Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1996-07-17
1998-06-02
Cook, Rebecca
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
514109, 514143, 514144, 514148, 514546, 514547, 514946, A61K 3166
Patent
active
057600228
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/SE95/00064 filed Jan. 24, 1995.
The present invention relates to an inositol phosphate containing pharmaceutical composition with improved bioavailability of inositol phosphate and the use of at least one aliphatic ester or ether compound with the formula I or II below for the preparing of an inositol phosphate containing medicament with improved bioavailability of inositol phosphate at non-parenteral administration.
Hydrophilic and ionized drugs most often encounter rather poor penetration of the epithelial barriers to the capillaries of the portal circulation as most of this type of substances are transported by passive diffusion. Inositol phosphates belong to this group.
Normally it is the unionized fraction of the drug that partition across the lipid membranes and this fraction is most often small over the pH-range encountered in the gastrointestinal tract.
It is known from the literature, for example M. Sekine et al., (1984), J.Pharm. Dyn. 7, 856-863 that a combination of specific glyceryl-containing compounds and some antibiotics render an improved absorption of the antibiotic after rectal administration. However the amount of the glyceryl containing compound is very high resulting in an inconvienient formulation with potential side effects.
Nothing has been described in the literature about the use of an aliphatic ester or ether compound with formula I or II together with inositol phosphate for improvement of the bioavailability of the inositol phosphate.
At oral administration the properties of inositol phosphates per se result in limitations in respect of the uptake of the compounds from the intestine. In order to optimize the effect of these substances in the body it is desirable that as large a portion as possible of the added amount can be utilized effectively. Thereby the added amount can be reduced which is advantageous for the patient for example when the drug D-myo-inositol-1,2,6-trisphosphate (IP.sub.3) is used.
According to the present invention it has now quite surprisingly been possible to meet the above desire and bring about an inositol phosphate containing pharmaceutical composition which comprises an aliphatic ester or ether compound with formula I or II below for improvement of the bioavailability of the inositol phosphate in mammals including man at non-parenteral administration.
The expression bioavailability stands for the measurement of how large a portion of an administered drug that occurs in the blood stream when the way of administration of the drug is non-parenteral. The term thus shows the amount of the drug that has been able to penetrate membrane barriers after for example oral administration. topical administration or intraperitoneal administration.
The aliphatic ester or ether compound with 3 to 18 carbon atoms can be defined by the formula I.
CH.sub.2 OR.sub.1 CHOR.sub.2 CH.sub.2 OR.sub.3 wherein R.sub.1 R.sub.2 and/or R.sub.3 independently are ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and pentadecyl; cyclopentyl and/or cyclohexyl; octadienyl, decenyl, dodecenyl and/or tetradecenyl; cyclopentadienyl, cyclohexenyl and/or cyclohexadienyl; acid with 1 to 15 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, pivaloyl, lauroyl and/or myristoyl; carboxylic acid with 1 to 15 carbon atoms such as acryloyl, propiolyl, oleoyl, maleoyl, fumaroyl and/or citraconoyl; cyclopentanoyl or furoyl.
The above groups (ii) to (ix) are unsubstituted or substituted with hydroxy; oxo; alkoxy; carboxy; esterified carboxy; amine, substituted amine; acyloxy or acylamine.
In one preferred embodiment of the invention where a compound with formula I is used R.sub.1 and R.sub.2 are propyl, butyl, pentyl, hexyl, heptyl and/or octyl
and R.sub.3 is octyl and/or decyl or acid with 1 to 15 carbon atoms such as butanoyl, hexanoyl, octanoyl and/or decanoyl.
Preferred compounds in this group are 1,2-dihydroxy-propylbutanoate, 2,3-dihydroxypropylbu
REFERENCES:
patent: 4969611 (1990-11-01), Katagiri et al.
patent: 4997761 (1991-03-01), Jett-Tilton
patent: 5082833 (1992-01-01), Shamsuddin
Chemical Abstracts, vol. 102, No. 1, Abstract No. 6465b, published Jan. 7, 1985.
Sekine et al., "Improvement of Bioavailability of Poorly Absorbed Drugs. I. Effect of Medium Chain Glyceride Base on the Rectal Absorption of Cefmetazole Sodium in Rats", J. Pharm. Dyn. 7:856-863 (1984).
Li et al., Synergistic Activation of Retinal Capillary Pericyte Proliferation in Culture by Inositol Triphosphate and Diacylglycerol, Exp. Eye Res., 44:29-35 (1987).
Gustafsson Torgny
Persson Lars
Rehnberg Nicola
Cook Rebecca
Perstorp AB
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