CA2396796A1

CA2396796A1 - Stabilized medicinal aerosol particulate formulations

Info

Publication number: CA2396796A1
Application number: CA002396796A
Authority: CA
Inventors: Akwete L. Adjei; Yaping Zhu; John Z. Sun; Simon Stefanos
Original assignee: Individual
Current assignee: Kos Life Sciences Inc
Priority date: 2000-01-25
Filing date: 2001-01-02
Publication date: 2001-08-23
Anticipated expiration: 2021-01-02
Also published as: MXPA02007187A; JP2003524646A; EP1292283A1; EP1292283A4; CA2396796C; AU783120B2; CN1440298A; AU2755901A

Abstract

A medicinal formulation is disclosed. The formulation comprises: a therapeut ic amount of a protein or peptide medicament, a fluid for containing said medicament having a molecular size ranging from 1 K Dalton to about 150 K Daltons, a fluid carrier for containing the medicament, and a stabilizer selected from an amino acid, a derivative thereof or a mixture of the foregoing.

Claims

1. A medicinal formulation, which comprises:
(a) a therapeutically effective amount of a protein or peptide medicament having a molecular size ranging from about 1K Dalton to about 150 K
Daltons;
(b) a fluid carrier for containing said medicament; and (c) a stabilizer selected from an amino acid, a derivative thereof, or a mixture of the foregoing.

2. The formulation as defined in claim 1 wherein said medicament is selected from the group consisting of an insulin, an insulin analog, an amylin, an immunomodulating protein, an interleukin, an interferon, an erythropoietin, a heparin, a thrombolytic, an antitrypsin, an anti-protease, a hormone, a growth factor, an enzyme, a nucleic acid, an immunoglobulin, an antibiotic, an antiinfective, a calcitonin, a hematopoietic factor, a vaccine, a vasoactive peptide, an antisense agent, an oligonucleotide, DNase, a cyclosporin, ribavirin or a mixture of any of the foregoing medicaments.

3. The formulation as defined in claim 1 wherein said medicament is selected from the group consisting of an insulin, an insulin analog, an amylin, glucagon, LH-RH, deltirex, leuprolide, gosorelin, nafarelin, octreotide, somatostatin, a calcitonin, parathyroid hormone, TRH, growth hormone-releasing hormone, G-CSF, G-SF, a cytokine, rhDNAse, a heparin, an antibiotic, albumin, ovalbumin, aminloride, DDAVP, VIP, a cyclosporin, an erythropoietin, an interferon, IgG, IgE, IgM, IgA, IgD, an interleukin, IRAP, papain, peroxidase, serratio peptidase, catalase, .alpha.-1-antitrypsin, a gene; a vector, an amiloride, a rhDNAse, an oligonucleotide, ribavirin or a mixture of any of the foregoing medicaments.

4. The formulation as defined in claim 1, wherein said stabilizer is selected from the group consisting of the twenty existing amino acids, any mixture thereof, and any derivative of the foregoing.

5. The formulation as defined in claim 1 wherein said stabilizer is selected from the group consisting of (1) a di-peptide selected from the group consisting of a salt and an ester of oxidized and unoxidized L-cysteinylglycine, gamma-L-glutamyl-L-cysteine, N-acetyl-L-cysteine-glycine; (2) a conjugated, unconjugated or polymeric form of L-Gly-L-Glu and L-Val-L-Thr; (3) L-aspartyl-L-phenylalanine; (4) a muramyl dipeptide; (5) a nutrient selected from the group consisting of L-tyrosyl-L-tyrosine, L-alanyl-L-tyrosine, L-arginyl-L-tyrosine, L-tyrosyl-L-arginine, N-Cbz-L-Leu-L-Leu-OCH and salts or esters of the foregoing;
(6) glycyl-glycine; (7) N-acetyl-L-aspartate-L-glutamate; (NAAG); (8) a tripeptide selected from the group consisting of an oxidized and an unoxidized form of gamma-L-glutamyl-L-cysteinylglycine or a muramyl tripeptide and (9) a mixture of any of the foregoing stabilizers.

6. The formulation as defined in claim 1 wherein said fluid carrier is a propellant selected form the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane or a mixture thereof.

7. The formulation as defined in claim 1 wherein said fluid carrier is a hydrocarbon propellant selected from the group consisting of n-butane, propane, isopentane or a mixture thereof.

8. The formulation as defined in claim 1 which further includes a cosolvent.

9. The formulation as defined in claim 8 wherein said cosolvent comprises ethanol.

10. The formulation as defined in claim 1 wherein said stabilizer is present in an amount effective to prevent settling, creaming or flocculation of the formulation for a time sufficient to allow reproducible dosing of the drug after agitation of the formulation.

11. The formulation as defined in claim 10 wherein said stabilizer is present in an amount ranging from about 0.001 parts per million to about 200,000 parts per million of the total weight of the formulation.

12. A method of preparing a stable medicinal aerosol formulation according to claim 1, which comprises:
(a) combining (i) said medicament in an amount sufficient to provide a plurality of therapeutically effective doses, (ii) said fluid carrier in an amount sufficient to propel a plurality of said therapeutically effective doses; and (iii) said stabilizer in an amount effective to stabilize the formulation; and (b) dispersing components (i), (ii) and (iii).

13. The method as defined in claim 12 wherein the medicinal aerosol formulation further comprises combining in step (a) a cosolvent and in step (b) dispersing components (i), (ii), (iii) with said cosolvent.

14. A method of treating in a human or an animal a condition capable of treatment by oral or nasal inhalation, which comprises, administering a formulation according to claim 1 to said human or animal by oral or nasal inhalation.

15. A formulation according to claim 1 in an aerosol canister equipped with a metered dose valve.

16. A method of stabilizing a suspension aerosol formulation comprising a propellant and a protein or peptide medicament, which comprises, incorporating into the formulation a stabilizer selected from the group consisting of a suitable amino acid, a derivative thereof, or any mixture of the foregoing, in an amount which is effective to prevent settling, creaming, or flocculation of the formulation for a time sufficient to allow reproducible dosing of the drug after agitation of the formulation.

17. A metered dose inhaler containing a medicinal aerosol formulation, the formulation comprising:
(a) a protein or peptide medicament in a therapeutically effective amount;
(b) a propellant; and (c) a suitable stabilizer selected from an amino acid, an amino acid derivative, or a mixture of the foregoing, present in an amount sufficient to stabilize the formulation to prevent settling, creaming or flocculation for a time sufficient to allow reproducible dosing of the drug after agitation of the formulation.

18. The metered dose inhaler as defined in claim 17 wherein the stabilizer is selected from the group consisting of the twenty existing amino acids any mixture of any of the foregoing, and any derivative of the foregoing.