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EP-4739289-A1 - ORAL COMPOSITIONS COMPRISING TEMOZOLOMIDE OR LENALIDOMIDE

EP4739289A1EP 4739289 A1EP4739289 A1EP 4739289A1EP-4739289-A1

Abstract

The present disclosure provides a composition comprising temozolomide or lenalidomide, a medium chain triglyceride such as miglyol, silicon dioxide and a surfactant, wherein the composition optionally comprises an antioxidant and/or a flavoring agent, and wherein the temozolomide composition is a non-aqueous, preservative free suspension. Also provided is a method for treating cancer in a subject, such as a child or a subject suffering dysphagia and/or has difficulty swallowing.

Inventors

  • CUNNINGHAM, Sharon
  • RYAN, Orlaith
  • DELANEY, Denis
  • CLANCY, MAURICE
  • BAKER, ROD

Assignees

  • Shorla Pharma Ltd

Dates

Publication Date
20260513
Application Date
20240705

Claims (20)

  1. 1. A composition comprising: about 0.25 to about 100 mg/mL active pharmaceutical ingredient (API); about 400 to about 960 mg/mL medium chain triglycerides (MCT); about 1 to about 20 mg/mL silicon dioxide; and about 20 to about 70 mg/mL surfactant; wherein the API is temozolomide or lenalidomide, wherein the composition is substantially free of water and anti-microbial preservatives, and wherein the composition is an oral suspension.
  2. 2. The composition of claim 1 , wherein the API is temozolomide, and an amount of temozolomide is between about 5 to about 100 mg/mL.
  3. 3. The composition of claim 1 , wherein the API is lenalidomide, and an amount of lenalidomide is between about 0.25 to about 50 mg/mL.
  4. 4. The composition of claim 1 , wherein the API is micronized.
  5. 5. The composition of any one of claims 1 to 4, wherein the MCT is present in an amount between about 850 to about 980 mg/mL.
  6. 6. The composition of any one of claims 1 to 5, wherein the silicon dioxide is present in an amount of about 12.1 mg/mL to about 12.5 mg/mL.
  7. 7. The composition of any one of claims 1 to 6, wherein the surfactant is present in an amount of between about 40 to about 50 mg/mL.
  8. 8. The composition of claim 7, wherein the surfactant is selected from the group consisting of aldehyde-free caprylocaproyl poloxyl-8 glycerides, caprylocaproyl poloxyl- 8 glycerides, polysorbate 80, polysorbate 20, sorbitan monolaurate, and vitamin E polyethylene glycol succinate.
  9. 9. The composition of any one of claims 1 to 8, wherein the composition further comprises a sweetener and/or a flavoring agent.
  10. 10. The composition of claim 9, herein the sweetener is present in an amount of 0.1 to about 3 mg/mL, and wherein the sweetener is selected from the group consisting of sucralose, aspartame, acesulfame potassium, saccharin, saccharin sodium, and neotame.
  11. 11. The composition of claim 9, wherein the flavoring agent is present in an amount of between about 0.1 to about 5 mg/mL, and wherein the flavoring agent is selected from the group consisting of grape flavoring, cola flavoring, cherry flavoring, berry flavoring, citrus flavoring, raspberry flavoring, mint flavoring, orange flavoring, caramel flavoring, and tutti frutti flavoring.
  12. 12. The composition of any one of claims 1 to 11 , further comprising an antioxidant.
  13. 13. The composition of claim 12, wherein the antioxidant is present in an amount of between about 0.05 to about 2 mg/mL, and wherein the antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, and propyl gallate.
  14. 14. The composition of any one of claims 1 to 13, wherein the composition is in the form of a multidose formulation.
  15. 15. The composition of any one of claims 1 to 14, wherein the composition is free or substantially free of an organic solvent.
  16. 16. The composition of any one of claims 1 to 15, wherein the composition is free or substantially free of an acid.
  17. 17. The composition of claim 1 , comprising: about 5 to about 100 mg/mL temozolomide; about 400 to about 960 mg/mL MCT; about 1 to about 20 mg/mL silicon dioxide; about 0.1 to about 3 mg/mL sweetener; about 20 to about 70 mg/mL surfactant; and about 0.1 to about 5 mg/mL flavoring agent.
  18. 18. The composition of claim 1 , comprising: about 5 to about 100 mg/mL temozolomide; about 400 to about 960 mg/mL MCT; about 1 to about 20 mg/mL silicon dioxide; about 0.1 to about 3 mg/mL sweetener; about 20 to about 70 mg/mL surfactant; about 0.1 to about 5 mg/mL flavoring agent; and about 0.05 to about 2 mg/mL antioxidant.
  19. 19. The composition of claim 17, comprising: about 40 mg/mL temozolomide; about 868.7 mg/mL MCT; about 12.1 mg/mL silicon dioxide; about 1.9 mg/mL sucralose; about 2.9 mg/mL grape flavoring agent; and about 44.4 mg/mL caprylocaproyl poloxyl-8 glycerides.
  20. 20. The composition of claim 18, comprising: about 40 mg/mL temozolomide; about 868.5 mg/ml MCT; about 12.1 mg/mL silicon dioxide; about 1.9 mg/mL sucralose; about 2.9 mg/mL grape flavoring agent; about 44.4 mg/mL caprylocaproyl poloxyl-8 glycerides; and about 0.2 mg/mL BHT.

Description

ORAL COMPOSITIONS COMPRISING TEMOZOLOMIDE OR LENALIDOMIDE CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit and priority to U.S. Ser. No. 63/525,276, filed on July 6, 2023. The entire disclosure of the application identified in this paragraph is incorporated herein by reference. FIELD [0002] The present disclosure relates to compositions for oral administration comprising temozolomide or lenalidomide and excipients, and methods for using the same for treating a disease in a subject. BACKGROUND [0003] Temozolomide (3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8- carboxamide) is an alkylating agent used as an oral chemotherapeutic drug. Temozolomide is indicated for treatment of glioblastoma multiforme (GBM) and refractory anaplastic astrocytoma. Temozolomide is unstable in aqueous solutions, which leads to the generation of impurities and/or temozolomide degradation products following storage. The instability renders ready-to-use liquid dosage forms difficult to store. [0004] Temozolomide is currently administered as 5-250 mg capsules or reconstituted from 10 mg powder for IV infusion. Although temozolomide is not indicated for pediatric use, it is administered to children in off-label use. [0005] Lenalidomide (1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline) is an immunomodulatory drug known as a cereblon E3 ligase modulator. It is used to treat multiple myeloma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma and myelodysplastic syndromes (MDS). Lenalidomide is unstable in aqueous solutions, which leads to the generation of impurities and/or lenalidomide degradation products following storage. The instability renders ready-to-use liquid dosage forms difficult to store. Lenalidomide is currently administered as 2.5-25 mg capsules. [0006] US 5,260,291 first reported temozolomide, polymorphs thereof, and compositions thereof. The reported compositions further comprise dimethyl sulphoxide and arachis oil. [0007] US 6,251 ,886 reports methods for treating neoplastic meningitis cancer with a microcrystalline suspension of temozolomide, DLPC, DMPC, mannitol, and sodium acetate. [0008] US 6,987,108 and US 7,786,118 disclose temozolomide compositions and at least one aqueous diluent. The diluent may be urea, L-histidine, L-threonine, L- asparagine, L-serine, and L-glutamine. Additional excipients include PEG. [0009] US 8,623,868 reports lyophilized temozolomide powder further comprising L-threonine. [0010] WO 2021/229442 reports stable formulations of temozolomide comprising formic acid, PEG, glycerol. [0011] Trissei, et al. (Int. J. Pharm. Compd. Sep-Oct 2006; 10(5): 396-9) describes oral temozolomide suspensions comprising ORA-Sweet® or ORA Sweet SF®, both of which comprise glycol. [0012] US 5,635,517 first reported lenalidomide and compositions thereof, including isotonic saline solutions. US 7,119,106 reports pharmaceutical compositions comprising lenalidomide. SUMMARY [0013] This section provides a general summary of disclosure, and is not a comprehensive disclosure of its full scope or all of its features. [0014] The present disclosure provides compositions comprising an active pharmaceutical ingredient (API), a medium chain triglyceride (MCT), silicon dioxide, a surfactant, and optionally one or more additional excipients, wherein the API can be temozolomide or lenalidomide, wherein the composition is substantially free of water and anti-microbial preservatives, and wherein the composition is an oral suspension. In an embodiment, the compositions further comprise a flavoring agent and/or an antioxidant. The disclosed compositions are stable for shipment and storage and suitable for oral administration. [0015] In another embodiment, the present disclosure provides methods or use of treating cancer comprising administering to a subject in need thereof a composition described herein. In an embodiment, the temozolomide or lenalidomide formulations can be administered to children, dysphagic patients, and/or patients having difficulty swallowing oral solid dosage forms. [0016] In yet another embodiment, the present disclosure provides a method for preparing a composition comprising: adding silicon dioxide, a sweetener, a surfactant, a flavoring agent, and an API to MCT; and mixing the components until homogenous. BRIEF DESCRIPTION OF THE DRAWINGS [0017] The drawings described herein are for illustrative purposes only of selected embodiments and not all possible implementations, and are not intended to limit the scope of the present disclosure. [0018] FIG. 1 depicts the dissolution profile in 0.1 N HCI of Embodiment 1 . [0019] FIG. 2 depicts the dissolution profile in 0.1 N HCI of Embodiment 2. [0020] FIG. 3 depicts the dissolution profile in 0.1 N HCI of Embodiment 3. [0021] FIG. 4 depicts the XRD diffractogram of Embodiment 1 after 6 months storage at 2-8°C [0022] FIG 5 depicts XRD diffractogram of Embodiment 4 after 6 months storage at 2- 8°C.