Pulmonary insulin crystals

• US 6,818,738 B2
• Filed: 05/20/2002
• Issued: 11/16/2004
• Est. Priority Date: 03/20/1997
• Status: Expired due to Term

• Current Assignee: Novo Nordisk A/S
• Original Assignee: Novo Nordisk A/S
• Inventors: Havelund, Svend
• Primary Examiner(s): Russel, Jeffrey Edwin
• Application Number:
  US10/152,535
• Publication Number:
  US 20020198140A1
• Time in Patent Office: 911 Days
• Field of Search: 530/303, 530/304, 530/305, 514/3, 514/4
• US Class Current: 530/303
• CPC Class Codes: A61K 38/28 Insulins
• 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 9/145 with organic compounds
• CPC Class Codes: C07K 14/62 Insulins

Abstract

Disclosed is a method of preparing zinc free rapid acting insulin analogue. In one embodiment insulin crystals are prepared by providing a solution of an analogue having a pH between 7 and 9.5. The solution is mixed with a salt of an alkali metal or salt and formed crystals are recovered.

Claims

1. A method for the preparation of zinc free crystals of a rapid-acting insulin analogue, comprising the steps of:

a) providing a solution of said analogue having a pH between 7.0 and 9.5;

b) mixing said solution with a solution of a salt of an alkali metal or an ammonium salt, wherein either or both of said first and second solutions comprises a water miscible organic solvent selected from the group consisting of ethanol, methanol, acetone and 2-propanol in an amount which provides a concentration of said organic solvent of 5 to 25% (v/v) in the solution obtained after mixing, wherein said mixing step is performed for no more than 2 hours; and

c) recovering the formed crystals.

2. A method according to claim 1, wherein the salt is selected from the group consisting of the hydrochloride or acetate of sodium, potassium, lithium, or ammonia, and mixtures of any of the foregoing.

3. A method according to claim 1, wherein the concentration of insulin after mixing is between 0.5% and 10% by weight.

4. A method according to claim 1, wherein the concentration of salt after mixing is between 0.2 M and 2 M.

5. A method according to claim 1, which further comprises a washing step, in which the crystals obtained are washed with a solution comprising auxiliary substances and optionally comprises 5-25% of an alcohol, 5-50 mM of a preservative, and 0.1-2 M of a salt.