Insulin-oligomer conjugates, formulations and uses thereof

• US 9,102,758 B2
• Filed: 01/18/2011
• Issued: 08/11/2015
• Est. Priority Date: 07/19/2004
• Status: Active Grant

• Current Assignee: Biocon Limited (Biocon Incorporated)
• Original Assignee: Biocon Limited (Biocon Incorporated)
• Inventors: Radhakrishnan, Balasingam, Aggarwal, Diti, Ferro, Michelle, James, Kenneth D., Malkar, Navdeep B., Miller, Mark A., Ekwuribe, Nnochiri N., Puskas, Monica E.
• Primary Examiner(s): Lukton, David
• Application Number:
  US13/008,094
• Publication Number:
  US 20110124553A1
• Time in Patent Office: 1,666 Days
• Field of Search: 530/303
• US Class Current: 1/1
• 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 conjugate is disclosed in which insulin is coupled to a modifying moiety of the formula X—R¹—Y-PAG-Z—R² wherein X, Y, and Z are linking groups, R² is a capping group, and PAG is a carbon chain that incorporates one or more alkylene glycol moieties.

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 Y and Z are each optionally present and if present is —

O—

, and X is —

C(O)—

, and wherein the linking group X is coupled to the insulin compound by a covalent bond;

R¹ and R² are present and are a lower alkyl of C₁ to C₅;

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 a formula (CH₂CH₂O)_n, wherein n is 2-7,

wherein the insulin is mammalian or an insulin analog thereof and wherein the modifying moiety is coupled to a lysine residue at position B28, B29 or B30 of insulin, wherein the modifying moiety has the following formula;

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.

4. 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.

5. The method of claim 4 wherein the insulin deficiency has a cause comprising:

diabetes;

pre-diabetes;

or

metabolic syndrome.

6. The method of claim 4 wherein the insulin compound is administered to effect post-prandial glucose control.

7. The method of claim 4 wherein the insulin compound is administered within one hour prior to a meal.

8. The method of claim 4 wherein the insulin compound is administered to effect overnight glucose control.