Nylon-3 co-polymers and synthetic lung surfactant compositions containing same

Patent metadata

Field	Value
Publication number	US-10736915-B2
Application number	US-201815888720-A
Country	US
Kind code	B2
Filing date	Feb 5, 2018
Priority date	Mar 19, 2010
Publication date	Aug 11, 2020
Grant date	Aug 11, 2020

Abstract

Non-natural oligomers have recently shown promise as functional analogues of lung surfactant proteins B and C (SP-B and SP-C), two helical and amphiphilic proteins that are critical for normal respiration. The generation of non-natural mimics of SP-B and SP-C has previously been restricted to step-by-step, sequence-specific synthesis, which results in discrete oligomers that are intended to manifest specific structural attributes. Presented herein an alternative approach to SP-B mimicry that is based on sequence-random copolymers containing cationic and lipophilic subunits. These materials, members of the nylon-3 family, are prepared by ring-opening polymerization of β-lactams. The best of the nylon-3 polymers display promising in vitro surfactant activities in a mixed lipid film. Pulsating bubble surfactometry data indicate that films containing the most surface-active polymers attain adsorptive and dynamic-cycling properties that surpass those of discrete peptides intended to mimic SP-B. Attachment of an N-terminal octadecanoyl unit to the nylon-3 copolymers affords further improvements by reducing the percent surface area compression to reach low minimum surface tension.

First claim

What is claimed is:

1. An artificial lung surfactant composition comprising a polymer, wherein the polymer is a random copolymer comprising monomers, wherein the monomers comprise a first set of monomers and a second set of monomers, wherein:
each monomer in the first set has a structure of:

wherein one of R 3 , R 4 , R 5 , and R 6 in each monomer in the first set is amino or amino-C 1 -C 6 -alkyl and three of R 3 , R 4 , R 5 , and R 6 in each monomer in the first set are independently selected from the group consisting of hydrogen and methyl; and
each monomer in the second set has a structure of:

wherein:
one of R 3 and R 4 combined with one of R 5 and R 6 in each monomer in the second set, together with the carbon atoms to which they are attached, define a cyclic moiety “A”

A together with the carbon atoms to which it is attached is unsubstituted C 8 cycloalkyl; and
the other of R 3 and R 4 and the other of R 5 and R 6 in each monomer in the second set are hydrogen;

the monomers of the first set and the monomers of the second set are present in the polymer in a proportion of from 1:2 to 2:1 (monomers of the first set:monomers of the second set);
the first set of monomers and the second set of monomers are present in the polymer in a degree of polymerization of from about 16 to about 22; and
the polymer yields:
an average surface tension no higher than 35 mN m −1 with 0.40-mm radius bubbles composed of 1,2-diacyl-sn-glycero-3-phosphocholine (DPPC):1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-rac-(1-glycerol)]:palmitic acid (POPG): palmitic acid (PA) at a ratio of 68:22:9 (wt:wt:wt) within 5 minutes of exposure thereto at 37° C. in static-bubble mode of pulsating bubble surfactometry;
a maximum average surface tension less than 45 mN m −1 and a minimum average surface tension less than 2 mN m −1 with 0.40-mm radius bubbles composed of DPPC:POPG:PA at a ratio of 68:22:9 (wt:wt:wt) at 5 minutes pulsation at 37° C. in dynamic-bubble mode of pulsating bubble surfactometry;
an average percent surface area compression of less than 26.4% to reach a surface tension of 20 mN m −1 with 0.40-mm radius bubbles composed of DPPC:POPG:PA at a ratio of 68:22:9 (wt:wt:wt) at 5 minutes pulsation at 37° C. in dynamic-bubble mode of pulsating bubble surfactometry; or
a combination thereof.

2. The artificial lung surfactant composition of claim 1 , wherein at least one of R 3 , R 4 , R 5 , and R 6 in at least some of the monomers in the first set is methyl.

3. The artificial lung surfactant composition of claim 2 , wherein two of R 3 , R 4 , R 5 , and R 6 in the at least some of the monomers in the first set is hydrogen.

4. The artificial lung surfactant composition of claim 1 , wherein at least two of R 3 , R 4 , R 5 , and R 6 in at least some of the monomers in the first set are methyl.

5. The artificial lung surfactant composition of claim 4 , wherein one of R 3 , R 4 , R 5 , and R 6 in the at least some of the monomers in the first set is hydrogen.

Assignees

• Wisconsin Alumni Res Found
• Univ Northwestern

Inventors

• Gellman Samuel H
• Stahl Shannon S
• Mowery Brendan P
• Barron Annelise
• Dohm Michelle

Classifications

• A61K31/785 Primary

  Polymers containing nitrogen · CPC title

• A61K9/0082

  Lung surfactant, artificial mucus · CPC title

• A61K47/32

  Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers {, poly(meth)acrylates, or polyvinyl pyrrolidone} · CPC title

• C08L77/02

  Polyamides derived from omega-amino carboxylic acids or from lactams thereof (C08L77/10 takes precedence) · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title