CA2423358A1 - Gamma-hydroxybutyrate compositions containing carbohydrate, lipid or amino acid carriers - Google Patents

Gamma-hydroxybutyrate compositions containing carbohydrate, lipid or amino acid carriers Download PDF

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CA2423358A1
CA2423358A1 CA002423358A CA2423358A CA2423358A1 CA 2423358 A1 CA2423358 A1 CA 2423358A1 CA 002423358 A CA002423358 A CA 002423358A CA 2423358 A CA2423358 A CA 2423358A CA 2423358 A1 CA2423358 A1 CA 2423358A1
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compound
alkyl
residue
amino acid
pharmaceutically acceptable
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CA2423358C (en
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Brian L. Miller
Mortimer Mamelak
William C. Houghton
Dayton T. Reardan
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Jazz Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/675—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids of saturated hydroxy-carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
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    • A61P23/00—Anaesthetics
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
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    • 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
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    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
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    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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    • A61P39/00—General protective or antinoxious agents
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    • A61P39/06—Free radical scavengers or antioxidants
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/24—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/49—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms

Abstract

The present invention provides compositions comprising at least one GHB moiety bonded to at least one physiologically compatible carrier molecule. The compositions can enhance the uptake of the drug, deliver effective therapeutic doses in a time-delayed fashion, or can target specific organs.

Claims (36)

1. A compound of the formula (I):
wherein Y is H or a hydroxyl-protecting group, X is the residue of a carbohydrate and n has a value of 1 to the number of available hydroxyl groups in said carbohydrate, or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 wherein X is a saccharide.
3. The compound of claim 1 wherein Y is H, a (C4-C6)acetal, (C1-C5)acyl or (C1-C5)alkyl.
4. The compound of claim 1 wherein X is the residue of a monosaccharide or the residue of a disaccharide.
5. The compound of claim 1 wherein X is the residue of a polysaccharide.
6. The compound of claim 4 or 5 wherein the residue contains at least one CHOH-CHOH moiety that is protected as an acetal or ketal.
7. The compound of claim 1 wherein X is the residue of a chemically modified cellulose.
8. The compound of claim 7 wherein the chemically modified cellulose is hydroxypropyl-methylcellulose, hydroxyethylcellulose or hydroxypropylcellulose.
9. The compound of claim 1 wherein the carbohydrate is a chemically modified saccharide or a chemically modified starch.
10. A pharmaceutical composition comprising the compound of claim 1 in combination with a pharmaceutically acceptable carrier.
11. The composition of claim 10 which is adapted for oral administration.
12. The composition of claim 10 which is adapted for topical or local administration.
13. A compound of the formula (II):
(R'O(CH2)3CO2)m(ROC(O)(CH2)3OC(O))q-(X)-(Y)n-(Z)n-(CO2(CH2)3CO2R)p(O2C(CH)2)3OR~I) wherein R' is H or a hydroxyl-protecting group, R is H, (C1-C4)alkyl or benzyl, X and Z are each residues of a hydroxy group-containing amino acid or a bis(carboxy)amino acid, Y is a moiety covalently linking X and Z, n is 0-1, m and k are 0 to the number of available hydroxy groups on the amino acids X and Z; q and p are 0 to the number of available CO2 groups on amino acids X and Z, with the proviso that both m and q and both p and k are not zero, or a pharmaceutically acceptable salt thereof.
14. A compound of the formula (III):
wherein R1 is H or a hydroxyl-protecting group, R is H, (C1-C4)alkyl or benzyl, X is a residue of a hydroxy group-containing amino acids, Z is the residue of a hydroxy group-containing amino acid or a bis(carboxy) group-containing amino acid, Y is a moiety covalently linking X and Z, n is 0-1, m is 1 to the number of available hydroxy groups in amino acid X, p is 1 to the number of available groups on the amino acid X or Z, or a pharmaceutically acceptable salt thereof.
15. The compound of claim 13 wherein each of m, q, p and k is 1.
16. The compound of claim 13 wherein m and k are 0, and q and p are 1.
17. The compound of claim 13 wherein n = 0, m = 0 and k = 0 and X is glutamic acid, aspartic acid or tyrosine.
18. The compound of claim 14 wherein m=p=1, n is 0 and X is tyrosine, threonine, or serine.
19. The compound of claim 14 wherein m=n=p=1 and Y is C(O)CH2CH2C(O) or C(O)CH=CH(CO).
20. A compound of formula (IV):
wherein L and L' are individually H, (C1-C6)alkyl or a hydroxyl protecting group or an organic moiety comprising at least one fatty alcohol, fatty ester or analog thereof, wherein at least one of L and L' is said moiety.
21. The compound of claim 17 wherein at least one of L' or L is -(A)(Y)(Z)n, wherein A is (C1-C6)alkyl, Y is H, OH N(R1)(R2)(R3) or [-O(PO3-)-AN(R1)(R2)(R3), wherein R1, R2 and R3 are each (C1-C4)alkyl or R1 and R2 together with N are a (C5-C7)heterocyclic ring, optionally substituted with 1 or 2 N(R3), S, non-peroxide O or a combination thereof; n is 1-2 and Z is YR, wherein Y is O, S, NH, N(CH3), NHC(O) or OC(O) and R is (C8-C22)alkyl, optionally substituted with 1-2 double bonds, or a pharmaceutically acceptable salt thereof, with the proviso that when one of L or L' is 1,3-dihexadecanoylprop-2-yl, the other is not H.
22. The compound of claim 21 wherein L' is -(A)(Y)(Z)n and L is H, (C1-C6)alkyl or a hydroxyl protecting group.
23. The compound of claim 21 or 22 wherein Y is OC(O).
24. The compound of claim 20 wherein R is (C10-C22)alkyl.
25. The compound of claim 21 or 22 wherein Y is -O(PO3-)CH2CH2N(CH3)3+.
26. The compound of claim 21 or 22 wherein (A)(Y)(Z)n is -CH[CH2Z][CH2Y].
27. A compound of the formula (V):
wherein L is individually H, (C1-C6)alkyl or a hydroxyl protecting group, n is 6, and L" is (C2-C12)alkyl, optionally interrupted by 1-3-O-.
28. The compound of claim 27 wherein L" is the alkyl residue of 1,.omega.-alkylene diol.
29. The compound of claim 27 wherein L" is -(CH2)3- and n is 2.
30. The compound of claim 27 wherein L is (C2-C7)acyl.
31. The compound of claim 27 where L is acetyl.
32. 1,3-bis(4-acetoxybutyroyl)propane.
33. The use of a compound of any of claims 1-32 in medical therapy.
34. The use of a compound of any of claims 1-32 to prepare a medicament to treat a condition or pathology amenable to treatment with gamma-hydroxybutyrate.
35. A method for treating a mammal afflicted with a condition or pathology amenable to treatment by gamma-hydroxybutyrate (GHB) comprising administering to said mammal an effective amount of a compound of any of claims 1-32.
36. A pharmaceutical composition comprising a compound of any of claims 1-32 in combination with a pharmaceutically acceptable carrier.
CA2423358A 2000-09-22 2001-09-21 Gamma-hydroxybutyrate compositions containing carbohydrate, lipid or amino acid carriers Expired - Fee Related CA2423358C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US23472000P 2000-09-22 2000-09-22
US60/234,720 2000-09-22
PCT/US2001/029569 WO2002024715A2 (en) 2000-09-22 2001-09-21 Gamma-hydroxybutyrate compositions containing carbohydrate, lipid or amino acid carriers

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CA2423358A1 true CA2423358A1 (en) 2002-03-28
CA2423358C CA2423358C (en) 2011-05-17

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US (4) US7015200B2 (en)
EP (1) EP1325014B1 (en)
JP (2) JP2004509900A (en)
AU (1) AU2001291173A1 (en)
CA (1) CA2423358C (en)
ES (1) ES2383673T3 (en)
WO (1) WO2002024715A2 (en)

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