Alpha 1-Antitrypsin Compositions and Treatment Methods Using Such Compositions
Alpha 1-antitrypsin compositions and treatment methods using such compositions for treating a variety of pulmonary diseases are provided. The compositions generally contain AAT, a stabilizing carbohydrate such as trehalose, a surfactant such as Polysorbate 80 and an antioxidant to stabilize AAT for use as a therapeutic. The formulations can be prepared as both liquids and solids and administered by nebulization of the liquid formulation or by conversion of dry powder formulation into an aerosol.
1 . A pharmaceutical composition comprising an alpha 1-antitrypsin (AAT), a stabilizing carbohydrate, a surfactant and an antioxidant, wherein the AAT is a native AAT, a recombinant AAT, or an AAT variant.
2 . The composition of claim 1 , wherein the composition is in a form suitable for administration to a patient via inhalation therapy.
3 . The composition of claim 2 , wherein the composition is formulated as a powder.
4 . The composition of claim 2 , wherein the composition is formulated as a liquid that can be nebulized.
5 . The composition of claim 1 , wherein the AAT is a native AAT.
6 . The composition of claim 1 , wherein the AAT is a recombinant AAT.
7 . The composition of claim 1 , wherein the AAT is an AAT variant.
8 . The composition of claim 1 , wherein the AAT is glycosylated.
9 . The composition of claim 1 , wherein the AAT is unglycosylated.
10 . The composition of claim 1 , wherein the stabilizing carbohydrate is selected from the group consisting of lactose, sucrose, trehalose, raffinose, maltodextrin and mannitol.
11 . The composition of claim 10 , wherein the stabilizing carbohydrate is trehalose.
12 . The composition of claim 1 , wherein the antioxidant is selected from the group consisting of methionine, glutathione, cysteine, ascorbic acid and N-acetyl cysteine.
13 . The composition of claim 3 , wherein the AAT, carbohydrate, surfactant and antioxidant are present in amounts such that if the powder is solubilized in aqueous solution for administration to a patient the AAT concentration is 1-100 mg/ml, the carbohydrate concentration is 1-5% (w/v), the surfactant concentration is 0.01-0.5% (w/v), and the antioxidant concentration is 1-10 mM.
14 . The composition of claim 13 , wherein the AAT concentration is 10-50 mg/ml.
15 . The composition of claim 4 , wherein the AAT concentration is 1-100 mg/ml, the carbohydrate concentration is 1-5% (w/v), the surfactant concentration is 0.01-0.5% (w/v), and the antioxidant concentration is 1-10 mM.
16 . The composition of claim 15 , wherein the AAT concentration is 10-50 mg/ml.
17 . The composition of claim 3 , further comprising a buffer and wherein. (a) the carbohydrate is trehalose and the antioxidant is methionine; and (b) the AAT, trehalose, surfactant and methionine are present in amounts such that if the powder is solubilized in aqueous solution for administration to a patient (i) the AAT concentration is 10-50 mg/ml, (ii) the trehalose concentration is 10-50 mg/ml, (iii) the surfactant concentration is 0.01-0.5% (w/v), and (iv) the methionine concentration is 1-10 mM.
18 . The composition of claim 4 , further comprising a buffer and wherein (a) the AAT concentration is 10-50 mg/ml; (b) the carbohydrate is trehalose and its concentration is 10-50 mg/ml; (c) the surfactant concentration is 0.01-0.5% (w/v); and (d) the antioxidant is methionine and its concentration is 1-10 mM.
19 . A pharmaceutical composition, comprising a recombinant alpha 1-antitrypsin (AAT), a stabilizing carbohydrate and at least one additional stabilizing agent selected from the group consisting of a surfactant and an antioxidant, wherein the AAT/carbohydrate ratio (weight:weight) is 1:1 to 5:1, and further wherein the AAT is a native AAT, a recombinant AAT, or an AAT variant.
20 . The composition of claim 19 , wherein the ratio is 1:1 to 2:1.
21 . The composition of claim 19 , wherein the stabilizing carbohydrate is trehalose.
22 . The composition of claim 19 , wherein the composition comprises the surfactant.
23 . The composition of claim 19 , wherein the composition comprises the antioxidant.
24 . The composition of claim 19 , wherein the composition comprises both the surfactant and the antioxidant.
25 . The composition of claim 24 , wherein the surfactant is Polysorbate 80 and the antioxidant is methionine.
26 . The composition of claim 19 , wherein the composition is formulated as a solid.
27 . The composition of claim 19 , wherein the composition is formulated as a liquid.
28 . The composition of claim 1 , wherein the AAT is a native AAT.
29 . The composition of claim 1 , wherein the AAT is a recombinant AAT.
30 . The composition of claim 1 , wherein the AAT is an AAT variant.
31 . The composition of claim 1 , wherein the AAT is glycosylated.
32 . The composition of claim 1 , wherein the AAT is unglycosylated.
33 - 68 . (canceled)