Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
2002-05-22
2004-07-06
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S046000, C514S220000, C514S414000, C128S200140, C128S203150, C128S200240
Reexamination Certificate
active
06759029
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the delivery of rizatriptan or zolmitriptan through an inhalation route. Specifically, it relates to aerosols containing rizatriptan or zolmitriptan that are used in inhalation therapy.
BACKGROUND OF THE INVENTION
There are a number of compositions currently marketed for the treatment of migraine headaches. The compositions contain at least one active ingredient that provides for observed therapeutic effects. Among the active ingredients given in such anti-migraine compositions are rizatriptan and zolmitriptan.
It is desirable to provide a new route of administration for rizatriptan and zolmitriptan that rapidly produces peak plasma concentrations of the compounds. The provision of such a route is an object of the present invention.
SUMMARY OF THE INVENTION
New routes of administration for the compounds may increase the rate at which their peak plasma concentrations are reached. Such routes are provided herein.
The present invention relates to the delivery of rizatriptan or zolmitriptan through an inhalation route. Specifically, it relates to aerosols containing rizatritpan or zolmitriptan that are used in inhalation therapy.
In a composition aspect of the present invention, the aerosol comprises particles comprising at least 5 percent by weight of rizatriptan or zolmitriptan. Preferably, the particles comprise at least 10 percent by weight of rizatriptan or zolmitriptan. More preferably, the particles comprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent or 99.97 percent by weight of rizatriptan or zolmitriptan.
Typically, the aerosol has a mass of at least 10 &mgr;g. Preferably, the aerosol has a mass of at least 100 &mgr;g. More preferably, the aerosol has a mass of at least 200 &mgr;g.
Typically, the particles comprise less than 10 percent by weight of rizatriptan or zolmitriptan degradation products. Preferably, the particles comprise less than 5 percent by weight of rizatriptan or zolmitriptan degradation products. More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of rizatriptan or zolmitriptan degradation products.
Typically, the particles comprise less than 90 percent by weight of water. Preferably, the particles comprise less than 80 percent by weight of water. More preferably, the particles comprise less than 70 percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent, or 5 percent by weight of water.
Typically, at least 50 percent by weight of the aerosol is amorphous in form, wherein crystalline forms make up less than 50 percent by weight of the total aerosol weight, regardless of the nature of individual particles. Preferably, at least 75 percent by weight of the aerosol is amorphous in form. More preferably, at least 90 percent by weight of the aerosol is amorphous in form.
EXAMPLE 2
Volatilization of Rizatriptan
A solution of 10 mg rizatriptan in 1 mL diethyl ether was spread out in a thin layer on a 10 cm×15 cm sheet of aluminum foil. The diethyl ether was allowed to evaporate. Assuming a drug density of about 1 g/cc, the calculated thickness of the rizatriptan coating on the 150 cm
2
aluminum solid support, after solvent evaporation, is about 0.7 microns. The coated aluminum foil sheet was inserted into a glass tube in a furnace (tube furnace). A glass wool plug was placed in the tube adjacent to the foil sheet, and an air flow of 2 L/min was applied. The furnace was heated to 250° C. for 30 s to volatilize the coated rizatriptan and then was allowed to cool. The glass wool was extracted, and HPLC analysis of the collected material showed it to be at least 99% pure rizatriptan.
EXAMPLE 3
Particle Size, Particle Density, and Rate of Inhalable Particle Formation of Rizatriptan Aerosol
A solution of 11.3 mg rizatriptan in 200 &mgr;L dichloromethane was spread out in a thin layer on the central portion of a 4 cm×9 cm sheet of aluminum foil. The dichloromethane was allowed to evaporate. Assuming a drug density of about 1 g/cc, the calculated thickness of the rizatriptan thin layer on the 36 cm
2
aluminum solid support, after solvent evaporation, is about 3.1 microns. The aluminum foil was wrapped around a 300 watt halogen tube, which was inserted into a T-shaped glass tube. One of the openings of the tube was sealed with a rubber stopper, another was loosely covered with the end of the halogen tube, and the third was connected to a 1 liter, 3-neck glass flask. The glass flask was further connected to a large piston capable of drawing 1.1 liters of air through the flask. Alternating current was run through the halogen bulb by application of 90 V using a variac connected to 110 V line power. Within 1 s, an aerosol appeared and was drawn into the 1 L flask by use of the piston, with collection of the aerosol terminated after 7 s. The aerosol was analyzed by connecting the 1 L flask to an eight-stage Andersen non-viable cascade impactor. Results are shown in table 1. MMAD of the collected aerosol was 1.2 microns with a geometric standard deviation of 1.7. Also shown in table 1 is the number of particles collected on the various stages of the cascade impactor, given by the mass collected on the stage divided by the mass of a typical particle trapped on that stage. The mass of a single particle of diameter D is given by the volume of the particle, &pgr;D
3
/6, multiplied by the density of the drug (taken to be 1 g/cm
3
). The inhalable aerosol particle density is the sum of the numbers of particles collected on impactor stages 3 to 8 divided by the collection volume of 1 L, giving an inhalable aerosol particle density of 3×10
7
particles/mL. The rate of inhalable aerosol particle formation is the sum of the numbers of particles collected on impactor stages 3 through 8 divided by the formation time of 7 s, giving a rate of inhalable aerosol particle formation of 5×10
9
particles/second.
TABLE 1
Determination of the characteristics of a rizatriptan
condensation aerosol by cascade impaction using an Andersen 8-stage
non-viable cascade impactor run at 1 cubic foot per minute air flow.
Particle size
Average particle
Mass
Number of
Stage
range (microns)
size (microns)
collected (mg)
particles
0
9.0-10.0
9.5
0.0
0
1
5.8-9.0
7.4
0.0
0
2
4.7-5.8
5.25
0.1
1.3 × 10
6
3
3.3-4.7
4.0
0.2
6.0 × 10
6
4
2.1-3.3
2.7
0.4
3.9 × 10
7
5
1.1-2.1
1.6
1.2
5.6 × 10
8
6
0.7-1.1
0.9
1.0
2.6 × 10
9
7
0.4-0.7
0.55
0.5
5.7 × 10
9
8
0-0.4
0.2
0.1
2.4 × 10
10
EXAMPLE 4
Drug Mass Density and Rate of Drug Aerosol Formation of Rizatriptan Aerosol
A solution of 11.6 mg rizatriptan in 200 &mgr;L dichloromethane was spread out in a thin layer on the central portion of a 4 cm×9 cm sheet of aluminum foil. The dichloromethane was allowed to evaporate. Assuming a drug density of about 1 g/cc. the calculated thickness of the rizatriptan thin layer on the 36 cm
2
aluminum solid support, after solvent evaporation, is about 3.2 microns. The aluminum foil was wrapped around a 300 watt halogen tube, which was inserted into a T-shaped glass tube. One of the openings of the tube was sealed with a rubber stopper, another was loosely covered with the end of the halogen tube, and the third was connected to a 1 liter, 3-neck glass flask. The glass flask was further connected to a large piston capable of drawing 1.1 liters of air through the flask. Alternating current was run through the halogen bulb by application of 90 V using a variac connected to 110 V line power. Within seconds, an aerosol appeared and was drawn into the 1 L flask by use of the piston, with formation of the aerosol terminated after 7 s. The aerosol was allowed to sediment onto the walls of the 1 L flask for approximately 30 minutes. The flask was then extracted with dichloromethane and the extract analyzed by HPLC with detection by light absorption at 225 nm. Comparison with standards containing known amounts of rizatriptan revealed tha
Hale Ron L.
Rabinowitz Joshua D.
Solas Dennis W.
Zaffaroni Alejandro C.
Alexza Molecular Delivery Corporation
Haghighatian Mina
Hartley Michael G.
Stracker Elaine C.
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