Cocrystalline DHEA formulations

Patent metadata

Field	Value
Publication number	US-10130713-B2
Application number	US-201414257594-A
Country	US
Kind code	B2
Filing date	Apr 21, 2014
Priority date	Apr 19, 2013
Publication date	Nov 20, 2018
Grant date	Nov 20, 2018

Abstract

A cocrystalline DHEA composition with at least one additional coformer is disclosed for therapeutic formulations. The cocrystalline DHEA/coformer formulation including at least one coformer chosen from the group consisting of glutaric acid, maleic acid, tartaric acid, fructose, and wherein the L-isomer of tartaric acid and the D-isomer of fructose are utilized. The cocrystalline DHEA/coformer formulations include certain excipients as a solubilizer or inhibitor.

First claim

What is claimed is:

1. A composition formulated to produce a supersaturated intestinal solution, said composition comprising:
dehydroepiandrosterone (DHEA), wherein the DHEA is a polymorph form I (FI) or polymorph form II (FII); and
a crystalline coformer selected from the group consisting of fructose and maleic acid, wherein the DHEA and the coformer are in an approximately 1:1 molar stoichiometric ratio; and wherein said supersaturated intestinal solution is maintained at between 50 micrograms/ml and 236 micrograms/ml for between 60 minutes and 240 minutes.

2. The composition of claim 1 , wherein the DHEA and the coformer form a cocrystalline formulation.

3. The composition of claim 2 , wherein the cocrystalline formulation dissolves in an aqueous solution.

4. The composition of claim 3 , wherein the cocrystalline formulation dissolves to form a supersaturated aqueous solution.

5. The composition of claim 1 , wherein the composition further comprises at least one excipient.

6. The composition of claim 5 , wherein the excipient is selected from the group consisting of polyethylene glycol (PEG), poly-vinylpyrrolidone (PVP), vinylpyrrolidone vinylacetate copolymer (PLASDONE™ S-630) and polyoxyethylene-sorbitan-mono-oleate ester (POLYSORBATE 80).

7. A cocrystalline composition comprising
dehydroepiandrosterone (DHEA); wherein the DHEA is a polymorph form I (FI) or polymorph form II (FII); and
a coformer selected from the group consisting of fructose and maleic acid, wherein the DHEA and the coformer are in an approximately 1:1 molar stoichiometric ratio; and
an excipient, wherein said cocrystalline composition is about three times more soluble in an intestinal fluid than DHEA itself.

8. The composition of claim 7 , wherein the excipient is selected from the group consisting of polyethylene glycol (PEG), poly-vinylpyrrolidone (PVP), vinylpyrrolidonevinylacetate copolymer (PLASDONE™ S-630), and polyoxyethylene-sorbitan-mono-oleate ester (POLYSORBATE 80).

9. The composition of claim 7 , wherein the excipient has a concentration of less than about 10% by weight.

10. A method for treating a neurological disease in a patient comprising:
identifying a neurological disease symptom in the patient;
determining the patient's tolerance to at least one crystalline coformer, wherein the coformer is selected from the group consisting of fructose and maleic acid;
providing the patient a cocrystalline formulation comprising DHEA, and the at least one coformer,
wherein said cocrystalline formulation forms a supersaturated intestinal solution;
wherein the supersaturated solution contains DHEA at between 50 and 236 micrograms/ml for between 60 and 240 minutes;
analyzing a response by the patient to the formulation; and
adjusting the cocrystalline formulation according to the patient's response.

11. The method of claim 10 , wherein the cocrystalline formulation further comprises an excipient.

12. The method of claim 11 , wherein the excipient is at least one chosen from the group consisting of polyethylene glycol (PEG), poly-vinylpyrrolidone (PVP), vinylpyrrolidone-vinylacetate copolymer (PLASDONE™ S-630), and polyoxyethylene-sorbitan-mono-oleate ester (POLYSORBATE 80).

13. A composition comprising:
a cocrystal, wherein the cocrystal comprises:
dehydroepiandrosterone (DHEA), wherein the DHEA is a polymorph form I (FI) or polymorph form II (FII); and
a coformer, wherein the coformer is selected from the group consisting of fructose and maleic acid, wherein the DHEA and the coformer are in an approximately 1:1 molar stoichiometric ratio; and wherein said cocrystal is about three times more intestinal soluble than DHEA itself.

14. A composition formulated to delay recrystallization of dehydroepiandrosterone (DHEA) from an aqueous intestinal solution, wherein said composition comprises:
dehydroepiandrosterone (DHEA) polymorph form I (FI); and a maleic acid cocrystal, wherein the DHEA and the maleic acid cocrystal are in approximately a 1:1 molar stoichiometric ratio, and wherein said aqueous intestinal solution is at a concentration of between 50 and 148 micrograms/ml for about 60 minutes prior to recrystallization.

15. A composition formulated to delay recrystallization of dehydroepiandrosterone (DHEA) polymorph form I (FI) from an aqueous intestinal solution wherein said composition comprises:
dehydroepiandrosterone (DHEA) polymorph form I (FI); and a crystalline coformer, wherein the coformer is fructose, and said conformer and the DHEA are in approximately a 1:1 molar stoichiometric ratio, and wherein said aqueous intestinal solution is at a concentration of between 50 and 236 micrograms/ml for about 60 minutes prior to recrystallization.

Assignees

• Univ Houston System
• Methodist Hospital

Inventors

• Berkenstam Anders
• Kuczynski Edward
• Andersson Alf S
• Gustafsson Jan-Ake
• Filgueira Carly Sue

Classifications

• C07C55/12

  Glutaric acid · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61K47/549

  Sugars, nucleosides, nucleotides or nucleic acids · CPC title

• C07C59/255

  Tartaric acid · CPC title

• A61K47/542 Primary

  Carboxylic acids, e.g. a fatty acid or an amino acid · CPC title