COMPOSITIONS AND METHODS OF PROVIDING THYROID HORMONE OR ANALOGS THEREOF

• US 20180064669A1
• Filed: 11/09/2017
• Published: 03/08/2018
• Est. Priority Date: 05/03/2016
• Status: Abandoned Application

• Current Assignee: Spectrix Therapeutics, LLC
• Original Assignee: Spectrix Therapeutics, LLC
• Inventors: Tengler, Mark
• Application Number:
  US15/808,494
• Publication Number:
  US 20180064669A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/56 the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
• CPC Class Codes: A61K 47/585 Ion exchange resins, e.g. polystyrene sulfonic acid resin
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/148 with compounds of unknown constitution, e.g. material from plants or animals with oils, fats, waxes, shellac A61K9/145
• 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 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: G01N 2800/046 Thyroid disorders
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 33/78 Thyroid gland hormones , e.g. T3, T4, TBH, TBG or their receptors

Abstract

The present invention includes a pharmaceutical composition and method of making and using comprising one or more thyroid hormones or analogs thereof, wherein a first portion of thyroid hormone is formulated for modified release and a second portion of the one or more thyroid hormones is formulated for modified release, wherein the combination of the first and second portion are provided in an amount effective to treat hypothyroidism.

Claims

1. A pharmaceutical composition comprising one or more thyroid hormones or analogs thereof, wherein a first portion of thyroid hormone is formulated for modified release and a second portion of the one or more thyroid hormones is formulated for modified release, wherein the combination of the first and second portion are provided in an amount effective to treat hypothyroidism.

2. The composition of claim 1, wherein the first portion is a T3 thyroid hormone provided at 1-50% modified release, and the second portion is a T4 thyroid hormone provided at 50-99% modified release.

3. The composition of claim 1, wherein the first portion is a T4 thyroid hormone provided at 50-99% modified release, and the second portion is a T3 thyroid hormone provided at 1-50% modified release.

4. The composition of claim 1, wherein the first portion is a T3 and T4 thyroid hormone provided at 10-90% modified release, and the second portion is a T3 and T4 thyroid hormone provided at 90-10% modified release.

5. The composition of claim 1, wherein at least one of the thyroid hormone(s) are bound to an ion resin, the one or more thyroid hormones are selected from at least one of T4, T3, T4 or T3 N-Methyl, T4 or T3 N-Ethyl, T4 or T3 N-Triphenyl, T4 or T3 N-Propyl, T4 or T3 N-Isopropyl, T4 or T3-N-Tertiary butyl, GC-1, DIPTA, Tetrac, or Triac, and optionally the modified release thyroid hormone is T3.

6. The composition of claim 1, wherein the composition further comprises one or more pharmaceutically acceptable carriers, one or more additional biologically active substances, and wherein the composition is adapted for the treatment of hypothyroidism.

7. The composition of claim 1, wherein at least one of the thyroid hormones is T4 or T3, and the ion exchange resin prevents polymorphism in the crystalline structure of the bound hormone.

8. The composition of claim 1, wherein the binding of thyroid hormone to resin provides a geometric dilution to aid in the ease of manufacturing and increase consistency in dosing.

9. The composition of claim 1, wherein the composition is a liquid suspension, chewable composition, orally disintegrating tablet, sublingual, a modified release orally disintegrating tablet, or a swallowed tablet composition.

10. The composition of claim 1, wherein the one or more thyroid hormones are T4 and T3, and are provided a ratio of T4:

T3 is from 1;

1 to 20;

1.

11. The composition of claim 1, wherein the ion-exchange resin particles are an acidic cation exchange resin, a basic anion exchange resin, and they are optionally coated with a triggered-release coating that is triggered by a pH change or a non-pH dependent controlled release coating.

12. The composition of claim 1, wherein the composition is coated and the coating is selected from at least one of cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters, co-polymerized methacrylic acid/acrylic acid ethyl esters, or mixtures thereof.

13. The composition of claim 1, wherein the amount of the one or more thyroid hormones is from 0.013 to 0.30 mg equivalent of levothyroxine sodium per dose.

14. The composition of claim 1, wherein greater than 40%, 50%, 60%, 70%, or 80% of the first thyroid hormone is released within the first 45 minutes after the product is introduced into an in vitro dissolution assay, wherein the conditions of the dissolution assay are an initial dissolution medium of 0.1 N HCl, and after 2 hours, the medium is adjusted to a pH of about 6.8, and the dissolution assay is performed using a USP Apparatus 2.

15. The composition of claim 1, wherein the composition consists essentially of at least two thyroid hormones or analogs thereof, wherein a first thyroid hormone or analogs thereof is formulated for immediate release and wherein a second thyroid hormone or analogs thereof is bound to ion resin particles, wherein the drug-resin particles may be uncoated or coated with an immediate release coating, wherein at least 80% of the drug is released within one hour, and wherein the one or more thyroid hormones are selected from at least one of T4, T3, T4 or T3 N-Methyl, T4 or T3 N-Ethyl, T4 or T3 N-Triphenyl, T4 or T3 N-Propyl, T4 or T3 N-Isopropyl, T4 or T3-N-Tertiary butyl, GC-1, DIPTA, Tetrac, or Triac.

16. A pharmaceutical composition comprising thyroid hormone(s) complexed with ion-exchange resin particles to form drug resin particles, wherein the composition comprises a first plurality of immediate release drug-resin particles and a second plurality of drug-resin particles that are coated for modified release, wherein the composition has an in vivo fasted serum profile with a first and second peak wherein the first peak occurs before 3 hours after ingestion of the composition and the second peak occurs after 3 hours after ingestion.

17. A method of making a pharmaceutical composition comprising:

attaching a first portion of a first thyroid hormone or analogs thereof to ion-exchange resin particles to form drug-resin particles;

attaching a second portion of a second thyroid hormone or analogs thereof to ion-exchange resin particles to form drug-resin particles; and

wherein at least 10-90% or more by weight of the first portion of thyroid hormone(s) is formulated for modified release, and at least 90-10% or more by weight of the second portion of thyroid hormone(s) is formulated for modified release, wherein the first and second portions are provided in an amount effective to treat hypothyroidism.

18. The method of claim 17, wherein the one or more thyroid hormones are selected from T4, T3, T4 or T3 N-Methyl, T4 or T3 N-Ethyl, T4 or T3 N-Triphenyl, T4 or T3 N-Propyl, T4 or T3 N-Isopropyl, T4 or T3-N-Tertiary butyl, GC-1, DIPTA, Tetrac and Triac, and optionally the modified release thyroid hormone is T3.

19. The method of claim 17, wherein the composition further comprises one or more pharmaceutically acceptable carriers, one or more additional biologically active substances, and wherein the composition is adapted for the treatment of hypothyroidism.

20. The method of claim 17, wherein at least one of the thyroid hormones is T4 or T3, and ion exchange resin prevents polymorphism in the crystalline structure of the bound hormone.

21. The method of claim 17, further comprising binding of thyroid hormone to resin provides a geometric dilution to aid in the ease of manufacturing and increase consistency in dosing.

22. The method of claim 17, further comprising formulating the composition as a liquid suspension, a chewable composition, an orally disintegrating tablet, a sublingual tablet, a modified release orally disintegrating tablet, or a swallowed tablet.

23. The method of claim 17, wherein the one or more thyroid hormones are T4 and T3, and are provided a ratio of T4:

T3 is from 1;

1 to 20;

1.

24. The method of claim 17, wherein the resin particles are ion-exchange resin particles selected from at least one of an acidic cation exchange resin or a basic anion exchange resin, and the resin particles are optionally coated with a triggered-release coating that is triggered by a pH change or a non-pH dependent controlled release coating.

25. The method of claim 17, further comprising coating the composition with a coating selected at least one of cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters, co-polymerized methacrylic acid/acrylic acid ethyl esters, or mixtures thereof.

26. The method of claim 17, wherein the amount of the one or more thyroid hormones is from 0.013 to 0.30 mg equivalent of levothyroxine sodium per dose.

27. The method of claim 17, wherein greater than 40%, 50%, 60%, 70%, or 80% of the first thyroid hormone is released within the first 45 minutes after the product is introduced into an in vitro dissolution assay, wherein the conditions of the dissolution assay are an initial dissolution medium of 0.1 N HCl, and after 2 hours, the medium is adjusted to a pH of about 6.8, and the dissolution assay is performed using a USP Apparatus 2.

28. The method of claim 17, wherein a second portion of thyroid hormone provided for modified release comprises greater than 10% by weight.

29. The method of claim 17, further comprising attaching thyroid hormone(s) or analogs thereof to ion-exchange resin particles to form drug-resin particles, wherein there is at least 30% or more weight gain in the drug-resin particles.

30. A method of evaluating a formulation believed to be useful in treating hypothyroidism, the method comprising:

(a) measuring the blood levels of one or more thyroid hormones from a first set of subjects suspected of having hypothyroidism;

(b) administering the formulation to a first subset of the patients, and a placebo to a second subset of the patients, wherein the formulation comprises a first portion of thyroid hormone is formulated for modified release and a second portion of the one or more thyroid hormones is formulated for modified release, wherein the combination of the first and second portion are provided in an amount effective to treat hypothyroidism;

(c) repeating step (a) after the administration of the formulation or the placebo; and

(d) determining if the formulation reduces the number of hypothyroidism that is statistically significant as compared to any reduction occurring in the second subset of patients, wherein a statistically significant reduction indicates that the formulation is useful in treating hypothyroidism.