Inhaler apparatus with modified surfaces for enhanced release of dry powders

In one aspect, the present invention provides an inhaler apparatus comprising interior surfaces having contact with a medicament for inhalation, the interior surfaces including an interior surface of a mouthpiece and a substrate with medicament deposited thereon at least one of such interior surfaces comprising indentations or raised areas therein, the raised areas having valleys therebetween. In certain preferred embodiments, the interior surface is a surface on a substrate having medicament deposited thereon, and in other preferred embodiments, the interior surface is an interior surface of the mouthpiece of the inhaler. In addition to providing surface topology for minimizing the area of contact between the medicament and the surfaces of the inhaler, the surfaces are preferably made of a material having a low surface energy, and more preferably, also having, when uncharged, no substantial van der Waals or electrostatic interaction with the medicament. Furthermore, the material is preferably substantially chemically unreactive with the medicament.

RELATED CO-PENDING U.S. PATENT APPLICATIONS 
Related co-pending U.S. patent applications, Ser. Nos. 08/661,212 ("Inhaler 
Apparatus with an Electronic Means for Enhanced Release of Dry Powders," 
filed simultaneously herewith), 08/630,049 ("Acoustic Dispenser," filed 
Apr. 9, 1996, and its continuation-in-part filed simultaneously herewith), 
08/630,050 ("Electrostatic Chucks," filed Apr. 9, 1996) and its 
continuation-in-part, filed simultaneously herewith, 08/630,012 ("Chucks 
and Methods for Positioning Multiple Objects on a Substrate," filed Apr. 
9, 1996), 08/471,889 ("Methods and Apparatus for Electronically Depositing 
a Medicament Powder Upon Predefined Regions of a Substrate," filed Jun. 6, 
1995, and continuation-in-part thereof filed Jun. 6, 1996), 08/467,647 
("Apparatus for Electrostatically Depositing and Retaining Materials Upon 
a Substrate," filed Jun. 6, 1995) and 08/506,703 ("Inhaler Apparatus Using 
a Tribo-Electric Charging Technique," filed Jul. 25, 1995) describe, inter 
alia, the electrostatic deposition of objects, such as particles of 
powder, on a substrate, such as an inhaler substrate The foregoing patent 
applications are hereby incorporated herein by reference, in their 
entirety. 
In one aspect, the present invention provides an inhaler apparatus 
comprising interior surfaces having contact with a medicament for 
inhalation, the interior surfaces including the interior of the mouthpiece 
and the substrate with medicament deposited thereon. According to the 
invention, at least one of such interior surfaces have indentations or 
raised areas therein, the raised areas having valleys between them. These 
surface modifications provide a mechanism for minimizing the area of 
contact between the medicament and the surfaces of the inhaler, thereby 
promoting release of the medicament from the inhaler. 
Numerous approaches have been taken in the design and manufacture of dry 
powder inhalers. For example, WO 93/09832 discloses an inhalation device 
having an elongate carrier of medicament powder, the medicament powder 
being released after impact from a hammer, the inhalation device having a 
convoluted channel to deagglomerate the medicament powder. 
The disadvantages of the inhalers of the prior art include, for example, 
the inability of a patient suffering from a respiratory disorder, such as 
asthma, to inhale with sufficient force to receive an entire dosage. For 
example, a patient may only be able to generate an air flow rate of about 
15 liters per minute. In most dry powder inhalers, the patient's 
inhalation supplies the energy required to dispense the medicament from 
the inhaler. The air flow rate generated by the patient's lungs 
significantly affects the amount of medicament that ultimately exits the 
inhaler and reaches the lungs. 
Another disadvantage of the inhalers of the prior art includes the 
inability to accurately determine the amount of medicament dispensed, 
since the inhaler may dispense a greater or lesser amount of medicament, 
depending upon the patient's air flow rate, for example. 
A further disadvantage of the inhalers of the prior art is a problem of 
agglomeration of the medicament powder. Agglomerated particles generally 
impact the mouth and throat rather than remaining in the air flow for 
deposition on the lungs. One of the approaches to remedying this problem 
has been the provision of tortuous channels in the inhalers of the prior 
art to promote deagglomeration. This approach suffers from drawbacks, 
however, such as the deposition of the medicament along the channels, 
thereby leading to inaccurate dosage dispensing. 
Another disadvantage encountered in the inhalers of the prior art is 
unintended dislodging, in which the medicament is discharged, for example, 
upon dropping the inhaler. 
For the foregoing reasons, there is a need for a dry powder inhaler capable 
of delivering an accurate unit dosage of medicament at a low flow rate, 
such as 15 liters per minute, yet which substantially retains the 
medicament upon impact, such as dropping the inhaler. 
SUMMARY OF THE INVENTION 
The present invention is directed, in part, to an inhaler apparatus 
comprising interior surfaces having contact with a medicament for 
inhalation, the interior surfaces including an interior surface of a 
mouthpiece and a substrate with medicament deposited thereon, at least one 
of such interior surfaces comprising indentations or raised areas therein, 
the raised areas having valleys therebetween. In certain preferred 
embodiments, the interior surface is a surface on a substrate having 
medicament deposited thereon, and in other preferred embodiments, the 
interior surface is an interior surface of the mouthpiece of the inhaler. 
Preferably, both the surface of the substrate and the mouthpiece and any 
other surfaces having contact with the medicament have indentations or 
raised areas therein, or any other surface structure for decreasing the 
area of contact between the selected medicament and the surface. 
In preferred embodiments, the width of the indentations or valleys have a 
diameter that is about 5% to about 20% smaller and more preferably, about 
10% to about 20% smaller than a minimum selected particle size to be 
administered by the inhaler. In certain preferred embodiments, the width 
of the indentations or valleys have a diameter of about one micron to 
about 2.5 microns. Preferably, the depth of the indentations or valleys is 
also smaller than a minimum selected particle size to be administered by 
the inhaler, and most preferably, the depth is about 5% to about 50% 
smaller, and more preferably, about 5% to about 20% smaller than a minimum 
selected particle size to be administered by the inhaler. 
In preferred embodiments, the indentations or valleys are substantially 
regularly spaced throughout the area of the substrate having medicament 
thereon or throughout the mouthpiece of the inhaler. In certain preferred 
embodiments, the indentations are substantially linear. 
The substrate having the medicament deposited thereon can be of any 
selected shape, including, in preferred embodiments, a disk or a tape. 
Preferably, the substrate comprises multiple dosage units of medicament. 
In preferred embodiments, the medicament is sealed onto the substrate. 
In addition to providing surface topology for minimizing the area of 
contact between the medicament and the surfaces of the inhaler, the 
surfaces are preferably made of a material having a low surface energy, 
and more preferably, also having, when uncharged, no substantial van der 
Waals or electrostatic interaction with the medicament. Furthermore, the 
material is preferably substantially chemically unreactive with the 
medicament. Examples of materials that can be used for such surfaces 
include perfluorinated polymers such as polytetrafluoroethylene 
("TEFLON"), silicone, silicon alumina ceramic, polymeric photoconductor, 
polycarbonate, polyimide, polypropylene and polyethylene. In some 
embodiments, the surface has reacted with a silane, such as fluorosilane 
or aminosilane, to form a film having a low surface energy. Alternatively, 
for example, the surface can be treated to apply a perfluorinated polymer 
film. 
Other preferred aspects of the invention include an inhaler apparatus 
comprising a mouthpiece, the mouthpiece having a wall with an exterior and 
an interior surface, the mouthpiece further comprising multiple air inlets 
extending from the exterior to the interior, the inlets each being in 
communication with a channel, each channel extending from the interior to 
the exterior of the mouthpiece. Preferably, each channel is positioned at 
an angle of about 20 to about 70 degrees, and more preferably, about 45 
degrees from the wall of the mouthpiece. Preferably, the channels are 
substantially cylindrical in shape. In certain preferred embodiments, the 
channels are preferably less than about 5 mm in diameter, such as about 
0.1 to about 5 mm in diameter or less than about 0.1 mm in diameter. 
Preferably, the interior surface of the mouthpiece further comprises 
indentations or raised areas therein, the raised areas having valleys 
therebetween, and the indentations or valleys are preferably substantially 
parallel to the direction of air flow in the mouthpiece during inhalation. 
In preferred embodiments, the width of the indentations or valleys is 
about 5% to about 20% smaller, and more preferably, about 10% to about 20% 
smaller than the minimum particle size to be administered by the inhaler. 
In certain preferred embodiments, the mouthpiece further comprises a 
shuttering mechanism for selectively closing at least one of the air 
inlets, such shuttering action preferably being capable of actuation by 
the patient. 
In another aspect, the present invention provides a method of manufacturing 
an inhaler apparatus, comprising: 
(a) providing a substrate having a surface for deposition of medicament, 
the substrate having indentations or raised areas therein, the raised 
areas having valleys therebetween; 
(b) depositing medicament on the substrate; and 
(c) incorporating the substrate into a housing. 
Preferably, the deposition Is performed electrostatically. 
Preferably, the medicament deposited on the substrate has a particle size 
of about one to about fifteen microns. In preferred embodiments, the 
methods of the invention include sealing the substrate having medicament 
deposited thereon.

DETAILED DESCRIPTION OF THE INVENTION 
After depositing a powder onto a substrate of an inhaler, the powder must 
be accurately released upon inhalation by a patient. One of the obstacles 
to overcome is the adherence of the powder particles to the substrate. One 
of the forces holding the particles onto the substrate is a van der Waals 
force. Another one of the holding forces is the electrostatic force. A 
third holding force is a charge image force, generated by the charge of 
the powder particle in the local area of the substrate upon which it is 
adhered. These forces vary in magnitude depending upon, for example, the 
conductivity of the substrate. The van der Waals attraction increases over 
time, and the rate of increase is related to the rate of particle 
deformation due to greater contact area. Furthermore, these forces 
increase as the particle size increases. See, for example, FIG. 1, which 
is a graphical representation of mathematical calculations of the 
foregoing forces. 
The above-described problems are addressed, among others, by the current 
invention. In one aspect, the present invention provides for inhalers with 
modified substrates which alter the attractive forces. Preferably, greater 
than about 70%, and preferably greater than about 80% of the medicament is 
released upon inhalation. Preferably, the air flow required for release of 
about 80% to about 100% of the medicament in a dosage unit is less than 
about 60 liters per minute; more preferably, less than about 30 liters per 
minute, and even more preferably, no greater than about 15 liters per 
minute. See, for example, FIGS. 2A-E which show release of a medicament 
from a textured substrate having grooved indentations at 15 liters per 
minute (B), 30 liters per minute (C), 45 liters per minute (D), and 57 
liters per minute (E). See also FIG. 2F which is a graph of the data 
obtained and which shows the increasing release of medicament from the 
substrate as air flow increases. Example 1 provides the data used to 
generate the graph shown in FIG. 2F. The deposition technique used in this 
example involved ion printing according to Ser. No. 08/471,889. In 
preferred embodiments of the present invention, an electrostatic chuck is 
used to deposit electrostatically charged medicament onto the inhaler 
substrate, as described, for example, in U.S. Ser. No. 08/630,050. A 
preferred deposition technique, using an electrostatic chuck, is believed 
to result in a higher percentage of release of the medicament from the 
inhaler substrate. Other deposition techniques can also be used with the 
modified inhaler substrates of the invention. 
The inhaler substrate is preferably modified to minimize the surface area 
of the contact between the particles of the powder and the surface of the 
substrate, for those particles having a selected size. Particles having 
the desired size will have minimal contact with the substrate, and will 
therefore be more likely to be released from the substrate. In addition to 
making it more likely to release the desired particles, the modified 
substrate can be configured so that particles having an undesirable size 
are trapped. For example, if the surface area of contact between the 
particle and the substrate is high, such as with a particle having a size 
below the selected size, the higher contact leads to trapping the particle 
on the substrate rather than releasing it. 
The minimization of the area of contact is preferably accomplished in the 
following ways. The surface area of contact can be minimized, for example, 
by providing indentations in the plane of the surface, or by providing 
raised areas in the plane of the surface. In preferred embodiments of the 
invention at least one interior surface of the inhaler has indentations or 
raised areas with valleys therebetween, or other surface modification for 
decreasing the area of contact between the selected medicament particles 
and the interior surface of the inhaler in contact with the medicament. 
The contact of the medicament with the surface can occur, for example, 
before inhalation or during inhalation, such as contact with the substrate 
during deposition before inhalation, or contact with an interior surface 
of the mouthpiece during inhalation. Preferably, both the surface of the 
substrate upon which medicament is deposited and the mouthpiece and any 
other surfaces having contact with the medicament have indentations or 
raised areas therein, or any other surface structure for decreasing the 
area of contact between the selected medicament and the surface. 
The indentation or raised area may be, for example, linear, tortuous, 
curved, circular, or any other desired configuration. In certain preferred 
embodiments the indentations are in the form of linear grooves, which 
provides, for example, for ease of manufacturing. See, for example, FIGS. 
3A-C, which show release from a polypropylene substrate having grooved 
indentations. 
Specifically, FIG. 3A is a micrograph of the substrate, which has grooved 
indentations therein, prior to deposition. FIG. 3B is a micrograph of the 
substrate of FIG. 3A after deposition of the medicament powder thereon. 
FIG. 3C is a micrograph of FIG. 3B after release of the medicament from 
the substrate. See, also, for example, FIGS. 4-6 which show three 
increasing magnifications of release from silicon. FIG. 4 has the lowest 
magnification, FIG. 5 has an intermediate magnification, and FIG. 6 has 
the highest magnification. A 100 micron bar is provided in FIGS. 4 and 5 
for size reference, and a 10 micron bar is provided in FIG. 6 for size 
reference. Part A of each of these figures is a photomicrograph of the 
substrate before deposition. Part B of each of these figures is a 
photomicrograph of the substrate after deposition of the medicament 
powder. Part C of each figures is a photomicrograph of the substrate after 
release of the powder. 
Preferably, the depth of an indentation or the height of a raised area is 
slightly smaller than the size of the smallest particle desired to 
released from the inhaler, such as about 5% to about 50% smaller, and more 
preferably, about 5% to about 20% smaller than the smallest selected 
particle. 
The width of the indentation or the valley between two raised areas is 
preferably slightly smaller than the diameter of the smallest particle 
selected to be released, such as about 5% to about 20% smaller, and more 
preferably, about 10% to about 20% smaller. For example, if the particles 
to be released from the inhaler have a selected size of about 2 to about 6 
microns, the width of the indentation or valley will preferably be about 
1.8 microns. Preferably, the diameter of the indentation or valley is less 
than the diameter of the minimum respirable medicament particle size. For 
example, the pitch of the substrate, measured from the center of a valley 
to the center of a raised area, is preferably about 1 to about 2.5 microns 
for dispensing particles from about 2 to about 6 microns. Particle size 
can be determined, for example, using scanning electron microscopy. 
In addition to indentations and raised areas, the surface area of the 
contact between the medicament and the substrate may be decreased, for 
example, by using a perforated substrate. Furthermore, more than one such 
modification may be made to a single substrate. Preferably, the entire 
surface area of the surface in contact with the powder particles is 
modified to have minimized contact with the medicament powder. 
A further aspect of the present invention is the use of a selected material 
to form the surface of the substrate in contact with the powder particles. 
Preferably, the material is selected in part on the basis of low surface 
energy. See, for example, Kaelble, Physical Chemistry of Adhesion at pages 
149-164 (John Wiley & Sons 1971), which is hereby incorporated by 
reference herein in its entirety. Preferably, the surface energy of the 
surface in contact with the powder particles is between about 10 to about 
25 dynes/cm. More preferably, the surfaces, when uncharged, have no 
substantial van der Waals or electrostatic interaction with the 
medicament. Furthermore, the material is preferably substantially 
chemically unreactive with the medicament. Examples of materials that can 
be used for such surfaces include perfluorinated polymers such as 
polytetrafluoroethylene ("TEFLON"), silicone, silicon alumina ceramic, 
polymeric photoconductor, polycarbonate, polyimide, polypropylene and 
polyethylene. In some embodiments, the surface has reacted with a silane, 
such as fluorosilane or aminosilane, to form a film having a low surface 
energy. Alternatively, for example, the surface can be treated to apply a 
perfluorinated polymer film. See, for example, U.S. Pat. No. 4,252,848, 
which is incorporated by reference herein in its entirety. See also, for 
example, the chapter entitled "The Properties of Fluorocarbon Films 
Prepared by Plasma Polymerization of 1,3-Perfluorodimethylcyclohexane" in 
S. Peprek and J. Hertz, eds., 4th International Symposium on Plasma 
Chemistry (vol. 1 1979) at pages 152-163, which is hereby incorporated by 
reference herein in its entirety. 
The material forming the surface in contact with the powder particles is 
also preferably selected on the basis of low chemical reactivity with the 
powder particles. For example, if the powder to be deposited upon the 
substrate is a charged or polar particle, the surface of the substrate is 
preferably not charged or polar. The materials used to form the surfaces 
in contact with the medicament are preferably selected to minimize the van 
der Waals and electrostatic adhesion of the medicament, as well as to 
minimize chemical reactivity. 
Further, the material used to form the surface in contact with the 
medicament is preferably hard, and not pliable, particularly since 
pliability tends to increase contact area. See, for example, Nielsen, 
Mechanical Properties of Polymers and Composites (Marcel Dekker Inc., NY 
1974) at pages 367-369, which is hereby incorporated by reference herein 
in its entirety. Preferably, the material has a Vickers hardness greater 
than about 10 kp/mm.sup.2, such as polystyrene, polymethyl methacrylate, 
polycarbonate, polyacetal, polyethylene terephthalate and phenolic resin. 
Preferably, the material used to make a surface in contact with the 
medicament is a polymer. Preferred materials for use in such surfaces 
include polytetrafluoroethylene, silicon, alumina ceramic, aluminized 
organic photoconductor, polyvinyl carbazole, polycarbonate, polyimide and 
polyethylene. In certain embodiments, the indentations are the grooves 
present in an alumina ceramic printed board. See, for example, FIGS. 4-6. 
In one embodiment, a die stamp having 2 micron spaced grooves is used to 
emboss a substrate, thereby creating a substrate with the desired 
indentations therein. See, for example, FIG. 3. 
In certain preferred embodiments, the surface is treated with a silane, 
such as fluorosilane or aminosilane. In some embodiments, polyimide is not 
preferred since in some instances, it may adhere a powder due to a 
chemical or electrostatic interaction. Preferably, the materials used and 
the surface treatment, if any, are pharmaceutically acceptable and do not 
cause substantial toxicity. 
The size and shape of the substrate can be selected based upon the 
application. In some instances, for example, the substrate will be in the 
form of a disk or elongated such as a tape. Preferably, multiple dosage 
units are deposited onto the substrate, each dosage unit being in a 
discrete area, separated by an area of the substrate having no powder 
deposited thereon. In preferred embodiments, the substrate is sealed for 
protection, such as against the environment, including humidity, as well 
as for sterility 
The advantages of the inhaler apparatus of the present invention include 
its operation in releasing powder without the use of mechanical force, 
such as a hammer. The requirement of mechanical force to release the 
powder may mean that the powder is unintentionally released, for example, 
upon dropping the inhaler. 
Although the inhalers of the present invention are designed for release of 
the medicament powder upon inhalation, preferably they do not release the 
medicament prior to inhalation. Preferably, for example, the medicament 
will remain on the substrate after the inhaler apparatus is subjected to a 
drop test, such as dropping the inhaler into a tube from a height of about 
48 inches at a temperature of about 65 degrees Celsius and a relative 
humidity of about 65%. 
In preferred aspects of the present invention, the inhaler apparatus 
further includes a mouthpiece with a configuration that prevents adherence 
of the medicament powder For example, the mouthpiece preferably has an 
interior surface that is selected to resist adhering the powder particles. 
For example, the interior surface preferably has indentations or raised 
areas thereon, such as the modifications described above, to promote 
release of the powder. Preferably, the surface area of the interior 
surface of the mouthpiece is increased by using indentations in the form 
of grooves that are parallel to the direction of air flow in the 
mouthpiece, preferably causing substantially laminar air flow. 
In additional preferred aspects of the present invention, the mouthpiece 
has multiple air inlets with a channel connected to each inlet for the 
enhancement of release of medicament powder. See, for example, FIG. 7, in 
which the arrows point to the inlets. The channel connects the interior of 
the mouthpiece to the ambient atmosphere through an opening termed an "air 
inlet hole." Preferably, the air inlet hole is created, such as drilled, 
at an angle, preferably about 20 to about 70 degrees, and more preferably, 
about 45 degrees. Preferably, each channel extends from the corresponding 
air inlet at an angle of about 20 degrees to about 70 degrees. More 
preferably, the channel forms an angle of about 45 degrees from the 
horizon. In preferred embodiments, the channels are cylindrical and have a 
diameter of less than about 5 mm, such as about 0.1 to about 5 mm. 
Preferably, the mouthpiece is configured to maximize air flow between the 
powder and the substrate so that the powder is readily released from the 
substrate upon inhalation. In certain preferred embodiments, there are 
about 2 to about 20 air inlets and corresponding channels, and in other 
preferred embodiments, there are about 4 to about 8 air inlets. 
Preferably, the air inlets can be opened and closed at will by the patient, 
or automatically via a shuttering mechanism, to maintain a constant 
pressure drop regardless of the air flow. 
Illustrations of embodiments of the inhaler apparatus of the invention 
having multiple air inlets with channels connected to each inlet are 
provided in FIGS. 8A and 8B. FIG. 8A shows a mouthpiece 94 with air inlets 
82 having channels 83 attached thereto. A shuttering mechanism 84 is 
provided for several of the air inlets. The mouthpiece 94 is in air flow 
communication with the substrate 86 having medicant 87 deposited thereon. 
The substrate 86 is in the form of an elongated tape, which is provided by 
reel 92 and taken up by reel 90. The substrate has a seal (not shown) 
which is taken up by reel 88. FIG. 8B illustrates the inhaler of FIG. 8A, 
further including an electronic release mechanism (not shown) powered by a 
battery 96. 
In certain embodiments, each air inlet is connected via the channel to a 
portion of an individual dosage. For example, a dosage of 100 micrograms 
can be administered by aligning each of four 25-microgram dosages with 
each of four air inlets. 
Preferably, only particles of the desired size, such as the respirable 
fraction, are deposited onto the substrate of the inhaler. Since the 
apparatus is preferably used with the medicament deposited in the desired 
particle range, and since in preferred embodiments, a substantial amount 
of undesired particle size range may be trapped on the substrate, there 
may be no need for additional devices to promote deagglomeration. Thus, 
the present invention provides advantages over inhalers requiring devices 
to deagglomerate, such as tortuous channels, that can trap medicament. In 
certain pharmaceutical applications, preferably the size of the particles 
dispensed by the inhaler is no greater than about 15 microns, and more 
preferably, no greater than about 10 microns. 
In preferred embodiments, the substrate of the inhaler is equipped with a 
conductive layer for electronic assistance of release of the powder, as 
described in co-pending application entitled "Inhaler Apparatus with an 
Electronic Means for Enhanced Release of Dry Powders", filed 
simultaneously herewith. 
The inhaler can also be equipped with other mechanisms for enhancing 
release, including an electron emitter such as a diamond tip emitter or 
other electron emitter, in order to neutralize the charge holding the 
powder onto the substrate. Alternatively, for example, the substrate upon 
which the medicament is deposited may be a photoconductive substrate that 
releases the medicament upon the application of light. 
It will be understood by those skilled in the art that the inhalers of the 
invention can be used with numerous types of medicaments, and in addition 
to oral administration, the inhalers of the invention can be used with 
nasal administration. 
The present invention is further illustrated by the following non-limiting 
examples. 
EXAMPLE 1 
Release of Powdered Medicament from Modified Substrate 
A modified polypropylene substrate, as shown in FIG. 3 was tested for 
release of a powdered medicament, mometasone furoate. A 2 cm.sup.2 square 
of substrate was first weighed in milligrams on a microbalance 
("sub(mg)"). Then, powdered medicament was deposited on the substrate, 
using the ion printing technique disclosed in U.S. Ser. No. 08/471,889. 
The medicament was deposited in four dots, using several bursts of air to 
dispense a powder cloud. Next, the substrate was weighed with the 
medicament thereon ("sub+drug," which is provided in mg). The weight of 
the medicament ("drug(mg)") was determined by substracting the weight of 
the substrate before deposition ("sub(mg)") from the weight of the 
substrate after deposition ("sub+drug"). Two weight measurements were 
taken for each data point, and the two weight measurements were averaged 
("average"). 
To dispense the powder, the substrate was placed in an apparatus such as 
that shown in FIG. 9, and an inhaler mouthpiece was attached to the 
cylinder 98. The inhaler mouthpiece included 8 air inlets, each having a 
channel (capillary tubes) at a 45 degree angle from the mouthpiece to 
enhance lift off of the medicament powder. The release of the powder from 
the substrate was tested at four different flow rates of air applied to 
the substrate through the mouthpiece; 15, 30, 45 and 57 liters per minute. 
"Flow rate" indicates the air flow rate used to release the medicament 
from the inhaler. The substrate was weighed after release of the drug 
("sub-drug," which is indicated in mg). The percentage of drug released 
from the substrate ("%drug") was determined using the weight of the drug 
left after release and the weight of the drug before release. 
"Humid./temp" indicates the percentage of humidity and ambient temperature 
(degrees Farenheit) at the time of the testing. The results are shown in 
Tables 1-2 below Table 3 summarizes the data in Tables 1-2 by providing 
the average percentage of medicament release for each of the three flow 
rates, and the standard deviations. The data in Table 3 is depicted 
graphically in FIG. 2F. 
TABLE 1 
__________________________________________________________________________ 
sub + drug 
sub (mg) 
drug(mg) 
sub-drug 
Drug left 
% drug 
flow rate 
humid./ 
Sample 
# appl/psi 
(mg) substrate 
(mg) after dispensing 
(mg) dispensed 
(liters/min) 
temp./ 
__________________________________________________________________________ 
1 5/7.5 
8.7735 
8.6095 8.6494 57 68/81 
8.7735 
8.6092 8.6495 
average 8.7735 
8.60935 
0.16415 
8.64945 
0.0401 
75.57112 
2 5/7.5 
7.2482 
7.1406 57 67/81 
7.2486 
7.1409 
average 7.2484 
7.14075 
0.10765 
7.16 0.01925 
82.11797 
8.2274 
3 4/7.5 
8.3174 
8.1912 8.2257 n/d 68/81 
8.3161 
8.1911 8.2238 
average 8.31675 
8.19115 
0.1256 
8.225633333 
0.0344833 
72.54512 
4 4/7.5 
6.8848 
6.7813 n/d 68/81 
6.8844 
6.7816 
average 6.8846 
6.78145 
0.10315 
n/d 
5 5/7.5 
8.7858 
8.681 45 68/81 
8.7862 
8.682 
average 8.786 
8.6815 
0.1045 
8.7215 0.04 61.72249 
6 3/7.5 
7.6297 
7.5486 7.5782 n/d 68/90 
7.63 7.547 7.582 
average 7.62985 
7.5478 
0.08205 
7.578133333 
0.0303333 
83.03067 
7 4/7.5 
8.1118 
7.9899 15 68/90 
8.1117 
7.9905 
average 8.11175 
7.9902 
0.12155 6.3 
8 5/7.5 
7.517 
7.4066 30 68/90 
7.5168 
7.4063 
average 7.5169 
7.40645 
0.11045 
7.4913 0.08485 
23.17791 
__________________________________________________________________________ 
TABLE 2 
__________________________________________________________________________ 
sub (mg) 
sub + drug 
drug(mg) 
sub-drug 
Drug left 
% drug 
flow rate 
humid./temp 
Sample 
# appl/psi 
(samp + subs) 
substrate 
(mg) after dispensing 
(mg) dispensed 
(liters/min) 
temp (F)t 
__________________________________________________________________________ 
9 6/7.5 
7.0404 6.9084 6.9337 60 67/83 
7.0408 6.9086 6.9344 
average 7.0406 6.9085 
0.1321 
6.93405 
0.02555 
80.658592 
10 4/7.5 
7.5945 7.4758 7.5067 45 66/83 
7.5938 7.4765 7.507 
average 7.59415 
7.47615 
0.118 
7.50685 
0.0307 
73.983051 
11 3/7.5 
8.037 7.9513 8.037 15 66/83 
8.0371 7.9514 8.0366 
average 8.03705 
7.95135 
0.0857 
8.0368 0.08545 
0.2917153 
12 4/7.5 
8.8213 8.7376 8.8202 15 65/83 
8.8207 8.7375 8.8212 
average 8.821 8.73755 
0.08345 
8.8207 0.08315 
0.3594967 
13 5/7.5 
7.1802 7.1081 7.1794 15 65/83 
7.1796 7.1081 7.1795 
average 7.1799 7.1081 
0.0718 
7.17945 
0.07135 
0.6267409 
14 3/7.5 
6.8602 6.7494 6.8293 30 70/84 
6.8597 6.7485 6.8294 
average 6.85995 
6.74895 
0.111 
6.82935 
0.0804 
27.567568 
15 5/7.5 
9.3052 9.1824 9.2381 45 70/86 
9.305 9.1825 9.238 
average 9.3051 9.18245 
0.12265 
9.23805 
0.0556 
54.667754 
16 5/7.5 
8.983 8.8723 8.9582 30 71/86 
8.9845 8.8727 8.958 
average 8.98375 
8.8725 
0.11125 
8.9581 0.0856 
23.05618 
17 7/7.8 
9.3624 9.2077 9.2326 60 70/86 
9.3623 9.2081 9.2324 
average 9.36235 
9.2079 
0.15445 
9.2325 0.0246 
84.072515 
__________________________________________________________________________ 
TABLE 3 
__________________________________________________________________________ 
flow rate 
57 45 30 15 
__________________________________________________________________________ 
80.658592 
54.6677538 
27.5675676 
0.29171529 
84.0725154 
73.9830508 
23.0561798 
0.3594967 
82.1179749 
61.722488 
23.1779086 
0.62674095 
average 82.28302743 
63.4577642 
242.600552 
0.425984313 
standard deviation 
1.712936076 
9.773871401 
2.570231634 
0.177132719 
80.658592 
54.6677538 
27.5675676 
0.29171529 
w/ one data point 
84.0725154 23.0561798 
0.3594967 
dropped 
82.1179749 
61.722488 
23.1779086 
0.62674095 
average 82.28302743 
58.1951209 
24.600552 
0.425984313 
standard deviation 
1.712936076 
4.988450392 
2.570231634 
0.177132719 
__________________________________________________________________________ 
EXAMPLE 2 
Comparison of Modified Substrate to Unmodified Substrate 
Approximately 50 .mu.g dots of inhalation medicament were deposited on a 2 
cm.sup.2 polypropylene substrate using the ion printing process described 
in Ser. No. 08/471,889 ("Methods and Apparatus for Electrostatically 
Depositing a Medicament Powder Upon Predefined Regions of a Substrate," 
filed Jun. 6, 1995). The weight of the medicament was verified using a 
microbalance. 
The release of medicament from an inhaler substrate having medicament 
deposited thereon was tested using the apparatus shown in FIG. 9. 
Referring to FIG. 9, air flow was generated through the use of a vacuum 
(not shown) attached to tubing 97, which was in turn attached to a 
cylinder 98, for attachment to an inhaler mouthpiece (not shown). The 
mouthpiece including 8 air inlets, each having a channel (capillary tubes) 
at 45 degree angles to the mouthpiece. A flow meter 99 was used to measure 
the rate of air flow. Three samples of each of two different substrates 
were tested, the first substrate having a grooved surface, as shown in 
FIG. 3, and the second substrate having an unmodified planar surface. Both 
substrates were made of polypropylene. The results of the testing are 
shown in Table 4 below. 
TABLE 4 
______________________________________ 
% medicament 
% medicament released 
released 
Sample number 
from grooved substrate 
from planar substrate 
______________________________________ 
1 80.5 62 
2 84 64.5 
3 82 67 
Average Value 
82.16 64.5 
Standard 1.84 2.5 
Deviation 
______________________________________ 
The data shown above is depicted graphically in FIG. 10, which shows that 
release of the medicament from the substrate with indentations in the form 
of grooves was much higher than the release from an unmodified substrate.