Insulin-oligomer conjugates, formulations and uses thereof

• US 7,872,095 B2
• Filed: 07/19/2005
• Issued: 01/18/2011
• Est. Priority Date: 07/19/2004
• Status: Active Grant

• Current Assignee: Biocon Limited (Biocon Incorporated)
• Original Assignee: Biocon Limited (Biocon Incorporated)
• Inventors: James, Kenneth D., Ferro, Michelle, Radhakrishnan, Balasingam, Ekwuribe, Nnochiri N., Aggarwal, Diti, Malkar, Navdeep B., Puskas, Monica, Miller, Mark A.
• Primary Examiner(s): Lukton; David
• Application Number:
  US11/184,594
• Publication Number:
  US 20060019873A1
• Time in Patent Office: 2,009 Days
• Field of Search: 514/3, 530/303, 530/345
• US Class Current: 530/303
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 33/30 Zinc; Compounds thereof
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 47/69 the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
• CPC Class Codes: A61K 9/0095 Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/48 of the pancreatic hormones
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: C07K 14/62 Insulins

Abstract

An insulin compound coupled to a modifying moiety having a formula:
—X—R¹—Y-PAG-Z—R  (Formula VI)

• • where,
  • X, Y and Z are independently selected linking groups and each is optionally present, and X, when present, is coupled to the insulin compound by a covalent bond,
  • either R¹ or R² is is a lower alkyl, optionally including a carbonyl group, and when R¹ is a lower alkyl, R² is a capping group, and
  • PAG is a linear or branched carbon chain incorporating one or more alkalene glycol moieties, and optionally incorporating one or more additional moieties selected from the group consisting of —S—, —O—, —N—, and —C(O)—, and
  • where the modifying moiety has a maximum number of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 heavy atoms.

Claims

1. An insulin compound coupled to a modifying moiety having a formula:

—

X—

R¹—

Y-PAG-Z—

R²  

 

(Formula VI)

where,

X, Y and Z are independently selected linking groups and each is optionally present, and X, when present, is coupled to the insulin compound by a covalent bond, wherein X, Y, and Z may be independently selected from —

C(O)—

, —

O—

, —

S—

, and —

N—

,

at least one of R¹ and R² is present and is a lower alkyl and may optionally include a carbonyl group;

PAG is a linear or branched carbon chain incorporating one or more alkylene glycol moiety wherein the alkylene glycol moiety is a substantially monodispersed PEG molecule having has a formula (CH₂CH₂O)_n, wherein n is 1 to 5 and optionally incorporating one or more additional moiety selected from the group consisting of —

S—

, —

O—

, —

N—

, and —

C(O)—

,

where the modifying moiety has a maximum number of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 heavy atoms, wherein the heavy atoms comprises one or more carbon atoms and one or more non-carbon heavy atoms selected from the group consisting of —

O—

, —

S—

, —

N—

, and ═

O;

wherein the insulin is mammalian or an insulin analog thereof and wherein the modifying moiety is coupled to a lysine within 5 amino acids of the C-terminus of the B chain of the mammalian insulin or insulin analog and wherein the lysine is at a position selected from the group consisting of position B26, B27, B28, B29 and B30 of insulin thereby providing a monoconjugate.

2. The insulin compound conjugate of claim 1, wherein the modifying moiety is selected to render the insulin compound conjugate equally as soluble or more soluble than a corresponding unconjugated insulin compound.

3. The insulin compound conjugate of claim 1 wherein the water solubility of the insulin compound conjugate is decreased by addition of the zinc.

10. A method of treating an insulin deficiency in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an insulin compound of claim 1.

11. The method of claim 10 wherein the insulin deficiency has a cause comprising:

diabetes;

pre-diabetes;

or

metabolic syndrome.

12. The method of claim 10 wherein the insulin compound is administered to effect post-prandial glucose control.

13. The method of claim 10 wherein the insulin compound is administered within one hour prior to a meal.

14. The method of claim 10 wherein the insulin compound is administered to effect overnight glucose control.

18. The insulin compound of claim 1, wherein the R¹ is a lower alkyl and R² is not present.

19. The insulin compound of claim 1, wherein the R² is a lower alkyl and R¹ is not present.

20. The insulin compound of claim 1, wherein R¹ is a lower alkyl and R² is a capping group, wherein the capping group is selected from the group consisting of linear C 1-6, branched C 1-6 or a carbonyl.

4. An insulin compound coupled to a modifying moiety comprising a substantially monodispersed PEG moiety, wherein the modifying moiety has a formula:

8. The insulin compound of claim 4 where the modifying moiety is:

16. The insulin compound of claim 4 wherein the modifying moiety has a formula:

5. An insulin compound coupled to a modifying moiety comprising a substantially monodispersed PEG moiety, wherein the modifying moiety has a formula:

6. An insulin compound coupled to a modifying moiety comprising a substantially monodispersed PEG moiety, wherein the modifying moiety has a formula:

7. An insulin compound coupled to a modifying moiety comprising a substantially monodispersed PEG moiety, wherein the modifying moiety has a formula:

9. An insulin compound coupled to a modifying moiety comprising a substantially monodispersed PEG moiety, wherein the modifying moiety has a formula:

15. An insulin compound coupled to a modifying moiety comprising a substantially monodispersed PEG moiety, wherein the modifying moiety has a formula:

17. An insulin compound coupled to a modifying moiety comprising a substantially monodispersed PEG moiety, wherein the modifying moiety has a formula: