Surgery – Liquid medicament atomizer or sprayer – Gas stream aspirating medicament from reservoir
Reexamination Certificate
1998-11-19
2001-03-06
Weiss, John G. (Department: 3761)
Surgery
Liquid medicament atomizer or sprayer
Gas stream aspirating medicament from reservoir
C128S200140, C239S102200
Reexamination Certificate
active
06196219
ABSTRACT:
The present invention relates generally to drug administration devices, and in particular to a device for administrating a drug to a patient by means of his or her respiratory system. Such an inhalation device, in its simplest form, is commonly called an inhaler. It may be used e.g. for the controlled administration of drugs or for a variety of therapies using aerosolised drug administration including anaesthetics. The inhaler delivers the drug, which is in the form of a liquid substance, as a dispersion of atomised droplets. Preferably, such a device is small in size and battery operated so that the patient may carry and use it in a discreet manner. Preferably also the device is made in such a way that it is possible to use the same device for administrating more than one drug and to distinguish one drug from another. More specifically, the present invention concerns the liquid droplet spray device which creates the droplet spray of the inhaler or aerosolised drug delivery system and its control means.
Various devices are known for atomising a liquid. Document EP 0 516 565 describes am ultrasonic wave nebuliser which atomises water. This apparatus is used as a room humidifier. Vibration is transmitted through the water to the water surface from which the spray is produced. A perforate membrane is provided to retain the water in absence of oscillation. Such devices are particularly ineffective in vaporising suspensions as explained in the Research Article “Comparison of a respiratory suspension aerosolised by an air-jet and an ultrasonic nebuliser” by Susan L. Tiano and Richard N. Dalby in Pharmaceutical Development and Technology, I(3), 261-268 (1996). Typically, inhaler devices do use the same principle to atomise the liquid into droplets, see for example the document WO 95/15822.
However, the droplet size does not only depend on the size of the outlet orifices of the perforate membrane, but is also dependent on the vibration frequency. In order to obtain a small droplet, a very high frequency must be used, typically over 1 MHz for droplets of about 10 &mgr;m in diameter. This leads to an increased power consumption due to the high frequency so that such a device is not suitable for a small battery operated device. Furthermore, the exact size of the droplet is not always constant due to frequency response fluctuations with temperature and to membrane fabrication tolerances.
As is generally known, the efficacy of a drug therapy treatment depends on the substance's activity, which depends on the composition, on the place of impact, i.e. the place at which it may carry out its activity, and on the dose repeatability, i.e. the fact that the volume of each dose ejected remains constant.
With a large variation of droplet size, it is almost impossible to determine the quantity and where exactly the droplets will arrive. In fact, the liquid atomised by the inhaler is to reach certain parts of the lungs to have a maximum effect dependant on the therapy. It is thus desirable to be able to determine or to “target” the impact or deposition position of the droplets to obtain an efficient therapy.
Further, the orifices can not be made too small, not only because of fabrication reasons, but also in order to avoid clogging of the outlet orifices by the substance. In fact, it is known that the aqueous solubility of the substance solution depends on the composition of the drugs used and on its temperature. It is also known that such orifices might be clogged by very small amounts of drug left in the liquid spray device after atomisation.
To ensure that a certain amount of substance is indeed released, it has been proposed to monitor the amount of liquid released when the inhaler is used. The document WO 92/11050 describes such an inhaler having means for cyclically pressurising the liquid such that the liquid is periodically expelled and also having control means for deactivating the droplet generator after a predetermined time, e.g. by using a timer, or after a predetermined volume of liquid has been expelled. However, this document is completely silent about droplet size control, aqueous solution or suspension characteristics as well as about any deposition target determination and control of the liquid.
Another prior art device is known from the document U.S. Pat. No. 5,497,763. This device has a breath actuated release of aerosolised drug and has a porous membrane located above a dosage unit container. The pores are preferably cone-shaped to reduce the force needed to move the drug substance therethrough when collapsing the container. However, such a membrane is difficult to manufacture as the reproducibility of the pores is poor. Also, the difference in length and diameter of the pore channel results in a considerable difference of pressure drop across this channel. This varying pressure drop will thus also lead to a variation of the quantity and droplet size dispersion of the drug being expelled. Another problem is the alignment of the movable membrane with pores over each unit container resulting in another source of uncertainty over the expelled amount of drug.
Indeed, the fabrication tolerance &Dgr;d of the pores, or outlet nozzles, is an essential factor in controlling and determining the amount, i.e. the volume of an expelled droplet. In fact, this volume V depends on d
3
(V=1/6 * &pgr;d
3
), d being the diameter of the outlet nozzle. For example, if d=5 &mgr;m, and &Dgr;d=±0.5 &mgr;m, the droplet volume V may vary from 47.5 (d=4.5) to 87 (d=5.5) which is a variation of 83%, far too high for usual industry standards. The United States FDA (Food and Drug Administration) imposes a repeatability of ±20% for 90% of the droplets, and ±25% for the remaining 10%. Both the device according to WO 92/11050 and to U.S.Pat. No. 5,497,763 do not allow for such precision and repeatability.
Also, the pre-cited documents are silent about avoiding layers or areas of liquid drug forming on the outside surface of the nozzle array by well known capillary action and stiction. This is especially the case with devices where the same nozzle array is used several times, such as for example in the documents WO 92/11050 or Wo 90/01997. Such layers lead to the forming of liquid meniscus in front of the nozzles which are broken up by the piezo-activated spraying action but lead to a larger droplet size dispersion than without such layers.
The document U.S. Pat. No. 5,497,763 partially overcomes this problem by separating dosage containers and the porous membrane through which the drug is aerosolised. However, the solution does not allow for the precision and repeatability of the cone-shaped pores used and the precise control of the drug delivery, requiring a pressure to be applied additionally to the piezoelectric vibrating means to force the liquid out. Also, the piezoelectric vibrating means is not compensated for its non-linearities adding to uncontrolled factors affecting the delivery of targeted delivery.
It is, therefore, an object of the present invention to provide a liquid droplet spray device for an inhaler, as well as an inhaler itself, suitable for respiratory therapies which overcomes, at least partially, the inconveniences of the prior art and which allows for a true targeting of the impact of droplets thereby assuring a constant droplet size. In fact, this virtually constant physical size of the droplets, or mono-dispersion of the droplets allows for an exact determination of the volume of liquid released and deposited.
It is another object of the present invention to provide such a device which is simple, reliable to manufacture, small in size and low in cost.
Thus, the present invention concerns a liquid droplet spray device according to present claim
1
as well as a liquid droplet spray device assembly according to present claim
8
. The present invention further concerns an inhaler according to claim
17
allowing for a predicted deposition, and to claim
21
comprising several inventive spray devices to obtain a highly reliable
Barraud Cédric
Bo Hu
de Heij Bas
de Rooij Nicolaas Frans
Hess Joseph
Griffin & Szipl, P.C.
Microflow Engineering SA
Weiss John G.
LandOfFree
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