Fatty acid formulations for oral delivery of proteins and peptides, and uses thereof

• US 7,605,123 B2
• Filed: 07/19/2005
• Issued: 10/20/2009
• 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., Pavliv, Leo, Puskas, Monica, Miller, Mark A., Polowy, Karen
• Primary Examiner(s): Lukton; David
• Application Number:
  US11/184,528
• Publication Number:
  US 20060018874A1
• Time in Patent Office: 1,554 Days
• Field of Search: 514/2, 514/3, 514/4, 530/303
• US Class Current: 514/1.1
• 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

Fatty acid compositions for administration of of pharmaceutical agents, such as proteins and peptides, protein and peptide conjugates, and/or cation-polypeptide conjugate complexes. In particular, the invention provides a solid pharmaceutical composition formulated for oral administration by ingestion, having from about 0.1 to about 75% w/w fatty acid component, where the fatty acid component comprises saturated or unsaturated C4, C5, C6, C7, C8, C9, C10, C11, or C12 fatty acids and/or salts of such fatty acids; and a therapeutic agent. Further, the invention provides a liquid pharmaceutical composition formulated for oral administration by ingestion, comprising: from about 0.1 to about 10% w/v fatty acid component, where the fatty acid component comprises saturated or unsaturated C4, C5, C6, C7, C8, C9, C10, C11, or C12 fatty acids and/or salts of such fatty acids; and a therapeutic agent.

Claims

1. A water soluble solid pharmaceutical composition formulated for oral administration by ingestion, comprising:

(a) from about 5 to about 65% w/w of a salt of a fatty acid component, where the salt of a fatty acid component comprises saturated or unsaturated C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, or C₁₂ fatty acids; and

(b) an insulin compound conjugate comprising an insulin protein 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 the linking group is selected from —

C(O)—

, —

O—

, —

S—

, —

C— and

—

N—

,

R¹, if present, is a lower alkyl and may optionally include a carbonyl group;

R² is selected from the group consisting of a lower alkyl, optionally including a carbonyl group, and a capping group selected from the group consisting of —

CH₃, —

H, tosylate, branched or linear C_1-6 and an activating group, wherein when R¹ present, R² is a member of the capping group; and

PAG is a linear or branched carbon chain incorporating one or more polyethylene glycol moieties, and optionally incorporating one or more additional moieties selected from the group consisting of —

S—

, —

O—

, —

N—

, and —

C(O)—

; and

an enteric coating material for coating of the water soluble solid composition fabricated into a solid form to survive passage through the stomach without substantial loss of the insulin protein.

2. The pharmaceutical composition of claim 1 comprising from about 40 to about 60% w/w of the salt of a fatty acid component.

3. The pharmaceutical composition of claim 1 where the insulin compound conjugated is complexed.

4. The pharmaceutical composition of claim 1 comprising a diluent selected from the group consisting of binders, disintegrants, fillers, diluents, lubricants, glidants, flow enhancers, compression aids, colors, sweeteners, preservatives, suspensing agents, dispersing agents, film formers, coatings, flavors, printing inks, celluloses, sugars, mannitols, lactoses, dissolution enhancers, and crosscarmaloses.

5. The pharmaceutical composition of claim 1 prepared in a form selected from the group consisting of tablets, minitabs, powders, hard gelatin capsules, or soft gelatin capsules.

6. The pharmaceutical composition of claim 1, wherein the salt of the fatty acid component is selected from salt of capric acid, salt of lauric acid and combination thereof.

7. The pharmaceutical composition of claim 1 comprising a buffer salt selected from the group consisting of phosphate buffer, sodium phosphate, tris buffer, citric acid buffer, and ethanolamine buffer.

8. The pharmaceutical composition of claim 1 comprising a buffer salt selected to achieve a buffering capacity at the site of absorption to maintain a local pH of from about 5 to about 8.

9. The pharmaceutical composition of claim 1 where the insulin compound conjugate consists of human insulin coupled at A1, B1 and/or B29 to a modifying moiety having a structure:

10. The pharmaceutical composition of claim 1 where the insulin compound conjugate consists of human insulin coupled at B29 to a modifying moiety having a structure:

11. The pharmaceutical composition of claim 1 where the insulin compound conjugate consists of human insulin coupled at A1, B1 and/or B29 to a modifying moiety having a structure:

12. The pharmaceutical composition of claim 1 where the modifying moiety has a structure:

13. The pharmaceutical composition of claim 1 where the insulin compound conjugate is coupled at A1, B1 and/or B29 to a linear or branched PEG moiety having from 2 to 15 PEG or from 2 to 10 PEG subunits.

14. The pharmaceutical composition of claim 1 wherein the insulin compound conjugate is complexed with zinc.

15. The pharmaceutical composition of claim 14 wherein the water solubility of the insulin compound conjugate is decreased by addition of the zinc.