Surgery – Respiratory method or device – Means for mixing treating agent with respiratory gas
Reexamination Certificate
2002-06-21
2004-01-27
Lo, Weilun (Department: 3761)
Surgery
Respiratory method or device
Means for mixing treating agent with respiratory gas
C128S203120, C604S058000
Reexamination Certificate
active
06681768
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The field of the invention is related to dry powder inhalers for delivery of a medicament, or a mixture of medicaments, to the respiratory tract. Dry powder inhalers are designed to store and provide a powder formulation, containing the drug in the correct particle size for effective deep lung deposition, comprising a dosing system for the reproducible administration of the required quantity of powder to the patient, a disintegration system for releasing drug particles from the powder formulation, and a mouthpiece.
2. Description of the Related Art
Dry Powder Inhalers
It is historical tradition to divide dry powder inhalers into (a) single dose, (b) multiple unit dose and (c) multi dose devices. For inhalers of the first type, single doses have been weighed by the manufacturer into small containers, which are mostly hard gelatin capsules. A capsule has to be taken from a separate box or container and inserted into a receptacle area of the inhaler. Next, the capsule has to be opened or perforated with pins or cutting blades in order to allow part of the inspiratory air stream to pass through the capsule for powder entrainment or to discharge the powder from the capsule through these perforations by means of centrifugal force during inhalation. After inhalation, the emptied capsule has to be removed from the inhaler. Generally, disassembling of the inhaler is necessary for inserting and removing the capsule, which is an operation that can be difficult and burdensome for some patients. Other drawbacks related to the use of hard gelatin capsules for inhalation powders are (a) poor protection against moisture uptake from the ambient air, (b) problems with opening or perforation after the capsules have been exposed previously to extreme relative humidity, which causes fragmentation or indenture, and (c) possible inhalation of capsule fragments. Moreover, for a number of capsule inhalers, incomplete expulsion has been reported (e.g. Nielsen, K. G., Skov, M., Klug, B., Ifversen, M. and Bisgaard, H. Flow-dependent effect of formoterol dry-powder inhaled from the Aerolizer®, Eur. Resp. J. 10 (1997) 2105-2109).
Some capsule inhalers have a magazine from which individual capsules can be transferred to a receiving chamber, in which perforation and emptying takes place, as described in WO 92/03175. Other capsule inhalers have revolving magazines with capsule chambers that can be brought in line with the air conduit for dose discharge (e.g., DE 3927170. They comprise the type of multiple unit dose inhalers together with blister inhalers, which have a limited number of unit doses in supply on a disk or on a strip. Blister inhalers provide better moisture protection of the medicament than capsule inhalers. Access to the powder is obtained by perforating the cover as well as the blister foil, or by peeling off the cover foil. When a blister strip is used instead of a disk, the number of doses can be increased, but it is inconvenient for the patient to replace an empty strip. Therefore, such devices are often disposable with the incorporated dose system, including the technique used to transport the strip and open the blister pockets.
Multi-dose inhalers do not contain pre-measured quantities of the powder formulation. They consist of a relatively large container and a dose measuring principle that has to be operated by the patient. The container bears multiple doses that are isolated individually from the bulk of powder by volumetric displacement. Various dose measuring principles exist, including rotatable membranes (e.g., EP0069715) or disks (e.g., FR 2447725; EP 0424790; DE 4239402 and U.S. Pat. No. 5,829,434), rotatable cylinders (e.g., EP 0166294; GB 2165159 and WO 92/09322) and rotatable frustums (e.g., U.S. Pat. No. 5,437,270), all having cavities which have to be filled with powder from the container. Other multi dose devices have measuring slides (e.g., U.S. Pat. Nos. 2,587,215; 5,113,855 and 5,840,279) or measuring plungers with a local or circumferential recess to displace a certain volume of powder from the container to a delivery chamber or an air conduit (e.g., EP 0505321, DE 4027391 and WO 92/04928).
Reproducible dose measuring is one of the major concerns for multi dose inhaler devices. The powder formulation has to exhibit good and stable flow properties because filling of the dose measuring cups or cavities is mostly under the influence of the force of gravity. The patient has to handle the inhaler correctly and especially, to keep the device in the correct position while operating the dose measuring principle. Only a few examples are known of special means to facilitate powder filling, e.g., EP 0424790 (vibratory means) and WO 92/04928 (collar-like portion for guiding the powder to the recess in a plunger). For preloaded single dose and multiple unit dose inhalers, the dose measuring accuracy and reproducibility can be guaranteed by the manufacturer. Multi dose inhalers on the other hand, can contain a much higher number of doses, whereas the number of handlings to prime a dose is generally lower.
Because the inspiratory air stream in multi-dose devices is often straight across the dose measuring cavity, and because the massive and rigid dose measuring systems of multi dose inhalers cannot be agitated by this inspiratory air stream, the powder mass is simply entrained from the cavity and little de-agglomeration is obtained during discharge. Consequently, separate disintegration means are necessary. However in practice, they are not always part of the inhaler design. Because of the high number of doses in multi-dose devices, powder adhesion onto the inner walls of the air conduits and the de-agglomeration means must be minimized and/or regular cleaning of these parts must be possible, without affecting the residual doses in the device. Some multi dose inhalers have disposable drug containers that can be replaced after the prescribed number of doses has been taken (e.g. U.S. Pat. No. 5,840,279). For such semi-permanent multi dose inhalers with disposable drug containers, the requirements to prevent drug accumulation are even more strict.
Powder Formulations
Many size ranges have been proposed as optimal for inhalation drugs, including 1-5 &mgr;m (WO 95/11666), 0.1-5 &mgr;m (WO 97/03649), 0.5-7 &mgr;m (Davies, P. J., Hanlon, G. W. and Molyneux, A. J. An investigation into the deposition of inhalation aerosol particles as a function of air flow rate in a modified ‘Kirk Lung’ J. Pharm. Pharmac. 28(1976) 908-911) and 2-7 &mgr;m (Kirk, W. F. Aerosols for inhalation therapy. Pharm. International (1986) 150-154). Particles larger than 7 &mgr;m are deposited mainly in the oropharynx by inertial impaction; most particles between 0.1 and 1 micron are exhaled again as the consequence of their low deposition efficiency in the whole respiratory tract (Martonen, T. B. and Katz, I. M. Deposition patterns of aerosolized drugs within human lungs: effects of ventilatory parameters. Pharm. Res. 10 (1993) 871-878). Different techniques are available for the production of such small particles, e.g., micronization of larger crystals with a jet mill or other comminution equipment, precipitation from (super) saturated solution, spray drying or supercritical fluid methods. Products obtained with different techniques may differ in their surface properties and therefore, in cohesiveness and/or adhesiveness. The degree of particle-to-particle interaction has influence on the de-agglomeration process during inhalation.
The very cohesive nature of micronized particles and the low quantities in which inhalation drugs are administered for obtaining desired therapeutic effects, generally between 10 and 400 &mgr;g, with an exception for profylactic (e.g. disodium cromoglycate) and antibiotic (e.g. colistin sulphate) drugs (both in the mg-range), make it very difficult to achieve the necessary reproducibility in the administration to the patient. Therefore, processing of the drug or drug combination into a suitable powder formulation is necessary. Currently,
de Boer Anne Haaije
Frijlink Henderik Willem
Gjaltema Doetie
Goede Joachim
Hagedoorn Paul
Baker & Daniels
Lo Weilun
Mendoza Michael G.
Sofotec GmbH & Co. KG
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