U.S. patent application number 17/509182 was filed with the patent office on 2022-02-10 for microneedle array assembly, drug delivery device and method for administering liquid across a broad area at low pressure.
The applicant listed for this patent is SORRENTO THERAPEUTICS, INC.. Invention is credited to Andrew T. Baker, Elizabeth Deibler Gadsby, Luke Hagan, Russell F. Ross.
Application Number | 20220040465 17/509182 |
Document ID | / |
Family ID | |
Filed Date | 2022-02-10 |
United States Patent
Application |
20220040465 |
Kind Code |
A1 |
Baker; Andrew T. ; et
al. |
February 10, 2022 |
MICRONEEDLE ARRAY ASSEMBLY, DRUG DELIVERY DEVICE AND METHOD FOR
ADMINISTERING LIQUID ACROSS A BROAD AREA AT LOW PRESSURE
Abstract
A uniformity control membrane can be securely engaged against an
upstream side of a microneedle array and configured so that
resistance to flow through the uniformity control membrane is
substantially greater than the resistance to flow through the
microneedle array. These differences in flow resistance can
facilitate uniform administration of a liquid formulation into the
patient's skin across a broad area and at a relatively low
pressure, such as by way of capillary action. The administration of
the liquid formulation into the patient's skin across the broad
area can result from the liquid formulation being administered by
way of at least a majority of the microneedles of the microneedle
array.
Inventors: |
Baker; Andrew T.; (Norcross,
GA) ; Ross; Russell F.; (Jacksonville Beach, FL)
; Gadsby; Elizabeth Deibler; (Marietta, GA) ;
Hagan; Luke; (Seattle, WA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SORRENTO THERAPEUTICS, INC. |
San Diego |
CA |
US |
|
|
Appl. No.: |
17/509182 |
Filed: |
October 25, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16095210 |
Oct 19, 2018 |
11179554 |
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PCT/US2017/027879 |
Apr 17, 2017 |
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17509182 |
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62329464 |
Apr 29, 2016 |
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International
Class: |
A61M 37/00 20060101
A61M037/00 |
Claims
1. A microneedle array assembly, comprising: a microneedle array
comprising a base having opposite upstream and downstream sides and
defining a plurality of apertures extending between the upstream
and downstream sides; and a plurality of microneedles extending
from the downstream side; wherein each of the plurality of
apertures are defined in the base proximate each of the plurality
of microneedles, and wherein the resistance to flow through the
upstream side of the base is at least about 30 times greater than
resistance to flow through the microneedle array, wherein the at
least about 30 times greater is a difference in the resistance to
flow between the upstream side and the downstream side of the
base.
2. The microneedle array assembly of claim 1, wherein each aperture
of the plurality of apertures comprises a pair of downstream
openings proximate one or more exterior channels extending along
each microneedle of the plurality of microneedles.
3. The microneedle array assembly of claim 1, wherein each aperture
of the plurality of apertures extends through each microneedle of
the plurality of microneedles to form an interior channel through
an interior of each microneedle of the plurality of
microneedles.
4. The microneedle array assembly of claim 3, wherein each aperture
of the plurality of apertures is positioned coaxial to each
interior channel of each microneedle of the plurality of
microneedles.
5. The microneedle array assembly of claim 1, further comprising at
least one membrane engaged against the upstream side of the
base.
6. The microneedle array assembly of claim 5, wherein the
resistance to flow through the at least one membrane is within a
range of from about 30 times to about 100 times the resistance to
flow through the microneedle array.
7. The microneedle array assembly of claim 5, wherein the
resistance to flow through the at least one membrane is at least
about 40 times greater than the resistance to flow through the
microneedle array.
8. The microneedle array assembly of claim 7, wherein the
resistance to flow through the at least one membrane is within a
range of from about 40 times to about 100 times the resistance to
flow through the microneedle array.
9. The microneedle array assembly of claim 5, wherein the
resistance to flow through the at least one membrane is at least
about 50 times greater than the resistance to flow through the
microneedle array.
10. The microneedle array assembly of claim 5, wherein the
resistance to flow through the at least one membrane is within a
range of from about 50 times to about 100 times the resistance to
flow through the microneedle array.
11. The microneedle array assembly of claim 5, wherein the at least
one membrane has a relatively smooth side and a relatively rough
side, and the at least one membrane being engaged against the
upstream side of the base is comprised of the smooth side of the at
least one membrane being engaged against the upstream side of the
base.
12. The microneedle array assembly of claim 5, wherein the at least
one membrane is a track etched membrane.
13. A drug delivery device, comprising: a microneedle array
assembly according to claim 5; and a reservoir operatively
associated with the microneedle array for supplying liquid to the
microneedle array by way of the at least one membrane.
14. The drug delivery device of claim 13, further comprising a
force provider for causing at least some of the liquid to flow from
the reservoir toward the microneedle array assembly.
15. The drug delivery device of claim 14, wherein: the force
provider is for causing an increase in pressure of the liquid; the
at least one membrane is for causing a decrease in pressure of the
liquid; and an absolute value of the increase in pressure is
approximately equal to an absolute value of the decrease in
pressure.
16. The drug delivery device of claim 14, further comprising a
plenum in fluid communication with an upstream side of the plenum,
wherein the force provider is for causing at least some of the
liquid to flow from the reservoir to the plenum.
17. The drug delivery device of claim 16, further comprising a
cannula in fluid communication with the plenum, wherein the drug
delivery device is configured so that, in use, the liquid passes
from the reservoir through the cannula into the plenum before
passing through the at least one membrane and out of the
microneedle array.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/095,210, filed on Oct. 19, 2018, which is
the national stage entry of PCT/US2017/027879, filed on Apr. 17,
2017, which claims the benefit of priority to U.S. Provisional
Patent Application No. 62/329,464, filed Apr. 29, 2016, which are
incorporated by reference in their entirety herein.
FIELD OF THE DISCLOSURE
[0002] The present invention generally relates to devices for
delivering liquid formulations into a patient's skin. Particularly,
this disclosure relates to devices having microneedle arrays for
transdermal delivery of liquid formulations.
BACKGROUND
[0003] Numerous apparatuses have previously been developed for the
transdermal delivery of fluidic drugs and other medicinal compounds
that utilize microneedle arrays. For example, microneedles have the
advantage of causing less pain to the patient as compared to larger
conventional needles. In addition, conventional subcutaneous (often
intra-muscular) delivery of fluidic drugs via a conventional needle
acts to deliver large amounts of a fluidic drug at one time,
thereby often creating a spike in the bioavailability of the drug.
For drugs with certain metabolic profiles this is not a significant
problem. However, many drugs benefit from having a steady state
concentration in the patient's blood stream; a well-known example
of such a drug is insulin.
[0004] In some situations, transdermal drug delivery apparatuses
including microneedle arrays are intended to administer liquid
formulations at a substantially constant rate over an extended
period of time, across a broad application area. It may also be
desirable in some situations for such microneedle arrays to
discharge liquid formulations at relatively low pressures so that
the liquid formulations are administered by way of capillary
action. However, there are conflicting factors associated with flow
through a microneedle array, such that the flow may be associated
with too few of the microneedles of the micro needle array.
SUMMARY
[0005] One aspect of this disclosure is the provision of a drug
delivery device including a microneedle array assembly adapted in a
manner that seeks to uniformly administer a liquid formulation into
a patient's skin across a broad area and at a relatively low
pressure. The device may administer the liquid formulation into the
patient's skin at a substantially constant rate over an extended
period of time and across a broad application area, wherein the
administration of the liquid formulation into the patient's skin
may occur at a relatively low pressure, such as by way of capillary
action.
[0006] For example, the microneedle array assembly may comprise at
least one uniformity control membrane securely engaged against an
upstream side of a microneedle array, and optionally an additional
membrane may be draped over the downstream side of the microneedle
array. The uniformity control membrane may be a track etched
membrane, or the like, and the uniformity control membrane and the
microneedle array may be cooperatively configured so that the
resistance to flow through the uniformity control membrane is
substantially greater than the resistance to flow through the
microneedle array. These differences in flow resistance seek to
facilitate, for example, the uniform administration of the liquid
formulation into the patient's skin across a broad area and at a
relatively low pressure, such as by way of capillary action. The
administration of the liquid formulation into the patient's skin
across the broad area may comprise the liquid formulation being
administered by way of at least a majority of the microneedles of
the microneedle array. That is, the number of participating
microneedles may be increased, to providing a larger area of
administration of the liquid formulation at low pressure.
[0007] The foregoing presents a simplified summary of some aspects
of this disclosure in order to provide a basic understanding. The
foregoing summary is not extensive and is not intended to identify
key or critical elements of the invention or to delineate the scope
of the invention. The purpose of the foregoing summary is to
present some concepts of this disclosure in a simplified form as a
prelude to the more detailed description that is presented later.
For example, other aspects will become apparent from the
following.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] In the following, reference is made to the accompanying
drawings, which are not necessarily drawn to scale and may be
schematic. The drawings are exemplary only, and should not be
construed as limiting the invention.
[0009] FIG. 1 is a cut-away view of a drug delivery device
according to a first embodiment of this disclosure.
[0010] FIG. 2 is a detailed view of a portion of the device shown
in FIG. 1.
[0011] FIG. 3 is a more detailed, schematic cross-sectional view of
a portion of a microneedle array assembly shown in FIG. 2.
[0012] FIG. 4 shows the emission pattern of a microneedle array
without a uniformity control membrane, as a comparative
example.
[0013] FIG. 5 is a diagrammatic representation of a portion of
micro needle array assembly according to a second embodiment of
this disclosure.
[0014] FIG. 6 is a graph that schematically illustrates how a
suitably configured uniformity control membrane may seek to
advantageously diminish the effects of variations in bubble
pressures associated with microneedles of a microneedle array, in
accordance with the second embodiment.
DETAILED DESCRIPTION
[0015] Exemplary embodiments are described below and illustrated in
the accompanying drawings, in which like numerals refer to like
parts throughout the several views. The embodiments described
provide examples and should not be interpreted as limiting the
scope of the invention. Other embodiments, and modifications and
improvements of the described embodiments, will occur to those
skilled in the art, and all such other embodiments, modification,
and improvements are within the scope of the present invention.
[0016] In the following, a very brief and general initial
discussion of a drug delivery device 10 of a first embodiment is
followed by more detailed discussions, such as more detailed
discussions of some of the separate subassemblies of the device 10.
Discussions directed primarily to structural features of the device
10 are followed by discussions more specifically directed to
methods of this disclosure.
[0017] Referring to FIG. 1, the device 10 is shown in a partially
activated configuration. The device 10 may be characterized as
including multiple main subassemblies that each may be
self-contained. The main subassemblies may include a receptacle 13,
a cartridge 16 or other suitable container or reservoir for being
movably mounted in the receptacle 13, and a mechanical controller
19 mounted to the cartridge 16.
[0018] The controller 19 can include a plunger 22 with, or
alternatively without, an internal force provider 25. The
controller 19 is for applying pressure to the reservoir or
cartridge 16 and, thereby, assisting in discharging of a liquid
drug formulation, or any other suitable liquid formulation, from
the cartridge 16 to a microneedle array 28.
[0019] The receptacle 13 of the first embodiment includes the
microneedle array 28. The microneedle array 28 includes a large
number of microneedles 31 (FIG. 2) for penetrating the user's skin,
such as for providing a fluid that may be in the form of a liquid
drug formulation into the user's skin. The microneedle array 28 may
be more generally referred to as a device for engaging the skin of
a patient or other user, and dispensing the liquid formulation to
the user's skin, such as by dispensing the liquid formulation into
the epidermis portion of the user's skin. In contrast to how the
device 10 is shown in FIG. 1, it is typical for at least a portion
of the microneedles 31 of the microneedle array 28 to be protruding
outwardly through a lower opening of the receptacle 13. An example
of the device 10 is further described in U.S. Provisional Patent
Application Nos. 61/996,149, 61/996,156, 61/996,157, and
61/996,158, each of which is incorporated herein by reference in
its entirety.
[0020] As examples, the micro needle array 28 may be configured as
disclosed in one or more of WO 2012/020332 to Ross, WO 20111070457
to Ross, WO 2011/135532 to Ross, US 2011/0270221 to Ross, US
2013/0165861 to Ross, and U.S. provisional patent application No.
61/996,148, each of which is incorporated herein by reference in
its entirety. Generally, the microneedle array 28 of the device 10
may have any suitable configuration known in the art for delivering
a liquid formulation onto, into, and/or through the user's skin,
such as by being configured to include the plurality of
microneedles 31 extending outwardly from a suitable substrate or
support, wherein this substrate or support may be referred to as a
base or base plate 34. As shown in FIG. 3, the base plate 34 has a
top surface 37 (e.g., upstream side) and a bottom surface 40 (e.g.
downstream side), and multiple microneedles 31 extend outwardly
from the bottom surface. The base plate 34 and microneedles 31 may
generally be constructed from a rigid, semi-rigid or flexible sheet
of material, such as a metal material, a ceramic material, a
polymer (e.g., plastic) material and/or any other suitable
material. For example, the base plate 34 and microneedles 31 may be
formed from silicon by way of reactive-ion etching, or in any other
suitable manner.
[0021] The base plate 34 typically defines a plurality of
passageways, which may be referred to as holes or apertures 43,
extending between the top and bottom surfaces 37, 40 for permitting
the liquid formulation to flow therebetween. For example, a single
aperture 43 may be defined in the base plate 34 proximate each
microneedle 31. However, in other embodiments, the base plate 34
may define any other suitable number of apertures 43 positioned at
and/or spaced apart from the location of each microneedle 31. In
the first embodiment, each aperture 43 leads to or includes a pair
of downstream openings or exit openings 46 that are open to
exterior channels 49 that are defined in and extend along each of
the microneedles 31. Alternatively, each aperture 43 may extend
through the base plate 34 as well as through the microneedle 31, as
will be discussed in greater detail below.
[0022] Each microneedle 31 of the microneedle array 28 may include
a base that extends downwardly from the bottom surface 40 and
transitions to a piercing or needle-like shape (e.g., a conical or
pyramidal shape or a cylindrical shape transitioning to a conical
or pyramidal shape) having a tip 52 that is distant from the bottom
surface 40. The tip 52 of each microneedle 31 is disposed furthest
away from the base plate 34 and may define the smallest dimension
(e.g., diameter or cross-sectional width) of each microneedle 31.
Additionally, each microneedle 31 may generally define any suitable
length L between its base and its tip that is sufficient to allow
the microneedles 31 to penetrate the stratum corneum and pass into
the epidermis of a user. It may be desirable to limit the length of
the microneedles 31 such that they do not penetrate through the
inner surface of the epidermis and into the dermis, which may
advantageously help minimize pain for the patient receiving the
liquid formulation.
[0023] Each microneedle 31 may have a length L of less than about
1000 micrometers (um), such as less than about 800 um, or less than
about 750 um, or less than about 500 um (e.g., a length ranging
from about 200 um to about 400 um), or any other sub-ranges
therebetween. In one specific example, the microneedles 31 may have
a length L of about 290 um. The length of the microneedles 31 may
vary depending on the location at which the device 10 is being used
on a user. For example, the length of the microneedles 31 for a
device 10 to be used on a user's leg may differ substantially from
the length of the microneedles for a device 10 to be used on a
user's arm. Each microneedle 31 may generally define any suitable
aspect ratio (i.e., the length Lover a cross-sectional width
dimension W of each microneedle 31). The aspect ratio may be
greater than 2, such as greater than 3 or greater than 4. In
instances in which the cross-sectional width dimension (e.g.,
diameter) varies over the length of each microneedle 31, the aspect
ratio may be determined based on the average cross-sectional width
dimension.
[0024] Each microneedle 31 may define the one or more exterior
channels 49 in fluid communication with the apertures 43 defined in
the base plate 34. In general, the exterior channels 49 may be
defined at any suitable location on each microneedle 31. For
example, the exterior channels 49 may be defined along an exterior
surface of each microneedle 31 as seen in FIG. 3. As a more
specific example, each exterior channel 49 may be an outwardly open
flute defined by the exterior surface of, and extending along the
length of, a microneedle 31. Alternatively and/or in addition, the
channels 49 may be defined through the interior of the microneedles
31 such that each microneedle forms a hollow shaft, in which case
the aperture 43 and the interior channel may have the same diameter
and be coaxial, as generally discussed in greater detail below.
Regardless, the exterior channels 49 in combination with the
apertures 43 may generally be configured to form a downstream
pathway that enables the liquid formulation to flow from the top
surface 37 of the base plate 34, through the apertures 43 and into
the channels 49, at which point the liquid formulation may be
delivered onto, into, and/or through the user's skin. The exterior
channels 49 may be configured to define any suitable
cross-sectional shape. For example, each exterior channel 49 may
define a semi-circular or circular shape. Alternatively, each
exterior channel 49 may define a non-circular shape, such as a "v"
shape or any other suitable cross-sectional shape.
[0025] The dimensions of the exterior channels 49 defined by the
microneedles 31 may be specifically selected to induce a capillary
flow of the liquid formulation. The capillary pressure within an
exterior channel 49 is inversely proportional to the
cross-sectional dimension of the exterior channel and directly
proportional to the surface energy of the subject liquid,
multiplied by the cosine of the contact angle of the liquid at the
interface defined between the liquid and the exterior channel.
Thus, to facilitate capillary flow of the liquid formulation
through the microneedle array 28, the cross-sectional width
dimension of the exterior channel(s) 49 (e.g., the diameter of the
exterior channel) may be selectively controlled, with smaller
dimensions generally resulting in higher capillary pressures. For
example, the cross-sectional width dimension of the exterior
channels 49 may be selected so that, with regard to the width of
each exterior channel 49, the cross-sectional area of each exterior
channel ranges from about 1,000 square microns (um.sup.2) to about
125,000 um.sup.2, such as from about 1,250 um.sup.2 to about 60,000
um.sup.2, or from about 6,000 um.sup.2 to about 20,000 um.sup.2, or
any other sub-ranges therebetween.
[0026] The microneedle array 28 may generally include any suitable
number of microneedles 31 extending from its base plate 34. For
example, the actual number of microneedles 31 included within the
microneedle array 28 may range from about 10 micro needles per
square centimeter (cm.sup.2) to about 1,500 microneedles per
cm.sup.2, such as from about 50 microneedles per cm.sup.2 to about
1250 microneedles per cm.sup.2, or from about 100 microneedles per
cm.sup.2 to about 500 microneedles per cm.sup.2, or any other
sub-ranges therebetween. The microneedles 31 may generally be
arranged on the base plate 34 in a variety of different patterns,
and such patterns may be designed for any particular use. For
example, in some embodiments, the microneedles 31 may be spaced
apart in a uniform manner, such as in a rectangular or square grid
or in concentric circles. In such embodiments, the spacing of the
microneedles 31 may generally depend on numerous factors,
including, but not limited to, the length and width of the
microneedles 31, as well as the amount and type of liquid
formulation that is intended to be delivered through or along the
microneedles 31.
[0027] As best understood with reference to FIG. 2, at least a
portion of the micro needle array's base plate 34 may have a
substantially rectangular periphery that is in the form of or
includes a peripheral exterior channel 55 that (considering the
base plate in isolation) is downwardly open and may have an overall
substantially rectangular shape, or any other suitable shape. In
the embodiment shown in FIG. 2, the microneedle array 28 is mounted
to a backing structure 58 having inner and outer exterior channels
61, 64 that (considering the backing structure in isolation) are
downwardly open and may have an overall rectangular shape, or any
other suitable shape.
[0028] A substantially rectangular gasket 67 may be securely
engaged in the backing structure's inner exterior channel 61 and
engaged securely against the margin of at least one uniformity
control membrane 70 that is engaged against and covers the top
surface 37 of the microneedle array 28. These secure engagements
associated with the gasket 67 may result at least partially from a
frame 73 being fixedly mounted between the peripheral exterior
channel 55 of the microneedle array 28 and the outer exterior
channel 64 of the backing structure 58. The frame 73 may be mounted
between the peripheral and outer exterior channels by way of one or
more mechanical connections such as an interference fit and/or any
other suitable fastening technique. In the first embodiment, the
microneedle array 28 is substantially fixedly connected to the
backing structure 58 of the support assembly of the receptacle 14
by way of the subject connections.
[0029] The frame 73 may be characterized as being a substantially
rectangular bezel having substantially S-shaped cross-sections. The
outer peripheral edge of the frame 73 may be press-fit into the
outer exterior channel 64 so that the outer peripheral edge of the
frame 73 is in compressing, opposing-face-to-face contact with a
flange 76 that is part of or otherwise associated with (e.g.,
partially defines) the outer exterior channel 64, and the inner
peripheral margin of the frame 73 is in compressing,
opposing-face-to-face contact with the bottom surface 40 of the
base plate 34. More specifically, the frame 73 engages against a
surface of the peripheral exterior channel 55 of the base plate
34.
[0030] Referring back to FIG. 1, the receptacle 13 further includes
at least one cannula 79 fixedly mounted to the backing structure 58
for moving therewith. For example, a lower portion of the cannula
79 may be fixedly mounted in a supply port extending through the
backing structure 58 by way of one or more mechanical connections
such as an interference fit, adhesive material and/or any other
suitable fastening technique. The lower open end of the cannula 79
is in fluid communication with the upstream side of the uniformity
control membrane 70 (FIG. 2), and the upper open end of the cannula
79, which is typically sharply pointed, extends axially upwardly
from the backing structure 58 for piercing a predetermined portion
of the cartridge 16 to access the reservoir 80 therein.
[0031] The combination of at least the microneedle array 28 and the
uniformity control membrane 70 may be referred to herein as the
microneedle array assembly 71. At least the backing structure 58
and the microneedle array assembly 71 are cooperatively configured
so that a peripherally closed plenum chamber 82 (FIG. 3) is defined
therebetween. The plenum chamber 82 is preferably hermetically
sealed or closed, except for being open to a supply port such as
provided by the cannula 79 extending through the backing structure
58, and being open to pores 85 (FIG. 3) of the uniformity control
membrane 70.
[0032] During operation of the device 10 after it is configured as
substantially shown in FIG. 1, the plunger 22 applies pressure to
the cartridge 16 and the liquid formulation flows through the
cannula 79 into the plenum chamber 82. The liquid formulation exits
the plenum chamber 82 by flowing through pores 85 of the uniformity
control membrane 70, and then the liquid formulation flows through
the apertures 43 in the base plate 34 to the exterior channels 49
associated with the microneedles 31 and into the user's skin.
[0033] Reiterating from above and as shown in FIG. 3, the top
surface 37 of the base plate 34 of the microneedle array 28 is
covered with one or more uniformity control membranes 70 to at
least partially form the microneedle array assembly 71. The
uniformity control membrane 70 may be fabricated from permeable,
semi-permeable or micro-porous materials configured for causing a
pressure drop as the liquid formulation flows therethrough. In one
example, at a predetermined flow rate with a predetermined drug
formulation, an appropriate pressure drop across the uniformity
control membrane 70 may be from 0.25 kPa to 50 kPa, from 10 kPa to
10 kPa, from 2.0 to 5.0 kPa, from about 0.25 kPa to about 50 kPa,
from about 10 kPa to about 10 kPa, from about 2.0 to about 5.0 kPa,
or any other subranges therebetween.
[0034] The uniformity control membrane 70 can be schematically
modeled as having several discrete pores 85 for allowing the
passage of liquid formulation from the plenum 82 (at the upstream
side of the uniformity control membrane) to the apertures 43 (at
the downstream side of the uniformity control membrane). In the
first embodiment, the collective area of the pores 85 is less than
the collective area of the apertures 43.
[0035] The uniformity control membrane 70 may be a track etched
membrane. Track etched membranes provide an advantage because
passage of the liquid formulation is generally limited to the
direction through the thickness of the uniformity control membrane
70 from one side to the other, substantially preventing spread of
the liquid formulation within the uniformity control membrane in a
in a lateral direction perpendicular to the to the thickness of the
uniformity control membrane. A suitable track etched membrane may
be available from Sterlitech Corporation of Kent Washington, USA,
and may be in the form of a 0.05 micron hydrophilic polycarbonate
track etch membrane, or the like.
[0036] In the first embodiment, the uniformity control membrane 70
is associated with the top surface 37 of the backing structure 34
in a matter that limits or prevents lateral movement of the liquid
formulation between the uniformity control membrane 70 and the base
plate 34. In other words, liquid formulation associated with (e.g.
proximate) one aperture 43 should be generally prevented from
traveling over the top surface 37 into an adjacent aperture 43.
When the uniformity control membrane 70 is a track etched membrane,
it may have a smooth side and a rough side. Generally it is
preferred to have the smooth side against the top surface 37 to
avoid the undesired lateral flow of liquid formulation.
[0037] The uniformity control membrane 70 may be intimately held to
the top surface 37 of base plate 34 by a pressing force applied by
the frame 73 and gasket 67 around the periphery of the uniformity
control membrane 70. During operation of the device 10, liquid
pressure of the drug formulation within the plenum chamber 82 may
be sufficient to hold the central area of the uniformity control
membrane 70 against the top surface 37.
[0038] With reference back to FIG. 1, during operation of the
device 10, the liquid formulation may be forced out of the
cartridge 16 by the plunger 22 and the internal force provider 25
of the controller 19 to cause the liquid formulation to
substantially uniformly fill the plenum chamber 82 (FIG. 3) and
substantially uniformly wet the uniformity control membrane 70. In
other words and referring to FIG. 3, the liquid formulation
typically becomes available to each aperture 43 at the top surface
37 of the base plate 34. Referring to FIG. 1, the internal force
provider 25 (e.g. at least one spring) functions in connection with
the plunger 22 to provide substantially complete emptying of liquid
formulation from the cartridge 16 through the cannula 79 and into
the plenum chamber 82. The plunger 22 and internal force provider
may provide a force in a range of 1.1 N to 1.3 N, about 1.1 N to
about 1.3 N, 2 N to 2.2 N, about 2 N to about 2.2 N, 2.4 N to 2.6
N, about 2.4 N to about 2.6 N, 2.7 N to 2.9 N, about 2.7 N to about
2.9 Nor any other sub-ranges therebetween. The device 10 shown in
FIG. 1 is provided as an example only. That is, the microneedle
array assembly 71 may be used with or otherwise incorporated into
any other suitable devices. For example, the plunger 22, force
provider 25 and/or controller 19 may be replaced with other
suitable features for forcing the liquid formulation into the
plenum chamber 82, or the like.
[0039] The uniformity control membrane 70 may be selected so that
the pressure drop resulting from the liquid formulation passing
through the uniformity control membrane consumes substantially all
of the pressure energy imparted into the liquid formulation by way
of the plunger 22 and internal force provider 25. For example, the
increase in pressure provided by the plunger 22 and internal force
provider 25 may have an absolute value that is approximately equal
to the absolute value of the decrease in pressure provided by the
uniformity control membrane 70. In accordance in a method of
operation of the first embodiment, the pressure remaining
immediately downstream from the uniformity control membrane 70 may
be only enough to cause or allow the liquid formulation to reach
the channels 49 in a manner such that there is capillary flow of
the liquid formulation in the exterior channels 49 of the
microneedles 31.
[0040] Several variables should be considered together in order to
produce the potentially desired capillary flow. For example, the
larger the force applied by the plunger 22, the higher the pressure
through the cannula 79 and the higher the pressure of the liquid
formulation within the plenum 82. In order to maintain the target
flow rate, the uniformity control membrane 70 should be capable of
an increased pressure drop to compensate for the increased pressure
within the plenum 82. As a result, the uniformity control membrane
70 typically has a resistance to flow that is selected in
association with the plenum pressure and the subsystem that
includes plunger 22 and force provider 25, if present.
[0041] Further regarding the microneedle array assembly 71 of the
first embodiment and as best understood with reference to FIG. 3,
the microneedle array assembly has numerous compound flow paths
that extend through the microneedle array assembly, and each
compound flow path may be characterized as including an upstream
flow path and at least one downstream flow path. For each compound
flow path extending through the microneedle array assembly 71, the
upstream flow path may consist of one or more respective pores 85
of the uniformity control membrane 70, so that each of the upstream
flow paths may be designated by the numeral 85. For each compound
flow path extending through the microneedle array assembly 71, the
at least one downstream flow path may comprise, consist essentially
of, or consist of a respective aperture 43 and a respective one or
more exit or downstream openings 46, so that each of the downstream
flow paths may be designated by the numerals 43, 46, or just the
numeral 43 for brevity. At least in theory, for each or a vast
majority of the compound flow paths of the first embodiment, the
downstream end of the upstream flow path 85 is in direct
communication with the upstream end of the respective downstream
flow path 43 for preventing lateral bypass flow, as generally
discussed above.
[0042] As a first comparative example, FIG. 4 shows the downstream
side of the microneedle array 28, wherein the uniformity control
membrane 70 is not associated with the upstream side of the micro
needle array, and the downstream side of the microneedle array is
discharging water at a relatively low pressure, such as by way of
capillary action, at a rate of about 200 .mu.l/hr. As shown in FIG.
4 for the first comparative example, even though water is uniformly
applied to the entire upstream side of the microneedle array 28,
the water has flowed through the microneedle array at only a small
number of discrete locations, so that the majority of the area of
the microneedle array remains dry on the downstream side thereof.
That is, FIG. 4 shows the water exiting out of a relatively small
percentage of the downstream flow paths 43, such that the number of
participating flow paths 43 is relatively small. This suggests
that, for the first comparative example, there is a substantial
lack of discharge uniformity through the microneedle array 28 and a
greatly reduced efficiency of the broad application site of the
microneedle array.
[0043] Manufacturing techniques typically limit the ability to form
the downstream openings of the downstream flow paths 43 with
exactly the same diameter or cross-sectional area, which in some
situations may result a substantial lack of discharge uniformity,
such as the lack of discharge uniformity shown in FIG. 4. More
specifically regarding the fact that manufacturing techniques may
limit the ability to form the downstream openings of the downstream
flow paths 43 with exactly the same diameter or cross-sectional
area, a bubble of the liquid formulation exiting from a relatively
large downstream flow path 43 will have a larger bubble radius, and
correspondingly, a smaller degree of surface tension, as compared
to a bubble of the liquid formulation exiting from a relatively
small downstream flow path 43. The energy required to add more
liquid formulation to the larger bubble is less than the energy
required to add liquid formulation to a smaller bubble pushing out
from a smaller downstream flow path 43. In the first comparative
example discussed above with reference to FIG. 4, the large bubble
will grow slightly larger, and the pressure in that bubble
decreases further. The result is that liquid formulation may flow
through one or a few of the larger downstream flow paths 43,
without flowing through the smaller downstream flow paths, even
though the smaller downstream flow paths fully contain the liquid
formulation.
[0044] In accordance with the first embodiment (e.g., in contrast
to the comparative example of FIG. 4), the uniformity control
membrane 70 may be adapted in a manner that seeks to increase the
discharge uniformity through the microneedle array 28. For example,
at least the uniformity control membrane 70 and the microneedle
array 28 are cooperatively configured in a manner that seeks to
allow the liquid formulation to be substantially uniformly
administered across a relatively broad area and at a relatively low
pressure, such as by way of capillary action, wherein the liquid
formulation being substantially uniformly administered across the
broad area comprises the liquid formulation steadily flowing
through and exiting out of a relatively large percentage of the
downstream flow paths 43, such that the number of participating
downstream flow paths is relatively large. That is, the uniformity
control membrane 70 may be configured to provide improved
efficiency of the useful area of the microneedle array 28 relative
to the first comparative example, by increasing the number of
participating downstream flow paths 43 while maintaining a
substantially similar target flow rate and relatively low
administration pressure.
[0045] For each participating downstream flow paths 43, the liquid
formulation may steadily flow through and exiting out of the flow
path. That is, a participating downstream flow path 43 through the
microneedle array 28 is a downstream flow path that has liquid
formulation flowing therethrough and exiting therefrom. Increasing
the number of participating downstream flow paths 43 means
increasing the percentage of the downstream flow paths from which
liquid formulation is flowing for a predetermined target flow rate
and pressure. By increasing the number of participating downstream
flow paths 43, administration of the liquid formulation can be
considered as being more uniform across the area of the microneedle
array 28. Because the body's response to a drug is area dependent,
increasing the uniformity of discharge from the microneedle array
28 may improve the effectiveness of the drug formulation upon the
body.
[0046] Using the uniformity control membrane 70 as herein described
provides unexpected and critical improvements to the number of
participating downstream flow paths 43 of the microneedle array 28
at a predetermined target flow rate and pressure. In this regard,
the uniformity control membrane 70 may have a resistance to flow
therethrough of at least about 30 times greater than, at least
about 40 times greater than, at least about 50 times greater than,
between about 30 and about 100 times greater than, between about 40
and about 100 times greater than, or between about 50 and about 100
times greater than the resistance to flow through the microneedle
array 28. These resistances to flow and associated flow paths are
discussed in greater detail below, sometimes with reference to the
first embodiment, a second embodiment of this disclosure, the first
comparative example, and a second comparative example.
[0047] The second embodiment of this disclosure may be like the
first embodiment, except for variations noted and variations that
will be apparent to those of ordinary skill in the art.
Accordingly, reference numerals for features of the second
embodiment that at least generally correspond to features of the
first embodiment are incremented by one hundred.
[0048] As diagrammatically shown in FIG. 5 for the second
embodiment, each downstream flow path 143 of the microneedle array
128 may alternatively or optionally be in the form of an interior
channel, wherein the interior channels extend through the interior
of the microneedles 131 such that each microneedle forms a hollow
shaft. That is, each downstream flow path 143 of the second
embodiment may comprise an interior channel and, for example, the
exterior channels 49 of the first embodiment may be omitted.
[0049] As an example, when the microneedle array assembly 171 is in
use and the liquid formulation flows through the upstream flow
paths 185 and reaches the upstream openings of the downstream flow
paths 143, the liquid formulation will attempt to enter the
upstream openings of the downstream flow paths 143. For example,
when the contact angle that the liquid formulation makes with the
downstream flow paths 143 is less than 90 degrees (e.g., when
adhesive forces are stronger than the cohesive forces), the
downstream flow paths 143 may fill up to the downstream openings of
the downstream flow paths due to the due to capillary action. At
this point, the downstream opening of each downstream flow path 143
can be generalized as having an independent boundary between the
liquid formulation and the air. The boundary between a liquid
(e.g., a liquid drug formulation) and a gas (e.g., air) has surface
tension. When that boundary between the liquid and the gas is
deformed, there is a change in surface tension due to a change in
the curvature of the surface formed at the boundary. As the liquid
formulation is pushed outwardly from the downstream openings of the
downstream flow paths 143, the liquid formulation is pushed into
the air and drops or bubbles of the liquid formulation can form
exiting each downstream openings of the downstream flow paths. The
curvature of these bubbles is small at first, and grows as liquid
formulation flows through the downstream flow paths 143. However,
as alluded to above, in some situations one of the exiting bubbles
of the liquid formulation may be larger than the other, such as due
to variations in sizes of the downstream openings of the downstream
flow paths 143, or for one or more other reasons.
[0050] Some aspects of the factors associated with the flow of the
liquid formulation and associated bubbles may be understood with
reference to the theoretical system of FIG. 5 and the equations and
calculations presented below. For the purposes of the following
equations and calculations, the plenum chamber 182 and upstream and
downstream flow paths 185, 143 are full of fluid, and there is a
fluid/air interface at the downstream openings of the downstream
flow paths. The flow through a first downstream flow path 143 is
Q.sub.1, and the flow through a second downstream flow path 143 is
Q.sub.2. R.sub.1 represents any resistance to flow immediately
upstream from the upstream openings of the upstream flow paths 185.
R.sub.2 and R.sub.4 are the resistance to flow through the
uniformity control membrane 170, or more specifically the
resistance to flow through the upstream flow paths 185. R.sub.3 is
the resistance to flow through a first downstream flow path 143,
and R.sub.5 is the resistance to flow through a second downstream
flow path 143. P.sub.in is the pressure at the source. P.sub.1 and
P.sub.4 respectively are the pressures at the upstream openings of
the upstream flow paths 185. P.sub.2 and P.sub.5 respectively are
the pressures at the upstream openings of the downstream flow paths
143. P.sub.3 and P.sub.6 respectively are the pressures at the
downstream openings of the downstream flow paths 143.
[0051] The pressures P.sub.3 and P.sub.6 respectively at downstream
openings of the downstream flow paths 143 are typically neither
constant nor zero. More specifically, these pressures P.sub.3 and
P.sub.6 are respectively dependent on the shape of the fluid
exiting the downstream openings of the of the downstream flow paths
143. In one example, the pressures P.sub.3 and P.sub.6 (e.g., the
bubble pressures) at the downstream openings of the downstream flow
paths 143 may each be about 1200 Pa, which represents the pressure
required to push fluid out the downstream opening of each
downstream flow path and into the air.
[0052] The pressures P.sub.3 and P.sub.6 respectively at the
downstream openings of the downstream flow paths 143 may be
calculated by the Young-Laplace equation which relates the surface
tension, fluid curvature and pressure drop across the fluid/gas
interface, as indicated below:
.DELTA. .times. .times. P = .gamma. .function. ( 1 r 1 + 1 r 2 )
Equation .times. .times. 1 ##EQU00001##
[0053] In the above Young-Laplace equation, r.sub.1 and r.sub.2 are
the principle radii of curvature of a bubble of the liquid
formulation exiting the downstream opening of a downstream flow
path 143. The radii of curvature change with the amount of fluid
that has flowed. At low volumes the curvature is small and the
pressure is large. As fluid flows the radius increases and the
pressure is reduced.
[0054] It is the reduced pressure mentioned in the immediately
prior sentence that may cause problems when attempting to
administer liquid formulations at a relatively low pressure. For
example, in the event that the downstream opening of the first
downstream flow path 143 is slightly larger than the downstream
opening of the second downstream flow path, the bubble pressure at
the downstream opening of the first downstream flow path may be
slightly less than the bubble pressure at the downstream opening of
the second downstream flow path, so that the upstream liquid
formulation may preferentially flow into the first downstream flow
path. As a result, a large bubble of the liquid formulation at the
downstream opening the first downstream flow path 143 may get
larger, a small bubble of the liquid formulation at the downstream
opening the second downstream flow path may get smaller, and the
liquid formulation may flow through the first downstream flow path
rather than the second downstream flow path. That is, the
differences in bubble pressure may cause low uniformity of flow in
microneedle array 128, as discussed above.
[0055] In accordance with one aspect of this disclosure, the
uniformity control membranes 70, 170 may be configured in a manner
that seeks to reduce the effects of differences in bubble pressure
for optimizing the number of participating downstream flow paths
43, 143 at a predetermined target flow rate and pressure. For
example, the uniformity control membranes 70, 170 may be
advantageously configured in a manner that seeks to inhibit the
pressure at the upstream opening of a downstream flow path 43, 143
from dropping substantially in response to flow through an adjacent
downstream flow path, so that the flow through the adjacent
downstream flow path does not negatively influence flow through the
other downstream flow path. This relationship between a pair of
adjacent downstream flow paths 43, 143 may be generally understood
with reference the equations discussed below.
[0056] For the theoretical system of FIG. 5, the flow into the
system is the sum of the flows through the first and second
downstream flow paths 143, as indicated by the following
equation:
Q.sub.in=Q.sub.1+Q.sub.2 Equation 2
[0057] Flow is proportional to the pressure drop and inversely
proportional to the resistance. Accordingly, flow through first
downstream flow path 143 may be determined from the following
equation:
.times. Q 1 = ? - ? R 1 + R 2 + ? .times. .times. ? .times.
indicates text missing or illegible when filed Equation .times.
.times. 3 ##EQU00002##
[0058] Similarly, flow through the second downstream flow path 43
may be determined from the following equation:
.times. Q 2 = ? - ? R 1 + ? + ? .times. .times. ? .times. indicates
text missing or illegible when filed Equation .times. .times. 4
##EQU00003##
[0059] From the foregoing equations, sets of equations relating
pressure drops, resistances, and flows may be produced and solved.
For example, the following table represents values associated with
a second comparative example that is based upon FIG. 5 but
effectively does not include any uniformity control
TABLE-US-00001 Second Comparative Example Input Data Set
Calc.mu.lated Data Set Q.sub.in = 100 ul/hr Q.sub.1 = 100.0 ul/hr
P.sub.in = 1,533.3 Pa Q.sub.2 = 0.0 ul/hr R.sub.1 = 2,000.00 Pa
s/um.sup.3 P.sub.1 = 1,478 Pa R.sub.2 = 0.00 Pa s/um.sup.3 P.sub.2
= 1,478 Pa R.sub.3 = 10,000.00 Pa s/um.sup.3 P.sub.4 = 1,533 Pa
R.sub.4 = 0.00 Pa s/um.sup.3 P.sub.5 = 1,533 Pa P.sub.3 = 1,200.00
Pa P.sub.6 = 1,533.33 Pa
[0060] In accordance with the first and second embodiment, the
uniformity control membranes 70, 170 may be configured in a manner
that seeks to have the pressure at the upstream opening of one
downstream flow path 43, 143 not change substantially in response
to flow through an adjacent downstream flow path. In this regard,
from the equations set forth above, an equation for determining
P.sub.2 may be derived, and it is set forth below:
P .times. .times. 2 = P .times. ? .times. ( 2 .times. R .times.
.times. 1 + R .times. .times. 2 + R .times. ? + ? .times. ? ) + R
.times. .times. 3 .times. ( ? .times. 6 + Qin .function. ( R
.times. .times. 1 + R .times. .times. 4 + R .times. ? ) ) ? .times.
R .times. .times. 1 + R .times. .times. 2 + R .times. .times. 3 + R
.times. .times. 4 + R .times. .times. 5 .times. .times. ? .times.
indicates text missing or illegible when filed Equation .times.
.times. 5 ##EQU00004##
[0061] For determining how P.sub.2 changes as P.sub.6 changes, the
above equation may be simplified by assuming that R.sub.1 is equal
to zero, R.sub.2 and R.sub.4 are equal to one another, and R.sub.3
and R.sub.5 are equal to one another, and the difference between
P.sub.6 and P.sub.3 may be represented by .beta., to produce the
following simplified equation:
P .times. .times. 2 = P .times. .times. 3 + R .times. .times. 3
.times. ( Qin .function. ( R .times. .times. 2 + R .times. .times.
3 ) + .beta. ) 2 .times. ( R .times. .times. 2 + R .times. .times.
3 ) Equation .times. .times. 6 ##EQU00005##
[0062] From the above simplified equation, sets of equations may be
produced and solved, for calculating the relationship between
P.sub.2 and the resistance of the uniformity control membrane 170
(i.e., R.sub.2) and deviations in pressure between adjacent
downstream openings of downstream flow paths 143 (i.e., .beta.).
For example, Equation 6 may be solved using Q.sub.in of 0.027
um.sup.3/s (i.e., 100 ul/hr), P.sub.3 of 1200 Pa, and R.sub.3 of
10,000 Pa s/um.sup.3, wherein the calculated relationships are
shown in FIG. 6, with the upright axis (i.e., z-axis) representing
P.sub.2.
[0063] FIG. 6 schematically illustrates how suitably configured
uniformity control membranes 70, 170 may seek to advantageously
diminish the effects of variations in bubble pressures (e. g.,
.beta., or more specifically variations between P.sub.3 and
P.sub.6) at downstream openings of downstream flow paths 143. For
example and with reference to the system of FIG. 5 and Equation 6,
the rate of change of P.sub.2 as a function of differences between
bubble pressures at adjacent downstream openings of downstream flow
paths 143 (e.g., variations between P.sub.3 and P.sub.6,
represented by .beta.) may be represented by the following
equation:
.times. dP .times. .times. 2 d .times. .times. .beta. = ? 2 .times.
( R .times. .times. 2 + ? .times. 3 ) .times. .times. ? .times.
indicates text missing or illegible when filed Equation .times.
.times. 7 ##EQU00006##
[0064] The foregoing equation provides insight into how a suitably
configured uniformity control membrane 70, 170 may seek to
advantageously diminish the effects of variations in bubble
pressures (e.g., .beta., or more specifically variations between
P.sub.3 and P.sub.6) at downstream openings of downstream flow
paths 143. For example, if bubble pressures (e.g., .beta., or more
specifically variations between P.sub.3 and P.sub.6) at downstream
openings of downstream flow paths 143 vary by up to 1200 Pa and it
is desirable for the pressure P.sub.2 to deviate by less than 1%,
Equation 7 may be represented as follows:
dP .times. .times. 2 d .times. .times. .beta. = 0.1 * 1200 1200 = R
.times. .times. 3 2 .times. ( R .times. .times. 2 + R .times.
.times. 3 ) Equation .times. .times. 8 ##EQU00007##
[0065] Equation 8 may be represented as shown below, for
determining how much larger R.sub.2 should be as compared to
R.sub.3, or more generally how much larger the resistance to flow
through the uniformity control membranes 70, 170 should be as
compared to the resistance to flow through the microneedle arrays
28, 128.
.times. 0.01 * 1200 1200 = ? 2 .times. ( k R .times. .times. 3 + ?
.times. ? ) = 1 2 .times. ( 1 + k ) .times. .times. ? .times.
indicates text missing or illegible when filed Equation .times.
.times. 9 ##EQU00008##
[0066] Solving Equation 9 results ink being 49; therefore, in this
example, R.sub.2 should be at least about fifty times larger than
R.sub.3, or more generally the resistance to flow through the
uniformity control membranes 70 and 170 should be at least about
fifty times larger than the resistance to flow through the
microneedle arrays 28 and 128, respectively. More generally, the
uniformity control membranes 70 and 170 may have a resistance to
flow therethrough of at least about 30 times greater than, at least
about 40 times greater than, at least about 50 times greater than,
between about 30 and about 100 times greater than, between about 40
and about 100 times greater than, or between about 50 and about 100
times greater than the resistance to flow through the microneedle
arrays 28 and 128, respectively.
[0067] As alluded to above with reference to FIG. 5 and in
accordance with one example, the pressures P.sub.3 and P.sub.6
(e.g., the bubble pressures of the fluid formulation) at the
downstream openings of each of the downstream flow paths 43, 143
may be about 1200 Pa, which may represent the pressure required to
push the fluid formulation out the downstream opening of the
downstream flow path and into air. In examples of methods of
operation, the pressure drop across the uniformity control
membranes 70 and 170 may be at least about 30 times greater than,
at least about 40 times greater than, at least about 50 times
greater than, between about 30 and about 100 times greater than,
between about 40 and about 100 times greater than, or between about
50 and about 100 times greater than the pressure required to push
the fluid formulation out the downstream openings of the downstream
flow paths 43, 143 and into air. The pressure required to push the
fluid formulation out the downstream openings of the downstream
flow paths 43, 143 and into air may be generally referred to as the
bubble pressures of the microneedle arrays 28 and 128. Accordingly,
the pressure drops across the uniformity control membranes 70 and
170 may be at least about 30 times greater than, at least about 40
times greater than, at least about 50 times greater than, between
about 30 and about 100 times greater than, between about 40 and
about 100 times greater than, or between about 50 and about 100
times greater than the bubble pressures of the microneedle arrays
28 and 128, respectively.
[0068] As alluded to above, for each compound flow path extending
through the microneedle array assemblies 71, 171, the downstream
openings of the upstream flow paths 85, 185 may be in direct
communication with the upstream openings of the downstream flow
paths 43, 143, for example as a result of the uniformity control
membranes 70, 170 being securely engaged against the upstream sides
of the microneedle arrays 28, 128. In accordance with one aspect of
this disclosure and at least partially reiterating from above, the
resistance to flow through the upstream flow paths 85, 185 may be
substantially higher than the resistance to flow through the
downstream flow paths 43, 143, wherein these differences in flow
resistance seek to facilitate, for example, the uniform
administration of the liquid formulation into the patient's skin
across a broad area and at a relatively low pressure, such as by
way of capillary action. The administration of the liquid
formulation into the patient's skin across the broad area may
comprise the liquid formulation being administered by way of at
least a majority of the downstream flow paths 43, 143, such that
the liquid formulation is administered by way of at least a
majority of the microneedles of the microneedle arrays 28, 128.
[0069] That is, the uniformity control membranes 70, 170 may have
the effect of significantly increasing the overall resistance to
flow through each compound flow path (e.g., upstream flow paths 85,
185 together with downstream flow paths 43, 143) in a manner that
minimizes differences in overall flow resistance among the numerous
compound flow paths. As a result, the liquid formulation may
actively utilize (i.e. flow through) an increased number of the
compound flow paths when the liquid formulation is administered at
a low pressure, such as a pressure that is low enough so that a
substantial portion of the liquid formulation is administered by
way of capillary action. That is, the number of participating
compound flow paths may be increased to provide a larger area of
administration of the liquid formulation at low pressure. The
liquid formulation being administered by way of at least a majority
of the downstream flow paths 43, 143 may comprise the liquid
formulation being administered by way of at least about 50%, at
least about 60%, at least about 70%, at least about 80% or at least
about 90% of the downstream flow paths 43, 143.
[0070] In one aspect of this disclosure, when the liquid
formulation is initially supplied to the upstream openings of the
upstream flow paths 85, 185 and fills the compound flow paths,
outwardly protruding bubbles of the liquid formulation may form at
the downstream openings of the downstream flow paths 43, 143, and
these bubbles contribute to the resistance to flow through the
downstream flow paths 43, 143. In one example, the bubbles of the
liquid formulation may be globules of the liquid formulation in the
ambient atmosphere or environment, such as a thin layer of air
covering a portion of a patient's skin where the liquid formulation
is to be administered, or the like. Further regarding the outwardly
protruding bubbles of the liquid formulation that initially form at
the downstream openings of the downstream flow paths 43, 143,
relatively small bubbles may form at some of the downstream
openings, and relatively large bubbles may form at other of the
downstream openings. The pressure of the liquid formulation in the
relatively small bubbles is larger than the pressure of the liquid
formulation in the relatively large bubbles, such that the
resistance to flow due to the small bubbles is greater than the
resistance to flow due to the large bubbles. At least in theory,
the resistance to flow through the uniformity control membranes 70,
170 may be sufficiently large so that the pressure drop through the
upstream flow path 85, 185 of a compound flow path with a
relatively large and expanding bubble may exceed the pressure drop
in the upstream portion of a compound flow path with a relatively
small bubble. In this regard, the pressure drop in the upstream
portion of the compound flow path with the relatively large and
expanding bubble may exceed any pressure drop in the upstream
portion of the compound flow path with the relatively small bubble
in a manner that substantially equalizes the flow through the
compound flow paths, so that a majority of the bubbles that form at
the downstream openings of the downstream portions of the compound
flow paths rupture and are replaced with a constantly outwardly
flowing stream of the liquid formulation.
[0071] The above examples are in no way intended to limit the scope
of the present invention. It will be understood by those skilled in
the art that while the present disclosure has been discussed above
with reference to exemplary embodiments, various additions,
modifications and changes can be made thereto without departing
from the spirit and scope of the invention, some aspects of which
are set forth in the following claims.
* * * * *