DRY POWDER FOR INHALATION
The present invention provides dry powder formulations for inhalation having improved moisture resistance such that the powders maintain a high fine particle dosage or fine particle fraction following storage under relatively extreme temperature and humidity conditions.
1 .- 13 . (canceled)
14 . A method of producing a dry powder formulation for inhalation having a fine particle fraction (FPF) with reduced sensitivity to penetrating moisture and comprising a pharmaceutically inactive carrier comprising particles of non-inhalable size and a pharmaceutically active component comprising at least one finely-divided pharmaceutically active compound comprising particles of inhalable size, the method comprising mixing together
(i) the pharmaceutically inactive carrier;
(ii) the pharmaceutically active component; and
(iii) pulverulent magnesium stearate, in an amount of 0.5 to 5% by weight, based on the total weight of the formulation, said amount being effective to provide the FPF with reduced sensitivity to penetrating moisture and to stabilize the dry powder formulation.
15 . The method of claim 14 , wherein wherein the pharmaceutically active compound is a hygroscopic compound capable of absorbing at least 0.5% by weight of its own weight of absorptively bound water when stored in air having a relative humidity of 50%.
16 . The method of claim 14 , wherein the magnesium stearate is present in an amount of 0.5% to 0.75% by weight, based on the total weight of the formulation.
17 . The method of claim 14 , wherein the carrier is selected from the group consisting of monosaccharides, disaccharides, sugar alcohols, polylactic acid and cyclodextrin.
18 . The method of claim 14 , wherein the carrier is selected from the group consisting of glucose, lactose monohydrate and trehalose.
19 . The method of claim 14 , wherein the formulation further comprises particles of micronized lactose monohydrate wherein at least 50% of the particles thereof have a maximum particle size of 10 um.
20 . The method of claim 14 , wherein the pharmaceutically active compound is formoterol or a pharmaceutically acceptable salt thereof.
21 . The method of claim 14 , wherein the pharmaceutically active compound is selected from the group consisting of formoterol fumarate, formoterol tartrate, ipratropium bromide and tiotropium bromide.
22 . The method of claim 14 , wherein the formulation further comprises a second pharmaceutically active compound having particles of inhalable size.
23 . The method of claim 14 , wherein the pharmaceutically active component comprises a) a member selected from the group consisting of formoterol fumarate, formoterol tartrate, levalbuterol sulfate and salmeterol xinafoate, and b) a corticosteroid.
24 . The method of claim 14 , wherein said dry powder formulation of a) comprises a fine particle fraction (FPF), said formulation exhibiting a reduction in said FPF by less than 50% within 10 days of storage at 40° C. and 75% relative atmospheric humidity.
25 . The method of claim 14 , wherein the pharmaceutically active component does not comprise salbutamol sulfate, salmeterol xinafoate, or beclomethasone dipropionate.
26 . The method of claim 14 , wherein the pharmaceutically active compound is fluticasone.
27 . The method of claim 14 , wherein the pharmaceutically active compound is tiotropium, ipratropium, oxitropium or glycopyrronium.
28 . A method of stabilizing a fine particle fraction (FPF) of a dry powder formulation for inhalation, said formulation comprising a pharmaceutically inactive carrier and a finely-divided pharmaceutically active compound; said method comprising: mixing said carrier having particles of noninhalable particle size, said pharmaceutically active compound having particles of inhalable particle size and pulverulent magnesium stearate, an amount of 0.5 to 5% by weight, based on the total weight of the formulation, said amount being effective to stabilize the FPF of the formulation against penetrating moisture.
29 . The method of claim 14 , wherein the powder exhibits improved stability of FPF and FPD following 4 to 10 days of storage at 40 C and 75% relative humidity compared to a reference lacking magnesium stearate as a pulverulent material.
30 . The method of claim 28 , wherein the powder exhibits improved stability of FPF and FPD following 4 to 10 days of storage at 40 C and 75% relative humidity compared to a reference lacking magnesium stearate as a pulverulent material.