Physical and chemical properties of thyroid hormone organic acid addition salts
First Claim
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1. A pharmaceutical composition comprising the salt of a thyroid hormone selected from the group consisting of levothyroxine and liothyronine and an organic acid comprising at least one aromatic ring having at least one hydroxyl moiety and at least one carboxylic acid moiety in an ortho relationship.
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Abstract
A pharmaceutical composition comprising the salt of a thyroid hormone selected from the group consisting of levothyroxine and liothyronine and an organic acid comprising at least one aromatic ring having at least one hydroxyl moiety and at least one carboxylic acid moiety in an ortho relationship.
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Citations
167 Claims
- 1. A pharmaceutical composition comprising the salt of a thyroid hormone selected from the group consisting of levothyroxine and liothyronine and an organic acid comprising at least one aromatic ring having at least one hydroxyl moiety and at least one carboxylic acid moiety in an ortho relationship.
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29. A method of administering a thyroid hormone comprising:
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forming a drug substance comprising a salt of a thyroid hormone selected from the group consisting of levothyroxine and liothyronine and an organic acid comprising at least one aromatic ring having at least one hydroxyl moiety and at least one carboxylic acid moiety in an ortho relationship; incorporating said drug substance into a drug product wherein said drug product has 25-300 μ
g of said thyroid hormone and a molar ratio of said thyroid hormone to said organic acid of at least 0.9;
1 to no more than 2.1;
1; andadministering said drug product to a patient. - View Dependent Claims (35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48)
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30. A method of manufacturing a stable drug substance as a thyroid treatment comprising:
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combining a thyroid hormone with a predetermined first stoichiometric ratio of an organic acid comprising at least one aromatic ring having at least one hydroxyl moiety and at least one carboxylic acid moiety in an ortho relationship thereby forming a thyroid hormone salt; storing said thyroid hormone salt for a predetermined time thereby forming an aged drug substance; and determining a second stoichiometric ratio of said thyroid hormone and said organic acid in said aged drug substance. - View Dependent Claims (49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84)
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31. A method of manufacturing a drug product as a thyroid treatment comprising:
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combining a thyroid hormone with a predetermined first stoichiometric ratio of organic acid comprising at least one aromatic ring having at least one hydroxyl moiety and at least one carboxylic acid moiety, both in an ortho or vicinal relationship thereby forming a thyroid hormone salt; forming a drug product comprising said thyroid hormone salt; storing said drug product for a predetermined time thereby forming an aged drug product; and determining a second stoichiometric ratio of said thyroid hormone and said organic acid salt in said aged drug product. - View Dependent Claims (85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119)
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32. A process for the preparation of an organic acid salt of a thyroid hormone comprising the steps of:
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a) preparing a first mixture comprising an alkali earth salt, free base or mineral acid salt of said thyroid hormone; b) preparing an organic acid mixture wherein said organic acid comprises at least one aromatic ring substituted with at least one hydroxyl group and at least one carboxyl group in an ortho relationship to one another, c) combining said first mixture and said organic acid mixture wherein said thyroid hormone and said aromatic acid form said organic acid salt of a thyroid hormone; d) isolating said organic acid salt of a thyroid hormone by at least one method selected from filtration, centrifugation and solvent evaporation; and e) purifying said organic acid salt of a thyroid hormone by at least one method selected from recrystallization, digestion and chromatographic separation. - View Dependent Claims (120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137)
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33. A process for the preparation of a purified thyroid hormone comprising the steps of:
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obtaining a first mixture comprising at least one thyroid hormone selected from liothyronine and levothyroxine; reacting said first mixture with an organic acid wherein said organic acid comprises at least one aromatic ring substituted with at least one hydroxyl group and at least one carboxyl group in an ortho relationship to one another thereby forming an organic acid salt of said thyroid hormone. - View Dependent Claims (138, 139, 140)
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- 34. A pharmaceutical composition comprising the salt of a thyroid hormone selected from the group consisting of levothyroxine and liothyronine and a stoichiometric amount of an organic acid comprising at least one aromatic ring having at least one hydroxyl moiety and at least one carboxylic acid moiety in an ortho relationship wherein said salt is stable for at least one year to variations in at least one of water content, heat, light, oxidative conditions and pH changes as indicated by said stoichiometric amount varying by less than 5% as measured by chromatographic techniques.
Specification