Compositions for delivery of a cortisol antagonist

• US 20020055512A1
• Filed: 03/16/2001
• Published: 05/09/2002
• Est. Priority Date: 01/21/2000
• Status: Abandoned Application

• Current Assignee: Cortendo AB (Xeris Biopharma Holdings, Inc.)
• Original Assignee: Cortendo AB (Xeris Biopharma Holdings, Inc.)
• Inventors: Marin, Per, Landh, Tomas, Ostholm, Ivan
• Application Number:
  US09/809,979
• Publication Number:
  US 20020055512A1
• Time in Patent Office: Days
• US Class Current: 514/254.07
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/03 aromatic
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/245 Amino benzoic acid types, e.g. procaine, novocaine salicylic acid esters A61K31/60
• CPC Class Codes: A61K 31/375 Ascorbic acid, i.e. vitamin C; Salts thereof
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• CPC Class Codes: A61K 31/4166 having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
• CPC Class Codes: A61K 31/4168 having a nitrogen attached in position 2, e.g. clonidine
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/451 having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/567 substituted in position 17 alpha, e.g. mestranol, norethandrolone
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• 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 47/24 containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/4858 Organic compounds

Abstract

The present invention relates to compositions for controlled release of a cortisol antagonist comprising at least one release rate controlling substance together with said cortisol antagonist and methods of preventing or treating metabolic syndrome, diabetes mellitis type II or symptoms or complications thereof in a mammal, which method comprises administering such a composition to said mammal in an amount effective to treat one or more of the clinical manifestations of metabolic syndrome or diabetes mellitis type II as well as complications thereof.

Claims

1. A composition for controlled release of a cortisol antagonist comprising at least one release rate controlling substance together with said cortisol antagonist.

2. A composition as claim 1 wherein the cortisol antagonist is selected from the group comprising sodium valporate, an enkephalin, an opioid, Clonidine, oxytocin, mifepristone, ketoconacole, aminogluthetimide, metyrapone, etomidate, trilostane, mitotane, Trilostan, phenyltoin, procaine, vitamin C, a salicylate, cimetidine, lidocaine and analogues and functionally equivalent derivatives thereof.

3. A composition as claimed in claim 1 wherein the cortisol antagonist is a compound of formula (I)

4. A composition as claimed in claim 1 wherein the cortisol antagonist is ketoconazole.

5. A composition as claimed in claim 1 wherein the cortisol antagonist is a cortisol synthesis inhibitor.

6. A composition as claimed in claim 1 which provides an in vitro release of cortisol antagonist which is sustained for at least 2 hours.

7. A composition as claimed in claim 6 which provides an in vitro release of cortisol antagonist which is sustained for at least 4 hours.

8. A composition as claimed in claim 1 which provides an in vivo uptake of cortisol antagonist which is sustained for at least 2 hours.

9. A composition as claimed in claim 8 which provides an in vivo uptake of cortisol antagonist which is sustained for at least 4 hours.

10. A composition as claimed in claim 4 wherein the composition provides circulating plasma levels of ketoconazole in excess of 200 ng/ml for at least 4 hours.

11. A composition as claimed in claim 1 wherein circulating plasma levels of cortisol antagonist do not reach pharmaceutically effective levels until more than 30 mins after administration of said composition to a patient.

12. A composition as claimed in claim 1 wherein at least one of the release rate controlling substances is a solid, semi-solid, amorphous, liquid crystalline or liquid matrix, preferably a solid or semi-solid matrix, in which the cortisol antagonist is dispersed.

13. A composition as claimed in claim 1 wherein at least one of the release rate controlling substances is a lipid.

14. A composition as claimed in claim 13 wherein the lipid is a polar lipid.

15. A composition as claimed in claim 1 wherein the release rate controlling substances is a fatty acid ester wherein the fatty acid component is a saturated or unsaturated fatty acid having between 6 and 26 carbon atoms.

16. A composition as claimed in claim 15 wherein the fatty acid component is selected from the group comprising palmitoleic acid, oleic acid, linoleic acid, linolenic acid and arachidonic acid.

17. A composition as claimed in claim 15 wherein the fatty acid ester is formed between a polyhydric alcohol selected from the group comprising glycerol, 1, 2-propanediol, 1, 3-propanediol, diacylgalactosylglycerol, diacyldigalactosylglycerol, erythritol, xylitol, adonitol, arabitol, mannitol, and sorbitol and a fatty acid.

18. A composition as claimed in claim 15 wherein the fatty acid ester is formed between a hydroxycarboxylic acid selected from the group comprising malic acid, tartaric acid, citric acid, and lactic acid and a fatty acid.

19. A composition as claimed in claim 15 wherein the hydroxy-containing component of the fatty acid ester is a saccharide selected from the group comprising glucose, mannose, fructose, threose, gluose, arabinose, ribose, erythrose, lyxose, galactose, sorbose, altrose, tallose, idose, rhamnose and allose or a glycerylphosphate derivative selected from the group comprising phosphatidic acid, phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, phosphatidylglycerol, phosphatidylinositole, and diphosphatidylglycerol.

20. A composition as claimed in claim 1 wherein at least one of the release rate controlling substances is a fatty acid ester selected from the group comprising dioleyol phosphatidyl-cholin, dilauryl phosphatidylcholin, dimyristyl phosphatidylcholin, dipalmitoyl phosphatidylcholin, distearoyl phosphatidylcholin, dibehenoyl phosphatidylcholin, dimyristyl phosphatidylethanolamine, dipalmitoyl phosphatidylethanolsmine, dioleyl phosphatidylglycerol, dilauryl phosphatidylglycerol, dimyristoyl phosphatidylycerol, dipalmitoyl phosphatidylglycerol, distearoyl phosphatidylglycerol, dipalmitoyl phosphatic acid and mixtures thereof.

21. A composition as claimed in claim 1 wherein at least one of the release rate controlling substances is a mono- or di-glyceride.

22. A composition as claimed in claim 21 wherein at least one of the release rate controlling substances is selected from the group comprising glycerol dioleate, glyceryl monooleate and glyceryl monolinoleate.

23. A composition as claimed in claim 1 wherein at lease one of the release rate controlling substances is a polymer.

24. A composition as claimed in claim 23 wherein the polymer is selected from the group comprising alginates, polyacrylic acids (carbopols), chitosan, carboxyvinyl polymers, cellulose and cellulose derivatives such as hydroxypropyl methylcellulose, calcium or sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose and starch and derivatives thereof.

25. A composition as claimed in claim 1 which comprises, as release rate controlling substances a mixture of a fatty acid ester, oleic acid or sesame oil and/or a cellulose based polymer.

26. A composition as claimed claim 1 which is adapted for oral administration to a mammal, particularly a human.

27. A composition as claimed in claim 1 which retains a substantially unitary form on administration and thoughout the controlled release of the cortisol antagonist.

28. A method of antagonising or inhibiting cortisol activity in a mammal which method comprises administering a composition comprising at least one release rate controlling substance and a cortisol antagonist to said mammal in an amount effective to reduce production of cortisol or circulating livels of cortisol or limit the biological effects of cortisol.

29. A method of preventing or treating metabolic syndrome, diabetes mellitis type II or sysmptoms or complications thereof in a mammal, which method comprises administering a composition comprising at least one release rate controlling substance and a cortisol antagonist, to said mammal in an amount effective to treat one or more of the clinical manifestations of metabolic syndrome or diabetes mellitis type II or complications thereof.

30. A method of making a composition for controlled release of a cortisol antagonist, which method comprises mixing said cortisol antagonist with at least one release rate controlling substance.