Sustained release of antiinfectives

Patent metadata

Field	Value
Publication number	US-2021121574-A1
Application number	US-202017085836-A
Country	US
Kind code	A1
Filing date	Oct 30, 2020
Priority date	Oct 29, 2002
Publication date	Apr 29, 2021
Grant date	—

Abstract

Provided are lipid antiinfective formulations substantially free of anionic lipids with a lipid to antiinfective ratio is about 1:1 to about 4:1, and a mean average diameter of less than about 1 μm. Also provided is a method of preparing a lipid antiinfective formulation comprising an infusion process. Also provided are lipid antiinfective formulations wherein the lipid to drug ratio is about 1:1 or less, about 0.75:1 or less, or about 0.50:1 or less prepared by an in line fusion process. The present invention also relates to a method of treating a patient with a pulmonary infection comprising administering to the patient a therapeutically effective amount of a lipid antiinfective formulation of the present invention. The present invention also relates to a method of treating a patient for cystic fibrosis comprising administering to the patient a therapeutically effective amount of a lipid antiinfective formulation of the present invention.

First claim

What is claimed:

1 . A lipid antiinfective formulation comprising a lipid formulation and an antiinfective, wherein the lipid formulation is substantially free of anionic lipids, and wherein the weight ratio of lipid to antiinfective is 4:1 to 1:1, 3:1 to 1:1, 2:1 to 1:1, or 1:1.

2 . The lipid antiinfective formulation of claim 1 , wherein the lipid formulation is a liposome.

3 . The lipid antiinfective formulation of claim 2 , wherein the liposome has a mean diameter of 0.1 μm to 1.0 μm, 0.2 μm to 0.5 μm, 0.2 μm to 0.4 μm, or 0.2 μm to 0.3 μm

4 . The lipid antiinfective formulation of claim 1 , wherein the antiinfective is selected from the following: an aminoglycoside, a tetracycline, a sulfonamide, p-aminobenzoic acid, a diaminopyrimidine, a quinolone, a β-lactam, a β-lactam and a β-lactamase inhibitor, chloraphenicol, a macrolide, penicillins, cephalosporins, corticosteroid, prostaglandin, linomycin, clindamycin, spectinomycin, polymyxin B, colistin, vancomycin, bacitracin, isoniazid, rifampin, ethambutol, ethionamide, aminosalicylic acid, cycloserine, capreomycin, a sulfone, clofazimine, thalidomide, a polyene antifungal, flucytosine, imidazole, triazole, griseofulvin, terconazole, butoconazole ciclopirax, ciclopirox olamine, haloprogin, tolnaftate, naftifine, terbinafine, or combination thereof.

5 . The lipid antiinfective formulation of claim 1 , wherein the antiinfective is an aminoglycoside.

6 . The lipid antiinfective formulation of claim wherein the antiinfective is amikacin.

7 . The lipid antiinfective formulation of claim wherein the antiinfective is tobramicin.

8 . The lipid antiinfective formulation of claim wherein the antiinfective is gentamicin.

9 . The lipid antiinfective formulation of claim, wherein the lipid formulation comprises neutral lipids.

10 . The lipid antiinfective formulation of claim 1 , wherein the lipids that make up the lipid formulation are all neutral lipids.

11 . The lipid antiinfective formulation of claim 1 , free of anionic lipids.

12 . The lipid antiinfective formulation of claim 1 , wherein the lipid formulation comprises a phospholipid.

13 . The lipid antiinfective formulation of claim 1 , wherein the lipid formulation comprises a steroid.

14 . The lipid antiinfective formulation of claim 1 , wherein the lipid formulation comprises a sterol.

15 . The lipid antiinfective formulation of claim 1 , wherein the lipid formulation comprises a phospholipid and a steroid.

16 . The lipid antiinfective formulation of claim 1 , wherein the lipid formulation comprises a phospholipid and a sterol.

17 . The lipid antiinfective formulation of claim 1 , wherein the lipid formulation comprises dipalmitoylphosphatidylcholine (DPPC) and cholesterol.

18 . The lipid antiinfective formulation of claim 1 , wherein the lipid formulation is a liposome with a mean diameter of 0.1 μm to 1.0 μm, 0.2 μm to 0.5 μm, 0.2 μm to 0.4 μm, or 0.2 μm to 0.3 μm; the antiinfective is amikacin; and the lipid formulation comprises a phospholipid and a steroid.

19 . The lipid antiinfective formulation of claim 1 , wherein the lipid formulation is a liposome with a mean diameter of 0.1 μm to 1.0 μm, 0.2 μm to 0.5 μm, 0.2 μm to 0.4 is μm, or 0.2 μm to 0.3 μm; the antiinfective is amikacin; and the lipid formulation comprises a phospolipid and a sterol.

20 . The lipid antiinfective formulation of claim 1 , wherein the lipid formulation is a liposome with a mean diameter of 0.1 μm to 1.0 μm, 0.2 is μm to 0.5 μm, 0.2 μm to 0.4 μm, or 0.2 μm to 0.3 μm; the antiinfective is amikacin; and the lipid formulation comprises DPPC and cholesterol.

21 . A method of preparing the lipid antiinfective formulation of claim 1 comprising infusing an aqueous or alcoholic solution or mixture of the antiinfective with a lipid-alcohol solution or mixture at a temperature below the phase transition of at least one of the lipids, wherein infusing the aqueous or alcoholic solution or mixture of the antiinfective is done from above.

22 . The method of claim 21 , wherein the lipid-alcohol solution or mixture has a concentration of 10 to 30 mg/mL.

23 . The method of claim 21 , wherein the aqueous or alcoholic solution or mixture of the antiinfective has a concentration of 20 to 70 mg/mL.

24 . The method of claim 21 , wherein the lipid-alcohol solution or mixture has a concentration of 10 to 30 mg/mL, and the aqueous or alcoholic solution or mixture of the antiinfective has a concentration of 20 to 70 mg/mL.

25 . The method of claim 21 , wherein the antiinfective is selected from the following: an aminoglycoside, a tetracycline, a sulfonamide, p-aminobenzoic acid, a diaminopyrimidine, a quinolone, a β-lactam, a β-lactam and a β-lactamase inhibitor, chloraphenicol, a macrolide, penicillins, cepalosporins, corticosteroid, prostaglandin, linomycin, clindamycin, spectinomycin, polymyxin B, colistin, vancomycin, bacitracin, isoniazid, rifampin, ethambutol, ethionamide, aminosalicylic acid, cycloserine, capreomycin, a sulfone, clofazimine, thalidomide, a polyene antifungal, flucytosine, imidazole, triazole, griseofulvin, terconazole, butoconazole ciclopirax, ciclopirox olamine, haloprogin, tolnaftate, naftifine, terbinafine, or combination thereof.

26 . The method of claim 21 , wherein the antiinfective is an aminoglycoside.

27 . The method of claim 21 , wherein the antiinfective is amikacin.

28 . The method of claim 21 , wherein the antiinfective is tobramycin.

29 . The method of claim 21 , wherein the antiinfective is gentamicin.

30 . The method of claim 21 , wherein the lipid-alcohol solution or mixture comprises a phospholipid.

31 . The method of claim 21 , wherein the lipid-alcohol solution or mixture comprises a sterol.

32 . The method of claim 21 , wherein the lipid-alcohol solution or mixture comprises DPPC and cholesterol.

33 . A lipid antiinfective formulation comprising a lipid formulation and an antiinfective, wherein the lipid to antiinfective ratio is 1:1 or less.

34 . The lipid antiinfective formulation of claim 33 , wherein the lipid to antiinfective ratio is less than 0.75:1.

35 . The lipid antiinfective formulation of claim 33 , wherein the lipid to antiinfective ratio is less than 0.5:1.

36 . The lipid antiinfective formulation of claim 33 , wherein the antiinfective is an aminoglycoside.

37 . The lipid antiinfective formulation of claim 33 , wherein the antiinfective is an aminoglycoside selected from the following: amikacin, gentamicin, or tobramycin.

38 . The lipid antiinfective formulation of claim 33 , wherein the antiinfective is amikacin.

39 . The lipid antiinfective formulation of claim 33 , wherein the antiinfective is gentamicin.

40 . The lipid antiinfective formulation of claim 33 , wherein the antiinfective is tobramycin.

41 . The lipid antiinfective formulation of claim 33 , wherein the lipid formulation is a liposome.

42 . The lipid antiinfective formulation of claim 33 , wherein the lipid formulation comprises a phospholipid.

43 . The lipid antiinfective formulation of claim 33 , wherein the

Assignees

• Insmed Inc

Inventors

• Boni Lawrence T
• Miller Brian S
• Malinin Vladimir
• Li Xingong

Classifications

• A61K9/127 Primary

  Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant · CPC title

• A61K9/0078 Primary

  for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61K47/28 Primary

  Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid · CPC title

• A61K31/407

  condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine · CPC title