A PHARMACEUTICAL FORMULATION FOR PRESSURISED METERED DOSE INHALER

Abstract

The present invention generally relates to pharmaceutical composition comprising a LABA agent, optionally in combination with other active ingredients, a mixture of at least two inorganic acids, a propellant and a co-solvent. The invention also provides a pharmaceutical composition for the treatment of respiratory diseases, such as asthma and COPD.

Claims

1. A pharmaceutical composition, comprising: a LABA agent; a co-solvent; a propellant; and a mixture of at least two inorganic acids.

2. The pharmaceutical composition according to claim 1 wherein the LABA agent is at least one selected from the group consisting of fenoterol, formoterol fumarate, formoterol fumarate dihydrate, arformoterol, carmoterol (TA-2005), indacaterol, milveterol, bambuterol, clenbuterol, vilanterol, olodaterol, abediterol, terbutaline, and salmeterol, or a diastereoisomeric mixture thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

3. The pharmaceutical composition according to claim 1, wherein the LABA agent is formoterol fumarate dihydrate.

4. The pharmaceutical composition according to claim 1, wherein the mixture of at least two inorganic acids comprises at least HCl.

5. The pharmaceutical composition according to claim 1, wherein the mixture of at least two inorganic acids comprises at least H.sub.3PO.sub.4.

6. The pharmaceutical composition according to claim 1, wherein the mixture of at least two inorganic acids is a mixture of HCl and H.sub.3PO.sub.4.

7. The pharmaceutical composition according to claim 6, wherein a molar ratio of HCl to H.sub.3PO.sub.4 in the composition is 0.0018 to 0.0030.

8. The pharmaceutical composition according to claim 7, wherein the molar ratio of HCl to H.sub.3PO.sub.4 is 0.0022 to 0.0028.

9. The pharmaceutical composition according to claim 7, wherein the molar ratio of HCl to H.sub.3PO.sub.4 is 0.0023 to 0.0027.

10. The pharmaceutical composition according to claim 1, comprising: 1M HCl in an amount of from about 0.019 to 0.021% w/w based on a total weight of the formulation; and H.sub.3PO.sub.4 85% w/w in an amount of from about 0.001 to 0.002% w/w based on the total weight of the formulation.

11. The pharmaceutical composition according to claim 10, comprising: 1M HCl in an amount of from about 0.019 to 0.021% w/w based on the total weight of the formulation; and H.sub.3PO.sub.4 85% w/w in an amount of 0.001% w/w based on the total weight of the formulation.

12. The pharmaceutical composition according to claim 1, further comprising at least one LAMA agent selected from the group consisting of glycopyrronium, ipratropium, oxitropium, trospium, tiotropium, aclidinium, and umeclidinium, with any pharmaceutically acceptable counterion thereof.

13. The pharmaceutical composition according to claim 12, wherein the LAMA agent is glycopyrronium bromide.

14. The pharmaceutical composition according to claim 1, further comprising at least one corticosteroid selected from the group consisting of: budesonide, beclometasone (BDP), flunisolide, fluticasone, ciclesonide, mometasone, mometasone desonide, rofleponide, hydrocortisone, prednisone, prednisolone, methyl prednisolone, naflocort, deflazacort, halopredone acetate, fluocinolone acetonide, fluocinonide, clocortolone, tipredane, prednicarbate, alclometasone dipropionate, halometasone, rimexolone, deprodone propionate, triamcinolone, betamethasone, fludrocoritisone, desoxycorticosterone, rofleponide, and etiprednol dicloacetate.

15. The pharmaceutical composition according to claim 14, wherein the corticosteroid is budesonide or beclometasone dipropionate (BDP).

16. The pharmaceutical composition according to claim 15, wherein the corticosteroid is beclometasone dipropionate (BDP).

17. The pharmaceutical composition according to claim 1, wherein the composition is a solution.

18. The pharmaceutical composition according to claim 1, wherein the co-solvent is an aliphatic alcohol having from 1 to 4 carbon atoms.

19. The pharmaceutical composition according to claim 18, wherein the co-solvent is ethanol.

20. The pharmaceutical composition according to claim 1, wherein the propellant is at least one selected from the group consisting of a hydrofluoroalkane (HFA) and a hydrofluoroolefin (HFO).

21. The pharmaceutical composition according to claim 20, wherein the propellant is at least one selected from the group consisting of HFA134a and HFA152a.

22. A canister, containing the pharmaceutical composition according to claim 1, wherein the canister is made of at least one selected from the group consisting aluminum, stainless steel, anodized aluminum, and fluorine passivated aluminum.

23. A canister configured for use in a pMDI device, containing the pharmaceutical composition according to claim 1.

24. The canister according to claim 23, made of aluminum.

25. (canceled)

26. A method for treating a respiratory disorder, comprising administering the pharmaceutical composition according to claim 1 to a subject in need of such treatment.

27. A method for treating asthma or COPD, comprising administering the pharmaceutical composition according to claim 1 to a subject in need of such treatment.

Description

EXPERIMENTAL PART

Example 1

[0106] A study was performed to investigate the chemical stability of formulation intended for pMDI administration comprising formoterol fumarate dihydrate (FF), glycopyrronium bromide (GB) and beclometasone dipropionate (BDP). Said formulation is a solution, contained in aluminum can crimped with a Bespak valve having a 63 μl metering volume.

[0107] A different type and amount of acids either alone or in mixture thereof were added to the formulation, thus providing Formulations 1-4, as reported in Table 1 and 2.

TABLE-US-00001 TABLE 1 Formulation 1 Formulation 2 Formulation 3 Formulation 4 COMPONENT % w/w % w/w % w/w % w/w FF 0.008 0.008 0.008 0.008 BDP 0.136 0.136 0.136 0.136 GB 0.034 0.034 0.034 0.034 1M HCI 0.019 0.021 0 0 H.sub.3PO.sub.4 (85% w/w) 0.001 0.001 0.001 0.002 Ethanol anhydrous 12 12 12 12 HFA 134a 87.8 87.8 87.8 87.8

[0108] The Formulations 1-4 were put in stability chambers at 40 C°, 75% R.H. in inverted position for 1 month (1M) and then check for API assay and relevant degradation products. APIs residue % are reported in Table 2.

TABLE-US-00002 TABLE 2 85% w/w Formu- 1M HCl H.sub.3PO.sub.4 Molar ratio lation % w/w % w/w HCl/H.sub.3PO.sub.4 FF % GB % BDP % 1 0.019 0.001 0.0025 97.0 99.6 99.8 2 0.021 0.001 0.0028 96.1 100.8 100.9 3 0 0.001 85.0 95.5 99.2 4 0 0.002 86.0 98.3 99.9

[0109] As it can be observed by Table 2 when a mixture of HCl and H.sub.3PO.sub.4 is added according to Formulations 1-2, a significant improvement of the chemical stability of formoterol (FF), glycopyrronium bromide (GB) and beclometasone dipropionate (BDP) is achieved. Of note, the % FF can reach values even higher than 95%. In fact, the formulations 1 and 2 show a significantly improved stability, in terms of FF %, GB % and BDP % residue, for example when compared to the stability of the formulation 3 and 4 wherein the H.sub.3PO.sub.4 is present alone, and where the % FF is actually lower than 90%.

Example 2

[0110] The same analysis of Example 1 has been ran using a correspondent formulation but in the presence of HCl only, and in an aluminum FEP coated can crimped with a Bespak valve having a 63 μl metering volume.

[0111] The thus obtained formulation (Form. FEP) was put in stability chambers at 40 C°, 75% R.H. in inverted position for 1 month (1M) and then check for API assay and relevant degradation products. API % residue and relevant total degradation products are reported in Table 3.

TABLE-US-00003 TABLE 3 1M 85% w/w HCI % H.sub.3PO.sub.4 w/w % w/w FF % GB % BDP % Form. FEP 0.019 0.0 97.4 100.2 101.4

[0112] As evident from the comparison of the above Tables 2 and 3, the mixture of inorganic acids according to the invention provides a stabilization, in terms of residue % of the APIs, particularly regarding the formoterol, comparable to the high stabilization degree obtainable using the FEP technology. In both cases in fact the % FF can be even higher that 95%, thus representing a significant degree of stability.