Pharmaceutical composition containing an active agent in an amino acid copolymer structure

• US 7,018,654 B2
• Filed: 11/08/2001
• Issued: 03/28/2006
• Est. Priority Date: 03/05/1999
• Status: Expired due to Term

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: New River Pharmaceuticals Inc. (Shire plc)
• Inventors: Kirk, Randal J., Latham, Keith R.
• Primary Examiner(s): Naff, David M.
• Assistant Examiner(s): Ware, Deborah K.
• Application Number:
  US09/986,426
• Publication Number:
  US 20020128177A1
• Time in Patent Office: 1,601 Days
• Field of Search: 424/484, 424/486, 424/78.08, 424/1.69, 424/9.34, 514/2, 514/773, 435/174
• US Class Current: 424/484
• CPC Class Codes: A61K 47/34 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 Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61K 47/645 Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/2045 Polyamides; Polyaminoacids, e.g. polylysine
• CPC Class Codes: C08G 69/10 Alpha-amino-carboxylic acids polysuccinimides C08G73/1092

Abstract

A method of protecting a chemical compound from degradation comprising combining the chemical compound with an amino acid polymer. Disclosed are methods of combining chemical compounds with synthetic amino acid polymers for protection from degradation of the chemical compounds and to provide for controlled release of the compounds. A method is described for the selective release of drug substances from a synthetic amino acid polymer in the stomach or small intestine, utilizing pH-dependent changes in a higher order structure. A pharmaceutical composition comprising a drug substance that has been combined with an amino acid polymer and a pharmaceutically acceptable combination of excipients is disclosed. A cell culture media comprising a polypeptide containing glutamine that has been co-polymerized with an amino acid is described.

Claims

1. A pharmaceutical composition comprising:

(i) an active agent non-covalently linked in an internalized domain or pocket of an amino acid copolymer structure wherein said amino acid copolymer structure comprises at least one hydrophilic component and at least one hydrophobic component designed to promote the formation of said internalized domain or pocket; and

(ii) said hydrophilic component and hydrophobic component are selected to manipulate the tertiary structure of said amino acid copolymer structure to control degradation and release of said active agent;

wherein said hydrophilic component is lysine, arginine, asparagine, cysteine, glutamic acid or combinations thereof;

wherein said hydrophobic component is valine, tyrosine, proline, leucine, tryptophan, methionine, phenylalanine, glycine, isoleucine, benzyl glutamic acid, or combinations thereof; and

wherein said composition is in a form suitable for oral administration.

2. The pharmaceutical composition of claim 1, wherein said amino acid copolymer structure comprises at least one D-amino acid.

3. The pharmaceutical composition of claim 1, wherein said amino acid copolymer structure has a length between 5 and 400 amino acids.

4. The pharmaceutical composition of claim 1, wherein said amino acid copolymer structure contains is a mixture of polypeptides of varying length.

5. The pharmaceutical composition of claim 1, wherein the active agent is selected from the group consisting of a nutrient, a hormone, a neurotransmitter, and a metabolic intermediate.

6. The pharmaceutical composition of claim 1, wherein said active agent is selected from L-Dopa, 3-iodo-tyrosine, 3, 5-diiodo-tyrosine, L-thyroxine, glutamine, iodothyronine, aspirin, tryptophan and hydrocortisone.

7. The pharmaceutical composition of claim 1, further comprising at least one excipient.

8. The pharmaceutical composition of claim 7, wherein said excipient is a filler, a pH buffer, an anti-oxidant, a disintegrant, a glidant, a lubricant, or a binder.

9. The pharmaceutical composition of claim 1, wherein said amino acid copolymer structure is a copolymer of glutamic and tyrosine.

10. The pharmaceutical composition of claim 1, wherein said amino acid copolymer structure is a co-polymer of lysine and phenylalanine and the active agent is hydrocortisone.

11. The pharmaceutical composition of claim 1, wherein said amino acid copolymer structure has a free energy of folding between about 3 kcal/mol and about 50 kcal/mol.

12. The pharmaceutical composition of claim 1, wherein said amino acid copolymer structure is formulated for release of a pharmaceutically effective amount of said active agent in the small intestine.

13. The pharmaceutical composition of claim 1, wherein said amino acid copolymer is formulated for release of a pharmaceutically effective amount of said active agent in the stomach.

14. The composition of claim 1, wherein said amino acid copolymer structure is selected from co-polymers of (1) glutamic acid and phenylalanine and (2) lysine and phenylalanine;

and the active agent is L-DOPA.

15. The composition of claim 1, wherein said amino acid copolymer structure is selected from co-polymers of (1) glutamic acid and phenylalanine and (2) lysine and phenylalanine;

and the active agent is aspirin.

17. The pharmaceutical composition of claim 1, or claim 16, wberein said amino acid copolymer structure is a copolymer of lysine and phenylalanine.

18. The pharmaceutical composition of claim 1, or claim 16, wherein said amino acid copolymer structure is a copolymer of lysine and tyrosine.

20. The pharmaceutical composition of claim 1 or claim 16, wherein said amino acid copolymer structure is a copolymer of glutamic acid and proline.

21. The pharmaceutical composition of claim 1 or claim 16, wherein said amino acid copolymer structure is a copolymer of lysine and tryptophan.

22. The pharmaceutical composition of claim 1 or claim 16, wherein said amino acid copolymer structure is a copolymer of glutainic acid and phenylalanine.

23. The pharmaceutical composition of claim 1 or claim 16, wherein said amino acid coplymer structure is a copolymer of glutamic acid, proline, and tyrosine.

24. The pharmaceutical composition of claim 1 or claim 16, wherein said amino acid copolymer structure is a copolymer of glutamic acid, proline, cysteine and tyrosine.

25. The pharmaceutical composition of claim 1 or claim 16, wherein said amino acid copolymer structure is a copolymer arginine and at least one amino acid selected from valine, tyrosine, proline, leucine, tryptophan, methionine, phenylalanine, glycine, isoleucine, and benzyl glutamic acid.

26. The pharmaceutical composition of claim 1 or claim 16, wherein said amino acid copolymer structure is a copolymer of arginine and glycine.

16. A pharmaceutical composition comprising:

(i) an active agent non-covalently linked in an internalized domain or pocket of an amino acid copolymer structure wherein said amino acid copolymer structure consists essentially of at least one hydrophilic component and at least one hydrophobic component designed to promote the formation of said internalized domain or pocket; and

(ii) said hydrophilic component and hydrophobic component are selected to manipulate the tertiary structure of said amino acid copolymer structure to control degradation and release of said active agent;

wherein said hydrophilic component is lysine, arginine, asparagine, cysteine, glutamic acid or combinations thereof;

wherein said hydrophobic component is valine, tyrosine, proline, leucine, tryptophan, methionine, phenylalanine, glycine, isoleucine, benzyl glutamic acid, or combinations thereof; and

wherein said composition is in a form suitable for oral administration.

19. The pharmaceutical composition of claim 16, wherein said amino acid copolymer structure is a copolymer of glutamic acid and tyrosine.