Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Reexamination Certificate
1999-01-28
2001-06-12
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
C128S203120, C128S203130, C128S203150, C128S203190, C128S203210, C128S203230
Reexamination Certificate
active
06245339
ABSTRACT:
The present invention relates, in general, to a medicament carrier containing particulate dry powder medicament and which is adapted to be positioned within a dry powder inhalator. More particularly, the present invention relates to a medicament carrier containing agglomerated dry powder medicament particles having a particle size of about 0.05 millimeter or greater.
Asthma and other respiratory diseases are typically treated by the inhalation of an appropriate medicament for deposition into the lungs to ease patient breathing and increase air capacity. The most widely used treatments for respiratory diseases have been (1) the inhalation of a medicament from a drug solution or suspension in a metered dose aerosol container (i.e., a pressurized inhalator) using a gas propellant and (2) the inhalation of a powdered drug (generally admixed with an excipient) from a dry powder inhalator.
However, in view of recent evidence of the link between chlorofluorocarbon gas emissions and the deterioration of the earth's protective ozone layer, use of drugs in pressurized aerosol inhalators using chlorofluorocarbons as the gas propellant is less desirable and interest in dry powder inhalation systems has substantially increased.
Applicants are presently aware of several different dry powder methods and devices for providing fine particulate powders to the respiratory tract of a patient. The dose of a powder type of medicament employed with such dry powder inhalator devices is, in most instances, significantly less than 50 mg, typically less than 5 mg, and usually about 50 to about 500 micrograms. The powdered particles contained in the inhalator are micronized, typically having a particle size of <10 micrometers, more particularly <6 micrometers, even more particularly <5 micrometers, which is an appropriate size so that the particles can be drawn deep into the lungs.
One such inhalator device utilizes hard gelatin capsules which contain a dose of the powdered medicament and possibly also various adjuvants. The inhalator includes a mechanism for perforating the capsule in order to open it after it has been inserted into the inhalator. An air stream generated by the patient on the mouthpiece of the inhalator removes and disaggregates the powder contained within the capsule which is inhaled by the patient. The empty capsule is then expelled from the inhalator, so that it may receive the next capsule. A drawback of this device is that the air stream created by the patient is generally not sufficient in duration and velocity to remove, disaggregate and aerosolize all of the powder from the capsule. Dry powder inhalators using this technology are disclosed in a number of patents including U.S. Pat. Nos. 3,906,950; 4,013,075; 3,807,400; and 3,991,761, all to Cocozza.
Also related to the above-mentioned capsule technology are the disclosures of U.S. Pat. No. 4,161,516 to Bell and U.S. Pat. No. 4,395,421 to Taylor et al. These patents show, respectively, an agglomerator-pelletizer apparatus and a wet granulator apparatus for preparing pellets or granules of the asthma medicament, disodium cromoglycate, which may then be placed inside of a capsule.
Another type of inhalator device is loaded with a package having a number of spaced-apart blisters, each containing powdered medicament for administration to the patient. As the patient moves each blister into a predetermined position, the patient breaks the blister by a mechanism in the device so as to release the powder and inhale it. However, moisture ingress into the blister package can cause aggregation into large agglomerates of the prepared medicament therein. Consequently, when the prepared medicament is inhaled by the patient, the preferred particle size for greatest efficacy in respiratory disease treatment may not necessarily be achieved. Instead, like the gelatin capsules previously discussed, the airstream created by the patient is not sufficient in duration and velocity to remove, disaggregate and aerosolize all of the powder from the blister to the desired particle size. This type of inhalation device is disclosed in a number of published patent applications including European Published Patent Application Nos. 0 455 463 Al to Velasquez et al., 0 211 595 A2 to Newell et al., and 0 4670 172 Al to Cocozza et al.
Yet another type of dry powder inhalator contains a quantity of powdered medicament therein which is sufficient for multiple doses. A representative example of this type of device is the TURBUHALER® inhalator which is disclosed in U.S. Pat. Nos. 4,668,218; 4,667,668; and 4,805,811. The inhalator includes a mechanism for withdrawing powdered medicament from a container therein and for preparing a dose for inhalation, including a plate having a number of cup-shaped holes therethrough. The plate can be moved by mechanical means from a position where a proportion of the holes are filled with powdered medicament taken from the container to another position in which the holes filled with the medicament are located within a channel. Air flows into the channel as a result of suction provided by the patient on a mouthpiece in communication with the channel so as to remove the powdered medicament from the holes. Several undesirable consequences are associated with this system. It has been found that when suction is applied to entrain the medicament from one or more holes in the plate, not all of the medicament is entrained in the air flow. Further, particle size distribution is strongly dependent on the inhalation profile of the patient, which is a disadvantage with patients suffering from acute respiratory problems. Moreover, the TURBUHALER® device is designed to administer large doses and is prone to significant variations in medicament delivery. Lastly, the powder must travel a lengthy path resulting in significant losses due to wall deposits.
A fourth dry powder inhalator device is disclosed in PCT Published Application No. WO 92/00115, published Jan. 9, 1992, to Gupte et al., which shows a velour-type or velvet-type fiber material loaded with powder between the fibers. An air stream acts to lift the powder from the velour-like carrier material and to entrain the powder within the air stream which is then inhaled by the patient. One potential shortcoming of this type of inhalator device is that there can be a tendency for the carrier fibers of velour or velvet to dislodge and to intermix with the medicament ultimately being deposited within the patient's lungs. In loading the velour or velvet carrier, powder is coated thereon and then pressed and scraped with a blade to press the powder between the fibers and disagglomerate large clumps of the powder. Alternatively, the powder may be loaded between the fibers from droplets of a suspension of the powder and a suspending agent (such as dichloromethane) dispersed from a metering device.
A new type of carrier disc for use with a dry powder inhalator is described in PCT Published Application No. WO 94/20164, published Sep. 15, 1994, to Mulhauser et al. The carrier disc is a screen mesh which is impregnated in spaced locations or interstices along its circumference with a dose of powdered asthma medicament, such as salmeterol hydroxynapthoate. During inhalation, air impinging on the powdered medicament impregnated into the interstices of the screen surrounds each medicament dose and entrains it to dispense it from the screen interstices into the air-stream and in turn into the patient's lungs. Shortcomings of the interstitial deposit of the powdered medicament into the screen (i.e., impregnation of the medicament in the screen interstices) are limitations of dose size to interstitial volume, and the necessity to disaggregate large clusters of medicament present in interstitial voids.
An improvement over the carrier screen disclosed in the above-mentioned PCT Published Application No. WO 94/20164 is described in U.S. patent application Ser. Nos. 08/328,577 and 08/328,578, both to Van Oort and both filed on Oct. 21, 1994, the disclosures of which are incorporated herein by r
Sacchetti Mark Joseph
Van Oort Michiel Mary
Glaxo Wellcome Inc.
Page Thurman K.
Riek James P.
Ware Todd D.
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