EP-4734967-A2 - LYOPHILIZED SOVATELTIDE-BASED INJECTABLE FORMULATION AND A PROCESS FOR PREPARATION

Abstract

A lyophilized Sovateltide-based injectable formulation, comprising sovateltide in the range from about 0.01 to about 0.02% w/w, trisodium citrate dihydrate is present in the range of from about 20 to about 80% w/w and mannitol is present in the range of from about 20 to about 80% w/w. A reconstituted liquid composition comprising sovateltide; trisodium citrate; mannitol and water or 0.9% aqueous sodium chloride solution and process for the preparation of a lyophilized pharmaceutical composition of sovateltide comprising: dissolving sovateltide, trisodium citrate dihydrate and mannitol in water for injection; filter the solution through 0.2μ membrane filter; fill the individual vials up to the target fill volume; and lyophilization of the filled vials.

Inventors

• LAVHALE, MANISH S.
• GULATI, ANIL

Assignees

• Pharmazz, Inc.

Dates

Publication Date

20260506

Application Date

20231218

Claims (1)

1. We Claim: 1. A lyophilized pharmaceutical composition comprising: a) sovateltide; b) trisodium citrate; and c) mannitol. 2. The lyophilized pharmaceutical composition of claim 1, wherein the composition is a lyophilized powder. 3. The lyophilized pharmaceutical composition of claim 1, wherein the sovateltide is present in the range from about 0.01 to about 0.02% w/w. 4. The lyophilized pharmaceutical composition of claim 1, wherein the trisodium citrate dihydrate is present in the range of from about 20 to about 80% w/w. 5. The lyophilized pharmaceutical composition of claim 1, wherein the mannitol is present in the range of from about 20 to about 80% w/w. 6. The lyophilized pharmaceutical composition of claim 1, wherein the sovateltide is present at about 30pg; trisodium citrate is present at about 50mg; and mannitol is present at about 160mg. 7. The lyophilized pharmaceutical composition of claim 1, wherein the composition further comprises sodium chloride. 8. The lyophilized pharmaceutical composition of claim 1, wherein the composition further comprises water. 9. A lyophilized pharmaceutical composition comprising: a) about 30pg of Sovateltide; b) about 50 mg of trisodium citrate dihydrate; and c) about 160 mg of mannitol. 10. The lyophilized pharmaceutical composition according to any of the preceding claims, wherein the said composition comprises: i) total impurities not more than 2%; or ii) any unspecified impurities not more than 0.5%; or iii) D-His- sovateltide impurity not more than 1.0%. 11. The lyophilized pharmaceutical composition according to claim 10, wherein the said composition comprises: i) total impurities not more than 0.7%; or ii) any unspecified impurities not more than 0.15%; or iii) D-His-sovateltide impurity not more than 0.22%. The lyophilized pharmaceutical composition according to any of the preceding claims, is reconstituted by 0.9% sodium chloride solution. The lyophilized pharmaceutical composition according to any of the preceding claims, is reconstituted by water for injection. A method of treating a neurological disorder or disease comprising administering the lyophilized pharmaceutical composition according to any of the preceding claims to a patient in need thereof. The method of claim 14, wherein the neurological disorder or disease is selected from cerebral stroke, Alzheimer’s disease, spinal cord injury, cognitive impairment, neurofibromatosis, Huntington's disease, Parkinson's, neonatal hypoxic-ischemic encephalopathy, traumatic brain injury, and multiinfarct dementia. The method of claims 14-15, wherein the neurological disorder or disease is a cerebral stroke. The method of claims 14-16, wherein the lyophilized pharmaceutical composition according to any of the preceding claims is administered intravenously. A reconstituted liquid composition comprising: a) sovateltide; b) trisodium citrate; c) mannitol; and d) water or 0.9% aqueous sodium chloride solution. The liquid composition of claim 18, wherein the sovateltide, trisodium citrate and mannitol are provided as a lyophilized powder. The liquid composition of claim 18 is prepared by reconstituting the lyophilized powder of sovateltide, trisodium citrate and mannitol in water or 0.9% aqueous sodium chloride solution. 21. The liquid pharmaceutical composition of claim 18, wherein the sovateltide is present in the range from about 0.01 to about 0.02% w/w. 22. The liquid composition of claim 18, wherein the trisodium citrate dihydrate is present in the range of from about 20 to about 80% w/w. 23. The liquid composition of claim 18, wherein the mannitol is present in the range of from about 20 to about 80% w/w. 24. The liquid composition of claim 18, wherein sovateltide is present at about 30pg; trisodium citrate is present at about 50mg; and mannitol is present at about 160mg. 25. The liquid composition of claims 18-24, wherein sovateltide is present at 6pg/ml strength. 26. The liquid composition according to claims 18-25, wherein the said composition comprises: i) total impurities not more than 2%; or ii) any unspecified impurities not more than 0.5%; or iii) D-His- sovateltide impurity not more than 1.0%. 27. The liquid composition according to claim 26, wherein the said composition comprises: i) total impurities not more than 0.7%; or ii) any unspecified impurities not more than 0.15%; or iii) D-His- sovateltide impurity not more than 0.22%. 28. The liquid composition of claims 18-27, wherein the said reconstituted liquid composition has an osmolality between 240 to 310 mOsm/L. 29. The liquid composition of claim 28, wherein the said reconstituted liquid composition has an osmolality of about 286 mOsm/L. 30. The liquid composition of claims 18-29, wherein the said reconstituted liquid composition has pH of about 7.0 to 8.5. 31. The liquid composition of claims 18-30 is administered intravenously. 32. A method of treating a neurological disorder or disease comprising administering the liquid composition according to claims 18-31 to a patient in need thereof. 33. The method of claim 32, wherein the neurological disorder or disease is selected from cerebral stroke, Alzheimer’s disease, spinal cord injury, cognitive impairment, neurofibromatosis, Huntington's disease, Parkinson's, neonatal hypoxic-ischemic encephalopathy, traumatic brain injury, and multiinfarct dementia. 34. The method of claim 33, wherein the neurological disorder or disease is a cerebral stroke. 35. A kit or a co-pack comprising: i) a vial containing lyophilized pharmaceutical composition of sovateltide; and ii) an ampoule containing 0.9% sodium chloride aqueous solution or water for injection. 36. The kit or co-pack of claim 35, wherein the vial containing lyophilized pharmaceutical composition of sovateltide comprises: a) about 30pg of sovateltide; b) about 50 mg of trisodium citrate dihydrate; and c) about 160 mg of mannitol. 37. The kit or co-pack according to claim 35, wherein the kit or co-pack comprises multiple vials containing lyophilized pharmaceutical composition of sovateltide and multiple ampoules of 0.9% sodium chloride aqueous solution or water for injection. 38. The kit or co-pack according to claim 37, wherein the kit or co-pack contains 3 vials of lyophilized pharmaceutical composition of sovateltide and 3 ampoules of 0.9% sodium chloride aqueous solution or water for injection. 39. The kit or co-pack of claims 37-38, wherein the vial containing lyophilized pharmaceutical composition of sovateltide comprises: a) about 30pg of sovateltide; b) about 50 mg of trisodium citrate dihydrate; and c) about 160 mg of mannitol. 40. A process for the preparation of a lyophilized pharmaceutical composition of sovateltide comprising: i) dissolving sovateltide, trisodium citrate dihydrate and mannitol in water for injection; ii) filter the solution through 0.2p membrane filter; iii) fill the individual vials up to the target fill volume; and iv) lyophilization of the filled vials. 41. The process according to claim 40, wherein the plugs on the vials are half stoppered, followed obtain the lyophilized Sovateltide-based injectable formulation by loading the vials in freeze dryer for lyophilization to 42. The process according to claim 40, wherein the solution in step i) is stirred at 300-350 rpm. 43. The process according to claim 40, wherein the pH of the solution in step i) is adjusted to pH of about 7.5 to 8.5. 44. A lyophilized Sovateltide-based injectable formulation, comprising: an active pharmaceutical ingredient in the range of 0.01-0.02% w/w; at least two soluble excipients in the range of 20-80% w/w; and water for injection in the range of 1-2% w/w. 45. The formulation as claimed in claim 1, wherein said active pharmaceutical ingredient is Sovateltide. 46. The formulation as claimed in claim 1, wherein said soluble excipient includes, but not limited to mannitol, Trisodium citrate Dihydrate, Citric Acid anhydrous, Dibasic sodium citrate, Dibasic sodium Phosphate, Sodium Chloride, Hydroxypropyl beta cyclodextrin. 47. The formulation as claimed in claim 1 or 3, wherein said soluble excipients are ideally mannitol as freeze-drying filler and Trisodium Citrate Dihydrate as buffering agent. 48. A method for preparation of said lyophilized Sovateltide-based injectable formulation as claimed in claim 1, comprising the steps: dissolving said Trisodium Citrate Dihydrate in said water for injection in order to obtain a mixture; 80 RECTIFIED SHEET (RULE 91) ISA/EP adding said active pharmaceutical ingredient in said mixture, followed by addition of said Mannitol in order to obtain a solution; checking the pH of said solution for making up the volume of said solution, followed by sterile filtering said solution and filling said sterile filtered solution in vials; and half stoppering of plugs on said vials, followed by loading said vials in freeze dryer for lyophilization to obtain said formulation. The method as claimed in claim 5, wherein the vials filled with the filtered solution are subjected to lyophilization by freezing at -45°C and then drying at -20°C, at 0°C and then at +10°C. The method as claimed in claim 5, wherein said vials are unloaded from said freeze dryer and sealed to obtain said lyophilized Sovateltide-based injectable formulation. The method as claimed in claim 5, wherein said formulation is administered through intravenous route. The method as claimed in claim 5, wherein said vials are washed and depyrogenated before filling said sterile filtered solution in said vials. The method as claimed in claim 5, wherein said lyophilized Sovateltide-based injectable formulation is stored at 2-8 degree Celsius or 22 °C to 28 °C. 81 RECTIFIED SHEET (RULE 91) ISA/EP

Description

LYOPHILIZED SOVATEL TIDE-BASED INJECTABLE FORMULATION AND A PROCESS FOR PREPARATION CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This international application claims priority to U.S. Non-Provisional patent application number 18/343,087, filed June 28, 2023 and U.S. Non-Provisional patent application number 18/478,528 filed September 29, 2023. The contents of which are incorporated by reference herein. FIELD OF THE INVENTION [0002] The present invention relates to a lyophilized sovateltide-based injectable pharmaceutical formulation and process for preparation thereof for treatment of various neurological diseases and disorders including but not limited to cerebral ischemic stroke and intracranial haemorrhage, by providing intravenous route of administration and avoiding pain or irritation caused due to conventional procedures. BACKGROUND OF THE INVENTION [0003] There are various diseases and disorders that are responsible for discomfort in life along with being fatal for life but have very limited therapeutic solutions. Few of such diseases/disorders includes neurological disorders or diseases including cerebral stroke, Alzheimer’s disease, spinal cord injury, cognitive impairment, neurofibromatosis, Huntington's disease, Parkinson's, neonatal hypoxic-ischemic encephalopathy, multi-infarct dementia. Although various drugs have been discovered and synthesized for addressing such diseases and disorders. However, there are still concerns regarding their effectiveness and potential side effects. [0004] Neurological conditions such as cerebral ischemic stroke, intracranial haemorrhage, and brain injury commonly cause cerebral edema. Stroke is one of the most common causes of death and is also an important cause of serious, long-lasting disability. Ischemic stroke caused by arterial occlusion is responsible for most strokes. Various treatment options have been developed for treatment of strokes. Mannitol is one such treatment option as it decreases brain volume by reducing overall water content, blood volume by vasoconstriction, and CSF volume by decreasing water content. Mannitol may also improve cerebral perfusion by reducing viscosity or altering red blood cell rheology. [0005] However, administration of mannitol alone is insufficient to reduce the morbidity and mortality of patients with cerebral stroke. Moreover, monitoring of fluids and electrolytes, serum osmolarity, and renal, cardiac, and pulmonary function needs to be carried out during and following mannitol infusion, which makes the treatment a cumbersome process. [0006] Another treatment option available for treatment of stroke is usage of tissue plasminogen activator (tPA). However, the use of tPA is limited to a short time window of <4.5 h from the onset of symptoms, and it also has a risk of intracranial haemorrhage. [0007] Sovateltide is one such drug having therapeutic potential for treatment of such diseases/disorders, preferably neurological disorders. Sovateltide or succinyl-(glutamyl(9)- alanyl(l l,15))-endothelin-l (8-21) is a compound with 15 amino acid long chain. Sovateltide mimics the properties of a naturally occurring peptide called endothelin-1 (ET-1). ET-1 is known to activate two types of receptors in the body, namely endothelin A (ETARs) and endothelin B (ETBRs). Sovateltide is designed to activate the ETBRs specifically, making it a selective agonist for this receptor type. In fact, the aqueous solution of Sovateltide is susceptible to deterioration during storage. [0008] US8623823 discloses methods of using an ETB receptor agonist, such as IRL-1620, for the treatment of stroke or cerebrovascular accidents. The ETB receptor agonist is used alone or in combination with a second agent useful in the treatment of stroke or other cerebrovascular accidents. [0009] US10561704 discloses compositions and methods for treating neuropsychiatric disorders in vertebrates and humans. More specifically, the present invention provides for use of IRL-1620, an endothelin-B receptor agonist, in appropriate doses to be a neuroprotective and a neuroregenerative agent. Accordingly, in one aspect, the disclosure provides a method of treating a neuropsychiatric disorder comprising administering to a patient in need thereof a therapeutically effective amount of an endothelin-B receptor agonist to treat the neuropsychiatric disorder. In some embodiments, the endothelin-B receptor agonist is coadministered with an additional agent to treat the neuropsychiatric disorder. In some embodiments, the additional agent is selected from the group consisting of an antidepressant, an anti-inflammatory agent, a CNS stimulant, a neuroleptic, and an anti-proliferative agent. [0010] RU2739382C1 discloses FIELD: medicine. SUBSTANCE: invention refers to treating stroke, particularly to a new method for treating stroke involving administration of Imatinib. Imatinib is administered to a patient in dose of 650 to 1600 mg/day on day 1 and in dose of 650 to 1200 mg/day fo