IP Library › Granted Patent US 12,201,591
Granted Patent B2
US 12,201,591 · App. 17/624,329 · Granted Jan 21, 2025

Sustained release compositions of endoxifen

Inventors: Steven C. Quay (Seattle, WA); Naresh Kumar Reddy Vutukuru (Ann Arbor, MI); Srinivasan Shanmugam (Ypsilanti, MI)
Assignee: Atossa Therapeutics, Inc.
A61K31/138A61K9/2013A61K9/2027A61K9/2054A61K9/2095A61K9/2813A61K9/282A61K9/2846A61K31/135A61K31/343A61K31/4525A61K31/496A61P35/00
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Quick Facts
Patent No.
US 12,201,591
App. No.
17/624,329
Granted
Jan 21, 2025
Kind
B2
Abstract

The present disclosure provides sustained release compositions of (Z)-endoxifen and polymorphs and salts thereof and methods of making sustained release compositions of (Z)-endoxifen and polymorphs and salts thereof. The present disclosure also provides methods for treating disorders susceptible to (Z)-endoxifen, including hormone dependent disorders and mood disorders.

Claims (46)

1. A sustained release composition comprising a core tablet coated with an enteric coating, wherein the core tablet comprises:

a therapeutic agent comprising (Z)-endoxifen,

a sustained release agent comprising not less than 16% and not more than 60% hydroxypropyl methylcellulose by weight relative to total core tablet weight, and

a hardness of not less than 10 kilopond (Kp) and not more than 16 Kp; and

wherein the enteric coating comprises a delayed release agent.

2. The sustained release composition of claim 1 , wherein the therapeutic agent comprises at least 90% (Z)-endoxifen by weight relative to total therapeutic agent weight.

3. The sustained release composition of claim 1 , wherein the core tablet comprises not less than 1% and not more than 40% therapeutic agent by weight relative to total core tablet weight.

4. The sustained release composition of claim 1 , wherein the sustained release agent further comprises an hydroxyalkyl cellulose, a cellulosic ether, a gum, an acrylic resin, or a combination thereof.

5. The sustained release composition of claim 4 , wherein the hydroxyalkyl cellulose comprises hydroxymethyl cellulose, hydroxyethyl cellulose, or hydroxypropyl cellulose.

6. The sustained release composition of claim 1 , wherein the core tablet comprises not less than 20% and not more than 40%, not less than 20% and not more than 50%, or not less than 20% or not more than 60% of sustained release agent by weight relative to total core tablet weight.

7. The sustained release composition of claim 1 , wherein the core tablet further comprises a binding agent.

8. The sustained release composition of claim 7 , wherein the core tablet comprises not less than 30% and not more than 97%, or not less than 40% and not more than 75% of the binding agent by weight relative to total core tablet weight.

9. The sustained release composition of claim 7 , wherein the binding agent comprises a monosaccharide, a disaccharide, a starch, a polyhydric alcohol, mannitol, xylitol, sorbitol, lactose, a polyethylene glycol, a gum, alginic acid, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methyl cellulose, crystalline cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, calcium carbonate, calcium phosphate, sodium carbonate, sodium phosphate, anhydrous dibasic calcium phosphate, talc, a dextrate, kaolin, silicic acid, or a combination thereof.

10. The sustained release composition of claim 9 , wherein the core tablet comprises not less than 10% and not more than 90% microcrystalline cellulose by weight relative to total core tablet weight.

11. The sustained release composition of claim 1 , wherein the core tablet further comprises a lubricant.

12. The sustained release composition of claim 11 , wherein the lubricant comprises stearic acid, calcium stearate, magnesium stearate, zinc stearate, potassium stearate, hydrogenated vegetable oil, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, a glycol, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, talc, ethyl oleate, ethyl laureate, agar, waxes, or a combination thereof.

13. The sustained release composition of claim 12 , wherein the core tablet comprises not less than 0.01% and not more than 5% magnesium stearate by weight relative to total core tablet weight.

14. The sustained release composition of claim 1 , wherein the delayed release agent comprises a poly(meth)acrylate polymer.

15. The sustained release composition of claim 14 , wherein the enteric coating comprises not less than 60% and not more than 80% of the poly(meth)acrylate polymer by weight relative to total enteric coating weight.

16. The sustained release composition of claim 1 , wherein the enteric coating further comprises a plasticizer.

17. The sustained release composition of claim 16 , wherein the plasticizer comprises triethyl citrate.

18. The sustained release composition of claim 17 , wherein the enteric coating comprises not less than 0.01% and not more than 5% triethyl citrate by weight relative to total enteric coating weight.

19. The sustained release composition of claim 1 , wherein the enteric coating further comprises an anti-adherent agent.

20. The sustained release composition of claim 19 , wherein the anti-adherent agent comprises talc.

21. The sustained release composition of claim 20 , wherein the enteric coating comprises not less than 1% and not more than 40% talc by weight relative to total enteric coating weight.

22. The sustained release composition of claim 1 , wherein the enteric coating constitutes not less than 5% and not more than 30%, not less than 5% and not more than 25%, or not less than 5% and not more than 20% by weight of total sustained release composition weight.

23. The sustained release composition of claim 1 , wherein the (Z)-endoxifen comprises a (Z)-endoxifen free base, a polymorph of (Z)-endoxifen, a salt of (Z)-endoxifen, or a combination thereof.

24. The sustained release composition of claim 1 , wherein the therapeutic agent has a percentage dissolution of less than 20% at 2 hours, less than 40% at 7 hours, at least 30% at 12 hours, or combinations thereof, as measured at 37° C. in simulated gastric fluid at pH 1.2 from hours 0 to 2 and in simulated intestinal fluid at pH 6.8 after 2 hours.

25. The sustained release composition of claim 1 , wherein the therapeutic agent has percentage dissolution of less than 35% at 3 hours, at least 50% at 24 hours, or both.

26. The sustained release composition of claim 1 , wherein at least 90%, at least 95%, or at least 99% by weight of the therapeutic agent is polymorphic Form I of (Z)-endoxifen polymorphic Form I is characterized by an x-ray powder diffraction pattern comprising major peaks at 16.8±0.3°, 17.1±0.3° and 21.8±0.3° two theta.

27. The sustained release composition of claim 26 , wherein polymorphic Form I is characterized by an x-ray powder diffraction pattern further comprising at least one peak selected from 12.3±0.3°, 16.0±0.3°, 18.8±0.3°, 26.5±0.3°, 28.0±0.3° and 29.0±0.3° two theta.

28. A method of treating a disorder in a subject in need thereof, wherein the subject has the disorder or is at risk of having the disorder, the method comprising orally administering to the subject a sustained release composition comprising a core tablet coated with an enteric coating, wherein the core tablet comprises:

a therapeutic agent comprising (Z)-endoxifen,

a sustained release agent comprising hydroxypropyl methylcellulose, and

a hardness of not less than 10 kilopond (Kp) and not more than 16 Kp; and

wherein:

the enteric coating comprises a delayed release agent, and

the sustained release composition shows a percentage dissolution ranging from no less than 35% and no more than 55% at 12 hours in a dissolution test according to a 75 RPM USP paddle method and using pH 1.2 at 37° C. for 2 hours in simulated gastric fluid and pH 6.8 at 37° C. for 24 hours in simulated intestinal fluid as a test medium.

29. The method of claim 28 , wherein the disorder is a breast disorder, a benign breast disorder, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, ductal carcinoma in situ, lobular carcinoma in situ, breast cancer, precocious puberty, or McCune-Albright Syndrome.

30. The sustained release composition of claim 23 , wherein the salt of (Z)-endoxifen comprises acetate, arecoline, benzathine, benzoic, besylate, benzosulfonate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, formate, fumarate, glucolate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, maleate, mandelate, meglumine, mesylate, methylbromide, methylbromide, methylnitrate, methylsulfate, methanesulfonate, mucate, napsylate, nitric, nitrate, oxalate, pamaoate (Embonate), pantothenate, perchloric, phosphate, diphosphate, piperazine, procaine, polygalacuronate, p-toluenesulfonate, salicylate, stearate, succinate, sulfate, sulfonate, sulfuric, tannate, tartarate, teoclate, triethiodide, trifluoroacetate, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc, or any combination thereof.

31. The sustained release composition of claim 1 , wherein the core tablet comprises:

a therapeutic agent comprising not less than 1% and not more than 40% of at least 90% (Z)-endoxifen by weight relative to total core tablet weight,

a sustained release agent comprising not less than 16% and not more than 60% of hydroxypropyl methylcellulose by weight relative to total core tablet weight,

not less than 10% and not more than 90% microcrystalline cellulose by weight relative to total core tablet weight,

not less than 0.01% and not more than 5% magnesium stearate by weight relative to total core tablet weight, and

a hardness of not less than 10 kilopond (Kp) and not more than 16 Kp.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 2, 2023
From: VUTUKURU, NARESH KUMAR REDDY; SHANMUGAM, SRINIVASAN
To: ELEMENT MATERIALS TECHNOLOGY ANN ARBOR LLC
Reel/Frame 064835/0421 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 28, 2023
From: ELEMENT MATERIALS TECHNOLOGY ANN ARBOR LLC
To: ATOSSA THERAPEUTICS, INC.
Reel/Frame 064149/0109 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 19, 2022
From: QUAY, STEVEN C.
To: ATOSSA THERAPEUTICS, INC.
Reel/Frame 061233/0220 →
Continuity (4)
Provisional Application 63021549 · May 7, 2020
Provisional Application 62989342 · Mar 13, 2020
Provisional Application 62870656 · Jul 3, 2019
Related Publication 20220175702A1 · Jun 9, 2022
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