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Claims for Patent: 6,627,228

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Summary for Patent: 6,627,228
Title: Polymeric delivery agents and delivery agents compounds
Abstract:Polymeric delivery agents, delivery agent compounds and compositions comprising them which are useful in the delivery of active agents are provided. Methods of administration and preparation are provided as well.
Inventor(s): Milstein; Sam J. (Larchmont, NY), Barantsevitch; Eugene N. (Scarsdale, NY), Wang; Nai Fang (Long Island City, NY), Liao; Jun (Tarrytown, NY), Smart; John E. (Katonah, NY), Conticello; Richard D. (Ossining, NY), Ottenbrite; Raphael M. (Midlothian, VA)
Assignee: Emisphere Technologies, Inc. (Tarrytown, NY)
Application Number:09/889,005
Patent Claims:1. A polymeric delivery agent comprising a polymer conjugated to a modified amino acid or derivative thereof via a linkage group selected from the group consisting of --NHC(O)NH--, --C(O)NH--, --NHC(O)--, --OOC--, --COO--, --NHC(O)O--, --OC(O)NH--, --CH.sub.2 NH--, --NHCH.sub.2 --, --CH.sub.2 NHC(O)O--, --OC(O)NH.sub.2 --, CH.sub.2 NHCOCH.sub.2 O--, --OCH.sub.2 C(O)NHCH.sub.2 --, --NHC(O)CH.sub.2 O--, --OCH.sub.2 C(O)NH--, --NH--, --O--, and carbon-carbon bond, with the proviso that the polymeric delivery agent is not a polypeptide or polyamino acid, wherein the modified amino acids are acylated or sulfonated amino acids, ketones or aldehydes of acylated or sulfonated amino acids, salts thereof, or polyamino acids or polypeptides of any of the foregoing, and the polymer is selected from the group consisting of polyethylene; polyacrylates; polymethacrylates; poly(oxyethylene); poly(propylene); polypropylene glycol; polyethylene glycol (PEG); PEG-maleic anhydride copolymers; and derivatives and combinations thereof.

2. The polymeric delivery agent of claim 1 wherein the polymer has a molecular weight of from about 100 to about 200,000 daltons.

3. The polymeric delivery agent of claim 2 wherein the molecular weight is from 200 to about 10,000 daltons.

4. The polymeric delivery agent of claim 3 wherein the molecular weight is from about 200 to about 600 daltons.

5. The polymeric delivery agent of claim 1 wherein the polymeric delivery agent comprises units having the formula ##STR18##

or salts thereof where R.sup.1 is a modified amino acid which is bonded to the polymer via a linkage group selected from the group consisting of --NHC(O)NH--, --C(O)NH--, --NHC(O)--, --OOC--, --COO--, --NHC(O)O--, --OC(O)NH--, --CH.sub.2 NH--, --NHCH.sub.2 --, CH.sub.2 NHC(O)O--, --OC(O)NHCH.sub.2 --, --CH.sub.2 NHCOCH.sub.2 O--, --OCH.sub.2 C(O)NHCH.sub.2 --, --NHC(O)CH.sub.2 O--, --OCH.sub.2 C(O)NH--, --NH--, --O--, and carbon-carbon bond; R.sup.2 is H or --CH.sub.3 ; and R.sup.19 is H or --COOH.

6. The polymeric delivery agent of claim 5 wherein R.sup.1 is --R.sup.3 --R.sup.4 where R.sup.3 is --NHC(O)NH--, --C(O)NH--, --NHC(O)--, --OOC--, --COO--, --NHC(O)O--, --OC(O)NH--, CH.sub.2 NH--, --NHCH.sub.2 --, --CH.sub.2 NHC(O)O--, --O.sub.2 C(O)NH--, --CH.sub.2 NHCOCH.sub.2 O--, --OCH.sub.2 C(O)NHCH.sub.2 --, --NHC(O)CH.sub.2 O--, --OCH.sub.2 C(O)NH--, --NH--, --O--, or carbon-carbon bond; and R.sup.4 has the formula ##STR19##

where R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are independently a bond to R.sup.3, or H, Cl, Br, F, --OH, --CH.sub.3, --OCH.sub.3, or --(CH.sub.2).sub.m CH.sub.3 ; R.sup.10 is a bond to R.sup.3 or --COOH or --C(O)NH--R.sup.11 --R.sup.12 ; R.sup.11 is a substituted or unsubstituted, linear or branched alkylene having a chain length of from about 1 to about 11 or --R.sup.13 --R.sup.14 --; R.sup.12 is a bond to R.sup.3 or is --COOH, --NH.sub.2, --OH, --C(O)--R.sup.15, --COO--R.sup.15, --NHR.sup.15, --CR.sup.15, Cl, or Br; R.sup.13 is a substituted or unsubstituted phenylene; R.sup.14 is a substituted or unsubstituted, linear or branched alkylene having a chain length of from about 1 to about 5; R.sup.15 is a bond to R.sup.3 ; and m is from about 1 to about 4.

7. The polmeric delivery agent of claim 6 wherein R.sup.4 is selected from the group consisting of ##STR20## ##STR21##

and salts thereof.

8. The polymeric delivery agent of claim 1 wherein the polymeric delivery agent comprises units having the formula:

or salts thereof where R.sup.16 is a modified amino acid which is bonded to the polymer via a linkage group selected from the group consisting of --NHC(O)NH--, --C(O)NH--, --NHC(O)--, --OOC--, --COO--, --NHC(O)O--, --OC(O)NH--, --CH.sub.2 NH--, --NHCH.sub.2 --, --CH.sub.2 NHC(O)O--, --OC(O)NHCH.sub.2 --, --CH.sub.2 NHCOCH.sub.2 O--, --OCH.sub.2 C(O)NHCH.sub.2 --, --NHC(O)CH.sub.2 O--, --OCH.sub.2 C(O)NH--, --NH--, --O--, and carbon-carbon bond; R.sup.17 is --OH, --OCH.sub.3, or --R.sup.18 ; R.sup.18 is defined as R.sup.16 above; and R.sup.24 is a polymer having units of --(CH.sub.2 CH.sub.2 O)--, --CH(CH.sub.3)CH.sub.2 O)--, or a combination thereof.

9. The polymeric delivery agent of claim 8 wherein the polymeric delivery agent comprises units having the formula: ##STR22##

or salts thereof where R.sup.23 is H or --CH.sub.3 ; and n is from about 3 to about 200.

10. The polymeric delivery agent of claim 9 wherein R.sup.16 and R.sup.18 are independently --R.sup.3 --R.sup.4 where R.sup.3 is --NHC(O)NH--, --C(O)NH--, --NHC(O)--, --OOC--, --COO--, --NHC(O)O--, --OC(O)NH--, --CH.sub.2 NH--, --NHCH.sub.2 --, --CH.sub.2 NHC(O)O--, --OC(O)NHCH.sub.2 --, --CH.sub.2 NHCOCH.sub.2 O--, --OCH.sub.2 C(O) NHCH.sub.2 --, --NHC(O)CH.sub.2 O--, --OCH.sub.2 C(O)NH--, --NH--, --O--, or carbon-carbon bond; and R.sup.4 has the formula ##STR23##

where R.sup.5 R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are independently a bond to R.sup.3, or H, Cl, Br, F, --OH, --CH.sub.3, --OCH.sub.3, or --(CH.sub.2).sub.m CH.sub.3 ; R.sup.10 is a bond to R.sup.3 or --COOH or --C(O)NH--R.sup.11 --R.sup.12 ; R.sup.11 is a substituted or unsubstituted, linear or branched alkylene having a chain length of from about 1 to about 11 or --R.sup.13 --R.sup.14 --; R.sup.12 is a bond to R.sup.3 or is --COOH, --NH.sub.2, --OH, --C(O)--R.sup.15, --COO--R.sup.15, --NHR.sup.15, --OR.sup.16, Cl, or Br; R.sup.13 is a substituted or unsubstituted phenylene; R.sup.14 is a substituted or unsubstituted, linear or branched alkylene having a chain length of from about 1 to about 5; R.sup.15 is a bond to R.sup.3 ; and m is from about 1 to about 4.

11. The polymeric delivery agent of claim 10 wherein R.sup.4 is selected from the group consisting of ##STR24## ##STR25##

and salts thereof.

12. The polymeric delivery agent of claim 1 wherein the polymeric delivery agent comprises units having the formula: ##STR26##

or salts thereof where R.sup.20, R.sup.21, and R.sup.22 independently are H or a modified amino acid which is bonded to the polymer via a linkage group selected from the group consisting of --NHC(O)NH--, --C(O)NH--, --NHC(O)--, --OOC--, --COO--, --NHC(O)O--, --OC(O)NH--, --CH.sub.2 NH--, --NHCH.sub.2 --, --CH.sub.2 NHC(O)O--, --OC(O)NHCH.sub.2 --, --CH.sub.2 NHCOCH.sub.2 O--, --OCH.sub.2 C(O)NHCH.sub.2 --, --NHC(O)CH.sub.2 O--, --OCH.sub.2 C(O)NH--, --NH--, --O--, and carbon-carbon bond; a, b, and c independently are integers from about 1 to about 50; and d ranges from about 2 to about 10.

13. The polymeric delivery agent of claim 12 wherein R.sup.20, R.sup.21 and R.sup.22 are independently --R.sup.3 --R.sup.4 where R.sup.3 is --NHC(O)NH--, --C(O)NH--, --NHC(O)--, --OOC--, --COO--, --NHC(O)O--, --OC(O)NH--, --CH.sub.2 NH--, --NHCH.sub.2 --, --CH.sub.2 NHC(O)O--, --OC(O)NHCH.sub.2 --, --CH.sub.2 NHCOCH.sub.2 O--, --OCH.sub.2 C(O)NHCH.sub.2 --, --NHC(O)CH.sub.2 O--, --OCH.sub.2 C(O)NH--, --NH--, --O--, or carbon-carbon bond; and 4 has the formula ##STR27##

where R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are independently a bond to R.sup.3, or H, Cl, Br, F, --OH, --CH.sub.3, --OCH.sub.3, or --(CH.sub.2).sub.m CH.sub.3 ; R.sup.10 is a bond to R.sup.3 or --COOH or --C(O)NH--R.sup.11 --R.sup.12 ; R.sup.11 is a substituted or unsubstituted, linear or branched alkylene having a chain length of from about 1 to about 11 or --R.sup.13 --R.sup.14 --; R.sup.12 is a bond to R.sup.3 or is --COOH, --NH.sub.2, --OH, --C(O)--R.sup.15, --COO--R.sup.15, --NHR.sup.15, --OR.sup.15, Cl, or Br; R.sup.13 is a substituted or unsubstituted phenylene; R.sup.14 is a substituted or unsubstituted, linear or branched alkylene having a chain length of from about 1 to about 5; R.sup.15 is a bond to R.sup.3 ; and m is from about 1 to about 4.

14. The polymeric delivery agent of claim 13 wherein R.sup.4 is selected from the group consisting of ##STR28## ##STR29##

and salts thereof.

15. A composition comprising (a) in active agent; and (b) the polymeric delivery agent of claim 1.

16. A composition comprising (a) an active agent; and (b) the polymeric delivery agent of claim 5.

17. A composition comprising (a) an active agent; and (b) the polymeric delivery agent of claim 8.

18. A composition comprising (a) an active agent; and (b) the polymeric delivery agent of claim 12.

19. The composition of claim 15, wherein the active agent is selected from the group consisting of a biologically active agent, a chemically active agent, and a combination thereof.

20. The composition of claim 19, wherein the biologically active agent comprises at least one protein, polypeptide, peptide, hormone, polysaccharide, mucopolysaccharide, carbohydrate, or lipid.

21. The composition of claim 20, wherein the biologically active agent is selected from the group consisting of human growth hormone, recombinant human growth hormone, bovine growth hormone, porcine growth hormone, growth hormone-releasing hormone, an interferon, .alpha.- interferon, .beta.- interferon, .gamma.-interferon, interleukin-1, interleukin-2, insulin, porcine insulin, bovine insulin, human insulin, human recombinant insulin, insulin-like growth factor (IGF), IGF-1, heparin, unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, calcitonin, salmon calcitonin, eel calcitonin, human calcitonin, erythropoietin, atrial naturetic factor, an antigen, a monoclonal antibody, somatostatin, protease inhibitors, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, leutinizing-hormone-releasing-hormone, follicle stimulating hormone, glucocerebrosidase, thrombopoietin, fugrastim, prostaglandins, cyclosporin, vasopressin, cromolyn sodium, soium chromoglycate, disodium chromoglycate, vancomycin, parathyroid hormone, fragments of parathyroid hormone; desferrioxamine, antimicrobials, anti-fungal agents, vitamins; analogs, fragments, mimetics and polyethylene glycol-modified derivatives of these compounds; and any combination thereof.

22. The composition of claim 21 wherein the active agent comprises insulin, unfractionated heparin, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, calcitonin, parathyroid hormone, erythropoietin, human growth hormone, recombinant human growth hormone, or combinations thereof.

23. A dosage unit form comprising: (A) the composition of claim 15; and (B) (a) an excipient (b) a diluent, (c) a disintegrant, (d) a lubricant, (e) a plasticizer, (f) a colorant, (g) a design vehicle, or (h) any combination thereof.

24. The dosage unit form of claim 23, comprising a tablet, a capsule, a powder, or a liquid.

25. A method for administering a biologically-active agent to an animal in need of the agent comprising orally administering to said animal the composition of claim 15.

26. A method for preparing a composition, said method comprising: mixing: (A) at active agent; (B) the polymeric delivery agent of claim 1; and (C) optionally, a dosing vehicle.

27. A method for administering a biologically-active agent to an animal in need of the agent comprising intracolonically administering to said animal the composition of claim 15.

Summary for Patent:   Start Trial

PCT Information
PCT FiledJanuary 07, 2000PCT Application Number:PCT/US00/00476
PCT Publication Date:July 13, 2000PCT Publication Number:WO00/40203

Details for Patent 6,627,228

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Nps Pharms Inc NATPARA parathyroid hormone INJECTABLE;INJECTION 125511 001 2015-01-23   Start Trial Emisphere Technologies, Inc. (Tarrytown, NY) 2019-01-08 RX Orphan search
Nps Pharms Inc NATPARA parathyroid hormone INJECTABLE;INJECTION 125511 002 2015-01-23   Start Trial Emisphere Technologies, Inc. (Tarrytown, NY) 2019-01-08 RX Orphan search
Nps Pharms Inc NATPARA parathyroid hormone INJECTABLE;INJECTION 125511 003 2015-01-23   Start Trial Emisphere Technologies, Inc. (Tarrytown, NY) 2019-01-08 RX Orphan search
Nps Pharms Inc NATPARA parathyroid hormone INJECTABLE;INJECTION 125511 004 2015-01-23   Start Trial Emisphere Technologies, Inc. (Tarrytown, NY) 2019-01-08 RX Orphan search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

International Patent Family for US Patent 6,627,228

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