Tiotropium (Formula I) is an anticholinergic agent with the chemical name (1α,2β,4β,7β)-7-[(hydroxidi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane.

Tiotropium was described in European patent application numbered EP0418716 for the first time. Processes to prepare tiotropium; pharmaceutical compositions containing tiotropium; long-acting, strong anticholinergic activity of tiotropium and its use in the treatment of respiratory disorders were disclosed in that patent document.
Tiotropium, especially tiotropium bromide, is a highly effective anticholinergic with the ease of use it provides as it requires once daily use in the treatment of respiratory disorders, particularly asthma and COPD.
Tiotropium antagonises the effect of acetylcholine by blocking cholinergic muscarinic receptors. Tiotropium is separated from M1 and M3 receptors that cause broncho-construction slowly while it is separated from M2 receptors that inhibit the release of acetylcholine from cholinergic nerve endings rapidly.
It is possible that the pharmaceutical formulation containing tiotropium is in the form of solution, aerosol or dry powder that are administered via inhalation route. In addition, dry powder formulations are given great importance because of several reasons such as the ease of use that the designed inhalation devices provide and the application possibilities providing long-term stability that they allow.
The delivery of the active agents, such as tiotropium, that shows high efficiency even at low doses to the lungs in efficient and sufficient amounts so as to obtain the desired effects is of great importance because it is considerably difficult to deliver sufficient amounts of these active substances including tiotropium to the lungs as they are very small in amount per dose required for the treatment. Therefore, said active substances have to be diluted with inactive excipients.
The dry powder formulation should have good flow properties in order to provide accurate dosing while the dry powder formulation is being packed and divided into the reservoirs of multi-dose inhalation devices which contain more than one dose or blister cavities of blister packages each of which contains one dose or capsules which contain one dose, after the preparation of the dry powder formulation containing active substance and excipient.
In addition to this, the fact that the dry powder formulation has good flow properties substantially affects the discharge capacity and discharge characteristics of said dry powder formulation during the inhalation from the capsule, blister or reservoir.
The amount of the excipient used in the preparation of the dry powder formulation is much more than the amount of the active substance used. Since the proportion of the excipient to the active agent in the dry powder formulation is high, the excipient choice is effective on the properties of the dry powder formulation to a considerable extent. Thus, the particle size which is one of the physical properties of the excipient directly affects the flow properties of the dry powder formulation. The desired efficiency would be gained as the active agent is sufficiently transmitted to the lungs in dry powder formulations that have good flow properties.
In order to describe the active substance used for the preparation of the dry powder formulation as inhalable, the particles of the active substance have to be conveyed deep into the branches of the lungs with inhaled air. Thus, the required particle size is in the range of 1 and 10 μm, preferably less than 6 μm.
The aim of the present invention is to prepare a dry powder formulation which contains tiotropium; allows highly accurate dosing that provides the inhalable active substance to be in equal and accurate amounts in each blister, capsule or reservoir during the manufacture process; and is inhaled from the capsule, blister or the reservoir in which it is kept with high discharge capacity.
The patent application WO 2004047796 is related to a preparation in dry powder form containing tiotropium and excipients.
The patent application WO 02080884 is related to a preparation in dry powder form containing at least one micronized or spray dried water-soluble active agent, excipient and fatty acid or alcohol derivative or a poloxamer.
The U.S. Pat. No. 5,478,578 is related to a preparation in dry powder form containing micronized active substance and physiologically acceptable excipient.
The dry powder formulation containing tiotropium that has a therapeutic efficacy even at very low doses has to be blended homogeneously in order to provide highly accurate dosing. It has a great significance for the delivery of tiotropiumin in the dry powder formulation to the lungs in efficient and sufficient amounts that the components constituting the dry powder formulation have uniform dispersion properties besides being blended homogeneously.
In accordance with this, a further aim of the present invention is to provide a dry powder formulation containing tiotropium, having uniform dispersion properties and homogeneously blended components. Therefore, the delivery of the inhalable active substance amount contained in the dry powder formulation is achieved with minimum possible variability in every inhalation.
USPTO Backgrounds
USPTO Backgrounds