US20140017303A1 - Accordion pill comprising levodopa for an improved treatment of parkinson's disease symptoms - Google Patents

Accordion pill comprising levodopa for an improved treatment of parkinson's disease symptoms Download PDF

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US20140017303A1
US20140017303A1 US13/882,768 US201113882768A US2014017303A1 US 20140017303 A1 US20140017303 A1 US 20140017303A1 US 201113882768 A US201113882768 A US 201113882768A US 2014017303 A1 US2014017303 A1 US 2014017303A1
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levodopa
subject
dose
blood plasma
twice daily
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US13/882,768
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Inventor
Nadav Navon
David Kirmayer
Julia Shvetz
Elena Kluev
Eva Abramov
Zeev Weiss
Giora Carni
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Indaptus Therapeutics Inc
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Intec Pharma Ltd
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Priority to US13/882,768 priority Critical patent/US20140017303A1/en
Assigned to INTEC PHARMA LTD. reassignment INTEC PHARMA LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ABRAMOV, EVA, CARNI, GIORA, KIRMAYER, DAVID, KLUEV, ELENA, NAVON, NADAV, SHVETZ, JULIA, WEISS, ZEEV
Publication of US20140017303A1 publication Critical patent/US20140017303A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • the present invention relates to the use of multi-layered, biodegradable, gastroretentive drug formulations, known as the Accordion Pill, for the controlled release of carbidopa/levodopa in an improved method of treatment of Parkinson's Disease symptoms.
  • Levodopa is the most effective drug for the symptomatic treatment of Parkinson's disease (PD).
  • PD Parkinson's disease
  • No other medical or surgical therapy currently available has been shown to provide anti-Parkinson benefits superior to what can be achieved with LD.
  • PK peripheral pharmacokinetic
  • the patients may find themselves during the day in either ON state, when the patients are capable of normal movement, or in OFF state, wherein the patients suffer from impaired movement.
  • the patients begin to fluctuate between the two states. These fluctuations are often accompanied by troublesome diskinesias in ON state and deep OFF state, wherein movement is severely impaired.
  • improving consistency of LD's plasma levels is essential for improving its anti-Parkinson effects.
  • Another concern with current LD treatment is that rapid elimination of LD and lack of means to sustain relevant LD levels for prolonged time intervals lead to the absence of sufficiently high LD plasma levels in patients in the morning, causing movement arrest and necessitating ultra-rapid LD dosage forms, generally unavailable on the market, or parenteral preparations which are cumbersome for self administration in deep OFF state.
  • Unified Parkinson's Disease Rating Scale (UPDRS) score. Most frequently, so-called “part 3 ” is used in evaluation by a clinician of motor abilities/impairment of PD patients.
  • the UPDRS was recently reviewed and updated, and is regarded as a standard mean to evaluate PD patients (see Movement Disorders, Vol. 22, No. 1, 2007, pp. 41-47; Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Process, Format, and Clinimetric Testing Plan, by Dr. Christopher G. Goetz et al, doi: 10.1002/mds.21198).
  • MDS-UPDRS Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale
  • gastric retention could significantly prolong the LD's absorption phase, by retaining the drug in proximity to its absorption site and releasing the drug in a continuous manner, towards that absorption site.
  • gastroretentive LD delivery systems are disclosed in WO2009/144558 (Intec Pharma), which is herein incorporated by reference in its entirety. These gastroretentive formulations are also frequently referred to as “Accordion Pill”, or AP.
  • WO2010/019915 (Depomed).
  • the challenge is to develop an oral, effective long-acting LD regimen that provides significantly more continuous and stable relevant LD plasma levels over 24 hours, with reduced Total OFF Time and significantly reduced doses per day, preferably a twice-daily dosing.
  • the present invention is directed to overcoming the problems of the prior art described above.
  • the invention provides for the use of an accordion pill comprising levodopa for the treatment of symptoms of Parkinson's disease in a subject in need thereof over a 24 hour period.
  • the accordion pill comprising levodopa is administered to the subject in a twice daily administration regimen, as a first dose and as a second dose, with an interval of about 8 to about 10 hours between the first dose and the second dose, and with an interval of about 14 to about 16 hours between the second dose and the first dose of the following day.
  • the twice daily administration regimen provides a stable blood plasma level of levodopa in the subject after multiple administrations.
  • the stable blood plasma levels of levodopa are effective in treating the symptoms of Parkinson's disease over a 24 hour period following the administration of the first dose.
  • the accordion pill comprises about 250 mg levodopa, and the twice daily administration regimen provides after multiple administrations average blood plasma levels of levodopa of 200-1,000 ng/ml in the subject over a 24 hour period following administration of the first dose.
  • the accordion pill comprises about 375 mg levodopa, and wherein the twice daily administration regimen provides after multiple administrations average blood plasma levels of levodopa of 500-1,500 ng/ml in the subject over a 24 hour period following administration of the first dose.
  • the accordion pill comprises about 500 mg levodopa, and the twice daily administration regimen provides after multiple administrations average blood plasma levels of levodopa of 700-2,000 ng/ml in the subject over a 24 hour period following administration of the first dose.
  • the accordion pill of the twice daily administration regimen provides absorption of levodopa into the blood plasma of the subject for about 6 to about 14 hours following administration of the accordion pill.
  • the twice daily administration regimen further comprises administering to the subject one or more dosage forms comprising immediate-release or controlled-release levodopa.
  • the stable blood plasma level of levodopa in the subject provides an absolute peak-to-trough ratio of levodopa blood plasma concentrations below 7.
  • the twice daily administration regimen reduces peak-to trough fluctuations in the blood plasma levels of levodopa in the subject by at least 50% in comparison to immediate-release formulations comprising daily equal-doses administered four times a day.
  • the twice daily administration regimen shortens or eliminates total OFF time during waking hours in the subject. In a different aspect of the invention, the twice daily administration regimen allows faster onset of the ON period in the subject.
  • the twice daily administration regimen alleviates or eliminates nightly sleep disturbances and daytime sleepiness or drowsiness in the subject.
  • the twice daily administration regimen further comprises administering to the subject one or more add-on dosage forms comprising immediate-release or controlled-release levodopa.
  • the invention provides for the use of an accordion pill comprising levodopa for the treatment of symptoms of Parkinson's disease in a subject in need thereof over a 24 hour period.
  • the accordion pill comprising levodopa is administered to the subject in a twice daily administration regimen, with an interval of about 8 to about 10 hours between the first dose and the second dose, and with an interval of about 14 to about 16 hours between the second dose and the first dose of the following day.
  • the twice daily administration regimen provides a stable blood plasma level of levodopa in the subject after multiple administrations.
  • the stable blood plasma level of levodopa in the subject is effective in treating the symptoms of Parkinson's disease over a 24 hour period following the administration of the first dose.
  • the twice daily administration regimen of the invention produces significantly high morning levels of levodopa in the blood plasma of the subject.
  • the significantly high morning levels of levodopa in the blood plasma of the subject allow faster onset of the ON period or shorten the OFF period after the first levodopa administration of the day.
  • the twice daily administration regimen alleviates or eliminates nightly sleep disturbances and daytime sleepiness or drowsiness in the subject.
  • the accordion pill comprises about 250 mg levodopa, and the twice daily administration regimen provides after multiple administrations average blood plasma levels of levodopa of 200-1,000 ng/ml in the subject over a 24 hour period following administration of the first dose.
  • the accordion pill comprises about 375 mg levodopa, and wherein the twice daily administration regimen provides after multiple administrations average blood plasma levels of levodopa of 500-1,500 ng/ml in the subject over a 24 hour period following administration of the first dose.
  • the accordion pill comprises about 500 mg levodopa, and the twice daily administration regimen provides after multiple administrations average blood plasma levels of levodopa of 700-2,000 ng/ml in the subject over a 24 hour period following administration of the first dose.
  • the accordion pill may further comprise about 50 mg to about 75 mg of carbidopa.
  • the twice daily administration regimen provides carbidopa blood plasma levels sufficient to adequately prevent peripheral levodopa side effects in the subject for a 24 hour period.
  • the stable blood plasma level of levodopa in the subject after multiple administrations provides values of area-under-the-curve over 24 hours and a relative bioavailability that is not less than 85% relative to the values obtained from immediate-release formulations comprising daily equal doses administered four times a day.
  • the stable blood plasma levels of levodopa in the subject after a single administration provides values of area-under-the-curve extrapolated to infinity and a relative bioavailability that is not less than 85% relative to the values obtained from immediate-release formulations comprising equal doses of levodopa.
  • the twice daily administration regimen of the invention after multiple administrations provides a reduction of total OFF time during waking hours from about 3 hours to about 1 hour.
  • the twice daily administration regimen of the invention after multiple administrations provides a reduction in total OFF time during waking hours of not less than 50% in comparison to the total OFF time associated with the administration of optimized prior treatment of the subject with levodopa.
  • the invention provides for the use of an accordion pill comprising levodopa for the treatment of symptoms responsive to levodopa in a subjects in need thereof over a nocturnal period.
  • the accordion pill comprising levodopa is preferably administered at bed time.
  • bed time administration improves sleep quality during the night following administration.
  • bed time administration alleviates or eliminates the symptoms of morning akinesia or morning dystonia.
  • FIG. 1 presents the results of a pharmacokinetic equidose study in early PD patients with AP CD/LD 50/250 mg, administered b.i.d vs IR q.i.d.
  • FIG. 2 presents the results of a pharmacokinetic equidose study in advanced PD patients with AP CD/LD 50/375 mg, administered b.i.d vs IR q.i.d.
  • FIG. 3 presents the results of a pharmacokinetic equidose study in healthy volunteers with AP CD/LD 50/500 mg, administered qd (once) vs IR b.i.d.
  • FIG. 4 presents the levodopa absorption profile as percentage of total bioavailable dose, as calculated from the data of the example 2.
  • FIG. 5 presents strong correlation between steady LD blood plasma levels and elevated UPDRS scores of the patients—AP-CD/LD—50/375 mg.
  • Gastroretentive dosage form or “Accordion Pill”, or “AP”, as used interchangeably herein refers to dosage forms with delayed gastric emptying as compared to food or to regular oral drug formulations (or retention in the stomach beyond the retention of food).
  • the term refers to a multilayered gastroretentive dosage form, folded into a capsule in undulated form, which unfolds upon contact with the gastric fluids.
  • degradable as used herein is intended as capable of being chemically and/or physically reduced, dissolved or broken down in the body of a patient and within a relevant time period.
  • a “patient” or “subject” as referenced herein is a human or non-human mammal suffering from symptoms of Parkinson's disease or of a related disorder.
  • Treating” or “treatment”, are used herein to refer to obtaining a desired pharmacological and physiological effect.
  • the effect may be prophylactic in terms of preventing or partially preventing a disease, symptom or pathological condition and/or may be therapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect attributed to a pathological condition.
  • treatment covers any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing a pathological condition from occurring in an individual which may be predisposed to develop a pathological condition but has not yet been diagnosed as having it, i.e., causing the clinical symptoms of a pathological condition not to develop in a subject that may be predisposed to develop the condition but does not yet experience or display symptoms of the condition; (b) inhibiting, i.e., arresting or reducing the development of the pathological condition or its clinical symptoms; or (c) relieving symptoms associating with the pathological condition.
  • the term refers to alleviating symptoms of Parkinson's disease and of related movement disorders, clinically responsive to levodopa.
  • “About” as used herein generally refers to approximate values. When referred to a dose of LD in milligrams, “about” should be construed as including the range of a value ⁇ 50 mg. When referred to time intervals of dose administration, “about” should be construed as including the range of a value ⁇ 1.0 hour. When referred to pharmacodynamic values of total ON or total OFF time, during waking hours or over 24 hours, the term should be construed as including the range of a value ⁇ 0.15 hour. When referred to blood plasma levels of LD and other values, the term should be construed as including the range of a value ⁇ 15%
  • equivalent dose refers to as containing the same total dose of an active material, administered over the dosing regimen, particularly, over 24 hours periods.
  • Additional dose refers to a medicinal product comprising levodopa.
  • An add-on dose provides additional levodopa to the regimen of the present invention.
  • add-on doses are taken by the patients to expedite the arrival to ON state.
  • the term should be construed as including an immediate-release product comprising levodopa, or a controlled-release product, comprising levodopa.
  • Effective LD blood plasma levels refer to LD levels that provide the desired pharmacodynamic effect in a subject in need of treatment with minimal side effects.
  • the effective LD blood plasma levels are usually not less than about 200 ng/ml at any point of time for 24 hours after administration of a first dose of the regimen.
  • the effective LD blood plasma levels usually do not exceed about 1000 ng/ml.
  • the effective LD blood plasma levels are usually not less than about 300 ng/ml, and preferably above about 500 ng/ml, and do not exceed about 1500 ng/ml.
  • the effective LD blood plasma levels are usually greater than about 500 ng/ml, and preferably greater than about 700 ng/ml, and do not exceed about 2000 ng/ml over a 24-hours period after administration of a first dose of the regimen.
  • “Significantly High Morning LD levels”, as used herein, are the LD levels achieved by PD patients as a result of multiple administrations according to the regimen of the invention about 0.5 hour or just prior to administration of the first dose of the consecutive treatment day. In early non-fluctuating patients these levels are usually above about 200 ng/ml. In more advanced non-fluctuating PD patients, the significantly high morning LD levels are not less than about 300 ng/ml and preferably above about 500 ng/ml. In fluctuating PD patients, the significantly high morning LD levels are above about 500 ng/ml, and preferably above about 700 ng/ml. The term is used as opposed to “significantly low morning LD levels”, which should be construed as confined to the values significantly below the abovedescribed.
  • Relevant therapeutic LD levels throughout the night and “Significant night levels of LD”, as used interchangeably herein, are effective nocturnal LD blood plasma levels that lead to significantly high morning LD levels.
  • LD Elimination Half Life is a pharmacokinetic parameter as known in the art, and represents the time required for levodopa blood plasma concentration to decrease to half of its initial value in absence of input of levodopa to the bloodstream.
  • Short Absorption phase is an absorption phase having a duration of less than 14 hours, and preferably less than 6 hours.
  • “Long arrival to ON state” and “Long duration of OFF time upon administration of a subsequent dose”, as used interchangeably herein, relate to the buildup of LD blood plasma levels required for conventional formulations for arrival usually from significantly low morning LD levels to effective LD blood plasma levels, as opposed to the “Quick arrival to ON state” and “Faster onset of the ON period”, as used interchangeably herein, which refer usually to the arrival from significantly high morning LD levels to effective LD blood plasma levels, said arrival does not require significant buildup of LD blood plasma levels. More specifically, the terms refer to the time intervals required for a patient to reach ON state following the first administration of LD of the day.
  • Morning OFF time refers to the time interval between the administration to a PD subject LD and the subject's arrival to ON state following the administration. Morning OFF time is usually associated with significantly low morning LD blood plasma levels.
  • Repetitive dosing or “multiple administrations”, as used interchangeably herein, refers to repetitive administration of LD according to a specified dosing regimen, for period over more than one day.
  • Induce rapidly ON state refers to a process of rapid arrival to ON state, usually as a consequence of administration of an add-on dose of levodopa, an immediate-release dose of levodopa, or prematurely taking a consecutive dose of a treatment.
  • the term usually refers to current treatment regimens of levodopa.
  • Peak-to-trough ratio refers to the ratio between the peak concentration of the regimen (Cmax) and the trough concentration of the regimen (Cmin) over 24 hours period.
  • “Absolute fluctuation”, as used herein, refers to the mathematical difference between the peak concentration of the regimen (Cmax) and the trough concentration of the regimen (Cmin) over 24 hours period.
  • Total OFF time refers to the duration of total of all OFF episodes over a specified time interval, either during waking hours, or over 24 hours.
  • Total ON time refers to the overall duration of all ON episodes over a specified time interval, either during waking hours, or over 24 hours.
  • Secondetter sleep quality refers to improved sleep quality, defined by fewer mid-night awakenings, increased total sleep time and extended depth of sleep.
  • the Accordion Pill is a dosage form designed to significantly increase efficacy and/or to reduce adverse drug reactions (ADRs) and/or frequent daily dosing of drugs that are characterized by poor absorption in the colon or which absorption is confined to yet narrower sites.
  • the AP is retained in the stomach and releases the drug in a predetermined release profile, enabling a prolonged exposure to the absorption area in the upper part of the small intestine, hence—to significantly prolong the actual absorption phase of the drug.
  • the Accordion Pill is composed of degradable pharmaceutically acceptable polymeric films.
  • the films are layered sandwich style and are folded in an undulated structure, like an accordion, into a standard capsule. After oral administration, the capsule dissolves and the dosage form unfolds and is retained in the stomach. While in the stomach, the Accordion Pill releases the active ingredients in a predetermined release profile (controlled release or combination of immediate and controlled release). Once the AP is expelled from the stomach and reaches the intestines, it degrades in the higher pH and within a few hours it totally dissolves.
  • the AP-CD/LD comprises an internal layer, one or more outer membranes, preferably two, sandwiching said internal layer, all said layers being ultrasonically welded together.
  • the internal layer comprises levodopa and a polymer, substantially uniformly distributed throughout the internal layer.
  • the polymer may be selected from the group consisting of a degradable hydrophilic polymer which is not instantly soluble in gastric fluid, a degradable enteric polymer which is substantially insoluble at pH less than 5.5, a hydrophobic polymer, or mixtures thereof.
  • Said internal layer may further comprise acceptable pharmaceutical additives, such as plasticizers, humectants, fillers and others. Examples of such additives are provided in various sources in the art, for example in the “Handbook of pharmaceutical excipients”, edited by Rowe, Ray C; Sheskey, Paul J; Quinn, Marian, printed by Pharmaceutical Press.
  • degradable hydrophilic polymers which are not instantly soluble in gastric fluid suitable for the invention include but not limited to hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, copovidone, polyethylene oxide, poloxamers and methylcellulose.
  • enteric polymers include but not limited to polymethacrylate copolymers, cellulose acetate phthalate, hypromelose acetate succinate or hypromellose phthalate.
  • hydrophobic polymers include but not limited to ethyl cellulose, cellulose acetate, cellulose butyrate and polyvinyl acetate.
  • the internal layer comprises levodopa, an enteric polymer, a degradable hydrophilic polymer which is not instantly soluble in gastric fluid and a plasticizer.
  • the enteric polymer is polymethacrylate copolymer-methacrylic acid copolymer type A or methacrylic acid copolymer type B, as defined in the United States Pharmacopea 34 /National Formulary 29 (USP/NF). These materials are also known under newer specifications of the USP/NF as “methacrylic acid and methyl methacrylate copolymer (1:1)”, and “methacrylic acid and methyl methacrylate copolymer (1:2)”, respectively.
  • the plasticizer is a mixture of polyethylene glycol and a poloxamer.
  • the internal layer provides substantial mechanical strength.
  • Each of the outer membranes of the AP-CD/LD comprises at least one polymeric combination of a hydrophilic polymer and a polymer, insoluble in gastric media, and at least one plasticizer.
  • hydrophilic polymers include but not limited to gelatin, hydroxypropylcellulose, hydroxypopyl methycellulose, pectin, polyethylene oxide, starch, and zein.
  • the hydrophilic polymer is gelatin.
  • the enteric polymers suitable for the outer membranes include but not limited to hypromellose phthalate, hypromellose acetate succinate and polymethacrylate co-polymers.
  • the enteric polymer is polymethacrylate copolymer-methacrylic acid copolymer type A or methacrylic acid copolymer type C, as defined in the USP/NF, or, under newer definitions, “methacrylic acid and methyl methacrylate copolymer (1:1)” and “methacrylic acid and ethyl acrylate copolymer (1:1)”.
  • Plasticizers suitable for the outer membrane include but not limited to glycols, including various MW polyethylene glycols, glycerin, poloxamers, triethyl citrate, or a mixture of any of the above.
  • the plasticizer is propylene glycol.
  • the plasticizer is a mixture of polyethylene glycol and poloxamer.
  • the outer membranes swell in the presence of gastric fluid.
  • the internal layer and two outer layers are joined together by ultrasonic welding.
  • the combination of swelling outer membrane layers with a non-swelling internal layer having planar accordion geometry causes the internal layer to undergo an unfolding process once the formulation reaches the stomach, thus extending gastric residence time and preventing the drug-containing dosage form from being evacuated until complete release.
  • the internal layer has a swelling rate less than the swelling rate of the membrane.
  • the AP-CD/LD comprises an internal layer and at least two outer membranes as described above, and may further comprise additionally one or more immediate release layers covering the outer membranes and comprising the active agent and a composition that provides for the immediate release of the active agent.
  • the additional layer comprises levodopa.
  • said additional layer comprises carbidopa.
  • two additional layers are provided covering both outer membranes, wherein a first additional layer comprises levodopa, and a second additional layer comprises carbidopa.
  • Said composition may comprise soluble polymers, enteric polymers, plasticizers, disintegrants, surface-active agents and other pharmaceutical excipients, as described above.
  • the soluble polymers of said composition for the use in said additional layers include but not limited to soluble cellulose derivatives, i.e. methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hypromelose, various grades of povidone, including copovidone, polyvinyl alcohol and its derivatives, i.e. Kollicoat IR, soluble gums and others.
  • the composition for the use in said additional layers may further include surface-active agents, plasticizers and humectants, such as PEGs, different grades of polysorbates and sodium lauryl sulfate.
  • the enteric polymers of said composition for the use in said additional layers include but not limited to polymethacrylate copolymers, hypromellose phthalate, hypromellose acetate succinate, cellulose acetate phthalate, or a mixture thereof.
  • the polymer is methacrylic acid copolymer type C, also known as “methacrylic acid and ethyl acrylate copolymer (1:1)”, as described in the USP/NF.
  • said composition further comprises a disintegrant. Disintegrants imbibe water upon contact and swell rapidly to provide separation of the adjacent parts.
  • the disintegrant of said composition for the use in said additional layers is crospovidone, croscarmellose, sodium starch glycolate, or mixtures of the above. In preferred embodiments, the disintegrant is sodium starch glycolate.
  • the AP-CD/LD may further comprise an optional additional layer covering each outer membrane or each additional layer and comprising a powder or a film.
  • the purpose of the layer is to avoid adhesion of the folds of the undulated form of AP-CD/LD upon capsulation, and the adhesion of the folds to the capsule. In some instances it may be found that the outer layers stick together in the capsule and do not unfold properly upon dissolving of the capsule.
  • said optional layer comprises at least one powder, and optionally at least one polymer.
  • the preferred polymers are rapidly-dissolving film formers, which can be selected from but not limited to soluble cellulose derivatives, i.e.
  • the films may further comprise surface-active agents, plasticizers and humectants.
  • the powders that may be used in said optional layer include but not limited to microcrystalline cellulose, talc, silica, colloidal silicon dioxide, a clay or a mixture of any of the above. In preferred embodiments, said optional layer comprises microcrystalline cellulose.
  • the AP-CD/LD is folded into undulated form and compacted into a standard pharmaceutical capsule.
  • the present invention provides a twice daily administration regimen of AP-CD/LD formulations in doses such as, for example, a 50/250 mg dosage form, targeted for early stage PD patients; 50/500 or 50/530 mg dosage forms targeted for advances stage PD patients; and 50/375 mg or 50/405 mg dosage forms for treatment of both populations.
  • the twice daily administration regimen of the AP-CD/LD formulations of the invention provide effective blood plasma level of levodopa for time intervals of about 24 hours, due to the absorption phase, provided by AP-CD/LD, which is between about 6 to about 14 hours.
  • of the absorption phase, provided by AP-CD/LD formulations of the invention are longer than 14 hours.
  • the length of the absorption phase is exemplified by the data presented in the examples provided herein.
  • Absorption data may be obtained from the concentration-vs-time curve by methods known in the art. These include modeling and de-convolution of functions, which describe the absorption.
  • One of the approaches is known as Wagner-Nelson approach.
  • the analysis of the data presented in Example 2 using Wagner-Nelson approach yields an absorption curve, which is presented in FIG. 4 .
  • the doses were administered at time 0, and after 8 hours.
  • FIG. 4 shows that the major absorption phase throughout the dosing regimen, for 24 hours, indicating individual absorption phases of over 6 hours, and over 14 hours, exemplifying some of the preferred embodiments.
  • the absorption phase may have duration of 6.5 hours, or 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, or 16.0 hours.
  • said dosage forms are administered twice a day, in a regimen generally known as b.i.d. regimen.
  • b.i.d. regimen is considered as administration every 12 hours.
  • the two doses are administered twice daily, every 12 hours.
  • the two doses of levodopa from the oral dosage form of the invention are administered as a first administration of a day and a second administration of the same day, with an interval of about 8 to about 10 hours between the first dose administration and the administration of a second dose of levodopa, and with an interval of about 14 to about 16 hours between the second dose of the first day and the first dose of the following consecutive day.
  • the second dose can be administered about 6.0 hours after administration of the first dose, or 6.5 hours, or 7.0 hours, or 7.5, hours, or 8.0 hours, or 8.5 hours, or 9.0 hours, or 9.5 hours, or 10.0 hours, or 10.5 hours, or 11 hours after administration of the first dose.
  • the regimen of administration of the two dosage forms according to the invention provides effective LD blood plasma levels in the subject for 24 hour consecutive periods.
  • repetitive administration of LD according to the specified dosing regimen (“repetitive dosing”) provides stable effective LD blood plasma levels in the subject for extended consecutive periods of time and decreases or prevents fluctuations in the blood plasma level of LD in the subject.
  • the repetitive dosing, or multiple administrations are referred to a period having duration of more than one day, for example, 2 days, 3 days, 4, 5, or 6 days, 1 week, 2 weeks or 3 weeks, 1 month, 1.5 months, 2 months, or 3 months.
  • said twice-daily treatment regimen of the present invention may be continued in the same or varied dosing and intervals for as long as benefit to a patient is sustained.
  • the regimen of administration of the two dosage forms according to the invention results in morning LD levels in the blood plasma of a patient that are significantly higher than the morning blood plasma LD levels provided by known current treatment methods.
  • the significantly high morning blood plasma LD levels that the invention provides indicate that the administration regimen of the invention maintains therapeutic LD levels in the blood plasma of the subject being treated throughout the night, and leads to clinically relevant, stable concentrations of LD in the blood plasma of the subject.
  • the retention of therapeutic LD levels throughout the night improves quality of sleep and reduces day time sleepiness in the subject being treated.
  • LD does not reach continuously effective LD blood plasma level when administered as immediate or controlled-release dosage forms, due to LD short elimination half-life and short absorption phase provided by these dosage forms; the parameters are not sufficiently increased by conventional controlled-release dosage forms.
  • conventional regimens do not afford significant blood plasma night levels of LD, thereby reducing quality of sleep, and as a result causing day sleepiness and drowsiness, as described above.
  • the lack of therapeutic LD blood plasma levels throughout the night leads to low morning LD blood plasma levels, significantly prolongs the duration of OFF time upon administration of a subsequent dose the next day, and results in a delayed arrival to the ON state, because the process requires a large LD blood plasma level buildup to reach the ON state.
  • the patients use high doses of IR levodopa, thus increasing fluctuations of blood plasma levels of LD.
  • the twice daily administration regimen of the invention wherein the two LD doses are administered with an interval of about 8 to about 10 hours between the first dose of a day and the second dose of the same day, and with an interval of about 14 to about 16 hours between the second LD dose of the first day and the first LD dose of the following consecutive day, affords effective night levels and thus reduces, alleviates or potentially eliminates nightly sleep disturbances and daytime sleepiness or drowsiness, which are major issues in subjects suffering from Parkinson's disease.
  • the twice daily administration regimen of the invention produces significantly high morning levels of LD, shortens or eliminates morning OFF time, and, because of the significantly high morning levels of LD, results in a quicker arrival to the ON state upon administration of the first dose in the consecutive morning, since the process does not require LD blood plasma level buildup to reach the ON state.
  • regular or reduced doses of LD can be used to arrive quickly to ON state.
  • LD is released from the oral dosage forms administered according to the regimen of the invention providing relatively stable LD blood plasma levels in the subjects being treated for extended periods of time.
  • the LD blood plasma levels are sustained for 24 hours in the subject after repetitive dosing according to the regimen.
  • the dose of LD in the oral dosage form is about 250 mg, and under the b.i.d. regimen of 8-10 h, as described above, the blood plasma in the subject being treated reaches a stable LD level of 200-1,000 ng/ml.
  • the blood plasma levels of levodopa would be therefore generally more than about 200 ng/ml, or 180, 200, 220, 240, 250, 260, 280 or 300 ng/ml, and generally less than 1000 ng/ml, or 980, 950, 925, 900, or 875 ng/ml.
  • the dose of LD in the oral dosage form is about 375 to about 405 mg, and the blood plasma of the subject being treated reaches a stable LD level of about 500-1,500 ng/ml.
  • the blood plasma levels of levodopa would be therefore generally more than about 500 ng/ml, or 450, 475, 500, 525, 550, 575, 600, 650 or 700 ng/ml, and generally less than 1500 ng/ml, or 1475, 1450, 1425, 1400, 1350, or 1300 ng/ml.
  • the dose of LD in the oral dosage form is from about 500 to about 530 mg, and the blood plasma of the subject being treated reaches a stable LD level of about 700-2,000 ng/ml.
  • the blood plasma levels of levodopa would be therefore generally more than about 700 ng/ml, or 625, 650, 675, 700, 725, 750, 775, 800, 825 or 850 ng/ml, and generally less than 2000 ng/ml, or 1950, 1925, 1900, 1875, 1850, 1825 or 1800 ng/ml.
  • the two oral dosage forms administered according to the regimen of the invention contain the same dose of LD.
  • the doses are different to accommodate the needs of the patient in either the first part of the day or the second part of the day.
  • One patient may require higher levels in the afternoon, whereas another may require higher levels in the first part of the day.
  • the doses can be varied by the prescriber to obtain optimal efficacy over 24 hours, according to individual needs of the patients. This gives rise to asymmetrical regimens, whereby the first dose is not necessarily equal to the second.
  • any such or similar combination represents the basal treatment regimen and provide treatment of Parkinson's disease symptoms over 24 hours, when administered to a patient in need thereof in an interval of about 8 to 10 hours, after repetitive dosing, thereby providing stable efficacious blood plasma levels of LD.
  • the treatment provided according to the regimen of the invention may be optionally enhanced by administration of “add-on” doses.
  • These comprise dosage forms comprising LD for either immediate release (IR), or controlled release (CR), or a combination thereof.
  • IR immediate release
  • CR controlled release
  • the need for these add-on doses arises from inevitable intra-subject variability, meaning that the same subject may not react the same way to the same dosage form administered on a different day.
  • This intra-subject variability in day-to-day response to LD is well-known in PD treatment.
  • the add-on doses are vastly used in current treatment schedules to induce rapidly ON state and to end OFF state.
  • the current regimens overburden the patients with the doses of LD.
  • said twice-daily regimen further comprises administration of one or more add-on LD doses.
  • said add-on doses are immediate-release doses.
  • said add-on doses are controlled release doses.
  • said doses comprise mixed immediate-release and controlled-release doses.
  • said doses are administered on the same time every treatment day. Alternatively, said add-on doses may be administered as needed on varying time during the treatment day.
  • the peak-to-trough ratio is calculated as maximal concentration achieved during the 24-hours period, over minimal concentration over the same period.
  • Said ratio is 1 for continuous delivery dosage forms, such as intravenous infusion.
  • Current treatment of immediate-release presents ratio of over 40.
  • said ratio is below about 10, preferably below about 9.5, 9.0, 8.5, 8.0, 7.5, or 7.
  • the fluctuations may be expressed by comparison to current treatment, and the fluctuations produced by the twice-daily regimen of the invention are reduced at least by about 50%, or by 44%, 46%, 48%, 50%, 52%, 54%, 56%, 58%, 62% or 64% in comparison to conventional daily equal-dose IR treatment four times a day.
  • said fluctuations are reduced by about 60%.
  • the reduction in LD blood plasma fluctuations provided by the regimen of the invention decreases adverse effects associated with LD treatment. Most significantly, the total OFF time during waking hours decreases, and total ON time increases. The side effects are usually associated with more progressive stage of the disease.
  • Administration of an oral dosage form of LD comprising about 375 mg or about 500 mg of LD according to the regimen of the invention with an interval of 8 to about 10 hours between the first and the second dose to a patient in need thereof produces a significant reduction of total OFF time during waking hours.
  • two dosage forms, with an LD amount of 375 mg and 500 mg, respectively, may be administered to a subject in need thereof according to the regimen of the invention for the treatment of symptoms of Parkinson's disease.
  • said add-on doses may comprise an IR levodopa dose, a CR levodopa dose, or a mixture of the IR and CR levodopa dose.
  • the doses may be taken preferably as fixed-time dose, or alternatively, on “as needed” basis, as rescue dose for the interruption or alleviation of the OFF state, thereby enhancing reduction of total OFF time during waking hours.
  • a method of treatment for reduction or alleviation of Parkinson's disease symptoms in patients in need thereof, said method comprising administration any of two oral dosage forms, comprising about 375 mg of LD, or about 500 mg of LD each, according to the regimen of the invention, which method further comprises administration of one or more add-on doses of IR or CR levodopa.
  • the effectiveness of an anti-parkinson treatment is estimated as reduction in total OFF time, or as reduction of total OFF time during waking hours, sometimes used interchangeably.
  • the total OFF time is an important parameter and varies within the population of PD patients, according to the severity of the disease. Early patients have very short periods of OFF during the waking hours, or do not suffer at all from the OFF phenomenon. As the disease advances, the patients may reach total OFF time of 0.5 hour to over 6.5 hours, and sometimes even to over 8.0 hours. In yet more advanced stage, the patients reach these “total OFF” values even being treated adequately by best available regimens.
  • the treatment provided according to the regimen of the invention significantly reduces total OFF time.
  • the total OFF time during waking hours is reduced by at least about 45%, but can be decreased by 44%, 45%, 46%, 48%, 52%, 54%, 56%, 58%, 60%, 62% or by 64%, versus either baseline values or versus the optimized LD treatment of a subject.
  • the treatment provided according to the regimen of invention reduces total OFF time by at least 1.2 hours, but can be decreased by 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or by 5.0 hours.
  • the regimen of present invention provides a reduction in total OFF time during waking hours from 2.9 hours to 1.2 hours, versus optimized levodopa treatment in the subject.
  • the reduction is obtained by administering to the patient in need the AP-CD/LD 375 mg twice daily, according to the regimen of the invention, without or practically without add-on doses (dosing frequency 2.2 ⁇ 0.2 per 24 hours).
  • the treatment regimen of the present invention resolves these issues by providing high blood plasma LD levels in the morning over 24 hour periods in subjects in need of treatment of Parkinson's disease symptoms.
  • the twice daily administration regimen of the invention wherein the two LD doses are administered with an interval of about 8 to about 10 hours between the first dose of a day and the second dose of the same day, and with an interval of about 14 to about 16 hours between the second, pre-midnight LD dose of the first day and the first LD dose of the following consecutive day, provides the subjects being treated with stable, effective LD blood plasma concentrations for consecutive 24 hour periods, affords effective LD night levels and thus reduces, alleviates or potentially eliminates nightly sleep disturbances and daytime sleepiness or drowsiness, and produces significantly high morning levels of LD.
  • the high morning pre-dose LD blood plasma levels provided by the treatment regimen of the present invention alleviate or eliminate symptoms related to degenerative disorders of the central nervous system, Parkinson's disease in particular, motor skills, speech and related impairments, prior to the subsequent administration of the next day consecutive dose.
  • the morning high LD blood plasma levels provided by the treatment regimen of the present invention allow a faster onset of the ON period and shorten the OFF period after the next day subsequent administration of the first dose.
  • the morning high LD blood plasma levels provided by the treatment regimen of the present invention result in better sleep quality throughout the night and alleviate or eliminate daytime sleepiness and drowsiness on the subsequent day.
  • an AP-CD/LD administered to a patient in need thereof prior to going to sleep.
  • Said bedtime, or nocturnal administration provides effective LD blood plasma levels throughout the night.
  • the dose should be administered no later than 3 hours apart from the last LD dose of the patient, but may be administered 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.50, 4.75 or 5.0 hours from the administration of the last LD dose.
  • the dose of levodopa in AP-CD/LD is about 250 mg. In another aspect, the dose of levodopa in AP-CD/LD is about 375 mg.
  • the dose of levodopa in AP-CD/LD is about 500 mg.
  • the nocturnal administration of AP-CD/LD provides better sleep quality to the patient in need thereof.
  • the nocturnal administration alleviates or eliminates morning akinesia symptoms in patients in need thereof.
  • Levodopa is usually administered with a DOPA-decarboxylaze inhibitor, such as benserazide or carbidopa. Normally, levodopa is co-administered with carbidopa.
  • DOPA-decarboxylaze inhibitor such as benserazide or carbidopa.
  • levodopa is co-administered with carbidopa.
  • the art discloses several effective carbidopa/levodopa combinations with different ratios between the two. There is much reasoning in favor of many ratios. Although there is a general consensus that the total daily dose of carbidopa should not exceed 150-200 mg, PD subjects are often treated with a vast variety of doses of LD that not always have the same carbidopa/levodopa ratio.
  • the treatment regimen of the present invention supplies carbidopa in sufficient quantity to provide a stable CD blood plasma concentration for 24 hour periods, regardless of the total LD daily dose administered according to the treatment regimen.
  • the subject being treated according to the regimen of the invention will not exceed the maximum allowed daily carbidopa amounts, as the regimen provides effective amounts of carbidopa to inhibit peripheral decarboxylaze activity sufficiently over 24 hour periods.
  • peripheral DOPA decarboxylase is saturated by carbidopa at approximately 70 to 100 mg a day.
  • the oral dosage forms administered according to the treatment regimen of the invention comprise carbidopa or pharmaceutically acceptable salt thereof, preferably in an amount from about 50 mg to about 75 mg of carbidopa each.
  • Carbidopa is released from the dosage forms.
  • the carbidopa released upon absorption provides blood plasma levels of carbidopa that are sufficient to adequately prevent peripheral LD side effects for consecutive 24 hour periods.
  • the treatment regimen of the present invention affords a relative bioavailability which is not less than 95%, preferably not less than 90%, and even more preferably not less than 89%, 88%, 87%, 86%, or 85%.
  • the treatment regimen of the present invention provides an area under concentration-vs-time curve over 24 hour periods (AUC 0-24 ), and thus a relative bioavailability (F), which is not less than 95%, preferably not less than 90%, and even more preferably not less that 85%, of the relative bioavailability obtained with an equivalent dose regimen of immediate release dosage forms.
  • the treatment regimen of the present invention after a single dose, provides an area under concentration-vs-time curve extrapolated to infinity (AUC 0-inf ), and consequently, a relative bioavailability (F) which is not less than 89%, 88%, 87%, 86%, or 85% of the AUC 0-inf obtained with an equivalent dose regimen of immediate release dosage forms.
  • the administration of said two doses is not restricted to specific alimentary requirements.
  • Parkinson's disease patients are advised to avoid high-protein food, high acidity food and beverages, and are warned against delayed gastric emptying that might impede the action of conventional dosage forms of levodopa.
  • Some levodopa products even advise taking the medicine on empty stomach.
  • the restriction can be complied with.
  • a patient may be required to fast for a significant portion of a day.
  • Some dosage forms that can provide benefit at three and more times a day administration require the medicine to be taken with a meal, sometimes a meal of no less than 750 kcal, whereof not less than 40% should be derived from fat.
  • patients normally comply better with medications that do not require extensive fasting or purposeful excessive eating.
  • a small meal may be recommended before the administration. No excessive restrictions on diet are imposed by said regimen, providing a significant advantage to the patient.
  • the meals to accompany the first dosing of the dosage forms have calorie value of below 550 kcal, preferably below 540 kcal, or below 530, 500, 450, 400, 350, 300, 250, 200, or 191 kcal.
  • the meal has calorie value of 191 kcal, with 49% of calories being derived from fat.
  • the meals to accompany the second dosing of the dosage forms have calorie value of ranging from about 430 kcal, to about 670 kcal, but can have the calorie value of 450, 475, 500, 525, 550, 575, 600, 625, 650 or 670 kcal.
  • the calorie value derived from fat, of said meal accompanying second administration of the regimen of the invention comprise about 40%, or about 38%, 36%, 34%, 32%, or 30%.
  • the amount fat in the meals is an average amount of fat in alimentary products for human consumption.
  • levodopa is used vastly and primarily for treatment of Parkinson's disease symptoms
  • conditions responsive to levodopa such as restless leg syndrome and others, that are not directly related to Parkinson's disease.
  • All the disadvantages of conventional regimens as disclosed above are valid for every other treatment of conditions, responsive to levodopa.
  • the treatment of night symptoms remains a significant challenge. Therefore, in some embodiments, there is provided use of an accordion pill comprising levodopa for the treatment of symptoms responsive to levodopa in a subject in need thereof over nocturnal period.
  • the AP-CD/LD is administered to the subject at or before bedtime.
  • said administration provides improvement in sleep quality in said subject over the night following administration.
  • the dose of levodopa in the AP-CD/LD is about 250 mg, or about 375 mg, or about 500 mg.
  • Phase IIA Included 12 Early Stage PD Patients
  • the primary objective was to evaluate the blood level profile of the AP-CD/LD relative to that of IR carbidopa/levodopa.
  • Another objective was to monitor the subjects for adverse events during the study period and to compare the safety of the test products with the reference products.
  • Subjects were randomized to start with either AP-CD/LD or with IR-CD/LD.
  • the AP-CD/LD was dosed at 0 and 8 hrs on each day, for seven days.
  • the reference product was the commercially available 25/250 mg Dopicar® (Teva Pharmaceuticals) CD/LD immediate-release tablet (IR-CD/LD), which was administered four times a-day, as a 1 ⁇ 2 tablet (12.5/125) at 0, 4, 8 and 12 hours on each day, for seven days. Since the amount of CD from the IR-CD/LD was half of that given by the AP-CD/LD and below the recommended amount of daily CD (70-100 mg), additional CD was given with each dose during the pharmacokinetics (PK) evaluation day (day 7 of the control treatment period). On the PK day Patients were co-administered an additional 12.5 mg IR CD capsule with each Dopicar® dose to provide a total CD dose of 100 mg. The total daily CD/LD doses for both products were equivalent.
  • test and reference products were self-administered at home every day.
  • patients were dosed in the clinic (PK day).
  • Amount/AP-CD/LD (mg) Immediate Internal layer Release Outer (sum Controlled Component Layer of two films) release Carbidopa 25.0 25.0 Levodopa 70.0 180.0 Eudragit S100 47.1 Eudragit L100 23.5 61.0 Eudragit L100-55 23.5 Fish Gelatin 94.2 Propylene glycol 94.2 KOH 6.0 Poloxamer 407 32.0 PEG 400 3.1 30.0 Tween 80 11.8 Povidone 90 13.7
  • FIG. 1 The results of primary objective (pharmacokinetic profile) are presented in FIG. 1 .
  • True controlled-release profile of LD has been accomplished.
  • BID administration of AP-CD/LD provided 15 monitored hours coverage of 400-1,000 ng/ml LD plasma levels, and in fact 24 hours coverage profile, since significant morning levels were achieved.
  • BID administration of AP-CD/LD provided average plasma levels within the range that is currently obtained with four times a-day (equivalent total daily dose) LD formulation that is on the market, with substantially reduced peaks.
  • Morning starting plasma levels of LD from AP product were significantly higher than these from IR treatment (200 vs 30 ng/ml). This capability of AP-CD/LD can improve morning akinesia, improve sleep quality and reduce day time sleepiness.
  • the group was crossed over with the patient's current treatment dose.
  • the study was conducted in three medical centers.
  • the primary objectives of the study was to evaluate the pharmacokinetic profile of AP-CD/LD relative to that of IR-CD/LD and to determine the relative pharmacodynamic profiles of the AP-CD/LD vs. IR-CD/LD under real conditions of use (i.e. derived from at-home diary entries). Another objective was to monitor the subjects for adverse events during the study period and to compare the safety of the test products with the reference products.
  • the secondary objectives of the study was to assess patient and investigator global evaluation of, and degree of satisfaction with, AP-CD/LD relative to IR-CD/LD; and to determine the pharmacodynamic profile of AP-CD/LD relative to that of IR-CD/LD during the PK day.
  • Subjects were randomized to start with either AP-CD/LD or current treatment, taken for 6 days at home.
  • Test arm BID administration of AP-CD/LD 50/375 mg (morning and +8 hours). Due to the individuality and variability of treatment of the fluctuating Parkinson's patient the subjects were allowed (if necessary) to take up to 3 daily add-on doses of IR-CD/LD on days 1-6 or 8-13 of the “at home” treatment. Each additional “add-on” doses was limited to either 1 ⁇ 2 tablet of Dopicar (12.5/125 mg CD/LD) or 1 ⁇ 4 tablet of Dopicar (6.25/62.5 mg CD/LD). All add-on doses were documented in the subject's daily diary.
  • Control arm The current, individual treatment of each subject.
  • Subjects were confined to the clinic from the previous night for the duration of the day until the next morning (36 hours).
  • Test arm BID AP-CD/LD, No add-on doses were allowed during the PK day (during the blood sampling), since they will interfere with the pharmacokinetic profile. Additional IR-CD/LD was allowed only after the last blood sample was taken.
  • Control arm 4 ⁇ 3 ⁇ 4 tablet of Dopicar (18.75/187.5 mg CD/LD) at 0, +4, +8, +12 hours.
  • Amount/AP-CD/LD (mg) Internal Immediate layer Outer Release Controlled (sum of capsule coating CD Component release two films)
  • Layer layer Carbidopa 50 Levodopa 375 50 Eudragit S100 52 Eudragit L100 80 26 Eudragit L100-55 26 11
  • Mean LD plasma concentrations are presented in FIG. 2 .
  • LD's absorption phase was increased by 6 folds and more, by the AP-CD/LD.
  • BID administration of AP-CD/LD provided 24 hours coverage of mean LD plasma levels of 522-1,710 ng/ml, in comparison to mean LD plasma levels of 91 (or 68—see below)-3,377 ng/ml, obtained with four times a-day administrations of IR-CD/LD, currently on the market (with equidose total daily LD of 750 mg, in both arms).
  • Peak to trough fluctuations (Mean Cmax ⁇ Mean Cmin) were statistically significantly reduced, by the AP-CD/LD, to a half. Similarly, peak to trough ratio (mean Cmax/mean Cmin) is reduced by almost sevenfold:
  • the number of daily doses in this patient group was reduced by half, from 6.0 times per day to 3.2 times per day (namely—BID administration of AP-CD/LD plus 1.2 add-on doses per day), with a statistically significance. This reduction was obtained due to an effective long acting AP-CD/LD. This achievement addresses one of the current unmet needs with respect to PD treatment—the daily significant pill burden, which is a result of the very short half-life of LDs preparations currently on the market.
  • AP-CD/LD Current Difference Mean Time to 0.64 0.97 ⁇ 0.33 ON Post Morning Dose The shorter Mean Time to On, with AP-CD/LD, was obtained due to two attributes: Significantly higher LD plasma levels at time 0 (7AM), due to the true-controlled release performances of the AP-CD/LDs given the day before (522.0 vs 90.9 ng/ml, as described above); An efficient IR component of the AP-CD/LD.
  • the significantly higher morning LD plasma levels provide a very important advantage in the treatment of advanced-stage PD patients.
  • the AP-CD/LD has demonstrated its potential to a significantly improve LD treatment through:
  • the purpose of this study was to evaluate pharmacodynamic changes in fluctuating PD patients upon treatment with AP-CD/LD 50/375 mg, following three weeks treatment.
  • Subjects were randomized to start with either AP-CD/LD or current treatments. There was no washout period between treatment periods due to the equilibration period prior to the test periods. The test period included 4 days of treatment. Pharmacodynamics evaluation was based on ON/OFF home diaries from 3 days prior to the clinic visit and on UPDRS part III performed every hour for 6 hours during a clinic visit on the last day of each test period (days 21 and 42).
  • the regimen was based on BID AP CD/LD 50/375 mg.
  • the Total OFF Time was reduced from 2.9 hours with the current treatment to 1.2 hours with the AP treatment.
  • a significant reduction (more than threefold) of LD doses was achieved.
  • the number of LD daily doses in their current treatment arm was 6.6 times a day.
  • the purpose of the study was to evaluate the pharmacokinetic parameters of AP-CD/LD 50/500 mg, in healthy volunteers, as single dose versus IR of 2 ⁇ 250 mg LD (Sinemet® 25/250 mg (Merck & Co., Inc.)).
  • the primary objective was to compare the pharmacokinetic profiles of LD and carbidopa, following oral administration of a single-dose of a controlled-release gastric retentive formulations, with that obtained following oral ingestion of two consecutive doses of the reference product Sinemet®, taken after a low-medium calorie meal.
  • the secondary objective was to monitor the subjects for adverse events during the study period and to compare the safety of the test formulation with the reference product.
  • Pretreatment 50 mg of carbidopa three times daily on the three days prior to each drug administration was administered to diminish or avoid the ADRs that were anticipated in LD-na ⁇ ve patients.
  • Dosing the dosing of either 2 ⁇ Sinemet® 25/250 mg or 1 ⁇ AP-CD/LD 50/500 mg was performed in a cross-over manner with washout period of 1 week.
  • Amount/AP-CD/LD (mg) Internal layer Outer Immediate Controlled (sum of Release CD Component release two films) Levodopa Layer layer Carbidopa 50 Levodopa 430.0 70.0 Eudragit S100 14.3 50.9 Eudragit L100 109.9 Eudragit L100-55 12.7 11 Fish Gelatin 50.9 Polyox WSR-205 5.9 KOH 2.1 Poloxamer 407 9.5 5.5 Poloxamer 124 62.1 14.9 PEG 400 62.1 35.7 Sodium Starch 50.0 Glycolate
  • the pharmacokinetic profile is presented in FIG. 3 .
  • Salami sandwich one, approx. 50 g), vegetable salad (120 g), fruit salad (1 cup)
  • Option 1 Salami sandwiches (two, approx. 100 g), vegetable salad (120 g), fruit salad (1 cup)
  • Option 2 Humus sandwiches (two, approx. 100 g), vegetable salad (120 g), fruit salad (1 cup)
  • Option 1 Salami sandwiches (two, approx. 100 g), vegetable salad (120 g), fruit salad (1 cup)
  • Option 2 Humus sandwiches (two, approx. 100 g), vegetable salad (120 g), fruit salad (1 cup)
  • Option 1 2 slices of bread with butter (40 g) with 1 small Plain croissant
  • Option 1 Salami sandwiches (two, approx. 100 g), vegetable salad (120 g), fruit salad (1 cup)
  • Option 2 Humus sandwiches (two, approx. 100 g), vegetable salad (120 g), fruit salad (1 cup)

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US20160220495A1 (en) 2016-08-04
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US9801826B2 (en) 2017-10-31
US20170119679A1 (en) 2017-05-04
CA2815959C (fr) 2020-10-06
US20170087091A9 (en) 2017-03-30
EP2635272A1 (fr) 2013-09-11
IL226000A0 (en) 2013-06-27
IL274400A (en) 2020-06-30
WO2012059815A1 (fr) 2012-05-10

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