD-021 and LH- 32, NBD-020 and LH-32, LH-11 and LH-32, LH-21 and LH-32, LH-31 and LH-32, and LH-B1 and LH-32.
  • a coarse particle L-HPC and a micronized particle L-HPC selected from any one of the following combinations: LH-11 and LH-31, LH-11 and LH-32, LH-B1 and LH-31, LH-B1 and LH-32, NBD-021 and LH- 32, NBD-020 and LH-32
  • the two or more grades of L-HPC include a medium particle L- HPC and a micronized particle L-HPC; such as a medium particle L-HPC and a micronized particle L-HPC selected from any one of the following combinations: LH-21 and LH-31, LH-22 and LH-31 , NBD-022 and LH-31, NBD-021 and LH-31 , NBD-020 and LH-31, LH-21 and LH-32, LH-22 and LH-32, NBD-022 and LH-32, NBD-021 and LH-32, and NBD-020 and LH-32.
  • a medium particle L-HPC and a micronized particle L-HPC selected from any one of the following combinations: LH-21 and LH-31, LH-22 and LH-31 , NBD-022 and LH-31, NBD-021 and LH-31 , NBD-020 and LH-31, LH-21 and L
  • the two or more grades of L-HPC include a low level hydroxypropyl content L-HPC and a high level hydroxypropyl content L-HPC; such as a low level and a high level hydroxypropyl content L-HPC selected from any one of the following combinations: NBD- 021 and NBD-022, NBD-020 and NBD-022, LH-11 and NBD-022, LH-21 and NBD- 022, LH-31 and NBD-022, LH-B1 and NBD-022, NBD-021 and LH-22, NBD-020 and LH-22, LH-11 and LH-22, LH-21 and LH-22, LH-31 and LH- 22, LH-B1 and LH-22.
  • the two or more grades of L-HPC include a low and a high level hydroxypropyl content L-HPC that are also a combination of a coarse and medium particle L-HPC; such as selected from any one of the following combinations: LH-11 and LH-22, LH11 and NBD-022, LH-B1 and LH-22, and LH-B1 and NBD-022.
  • the two or more grades of L-HPC include a low and a high level hydroxypropyl content L-HPC that are also a combination of a medium and micronised particle L-HPC; such as selected from any one of the following combinations: LH-22 and LH-31 , NBD-022 and LH-31, LH-21 and LH-32, NBD-021 and LH-32, and NBD- 020 and LH 32.
  • the two or more L-HPC are LH-21 and L-HPC LH-32.
  • the two or more L-HPC are an L-HPC with a hydroxypropyl content of about 11 weight% (10.0-12.9%), a molecular weight of about 120,000, and optionally a mean particle size of 45 urn (35-55 urn); and an L-HPC with a hydroxypropyl content of about 8 weight% (7.0-9.9%), a molecular weight of about 115,000, and optionally a mean particle size of 20 urn (17-23 urn).
  • the barrier layer comprises or consists of a wax and one or more L-HPC such as two L-HPC.
  • the barrier layer comprises i) an L-HPC with a hydroxypropyl content of about 11 weight% (10.0-12.9%), a molecular weight of about 120,000 and optionally a mean particle size of 45 urn (35-55 urn); such as wherein said one or more L-HPC is LH-21; and ii) an L-HPC with a hydroxypropyl content of about 8 weight% (7.0-9.9%), a molecular weight of about 115,000, and optionally a mean particle size of 20 urn (17-23 urn); such as wherein said one or more L-HPC is LH-32; and wherein the i) L-HPC and the ii) L-HPC in the barrier layer is provided in a weight ratio of i) L-HPC to ii) L-HPC of 20:80 to 80:20 w/w, such as of 25:75 to 75:25 w/w, such as of 30:70 to 70:30 w/w,
  • the delayed release layer comprises or consists of a wax and one or more L-HPC such as two L-HPC.
  • the delayed release layer comprises i) an L-HPC with a hydroxypropyl content of about 11 weight% (10.0-12.9%), a molecular weight of about 120,000, and optionally a mean particle size of 45 urn (35-55 urn); such as wherein said one or more L-HPC is LH-21; and ii) an L-HPC with a hydroxypropyl content of about 8 weight% (7.0-9.9%), a molecular weight of about 115,000, and optionally a mean particle size of 20 urn (17-23 urn); such as wherein said one or more L-HPC is LH-32; and wherein the i) L-HPC and the ii) L-HPC in the delayed release layer is provided in a weight ratio of i) L-HPC to ii) L-HPC of 30:70 to 70:30 w/w, such as of 35:65 to 65:35 w/w, such as of 40:60 to 60:40 w
  • HPC Hydroxypropyl cellulose
  • the delayed release layer and/or the barrier layer further comprises a HPC.
  • the delayed release layer and/or the barrier layer comprises a wax and one or more binders, wherein said binder is HPC.
  • the delayed release layer and/or the barrier layer comprises or consists of a wax, one or more L-HPC such as two L-HPC, and a HPC.
  • the HPC has a viscosity of 2.0 to 50 mPa-s (at 20°C/2% aq. solution).
  • HPC with a viscosity of 2.0 to 50 mPa s at 20°C/2% aq. solution is HPC with a viscosity of 2.0 to 50 mPa s at 20°C/2% w/w aq. solution, i.e. weight/weight, which in an aqueous solution is very similar to weight/volume (w/V).
  • HPC viscosity i.e. % w/w aq. solution
  • the delayed release layer and/or the barrier layer comprises a wax, one or more LHPC such as two L-HPC , and a HPC with a viscosity of 2.0 to 50 mPa s (at 20°C/2% aq. solution).
  • the delayed release layer and/or the barrier layer comprises a wax, one or more L-HPC such as two L-HPC, and a HPC, wherein the wax and the HPC are provided in a weight ratio of wax to HPC of 80:20 to 95:5 w/w; such as of 85:15 to 90:10 w/w; such as of about 85:15 w/w, such as of about 86:14 w/w, such as of about 87:13 w/w, such as of about 87.5:12:5 w/w, such as of about 88:12 w/w, such as of about 89:11 w/w, such as of about 90:10 w/w.
  • the delayed release layer and/or the barrier layer comprises a wax, one or more L-HPC such as two L-HPC, and a HPC, wherein the one or more L- HPC and the HPC are provided in a weight ratio of L-HPC to HPC of 80:20 to 95:5 w/w; such as of 85: 15 to 90: 10 w/w; such as of 85: 15 to 95: 15 w/w; such as of about 85:15 w/w, such as of about 86:14 w/w, such as of about 87:13 w/w, such as of about 88:12 w/w, such as of about 89:11 w/w, such as of about 90:10 w/w, such as of about 91 :9 w/w, such as of about 92:8 w/w, such as of about 93:7 w/w, such as of about 94:6 w/w, such as of about 95:5 w/w.
  • the HPC of the present disclosure has a viscosity of 2.0 to 2.9 mPa s (HPC-SSL); such as a viscosity of 3.0 to 5.9 mPa s (HPC-SL); such as a viscosity of 6.0 to 10.0 mPa s (HPC-L); such as a viscosity of 11 to 20 mPa s (HPC- LM); such as a viscosity of 21 to 50 mPa s (HPC-LMM) (at 20°C/2% aq. Solution).
  • HPC-SSL a viscosity of 2.0 to 2.9 mPa s
  • HPC-SL such as a viscosity of 3.0 to 5.9 mPa s (HPC-SL)
  • HPC-L such as a viscosity of 6.0 to 10.0 mPa s (HPC-L)
  • HPC-LM a viscosity of 11 to 20 mP
  • the HPC has a molecular weight of 40,000 - 280,000; such as a molecular weight of about 40,000, such as of about 100,000, such as of about 140,000, such as of about 280,000, such as of about 180,000.
  • the HPC has a molecular weight of about 140,000.
  • the HPC has a viscosity of 2.0 to 50 mPa s (at 20°C/2% aq. solution) and a molecular weight of 40,000 - 280,000.
  • the HPC has a viscosity of 6.0 to 10.0 mPa s (at 20°C/2% aq. solution) and a molecular weight of about 140,000.
  • the HPC has a viscosity of 150 to 300 mPa s (at 20°C/2% aq. solution) and a molecular weight of about 40,000.
  • the HPC has a viscosity of 300 to 600 mPa s (at 20°C/2% aq. solution) and a molecular weight of about 80,000.
  • the HPC has a viscosity of 1 ,500 to 3,000 mPa s (at 20°C/2% aq. solution) and a molecular weight of about 1 ,150,000.
  • the delayed release layer and/or the barrier layer comprises 2 to 10% w/w HPC, such as 3 to 9% w/w HPC, such as 4 to 8% w/w HPC, such as 5 to 7% w/w HPC, such as about 6% w/w HPC.
  • the delayed release layer and/or the barrier layer comprises 2 to 3% w/w HPC, such as 3 to 4% w/w HPC, such as 4 to 5% w/w HPC, such as 5 to 6% w/w HPC, such as 6 to 7% w/w HPC, such as 7 to 8% w/w HPC, such as 8 to 9% w/w HPC, such as 9 to 10% w/w HPC.
  • the delayed release layer and/or the barrier layer comprises or consists of 35 to 65% w/w wax, 30 to 70% w/w L-HPC, and 2 to 10% w/w HPC.
  • the delayed release layer and/or the barrier layer comprises or consists of
  • 35 to 65% w/w of a wax such as 35 to 65% w/w of a wax, such as 35 to 60% w/w of a wax, such as 40 to 60% w/w of a wax, such as 42 to 50% w/w of a wax, such as about 42% w/w of a wax, such as about 50% w/w of a wax, and
  • L-HPC one or more L-HPC, such as of two L-HPC, such as 35 to 65% w/w, such as 40 to 60% w/w, such as 45 to 60% w/w, such as 45 to 55% w/w, such as 42 to 62% w/w, such as 47 to 57% w/w, such as about 52% w/w, and 1 to 15 % w/w of a HPC, such as 1 to 10% w/w, such as 2 to 10% w/w, such as 3 to 9% w/w HPC, such as 4 to 8% w/w HPC, such as 5 to 7% w/w HPC, such as about 6% w/w HPC.
  • a HPC such as 1 to 10% w/w, such as 2 to 10% w/w, such as 3 to 9% w/w HPC, such as 4 to 8% w/w HPC, such as 5 to 7% w/w HPC, such as about 6% w
  • composition of the barrier layer and the delayed release layer is the same.
  • composition of the barrier layer and the delayed release layer are different.
  • the barrier layer does not comprise a HPC.
  • the delayed release layer comprises a HPC and the barrier layer does not comprise a HPC.
  • the delayed release layer and/or the barrier layer comprises 32- 52% w/w of wax, 42-62% w/w of one or more L-HPC such as two L-HPC, and 1-15% w/w HPC; such as comprises 38-46% w/w of wax, 48-56% w/w of one or more L-HPC such as two L-HPC, and 2-10% w/w HPC; such as comprises 38-40, 40-41, 41-42, 42-43, 43-44, 44-46% w/w of wax, 48-50, 50- 51, 51-52, 52-53, 53-54, 54-56% w/w of one or more L-HPC such as two L-HPC, and 2-4, 4-5, 5-6, 6-7, 7-8, 8-10% w/w HPC.
  • the delayed release layer and/or barrier layer comprises 32-52% w/w of wax, 42-62% w/w of one or more L-HPC such as two L-HPC, and 1-15% w/w HPC; such as comprises 38-46% w/w of wax, 48-56% w/w of one or more L-HPC such as two L-HPC, and 2-10% w/w HPC; wherein said wax is selected from
  • a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof; or
  • a wax selected from a petroleum based wax such as microcrystalline wax a hydrogenated oil, such as hydrogenated castor oil and hydrogenated cotton seed oil; a plant wax such as carnauba wax and candelilla wax; an animal wax such as beeswax, a PEG having a molecular weight of at least 1000; a saturated long chain monoglyceride such as glycerol monostearate; a long chain saturated carboxylic acid such as stearic acid and/or palmitic acid; Montan wax; and a long chain alcohol such as stearyl alcohol; or wherein said wax consist of 25-75% w/w of a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof, and 25- 75% w/w of a wax selected from a petroleum based wax such as microcrystalline wax; a hydrogenated oil, such as hydrogenated castor oil and hydrogenated
  • the delayed release layer and/or the barrier layer comprises about 42% w/w of wax, about 52% w/w of one or more L-HPC such as two L-HPC, and about 6% w/w HPC.
  • the delayed release layer and/or the barrier layer comprises 38- 46% w/w of a wax, such as about 42% w/w, wherein said wax is selected from 100% w/w of a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof; or
  • a wax selected from a petroleum based wax such as microcrystalline wax such as microcrystalline wax
  • a hydrogenated oil such as hydrogenated castor oil and hydrogenated cotton seed oil
  • a plant wax such as carnauba wax and candelilla wax
  • an animal wax such as beeswax, a PEG having a molecular weight of at least 1000
  • a saturated long chain monoglyceride such as glycerol monostearate
  • a long chain saturated carboxylic acid such as stearic acid and/or palmitic acid
  • Montan wax and a long chain alcohol such as stearyl alcohol
  • said wax consist of 25-75% w/w, such as about 50% w/w, of a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof, and 25-75% w/w, such as about 50% w/w, of a wax selected from a petroleum based wax
  • the delayed release layer and/or the barrier layer comprises 38- 46% w/w of a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof;
  • the delayed release layer and/or the barrier layer comprises 38- 40, 40-42, 42-43, 43-44, 44-46% w/w of a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof; 18-20, 20-22, 22-23, 23-24,24-26% w/w of an L-HPC with a hydroxypropyl content of about 11% (10.0-12.9%), a molecular weight of about 120,000, and optionally a mean particle size of 45 urn (35-55 urn);
  • the barrier layer does not comprise a HPC, such as does not comprise a HPC with a viscosity of 2.0 to 50.0 mPa s (at 20°C/2% aq. solution).
  • the barrier layer comprises or consists of 32-52% w/w of wax and 48-68% w/w of one or more L-HPC, such as two L-HPC; such as comprises or consists of 38-46% w/w of wax and 44-52% w/w of one or more L-HPC, such as two L-HPC; such as comprises or consists of 38-40, 40-41, 41-42, 42-43, 43-44, 44-46% w/w of wax and 44-46, 46-48, 48-50, 50-52% w/w of one or more L-HPC, such as two L-HPC.
  • the barrier layer comprises or consists of about 42% w/w of wax and about 58% w/w of one or more L-HPC, such as two L-HPC.
  • the barrier layer comprises or consists of 38-46% w/w of a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof;
  • the barrier layer comprises or consists of 38-40, 40-42, 42-43, 43-44, 44-46% w/w of a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof;
  • the barrier layer comprises about 42% w/w of a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof; about 19.5% w/w of an L-HPC with a hydroxypropyl content of about 11% (10.0- 12.9%), a molecular weight of about 120,000, and optionally a mean particle size of 45 urn (35-55 urn), and about 38.5% w/w an L-HPC with a hydroxypropyl content of about 8% (7.0-9.9%), a molecular weight of about 115,000, and optionally a mean particle size of 20 urn (17-23 urn).
  • a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof
  • the delayed release layer and/or the barrier layer comprises a wax and one or more binders, such as selected from L-HPC, HPC, isomalt, MCC, starch and pregelatinized starch.
  • binders such as selected from L-HPC, HPC, isomalt, MCC, starch and pregelatinized starch.
  • the delayed release layer and the barrier layer comprises a wax and two or more binders, such as two binders, wherein said two or more binders are selected from from L-HPC, HPC, isomalt, MCC, starch and pregelatinized starch.
  • the delayed release layer and the barrier layer comprises a wax and two or more binders, wherein the delayed release layer and/or the barrier layer comprises said two binders in a ratio of binder to binder of about 50:50, such as of about 40:60 to 60:40, such as of about 35:65 to 65:35, such as of about 30:70 to 70:30, such as of about 25:75 to 75:25.
  • the delayed release layer and/or the barrier layer comprises a wax and one or more binders, wherein said binder comprises or consist of isomalt. In some embodiments the delayed release layer and/or the barrier layer comprises a wax and isomalt. In some embodiments the delayed release layer and/or the barrier layer comprises a wax and isomalt, and optionally one or more L-HPC and/or HPC.
  • the delayed release layer and/or the barrier layer comprises a wax and isomalt in a ratio of wax to isomalt of about 50:50, such as of about 40:60 to 60:40, such as of about 35:65 to 65:35, such as about 66.6:33.3.
  • the delayed release layer and/or the barrier layer comprises a wax and binders isomalt and MCC.
  • the delayed release layer and/or the barrier layer comprises a wax and binders isomalt and MCC in a ratio of wax to isomalt and MCC of about 50:50, such as of about 40:60 to 60:40, such as of about 35:65 to 65:35;
  • the delayed release layer and/or the barrier layer comprises a wax and isomalt and MCC in a ratio of about 50:25:25.
  • the delayed release layer and/or the barrier layer comprises a wax and one or more binder, wherein said binder comprises or consist of MCC.
  • the barrier layer comprises a wax and MCC.
  • the barrier layer comprises a wax and MCC, and optionally one or more L-HPC and/or HPC.
  • the delayed release layer and/or the barrier layer comprises a wax and MCC in a ratio of wax to MCC of about 50:50, such as of about 40:60 to 60:40, such as of about 35:65 to 65:35.
  • the delayed release layer and/or the barrier layer comprises a wax and one or more binder, wherein said binder comprises or consist of starch and/or pregelatinized starch. In some embodiments the delayed release layer and/or the barrier layer comprises a wax and starch or pregelatinized starch. In some embodiments the delayed release layer and/or the barrier layer comprises a wax and starch or pregelatinized starch, and optionally one or more L-HPC and/or HPC.
  • the delayed release layer and/or the barrier layer comprises a wax and pregelatinized starch in a ratio of wax to pregelatinized starch of about 50:50, such as of about 40:60 to 60:40, such as of about 35:65 to 65:35.
  • the delayed release layer and/or the barrier layer comprises a wax and 25 to 65% w/w pregelatinized starch, such as 25 to 35, such as 35 to 45, such as 45 to 55, such as 55 to 65% w/w pregelatinized starch.
  • the barrier layer comprises more than 30% w/w and less than 70% w/w of a wax, such as 35-65, such as 40-60, such as 45-65% w/w, such as about 50% w/w, wherein said wax is selected from
  • a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof; or
  • a wax selected from a petroleum based wax such as microcrystalline wax such as microcrystalline wax
  • a hydrogenated oil such as hydrogenated castor oil and hydrogenated cotton seed oil
  • a plant wax such as carnauba wax and candelilla wax
  • an animal wax such as beeswax, a PEG having a molecular weight of at least 1000
  • a saturated long chain monoglyceride such as glycerol monostearate
  • a long chain saturated carboxylic acid such as stearic acid and/or palmitic acid
  • Montan wax and a long chain alcohol such as stearyl alcohol
  • said wax consist of 25-75% w/w, such as about 50% w/w, of a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof, and 25-75% w/w, such as about 50% w/w, of a wax selected from a petroleum based wax
  • the delayed release layer and/or the barrier layer comprises a wax and one or more fillers, such as selected from mannitol, sorbitol, xylitol, lactose, sucrose, calcium phosphate and calcium hydrogen phosphate dihydrate.
  • fillers such as selected from mannitol, sorbitol, xylitol, lactose, sucrose, calcium phosphate and calcium hydrogen phosphate dihydrate.
  • the delayed release layer and/or the barrier layer comprises a wax and one or more water-soluble fillers, such as selected from mannitol, sorbitol and lactose.
  • the delayed release layer comprises a wax and one or more fillers.
  • the barrier layer comprises a wax but does not comprise one or more fillers.
  • the delayed release layer and/or the barrier layer comprises a wax and lactose. In some embodiments the delayed release layer and/or the barrier layer comprises a wax and lactose in a ratio of wax to lactose of about 50:50, such as of about 40:60 to 60:40, such as of about 35:65 to 65:35.
  • the delayed release layer comprises a wax and mannitol and/or sorbitol. In some embodiments the delayed release layer and comprises a wax and mannitol and/or sorbitol in a ratio of wax to mannitol and/or sorbitol of about 50:50, such as of about 40:60 to 60:40, such as of about 35:65 to 65:35.
  • the delayed release layer comprises a wax and 10 to 65% w/w of mannitol, sorbitol, and/or lactose, such as 20 to 60% w/w, such as 30 to 60% w/w, such as 40 to 60% w/w, such as about 50% w/w.
  • the delayed release layer comprises more than 30% w/w and less than 70% w/w of a wax, such as 35-65, such as 40-60, such as 45-65% w/w, such as about 50% w/w, wherein said wax is selected from
  • a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof; or
  • a wax selected from a petroleum based wax such as microcrystalline wax such as microcrystalline wax
  • a hydrogenated oil such as hydrogenated castor oil and hydrogenated cotton seed oil
  • a plant wax such as carnauba wax and candelilla wax
  • an animal wax such as beeswax, a PEG having a molecular weight of at least 1000
  • a saturated long chain monoglyceride such as glycerol monostearate
  • a long chain saturated carboxylic acid such as stearic acid and/or palmitic acid
  • Montan wax and a long chain alcohol such as stearyl alcohol
  • said wax consist of 25-75% w/w, such as about 50% w/w, of a glyceryl ester selected from glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof, and 25-75% w/w, such as about 50% w/w, of a wax selected from a petroleum based wax
  • the delayed release layer and/or the barrier layer according to the present disclosure comprises a wax and one or more binders and/or fillers, and further comprises a disintegrant, such as a disintegrant selected from crospovidone, sodium starch glycolate and croscarmellose sodium. These disintegrants are also known as superdisintegrants.
  • Superdisintegrants are defined as highly effective disintegrants that, when used at low levels, provide rapid disintegration and dissolution.
  • the delayed release layer and/or the barrier layer according to the present disclosure comprises a wax and one or more binders, and crospovidone.
  • the delayed release layer and/or the barrier layer comprises 1% to 2% w/w of a disintegrant, such as about 2% to 3% w/w, such as about 3% to 4% w/w, such as about 4% to 5% w/w, such as about 5% to 6% w/w, such as about 6% to 7% w/w, such as about 7% to 8% w/w, such as about 8% to 9% w/w, such as about 9% to 10% w/w of a disintegrant selected from crospovidone, sodium starch glycolate and croscarmellose sodium.
  • a disintegrant selected from crospovidone, sodium starch glycolate and croscarmellose sodium.
  • the delayed release layer and/or the barrier layer comprises 1% to 10% w/w of a disintegrant, such as about 2% to 8% w/w, such as about 3% to 7% w/w, such as about 4% to 6% w/w, such as about 5% w/w of a disintegrant selected from crospovidone, sodium starch glycolate and croscarmellose sodium.
  • a disintegrant selected from crospovidone, sodium starch glycolate and croscarmellose sodium.
  • the tablet formulation further comprises one or more coatings, such as an outer coating.
  • the one or more coatings are in some embodiments applied to the outer surface of the tablet formulation, i.e. on the outer delayed release layer.
  • the tablet formulation comprises a film coating.
  • Film coating is the deposition of a thin film of polymer (usually between 20 and 100 pm) applied mainly to tablets.
  • Film-coating formula generally consists of polymers, plasticizer, colorants/opacifiers, solvents, etc.
  • Reference to tablet and tablet formulation is meant to encompass the final tablet formulation (core, or triple-layer core, with an outer delayed release layer).
  • the tablet formulation has a weight of 500-1000 mg, such as 500-600, 600-650, 650-700, 700-750, 750-800, 800-850, 850-900, 900-1000 mg.
  • the tablet formulation is essentially round. Round is shaped like a circle or cylinder. In some embodiments the tablet formulation is essentially oval.
  • the release of the two or more active agents is delayed for 3.5 to
  • said tablet has a weight of 600-800 mg, such as 650-750 mg, such as 675-750, such as 675-725 mg, such as 700-750 mg, such as wherein the tablet has a weight of about 685 mg, about 715 mg, about 745 mg.
  • said tablet has a weight of 700-900 mg; such as 750-850 mg, such as about 750 mg, such as about 770 mg, such as about 770 mg, such as about 800 mg, such as about 825 mg, such as about 830 mg, such as about 850 mg.
  • the delayed release layer constitutes 50 to 75% w/w of the final tablet weight, such as 55 to 70% w/w, such as 59 to 68% w/w, such as 60 to 67% w/w; such as 50-55% w/w, such as 55-56, 56-57, 57-58, 58-59, 59-60, 60-61, 61-62, 62-63, 63-64, 64-65, 65-66, 66-67, 67-68, 68-69, 69-70 or 70-75% w/w of the final tablet weight.
  • the release of the two or more active agents is delayed for 5 to 7 hours, such as for 5.5 to 6.5 hours, such as for about 6 hours, and wherein said delayed release layer constitutes 63.5 to 68% w/w, such as 64 to 67% w/w of the final tablet weight; such as wherein said delayed release layer constitutes 63.5 to 64.0% w/w, 64.0-64.5% w/w, 64.5-65.0% w/w, 65.0-65.5% w/w, 65.5-66.0% w/w, 66.0-66.5% w/w, 66.5-67.0% w/w, 67.0 to 67.5% w/w, 67.5 to 68.0% w/w of the final tablet weight; such as wherein said delayed release layer constitutes about 64.0% w/w, about 64.5% w/w, about 65.0% w/w, about 65.5% w/w, about 66.0% w/w, about 66.5% w/w,
  • the barrier layer is of a certain minimum thickness to be able to control the release of the two or more active ingredients.
  • the barrier layer constitutes 5 to 25% w/w of the final tablet weight; such as 5-10, 10-15, 15-20, 20-25% w/w of the final tablet weight; such as 10 to 20% w/w, such as 10 to 17.5% w/w of the final tablet weight; such as about 12.5% w/w of the final tablet weight, such as about 14% w/w of the final tablet weight.
  • a tablet formulation for oral administration of two or more active agents such as two active agents, the tablet comprising: i) A core, such as a triple-layer core, comprising or consisting of a.
  • a first core, or first core layer comprising an amount of a first active agent and one or more excipients, wherein said first active agent prevents peripheral metabolism of levodopa (L-DOPA); alternatively wherein said first active agent is selected from dopamine, a dopamine agonist, a dopamine precursor and a dopamine prodrug, b.
  • a second core, or second core layer comprising an amount of a second active agent and one or more excipients, wherein said second active agent is selected from dopamine, a dopamine agonist, a dopamine precursor and a dopamine prodrug, and c.
  • the release of the active agents is delayed for 3 to 5 hours, such as for 3.5 to 4.5 hours, such as for about 4 hours, and said barrier layer constitutes 13.25 to 25% w/w of the final tablet weight.
  • the release of the active agents is delayed for 3 to 5 hours, such as for 3.5 to 4.5 hours, such as for about 4 hours, and said delayed release layer constitutes 59 to 63.5% w/w of the final tablet weight.
  • Reference to dimension (final thickness) in this context refers to the thickness measured from the top side of the tablet formulation to the bottom side of the tablet formulation.
  • the tablet formulation has a dimension (final thickness) of 4 mm to 9 mm. In some embodiments the tablet formulation has a dimension (final thickness) of 5 mm to 8 mm.
  • the tablet formulation has a dimension (final thickness) of 5.5 mm to 7.5 mm, such as 5.5 - 6.0 mm, 6.0 - 6.5 mm, 6.5 - 7.0 mm, or 7.0 - 7.5 mm.
  • the release of the two or more active agents is delayed for 3.5 to
  • said tablet formulation has a dimension (final thickness) of 5 mm to 7 mm, such as 5.5 mm to 6.5 mm, such as 5.5-
  • said tablet formulation has a dimension (final thickness) of 5.5 mm to 8.0 mm, such as 6.0 mm to 7.5 mm, such as 6.0-6.1 , 6.1-6.2, 6.2-6.3, 6.3-6.4, 6.4-6.5, 6.5-6.6, 6.6-6.7, 6.7-6.8, 6.8-6.9, 6.9-7.0, 7.0- 7.1 , 7.1-7.2, 7.2-7.3, 7.3-7.4, 7.4-7.5 mm; such as wherein the tablet formulation has a dimension (final thickness) of about 6.0 mm, about 6.1 mm, about 6.2 mm, about 6.3 mm, about 6.4 mm, about 6.5 mm, about
  • the delayed release layer substantially covers or coats all sides of the core or triple-layer core. In some embodiments the delayed release layer is essentially equally thick on all sides of the core or triple-layer core.
  • the delayed release layer is essentially equally thick on the top and bottom side of the core or triple-layer core. In some embodiments the delayed release layer is essentially equally thick on the planar side of the second core layer and the planar side of the first core layer.
  • the core such as at the triple-layer core, is essentially symmetrically placed within the tablet formulation, i.e. within the delayed release layer.
  • the core such as the triple-layer core, is asymmetrically placed within the tablet formulation, i.e. within the delayed release layer.
  • the delayed release layer is thicker on the planar side surrounding the second core, or second core layer, than the planar side surrounding the first core, or first core layer.
  • Reference to first core and first core layer, and second core and second core layer, may be used interchangeably herein.
  • the delayed release layer is 0.05 to 1.0 mm thicker on the planar side of the second core, or second core layer, than the planar side of the first core, or first core layer, such as 0.05 to 0.1 mm, such as 0.1 to 0.2 mm, such as 0.2 to 0.3 mm, such as 0.3 to 0.4 mm, such as 0.4 to 0.5 mm, such as 0.5 to 0.6 mm, such as 0.6 to 0.7 mm, such as 0.7 to 0.8 mm, such as 0.8 to 0.9 mm, such as 0.9 to 1.0 mm thicker; such as about 0.05 mm thicker, such as about 0.1 mm thicker, such as about 0.2 mm thicker, such as about 0.3 mm thicker, such as about 0.4 mm thicker such as about 0.5 mm thicker, such as about 0.6 mm thicker such as about 0.7 mm thicker, such as about 0.8 mm thicker such as about 0.9 mm thicker, such as about 1.0 mm thicker, such
  • the delayed release layer is heavier or larger on the planar side of the second core layer than the planar side of the first core layer.
  • the delayed release layer weighs more on the planar side of the second core layer than the planar side of the first core layer. In some embodiments the weight of the delayed release layer is higher on the planar side of the second core layer than the planar side of the first core layer.
  • the delayed release layer weighs 1 mg to 100 mg more on the planar side of the second core layer than the planar side of the first core layer, such as 1 to 50 mg more, 2.5 to 50 mg more, such as 2.5 to 25 mg more, such as 5 to 20 mg more, such as 2.5 to 5 mg more, such as 5 to 10 mg more, such as 10 to 20 mg more, such as 20 to 25 mg more, such as 25 to 50 mg more, such as 50 to 75 mg more, such as 75 to 100 mg more, such as about 1 mg, such as about 2.5 mg, such as about 5 mg, such as about 10 mg, such as about 15 mg, such as about 20 mg, such as about 25 mg, such as about 30 mg, such as about 35 mg, such as about 40 mg, such as about 45 mg, such as about 50 mg more, such as about 75 mg more, such as about 100 mg more than the planar side of the second core layer than the planar side of the first core layer.
  • the delayed release layer weighs at least about 0.25% more on the planar side of the second core layer than the planar side of the first core layer, such as at least about 0.5% more, such as at least about 0.6% more, such as at least about 0.7% more, such as at least about 0.8% more, such as at least about 0.9% more, such as at least about 0.95% more, such as at least about 1.0% more, such as at least about 1.5% more, such as at least about 2.0% more, such as at least about 2.5% more, such as at least about 3.0% more, such as at least about 3.5%, such as at least about 4.0%, such as at least about 4.5%, such as at least about 5.0% more on the planar side of the second core layer than the planar side of the first core layer.
  • the delayed release layer weighs 0.25 to 10% more, such as 0.25 to 5%, more, on the planar side of the second core layer than the planar side of the first core layer, such as 0.25 to 0.5% more, such as 0.5 to 0.6% more, such as 0.6 to 0.7% more, such as 0.7 to 0.8% more, such as 0.8 to 0.9% more, such as 0.9 to 1.0% more, such as 1.0 to 1 .5% more, such as 1 .5 to 2.0% more, such as 2.0 to 2.5% more, such as 2.5 to 3.0% more, such as 3.0 to 3.5% more, such as 3.5 to 4.0% more, such as 4.0 to 4.5% more, such as 4.5 to 5.0% more, such as 5.0 to 7.5% more, such as 7.5 to 10% more on the planar side of the second core layer than the planar side of the first core layer.
  • the planar side of the second core layer constitutes at least about 50.1 % of the delayed release layer, such as constitutes at least about 50.2%, such as at least about 50.3%, such as at least about 50.4%, such as at least about 50.5%, such as at least about 50.6%, such as at least about 50.7%, such as at least about 50.8%, such as at least about 50.9%, such as at least about 51%, such as at least about 51 .5%, such as at least about 52%, such as at least about 52.5%, such as at least about 53%, such as at least about 53.5%, such as at least about 54% such as at least about 54.5%, such as at least about 55%.
  • the planar side of the second core layer constitutes about 50.1% of the delayed release layer, such as about 50.2%, such as about 50.3%, such as about 50.4%, such as about 50.5%, such as about 50.6%, such as about 50.7%, such as about 50.8%, such as about 50.9%, such as about 51%, such as about 51.5%, such as about 52%, such as about 52.5%, such as about 53%, such as about 53.5%, such as about 54% such as about 54.5%, such as about 55%, such as about 56%, such as about 57%, such as about 58%, such as about 59%, such as about 60%.
  • the planar side of the second core layer constitutes 50.1 % to 60% of the delayed release layer, such as 50.1 % to 55%, such as 50.1 to 50.2%, such as 50.2 to 50.3%, such as 50.3 to 50.4%, such as 50.4 to 50.5%, such as 50.5 to 50.6%, such as 50.6 to 50.7%, such as 50.7 to 50.8%, such as 50.8 to 50.9%, such as 50.9 to 51 %, such as 51 to 51.5%, such as 51.5 to 52%, such as 52 to 52.5%, such as 52.5 to 53%, such as 53 to 53.5%, such as 53.5 to 54%, such as 54 to 54.5%, such as 54.5 to 55%, such as 55 to 56%, such as 56 to 57%, such as 57 to 58%, such as 58 to 59%, such as 59 to 60%.
  • 50.1 % to 55% such as 50.1 to 50.2%, such as 50.2 to 50.3%, such as 50.3 to 50.4%, such as 5
  • a tablet formulation for oral administration of two or more active agents such as two active agents
  • the tablet comprising: i) A core, such as a triple-layer core, comprising or consisting of a.
  • a first core, or first core layer comprising an amount of a first active agent and one or more excipients, wherein said first active agent prevents peripheral metabolism of levodopa (L-DOPA); alternatively wherein said first active agent is selected from dopamine, a dopamine agonist, a dopamine precursor and a dopamine prodrug, b.
  • L-DOPA levodopa
  • a tablet formulation for oral administration of two or more active agents such as two active agents
  • the tablet comprising: i) A core, such as a triple-layer core, according to the present disclosure, ii) A delayed release layer comprising or consisting of more than 30% w/w and less than 70% w/w of a wax, and one or more binders and/or fillers, wherein the delayed release layer constitutes 50 to 75% w/w of the final tablet weight; wherein the planar side of the second core layer constitutes 50.1% to 60% of the delayed release layer, such as 50.1% to 55%, alternatively wherein the delayed release layer weighs 0.25 to 10%, such as 0.25 to 5%, more on the planar side of the second core layer than the planar side of the first core layer; wherein the release of the two or more active agents is delayed for 2 to 8 hours, and the pulse release of the second active agent is delayed for 10 to 120 minutes, such as 15 to 90 minutes, such as 15 to 60 minutes, longer than the first active
  • a tablet formulation for oral administration of two or more active agents such as two active agents
  • the tablet comprising: i) A core, such as a triple-layer core, according to the present disclosure, ii) A delayed release layer comprising or consisting of more than 30% w/w and less than 70% w/w of a wax, and one or more binders and/or fillers, wherein the delayed release layer constitutes 59 to 63.5% w/w of the final tablet weight; wherein the planar side of the second core layer constitutes 50.1% to 60% of the delayed release layer, such as 50.1% to 55%, alternatively wherein the delayed release layer weighs 0.25 to 10%, such as 0.25 to 5%, more on the planar side of the second core layer than the planar side of the first core layer; wherein the release of the two or more active agents is delayed for 3 to 5 hours, and the pulse release of the second active agent is delayed for 15 to 90 minutes, such as 15 to 60 minutes, longer than the first active agent; and thereafter
  • a tablet formulation for oral administration of two or more active agents such as two active agents
  • the tablet comprising: i) A core, such as a triple-layer core, according to the present disclosure, ii) A delayed release layer comprising or consisting of more than 30% w/w and less than 70% w/w of a wax, and one or more binders and/or fillers, wherein the delayed release layer constitutes 63.5 to 68% w/w of the final tablet weight; wherein the planar side of the second core layer constitutes 50.1% to 60% of the delayed release layer, such as 50.1% to 55%, alternatively wherein the delayed release layer weighs 0.25 to 10%, such as 0.25 to 5%, more on the planar side of the second core layer than the planar side of the first core layer; wherein the release of the two or more active agents is delayed for 5 to 7 hours, and the pulse release of the second active agent is delayed for 15 to 90 minutes, such as 15 to 60 minutes, longer than the first active agent; and thereafter the two
  • the tablet formulation of the present disclosure comprises a core, such as a triple-layer core, surrounded by a delayed release layer.
  • the first and the second core, or first and second core layers, of said core each comprise an active agent and one or more excipients.
  • An active agent of the present disclosure is also known as an active ingredient or active pharmaceutical ingredient (API), and may be used interchangeably herein.
  • An excipient may also be referred to as an inactive pharmaceutical ingredient. Excipients are substances other than the active pharmaceutical ingredient that produce the intended pharmaceutical effect, which are used in the formulation of a drug product.
  • the two or more active agents can be the same or different. In a preferred embodiment the two active agents are different. In some embodiments the two or more active agents are different derivatives of same active agent which have different properties, such as different solubility or different absorption profiles.
  • the first core or core layer comprises an amount of a first active agent, wherein said first active agent prevents peripheral metabolism of levodopa (L- DOPA); and the second core or core layer comprises an amount of a second active agent, wherein said second active agent is selected from dopamine, a dopamine agonist, a dopamine precursor and a dopamine prodrug.
  • a first active agent prevents peripheral metabolism of levodopa (L- DOPA)
  • the second core or core layer comprises an amount of a second active agent, wherein said second active agent is selected from dopamine, a dopamine agonist, a dopamine precursor and a dopamine prodrug.
  • the first core or core layer comprises an amount of a first active agent, wherein said first active agent is selected from dopamine, a dopamine agonist, a dopamine precursor and a dopamine prodrug; and the second core or core layer comprises an amount of a second active agent, wherein said second active agent is selected from dopamine, a dopamine agonist, a dopamine precursor and a dopamine prodrug.
  • the first active agent prevents conversion of levodopa (L-DOPA) to dopamine by DOPA decarboxylase.
  • the first active agent is a DOPA decarboxylase inhibitor.
  • the first active agent is a DOPA decarboxylase inhibitor, and the second active agent is a dopamine precursor or a dopamine prodrug.
  • the first active agent is a DOPA decarboxylase inhibitor
  • the second active agent is levodopa (L-DOPA; 3,4-dihydroxyphenylalanine), or a pharmaceutically acceptable derivative of levodopa.
  • the DOPA decarboxylase inhibitor is selected from carbidopa, benserazide, methyldopa and a-Difluoromethyl-DOPA (DFMD), or a pharmaceutically acceptable derivative thereof.
  • Medicines containing methyldopa are branded as Aldomet, Aldoril, Dopamet, Dopegyt, and others.
  • the DOPA decarboxylase inhibitor is carbidopa, or a pharmaceutically acceptable derivative thereof.
  • the first active agent is carbidopa or a pharmaceutically acceptable derivative of carbidopa
  • the second active agent is levodopa, or a pharmaceutically acceptable derivative of levodopa.
  • the first active agent prevents conversion of levodopa (L-DOPA) to 3-O-methyldopa (3-OMD) by catechol-O-methyltransferase (COMT)
  • the first active agent is a catechol-O-methyltransferase (COMT) inhibitor.
  • the COMT inhibitor is selected from tolcapone, entacapone, opicapone, nitecapone and nebicapone
  • the first active agent is COMT inhibitor and the second active agent is levodopa, or a pharmaceutically acceptable derivative thereof.
  • the first active agent is a DOPA decarboxylase inhibitor and a COMT inhibitor, and wherein the second active agent is levodopa, or a pharmaceutically acceptable derivative thereof.
  • L-DOPA is sold as a psychoactive drug with the INN levodopa.
  • L- DOPA is converted to dopamine by the enzyme aromatic L-amino acid decarboxylase (AADC), also known as DOPA decarboxylase (DDC).
  • AADC aromatic L-amino acid decarboxylase
  • DDC DOPA decarboxylase
  • DDCI peripheral DOPA decarboxylase inhibitor
  • said levodopa comprises pharmaceutically acceptable derivatives of levodopa, including but not limited to modified levodopa, such as deuterated levodopa and partially deuterated levodopa.
  • said levodopa comprises pharmaceutically acceptable derivatives of levodopa, including pharmaceutically acceptable salts, solvates, crystals and cocrystals.
  • the first active agent is levodopa
  • the second active agent is a pharmaceutically acceptable derivative of levodopa
  • the first active agent is levodopa
  • the second active agent is a prodrug of levodopa
  • the first active agent is a pharmaceutically acceptable derivative of levodopa
  • the second active agent is levodopa.
  • the first active agent is a prodrug of levodopa
  • the second active agent is levodopa
  • said levodopa prodrug is selected from an ester, amide, dimeric amide, carrier-mediated, peptide transport-mediated, peptidyl, cyclic, chemical delivery systems and enzyme-model levodopa prodrugs; such as a levodopa prodrug selected from a levodopa ester, levodopa methyl ester and XP21279.
  • the first active agent is levodopa or a pharmaceutically acceptable derivative thereof
  • the second active agent is levodopa or a pharmaceutically acceptable derivative thereof, wherein said first and second agent are different derivatives of levodopa.
  • the first active agent is levodopa or a pharmaceutically acceptable derivative thereof
  • the second active agent is a levodopa prodrug, or a pharmaceutically acceptable derivative thereof.
  • the first active agent is a levodopa prodrug or a pharmaceutically acceptable derivative thereof
  • the second active agent is levodopa, or a pharmaceutically acceptable derivative thereof.
  • the first active agent and/or the second active agent is selected from dopamine, a dopamine agonist, a dopamine precursor and a dopamine prodrug. These may collectively be referred to as ‘dopamine-active agents’ herein.
  • the first active agent and/or the second active agent is dopamine, a dopamine precursor or a dopamine prodrug.
  • a dopamine precursor is in some embodiments a substance that can be converted into dopamine in the body.
  • Known dopamine precursors include L-phenylalanine, L-tyrosine and L-DOPA.
  • the first active agent and/or the second active agent is a dopamine precursor selected from L-phenylalanine, L-tyrosine and L-DOPA (levodopa), or a pharmaceutically acceptable derivative thereof. Levodopa is disclosed in detail elsewhere herein.
  • the first active agent and/or the second active agent is a dopamine agonist.
  • a dopamine agonist may also be referred to as a dopamine receptor agonist.
  • the first active agent and/or the second active agent is a D2-like dopamine receptor agonist.
  • the first active agent and/or the second active agent is a dopamine agonist selected from a biased dopamine agonist, a partial dopamine agonist, a selective dopamine agonist, and a full dopamine agonist.
  • the first active agent and/or the second active agent is a dopamine agonist selected from bromocriptine (Parlodel), pergolide (Permax), pramipexole (Mirapexin, Sifrol), ropinirole (Requip), piribedil (Pronora, Trivastal), cabergoline (Dostinex), apomorphine (Apokyn), dihydroergocryptine, propylnorapomorphine, lisuride, Ciladopa, dihydrexidine, dinapsoline, doxanthrine, epicriptine, quinagolide (Norprolac), rotigotine (Neupro), roxindole, sumanirole, fenoldopam, and any pharmaceutically acceptable derivatives thereof.
  • dopamine agonist selected from bromocriptine (Parlodel), pergolide (Permax), pramipexole (Mirapexin, Sifrol), ropinirole
  • the core, or triple-layer core, of the present disclosure comprises a first core or core layer, and a second core or core layer, wherein each of said two cores are tablet cores or dosage units each comprising an active agent and one or more excipients.
  • said first core or core layer, a second core or core layer are each immediate release cores.
  • Immediate release cores or tablet cores I dosage units may be prepared by conventional methods, to achieve a pulse (burst/immediate) release of at least 70% by weight of the amount of the two or more active agents in the first and second core, or core layer, within 5 to 80 minutes.
  • first core, or first core layer, and the second core, or second core layer, of the present disclosure each comprises 40-90% w/w of an active agent and 10-60% w/w of one or more excipients; such as comprises 30-80% w/w of an active agent and 20-70% w/w of one or more excipients; such as wherein the first core or core layer and the second core or core layer each comprises 30-35, 35-40, 40-45, 45-50, 50-55, 55-60, 60-65,65-70,70-75,75-80, 80-85, 85-90% w/w of an active agent and 10-15, 15-20, 20-25, 25-30, 30-35, 35-40, 40-45, 45-50, 50-55, 55-60, 60-65, 65-70% w/w of one or more excipients.
  • the first core or core layer comprises 30-70% w/w, such as 40- 60% w/w of a first active agent, such as a DOPA decarboxylase inhibitor such as carbidopa, or a pharmaceutically acceptable derivative thereof, and 30 to 70% w/w, such as 40-60% w/w of one or more excipients.
  • a first active agent such as a DOPA decarboxylase inhibitor such as carbidopa, or a pharmaceutically acceptable derivative thereof
  • 70% w/w such as 40-60% w/w of one or more excipients.
  • the first core or core layer comprises about 50% w/w of a first active agent, such as a DOPA decarboxylase inhibitor such as carbidopa, or a pharmaceutically acceptable derivative thereof, and about 50% w/w of one or more excipients.
  • a first active agent such as a DOPA decarboxylase inhibitor such as carbidopa, or a pharmaceutically acceptable derivative thereof
  • the first core or core layer comprises 2.5 to 250 mg of a first active agent, such as a DOPA decarboxylase inhibitor such as carbidopa, or a pharmaceutically acceptable derivative thereof; such as comprises 2.5-5 mg, 5-10, IQ- 15, 15-20, 20-25, 25-30, 30-35, 35-40, 40-50, 50-60, 60-70, 70-75, 75-80, 80-90, 90- 100, 100-125, 125-150, 150-200, 200-250 mg of a first active agent, such as a DOPA decarboxylase inhibitor such as carbidopa, or a pharmaceutically acceptable derivative thereof.
  • a first active agent such as a DOPA decarboxylase inhibitor such as carbidopa
  • a pharmaceutically acceptable derivative thereof such as comprises 2.5-5 mg, 5-10, IQ- 15, 15-20, 20-25, 25-30, 30-35, 35-40, 40-50, 50-60, 60-70, 70-75, 75-80, 80-90, 90- 100, 100-125, 125-150, 150-
  • the first core or core layer comprises 10-100 mg, 10-75 mg, 10-50 mg, 10-40 mg or 15-35 mg of a first active agent, such as a DOPA decarboxylase inhibitor, such as carbidopa or a pharmaceutically acceptable derivative thereof.
  • a first active agent such as a DOPA decarboxylase inhibitor, such as carbidopa or a pharmaceutically acceptable derivative thereof.
  • the first core or core layer comprises about 25 mg of a first active agent, such as a DOPA decarboxylase inhibitor, such as carbidopa or a pharmaceutically acceptable derivative thereof.
  • a first active agent such as a DOPA decarboxylase inhibitor, such as carbidopa or a pharmaceutically acceptable derivative thereof.
  • the second core or core layer comprises 50-80% w/w, such as 50-70% w/w, of a second active agent, such as levodopa or a pharmaceutically acceptable derivative thereof, and 20-50% w/w, such as 30-50% w/w of one or more excipients.
  • a second active agent such as levodopa or a pharmaceutically acceptable derivative thereof
  • the second core or core layer comprises 60-80% w/w, such as 60-70% w/w, of a second active agent, such as levodopa or a pharmaceutically acceptable derivative thereof, and 20-40% w/w, such as 30-40% w/w of one or more excipients.
  • a second active agent such as levodopa or a pharmaceutically acceptable derivative thereof
  • 20-40% w/w such as 30-40% w/w of one or more excipients.
  • the second core or core layer comprises about 80% w/w of a second active agent, such as levodopa or a pharmaceutically acceptable derivative thereof, and about 20% w/w of one or more excipients. In some embodiments the second core or core layer comprises about 66.67% w/w of a second active agent, such as levodopa or a pharmaceutically acceptable derivative thereof, and about 33.33% w/w of one or more excipients.
  • the second core or core layer comprises 10 to 1000 mg of a second active agent, such as levodopa or a pharmaceutically acceptable derivative thereof, such as comprises 10-20 mg, 20-25, 25-30, 30-40, 40-50, 50-60, 60-70, 70-75, 75-80, 80-90, 90-100, 100-125, 125-150, 150-175, 175-200, 200-250, 250-300, 300- 400, 400-500, 500-750, 750-1000 mg of a second active agent, such as levodopa or a pharmaceutically acceptable derivative thereof; such as comprises 25-250 mg, 25-200 mg, 50-200 mg or 50-150 mg of a second active agent, such as levodopa or a pharmaceutically acceptable derivative thereof.
  • a second active agent such as levodopa or a pharmaceutically acceptable derivative thereof
  • the second core or core layer comprises about 100 mg of a second active agent, such as levodopa or a pharmaceutically acceptable derivative thereof.
  • the first core or core layer and the second core or core layer comprises a filler and/or a compressing agent, a disintegration agent and a lubricant; and optionally a binder.
  • the first core or core layer and the second core or core layer comprises a filler and/or a compressing agent selected from isomalt, microcrystalline cellulose, calcium hydrogen phosphate, lactose, mannitol, sorbitol, cellulose, dextrose, starch, hydrolysed starch, and mixtures thereof.
  • a compressing agent selected from isomalt, microcrystalline cellulose, calcium hydrogen phosphate, lactose, mannitol, sorbitol, cellulose, dextrose, starch, hydrolysed starch, and mixtures thereof.
  • first core or core layer and the second core or core layer comprises a disintegration agent selected from croscarmellose sodium, sodium starch glycolate, starch, starch derivatives, cellulose derivatives, bentonite, polyvinylpyrrolidone (PVP), and mixtures thereof.
  • first core or core layer and the second core or core layer comprises a lubricant selected from magnesium stearate, steric acid, talc, PEG, silica, colloidal silicas, silicone dioxide, and mixtures thereof.
  • the first core or core layer and the second core or core layer comprises a binder selected from methyl cellulose, polyvinylpyrrolidone (PVP), hydroxy propyl methyl cellulose, hydroxy propyl cellulose, gelatine, sorbitol, sodium alginate, and mixtures thereof
  • a binder selected from methyl cellulose, polyvinylpyrrolidone (PVP), hydroxy propyl methyl cellulose, hydroxy propyl cellulose, gelatine, sorbitol, sodium alginate, and mixtures thereof
  • the first core or core layer and the second core or core layer comprises one or more excipients selected from microcrystalline cellulose, isomalt, croscarmellose sodium, sodium starch glycolate, and magnesium stearate
  • the first core or core layer and the second core or core layer comprises microcrystalline cellulose and/or isomalt.
  • the first core or core layer and the second core or core layer comprises 15 to 50% w/w of filler and/or compressing agent, such as 15-20, 20-25, 25- 30, 30-35, 35-40, 40-45, 45-50% w/w filler and/or compressing agent.
  • the first core or core layer and the second core or core layer comprises 15 to 50% w/w of microcrystalline cellulose and/or isomalt, such as 15-20, 20-25, 25-30, 30-35, 35-40, 40-45, 45-50% w/w microcrystalline cellulose and/or isomalt.
  • the first core or core layer and the second core or core layer comprises 1.0 to 8.0% w/w of disintegration agent, such as 1.0-2.0, 2.0-3.0, 3.0-4.0, 4.0-5.0, 5.0-6.0, 6.0-7.0, 7.0-8.0% w/w of disintegration agent.
  • the first core or core layer and the second core or core layer comprises 0.5 to 5.0% w/w sodium starch glycolate, such as 0.5-1.0, 1.0-1.5, 1.5-2.0, 2.0-2.5, 2.5-3.0, 3.0-3.5, 3.5-4.0, 4.0-4.5, 4.5-5.0% w/w sodium starch glycolate
  • the first core or core layer and the second core or core layer comprises 1.0 to 10% w/w PVP, such as 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10% w/w PVP.
  • the first core or core layer and the second core or core layer comprises 0.1 to 5.0% w/w of lubricant, such as 0.1 -0-2, 0.2-0.3, 0.3-0.4, 0.4-0.5, 0.5- 0.75, 0.75-1.0, 1.0-1.25, 1.25-1.5, 1.5-1.75, 1.75-2.0, 2.0-2.25, 2.25-2.5, 2.5-2.75, 2.75- 3.0, 3.0-3.5, 3.5-4.0, 4.0-4.5, 4.5-5.0 % w/w of lubricant.
  • lubricant such as 0.1 -0-2, 0.2-0.3, 0.3-0.4, 0.4-0.5, 0.5- 0.75, 0.75-1.0, 1.0-1.25, 1.25-1.5, 1.5-1.75, 1.75-2.0, 2.0-2.25, 2.25-2.5, 2.5-2.75, 2.75- 3.0, 3.0-3.5, 3.5-4.0, 4.0-4.5, 4.5-5.0 % w/w of lubricant.
  • the first core or core layer and the second core or core layer comprises 0.1 to 5.0% w/w of one or more lubricant selected from magnesium stearate, steric acid, talc, PEG, silica, colloidal silicas, silicone dioxide and mixtures thereof, such as 0,.1-0-2, 0.2-0.3, 0.3-0.4, 0.4-0.5, 0.5-0.75, 0.75-1.0, 1.0-1.25, 1.25-1.5, 1.5-1.75, 1.75-2.0, 2.0-2.25, 2.25-2.5, 2.5-2.75, 2.75-3.0, 3.0-3.5, 3.5-4.0, 4.0-4.5, 4.5-5.0 % w/w of one or more lubricant selected from magnesium stearate, steric acid, talc, PEG, silica, colloidal silicas, and mixtures thereof.
  • the first core or core layer and the second core or core layer comprises 0.2 to 3.0% w/w magnesium stearate, such as 0.2-0.3, 0.3-0.4, 0.4-0.5, 0.5- 0.75, 0.75-1.0, 1.0-1.25, 1.25-1.5, 1.5-1.75, 1.75-2.0, 2.0-2.25, 2.25-2.5, 2.5-2.75, 2.75- 3.0% w/w magnesium stearate
  • the first core or core layer and the second core or core layer comprises 0.2 to 2.0% w/w silicone dioxide, such as 0.2-0.3, 0.3-0.4, 0.4-0.5, 0.5-0.75, 0.75-1.0, 1.0-1.25, 1.25-1.5, 1.5-1.75, 1.75-2.0% w/w silicone dioxide.
  • the first core or core layer comprises 40-60% w/w of a first active agent, such as a DOPA decarboxylase inhibitor, such as carbidopa or a pharmaceutically acceptable derivative thereof; 20-25% w/w microcrystalline cellulose, 20-25% w/w isomalt, 1-5% w/w croscarmellose sodium, 1-5% w/w sodium starch glycolate and 0.5-2.0 % w/w magnesium stearate.
  • a first active agent such as a DOPA decarboxylase inhibitor, such as carbidopa or a pharmaceutically acceptable derivative thereof
  • 20-25% w/w microcrystalline cellulose 20-25% w/w isomalt, 1-5% w/w croscarmellose sodium, 1-5% w/w sodium starch glycolate and 0.5-2.0 % w/w magnesium stearate.
  • the first core or core layer comprises about 50% w/w of a first active agent, such as a DOPA decarboxylase inhibitor, such as carbidopa or a pharmaceutically acceptable derivative thereof; about 22.22% w/w microcrystalline cellulose, about 22.22% w/w isomalt, about 2.22% w/w croscarmellose sodium, about 2.22% w/w sodium starch glycolate and about 1.12% w/w magnesium stearate.
  • a first active agent such as a DOPA decarboxylase inhibitor, such as carbidopa or a pharmaceutically acceptable derivative thereof
  • a DOPA decarboxylase inhibitor such as carbidopa or a pharmaceutically acceptable derivative thereof
  • the first core or core layer comprises 40-60% w/w of a first active agent, such as a DOPA decarboxylase inhibitor, such as carbidopa or a pharmaceutically acceptable derivative thereof; 15-25% w/w microcrystalline cellulose, 15-25% w/w isomalt, 1-8 % w/w PVP, 1-5% w/w croscarmellose sodium, 1-5% w/w sodium starch glycolate, 0.5-2.0 % w/w magnesium stearate and 0.1-1.0 % w/w silicon dioxide.
  • a first active agent such as a DOPA decarboxylase inhibitor, such as carbidopa or a pharmaceutically acceptable derivative thereof
  • a DOPA decarboxylase inhibitor such as carbidopa or a pharmaceutically acceptable derivative thereof
  • 15-25% w/w microcrystalline cellulose 15-25% w/w isomalt
  • 1-8 % w/w PVP 1-5% w/w croscarmellose sodium
  • the second core or core layer comprises 70-90% w/w of a second active agent, such as levodopa or a pharmaceutically acceptable derivative thereof; 5-14% w/w microcrystalline cellulose, 5-14% w/w isomalt, 0.2-2.0% w/w croscarmellose sodium, 0.2-2.0% w/w sodium starch glycolate and 0.1-1.5 w/w magnesium stearate.
  • a second active agent such as levodopa or a pharmaceutically acceptable derivative thereof
  • 5-14% w/w microcrystalline cellulose 5-14% w/w isomalt
  • 0.2-2.0% w/w croscarmellose sodium 0.2-2.0% w/w sodium starch glycolate and 0.1-1.5 w/w magnesium stearate.
  • the second core or core layer comprises about 80% w/w of a second active agent, such as levodopa or a pharmaceutically acceptable derivative thereof; about 8.89% w/w microcrystalline cellulose, about 8.89% w/w isomalt, about 0.89% w/w croscarmellose sodium, about 0.89% w/w sodium starch glycolate and about 0.45% w/w magnesium stearate.
  • a second active agent such as levodopa or a pharmaceutically acceptable derivative thereof
  • about 8.89% w/w microcrystalline cellulose about 8.89% w/w isomalt
  • about 0.89% w/w croscarmellose sodium about 0.89% w/w sodium starch glycolate and about 0.45% w/w magnesium stearate.
  • the second core or core layer comprises 60-75% w/w of a second active agent, such as levodopa or a pharmaceutically acceptable derivative thereof; 7-17% w/w microcrystalline cellulose, 7-17% w/w isomalt, 1-8% w/w PVP, 0.5- 5.0% w/w croscarmellose sodium, 0.1 -1.5% w/w magnesium stearate and 0.1 -1.0% w/w silicon dioxide.
  • a second active agent such as levodopa or a pharmaceutically acceptable derivative thereof
  • 7-17% w/w microcrystalline cellulose 7-17% w/w isomalt
  • 1-8% w/w PVP 1-8% w/w/w PVP
  • the second core or core layer comprises about 66.67% w/w of a second active agent, such as levodopa or a pharmaceutically acceptable derivative thereof; about 12.92% w/w microcrystalline cellulose, about 12.92% w/w isomalt, about 4% w/w PVP, about 2% w/w croscarmellose sodium, about 1% w/w magnesium stearate and about 0.5% w/w silicon dioxide.
  • a second active agent such as levodopa or a pharmaceutically acceptable derivative thereof
  • a second active agent such as levodopa or a pharmaceutically acceptable derivative thereof
  • about 12.92% w/w microcrystalline cellulose about 12.92% w/w isomalt
  • about 4% w/w PVP about 2% w/w croscarmellose sodium
  • about 1% w/w magnesium stearate and about 0.5% w/w silicon dioxide.
  • the dimension (thickness) of the core, or triple-layer core, comprising a first and second core, or first and second core layer, and a barrier layer is 2.5 mm to 6.0 mm, such as 3.0 mm to 5.5 mm, such as 3.0-3.5 mm, 3.5-4.0 mm, 4.0- 4.1 mm, 4.1-4.2 mm, 4.2-4.3 mm, 4.3-4.4 mm, 4.4-4.5 mm, 4.5-5.0, 5.0-5.5 mm.
  • the dimension (thickness) of the core comprising a first and second core, or core layer, and a barrier layer is about 4.0 mm, about 4.1 mm, about 4.2 mm, about 4.3 mm, about 4.4 mm, or about 4.5 mm.
  • a method of making a tablet formulation according to the present disclosure comprising: i) manufacturing a triple-layer core tablet comprising the steps of: a) the second active agent and the one or more excipients are mixed or granulated together and placed into a tablet-press die to form a second core layer; b) one or more wax and one or more binders, such as one or more L-HPC, are mixed and melted to form granules and the resulting mixture placed on top of the second core layer to form a barrier layer, c) the first active agent and the one or more excipients are mixed or granulated together and placed on top of the second core layer to form a first core layer, d) the tablet (tablet core) is compressed, such as compressed at 10-14 kN, such as at about 11-13 kN, such as about 10 kN, such as about 12 kN, such as about 14 kN, to produce a triple-layer core, ii) manufacturing a triple-layer core tablet comprising the
  • the release of the two or more active agents is delayed for 3.5 to
  • step i) wherein said tablet formulation in step i) is compressed at 6-10 kN, such as at 7-9 kN, such as at 7.5-9.5 kN, such as about 7 kN, such as about 8 kN, such as about 9 Kn.
  • the release of the two or more active agents is delayed for 5.5 to
  • step i) wherein said tablet formulation in step i) is compressed at 8-12 kN, such as at 9-11 kN, such as at 9.5-10.5 kN, such as about 9 kN, such as about 10 kN, such as about 11 Kn.
  • the tablet-press die of step i) a) is an 8.0 mm die and punch set. In some embodiments the tablet-press die of step i) a) is an 8.0 mm FBE die and punch set. In some embodiments the tablet-press die of step ii) f) is an 12.0 mm die and punch set. In some embodiments the tablet-press die of step ii) f) is an 12.0 mm round biconvex R24 die and punch set.
  • Oral levodopa typically provides robust dependable relief of symptoms when it is first started. However, after taking the medicine for many months or years, most patients with Parkinson’s disease begin to develop a fluctuating response to levodopa. Fluctuating responses are divided into “ON” time, when the medication is working well and controlling Parkinson’s symptoms, and “OFF” time when the medication fails or is delayed in working and Parkinson’s disease symptoms are poorly controlled.
  • Morning akinesia is one form of “OFF” episode, and is often referred to as ‘Early morning OFF’ (EMO). Motor symptoms of morning akinesia include tremor, slowness, muscle stiffness, freezing and falls, and difficulty in moving and walking in the morning.
  • Reference to morning akinesia may be used herein interchangeably with EMO (early morning OFF), morning immobility and morning hypomobility.
  • the tablet formulation according to the present disclosure is for use in the treatment of early morning OFF/morning akinesia in a patient with Parkinson’s disease presenting with one or more motor symptoms selected from tremor, slowness, muscle stiffness, freezing and falls, and difficulty in moving and walking in the morning.
  • the tablet formulation according to the present disclosure is for use in the treatment of early morning OFF/morning akinesia in a patient with Parkinson’s disease presenting with one or more non-motor symptoms selected from anxiety, low mood, paraesthesia, pain, dribbling and urgency.
  • nocturnal symptoms may be used herein interchangeably with nocturnal akinesia and nocturnal immobility.
  • a tablet formulation for oral administration of two or more active agents for use in the treatment of morning akinesia and/or nocturnal symptoms, such as in a patient with Parkinson’s disease
  • the tablet comprising: i) A core, such as a triple-layer core, comprising or consisting of a.
  • L-DOPA levodopa
  • a second core, or second core layer comprising an amount of a second active agent and one or more excipients, wherein said second active agent is levodopa, or a pharmaceutically acceptable derivative thereof, and c.
  • a barrier layer interposed between the first and the second core, or first and second core layer, said barrier layer comprising or consisting of a wax and one or more binders and/or fillers, and ii) A delayed release layer surrounding the core, said delayed release layer comprising or consisting of a wax and one or more binders and/or fillers, wherein the release of the two or more active agents is delayed for 2 to 10 hours, and thereafter the two or more active agents are pulse released such that at least 70% by weight of the amount of the two or more active agents in the first and second core, or core layer, is released within 5 to 80 minutes.
  • said nocturnal symptoms in a patient with Parkinson’s disease are motor symptoms.
  • said nocturnal symptoms in a patient with Parkinson’s disease are selected from motor complications, immobility episodes, nocturnal immobility, tremor.
  • said nocturnal symptoms in a patient with Parkinson’s disease are non-motor symptoms such as anxiety, depression, pain, urinary urge, dribbling of saliva, low mood, limb paresthesia, dizziness, post-prandial bloating, abdominal discomfort, early satiety, nausea, vomiting, weight loss, and malnutrition.
  • the tablet formulation disclosed herein is preferably administered to individuals in need of treatment in pharmaceutically effective doses.
  • a therapeutically effective amount of a compound or active pharmaceutical ingredient is an amount sufficient to cure, prevent, reduce the risk of, alleviate or partially arrest the clinical manifestations of a given disease and its complications.
  • the amount that is effective for a particular therapeutic purpose will depend on the severity and the sort of the disease as well as on the weight and general state of the subject.
  • the tablet formulation of the present disclosure is administered prior to sleep.
  • the tablet formulation of the present disclosure is administered once daily prior to sleep.
  • the tablet formulation of the present disclosure is administered before bedtime.
  • the tablet formulation of the present disclosure is administered once daily before bedtime.
  • the tablet formulation of the present disclosure is administered 4 to 0 hours prior to sleep I before bedtime, such as 4 hours to 314 hours, such as 314 hours to 3 hours, such as 3 hours to 214 hours, such as 214 hours to 2 hours, such as 2 hours to 114 hours, such as 114 hours to 1 hour, such as 1 hour to 45 minutes, such as 45 minutes to 30 minutes, such as 30 minutes to 20 minutes, such as 20 minutes to 15 minutes, such as 15 minutes to 10 minutes, such as 10 minutes to 5 minutes, such as 5 minutes to 1 minute, such as 1 minute to 0 minutes prior to sleep I before bedtime.
  • Administration may occur for a limited time or administration may be chronic such as chronic from the onset of diagnosis, such as throughout the lifetime of the individual or as long as the individual will benefit therefrom i.e. when a disease is present or while having an increased risk of developing a disease.
  • the concentration of each of the active agents in the present pharmaceutical composition are optimized to achieve an appropriate dosage of each drug.
  • Levodopa is often administered at an initial dosage and later administered at a maintenance dosage.
  • said levodopa, or pharmaceutically acceptable derivative thereof is administered at a dosage of 25 to 250 mg/day, such as 25-200 mg/day, such as 50-200 mg/day, such as 50-150 mg/day, such as 75-125 mg/day, such as about 100 mg/day.
  • said levodopa, or pharmaceutically acceptable derivative thereof is administered at a daily dosage of 0.01 to 100 mg/kg bodyweight, such as 0.1 to 10 mg/kg bodyweight, such as 0.1 to 1 mg/kg bodyweight, such as 1 to 2 mg/kg bodyweight, such as 2 to 3 mg/kg bodyweight, such as 3 to 4 mg/kg bodyweight, such as 4 to 5 mg/kg bodyweight, such as 5 to 6 mg/kg bodyweight, such as 6 to 7 mg/kg bodyweight, such as 7 to 8 mg/kg bodyweight, such as 8 to 9 mg/kg bodyweight, such as 9 to 10 mg/kg bodyweight.
  • 0.01 to 100 mg/kg bodyweight such as 0.1 to 10 mg/kg bodyweight, such as 0.1 to 1 mg/kg bodyweight, such as 1 to 2 mg/kg bodyweight, such as 2 to 3 mg/kg bodyweight, such as 3 to 4 mg/kg bodyweight, such as 4 to 5 mg/kg bodyweight, such as 5 to 6 mg/kg bodyweight, such as 6 to 7 mg/kg body
  • said carbidopa, or pharmaceutically acceptable derivative thereof is administered at a dosage of 5 to 1000 mg/day, such as 5-10 mg/day, such as 10-25 mg/day, such as 25-50 mg/day, such as 50-75 mg/day, such as 75-100 mg/day, such as 100-150 mg/day, such as 150-200 mg/day, such as 200-250 mg/day, such as 250- 500 mg/day, such as 500-750 mg/day, such as 750-1000 mg/day.
  • said carbidopa, or pharmaceutically acceptable derivative thereof is administered at a dosage of 5 to 200 mg/day, such as 10-100 mg/day, such as 10-75 mg/day, such as 10-50 mg/day, such as about 25 mg/day.
  • said levodopa, or pharmaceutically acceptable derivative thereof is administered at a daily dosage of 0.01 to 100 mg/kg bodyweight, such as 0.1 to 10 mg/kg bodyweight, such as 0.1 to 0.5 mg/kg bodyweight, such as 0.5 to 1 mg/kg bodyweight such as 1 to 2 mg/kg bodyweight, such as 2 to 3 mg/kg bodyweight, such as 3 to 4 mg/kg bodyweight, such as 4 to 5 mg/kg bodyweight, such as 5 to 6 mg/kg bodyweight, such as 6 to 7 mg/kg bodyweight, such as 7 to 8 mg/kg bodyweight, such as 8 to 9 mg/kg bodyweight, such as 9 to 10 mg/kg bodyweight.
  • 0.01 to 100 mg/kg bodyweight such as 0.1 to 10 mg/kg bodyweight, such as 0.1 to 0.5 mg/kg bodyweight, such as 0.5 to 1 mg/kg bodyweight such as 1 to 2 mg/kg bodyweight, such as 2 to 3 mg/kg bodyweight, such as 3 to 4 mg/kg bodyweight, such as 4 to 5 mg/
  • said carbidopa, or pharmaceutically acceptable derivative thereof is administered at 5-150 mg per dosage, such as at 10-20 mg, 20-25 mg, 25-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, 90-100 mg, 100-125 mg, 125-150 mg per dosage.
  • said carbidopa, or pharmaceutically acceptable derivative thereof is administered at 10-50 mg per dosage.
  • said carbidopa, or pharmaceutically acceptable derivative thereof is administered at about 25 mg per dosage.
  • a tablet formulation according to the present disclosure for use in the treatment of morning akinesia and/or nocturnal symptoms, such as in a patient with Parkinson’s disease, the tablet comprising: i) A core, such as a triple-layer core, comprising or consisting of i) A first core, or first core layer, comprising 5 to 150 mg of carbidopa, or a pharmaceutically acceptable derivative thereof, and one or more excipients, ii) A second core, or second core layer, comprising 1 to 1000 mg levodopa, or a pharmaceutically acceptable derivative thereof, and one or more excipients, iii) A barrier layer interposed between the first and the second core, or first and second core layer, said barrier layer comprising or consisting of a wax and one or more binders and/or fillers, and ii) A delayed release layer surrounding the core, said delayed release layer comprising or consisting of a wax and one or more binders and/or fillers, wherein the release of
  • said first core, or first core layer comprises 5 to 150 mg, such as at 10-20 mg, 20-25 mg, 25-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, 90-100 mg, 100-125 mg, 125-150 mg carbidopa, or a pharmaceutically acceptable derivative thereof.
  • said first core, or first core layer comprises 10 to 50 mg carbidopa, or a pharmaceutically acceptable derivative thereof, such as about 25 mg carbidopa, or a pharmaceutically acceptable derivative thereof.
  • said second core, or second core layer comprises 10-1000 mg, such as 10-500 mg, such as at 10-25 mg, 25-50 mg, 50-75mg, 75-100 mg, 100-125 mg, 125-150 mg, 150-175 mg, 175-200 mg, 200-250 mg, 250-500 mg levodopa, or a pharmaceutically acceptable derivative thereof.
  • second first core, or second core layer comprises 25 to 250 mg levodopa, or a pharmaceutically acceptable derivative thereof, such as about 50 to 200 mg, 50 to 150 mg, 75 to 125 mg levodopa, such as about 100 mg or a pharmaceutically acceptable derivative thereof.
  • a tablet formulation for oral administration of two or more active agents comprising: i) A core, such as a triple-layer core, comprising or consisting of a.
  • a first core, or first core layer comprising an amount of a first active agent and one or more excipients, wherein said first active agent prevents peripheral metabolism of levodopa;
  • a second core, or second core layer comprising an amount of a second active agent and one or more excipients, wherein said second active agent is levodopa, or a pharmaceutically acceptable derivative thereof; and c.
  • the tablet formulation according to item 1 wherein the first active agent is a DOPA decarboxylase inhibitor and/or a COMT inhibitor, and the second active agent is levodopa, or a pharmaceutically acceptable derivative thereof.
  • the delayed release layer comprises a wax, two or more such as two L-HPC and a HPC; and the barrier layer comprises or consist of a wax and two or more such as two L-HPC.
  • the tablet formulation according to any of the preceding items wherein the one or more L-HPC has a hydroxypropyl content of about 11% by weight (10.0- 12.9% by weight), a molecular weight of about 120,000, and optionally a mean particle size of 45 urn (35-55 urn); such as wherein said one or more L-HPC is LH-21 ; and/or wherein the one or more L-HPC has a hydroxypropyl content of about 8% by weight (7.0-9.9% by weight), a molecular weight of about 115,000, and optionally a mean particle size of 20 urn (17-23 urn); such as wherein said one or more L-HPC is LH-32.
  • the wax is selected from a glyceryl ester, microcrystalline wax, a hydrogenated castor oil, carnauba wax and beeswax, and any combination of waxes; such as wherein the glyceryl ester is glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, and any mixture thereof.
  • the delayed release layer constitutes 50 to 75% w/w of the final tablet weight and the delayed release layer weighs at least about 0.25% more on the planar side of the second core layer than the planar side of the first core layer, such as at least about 0.5% more, such as at least about 0.6% more, such as at least about 0.7% more, such as at least about 0.8% more, such as at least about 0.9% more, such as at least about 0.95% more, such as at least about 1.0% more on the planar side of the second core layer than the planar side of the first core layer.
  • the tablet formulation according to any of the preceding items wherein the barrier layer constitutes 25 to 50% w/w of the combined weight of the core such as the triple-layer core; and/or wherein the barrier layer constitutes 5 to 25% w/w of the final tablet weight.
  • Prototype 1 A bilayer core tablet containing, in each layer, Carbidopa and Levodopa surrounded by an outer erodible barrier layer, EBL, functioning as a delayed release layer.
  • Prototype 2 A triple-layer core tablet containing Carbidopa and Levodopa surrounded by an outer erodible barrier layer, EBL, functioning as a delayed release layer.
  • the core has an additional barrier layer between the two API core layers to achieve a difference in release time of the Carbidopa and Levodopa.
  • the composition of the additional barrier layer is in some embodiments different from the outer erodible barrier layer (delayed release layer).
  • Prototype 3 A core with two core tablets containing Carbidopa and Levodopa, respectively, are compressed within the erodible barrier layer (delayed release layer), mimicking a triple-layer core. The outer erodible barrier layer is found also between the two core tablets.
  • the barrier layer ‘formulation T is identical to the outer erodible barrier layer and contains a low fine powder hydroxypropyl cellulose (HPC Nisso LFP), which acts a binder.
  • HPC Nisso LFP low fine powder hydroxypropyl cellulose
  • a barrier layer ‘formulation 2’ without HPC LFP was manufactured for use in the core tablet between the CD and LD core layers (Prototype-2 (4); 110 mg barrier layer, 200/200 mg outer layer; half-dose tablet).
  • a 6-hour delayed release dual pulse tablet was developed by changing the weight of the outer erodible barrier layer around the core tablet to achieve a longer lag time. For 6-h delayed release Tab-in-Tabs, 10 KN compression force was used to obtain a suitable size tablet. Variations in the weight of the outer erodible barrier layer for the Tab-in-Tab were investigated to achieve the target delay time.
  • the below table illustrates the composition of a Dual Pulse tablet releasing 25mg of Carbidopa after a 4-hour delay followed by 100mg of Levodopa after a further 0.5-1 hour delay:
  • the barrier layer in between the CD and LD cores is a factor that impact release rate.
  • Formulation 1 was utilised as the outer erodible barrier layer and allowed for the 4 or 6 hours delays to be achieved.
  • Formulation 2 was positioned between the API layers (as a barrier layer) allowing for the short delay between release in some prototypes.
  • the method for manufacture of the barrier layer granules is as follows: All excipients were weighed, combined, and mixed via a tumbling method for 10 minutes. The premixed blend was heated to 90 °C and mixed prior to sizing through a 1 mm sieve and allowed to cool.
  • the manufacturing parameters for the 4-hour core tablets can be found in the below.
  • Dual pulse Carbidopa and Levodopa tablets intended for improved management of nocturnal immobility and morning akinesia in individuals with Parkinson’s disease have been developed, one with a four-hour lag time before onset of release of the Carbidopa and one with a six-hour lag time before onset of release of the Carbidopa.
  • the two prototype tablets have been assessed in a clinical proof of principle study against the comparator product, half Sinemet, to confirm tablet performance and determine pharmacokinetics.
  • Test item 1 Carbidopa release start at 4 hrs after oral administration, levodopa release start at 414 hrs after oral administration.
  • Test item 2 Carbidopa release start at 6 hrs after oral administration, levodopa release start at 614 hrs after oral administration.
  • the study was a single centre, phase 1 , three arm, open label cross-over, overnight study in 19 healthy male volunteers, with the following treatments:
  • Treatment A One radiolabelled dual pulse tablet containing 25mg carbidopa and 100mg levodopa designed to release carbidopa at 4 hours post dose with a second pulse of levodopa 0.5-1 hours later.
  • Treatment B One radiolabelled dual pulse tablet containing 25mg carbidopa and 100mg levodopa designed to release carbidopa at 6 hours post dose with a second pulse of levodopa 0.5-1 hours later.
  • Treatment C One currently marketed extended-release formulation containing 25mg carbidopa and 100mg levodopa (Half Sinemet CR 25mg/100mg Prolonged release tablet).
  • Treatment A and B were radiolabelled to contain a total dose of approximately 4 MBq 99mTc-DTPA at time of dosing.
  • Each subject received one dose of Treatment A at Assessment Visit 1 and one dose of T reatment B at Assessment Visit 2.
  • Each treatment was administered orally with 240 mL room temperature noncarbonated water. Subjects were dosed in the fed state (standard dinner served at approximately 2 hours before dosing).
  • the primary objective of the study was to evaluate the absorption (PK) of levodopa and carbidopa from two delayed pulsatile release formulations and correlate with scintigraphic time and site of release.
  • Pharmacokinetic (PK) parameters of carbidopa and levodopa include: Maximum Concentration (Cmax), Time of Maximum Concentration (Tmax), Lag Time (Tlag), Area Under the Curve from time 0 to 24 hours (AUCIast), Area Under the Curve from time 0 to infinity (AUCO-inf), Terminal First Order Rate constant (K), and Terminal Elimination Half Life (t1/2).
  • PK parameters were derived by non-compartmental analysis methods performed using Phoenix WinNonlin software (v8.4, Certara USA, Inc., USA).
  • the study was designed primarily to evaluate the absorption of levodopa and carbidopa from delayed, dual pulse release tablets and correlate with scintigraphic time and site of release. Secondary objectives included comparing the PK performance of levodopa and carbidopa in two forms of the dual pulse tablets with a commercially available extended release formula tablet. The study was also designed to evaluate the safety and tolerability of the dual pulse tablets.
  • a pharmacoscintigraphic single-centre, open-label, randomised, 3-way cross-over study in patients with Parkinson’s disease will be conducted to evaluate the delayed release, dual pulse carbidopa and levodopa tablets (the two prototypes described in Example 2 above).
  • the two formulations are designed to be taken at bedtime and will release a pulse of carbidopa about 4 hours or 6 hours after dose followed by a second delayed pulse of levodopa 30-60 minutes later with the objective of achieving clinically relevant therapeutic plasma levels of levodopa during the late night and/or early morning hours prior to waking.
  • phase la pharmacoscintigraphic study in healthy volunteers has been completed demonstrating successful targeted release of carbidopa/levodopa at the intended time points and clinically relevant plasma levels of levodopa (cf. Example 2 herein), supportive of this treatment concept.
  • This study aims to confirm the phase la results in the targeted patient population.
  • enrolled participants will attend for three overnight visits on each of which they will receive a single dose of one of three different treatments. Participants will be randomised to sequence of treatments. Dosing will be separated by a minimum of 3 days to allow sufficient washout of radiolabel. A follow up visit will be conducted within 7-14 days of the last treatment visit. On treatment visits, participants will be dosed at approximately 9 pm. Pre-existing treatment regimen doses can be taken as normal up to and including at 5 pm.
  • Treatment A One radiolabelled dual pulse tablet containing 25mg carbidopa and 100mg levodopa designed to release carbidopa at 4 hours post dose with a second pulse of levodopa 0.5-1 hours later.
  • Treatment B One radiolabelled dual pulse tablet containing 25mg carbidopa and 100mg levodopa designed to release carbidopa at 4 hours post dose with a second pulse of levodopa 0.5-1 hours later.
  • Treatment C - (reference therapy): One tablet of a currently marketed immediate-release product containing 25mg carbidopa and 100mg levodopa (SINEMET® Plus 25 mg/100 mg Tablets).
  • Treatments A and B will be radiolabelled to contain a total dose of approximately 4 MBq 99mTc-DTPA at time of dosing. Each treatment will be administered orally with 240 mL room temperature noncarbonated water. Participants will be dosed in the fed state (2 hours post standardised dinner).
  • blood samples will be drawn by suitably trained site staff at appropriate timepoints to allow an assessment of carbidopa and levodopa concentrations in plasma.
  • Example 1 the inventors tested additional excipients in the outer delayed release layer, and in the barrier layer, of the dual pulse tablets.
  • the data demonstrates that the glyceryl ester wax (glyceryl dibehenate) as used in Example 1 can be exchanged or supplemented with another wax or wax-like solid, while retaining a delay of release in a dissolution assay and subsequent burst release. Also, the data demonstrates that the delayed release layer should comprise more than about 30% w/w and below about 70% w/w of a wax.
  • the following formulations were tested for ability to delay carbidopa (CD) and levodopa (LD).
  • CD carbidopa
  • LD levodopa
  • the data demonstrates that formulations comprising as wax 100% montan wax or 50% stearyl alcohol (with 50% glyceryl di behenate) are inferior; and formulations comprising a wax and 100% filler which is mannitol or sorbitol does not work, in the barrier layer:
  • Carbidopa-containing core in triple-layer core

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Abstract

L'invention concerne un système d'administration de médicament pulsatile qui permet une libération pulsée retardée d'au moins deux agents actifs pour la gestion de périodes d'arrêt chez les patients atteints de la maladie de Parkinson, le premier agent actif étant éventuellement libéré avant le second agent actif.
PCT/EP2025/053697 2024-02-12 2025-02-12 Formulation orale à double libération pulsée retardée Pending WO2025172348A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040166159A1 (en) * 2002-05-29 2004-08-26 Chien-Hsuan Han Pharmaceutical dosage forms having immediate and controlled release properties that contain an aromatic amino acid decarboxylase inhibitor and levodopa
US20070275060A1 (en) * 2005-08-05 2007-11-29 Osmotica Costa Rica Sociedad Anonima Extended release solid pharmaceutical composition containing carbidopa and levodopa
US20190290587A1 (en) * 2016-07-11 2019-09-26 Contera Pharma Aps Pulsatile drug delivery system for treating morning akinesia

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040166159A1 (en) * 2002-05-29 2004-08-26 Chien-Hsuan Han Pharmaceutical dosage forms having immediate and controlled release properties that contain an aromatic amino acid decarboxylase inhibitor and levodopa
US20070275060A1 (en) * 2005-08-05 2007-11-29 Osmotica Costa Rica Sociedad Anonima Extended release solid pharmaceutical composition containing carbidopa and levodopa
US20190290587A1 (en) * 2016-07-11 2019-09-26 Contera Pharma Aps Pulsatile drug delivery system for treating morning akinesia

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KHAN ZAHEEDA ET AL: "A Novel Multilayered Multidisk Oral Tablet for Chronotherapeutic Drug Delivery", BIOMED RESEARCH INTERNATIONAL, vol. 2013, 1 January 2013 (2013-01-01), pages 1 - 16, XP093273001, ISSN: 2314-6133, Retrieved from the Internet <URL:http://downloads.hindawi.com/journals/bmri/2013/569470.pdf> [retrieved on 20250428], DOI: 10.1155/2013/569470 *

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