Polymeric delivery agents and delivery agents compounds

• US 6,627,228 B1
• Filed: 10/09/2001
• Issued: 09/30/2003
• Est. Priority Date: 01/08/1999
• Status: Expired due to Term

• Current Assignee: NOVO Nordisk North America Operations A/S, Virginia Commonwealth University
• Original Assignee: Emisphere Technologies, Inc. (Novo Nordisk A/S)
• Inventors: Liao, Jun, Wang, Nai Fang, Barantsevitch, Eugene N., Conticello, Richard D., Milstein, Sam J., Smart, John E., Ottenbrite, Raphael M.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): TRAN, SUSAN T
• Application Number:
  US09/889,005
• Time in Patent Office: 721 Days
• Field of Search: 424/78.16, 424/451, 424/452, 424/464, 424/465, 424/489, 514/553, 514/561
• US Class Current: 424/489
• CPC Class Codes: A61K 38/27 Growth hormone [GH], i.e. somatotropin
• CPC Class Codes: A61K 38/29 Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 47/56 the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 5/06 of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
• CPC Class Codes: A61P 5/18 of the parathyroid hormones
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C08F 8/30 Introducing nitrogen atoms or nitrogen-containing groups
• CPC Class Codes: C08G 65/329 with organic compounds
• CPC Class Codes: C08G 65/33396 having oxygen in addition to nitrogen
• CPC Class Codes: C08L 2203/02 for biomedical use

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.

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—

, —

CH₂NH—

, —

NHCH₂—

, —

CH₂NHC(O)O—

, —

OC(O)NH₂—

, CH₂NHCOCH₂O—

, —

OCH₂C(O)NHCH₂—

, —

NHC(O)CH₂O—

, —

OCH₂C(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

or salts thereof where

R¹ 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—

, —

CH₂NH—

, —

NHCH₂—

, CH₂NHC(O)O—

, —

OC(O)NHCH₂—

, —

CH₂NHCOCH₂O—

, —

OCH₂C(O)NHCH₂—

, —

NHC(O)CH₂O—

, —

OCH₂C(O)NH—

, —

NH—

, —

O—

, and carbon-carbon bond;

R² is H or —

CH₃; and

R¹⁹ is H or —

COOH.

6. The polymeric delivery agent of claim 5 wherein R¹ is —

R³—

R⁴ where R³ is —

NHC(O)NH—

, —

C(O)NH—

, —

NHC(O)—

, —

OOC—

, —

COO—

, —

NHC(O)O—

, —

OC(O)NH—

, CH₂NH—

, —

NHCH₂—

, —

CH₂NHC(O)O—

, —

O₂C(O)NH—

, —

CH₂NHCOCH₂O—

, —

OCH₂C(O)NHCH₂—

, —

NHC(O)CH₂O—

, —

OCH₂C(O)NH—

, —

NH—

, —

O—

, or carbon-carbon bond; and

R⁴ has the formula

where

R⁵, R⁶, R⁷, R⁸ and R⁹ are independently a bond to R³, or H, Cl, Br, F, —

OH, —

CH₃, —

OCH₃, or —

(CH₂)_mCH₃;

R¹⁰ is a bond to R³ or —

COOH or —

C(O)NH—

R¹¹—

R¹²;

R¹¹ is a substituted or unsubstituted, linear or branched alkylene having a chain length of from about 1 to about 11 or —

R¹³—

R¹⁴—

;

R¹² is a bond to R³ or is —

COOH, —

NH₂, —

OH, —

C(O)—

R¹⁵, —

COO—

R¹⁵, —

NHR¹⁵, —

CR¹⁵, Cl, or Br;

R¹³ is a substituted or unsubstituted phenylene;

R¹⁴ is a substituted or unsubstituted, linear or branched alkylene having a chain length of from about 1 to about 5;

R¹⁵ is a bond to R³; and

m is from about 1 to about 4.

7. The polmeric delivery agent of claim 6 wherein R⁴ is selected from the group consisting of

and salts thereof.

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

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

or salts thereof where

R²³ is H or —

CH₃; and

n is from about 3 to about 200.

10. The polymeric delivery agent of claim 9 wherein R¹⁶ and R¹⁸ are independently —

R³—

R⁴ where R³ is —

NHC(O)NH—

, —

C(O)NH—

, —

NHC(O)—

, —

OOC—

, —

COO—

, —

NHC(O)O—

, —

OC(O)NH—

, —

CH₂NH—

, —

NHCH₂—

, —

CH₂NHC(O)O—

, —

OC(O)NHCH₂—

, —

CH₂NHCOCH₂O—

, —

OCH₂C(O) NHCH₂—

, —

NHC(O)CH₂O—

, —

OCH₂C(O)NH—

, —

NH—

, —

O—

, or carbon-carbon bond; and

R⁴ has the formula

where

R⁵ R⁶, R⁷, R⁸, and R⁹ are independently a bond to R³, or H, Cl, Br, F, —

OH, —

CH₃, —

OCH₃, or —

(CH₂)_mCH₃;

R¹⁰ is a bond to R³ or —

COOH or —

C(O)NH—

R¹¹—

R¹²;

R¹¹ is a substituted or unsubstituted, linear or branched alkylene having a chain length of from about 1 to about 11 or —

R¹³—

R¹⁴—

;

R¹² is a bond to R³ or is —

COOH, —

NH₂, —

OH, —

C(O)—

R¹⁵, —

COO—

R¹⁵, —

NHR¹⁵, —

OR¹⁶, Cl, or Br;

R¹³ is a substituted or unsubstituted phenylene;

R¹⁴ is a substituted or unsubstituted, linear or branched alkylene having a chain length of from about 1 to about 5;

R¹⁵ is a bond to R³; and

m is from about 1 to about 4.

11. The polymeric delivery agent of claim 10 wherein R⁴ is selected from the group consisting of

and salts thereof.

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

or salts thereof where

R²⁰, R²¹, and R²² 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—

, —

CH₂NH—

, —

NHCH₂—

, —

CH₂NHC(O)O—

, —

OC(O)NHCH₂—

, —

CH₂NHCOCH₂O—

, —

OCH₂C(O)NHCH₂—

, —

NHC(O)CH₂O—

, —

OCH₂C(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 R²⁰, R²¹ and R²² are independently —

R³—

R⁴ where R³ is —

NHC(O)NH—

, —

C(O)NH—

, —

NHC(O)—

, —

OOC—

, —

COO—

, —

NHC(O)O—

, —

OC(O)NH—

, —

CH₂NH—

, —

NHCH₂—

, —

CH₂NHC(O)O—

, —

OC(O)NHCH₂—

, —

CH₂NHCOCH₂O—

, —

OCH₂C(O)NHCH₂—

, —

NHC(O)CH₂O—

, —

OCH₂C(O)NH—

, —

NH—

, —

O—

, or carbon-carbon bond; and

4 has the formula

where

R⁵, R⁶, R⁷, R⁸, and R⁹ are independently a bond to R³, or H, Cl, Br, F, —

OH, —

CH₃, —

OCH₃, or —

(CH₂)_mCH₃;

R¹⁰ is a bond to R³ or —

COOH or —

C(O)NH—

R¹¹—

R¹²;

R¹¹ is a substituted or unsubstituted, linear or branched alkylene having a chain length of from about 1 to about 11 or —

R¹³—

R¹⁴—

;

R¹² is a bond to R³ or is —

COOH, —

NH₂, —

OH, —

C(O)—

R¹⁵, —

COO—

R¹⁵, —

NHR¹⁵, —

OR¹⁵, Cl, or Br;

R¹³ is a substituted or unsubstituted phenylene;

R¹⁴ is a substituted or unsubstituted, linear or branched alkylene having a chain length of from about 1 to about 5;

R¹⁵ is a bond to R³; and

m is from about 1 to about 4.

14. The polymeric delivery agent of claim 13 wherein R⁴ is selected from the group consisting of

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, α

- interferon, β

- interferon, γ

-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.