Drug-loaded amino acid based poly (esterurea)films for controlled local release of non-opioid analgesic compounds

Patent metadata

Field	Value
Publication number	US-2025090475-A1
Application number	US-202117797567-A
Country	US
Kind code	A1
Filing date	Feb 4, 2021
Priority date	Feb 4, 2020
Publication date	Mar 20, 2025
Grant date	—

Abstract

In various embodiments, the present invention provides a drug-loaded amino acid-based poly(ester urea) film for controlled local release of non-opioid analgesic compounds and various methods for their making and use. In one or more embodiments, he present invention is directed to a drug-loaded amino acid-based poly(ester urea) film for controlled local release of non-opioid analgesic compounds comprising an amino acid-based poly(ester urea) polymer or copolymer and a therapeutically effective amount of a non-opioid analgesic compound. In various embodiments, these amino acid-based poly(ester urea) polymers or copolymers will comprise a plurality of diester monomer units connected by a carboxyl group to form a poly(ester urea) (PEU) polymer.

First claim

1 . A drug-loaded amino acid-based poly(ester urea) film for controlled local release of non-opioid analgesic compounds comprising:
an amino acid-based poly(ester urea) polymer or copolymer; and a therapeutically effective amount of a non-opioid analgesic compound.

2 . The drug-loaded amino acid-based poly(ester urea) film of claim 1 wherein said amino acid-based poly(ester urea) polymer or copolymer comprises a plurality of diester monomer units, said diester monomer units comprising the residues of two amino acids separated by from 6 to 12 carbon atoms.

3 . (canceled)

4 . The drug-loaded amino acid-based poly(ester urea) film of claim 1 wherein said amino acid-based poly(ester urea) polymer or copolymer is a polymer having the formula:

where a is an integer from 6 to 12, and p is an integer from 30 to 300.

5 . The drug-loaded amino acid-based poly(ester urea) film of claim 1 wherein said amino acid-based poly(ester urea) polymer or copolymer is a copolymer comprising:
a plurality of first diester monomer units, said first diester monomer units comprising the residues of two amino acids separated by from 6 to 12 carbon atoms; and
a plurality of second diester monomer units, said second diester monomer units comprising the residues of two amino acids separated by from 6 to 12 carbon atoms;
wherein the amino acid residues in said first diester-monomer units are different from the amino acid residues in said second diester monomer units.

6 . The drug-loaded amino acid-based poly(ester urea) film of claim 5 wherein said plurality of first diester monomer units comprise the residues of two valine molecules separated by from 6 to 12 carbon atoms.

7 . (canceled)

8 . (canceled)

9 . The drug-loaded amino acid-based poly(ester urea) film of claim 5 wherein said plurality of second diester monomer units comprise the residues of two phenylalanine molecules separated by from 6 to 12 carbon atoms.

10 . (canceled)

11 . (canceled)

12 . The drug-loaded amino acid-based poly(ester urea) film of claim 5 wherein said second diester monomer units comprise from about 10 mol % to about 50 mol % of said amino acid-based poly(ester urea) copolymer.

13 . The drug-loaded amino acid-based poly(ester urea) film of claim 5 wherein said amino acid-based poly(ester urea) copolymer is the reaction product of a first ion-protected diester monomer, a second ion-protected diester monomer, and a urea forming compound.

14 . (canceled)

15 . The drug-loaded amino acid-based poly(ester urea) film of claim 5 wherein said amino acid-based poly(ester urea) copolymer has a formula selected from:

where a is an integer from 5 to 11; b is an integer from 5 to 11; R is —CH(CH 3 ) 2 , —CH 3 , —(CH 2 ) 3 NHC(NH 2 )C═NH, —CH 2 CONH 2 , —CH 2 COOH, —CH 2 SH, —(CH 2 ) 2 COOH, —(CH) 2 CONH 2 , —NH 2 , —CH 2 C═CH—N═CH—NH, —CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —(CH 2 ) 4 NH 2 , —(CH 2 ) 2 SCH 3 , —CH 2 Ph, —CH 2 OH, —CH(OH)CH 3 , —CH 2 —C═CH—NH-Ph, —CH 2 -Ph-OH, or —CH 2 C 6 H 4 OCH 2 C 6 H 5 ; R′ is CH 2 Ph; n is a mole fraction from 0.9 to 0.6, and in is a mole fraction from 0.1 to 0.4.

16 . The drug-loaded amino acid-based poly(ester urea) film of claim 1 wherein said amino acid-based poly(ester urea) polymer or copolymer has a number average molecular weight of from about 10,000 Da to about 80,000 Da.

17 . The drug-loaded amino acid-based poly(ester urea) film of claim 1 wherein said non-opioid analgesic compound is selected from the group consisting of etoricoxib, bupivicaine, ropivacaine, lidocaine and pharmaceutically acceptable salts thereof.

18 . The drug-loaded amino acid-based poly(ester urea) film of claim 1 wherein said non-opioid analgesic compound is etoricoxib or a pharmaceutically acceptable salt thereof.

19 . The drug-loaded amino acid-based poly(ester urea) film of claim 1 wherein the non-opioid analgesic compound is substantially homogeneously distributed throughout the amino acid-based poly(ester urea) polymer or copolymer.

20 . The drug-loaded amino acid-based poly(ester urea) film of claim 1 comprising from about 1% to about 50%.

21 . The drug-loaded amino acid-based poly(ester urea) film of claim 1 having a thickness of from about 50 μm to about 500 μm

22 . The drug-loaded amino acid-based poly(ester urea) film of claim 1 having a thickness of from about 10 m to about 1000 μm.

23 . The drug-loaded amino acid-based poly(ester urea) film of claim 1 wherein said film continuously releases the non-opioid analgesic compound for from about 1 to about 187 days.

24 . The drug-loaded amino acid-based poly(ester urea) film of claim 1 wherein said film continuously releases the non-opioid analgesic compound for from about 3 to about 10 days.

25 . The drug-loaded amino acid-based poly(ester urea) film of claim 1 wherein the non-opioid analgesic compound is released by diffusion.

26 . The drug-loaded amino acid-based poly(ester urea) film of claim 18 having a Diffusivity Constant of from about 8.0×10 −7 cm 2 /s to about 2.0×10 −5 cm 2 /s.

27 . An amino acid-based poly(ester urea) film for controlled local release of at least one of etoricoxib and bupivacaine comprising from about 50 to about 99 weight percent of an amino acid-based poly(ester urea) polymer or copolymer and from about 1 to about 50 weight percent etoricoxib, bupivacaine or a pharmaceutically acceptable salt thereof.

28 . The amino acid-based poly(ester urea) film of claim 27 , wherein the amino acid-based poly(ester urea) polymer or copolymer has the formula:

where a is an integer from 5 to 11; b is an integer from 5 to 11; n is a mole fraction from 0.90 to 0.60; and m is a mole fraction from −0.10 to 0.40.

29 . The amino acid-based poly(ester urea) film of claim 27 , wherein the amino acid-based poly(ester urea) polymer or copolymer has the formula:

where n is a mole fraction from 0.90 to 0.70; m is a mole fraction from 0.10 to 0.30, and p is an integer from about 30 to about 300.

30 . (canceled)

31 . The amino acid-based poly(ester urea) film of claim 27 ,
comprising etoricoxib or a pharmaceutically acceptable salt thereof.

32 . The amino acid-based poly(ester urea) film claim 27 comprising bupivacaine or a pharmaceutically acceptable salt thereof.

33 . The amino acid-based poly(ester urea) film of claim 27 , wherein the amino acid-based poly(ester urea) polymer or copolymer has the formula:

where R is —CH(CH 3 ) 2 , —CH 3 , —(CH 2 ) 3 (NH 2 )C═NH, —CH 2 CON 2 , —CH 2 COOH, —CH 2 SH, —(CH 2 ) 2 COOH, —(CH 2 ) 2 CONH 3 , —NH 2 , —CH 2 C═CH—N═CH—NH, —CH(CH 3 )(CH 2 CH 3 ), —CH 2 CH(CH 3 ) 2 , —CH 2 ) 4 NH 2 , —CH 2 ) 2 SCH 3 , —CH 2 PH, —CH 2 OH, —CH(OH)CH 3 , —CH 2 —C═CH—NH-Ph, —CH 2 -Ph-OH, or —CH 2 C 6 H 4 OCH 2 C 6 H 5

Assignees

• Becker Matthew
• Forster Seth P
• Brigham Natasha
• Gustafson Tiffany
• Hermans Andre
• Nofsinger Rebecca
• Merk Sharp & Dohme Corp
• Univ Akron

Inventors

• Becker Matthew
• Forster Seth P
• Brigham Natasha
• Gustafson Tiffany
• Hermans Andre
• Nofsinger Rebecca

Classifications

• A61K9/0024

  Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue (compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L) · CPC title

• A61K47/34

  Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence) · CPC title

• A61P23/00

  Anaesthetics · CPC title

• A61K9/7007 Primary

  Drug-containing films, membranes or sheets (A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence) · CPC title

• A61K31/444 Primary

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title