Pharmaceutical composition with improved bioavailability of inositol phosphate

• US 5,760,022 A
• Filed: 07/17/1996
• Issued: 06/02/1998
• Est. Priority Date: 01/25/1994
• Status: Expired due to Fees

• Current Assignee: Perstorp AB
• Original Assignee: Perstorp AB
• Inventors: Persson, Lars, Rehnberg, Nicola, Gustafsson, Torgny
• Primary Examiner(s): Cook, Rebecca
• Application Number:
  US08/676,238
• Time in Patent Office: 685 Days
• Field of Search: 514/103, 514/109, 514/143, 514/144, 514/148, 514/546, 514/547, 514/946
• US Class Current: 514/103
• CPC Class Codes: A61K 31/66 Phosphorus compounds
• CPC Class Codes: A61K 31/6615 Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The invention relates to an inositol phosphate containing pharmaceutical composition which comprises an aliphatic ester or ether for improvement of the bioavailability of the inositol phosphate in mammals including man at non-parenteral administration. The invention also covers the use of at least one aliphatic ester or ether compound for the preparing of an inositol phosphate containing medicament with improved bioavailability of inositol phosphate in mammals including man at non-parenteral administration.

Claims

1. A non-parenteral pharmaceutical composition which comprises a mixture of at least one inositol phosphate and an aliphatic ester or ether having the formula CH₂ OR₁ CHOR₂ CH₂ OR₃, in the amount effective to improve the bioavailability of said inositol phosphate wherein R₁, R₂ and R₃ independently are

i) hydrogen;

ii) a straight or branched alkyl having 1 to 15 carbon atoms;

iii) a cycloalkyl having 3 to 15 carbon atoms;

iv) an alkenyl having 2 to 14 carbon atoms;

v) a cycloalkenyl having 5 to 14 carbon atoms;

vi) a straight or branched acyl radical of a saturated aliphatic carboxylic acid having 1 to 15 carbon atoms;

vii) a straight or branched acyl radical of an unsaturated aliphatic carboxylic acid having 1 to 15 carbon atoms;

viii) an acyl radical of a saturated cyclic carboxylic acid or ix) an acyl radical of an unsaturated cyclic carboxylic acid,

wherein groups (ii) to (ix) are unsubstituted or substituted with hydroxy;

oxo;

alkoxy;

carboxy;

esterified carboxy;

amino;

acyloxy;

or acylamine.

2. A composition according to claim 1 wherein R₁, R₂ and R₃ are independently

hydrogen, or

a straight or branched acyl radical of a saturated aliphatic carboxylic acid having 1 to 15 carbon atoms.

3. A composition according to claim 2 wherein R₁ and R₂ are hydrogen and R₃ is a straight or branched acyl radical of a saturated aliphatic carboxylic acid having 1 to 15 carbon atoms.

4. A composition according to claim 1 wherein the inositol phosphate is at least one isomer of inositol triphosphate.

5. A composition according to claim 4 wherein said isomer of inositol triphosphate is D-myo-inositol-1,2,6-triphosphate.

6. A composition according to claim 4 wherein the inositol triphosphate is present in salt form.

7. A composition according to claim 5 wherein the inositol triphosphate is present in salt form.

8. A composition according to claim 5 in capsule, tablet or granulated form.

9. A composition according to claim 5 in a combined dosage form.

10. A composition according to claim 1 wherein R₁, R₂ and R₃ are independently methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, cyclopropyl, cyclopentyl, cyclohexyl, vinyl, allyl, propenyl, octadienyl, decenyl, dodecenyl, tetradecenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, pivaloyl, lauroyl, myristoyl, acryloyl, propiolyl, oleoyl, maleoyl, fumaroyl, citraconoyl, cyclopentanoyl or furoyl.

11. A composition according to claim 10 wherein R₁, R₂ and R₃ are independently hydrogen, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, pivaloyl, lauroyl or myristoyl.

12. A composition in accordance with claim 3 wherein R₃ is formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, pivaloyl, lauroyl or myristoyl.

13. A composition according to claim 12 wherein R₁ and R₂ are hydrogen and R₃ is octanoyl.

14. A non-parenteral pharmaceutical composition which comprises a mixture of at least one inositol phosphate and an aliphatic ester having the formula R₄ COOR₅, in an amount effective to improve the bioavailability of said inositol phosphate, wherein R₄ is

i) hydrogen;

ii) a straight or branched alkyl having 1 to 15 carbon atoms;

iii) a cycloalkyl having 3 to 15 carbon atoms;

or

iv) an alkenyl with 2 to 14 carbon atoms,

wherein groups (ii) to (iv) are unsubstituted or substituted with hydroxy;

oxo;

alkoxy;

carboxy;

esterified carboxy;

amino;

acyloxy or acylamine; and

R₅ is R₄ or a cation.

15. A composition in accordance with claim 14 wherein R₄ is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, cyclopropyl, cyclopentyl, cyclohexyl, vinyl, allyl, propenyl, octadienyl, decenyl, dodecenyl or tetradecenyl, with the proviso that, except for hydrogen, the above meanings of R₄ are unsubstituted or substituted with hydroxy, oxo, alkoxy, carboxy, esterified carboxy, amino, acyloxy or acylamine;

and R₅ is R₄, sodium or potassium.

16. A composition in accordance with claim 14 wherein the inositol phosphate is at least one specific isomer of inositol triphosphate.

17. A composition according to claim 15 wherein the inositol phosphate is at least one specific isomer of inositol triphosphate.

18. A composition according to claim 16 wherein the inositol triphosphate is D-myo-inositol-1,2,6-triphosphate.

19. A composition according to claim 17 wherein the inositol triphosphate is D-myo-inositol-1,2,6-triphosphate.

20. A composition according to claim 17 wherein the inositol triphosphate is present in salt form.

21. A composition according to claim 19 in capsule, tablet or granulated form.