Pharmaceutical composition comprising thrombolytic peptide-tetrahydroisoquinoline conjugate
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Publication Number
US-12059448-B2
Publication Date
2024-08-13
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 DC009 (LT3001) binary conjugate that includes the thrombolytic peptide Pro-Ala-Lys linked via a Lysine linking arm to a tetrahydroisoquinoline having two C1-4 alkyl groups. The DC009 conjugate is provided as a pharmaceutical composition formulated with pharmaceutically acceptable carriers and excipients.
The pharmaceutical composition is characterized by having a pH below 6.5, including pH about pH 2–5.5 and conditions exemplified around pH 4.5. The composition is described with acidic pH conditions together with buffer systems such as sodium acetate buffer, sodium citrate buffer, and sodium phosphate buffer, and it includes mannitol, sorbitol, sucrose, lactose, and trehalose, with an optional hydrochloride salt form.
The disclosed compositions are also provided in lyophilized formulation form intended for reconstitution for intravenous use. The document reports that physically and chemically stable lyophilized formulations remain stable over months at 25–40°C under the acidic formulation conditions, while neutral-to-basic pH shows reduced assay recovery.
Claims Coverage
The document includes two independent claim sets. Each independent claim is directed to a pharmaceutical composition comprising the stated compound (or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier/excipient, with the composition characterized by pH<6.5, and in one independent claim further limited to a specified list of excipients.
Pharmaceutical composition with pH<6.5
A pharmaceutical composition comprising a compound in a formula form (or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, wherein the composition has a pH<6.5.
Pharmaceutical composition with selected excipients and pH<6.5
A pharmaceutical composition comprising a compound in a formula form (or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient, wherein the composition has a pH of pH<6.5 and the pharmaceutically acceptable excipient is mannitol, sorbitol, sucrose, lactose, or trehalose.
Overall claim coverage centers on acidic pharmaceutical compositions (pH<6.5) of the compound (or pharmaceutically acceptable salts) formulated with pharmaceutically acceptable carriers/excipients, including formulations where the excipient is selected from mannitol, sorbitol, sucrose, lactose, or trehalose. Dependent claims further narrow pH ranges, optionally specify a hydrochloride salt, and include compound-to-excipient weight-ratio constraints and a lyophilized formulation.
Stated Advantages
Improved stability under acidic conditions is described, including reduced degradation and increased stability with certain excipients such as mannitol and trehalose/sucrose/lactose compared with other listed components.
Reduced assay recovery is described at neutral-to-basic pH, contrasted with better recovery/stability under the defined acidic conditions.
Physically and chemically stable lyophilized formulations remain stable over months at 25–40°C.
Documented Applications
Reconstitution for intravenous use is described for the lyophilized formulation.
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