Formulations of steroid solutions for inhalatory administration

• US 6,967,017 B1
• Filed: 07/20/2000
• Issued: 11/22/2005
• Est. Priority Date: 07/23/1999
• Status: Expired due to Fees

• Current Assignee: Chiesi Farmaceutici SPA (Valline Srl)
• Original Assignee: Chiesi Farmaceutici SPA (Valline Srl)
• Inventors: Garzia, Raffaella, Chiesi, Paolo, Brambilla, Gaetano, Malvolti, Chiara
• Primary Examiner(s): Kunz, Gary
• Assistant Examiner(s): Haghighatian, Mina
• Application Number:
  US10/030,101
• Time in Patent Office: 1,951 Days
• Field of Search: 424/45, 424/46, 424/434, 424/489, 424/450, 424/198.1
• US Class Current: 424/45
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 9/0078 for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• CPC Class Codes: A61P 11/06 Antiasthmatics

Abstract

The present invention relates to optimized formulations of antiinflammatory steroids for nebulisation and a process for the preparation thereof. More particularly, the invention relates to formulations for monodose or multidose vials in the form of preservative-free stable solutions of a more acceptable osmolarity, which can effectively be nebulised with the nebulisers currently available on the market and are well-tolerated by patients.

Claims

1. A stable pharmaceutical formulation for inhalation through nebulisation consisting of a solution of a steroid in which:

a) the steroid concentration ranges from 0.01% to 0.1%;

b) the liquid component of the solution is a mixture of water and propylene glycol in a ratio ranging from 60;

40 to 30;

70 v/v; and

c) the pH ranges from 3.5 to 5.0, the pH of the formulation having been adjusted by the addition of a concentrated strong acid to the solution;

wherein the percentage of nebulised active ingredient particles with MAD below 6 μ

m is higher than 70% and the nebulisation efficiency is higher than 20%.

2. The formulation according to claim 1, wherein the liquid component of the solution consists of water and propylene glycol in a 50:

50 v/v ratio.

3. The formulation according to claim 1, wherein the pH of the solution ranges from 4.0 to 4.5 and has been adjusted by the addition of HCl to the solution.

4. The formulation according to claim 1, wherein the steroid is in the form of an acetal or is in the form of an acetonide.

5. The formulation according to claim 4, wherein the steroid in the form of an acetal is budesonide.

6. The formulation according to claim 4, wherein the steroid in the form of an acetonide is flunisolide.

7. The formulation according to claim 5, wherein the concentration of budesonide in the solution ranges from 0.025 to 0.05%.

8. The formulation according to claim 6, wherein the concentration of flunisolide in the solution is 0.1%.

9. The formulation according to claim 1, wherein the osmolarity of the solution is not more than 7500 mOsm/l.

10. The formulation according to claim 9, wherein the osmolarity of the solution is not more than 7000 mOsm/1.

11. A process for the preparation of pharmaceutical formulations according to claim 1, which comprises:

a) preparing a propylene glycol solution of a steroid at a temperature of 40 to 50°

C.;

b) cooling the solution, and then diluting the solution with water;

c) adjusting the pH of the solution by the addition of a concentrated, strong acid thereto; and

d) filtering the solution and distributing the solution to containers for the treatment of individuals by nebulisation.

12. The process according to claim 11, wherein the pH of the solution is adjusted to a range of 3.5 to 5.0.

13. The process according to claim 11, wherein the propylene glycol solution of the steroid is diluted with water to a water and propylene glycol ratio ranging from 60:

40 to 30;

70 v/v.

14. The process according to claim 11, wherein the strong acid is hydrochloric acid.