Methods and compositions for delivering peptides

• US 8,889,099 B2
• Filed: 01/30/2013
• Issued: 11/18/2014
• Est. Priority Date: 06/29/1999
• Status: Expired due to Fees

• Current Assignee: Mannkind Corporation
• Original Assignee: Mannkind Corporation
• Inventors: Steiner, Solomon S., Woods, Rodney J., Sulner, Joseph W.
• Primary Examiner(s): Oswecki, Jane C
• Application Number:
  US13/754,698
• Publication Number:
  US 20130143801A1
• Time in Patent Office: 657 Days
• Field of Search: 424/1.13, 424/489, 514/5.9, 514/6.8, 530/303
• US Class Current: 424/1.13
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 47/6949 inclusion complexes, e.g. clathrates, cavitates or fullerenes
• 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: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1676 having a drug-free core with discrete complete coating layer containing drug adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C07D 241/08 with oxygen atoms directly attached to ring carbon atoms
• CPC Class Codes: C07K 1/30 by precipitation
• CPC Class Codes: C07K 1/32 as complexes
• CPC Class Codes: C07K 14/605 Glucagons
• CPC Class Codes: C07K 14/62 Insulins

Abstract

Methods are provided for purifying peptides and proteins by incorporating the peptide or protein into a diketopiperazine or competitive complexing agent to facilitate removal one or more impurities, from the peptide or protein. Formulations and methods also are provided for the improved transport of active agents across biological membranes, resulting for example in a rapid increase in blood agent concentration. The formulations include microparticles formed of (i) the active agent, which may be charged or neutral, and (ii) a transport enhancer that masks the charge of the agent and/or that forms hydrogen bonds with the target biological membrane in order to facilitate transport. In one embodiment, insulin is administered via the pulmonary delivery of microparticles comprising fumaryl diketopiperazine and insulin in its biologically active form. This method of delivering insulin results in a rapid increase in blood insulin concentration that is comparable to the increase resulting from intravenous delivery.

Claims

1. A method of delivering insulin to a human comprising administering a composition comprising insulin bound to a complexing agent to said human by pulmonary inhalation, wherein the composition delivers insulin to the patient in biologically active form after inhalation, wherein said composition produces a rapid onset of insulin action wherein (a) peak blood insulin levels (Tmax_[INS]) are achieved about 13 minutes after inhalation, or (b) peak biological action, measurable as glucose infusion rate (Tmax_GIR) is achieved about 39 minutes after inhalation.

2. The method of claim 1 wherein (Tmax_[INS]) is achieved about 13 minutes after inhalation.

3. The method of claim 1 wherein peak biological action, measurable as (Tmax_GIR), is achieved about 39 minutes after inhalation.

4. The method of claim 1 wherein the complexing agent is a diketopiperazine derivative.

5. The method of claim 4 wherein the diketopiperazine derivative has the formula 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine, wherein X is selected from the group consisting of fumaryl, succinyl, maleyl, and glutaryl.

6. The method of claim 5 wherein the diketopiperazine derivative is 2,5-diketo-3,6-di(4-fumaryl-aminobutyl)piperazine.

7. The method of claim 1 wherein the composition is provided as a dry powder.

8. A composition comprising insulin bound to a complexing agent wherein the composition is-prepared by a method comprising:

formulating a composition for pulmonary inhalation;

wherein the composition delivers insulin to the patient in biologically active form after inhalation, wherein said composition produces a rapid onset of insulin action when administered to a human wherein (a) peak blood insulin levels (Tmax_[INS]) are achieved about 13 minutes after inhalation, or (b) peak biological action, measurable as glucose infusion rate (Tmax_GIR), is achieved about 39 minutes after inhalation.

9. The composition of claim 8 wherein (Tmax_[INS]) is achieved about 13 minutes after inhalation.

10. The composition of claim 8 wherein peak biological action, measurable as (Tmax_GIR), is achieved about 39 minutes after inhalation.

11. The composition of claim 8 wherein the complexing agent is a diketopiperazine derivative.

12. The composition of claim 11 wherein the diketopiperazine derivative has the formula 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine, wherein X is selected from the group consisting of fumaryl, succinyl, maleyl, and glutaryl.

13. The composition of claim 12 wherein the diketopiperazine derivative is 2,5-diketo-3,6-di(4-fumaryl-aminobutyl)piperazine.

14. The composition of claim 8 wherein the composition is provided as a dry powder.