Pharmaceutical composition with improved bioavailability of inositol phosphate

• US 5,614,510 A
• Filed: 08/22/1994
• Issued: 03/25/1997
• Est. Priority Date: 02/25/1992
• Status: Expired due to Fees

• Current Assignee: Perstorp AB
• Original Assignee: Perstorp AB
• Inventors: Persson, Lars
• Primary Examiner(s): Kumar, Shailendra
• Application Number:
  US08/290,914
• Time in Patent Office: 946 Days
• Field of Search: 536/26.74, 536/27.8, 514/23, 514/103, 514/104, 514/109, 514/554, 514/555, 514/556, 514/642, 514/643, 558/155
• US Class Current: 514/103
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/205 Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
• CPC Class Codes: A61K 31/66 Phosphorus compounds
• CPC Class Codes: A61K 31/685 one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin

Abstract

The invention relates to an inositol phosphate containing pharmaceutical composition which comprises a nitrogen-containing compound 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 nitrogen-containing compound for the preparing of an inositol phosphate containing medicament with improved bioavailibility of inositol phosphate in mammals including man at non-parenteral administration.

Claims

1. An inositol phosphate containing pharmaceutical composition comprising an ion-pair structure obtained by combining an inositol phosphate with a compound of the formula ⁺ N(R₁ R₂ R₃)R₅ wherein R₁, R₂ and R₃ are independently

i) hydrogen

ii) a straight or branched alkyl with 1 to 24 carbon atoms,

iii) cycloalkyl with 3 to 16 carbon atoms,

iv) alkenyl, with 2 to 24 carbon atoms,

v) cycloalkenyl with 5 to 16 carbon atoms,

vi) aryl with 6 to 24 carbon atoms or

vii) aralkyl, alkaryl, aralkenyl, alkenaryl wherein alkyl, aryl and alkenyl are as previously defined,

the above groups (ii) to (vii) being unsubstituted or substituted with hydroxy, oxo, alkoxy, aryloxy, carboxy, esterified carboxy, amino, substituted amino, formyl, acyl, aryloxy or acylamine and R₅ is

i) --(CH₂)_n OCOR₆ wherein n≧

2 and wherein R₆ is

(1) a straight or branched alkyl with 1 to 24 carbon atoms,

(2) alkenyl with 2 to 24 carbon atoms or

(3) --CH₂ CH(CH₃)OCOR₁, --CH(CH₃)CH₂ OCOR₁, --CH₂ CH(OCOR₁)CH₂ OCOR₁, --CH(CH₂ OCOR₁)₂, --CH₂ CH(OH)CH₂ OCOR₁, --CH₂ CH(CH₂ OH)OCOR₁, --CH(CH₂ OH)CH₂ OCOR₁ or --CH(CH₃)COOR₁ wherein R₁ is as defined above,

ii) --(CH₂)_n OR₆ wherein n and R₆ are as defined above

iii) --(C(R₇)₂)_n COOR₆ wherein n≧

1 and wherein R₆ is as defined above and wherein R₇ is

(1) hydrogen, or

(2) methyl, ethyl, propyl, butyl or pentyl

iv) --C(R₇)₂ OCOR₆ wherein R₆ and R₇ are as defined above,

for improvement of the bioavailability of the inositol phosphate in a mammal at non-parenteral administration.

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

i) hydrogen or

ii) a straight or branched alkyl selected from the group of methyl, ethyl, propyl, butyl, pentyl, hexyl and/or octyl;

and wherein R₅ is --(CH₂)OCOR₆ wherein R₆ is selected from hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tridecyl, tetradecyl, pentadecyl and/or hexadecyl.

3. A composition according to claim 1 wherein R₁, R₂ and/or R₃ are

i) hydrogen or

ii) a straight or branched alkyl selected from the group of methyl, ethyl, propyl, butyl, pentyl, hexyl, hepty and/or octyl;

and wherein R₅ is --(CH₂)₂ OR₆ wherein R₆ is selected from the group of hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tridecyl, tetradecyl, pentadecyl and/or hexadecyl.

4. A composition according to claim 1 wherein R₁, R₂ and/or R₃ are

i) hydrogen or

ii) a straight or branched alkyl selected from the group of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and/or octyl;

and wherein R₅ is --C(R₇)₂ COOR₆ wherein R₆ is selected from the group of hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tridecyl, tetradecyl, pentadecyl and/or hexadecyl and wherein R₇ is

i) hydrogen or

ii) a straight or branched alkyl selected from the group of methyl, ethyl, propyl and/or butyl.

5. A composition according to claim 1 wherein R₁, R₂ and/or R₃ are

i) hydrogen or

ii) a straight or branched alkyl selected from the group of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and/or octyl;

and wherein R₅ is --C(R₇)₂ COOR₆ wherein R₆ is selected from the group of hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tridecyl, tetradecyl, pentadecyl and/or hexadecyl and wherein R₇ is

i) hydrogen or

ii) a straight or branched alkyl selected from the group of methyl, ethyl, propyl and/or butyl.

6. A composition according to any one of claims 1-5, wherein the inositol phosphate is at least one specific isomer of inositoltriphosphate (IP₃).

7. A composition according to claim 6, wherein the isomer of IP₃ is D-myo-inositol-1,2,6-triphosphate.

8. A composition according to any one of claims 1-7 in capsule, tablet or granulated form.

9. A composition according to any one of claims 1-7 in a combined dosage form.

13. The inositol phosphate according to claim 1 wherein R₁, R₂ and R₃ are independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, eicosyl, docosyl, cyclopropyl, cyclopentyl, cyclohexyl, vinyl , allyl, propenyl, octadienyl, octenyl, decenyl, dodecenyl, tetradecenyl, hexadecenyl, octadecenyl, octadecadienyl, nonadecenyl, octadecatrienyl, arachidonyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, phenyl, biphenyl, aralkyl, alkaryl, aralkenyl or alkenaryl, said R₁, R₂ and R₃ being unsubstituted or substituted with hydroxy, oxo, alkoxy, aryloxy, carboxy, esterified carboxy, amino, substituted amino, formyl, acyl, aryloxy or acylamine.

14. The inositol phosphate according to claim 1 wherein R₆ is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, eicosyl, docosyl, vinyl, allyl, propenyl, octadienyl, octenyl, decenyl, dodecenyl, tetradecenyl, hexadecenyl, octadecenyl, octadecadienyl, nonadecenyl, octadecatrienyl, arachidonyl, --CH₂ CH(CH₃)OCOR₁, --CH(CH₃)CH₂ OCOR₁, --CH₂ CH(OCOR₁)CH₂ OCOR₁, --CH(CH₂ OCOR₁)₂, --CH₂ CH(OH)CH₂ OCOR₁, --CH₂ CH(CH₂ OH)OCOR₁, --CH(CH₂ OH)CH₂ OCOR₁ or --CH(CH₃)COOR₁.

10. A method for improving bioavailability in a mammal of an inositol phosphate, comprising administering to said mammal an ion-pair structure obtained by combining an inositol phosphate with a compound of the formula ⁺ N(R₁ R₂ R₃)R₅ wherein R₁, R₂ and R₃ are independently

i) hydrogen

ii) a straight or branched alkyl with 1 to 24 carbon atoms,

iii) cycloalkyl with 3 to 16 carbon atoms,

iv) alkenyl, with 2 to 24 carbon atoms

v) cycloalkenyl with 5 to 16 carbon atoms,

vi) aryl with 6 to 24 carbon atoms or

vii) aralkyl, alkaryl, aralkenyl, alkenaryl wherein alkyl, aryl and alkenyl are as previously defined,

the above groups (ii) to (vii) being unsubstituted or substituted with hydroxy, oxo, alkoxy, aryloxy, carboxy, esterified carboxy, amino, substituted amino, formyl, acyl, aryloxy or acylamine and

R₅ is

i) --(CH₂)_n OCOR₆ wherein n≧

2 and wherein R₆ is

(1) a straight or branched alkyl with 1 to 24 carbon atoms,

(2) alkenyl with 2 to 24 carbon atoms or

(3) --CH₂ CH(CH₃)OCOR₁, --CH(CH₃)CH₂ OCOR₁, --CH₂ CH(OCOR₁)CH₂ OCOR₁, --CH(CH₂ OCOR₁)₂, --CH₂ CH(OH)CH₂ OCOR₁, --CH₂ CH(CH₂ OH)OCOR₁, --CH(CH₂ OH)CH₂ OCOR₁ or --CH(CH₃)COOR₁ wherein R₁ is as defined above,

ii) --(CH₂)_n OR₆ wherein n and R₆ are as defined above,

iii) --(C(R₇)₂)_n COOR₆ wherein n≧

1 and wherein R₆ is as defined above and wherein R₇ is

(1) hydrogen or

(2) methyl, ethyl, propyl, butyl or pentyl or

iv) --C(R₇)₂ OCOR₆ wherein R₆ and R₇ are as defined above.

11. The method according to claim 10, wherein the inositol phosphate is an isomer of inositoltriphosphate.

12. The method according to claim 11, wherein the isomer of inositoltriphosphate is D-myo-inositol-1,2,6-tris-phosphate.

15. The method according to claim 10 wherein R₁, R₂ and R₃ are independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, eicosyl, docosyl, cyclopropyl, cyclopentyl, cyclohexyl, vinyl, allyl, propenyl, octadienyl, octenyl, decenyl, dodecenyl, tetradecenyl, hexadecenyl, octadecenyl, octadecadienyl, nonadecenyl, octadecatrienyl, arachidonyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, phenyl, biphenyl, aralkyl, alkaryl, aralkenyl or alkenaryl, said R₁, R₂ and R₃ being unsubstituted or substituted with hydroxy, oxo, alkoxy, aryloxy, carboxy, esterified carboxy amino, substituted amino, formyl, acyl, aryloxy or acylamine.

16. The method according to claim 10 wherein R₆ is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, eicosyl, docosyl, vinyl , allyl, propenyl, octadienyl, octenyl, decenyl, dodecenyl, tetradecenyl, hexadecenyl, octadecenyl, octadecadienyl, nonadecenyl, octadecatrienyl, arachidonyl, --CH₂ CH(CH₃)OCOR₁, --CH(CH₃)CH₂ OCOR₁, --CH₂ CH(OCOR₁)CH₂ OCOR₁, --CH(CH₂ OCOR₁)₂, --CH₂ CH(OH)CH₂ OCOR₁, --CH₂ CH(CH₂ OH)OCOR₁, --CH(CH₂ OH)CH₂ OCOR₁ or --CH(CH₃)COOR₁.