Stabilised supersaturated solids of lipophilic drugs

• US 20050207990A1
• Filed: 03/10/2005
• Published: 09/22/2005
• Est. Priority Date: 03/10/2004
• Status: Active Grant

• Current Assignee: Bayer Intellectual Property GmbH (Bayer AG)
• Original Assignee: Bayer Intellectual Property GmbH (Bayer AG)
• Inventors: Funke, Adrian, Wagner, Torsten, Lipp, Ralph
• Granted Patent: US 8,715,735 B2
• Time in Patent Office: Days
• US Class Current: 424/46
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 31/585 containing lactone rings, e.g. oxandrolone, bufalin
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/44 Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61K 9/143 with inorganic compounds
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/24 of the sex hormones
• CPC Class Codes: A61P 5/30 Oestrogens
• CPC Class Codes: A61P 5/38 of the suprarenal hormones

Abstract

Methods for improving solubility and bioavailability of lipophilic compounds are described. Particularly, described are stabilized superstaturated solid solutions, particularly in power form, of lipophilic drugs, such as steroidal molecules.

Claims

1. A powdery composition comprising a steroidal molecule;

and amorphous silica having a specific surface area of at least 250 m²/g;

wherein the steroidal molecule is molecularly dispersed in a solvent.

2. The composition according to claim 1, wherein the steroidal molecule is selected from the group consisting of estradiol and esters thereof, ethinyl estradiol, conjugated estrogens, testosterone and esters thereof, cyproterone, drospirenone, etonogestrel, desogestrel, gestodene, levonorgestrel, norethisterones, norgestimate, norethindrone, norethindrone acetate, norethynodrel, norgestimate, norgestrel, medrogestone, medroxyprogesterone acetate, progesterone, spironolactones, eplerenone, canrenoate, canrenone, dicirenone, mexrenoate, prorenoate, epostane, mespirenone, oxprenoate, spirorenone, spiroxasone, prorenone, asoprisnil, beclomethasone dipropionate, betamethasone, betamethasone valerate, budesonide, clobetasol propionate, clobetasone butyrate, cortisone acetate, dexamethasone, fludrocortisone acetate, prednisolone, prednisone, alfacalcidol, calcifediol, calciferol and calcitriol.

3. The composition according to claim 2, wherein the steroidal molecule is drospirenone and/or estradiol valerate.

4. The composition according to claim 1, wherein the steroidal molecule is present in the solvent in a supersaturated concentration.

5. The composition according to claim 1, wherein the solvent is ethanol;

partial synthetic triglyceride;

or a vegetable oil.

13. A pharmaceutical dosage form in the form of granules, a tablet, a capsule, or a pill comprising the composition as defined in claim 1.

6. A process for the preparation of a powdery composition comprising a steroidal molecule, the process comprising the steps of

a) dissolving completely in a solvent a steroidal molecule in an amount that exceed the saturation concentration of the steroidal molecule in the solvent;

and

b) mixing the resulting supersaturated solution of step a) with amorphous silica having a specific surface area of at least 250 m²/g.

8. The process according to claim 6, wherein the steroidal molecule is selected from the group consisting of estradiol and esters thereof, ethinyl estradiol, conjugated estrogens, testosterone and esters thereof, cyproterone, drospirenone, etonogestrel, desogestrel, gestodene, levonorgestrel, norethisterones, norgestimate, norethindrone, norethindrone acetate, norethynodrel, norgestimate, norgestrel, medrogestone, medroxyprogesterone acetate, progesterone, spironolactones, eplerenone, canrenoate, canrenone, dicirenone, mexrenoate, prorenoate, epostane, mespirenone, oxprenoate, spirorenone, spiroxasone, prorenone, asoprisnil, beclomethasone dipropionate, betamethasone, betamethasone valerate, budesonide, clobetasol propionate, clobetasone butyrate, cortisone acetate, dexamethasone, fludrocortisone acetate, prednisolone, prednisone, alfacalcidol, calcifediol, calciferol and calcitriol.

9. The process according to claim 6, wherein the steroidal molecule is drospirenone and/or estradiol valerate.

10. The process according to claim 6, wherein the solvent is ethanol;

partial synthetic triglyceride;

or a vegetable oil.

11. The process according to claim 6, further comprising the step of evaporating off the solvent.

12. A powdery composition obtained by the process as defined in claim 6.

7. A process for the preparation of a powdery composition comprising a steroidal molecule, the process comprising the steps of

a) dissolving completely in a solvent a steroidal molecule in an amount that equals the saturation concentration of the steroidal molecule in the solvent;

and

b) mixing the resulting saturated solution of step a) with amorphous silica having a specific surface area of at least 250 m²/g; and

c) evaporating off a part of the solvent.

14. Use of amorphous silica with a specific surface area greater than 250 m²/g for inhibiting re-crystallisation of a steroidal molecule that is present in a solvent in a supersaturated concentration.