Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1998-06-16
2002-11-05
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S045000, C424S046000, C514S951000
Reexamination Certificate
active
06475523
ABSTRACT:
BACKGROUND OF THE INVENTION
This application is a 371 of PCT/GB96/01783, filed Jul. 24, 1996.
This invention relates to powders for use in dry powder inhalers.
BRIEF SUMMARY OF THE INVENTION
Inhalers are well known devices for administering pharmaceutical products to the respiratory tract by inhalation. Inhalers are widely used particularly in the treatment of diseases of the respiratory tract.
There are a number of types of inhaler currently available. The most widely used type is a pressurised metered dose inhaler (MDI) which uses a propellant to expel droplets containing the pharmaceutical product to the respiratory tract. Those devices are disadvantageous on environmental grounds as they often use CFC propellants, and on clinical grounds related to the inhalation characteristics of the devices.
An alternative device to the MDI is the dry powder inhaler. The delivery of dry powder particles of pharmaceutical products to the respiratory tract presents certain problems. The inhaler should deliver the maximum possible proportion of the active particles expelled to the lungs, including a significant proportion to the lower lung, preferably at the low inhalation capabilities to which some patients, especially asthmatics, are limited. It has been found, however, that, when currently available dry powder inhaler devices are used, in many cases only about 10% of the active particles that leave the device on inhalation are deposited in the lower lung. More efficient dry powder inhalers would give clinical benefits.
The type of dry powder inhaler used is of significant importance to the efficiency of delivery over a range of airflow conditions of the active particles to the respiratory tract. Also, the physical properties of the powder used affect both the efficiency and reproducibility of delivery of the active particles and the site of deposition in the respiratory tract.
On exit from the inhaler device, the active particles should form a physically and chemically stable aerocolloid which remains in suspension until it reaches a conducting bronchiole or smaller branching of the pulmonary tree or other absorption site preferably in the lower lung. Once at the absorption site, the active particle should be capable of efficient collection by the pulmonary mucosa with no active particles being exhaled from the absorption site.
The size of the active particles is particularly important. For effective delivery of active particles deep into the lungs, the active particles should be small, with an equivalent aerodynamic diameter substantially in the range of 0.1 to 5 &mgr;m, approximately spherical and monodispersed in the respiratory tract. Small particles are, however, thermodynamically unstable due to their high surface area to volume ratio, which provides significant excess surface free energy and encourages particles to agglomerate. In the inhaler, agglomeration of small particles and adherence of particles to the walls of the inhaler are problems that result in the active particles leaving the inhaler as large stable agglomerates or being unable to leave the inhaler and remaining adhered to the interior of the inhaler.
The uncertainty as to the extent of formation of stable agglomerates of the particles between each actuation of the inhaler and also between different inhalers and different batches of particles, leads to poor dose reproducibility.
In an attempt to improve that situation, dry powder for use in dry powder inhalers often include coarse carrier particles mixed with fine particles of active material. The active particles adhere to the surfaces of the carrier particles whilst in the inhaler device, and are dispersed on inhalation into the respiratory tract to give a fine suspension. The carrier particles are often large particles greater than 90 &mgr;m in diameter to give good flow properties because small particles with a diameter of less than 10 &mgr;m may become coated on the wall of the delivery device and have poor flow and entrainment properties leading to poor dose uniformity.
There are, however, problems associated with the addition of carrier particles to the active particles in the dry powder, for example problems related to the efficient release of the active particles from the surfaces of the carrier particles on inhalation. Furthermore, in some cases it is preferred for no carrier particles to be present in the powder administered.
In known dry powder inhaler devices, doses of powder containing only active particles are dispensed. The powder contains no carrier particles or other additives and the amount of powder in each dose is small, usually less than 1 mg. The volume of the dose may be, for example, approximately 6.5 &mgr;l.
Problems involved in dispensing a powder containing only particles of active material include
(i) formation of stable agglomerates of the small particles which often are not broken down into individual particles in the airstream when the particles are inhaled and are, therefore, less likely to reach the lower lung on inhalation of the powder than the fine individual active particles;
(ii) variations in the amount of powder metered from a reservoir of the inhalation device due to poor flow properties of the powder and inconsistent agglomeration, leading to inconsistency in the size of dose, which may vary as much as ±50% compared with the nominal dose for the device;
(iii) incomplete removal of the dose from the device due to adherence of the particles to the walls of the device, leading to poor dose reproducibility.
An object of the present invention is to provide a dry powder for use in dry powder inhalers which overcomes or mitigates at least one of the above disadvantages.
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Davidson Davidson & Kappel LLC
Page Thurman K.
Seidleck Brian K.
Vectura Limited
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