Pharmaceutical composition comprising thrombolytic peptide-tetrahydroisoquinoline conjugate
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Publication Number
US-11707501-B2
Publication Date
2023-07-25
Expiration Date
Abstract
The present invention provides a pharmaceutical composition comprising a binary conjugate, DC009, which is a conjugate of a thrombolytic peptide (Pro-Ala-Lys) and a tetrahydroisoquinoline compound having two C1-4 alkyl groups via a lysine linking arm, and a pharmaceutical acceptable carrier. The composition has a pH less than 6.5, preferably has a pH about pH 2-5.5 The composition may comprise a pharmaceutical acceptable excipient such as mannitol, sorbitol, sucrose, lactose, or trehalose.
Core Innovation
The invention relates to a pharmaceutical composition containing DC009 (LT3001), a lysine-linked thrombolytic peptide–tetrahydroisoquinoline conjugate, in combination with a pharmaceutically acceptable carrier and formulated at an acidic pH of less than 6.5, described as about pH 2–5.5. The composition includes pharmaceutically acceptable excipients selected from mannitol, sorbitol, sucrose, lactose, and trehalose, and defines a compound versus excipient weight ratio from about 1:1 to about 1:9 to support the stability of DC009 (LT3001) under acidic conditions.
The invention further provides lyophilized pharmaceutical compositions using lyophilization-capable excipients, with stability results described for acidic buffers and improved stability for selected excipients, particularly mannitol and sorbitol. The lyophilized formulations can be reconstituted for IV use while remaining physically and chemically stable.
Claims Coverage
The disclosed independent claims define two composition types: a non-lyophilized pharmaceutical composition with an acidic pH and an excipient selected from a defined group, and a lyophilized pharmaceutical composition with mannitol, a specified compound-to-mannitol weight ratio, and a reconstituted pH target. Each independent claim is built around the specified conjugate or its pharmaceutically acceptable salt together with tightly constrained pH and excipient/ratio parameters.
Acidic pharmaceutical composition with defined excipient group and ratio
A pharmaceutical composition comprising a compound having the following formula or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient selected from the group consisting of mannitol, sorbitol, sucrose, lactose, and trehalose, wherein the composition has a pH of about pH 2–pH 5.5, and the weight ratio of the compound versus the pharmaceutically acceptable excipient is about 1:1 to 1:9.
Lyophilized composition with mannitol, defined compound-to-mannitol ratio, and reconstituted pH
A lyophilized pharmaceutical composition comprising a compound having the following formula or a pharmaceutically acceptable salt thereof and mannitol, wherein the weight ratio of the compound versus mannitol is about 1:1.3 to 1:3.8, and the pH of the pharmaceutical composition is about 4.5 after reconstituted to 10 mg/mL to 20 mg/mL by saline.
Across the independent claims, the main inventive coverage is directed to stabilizing DC009 (LT3001) formulations by restricting the formulation pH to an acidic range, selecting specific pharmaceutically acceptable excipients including mannitol, and controlling the compound-to-excipient weight ratio; for lyophilized products, the claim further specifies a compound-to-mannitol ratio and a pH requirement after saline reconstitution.
Stated Advantages
Improved stability with specific excipients, particularly mannitol and sorbitol, in acidic buffers.
Lyophilized formulations remain physically and chemically stable and can be reconstituted.
Documented Applications
IV use after reconstitution of a lyophilized formulation.
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