Inhalable formulations for treating pulmonary hypertension and methods of using same

• US 9,498,437 B2
• Filed: 12/22/2005
• Issued: 11/22/2016
• Est. Priority Date: 06/27/2003
• Status: Expired due to Term

• Current Assignee: Mylan Specialty L.P. (Pfizer Inc.)
• Original Assignee: Mylan Specialty L.P. (Pfizer Inc.)
• Inventors: Chaudry, Imtiaz
• Primary Examiner(s): Oswecki, Jane C
• Application Number:
  US11/316,458
• Publication Number:
  US 20060104913A1
• Time in Patent Office: 3,988 Days
• Field of Search: 514/356, 514/183, 514/211.03, 514/252.12, 514/315, 514/351, 514/422, 514/929, 514/958, 424/78.1, 424/78.12, 424/78.23, 424/43, 424/45, 424/434
• US Class Current: 1/1
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/472 Non-condensed isoquinolines, e.g. papaverine
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/5575 having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
• CPC Class Codes: A61K 31/5585 having five-membered rings containing oxygen as the only ring hetero atom, e.g. prostacyclin
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 38/556 Angiotensin converting enzyme inhibitors
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/10 Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

The present invention is directed to an inhalable formulation for the treatment of pulmonary hypertension in a mammal (e.g., humans), wherein the formulation comprises at least one hypertension reducing agent, including but not limited to an angiotensin converting enzyme inhibitor, angiotensin receptor blocker, beta-blocker, calcium-channel blocker or vasodilator, or any combination thereof. The formulations of the present invention may be a solution or suspension, and preferably are suitable for administration via nebulization. The present invention is also directed to a method and kit for treating a mammal suffering from pulmonary hypertension.

Claims

1. An inhalable formulation for the treatment of pulmonary hypertension, said formulation consisting essentially of about 0.001 mg/ml to about 0.5 mg/ml of a hypertension reducing agent, a complexing agent, and about 0.001% to about 10% by weight emulsifying agent, said hypertension reducing agent consists of a calcium-channel blocker, said formulation is adapted for localized delivery to the lungs of a mammal via oral inhalation such that the formulation is deposited into the lungs of a patient and absorption of the hypertension reducing agent into the systemic blood circulation is less than the absorption of the hypertension reducing agent into the systemic blood circulation when administered intravenously or orally to the gastrointestinal tract and systemic side-effects associated with the hypertension reducing agent are less than the systemic side-effects realized when administered intravenously or orally to the gastrointestinal tract, said formulation is isotonic and has a pH of about 3 to about 8, said formulation is free of a preservative yet sterile and exhibits greater than 80% of the calcium-channel blocker originally present in the formulation after storage for 12 months at a temperature between 15 to 30°

C., and said complexing agent is sodium edetate.

2. The formulation of claim 1, wherein said formulation is adapted for localized delivery to the lungs of a mammal by oral inhalation via nebulization.

3. The formulation of claim 2, further comprising a buffer.

4. The formulation of claim 2, wherein said formulation is an aqueous suspension.

5. The formulation of claim 2, wherein said calcium-channel blocker is at least one of the group consisting of amlodipine, bepridil, diltiazem, felodipine, flunarizine, isradipine, nicardipine, nifedipine, nimodipine and verapamil.

6. The formulation of claim 2, wherein said formulation is suitable for treating primary pulmonary hypertension.

7. The formulation of claim 2, wherein said formulation is suitable for treating secondary pulmonary hypertension.

9. The formulation of claim 1, further comprising from 0.001 to 5% by weight of a humectant consisting of sorbitol.

10. The formulation of claim 1, wherein the complexing agent is selected from the group consisting of ethylenediaminetertraacetic acid, nitrilotriacetic acid, and salts thereof.

11. The formulation of claim 1, wherein said formulation is provided in a pre-mixed, pre-measured, and unit dose form having a fill volume of from 0.1 to 2.0 ml.

12. The formulation of claim 1, wherein said formulation is provided in a pre-mixed, pre-measured, and unit dose form having a fill volume of from 0.1 to 1.5 ml.

13. The formulation of claim 1, wherein said emulsifying agent comprises polyoxyethylene sorbitan fatty esters.

14. The formulation of claim 1, wherein said emulsifying agent comprises sorbitan trioleate.

15. The formulation of claim 1, wherein said formulation is BAC-free.

17. The formulation of claim 1, further comprising a tonicity agent comprising zinc chloride.

8. An inhalable formulation for the treatment of pulmonary hypertension, said formulation consisting essentially of an aqueous suspension comprising:

(a) 0.005 mg of a calcium-channel blocker;

(b) 0.05 mg/ml of sodium edetate, (c) 0.001 to 5% by weight of a humectant consisting of sorbitol; and

(d) about 0.001% to about 10% by weight emulsifying agent; and

a pH of about 3 to about 4, wherein said formulation is adapted for localized delivery to the lungs of a mammal via oral inhalation such that the absorption of the calcium-channel blocker into the systemic blood circulation is less than the absorption of the hypertension reducing agent into the systemic blood circulation when administered intravenously or orally to the gastrointestinal tract and systemic side effects associated with the hypertension reducing agent are less than the systemic side-effects realized when administered intravenously or orally to the gastrointestinal tract;

wherein said formulation is sterile and BAC-free and is provided in a pre-mixed, pre-measured, and unit dose form having a fill volume of from 0.1 to 1.5 ml; and

wherein said formulation is free of a preservative yet sterile and exhibits greater than 80% of the calcium-channel blocker originally present in the formulation after storage for 12 months at a temperature between 15 to 30°

C.

16. An inhalable formulation for the treatment of pulmonary hypertension, said formulation consisting essentially of about 0.001 mg/ml to about 0.5 mg/ml of a hypertension reducing agent, a complexing agent, and about 0.001% to about 10% by weight emulsifying agent, said hypertension reducing agent consists of a calcium-channel blocker, wherein said formulation is adapted for localized delivery to the lungs of a mammal via oral inhalation such that the formulation is deposited into the lungs of a patient and absorption of the hypertension reducing agent into the systemic blood circulation is less than the absorption of the hypertension reducing agent into the systemic blood circulation when administered intravenously or orally to the gastrointestinal tract and systemic side-effects associated with the hypertension reducing agent are less than the systemic side-effects realized when administered intravenously or orally to the gastrointestinal tract, said formulation is isotonic and has a pH of about 3 to about 8 and wherein said formulation is free of a preservative yet sterile and exhibits greater than 80% of the calcium-channel blocker originally present in the formulation after storage for 12 months at a temperature between 15 to 30°

C., wherein said calcium-channel blocker comprises isradipine.