US-12616679-B2 - Lyophilized composition comprising (s)-isopropyl 2-((s)-2-acetamido-3-(1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate for subcutaneous administration and the use thereof

Abstract

The present disclosure provides lyophilates comprising (S)-isopropyl 2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate: for subcutaneous administration to a subject, and pharmaceutical compositions, pharmaceutical formulations, and uses thereof

Inventors

• Steven DYKSTRA
• Gary Elliot
• Thomas M. Estok
• Stuart R. GALLANT
• ROBERT CHRISTIAN WILD
• Jianmin Xu
• Henry Acken Havel

Assignees

• DRACEN PHARMACEUTICALS, INC.

Dates

Publication Date

20260505

Application Date

20211001

Claims (19)

1. 1 . A lyophilate comprising about 20% wt/wt to about 45% wt/wt of (S)-isopropyl 2-((S)-2-acetamido-3-(1H-indol-3-yl) propanamido)-6-diazo-5-oxohexanoate, about 35% wt/wt to about 55% wt/wt of a bulking agent, and about 1% wt/wt to about 10% wt/wt of a cellulose-based suspension modulator.
2. 2 . The lyophilate of claim 1 further comprising about 1% wt/wt to about 5% wt/wt of a poloxamer-based suspension modulator.
3. 3 . The lyophilate of claim 1 further comprising about 10% wt/wt to about 20% wt/wt of a lecithin-based suspension modulator.
4. 4 . The lyophilate of claim 1 further comprising about 0.5% wt/wt to about 2.5% wt/wt of a buffer.
5. 5 . The lyophilate of claim 1 comprising: (i) about 20% wt/wt to about 30% wt/wt of(S)-isopropyl 2-((S)-2-acetamido-3-(1H-indol-3-yl) propanamido)-6-diazo-5-oxohexanoate; (ii) about 45% wt/wt to about 55% wt/wt of a bulking agent; (iii) about 1% wt/wt to about 9% wt/wt of a cellulose-based suspension modulator; (iv) about 1% wt/wt to about 4% wt/wt of a poloxamer-based suspension modulator; (v) about 12% wt/wt to about 20% wt/wt of a lecithin-based suspension modulator; and (vi) about 1% wt/wt to about 2% wt/wt of a buffer.
6. 6 . The lyophilate of claim 1 comprising: (i) about 62.5 mg of (S)-isopropyl 2-((S)-2-acetamido-3-(1H-indol-3-yl) propanamido)-6-diazo-5-oxohexanoate; (ii) about 125 mg of mannitol; (iii) about 8.3 mg of sodium carboxymethyl cellulose; (iv) about 7.1 mg of Poloxamer 188, NF; (v) about 41.7 mg of soy lecithin; and (vi) about 4.3 mg of histidine.
7. 7 . A pharmaceutical composition comprising the lyophilate of claim 1 , wherein the lyophilate is suspended in a pharmaceutically acceptable carrier.
8. 8 . The pharmaceutical composition of claim 7 , wherein the (S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate isopropyl concentration is about 20 mg/mL to about 60 mg/mL.
9. 9 . The pharmaceutical composition of claim 7 , wherein the average particle size distribution of (S)-isopropyl 2-((S)-2-acetamido-3-(1H-indol-3-y1)propanamido)-6-diazo-5-oxohexanoate in the suspension is about 1 μm to about 30 μm.
10. 10 . A method for treating cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 7 to the subject.
11. 11 . The method of claim 10 , wherein the cancer is one or more of adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentigious melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological cancer, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogeous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, merkel cell cancer, mesothelioma, metastatic urothelial carcinoma, mixed Mullerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, preimary primary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma periotonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease, small intestine cancer, squamous carcinoma, stomach cancer, T-cell lymphoma, testicular cancer, thecoma, thyroid cancer, transitional cell carcinoma, throat cancer, urachal cancer, urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, or Wilms' tumor.
12. 12 . The method of claim 10 , wherein the cancer is hepatocellular carcinoma, glioblastoma, lung cancer, breast cancer, head and neck cancer, prostate cancer, melanoma, or colorectal cancer.
13. 13 . The method of claim 10 , wherein the pharmaceutical composition is administered subcutaneously to the subject.
14. 14 . The method of claim 13 , wherein the pharmaceutical composition is administered to the subject according to an intermittent dosing schedule.
15. 15 . The method of claim 10 further comprising administering one or more optional therapeutic agents to the subject.
16. 16 . The method of claim 15 , wherein the one or more optional therapeutic agents comprise one or more immune checkpoint inhibitors.
17. 17 . A kit comprising the lyophilate of claim 1 packaged as single unit dose in a container.
18. 18 . The kit of claim 17 further comprising instructions for suspending the lyophilate in a solvent to give a pharmaceutical composition.
19. 19 . A method of making the lyophilate of claim 1 , the method comprising: (i preparing a pre-lyophilization solution comprising (S)-isopropyl 2-((S)-2-acetamido-3-(1H-indol-3-yl) propanamido)-6-diazo-5-oxohexanoate, a bulking agent, a cellulose-based suspension modulator, and water; (ii) cooling the pre-lyophilization solution until it is frozen or partially frozen; and (iii) applying a vacuum to the frozen or partially frozen pre-lyophilization solution to give the lyophilate.

Description

BACKGROUND OF THE INVENTION 6-Diazo-5-oxo-L-norleucine (DON) is a glutamine antagonist that exhibits promising activity in preclinical models to treat a variety of diseases such as cancer. See, e.g., Ahluwalia et al., Pharmac The. 46:243-371 (1990). But the clinical development of DON has been hampered by its dose-limiting toxicity in humans, especially in the intestinal epithelium. See, e.g., Rosenfeld and Roberts, Cancer Research 41:1324-1328 (1981) and Lynch et al., Am J Clin Oncol (CCT) 5:541-543 (1982). Administering DON as a prodrug may help mitigate this toxicity. U.S. Pat. No. 10,336,778 B2 discloses (S)-isopropyl 2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate (“Compound 1”) and other prodrugs of DON for the treatment of cancer and other diseases. There exists a need for pharmaceutical compositions comprising Compound 1 for subcutaneous administration to a subject in need thereof. BRIEF SUMMARY OF THE INVENTION In one aspect, the disclosure provides a lyophilate comprising Compound 1 for subcutaneous administration to a subject in need thereof. In another aspect, the disclosure provides a lyophilate comprising Compound 1 and a bulking agent, e.g., mannitol. In another aspect, the disclosure provides a lyophilate comprising Compound 1 and a cellulose-based suspension modulator, e.g., sodium carboxymethyl cellulose. In another aspect, the disclosure provides a lyophilate comprising Compound 1 and a poloxamer-based suspension modulator, e.g., Poloxamer 188. In another aspect, the disclosure provides a lyophilate comprising Compound 1 and a lecithin-based suspension modulator, e.g., soy lecithin. In another aspect, the disclosure provides a lyophilate comprising Compound 1 and a buffering agent, e.g., L-histidine. In another aspect, the disclosure provides a pharmaceutical composition comprising a lyophilate comprising Compound 1 that has been suspended in a pharmaceutically acceptable excipient, e.g., a solvent, e.g., water. In another aspect, the disclosure provides a method for treating a cancer in a subject in need thereof comprising subcutaneously administering a therapeutically effective amount of a pharmaceutical composition comprising a lyophilate comprising Compound 1. In another aspect, the disclosure provides a method of making the lyophilate comprising Compound 1. In another aspect, the disclosure provides a method of making the pharmaceutical composition comprising a lyophilate comprising Compound 1. In another aspect, the disclosure provides a kit comprising the lyophilate comprising Compound 1 packaged as single unit dose in a vial. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is an image showing the lyophilized cake appearance of five lyophilates comprising Compound 1. FIG. 2 is an image showing the appearance of a pharmaceutical composition comprising Compound 1 suspended in 2.5 mL of water for injection. DETAILED DESCRIPTION OF THE INVENTION I. Lyophilates of the Disclosure In one embodiment, the disclosure provides a lyophilate comprising Compound 1 for subcutaneous administration to a subject in need thereof. In another embodiment, the disclosure provides a lyophilate comprising Compound 1 and a bulking agent. In another embodiment, the Compound 1/bulking agent weight ratio is about 5 to about 0.05. In another embodiment, the Compound 1/bulking agent weight ratio is about 3 to about 0.1. In another embodiment, the Compound 1/bulking agent weight ratio is about 1 to about 0.2. In another embodiment, the Compound 1/bulking agent weight ratio is about 3, about 2, about 1, about 0.9, about 0.8, about 0.7, about 0.6, about 0.5, about 0.4, about 0.3, about 0.2, or about 0.1. In another embodiment, the bulking agent is mannitol. In another embodiment, the disclosure provides a lyophilate comprising Compound 1 and a cellulose-based suspension modulator. In another embodiment, the Compound 1/cellulose-based suspension modulator weight ratio is about 25 to about 0.3. In another embodiment, the Compound 1/cellulose-based suspension modulator weight ratio is about 15 to about 0.5. In another embodiment, the Compound 1/cellulose-based suspension modulator weight ratio is about 10 to about 1. In another embodiment, the Compound 1/cellulose-based suspension modulator weight ratio is about 5 to about 2. In another embodiment, the Compound 1/cellulose-based suspension modulator weight ratio is about 10, about 9, about 8, about 7.5, about 7, about 6, about 5, about 4, about 3, about 2.7, about 2, or about 1. In another embodiment, the cellulose-based suspension modulator is sodium carboxymethyl cellulose. In another embodiment, the disclosure provides a lyophilate comprising Compound 1 and a poloxamer-based suspension modulator. In another embodiment, the Compound 1/poloxamer-based suspension modulator weight ratio is about 80 to about 1. In another embodiment, the Compound 1/poloxamer-based suspension modulator weight ratio is about 40 to about 2. In another embodiment, the Compo