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Sustained delivery of angiopoetin-like 3 polypeptides

A delivery system, C3-C6 technology, applied in the field of sustained release of therapeutic agents, can solve problems such as difficult controllability and difficult drug release

Pending Publication Date: 2021-05-07
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Often, drug release is not easily controllable and difficult to maintain for long periods of time

Method used

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  • Sustained delivery of angiopoetin-like 3 polypeptides
  • Sustained delivery of angiopoetin-like 3 polypeptides
  • Sustained delivery of angiopoetin-like 3 polypeptides

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0659] Seamless joint

[0660] This example describes the synthesis of a number of traceless linkers capable of conjugating both amine-containing drugs and carriers.

[0661]

[0662]

[0663] Synthesis of seamless joints

[0664] Common intermediate: L-INT-1c

[0665]

[0666] L-INT-1c.1-(Boc)-2-(hydroxymethyl)-4-(N-Cbz-β-alanyl)piperazine

[0667]

[0668] A 250-mL flask was charged with tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate SM-2 (5.81 g, 26.9 mmol), 3-(((benzyloxy)carbonyl)amino)propane Acid SM-1 (5 g, 22.4 mmol) and acetonitrile (100 mL). To this suspension was added triethylamine (9.37 mL, 67.2 mmol), HOBt (0.686 g, 4.48 mmol) and EDC.HCl (6.44 g, 33.6 mmol) in sequence. The reaction mixture was stirred at room temperature for 15 h. After this time, the mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed sequentially with 1M HCl solution, NaHCO 3 Wash with saturated solution...

example 2

[0775] Adducts of traceless linkers with bioactive moieties

[0776] This example describes the synthesis of a number of traceless linker-drug adducts that are also capable of being conjugated to a carrier. D1 as depicted below comprises an ANGPTL3 polypeptide (SEQ ID NO: 19) comprising amino acid residues 242-460 of reference SEQ ID NO: 1 and a K423Q substitution.

[0777]

[0778]

[0779] Synthesis of adducts

[0780] Acylation of bioactive moieties with traceless linkers:

[0781] L2-NHS.2-(Acetoxymethyl)-4-(N-(((1R',8'S,9's)-bicyclo[6.1.0]non-4'-yne-9'- Base) methoxycarbonyl) -β-alanyl) -1-piperazine acetic acid N-hydroxysuccinimidyl ester

[0782]

[0783] L2 (16 mg, 0.031 mmol) was dissolved in dimethyl sulfoxide (0.818 mL) to achieve a concentration of 38 mM. Triethylamine (3.46 μL, 0.025 mmol) was added followed by N,N′-disuccinimidyl carbonate (11.94 mg, 0.047 mmol) and the resulting clear solution was stirred at room temperature under argon for 1 h . ...

example 3

[0800] Functionalization of hyaluronic acid

[0801] This example describes the synthesis of functionalized hyaluronic acid, which can be a carrier itself, or can also be reacted with a crosslinking moiety to form a hydrogel.

[0802] Synthesis of hyaluronic acid intermediate [HA-N3]:

[0803]

[0804] Hyaluronic acid sodium salt is a linear polymer consisting of repeating dimer units of glucuronic acid and N-acetylgalactosamine, wherein the repeating unit has a molecular weight of 401.3Da. In this example, the number of moles of hyaluronic acid reported refers to the number of moles of repeating units, and the equivalents of reagents used to react with hyaluronic acid are reported relative to the number of moles of repeating units of hyaluronic acid. The average molecular weight of a polymer determines the average number of repeating units per polymer chain. Batches of hyaluronic acid sodium salt labeled as having a nominal average molecular weight of 200 kDa by the supp...

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PUM

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Abstract

Described herein are drug delivery systems for delivering biologically active agents comprising primary or secondary amines, or a ring nitrogen atom of an azaheteroaryl ring, pharmaceutically acceptable salts thereof, drug delivery reagents related thereto, pharmaceutical compositions comprising the drug delivery systems, and the use of the drug delivery systems as sustained release therapeutics.

Description

[0001] This application claims the benefit of US Provisional Application Serial No. 62 / 740,609, filed October 3, 2018, which is hereby incorporated by reference in its entirety. technical field [0002] Described herein are drug delivery systems for the delivery of bioactive agents comprising primary or secondary amines or ring nitrogen atoms of azaheteroaryl rings, pharmaceutically acceptable salts thereof, drug delivery agents related thereto, drugs comprising these Pharmaceutical compositions of delivery systems and the use of these drug delivery systems as sustained release therapeutic agents. [0003] References to Sequence Listings [0004] This application is filed with a Sequence Listing in computer readable form pursuant to 37 C.F.R. §1.821(c). The submitted text file "PAT058317-WO-PCT_SL.txt" was created on October 31, 2019, has a file size of 99,303 bytes, and is hereby incorporated by reference in its entirety. Background technique [0005] Modulation of the ph...

Claims

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Application Information

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IPC IPC(8): A61K47/61A61K47/69A61P27/02
CPCA61K47/6903A61K47/61A61K47/10A61K47/18A61K47/26A61K47/555A61K47/65A61P19/02C07K14/515A61K47/22A61K38/1891A61P27/02A61P21/00
Inventor C·亚当斯M·阿普里T·法扎尔C·J·福斯特N·格温E·C·霍尔J·B·G·A·朗格洛伊斯C·C-M·李
Owner NOVARTIS AG
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