WO2013035053A2 - Novel conjugation-facilitated transport of drugs across blood brain barrier - Google Patents
Novel conjugation-facilitated transport of drugs across blood brain barrier Download PDFInfo
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- 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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- 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
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- 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
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- 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
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- 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
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- 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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Abstract
The present invention provides a conjugated therapeutic agent of formula I that can facilitate transport of therapeutic agent across the blood brain barrier thereby providing drug levels in brain to impart beneficial therapeutic effect.
Description
Novel Conjugation-Facilitated Transport of Drugs across Blood Brain Barrier
Related Applications
This application is related to and takes priority from Indian Patent Application 2536/MUM/201 1 filed 9 September 201 1 and US Application 61/564,618 filed 29 November 201 1 and are incorporated herein in their entirety.
Field of the invention
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.
Background
The delivery of drugs to central nervous system (CNS) is perhaps the most challenging task in pharmaceutical industry. This is because of a tightly regulated gate -keeping function of the blood brain barrier (BBB). The BBB composed of the microvsacular endothelium acts as a fence to prevent drugs from entering the CNS. In fact over 98% of small molecule drugs and 100% of large molecules drugs do not cross the BBB (See Ann. Int Med. 1986, 105:82-95). Similarly biologic macromolecules such as proteins, antibodies and large nucleic acids also do not get into the CNS.
As a result of the above-mentioned difficulties the market for CNS drugs has been severely underserved. Several diseases such as Alzheimer's, Parkinson's, stroke and ischemia as well as brain tumors (gliomas) have either no good drugs or have very limited drugs available for treatment. Therefore there is urgent need to devise new methods to better deliver drugs to the CNS.
There are clearly defined parameters that impact the crossing of drugs across BBB (See Toxicol Methods, 2000, 44:235-249). Only small molecule drugs with high lipophilicity and a low molecular weight (<400-500 Daltons) can penetrate the BBB (See J Med Chem, 1999, 42:4942-
4951 and J Comb. Chem, 1999, 1 :55-68). Conversely, hydrophilic water soluble drugs or large molecular weight drugs are unlikely to be deliverable to the CNS. There are physiological mechanisms that facilitate the entry of small molecules to the CNS (Brain Drug Targeting, 2001, Cambridge University Press, Cambridge, UK). These are largely designed for the brain to get nutrients such as glucose, lactate, and amino acids in the form of transport systems/ transport proteins. There are two examples of drugs, which utilize the amino acid transport system, L- DOPA used for Parkinson's disease and gabapentin. But besides these there are no good examples of marketed drugs successfully using transport systems to breach the BBB. As can be seen from above, the delivery of water soluble, hydrophilic drugs can be particularly challenging. In this invention we describe a novel method to deliver water-soluble niacin to CNS by conjugating it with malic acid.
Brief summary of the invention
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):
Formula I
Wherein, 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
In one aspect of the invention, there is provided 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.
In accordance with another aspect of the present invention there is provided 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 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.
In accordance with another aspect of the present invention there is provided use of 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
Formula I
Wherein, 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.
In one aspect of the invention the compound of formula I includes but not restricted to the compounds presented in Tables la, lb and lc.
Table 1a:
L (-) MALIC ACID CONJUGATES WITH NIACIN AND EUGENOL
S.No Niacin - L (-) Malic acid - Eugenol Structure
Niacin - L (-) Malic acid - Eugenol
C6H5N02 C4H605 C10H12O2 A) R = Me C21 H21 N07 (399.39) 123.1 1 134.09 164.20 B) R= H C20H19NO7 (385.37)
Niacin L (-) Malic acid
C6H5N02 C4H605 A) R = Me C12H13N06 (267.23)
123.1 1 134.09 B) R= H C10H9NO6 (239.18)
Table lb: L (-) MALIC ACID CONJUGATES: OTHER CNS DRUGS
S.no D1 - L - D2 Structure
I With Levo- Dopa (L-DOPA)
Niacin - L (-) Malic acid - L - Dopa
A) R = Me C20H20N2O9 (432.38)
C6H5N02 C4H605 C9H1 1 N04 B) R = H C19H18N209 (418.35)
123.1 1 134.09 197.19 * may be in protected form eg. OAc
L-Dopa - L (-) Malic acid
A) R = Me C14H17N08 ( 327.29)
C9H1 1 N04 C4H605 B) R = H C13H15N08 (313.26)
197.19 134.09 * may be in protected form eg. OAc
II with Galantamine
B) R= H C22H30O7 (406.47)
0 COOR 0
Valproic acid - L (-) Malic acid
C8H1602 C4H605 A) R= Me C14H2406 (288.34)
144.21 134.09 B) R= H C12H20O6 (260.28)
Table lc:
L (+)TARTARIC ACID CONJUGATES WITH NIACIN AND EUGENOL
S.No Niacin - L (+)Tartaric acid - Eugenol Structure
Niacin - L (+) Tartaric acid - Eugenol
A) R = Me C21 H21 N08 (415.39)
C6H5N02 C4H606 C10H12O2 B) R= H C20H19NO8 (401.37)
123.1 1 150.08 164.20 * may be in protected form eg. OAc
Niacin - L (+) Tartaric acid
A) R = Me C12H13N07 (283.23)
B) R= H C10H9NO7 (255.18)
C6H5N02 C4H606
123.1 1 150.08 * may be in protected form eg. OAc
L (+) Tartaric acid - Eugenol
A) R = Me C15H 1807 (310.30)
B) R= H C14H1607 (296.27)
C4H606 C10H12O2
150.08 164.20 * may be in protected form eg. 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
Our PCT publication WO201 1/089576 A2 disclosing novel compositions and methods of making pyridine carboxylic acid derivatives capable of inhibiting/reducing the production of A- beta in cells is incorporated in its entirety herein by reference.
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.
In addition, in contrast to several conjugates made with other linkers such as amino acids fail to deliver the drug in CNS compared to the hydroxyl substituted dicarboxylic acid as linker. In one aspect of the invention, there is provided a method of preparing compounds of formula I, essentially following the methods described in our pending Patent Application number PCT/ IB201 1/050290 (corresponding PCT publication WO2011/089576 A2) which is incorporated herein in its entirety by reference. In accordance with another aspect of the present invention there is provided a pharmaceutical composition for transporting Drug 1 across the blood brain barrier, comprising a conjugate therapeutic agent and pharmaceutically acceptable excipient.
In accordance with another aspect of the present invention there is provided a pharmaceutical composition for treating neurological disease or disorder.
In accordance with yet another aspect of the present invention there is provided 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.
In accordance with still another aspect of the present invention there is provided use of 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
The invention is further demonstrated by the following:
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. However 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.
These results from in vivo studies establish the transport of niacin across BBB through malic acid conjugation as described in figures 1 -10 given below.
The term "treating" or "treatment" of a state, disease, disorder or condition includes:
(1) preventing or delaying the appearance of clinical symptoms of the state, disease, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disease, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disease, disorder or condition;
(2) inhibiting the state, disease, disorder or condition, i.e., arresting or reducing the development of the state, disease, disorder or condition or at least one clinical or subclinical symptom thereof; or
(3) relieving the state, disease, disorder or condition, i.e., causing
regression of the state, disease.
The term "therapeutically effective", "therapeutically beneficial" or
"therapeutically 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.
Pharmaceutical 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.
The compound described in the present patent application may form salts. 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.
To the extent prior art teaches synthesis or separation of particular stereoisomers, the different stereoisomeric forms of the present patent application may be separated from one another by the method known in the art, or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated. Pharmaceutically acceptable 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.
Pharmaceutical Compositions:
The pharmaceutical 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). Preferably, 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.
Examples of 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.
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). For example, 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. When 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.
The pharmaceutical 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. Preferable carriers for ta modified cellulose gum (Ac- Di-Sol®), and 7.5 mg magnesium stearate; (2) Coating: HPMC, approx. 9 mg Mywacett 9-40 T and approx. 0.9 mg acylated monoglyceride.
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.
For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
Methods
PREPARATION OF SOLUTIONS
Mobile Phase and Solutions
Buffer (0.1% Formic acid)
Exactly 1.0 ml of formic acid was added to 999 ml of milli-Q-water to obtain 0.1% buffer. This solution was stored at room temperature and used within two days.
Dilution solvent (Methanol: Water 80:20 v/v)
Exactly 800 mL of methanol and 200 mL of water were added to the reagent bottle, mixed well and sonicated. This solution was stored at room temperature and used within seven days.
Stock solutions Preparation of Niacin stock solution
Exactly 5 mg of Niacin 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 μg/mL stock solution.
Preparation of Eugenol stock solution
Exactly 5 mg of Eugenol 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 μg/mL stock
solution.
Preparation of calibration curve for Niacin in plasma or brain homogenate
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.
Quality control samples LQC, MQC and HQC falling in the calibration curve range were prepared (Prepared concentrations: 30.00, 5000.00 and 12500.00 ng/ml) in control plasma or brain homogenate by spiking with suitable aqueous analyte standard solutions.
Preparation of calibration curve for Eugenol in plasma or brain homogenate
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.
Quality control samples LQC, MQC and HQC falling in the calibration curve range were prepared (Prepared concentrations: 22.50, 2000.00 and 5000.00 ng/ml) in control plasma or brain homogenate by spiking with suitable aqueous analyte standard solutions.
BIOANALYTICAL METHOD
Protein precipitation extraction method for Niacin from plasma and Brain homogenates samples
Step 1: 100 μΐ of plasma or brain homogenate samples were added to the 2ml centrifuge tubes Step 2: 400 μΐ 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 μΐ 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.
Liquid-Liquid extraction method for Eugenol from plasma and brain homogenates samples
Step 1: 100 μΐ of plasma or brain homogenate samples were added to the 2ml centrifuge tubes
Step 2: 400 μΐ 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 μΐ supernatant organic layer was separated
Step 5: 50 μΐ of dansyl chloride , 20 μΐ 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.
INSTRUMENTATION CONDITION FOR NIACIN LC parameters:
MS parameters:
Column: Mobile phase: Separation mode: Flow rate: Injection volume: Auto sampler temperature: Column oven temperature:
Hypersil gold, 150 x 4.6mm, 5μπι Methanol: 0.1 % Formic acid (75:25 v/v) Isocratic 0.7 mL/min 10 μΐ 10°C ± 4°C 40°C ± 2°C
Source: Polarity: MRM transition of analyte (Niacin):
MRM transition of IS (Theophylline): Curtain Gas (CUR): Ion Spray Voltage (IS): Temperature (TEM): Gas 1 (GS1): Gas 2 (GS2): Dwell Time (msec):
LCMS:
API 3200 Turbo Ion Spray Positive 124.1/80.00 181.05/124.1 20 5500 500 20 40 200
Niacin 35 35 8 3 Theophylline (IS) 46 23 7 5
INSTRUMENTATION CONDITION FOR EUGENOL LC parameters:
Column: Mobile phase: Separation mode: Flow rate: Injection volume: Auto sampler temperature: Column oven temperature:
MS parameters:
Hypersil gold, 150 x 4.6mm, 5μπι Methanol: 0.1 % Formic acid (85: 15 v/v) Isocratic 0.7 mL/min
10 μΐ 10°C ± 4°C 40°C ± 2°C
LCMS:
Source: Polarity: MRM transition of analyte (Eugenol): Curtain Gas (CUR): Ion Spray Voltage (IS): Temperature (TEM): Gas 1 (GS 1): Gas 2 (GS2): Dwell Time (msec):
DATA PROCESSING
Chromatograms data acquired using the Analyst software version 1.4.2, were processed by peak area ratio method. The concentration of the unknown is calculated from the following equation, y = mx + c Where, x = concentration of drug
m = slope of calibration curve y = peak area ratio c = intercept of the calibration curve l/x2 was used as the weighting factor
Examples
a. Single dose pharmacokinetic (PK) parameters of a physical mixture of malic acid and niacin given orally in rats:
To test if niacin mixed with malic acid would penetrate BBB, we performed a PK study where a physical (unconjugated) mixture of niacin and malic acid was given orally to rats and then niacin levels in plasma and brain were tracked. The study design is shown in Table 1. As shown in Table 2, oral dosing produced significant plasma levels with the time taken after dosing to reach maximum concentration (Tmax) of 0.30 hr and maximum concentration reached (Cmax) of 55844 nM. Surprisingly there were no detectable levels of niacin in the brain.
These data suggest that niacin is absorbed when dosed orally and is found in the plasma but is not found in brain over the 24 hrs of brain sampling. b. Single dose pharmacokinetic (PK) parameters of niacin conjugated to malic acid (niacin-malic acid):
To test if covalent conjugation of niacin to malic acid would facilitate its entry into the brain, we performed a PK study with niacin covalently conjugated to malic acid via an ester bond. The niacin dose in the form of the conjugate was matched to that of free niacin dose used above.
The study design is shown in Table 3. As shown in Table 4, oral dosing produced significant plasma levels of niacin-malic acid conjugate with Tmax of 1 hr and Cmax of 39100 nM. There were significant levels of niacin-malic acid conjugate in the brain as well with Tmax of 0.30 hr and Cmax of 520 nM (Table 5).
The data show that niacin conjugated to malic acid is absorbed when dosed orally and is found in the plasma as well as in the brain. These data suggest that 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).
Single dose pharmacokinetic (PK) parameters of niacin conjugated to malic acid and eugenol:
To test if covalent conjugation of niacin to malic acid as well as conjugating another compound (eugenol) on the other end would still facilitate niacin entry into the brain, we performed a PK study where 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.
The study design is shown in Table 6. As shown in Table 7, oral dosing of niacin-malic acid- eugenol produced significant plasma levels of niacin with Tmax of 0.16 hr and Cmax of 23974 nM. There were significant levels of niacin in the brain as well with Tmax of 0.25 hr and Cmax of 565 nM (Table 8). We also tracked niacin-malic acid conjugate. As shown in Table 9, the data show that niacin-malic acid conjugate is found in the plasma with Tmax of 0.16 hr and Cmax of 14314 nM. In the brain the Tmax of niacin-malic acid conjugate was 0.16 hr and Tmax was 360 nM (Table 10).
The data show that when niacin conjugate to malic acid and a second compound eugenol, it is still able to deliver niacin as well as niacin-malic acid to the brain. These data suggest that conjugation of niacin to malic acid and another compound still allows penetration of niacin- malic conjugate as well as niacin thru the BBB and delivers it to the brain. It's possible that niacin-malic conjugate penetrates the BBB and generates free niacin in the brain.
Table 1 : Study Design
Pharmacokinetics and Brain distribution studies of Niacin + Malic acid physical mixture in S.D. Rats
Compound : Niacin- Malic acid Physical Mixture Radioactive : No
Species : Rat Strain/sex : Sprague Dawley, Male
Numbers : 3 Rats / group Route : Oral
Dose : Niacin + Malic acid physical mixture -
Dosing Date: 08 July, 201 1
15.4 mg/kg b.w + 16.9 mg/kg b.w
Dose volume : 10 ml/kg b.w. Fasting : yes
Formulation A : 0.5 % Tween 80 + 45 % PEG
Mode of administration : Oral gavage
-400+0.5 % CMC in water
Sampling details
Sample Time point (h) Storage Anticoagulant
Plasma 0.16, 0.25,0.5, 1 .0,2.0,4.0, 6.0 and 24.0 Crushed ice K2EDTA
Brain 0.16, 0.25,0.5, 1.0,2.0,4.0, 6.0 and 24.0 Crushed ice NA
Table 2: Niacin Plasma PK parameters
Table 3: Study Design
Mode of administration : Oral gavage
400+0.5 % CMC in water
Sampling details
Sample Time point (h) Storage Anticoagulant
Plasma 0.16, 0.25,0.5,1 .0,2.0,4.0, 6.0 and 24.0 Crushed ice KzEDTA
Brain 0.16, 0.25,0.5, 1 .0,2.0,4.0, 6.0 and 24.0 Crushed ice NA
Table 4: Niacin-Malic acid Plasma PK parameters
Table 5: Niacin-Malic acid Brain PK parameters
Table 6: Study Design
Compound : Niacin- Malic acid - Eugenol Radioactive : No
Species : Rat Strain/sex : Sprague Dawley, Male
Numbers : 3 Rats / group Route : Oral
Dosing Date: 14 July, 201 1 Dose : 50 mg/kg b.w (0.125 milli moles)
Dose volume : 10 ml /kg b.w. Fasting : yes
Formulation A: 0.5% Tween 80 + 45% PEG
Mode of administration : Oral gavage
+0.5% CMC
Sampling details
Sample Time point (h) Storage Anticoagulant
Plasma 0.16, 0.25,0.5,1.0,2.0,4.0, 6.0 and 24.0 Crushed ice KzEDTA
Brain 0.16, 0.25,0.5, 1.0,2.0,4.0, 6.0 and 24.0 Crushed ice NA
Table 7: Niacin Mean Plasma PK parameters
Table 8: Niacin Mean Brain PK parameters
AUCinf (hr*nmol) NC
AUCo /oextrap (%) NC
T½ (hr) NC
MRTiast (hr) 0.82
Table 9: Niacin-Malic acid Plasma PK parameters
Claims
1. A compound of formula I
Formula I
wherein, Drug 1 in formula I is selected from a group consisting of niacin,and any drug for treating neurological disorders;
Linker is hydroxyl substituted dicarboxylicacid; and
An optionally chosen Drug-2 is selected from a group consisting of a nutraceutical, an antioxidant, a therapeutic agent or a drug of same class or different class as drug 1 or drug-2.
2. The compound of claim 1 wherein the drug for treating neurological disorders is selected from the group consisting of valproic acid, galantamin, L-dopa and gabapentin.
3. The compound of claim 1 wherein the hydroxyl substituted dicarboxylic acid linker is selected from malic acid and tartaric acid.
4. The compound of claim 1 wherein the Drugl is covalently bound to the Linker through one of its hydroxyl group or carboxylic acid group forming an ester bond, and Drug 2 is covalently bound to hydroxyl or carboxylic group of Linker,
5. A pharmaceutical composition comprising compound of formula I as claimed in claim 1 and a pharmaceutically acceptable excipient for transporting Drug 1 across the blood brain barrier and modulating drug levels in brain.
6. A pharmaceutical composition as claimed in claim 5 for treating neurological disease or disorder.
7. A pharmaceutical composition as claimed in claim 5 for delivery of an agent to the CNS of an individual comprising conjugate therapeutic and a pharmaceutical excipient by administering a therapeutically effective dose.
8. Use of compound of formula I or pharmaceutical composition comprising compound of formula I as claimed in claims 1 and 6 for treating neurological disease.
9. Use of compound of formula I or pharmaceutical composition comprising compound of formula I as claimed in claim 5 and 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.
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 |
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| Publication Number | Publication Date |
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| WO2013035053A2 true WO2013035053A2 (en) | 2013-03-14 |
| WO2013035053A3 WO2013035053A3 (en) | 2015-08-06 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE602004031134D1 (en) * | 2003-08-29 | 2011-03-03 | Transform Pharmaceuticals Inc | PHARMACEUTICAL COMPOSITIONS AND METHOD FOR THE USE OF LEVODOPA AND CARBIDOPA |
| JP5721426B2 (en) * | 2007-04-05 | 2015-05-20 | ザ ジェイ．ディヴィッド グラッドストン インスティテューツ | How to identify drugs that relieve excessive nerve excitement |
| WO2009085306A1 (en) * | 2007-12-28 | 2009-07-09 | Impax Laboratories, Inc. | Controlled release formulations of levodopa and uses thereof |
| EP2310004A1 (en) * | 2008-07-11 | 2011-04-20 | Kareus Therapeutics SA | Niacin compositions for reduction of amyloid beta peptide 42 (abeta 42) production and for treatment of alzheimer's disease (ad) |
| EP2456434A1 (en) * | 2009-07-23 | 2012-05-30 | Shire LLC | Galantamine amino acid and peptide prodrugs and uses thereof |
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