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WO2013035053A2 - Procédé inédit de transport de médicaments, facilité par un processus de conjugaison, à travers la barrière hémato-encéphalique - Google Patents

Procédé inédit de transport de médicaments, facilité par un processus de conjugaison, à travers la barrière hémato-encéphalique Download PDF

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Publication number
WO2013035053A2
WO2013035053A2 PCT/IB2012/054593 IB2012054593W WO2013035053A2 WO 2013035053 A2 WO2013035053 A2 WO 2013035053A2 IB 2012054593 W IB2012054593 W IB 2012054593W WO 2013035053 A2 WO2013035053 A2 WO 2013035053A2
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WO
WIPO (PCT)
Prior art keywords
drug
compound
formula
niacin
brain
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.)
Ceased
Application number
PCT/IB2012/054593
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English (en)
Other versions
WO2013035053A3 (fr
Inventor
Uday Saxena
Venkateswarlu Akella
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.)
Kareus Therapeutics SA
Original Assignee
Kareus Therapeutics SA
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 Kareus Therapeutics SA filed Critical Kareus Therapeutics SA
Publication of WO2013035053A2 publication Critical patent/WO2013035053A2/fr
Anticipated expiration legal-status Critical
Publication of WO2013035053A3 publication Critical patent/WO2013035053A3/fr
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/06—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • 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
    • 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
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3

Definitions

  • the present invention is related to a conjugated therapeutic agent of formula I that can facilitate transport of therapeutic agent across blood brain barrier thereby providing drug levels in brain to impart beneficial therapeutic effect.
  • BBB blood brain barrier
  • the present invention provides novel composition comprising conjugated therapeutic agent of formula I for facilitating transport of therapeutic agents /drugs across Blood Brain Barrier (BBB):
  • Drug 1 in formula I is niacin or a drug approved by regulatory agencies for treating neurological disorders or conditions for example valproic acid, galantamine, L-DOPA and gabapentin;
  • Linker is selected from hydroxyl substituted dicarboxylic acid like malic acid or tartaric acid;
  • An optionally chosen Drug 2 is selected from a nutraceutical, an antioxidant, a therapeutic agent or a CNS drug of same class or different class, or one more molecule of the same drug as selected above ;
  • Drag 1 can be covalently bound to the linker through one of its hydroxyl group or carboxylic acid group forming an ester bond, whereas an optionally chosen second drag can covalently bind to hydroxyl / carboxylic group of linker, leaving second carboxylic acid of linker to facilitate the transportation of drag 1 across BBB, further this carboxylic acid group of linker can be converted to an ester or an amide to prevent the instability if any associated with free carboxylic acid ,and to make it cross the BBB and dissociable in brain to release Drag 1 ;
  • Neurological disease or disorder is chosen from diseases such as Alzheimer's, Parkinson's, stroke and ischemia as well as brain tumors (gliomas) and brain infections such as meningitis and encephalitis
  • a method of preparing compound of formula I in accordance with another aspect of the present invention, there is provided a pharmaceutical composition for transporting Drag 1 across the Blood Brain Barrier, comprising a conjugate therapeutic agent and pharmaceutically acceptable excipient.
  • a pharmaceutical composition for treating neurological disease or disorder there is provided a pharmaceutical composition for treating neurological disease or disorder.
  • a pharmaceutical composition for delivery of an agent to the CNS of an individual comprising conjugate therapeutic and a pharmaceutical excipient by administering a therapeutically effective dose either by a oral route or like.
  • compound of formula I or pharmaceutical composition comprising compound of formula I for treating neurological disease, wherein the disease is selected from Alzheimer's, Parkinson's, stroke and ischemia as well as brain tumors (gliomas) and brain infections such as meningitis and encephalitis Detailed description of the present invention
  • the present invention provides novel composition comprising conjugated therapeutic agent of formula I for modulating blood brain barrier transport of therapeutic agents/compounds
  • Drugl in formula I is niacin or selected from a drug approved by regulatory agencies for treating neurological disorders or conditions for example valproic acid, galantamine, L- DOPA and gabapentin;
  • Linker is selected from hydroxyl substituted dicarboxylic acid like malic acid or tartaric acid;
  • An optionally chosen Drug 2 is selected from a nutraceutical, an antioxidant, a therapeutic agent or a CNS drug of same class or different class, or one more molecule of the same drug as selected above ;
  • Drugl can be covalently bound to the liker through one of its hydroxyl groups or carboxylic acid groups forming an ester bond, whereas an optionally chosen Drug 2 can covalently bind to hydroxyl /carboxylic group of linker, leaving second carboxylic acid of linker to facilitate the transportation of CNS drug across BBB, further this carboxylic acid group of linker can be converted to an ester or an amide to prevent the instability if any associated with free carboxylic acid, and to make it cross the BBB and dissociable in brain to release the CNS drug.
  • the compound of formula I includes but not restricted to the compounds presented in Tables la, lb and lc.
  • 197.19 134.09 * may be in protected form eg. OAc
  • 123.1 1 150.08 * may be in protected form eg. OAc
  • OAc Neurological disease or disorder are selected from diseases such as Alzheimer's, Parkinson's, stroke and ischemia as well as brain tumors (gliomas) and brain infections such as meningitis and encephalitis
  • the invention is based on discovery, disclosed here for the first time that certain water soluble, hydrophilic drugs like niacin can be conjugated covalently to a hydro xyl substituted carboxylic acid and an optionally chosen second drug as described in formula I can deliver niacin preferably in brain as characterized by measuring the drug concentration in the brain by administering the compound of formula I to a subject through oral route.
  • This surprising discovery provides a novel method for delivery of the drug in CNS, as the conjugate therapeutic agent of formula I is dissociable in the brain.
  • a pharmaceutical composition for treating neurological disease or disorder in accordance with another aspect of the present invention there is provided a pharmaceutical composition for treating neurological disease or disorder.
  • a pharmaceutical composition for delivery of an agent to the CNS of an individual comprising conjugate therapeutic and a pharmaceutical excipient by administering a therapeutically effective dose either by an oral route or like.
  • compound of formula I or pharmaceutical composition comprising compound of formula I for treating neurological disease, wherein the disease is selected from Alzheimer's, Parkinson's, stroke and ischemia as well as brain tumors (gliomas) and brain infections such as meningitis and encephalitis
  • niacin When an admixture of niacin, a water soluble hydrophilic drug and malic acid was administered orally to rats, there were no detectable niacin levels found in the brain.
  • a pharmaceutical composition of a conjugate of formula I wherein drug 1 is niacin, linker is malic acid and an optionally chosen drug is eugenol when administered orally to rats surprisingly resulted niacin and niacin-malic acid conjugate levels in the brain. Free eugenol was also found in the brain likely as a result of its cleavage by esterases in the plasma.
  • treating or “treatment” of a state, disease, disorder or condition includes:
  • terapéuticaally remedial are intended to mean an amount of a compound sufficient to substantially improve some symptom associated with a CNS disease or a medical condition.
  • Conjugate is intended to mean compounds covalently bound to a linker like malic acid or tartaric acid.
  • compositions can be in the form of tablets, drugs, or capsules and may include lactose, cornstarch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet that may be prepared by conventional techniques may contain: (1) Core: Active compound (as free compound or salt thereof), 250 mg colloidal silicon dioxide (Aerosil®), 1.5 mounds microcrystalline cellulose (Avicel®), 70 mg.
  • Non-limiting examples of pharmaceutically acceptable salts forming part of this patent application include salts derived from inorganic bases salts of organic bases salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids.
  • Certain compounds of present patent application are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers). With respect to the overall compounds described by the Formula (I), the present patent application extends to these stereoisomeric forms, preferably the linker is L(-) malic acid, and to mixtures thereof.
  • solvates includes hydrates and other solvents of crystallization (such as alcohols).
  • the compounds of the present invention may form solvates with low molecular weight solvents by methods known in the art.
  • compositions provided in the present patent application include at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the contemplated pharmaceutical compositions include a compound(s) described herein in an amount sufficient to treat viral infection in a subject.
  • the subjects contemplated include, for example, a living cell and a mammal, including human mammal.
  • the compound of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include a sustained release material, such as, for example, glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • a sustained release material such as, for example, glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing.
  • the pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
  • the pharmaceutical compositions described herein may be prepared, e.g., as described in Remington: The Science and Practice of Pharmacy, 20th Ed., 2003 (Lippincott Williams & Wilkins).
  • the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be a solid, semi -solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container, for example, in a sachet.
  • compositions may be, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.
  • the route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action.
  • Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).
  • the oral route is preferred.
  • Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Niacin Exactly 5 mg was weighed accurately and transferred into a 5.0 mL volumetric flask and dissolved in methanol. The volume was made up with methanol to obtain 1000 ⁇ g/mL stock solution.
  • Calibration curve standards were prepared in the range 1 1.25 to 12500.00 ng/mL (Prepared concentrations: 11.25, 30.00, 56.25, 112.50, 225.00, 375.00, 750.00, 1500.00, 2500.00, 5000.00, 10000.00 and 12500.00 ng/mL) in control plasma or brain homogenate by spiking with suitable aqueous analyte standard solutions.
  • Calibration curve standards were prepared in the range 4.50 to 5000.00 ng/mL (Prepared concentrations: 4.50, 7.00, 22.50, 45.00, 90.00, 115.00, 230.00, 600.00, 2500.000, 1000.00, 2000.00, 4000.00 and 5000.00 ng/mL) in control plasma or brain homogenate by spiking with suitable aqueous analyte standard solutions.
  • Step 1 100 ⁇ of plasma or brain homogenate samples were added to the 2ml centrifuge tubes
  • Step 2 400 ⁇ of Acetonitrile were added and vortexed for 1 minute
  • Step 3 The samples were centrifuged at 4000 rpm for 15 Minutes at 10°C
  • Step 4 The supernatant organic layer was separated and evaporated to dryness
  • Step 5 The sample residues were reconstituted with 200 ⁇ of Mobile Phase.
  • Step 6 The reconstituted samples were then transferred into the auto sampler vials and placed in the auto sampler of the LC-MS/MS system cooled to 10°C.
  • Step 1 100 ⁇ of plasma or brain homogenate samples were added to the 2ml centrifuge tubes
  • Step 2 400 ⁇ of Acetonitrile were added and vortexed for 1 minute
  • Step 3 The samples were centrifuged at 4000 rpm for 15 Minutes at 10°C
  • Step 4 The 300 ⁇ supernatant organic layer was separated
  • Step 5 50 ⁇ of dansyl chloride , 20 ⁇ of 100 mM NaoH were added to the separated supernatant and vortexed for 2 min
  • Step 6 The mixture were kept at water bath maintained at 50°C for 15 min
  • Step 7 The samples were then transferred into the auto sampler vials and placed in the auto sampler of the LC- MS/MS system cooled to 10°C.
  • ABD-2030R-ADME-001 Pharmacokinetics and brain distribution studies of KU-046 CMC batch in male Sprague dawley rats at 50 mg/kg b.w.
  • Hypersil gold 150 x 4.6mm, 5 ⁇ Methanol: 0.1 % Formic acid (75:25 v/v) Isocratic 0.7 mL/min 10 ⁇ 10°C ⁇ 4°C 40°C ⁇ 2°C
  • Hypersil gold 150 x 4.6mm, 5 ⁇ Methanol: 0.1 % Formic acid (85: 15 v/v) Isocratic 0.7 mL/min 10 ⁇ 10°C ⁇ 4°C 40°C ⁇ 2°C
  • PK pharmacokinetic
  • PK pharmacokinetic
  • niacin conjugated to malic acid is absorbed when dosed orally and is found in the plasma as well as in the brain.
  • conjugation of niacin to malic acid allows its penetration thru the BBB and delivers it to the brain. This is in complete contrast to dosing with free niacin, which is unable to breach BBB as indicated by lack of brain levels (see data above).
  • PK pharmacokinetic
  • niacin-malic acid-eugenol conjugate was given orally to rats.
  • the niacin dose in the form of the conjugate was matched to that of free niacin dose used above.
  • Rat Strain/sex Sprague Dawley, Male
  • Formulation A 0.5 % Tween 80 + 45 % PEG
  • Formulation A 0.5 % Tween 80 + 45 % PEG -
  • Rat Strain/sex Sprague Dawley, Male
  • Formulation A 0.5% Tween 80 + 45% PEG

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un agent thérapeutique conjugué de formule I capable de faciliter le transport d'un agent thérapeutique à travers la barrière hémato-encéphalique, ce qui permet d'obtenir une concentration en médicament au niveau du cerveau suffisante pour exercer un effet thérapeutique bienfaisant.
PCT/IB2012/054593 2011-09-09 2012-09-06 Procédé inédit de transport de médicaments, facilité par un processus de conjugaison, à travers la barrière hémato-encéphalique Ceased WO2013035053A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN2536/MUM/2011 2011-09-09
IN2536MU2011 2011-09-09
US201161564618P 2011-11-29 2011-11-29
US61/564,618 2011-11-29

Publications (2)

Publication Number Publication Date
WO2013035053A2 true WO2013035053A2 (fr) 2013-03-14
WO2013035053A3 WO2013035053A3 (fr) 2015-08-06

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PCT/IB2012/054593 Ceased WO2013035053A2 (fr) 2011-09-09 2012-09-06 Procédé inédit de transport de médicaments, facilité par un processus de conjugaison, à travers la barrière hémato-encéphalique

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Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050070608A1 (en) * 2003-08-29 2005-03-31 Julius Remenar Pharmaceutical compositions and method of using levodopa and carbidopa
US20080249058A1 (en) * 2007-04-05 2008-10-09 Erik Roberson Agents that reduce neuronal overexcitation
JP5783725B2 (ja) * 2007-12-28 2015-09-24 インパックス ラボラトリーズ、 インコーポレイテッドＩｍｐａｘ Ｌａｂｏｒａｔｏｒｉｅｓ， Ｉｎｃ． レボドパの放出制御製剤及びその使用
WO2010005581A1 (fr) * 2008-07-11 2010-01-14 Kareus Therapeutics, Llc Compositions de niacine pour la réduction de la production de peptide amyloïde bêta-42(aβ42)et pour le traitement de la maladie d'alzheimer (ad)
KR20120046268A (ko) * 2009-07-23 2012-05-09 샤이어 엘엘씨 갈란타민 아미노산과 펩티드 프로드러그 및 이들의 용도

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