3,5,3′-triiodothyronine sulfate as thyromimetic agent and pharmaceutical formulations thereof

• US 9,468,619 B2
• Filed: 06/13/2013
• Issued: 10/18/2016
• Est. Priority Date: 11/13/2002
• Status: Active Grant

• Current Assignee: Bracco SPA
• Original Assignee: Bracco SPA
• Inventors: Pinchera, Aldo, Cavalieri, Livio, Maisano, Federico, Rivolta, Giovanni, Santini, Ferruccio, Vella, Fulvia
• Primary Examiner(s): Klinkel, Kortney L
• Application Number:
  US13/916,710
• Publication Number:
  US 20130281536A1
• Time in Patent Office: 1,223 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/197 the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid carnitine A61K31/205
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/28 Compounds containing heavy metals
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: G01N 21/76 Chemiluminescence; Bioluminescence
• CPC Class Codes: G01N 33/561 Immunoelectrophoresis
• CPC Class Codes: G01N 33/78 Thyroid gland hormones , e.g. T3, T4, TBH, TBG or their receptors

Abstract

The invention regards the use of triiodothyronine sulfate, commonly named T₃S, as a medicament having thyromimetic activity for the treatment of pathologies due to organic deficiency of triiodothyronine (T₃), as such or in association with thyroxine (T₄), and pharmaceutical formulations for oral administration thereof.

Claims

1. A stable solid oral dosage composition comprising T₃S as the active principle, in a quantity ranging from 1 to 1000 μ

g further comprising;

a) a diluent present at an amount from 50% to 99.99% by weight consisting of;

at least one alkaline inorganic salt selected from the group consisting of;

trisodium phosphate, tri-calcium phosphate, calcium sulphate, calcium carbonate and magnesium carbonate, wherein said alkaline inorganic salt is present at an amount up to 35% of the total diluent w/w and

microcrystalline cellulose of the alpha type;

b) at least one disintegrant selected from the group consisting of;

croscarmellose or salts thereof, crospovidone or salts thereof, polymethacrylates and maltodextrin or salts thereof;

c) at least one glidant selected from the group consisting of;

glycerol dibehenate silica derivatives, talc, and magnesium trisilicate; and

d) at least one lubricant selected from the group consisting of silicates, hydrate silicon dioxide, hydrate colloidal silica;

magnesium stearate; and

zinc stearate.

2. The solid dosage of claim 1 wherein the alkaline inorganic salt is calcium carbonate or magnesium carbonate.

3. The solid dosage of claim 2 wherein the alkaline inorganic salt is calcium carbonate.

4. The solid dosage of claim 1 wherein the disintegrant is croscarmellose or salts thereof.

5. The solid dosage of claim 1 wherein the glidant is glycerol dibehenate.

6. The solid dosage of claim 1 wherein the glidant is glycerol dibehenate, the disintegrant is croscarmellose sodium salt, and the lubricant is hydrate colloidal silica and magnesium stearate.

7. The solid dosage of claim 1 in the form of a tablet.

8. The solid dosage of claim 1 wherein T₃S is in a quantity from 2.5 to 500 μ

g.

9. The solid dosage of claim 8 comprising T₃S in a range from 5-250 μ

g.

10. The solid dosage of claim 9 further comprising T₄ in a quantity from 5-400 μ

g.

11. The solid dosage of claim 1 administered as a daily dose.

13. The solid dosage of any one of claim 1 or 12 further comprising T₄ (thyroxine).

15. A kit comprising a container for a solid oral dosage composition according to claim 1 and, optionally, a container for a non-radioactive immunoassay for T₃S quantitation comprising a non radioactive T₃S-conjugate.

18. A therapeutic treatment method for a hypothyroid condition comprising administering a composition according to claim 1.

19. The therapeutic treatment method of claim 18 wherein said hypothyroid condition is selected from the group consisting of:

asthenia, fatigue, skin dryness, somnolence, speech fluency impairment, cold intolerance, weight gain and memory deficit.

12. A stable solid oral dosage 80-150 mg tablet comprising T₃S as the active principle, in a quantity ranging from 1 to 1000 μ

g further comprising;

a) a diluent present at an amount from 50% to 99.99% by weight consisting of;

20-40 mg calcium carbonate present at an amount up to 35% of the total w/w and less than or equal to 110 mg microcrystalline cellulose of the alpha type;

b) 2-15 mg of Glycerol dibehenate;

c) 1-10 mg of Croscarmellose sodium salt;

d) 0.1-5 mg of Hydrate colloidal silica; and

e) 0.01-2 mg of Magnesium stearate.

14. The stable solid or dosage of claim 12 wherein the amount of Calcium carbonate is 25-35 mg, the amount of Glycerol dibehenate is 4-8 mg, the amount of Croscarmellose sodium salt is 2-6 mg, the amount of Hydrate colloidal silica is 0.5-4 mg, and the amount of Magnesium stearate is 0.1-1 mg.

16. A therapeutic or prophylactic treatment method for a hypothyroid condition due to total thyroid hormone depletion before ¹³¹I radiotherapy comprising administering a composition according to claim to a thyroidectomised patient as the sole thyroid hormone replacement up to 5 days before administration of a radioactive isotope to said patient.

17. The therapeutic treatment method of claim 16 wherein said hypothyroid condition is selected from the group consisting of:

asthenia, fatigue, skin dryness, somnolence, speech fluency impairment, cold intolerance, weight gain and memory deficit.