U.S. patent application number 17/645503 was filed with the patent office on 2022-04-14 for microneedle arrays and methods for making and using.
The applicant listed for this patent is JOHNSON & JOHNSON CONSUMER INC.. Invention is credited to Marc Alary, Peyton Hopson, Jan-Joo Liu, Erik Lunde, Emanuel Morano, Bharat Patel.
Application Number | 20220111189 17/645503 |
Document ID | / |
Family ID | |
Filed Date | 2022-04-14 |
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United States Patent
Application |
20220111189 |
Kind Code |
A1 |
Alary; Marc ; et
al. |
April 14, 2022 |
MICRONEEDLE ARRAYS AND METHODS FOR MAKING AND USING
Abstract
An array of differing microneedles can be accurately achieved
including a film having first and second, outwardly facing major
surfaces. The first, outwardly facing major surface has a plurality
of stratum corneum piercing microneedles extending therefrom, and
the plurality of microneedles includes a plurality of first
microneedles having a first benefit agent and a plurality of second
microneedles having a second benefit agent.
Inventors: |
Alary; Marc; (Newtown,
PA) ; Hopson; Peyton; (Jacksonville, FL) ;
Liu; Jan-Joo; (Belle Mead, NJ) ; Lunde; Erik;
(Morganville, NJ) ; Patel; Bharat; (Princeton,
NJ) ; Morano; Emanuel; (Totowa, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
JOHNSON & JOHNSON CONSUMER INC. |
Skillman |
NJ |
US |
|
|
Appl. No.: |
17/645503 |
Filed: |
December 22, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15848905 |
Dec 20, 2017 |
11241563 |
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17645503 |
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62437800 |
Dec 22, 2016 |
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International
Class: |
A61M 37/00 20060101
A61M037/00 |
Claims
1.-8. (canceled)
9. A microneedle array comprising a film having first and second,
outwardly facing major surfaces, wherein the first, outwardly
facing major surface has a plurality of stratum corneum piercing
microneedles extending therefrom, and wherein the plurality of
microneedles includes a plurality of first microneedles having a
first benefit agent and a plurality of second microneedles having a
second benefit agent, wherein individual microneedles comprise at
least two distinct benefit agents and at least one individual
microneedle comprises a core section and a sheath section.
10. The microneedle array of claim 9 wherein the core section of
the at least one individual microneedle comprises a rigid
composition.
11. A microneedle array comprising a film having first and second,
outwardly facing major surfaces, wherein the first, outwardly
facing major surface has a plurality of stratum corneum piercing
microneedles extending therefrom, and wherein the plurality of
microneedles includes a plurality of first microneedles having a
first benefit agent and a plurality of second microneedles having a
second benefit agent wherein at least one microneedle has an
initial, substantially linear form, extending substantially normal
to the first, outwardly facing major surface, and a second,
deployed form in which a distal end curves to a hook-like form.
12.-13. (canceled)
Description
FIELD OF THE INVENTION
[0001] The present invention relates to devices for the transdermal
administration of benefit agents to patients through the skin. More
particularly, this invention relates to microneedle arrays
comprising a plurality of benefit agents, and methods for making
and using these arrays.
BACKGROUND OF THE INVENTION
[0002] Transdermal drug delivery provides several advantages over
other routes for administering a benefit agent formulation to a
patient. For example, oral administration of some benefit agents
may be ineffective because the benefit agent is destroyed in the
gastrointestinal tract or eliminated by the liver, both of which
are avoided by transdermal drug delivery. Parenteral injection with
a conventional hypodermic needle also has drawbacks, as it is often
painful and inconvenient.
[0003] Transdermal drug delivery avoids these problems. However,
there are obstacles to its use. In particular, the physical barrier
properties of the stratum corneum of human skin pose a significant
challenge to transdermal drug delivery. These barrier properties
only allow relatively small molecules to be transported through the
intact stratum corneum, and many useful drugs are too large to pass
through the stratum corneum without some type of modification of
the stratum corneum or other transport enhancement. Various
transdermal enhancement methods are known, including those based on
iontophoresis, ultrasound, and chemical penetration enhancers.
However, these methods may be inadequate to assist in the delivery
of many medications through an intact skin layer and/or they may be
inconvenient or undesirably complicated to use.
[0004] To address the challenge of intact skin, a variety of
microneedle-array based drug delivery devices have been developed.
These known microneedle array generally fall into one of two design
categories: (1) solid microneedles arrays with no active component,
and (2) microneedles with a central hollow bore, which are similar
to conventional hypodermic needle.
[0005] Solid microneedle arrays can pre-condition the skin by
piercing the stratum corneum and the upper layer of epidermis to
enhance percutaneous drug penetration prior to topical application
of a biologic-carrier or a traditional patch. If solid microneedle
arrays are kept in the skin, then the drug cannot readily flow into
and through the holes in the skin because the holes remain plugged
by the microneedles. This method has been shown to significantly
increase the skin's permeability; however, this method provides
only limited ability to control the dosage and quantity of
delivered drugs or vaccine.
[0006] To increase the dosage control some methods uses solid
microneedles that are surface-coated with a drug. Although this
method provides somewhat better dosage control, it greatly limits
the quantity of drug delivered. Also, the deposition process is
unreliable, and the thin layer of drug formulation on the
microneedle could be easily chipped off of the microneedle during
storage, transport, or administration (insertion) of the
microneedles. The application of a thicker and stronger layer of
drug formulation can be undesirable because it reduced the
sharpness of the microneedles and therefore made insertion more
difficult and painful. This shortcoming has limited the widespread
application of this approach and precludes, for example, the
simultaneous delivery of optimal quantities of combinations of
antigens and/or adjuvant in vaccine applications.
[0007] Microneedles with a central hollow bore attached to a
reservoir of benefit agents are also known. The syringe needle-type
characteristics of these arrays can significantly increase the
speed and precision of delivery, as well as the quantity of the
delivered agent. However, reservoir-based microneedle arrays are
expensive to make and require complex and expensive micromachining
procedures. In particular, it is difficult to make sharp tips on
hollow microneedles with machining techniques. Consequently,
insertion of the microneedles into a patient's skin can be
difficult and often painful. In addition, the central bore of the
microneedle is quite small and may be easily plugged by skin tissue
during the insertion process, thereby blocking the drug delivery
conduit. It may be even slower than the diffusion of the drug
through the stratum corneum in the absence of the microneedle. It
therefore would be desirable to provide a microneedle array for
drug delivery that avoids the disadvantages associated with known
hollow microneedle array designs.
[0008] Also known methods involve using solid microneedle arrays
that are biodegradable, bioabsorbable, or dissolvable. This method
combines the physical toughness of solid microneedles with
relatively high bioactive material capacity, while retaining
desired attributes of simple fabrication, storage and application.
Current fabrication approaches for dissolvable polymer-based
microneedles generally use microcasting processes. For example, a
primary master mold is commonly produced using a combination of
complex lithographic and laser etching technologies. However,
lithographic and laser-based technologies are limited in the range
of geometric features they can create, and the materials to which
they can be applied. Also, these highly complex fabrication
technologies do not allow rapid or low cost fabrication of master
molds, which can be particularly useful for systematic testing of
the bio-effectiveness of various different microneedle and array
geometries.
[0009] Finally, the microcasting process for producing dissolvable
polymer-based microneedle arrays is limited to producing arrays of
a single composition. If there is a desire for personalized
treatment requiring dissolvable arrays using microneedles with
different compositions or benefit agents, the microcasting process
cannot produce such arrays.
[0010] In summary, transdermal delivery of benefit agents using
microneedle-array based devices offer attractive theoretical
advantages over prevailing oral and needle-based drug delivery
methods. However, considerable practical limitations exist in the
design, fabrication, and testing associated with microneedle arrays
constructed using conventional processes. Also, there is a need for
a simple, effective, and economically desirable device for
transdermal administration of using microneedle arrays
simultaneously delivering more than one benefit agent.
SUMMARY OF THE INVENTION
[0011] Surprisingly, we have found that an array of differing
microneedles can be accurately achieved including a film having
first and second, outwardly facing major surfaces. The first,
outwardly facing major surface has a plurality of stratum corneum
piercing microneedles extending therefrom, and the plurality of
microneedles includes a plurality of first microneedles having a
first benefit agent and a plurality of second microneedles having a
second benefit agent.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1 is a perspective view of one embodiment of a
microneedle array;
[0013] FIG. 2 is a cross-sectional view of a section of the
microneedle array of FIG. 1 along the 2-2 plane;
[0014] FIG. 3 is a top view of a section of the microneedle array
of FIG. 1;
[0015] FIG. 4 is a cross-sectional view of a section of a second
embodiment microneedle array;
[0016] FIG. 5 is a cross-sectional view of a section of a third
embodiment microneedle array;
[0017] FIG. 6 is a cross-sectional view of section of a fourth
embodiment microneedle array;
[0018] FIG. 7 is a cross-sectional view of a section of the
microneedle array of FIG. 6 after the microneedles have penetrated
the patient's skin;
[0019] FIG. 8 is a cross-sectional view of a section of a fifth
embodiment microneedle array; and
[0020] FIG. 9 is a cross-sectional view of a section of a sixth
embodiment microneedle array.
DETAILED DESCRIPTION OF THE INVENTION
[0021] The present invention relates to devices for the transdermal
administration of a plurality of benefit agents to patients through
the skin using microneedle array systems, and methods for making
and employing these systems. The following description is presented
to enable one of ordinary skill in the art to make and use the
invention. Various modifications to the embodiments and the generic
principles and features described herein will be readily apparent
to those skilled in the art. Thus, the present invention is not
intended to be limited to the embodiments shown, but is to be
accorded the widest scope consistent with the features described
herein.
[0022] As used herein the specification and the claims, the term
"topical" and variants thereof mean "of or applied to an isolated
part of the body". This includes, without limitation skin, mucosa,
and enamel, either directly or through an intermediate such as a
biofilm.
[0023] As used herein, "benefit agent" means an ingredient or
material that provides a benefit, e.g., improves, relieves,
reduces, or treats symptoms or conditions of the skin or body,
either cosmetic or therapeutic. Other terms of use for "benefit
agent" include "biologic," "active component," or "bioactive
material". These terms all refer to pharmaceutically active agents,
such as analgesic agents, anesthetic agents, anti-asthmatic agents,
antibiotics, anti-depressant agents, anti-diabetic agents,
anti-fungal agents, anti-hypertensive agents, anti-inflammatory
agents, anti-neoplastic agents, anxiolytic agents, enzymatically
active agents, nucleic acid constructs, immunostimulating agents,
immunosuppressive agents, vaccines, and the like. The benefit agent
material can comprise dissoluble materials, insoluble but
dispersible materials, natural or formulated macro, micro and nano
particulates, and/or mixtures of two or more of dissoluble,
dispersible insoluble materials and natural and/or formulated
macro, micro and nano particulates.
[0024] In some embodiments, the microneedle array systems described
herein are flexible so as to be conformable to the
three-dimensional shape corresponding to the site of delivery of
benefiting agent substance to the skin of the consumer. In other
embodiments, the microneedle array may be more rigid; built as the
described three-dimensional shape to match the topical contour. The
array may have varying personalized area-specific treatment zones
to enable the treatment application more effectively. With an array
matched to the individual user's body part profile as physical
guides, the application becomes easier and more effective, and can
help in locating specific target zones to the precise area for
applications.
[0025] Referring to the drawings, FIG. 1 is a perspective view of
one embodiment of a microneedle array 10 which may be used in the
present invention. Microneedle array 10 includes a film 20 having
first outwardly facing major surface 22 and second outwardly facing
major surface 24. First outwardly facing major surface 22 has a
plurality of stratum corneum piercing microneedles 30 extending
therefrom. Each microneedle 30 has a proximal end 32 and a distal
end 34, where proximal end 32 is the end of microneedle 30 disposed
on first outwardly facing major surface 22 of a microneedle array
10.
[0026] In FIG. 1, microneedle array 10 is shown to have a
rectangular footprint. Film 20 of microneedle array 10 may also
have a variety of shapes, depending on the location of skin
treatment. Possible shapes of the footprint left by film 20
include, but are not limited to, squares, rectangles, triangles,
circles, ovals, kidneys, stars, crosses, characters, etc. The
corners of such shapes, if any, may be angular or curved to reduce
potential lift/removal points. The zone of the treatment could be
greater than about 1,000 cm.sup.2, about 1,000 cm.sup.2, or about
100 cm.sup.2, or about 10 cm.sup.2, or about 1 cm.sup.2, or less
than 1 cm.sup.2.
[0027] Film 20 element of microneedle array 10 preferably is
relatively thin and flexible, so that they preferably readily
conform to the user's skin and are comfortable to wear, both
because of the flexibility and conformability, as well as from the
thinness. Microneedle array 10 of the present invention may be
intended for extended wear preferably are also formed to be
aesthetically elegant without either peeling, wrinkling, cracking,
or appearing greasy or tacky, or otherwise unpleasant or unsightly
in nature. Microneedle array 10 preferably is formed with
sufficient rigidity and integrity to be able to withstand normal
use when on the skin. In some embodiments, microneedle array 10 of
the invention preferably is formed with sufficient strength to stay
intact on the skin when exposed to normal external forces that the
skin may experience, rubbing of clothing.
[0028] In some embodiments, first outwardly facing major surface 22
of film 20 has disposed thereon an adhesive layer. The adhesive
layer may be used to give microneedle array 10 the sufficient
strength to stay intact on the skin when exposed to normal external
forces. Other means of creating sufficient strength to microneedle
array 10 so that the array stays intact on the skin will be
discussed below.
[0029] FIG. 2 is a cross-sectional view of a section of the
microneedle array along the 2-2 plane of FIG. 1. The figure shows a
plurality of first stratum corneum piercing microneedles 30a and a
plurality of second stratum corneum piercing microneedles 30a. Each
microneedle 30a has a proximal end 32a and a distal end 34a, while
each microneedle 30b has a proximal end 32b and a distal end 34b.
Plurality of first microneedles 30a comprises a first benefit agent
and plurality of second microneedles 30b comprises a second benefit
agent.
[0030] The dimensions of stratum corneum piercing microneedles 30a,
30b may vary depending on a variety of factors such as the type of
benefit agent to be delivered, the dosage of the benefit agent to
be delivered, and the desired penetration depth. Generally, the
stratum corneum piercing microneedles are constructed to provide
skin-piercing and benefit agent delivery functions and thus will be
designed to be sufficiently robust to withstand insertion into and
withdrawal from the skin. Each microneedle has a length of about 1
micrometer (.mu.m) to about 5000 micrometers (.mu.m), or about 1
.mu.m to about 500 .mu.m, or about 100 .mu.m to about 500 .mu.m.
The penetration length of the microneedles into the biological
barrier is about 50 .mu.m to about 200 .mu.m. In addition, each of
the microneedles has a width of about 1 .mu.m to about 500 .mu.m.
Furthermore, each microneedle has a thickness of about 1 .mu.m to
about 200 .mu.m. It will be understood by one skilled in the art
that the width and thickness of the stratum corneum piercing
microneedle may vary along its length. For instance, the base
portion may be wider (thicker) than the body portion, or the body
portion may have a slight taper approaching the tip portion.
[0031] FIG. 3 is a top view of a section of the microneedle array
of FIG. 1. The figure shows stratum corneum piercing microneedles
30 which extend from first outwardly facing major surface 22 of
microneedle array 10. Each microneedle 30 has a proximal end 32 and
a distal end 34. As shown in the figure, microneedles 30 are
arranged in a square pattern on first outwardly facing major
surface 22 of microneedle array 10. In other embodiments,
microneedles 30 are arranged in other patterns, such as triangular,
square, pentagonal, hexagonal, octagonal, etc.
[0032] Microneedles 30 in microneedle array 10 of the invention may
also be of a variety of lengths and geometries. FIG. 4 is a
cross-sectional view of a section of a second embodiment
microneedle array. In this embodiment, plurality of first stratum
corneum piercing microneedles 30a comprise a first benefit agent
and plurality of second stratum corneum piercing microneedles 30c
comprise a second benefit agent. In addition, plurality of first
microneedles 30a extend from first outwardly facing major surface
22 of film 20 to a height of h.sub.1, while plurality of second
microneedles 30b extend from first surface 22 of film 20 to a
height of h.sub.2. In this embodiment, there may be a desire for a
deeper penetration into the skin of the user for first benefit
agent contained in plurality of first microneedles 30a than from
second benefit agent contained in plurality of second microneedles
30b.
[0033] Although the figure shows first stratum corneum piercing
microneedles 30a are of uniform height h.sub.1, while second
stratum corneum piercing microneedles 30b are of uniform height
h.sub.2, it is to be understood that in other embodiments the
microneedles may be of any number of different heights. In
addition, it is important to note that neither all microneedles 30a
are comprised of a first benefit agent, nor that all microneedles
30b are comprised of a second benefit agent. In some embodiments,
some of the microneedles will not comprise any benefit agent.
[0034] Generally, stratum corneum piercing microneedles 30 can be
in any elongated shape suitable for providing the skin piercing and
benefit agent delivery, with minimal pain to the patient. In
various embodiments, an individual microneedle is substantially
cylindrical, wedge-shaped, cone-shaped, or triangular (e.g.,
blade-like). The cross-sectional shape (cut along a plane
approximately parallel to the planar substrate or approximately
perpendicular to the longitudinal axis of the microneedle) of the
microneedle, or at least the portion of the microneedle that is
penetrable into the skin, may take a variety of forms, including
rectangular, square, oval, circular, diamond, triangular, or
star-shaped.
[0035] The tip portions of stratum corneum piercing microneedles 30
are designed to pierce a biological barrier, e.g., to pierce the
stratum corneum of the skin of a patient, to deliver benefit agents
into the patient's tissue. Preferably, the tip portion of each
microneedle should be sufficiently small and sharp to enable
piercing and penetration of the skin with minimal pain. In a
preferred embodiment, individual microneedles 30 are tapered from
the first, outwardly facing major surface 22 of microneedle array
10 to a point distal therefrom. In various embodiments, the tapered
tip portion may be in the form of an oblique angle at the tip, or a
pyramidal or conical or triangular shape.
[0036] FIG. 5 is a cross-sectional view of a section of a third
embodiment microneedle array showing a variety of stratum corneum
piercing microneedle shapes. Microneedle 30a is conical in shape,
with a taper from proximal end 32a to distal end 34a. Microneedle
30d has a cylindrical proximal end 32d, which tapers to a point at
distal end 34d. Microneedle 30e has a proximal end 32e and a distal
end 34e, and has an undulating shape. Microneedle 30f is
cylindrical in shape, with no taper from proximal end 32f to distal
end 34f Finally, microneedle 30g is pyramidal in shape, with a
taper from proximal end 32g to distal end 34g.
[0037] Although FIG. 5 shows all stratum corneum piercing
microneedles 30 of substantially uniform height, it is to be
understood that in other embodiments the microneedles may be of any
number of different heights. In addition, microneedles 30a, 30d,
30e, 30f, and 30g comprise at least one benefit agent. Some
comprise a first benefit agent, while others comprise a second
benefit agent, so that microneedle arrays 10 comprises microneedles
with two distinct benefit agents. Of course, not all microneedles
30 of any given shape or height are required to all comprised
either first or second benefit agent.
[0038] Microneedle arrays 10 of the present invention may also
comprise stratum corneum piercing microneedles 30 comprised of
multiple compositions. FIG. 6 is a cross-sectional view of a
section of a fourth embodiment microneedle array 10 with such
microneedles. The figure shows four different microneedles, with
the microneedles being of variable heights, and comprising at least
two distinct benefit agents. Microneedle 30h has a cylindrical
proximal end 32h, which tapers to a point at distal end 34h. In
addition, proximal end 32h of microneedle 30h is of a different
composition than distal end 34h of microneedle 30h. Microneedle 30i
is cylindrical, and has a core section 32i and a sheath section
34i. Here, core section 32i is of a different composition than
sheath section 34i. Microneedle 30j has a cylindrical proximal end
32j and a cylindrical distal end 34j, and has a substantially
linear form. Here, proximal end 32j of microneedle 30j is of a
different composition than distal end 34j of microneedle 30j.
Finally, microneedle 30k is conical in shape, with a taper from
proximal end 32k to distal end 34k. Proximal end 32k of microneedle
30k is of a different composition than distal end 34k of
microneedle 30k.
[0039] Special attention is now paid to microneedle 30i.
Microneedle 30i comprises a core section 32i and a sheath section
34i. Core section 32i is of a different composition than sheath
section 34i. In some embodiments, core section 32i does not have
the mechanical strength or rigidity to penetrate the skin, while
sheath section 34i does. In other embodiments, sheath section 34i
does not have the mechanical strength or rigidity to penetrate the
skin, while core section 32i does. Therefore, at least one of the
sheath sections comprised a rigid composition. So,
materials/active/drugs which are not strong enough to penetrate the
skin can still be delivered.
[0040] Special attention is now paid to microneedle 30j.
Microneedle 30j has a cylindrical distal end 34j, and has an
initial, substantially linear form. Upon insertion into the skin,
distal end 34j is designed to curve to form a hook-like structure
or form. As mentioned earlier, in some embodiments, first outwardly
facing major surface 22 of film 20 has disposed thereon an adhesive
layer to give microneedle array 10 the sufficient strength to stay
intact on the skin when exposed to normal external forces. In some
embodiments, microneedle array 10 may have a plurality of
microneedles which form hook-like structures. Hook-like
microneedles 30j, once they penetrate the skin, may have sufficient
strength so as to hold microneedle array 10 intact on the skin
during use.
[0041] The figure also shows that the stratum corneum piercing
microneedles are of different lengths. In this embodiment,
microneedles 30h and 30i extend from first outwardly facing major
surface 22 of film 20 to a height of h.sub.1, microneedle 30j
extends from first surface 22 of film 20 to a height of h.sub.2,
and microneedle 30k extends from first surface 22 of film 20 to a
height of h.sub.3. In this embodiment, there may be a desire for a
deeper penetration into the skin of the user for the different
benefit agents.
[0042] Although FIG. 6 figure shows stratum corneum piercing
microneedles 30 of different heights, it is to be understood that
in other embodiments the microneedles may all be of the same
height, or any number of different heights. In addition, it is
important to note that all microneedles 30 are neither comprised of
a first benefit agent nor a second benefit agent. Also, not all
microneedles 30 are composed of multiple benefit agents. In some
embodiments, some of the stratum corneum piercing microneedles will
not comprise any benefit agent.
[0043] The different sizes, compositions, and geometries of the
stratum corneum piercing microneedles are demonstrated in a
prophetic use. FIG. 7 is a cross-sectional view of a section of the
microneedle array of FIG. 6 after the microneedles have have been
deployed and penetrated the patient's skin. The figure shows skin
tissue 50 with an outer surface 52. Beneath the outer surface 52
lie the epidermis 54, dermis 56, and the subcutis or hypodermis 54
layers. The first outwardly facing major surface 22 of film 20 is
in contact with outer surface 52 of skin tissue 50.
[0044] Microneedles 30h, 30i, 30j, and 30k all penetrate outer
surface 52 and epidermis 54. Microneedles 30h, 30i and 30j
penetrate deeper into dermis 56 than microneedle 30k. Also, since
proximal end 32h of microneedle 30h is of a different composition
than distal end 34h of microneedle 30h, the distal end composition
is deposited deeper into the dermis than the proximal. The same is
true for microneedles 30j and 30k. So, if there is a desire for
personalized treatment at different skin depths, microneedle arrays
10 of the present invention allow a degree of flexibility not
available to microneedle arrays produced using the microcasting
process.
[0045] Also, as discussed earlier, distal end 34j of microneedle
30j is designed to curve to form a hook-like deployed form upon
insertion into the skin. Hook-like microneedle 30j may have
sufficient strength so as to hold microneedle array 10 intact on
the skin during use. This may allow first outwardly facing major
surface 22 of film 20 to be free of adhesive.
[0046] In the embodiments shown so far, microneedle array 10 is
shown to be planar. In some embodiments, the array may be
curvilinear. FIG. 8 is a cross-sectional view of a section of a
fifth embodiment microneedle array of the present invention.
Microneedle array 100 includes a curved film 120 having first
outwardly facing major surface 122 and second outwardly facing
major surface 124. First outwardly facing major surface 122 has a
plurality of stratum corneum piercing microneedles 130 extending
therefrom. The figure shows a plurality of first stratum corneum
piercing microneedles 130a and a plurality of second stratum
corneum piercing microneedles 130a. Each microneedle 130a has a
proximal end 132a and a distal end 134a, while each microneedle
130b has a proximal end 132b and a distal end 134b. Plurality of
first microneedles 130a comprises a first benefit agent and
plurality of second microneedles 130b comprises a second benefit
agent. Proximal ends 132a, 132b are the end of microneedle 130a,
130b disposed on first outwardly facing major surface 122 of a
microneedle array 100.
[0047] FIG. 8 shows microneedle array 100 having a concave shape
with respect to microneedles 130. FIG. 9 is a cross-sectional view
of a section of a sixth embodiment microneedle array of the present
invention. In this embodiment, microneedle array 200 has concave
and convex curvature within the array. Microneedle array 200
includes a curved film 220 having first outwardly facing major
surface 222 and second outwardly facing major surface 224. First
outwardly facing major surface 222 has a plurality of stratum
corneum piercing microneedles 230 extending therefrom. As with all
other embodiments, microneedle array 200 comprise at least a first
benefit agent and a second benefit agent.
[0048] Although FIGS. 8 and 9 show curvilinear microneedle arrays
in one direction, the array may have multiple axes of curvature in
localized regions or overall. Other embodiments may employ multiple
axes of curvature to shape the microneedle array.
[0049] The curvilinear microneedle arrays shaped to the body
surface provides the microneedles oriented normal to that surface.
This provides better penetration of the microneedles and retention
of the array for treatment.
[0050] In preferred embodiments, film 20, 120, 220, stratum corneum
piercing microneedles 30, 130, 230, or both, are formed of, or
coated with, a biocompatible material. Microneedles 30, 130, 230
may be formed from the same material used in film 20, 120, 220, or
alternatively, the microneedles can include a material different
from the film material. Representative examples of suitable
materials of construction include metals and alloys such as
stainless steels, palladium, titanium, and aluminum; plastics such
as polyetherimide, polycarbonate, polyetheretherketone, polyimide,
polymethylpentene, polyvinylidene fluoride, polyphenylsulfone,
liquid crystalline polymer, polyethylene terephthalate (PET),
polyethylene terephthalate-glycol modified (PETG), and polyimide;
and ceramics such as silicon and glass. The material preferably is
selected such that the microneedle is strong enough at its designed
dimensions for the microneedle to effectively pierce the skin
without significant bending or breaking of the microneedle. The
microneedle and substrate materials also should be non-reactive
with the drug formulation being delivered by the microneedle
array.
[0051] In some embodiments, film 20, 120, 220, microneedles 30,
130, 230, or both, are formed of biodegradable or bioabsorbable
materials. Representative examples of suitable materials include,
but are not limited to, poly(lactic acid) (PLA), poly(glycolic
acid) (PGA), polydioxanone (PDO), poly(epsilon-caprolactone) (PCL),
poly(lactic-co-glycolic acid) (PLGA), poly(ortho ester) (POE),
copoly(ether-ester) (CEE), carboxymethylcellulose (CMC) based
formulations, or combinations of such materials.
[0052] Film 20, 120, 220, stratum corneum piercing microneedles 30,
130, 230, or both, optionally may further include secondary
materials of construction embedded therein or coated thereon. For
example, microparticles, nanoparticles, fibers, fibrids, or other
particulate materials may be included. These secondary materials
may enhance one or more physical or chemical characteristics of
microneedle array 10, 100, 200.
[0053] In some embodiments, stratum corneum piercing microneedles
30, 130, 230 are formed of biodegradable materials, while film 20,
120, 220 is not biodegradable. In these embodiments the benefit
agent material can comprise dissoluble materials or insoluble but
dispersible materials. So, the mechanism of delivery of the benefit
agent can be, for example, the simultaneous biodegradation of the
microneedles with the dissolution or dispersing of the benefit
agent. The rate of degradation of the microneedles could be
controlled to allow predetermined drug-delivery rates of the
benefit agent. In some embodiments, the release rate of first
benefit agent could differ from that of second benefit agent. At
the point in time when all of the stratum corneum piercing
microneedles have degraded, film 20, 120, 220 can be removed from
the site of treatment.
[0054] In another embodiment, a number of hook-like microneedles
30j may have sufficient strength so as to hold microneedle array 10
intact on the skin during use. This may allow first outwardly
facing major surface 22 of film 20 to be free of adhesive. In this
embodiment, proximal end 32j of microneedle 30j is of a different
composition than distal end 34j of microneedle 30j. If distal end
34j composition is biodegradable, microneedle array 10 may be kept
intact on the skin until distal end 34j of hook-like microneedles
30j have degraded. At this point in time, microneedle array 10 may
be easily removed from the patient's skin.
[0055] In some embodiments, the microneedle array 10 may be further
coated with a benefit agent, either the microneedles alone or in
combination with the substrate.
[0056] Alternatively, the microneedles may have a desired surface
structure, such as slight directional ridges, to hold the
microneedles in place. The benefit agents may include lubricants,
slip agents and the like. Alternatively, the benefit agents may
provide one or more benefits to the targeted topical region. Such
benefit agents may be any of a variety of compositions, including,
without limitation, waxes, oils, emollients, moisturizers, and the
like.
[0057] Benefit agents may include hyaluronic acid; hydroxyl acids
(e.g., glycolic acid, lactic acid, malic acid, salicylic acid,
citric acid, tartaric acid); anti-acne agents (e.g., salicylic
acid, retinol, retinoids, or other keratolytics, and benzoyl
peroxide, or other antimicrobial agents used to treat acne); shine
control agents (e.g., rice protein, cotton powder, elubiol
(dichlorophenyl-imidazoltioxolan); a retinoid or its derivative
such as tretinoin, isotretinoin, motretinide, adapalene,
tazarotene, azelaic acid, and retinol; a 5-alpha-reductase
inhibitor of amino acids, e.g., glycine derivatives; hydrolyzed
vegetable proteins, including soy protein and wheat protein, etc.,;
green tea (Camellia sinesis) extract, and cinnamon bark extract);
moisturizers; anti-microbial agents (e.g., cationic antimicrobials
such as benzylkonium chloride, benzethonium chloride, triclocarbon,
polyhexamethylene biguanide, cetylpyridium chloride, methyl and
benzothonium chloride; salts of chlorhexidine, such as lodopropynyl
butylcarbamate, diazolidinyl urea, chlorhexidene digluconate,
chlorhexidene acetate, chlorhexidine isethionate, and chlorhexidene
hydrochloride; halogenated phenolic compounds, such as
2,4,4'-trichloro-2-hydroxy diphenyl ether (Triclosan);
parachlorometa xylenol (PCMX); short chain alcohols, such as
ethanol, propanol, and the like); antibiotics or antiseptics
(mupirocin, neomycin sulfate bacitracin, polymyxin B, 1-ofloxacin,
tetracyclines (chlortetracycline hydrochloride,
oxytetracycline-10hydrochloride and tetracycline hydrochloride),
clindamycin phosphate, gentamicin sulfate, metronidazole,
hexylresorcinol, methylbenzethonium chloride, phenol, quaternary
ammonium compounds, tea tree oil, and their pharmaceutically
acceptable salts and prodrugs), anti-inflammatory agents (e.g.,
suitable steroidal anti-inflammatory agents such as corticosteroids
such as hydrocortisone, hydroxyltriamcinolone alphamethyl
dexamethasone, dexamethasone-phosphate, beclomethasone
dipropionate, clobetasol valerate, desonide, desoxymethasone,
desoxycorticosterone acetate, dexamethasone, dichlorisone,
diflorasone diacetate, diflucortolone valerate, fluadrenolone,
fluclarolone acetonide, fludrocortisone, flumethasone pivalate,
fluosinol one acetonide, fluocinonide, flucortine butylester,
fluocortolone, fluprednidene (fluprednylidene) acetate,
flurandrenolone, halcinonide, hydrocortisone acetate,
hydrocortisone butyrate, methylprednisolone, triamcinolone
acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone,
difluorosone diacetate, fluradrenalone acetonide, medrysone,
amciafel, amcinafide, betamethasone, chlorprednisone,
chlorprednisone acetate, clocortelone, clescinolone, dichlorisone,
difluprednate, flucloronide, flunisolide, fluoromethalone,
fluperolone, fluprednisolone, hydrocortisone valerate,
hydrocortisone cyclopentylproprionate, hydrocortamate,
meprednisone, paramethasone, prednisolone, prednisone,
beclomethasone dipropionate, betamethasone dipropionate,
triamcinolone, and salts, nonsteroidal anti-inflammatory agents,
feverfew (Tanacetum parthenium), goji berry (Lycium barbarum), milk
thistle extract (Silybum marianum), amaranth oil (Amaranthus
cruentus), pomegranate (Punica granatum), yerbe mate (Ilex
paraguariensis leaf extract), white lily flower extract (Lilium
candidum), olive leaf extract (Olea europaea) and phloretin (apple
extract)); anti-mycotic/antifungal agents (e.g., miconazole,
econazole, ketoconazole, sertaconazole, itraconazole, fluconazole,
voriconazole, clioquinol, bifoconazole, terconazole, butoconazole,
tioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole,
undecylenic acid, haloprogin, butenafine, tolnaftate, nystatin,
ciclopirox olamine, terbinafine, amorolfine, naftifine, elubiol,
griseofulvin, and their pharmaceutically acceptable salts and
prodrugs; an azole, an allylamine, or a mixture thereof); external
analgesics (e.g., ibuprofen- or diclofenac; capsaicin, fentanyl,
and salts thereof such fentanyl citrate; paracetamol (as
acetaminophen); non-steroidal anti-inflammatory drugs (NSAIDs) such
as salicylates; opioid drugs such as morphine and oxycodone;
ibuprofen- or diclofenac-containing gel); anti-oxidants (e.g.,
sulfhydryl compounds and their derivatives (e.g., sodium
metabisulfite and N-acetyl cysteine), lipoic acid and dihydrolipoic
acid, resveratrol, lactoferrin; ascorbic acid, ascorbic acid
esters, and ascorbic acid derivatives (e.g., ascorbyl palmitate and
ascorbyl polypeptide); butylhydroxy anisole, butylated
hydroxytoluene (butylhydroxy toluene), retinoids (e.g., retinol and
retinyl palmitate), tocopherols (e.g., tocopherol acetate),
tocotrienols, and ubiquinone; cysteine, N-acetylcysteine, sodium
bisulfite, sodium metabisulfite, sodium formaldehydesulfoxylate,
acetone sodium bisulfite, tocopherols, and nordihydroguaiaretic
acid; extracts containing flavonoids and isoflavonoids and their
derivatives (e.g., genistein and diadzein); extracts containing
resveratrol and the like; grape seed, green tea, pine bark, and
propolis; plant-derived polyphenol antioxidants such as clove,
cinnamon, oregano, turmeric, cumin, parsley, basil, curry powder,
mustard seed, ginger, pepper, chili powder, paprika, garlic,
coriander, onion and cardamom; typical herbs such as sage, thyme,
marjoram, tarragon, peppermint, oregano, savory, basil and dill
weed)); depilatory agents (e.g., calcium thioglycolate or potassium
thioglycolate); vitamins (e.g., Vitamin A, Vitamin B, Vitamins C,
Vitamin E; either alpha, beta, gamma or delta tocopherols, niacin
or niacinamide) and vitamin salts or derivatives such as ascorbic
acid diglucoside and vitamin E acetate or palmitate; sunblock
(e.g., titanium dioxide) and/or sunscreen (e.g., inorganic
sunscreens such as titanium dioxide and zinc oxide; organic
sunscreens such as octyl-methoxy cinnamates, octyl salicylate,
homosalate, avobenzone); vasodilators (e.g., niacin); humectants
(e.g., glycerin); anti-aging agents (e.g., retinoids;
dimethylaminoathanol (DMAE), copper containing peptides); alpha
hydroxy acids or fruit acids and their precursors such as glycolic
acid, citric acid, lactic acid, malic acid, mandelic acid, ascorbic
acid, alpha-hydroxybutyric acid, alpha-hydroxyisobutyric acid,
alphahydroxyisocaproic acid, atrrolactic acid,
alpha-hydroxyisovaleric acid, ethyl pyruvate, galacturonic acid,
glucoheptonic acid, glucoheptono 1,4-lactone, gluconic acid,
gluconolactone, glucuronic acid, glucuronolactone, isopropyl
pyruvate, methyl pyruvate, mucic acid, pyruvic acid, saccharic
acid, saccaric acid 1,4-lactone, tartaric acid, and tartronic acid;
beta hydroxy acids such as beta-hydroxybutyric acid,
beta-phenyl-lactic acid, and beta-phenylpyruvic acid; zinc and zinc
containing compounds such as zinc oxides; botanical extracts such
as green tea, soy, milk thistle, algae, aloe, angelica, bitter
orange, coffee, goldthread, grapefruit, hoellen, honeysuckle, Job's
tears, lithospermum, mulberry, peony, puerarua, nice, and
safflower, and salts and prodrugs thereof); carotenoids, ceramides,
fatty acids, enzymes, enzyme inhibitors, minerals, steroids,
peptides, amino acids, botanical extracts, colorants, etc. The
substances may affect the skin in any of a variety of manners, such
as by moisturizing; enhancing skin tone or color (such as with
pigments); treating or at least mitigating various skin conditions
(such as dry or severe dry skin, eczema, psoriasis, atopic
dermatitis, allergic rashes, acne, blackheads, pustules, comedones,
rosacea, shingles, wrinkles, cold sores, herpes, corns, warts,
sunburn, insect bites, poison ivy, etc.); applying a mechanical
force (such as shrinkage) to smooth wrinkles; or, more generally,
treating or mitigating the symptoms and appearance of undesired
skin imperfections (such as under eye dark circle, redness of acne,
fine lines and wrinkles, post inflammatory hyperpigmentation (PIH),
redness, inflammation, cellulite, wrinkles, age spots, mottled
pigmentation, dark spots, liver spots, under eye puffiness);
removing unwanted facial or body hair; aiding in wound healing;
etc. For instance, lotions, creams, oils, and even masks may be
applied to skin to treat or otherwise to affect the skin. Such
personal or consumer healthcare substances are absorbed into the
skin generally following the principles of diffusion, under which
the rate of diffusion or transport across the skin is correlated
with the difference in active concentration on both sides of the
skin.
[0058] As mentioned earlier, the micromachining or microcasting
process for producing microneedle arrays are limited to producing
arrays of a single composition. In the present invention, the
personalized treatment uses stratum corneum piercing stratum
corneum piercing microneedles with more than one benefit agent. So,
the micromachining or microcasting process cannot be used.
[0059] The microneedle arrays of the present invention can be
produced using Additive Manufacturing technology. Additive
Manufacturing is a group of techniques used to quickly fabricate a
physical part or assembly using three-dimensional computer aided
design (CAD) data. Construction of the part or assembly is usually
done using "additive layer manufacturing" technologies such as 3D
printing. Additive manufacturing is a simple, effective, and
economically method of making microneedle arrays which
simultaneously delivering more than one benefit agent.
[0060] In general, the computer-aided-design-computer-aided
manufacturing CAD-CAM workflow is the traditional additive
manufacturing process. The process starts with the creation of
geometric data, either as a 3D solid using a CAD workstation, or 2D
slices using a scanning device. For Additive Manufacturing, this
data must represent a valid geometric model; namely, one whose
boundary surfaces enclose a finite volume, contains no holes
exposing the interior unless they are designed into the structure,
and do not fold back on themselves. In other words, the object must
have an "inside." The model is valid if for each point in 3D space
the algorithm can determine uniquely whether that point lies
inside, on, or outside the boundary surface of the model. CAD
post-processors will approximate the internal CAD geometric forms
with a simplified mathematical form, which in turn is expressed in
a specified data format which is a common feature in Additive
Manufacturing. To obtain the necessary motion control trajectories
to drive the Additive Manufacturing mechanism, the prepared
geometric model is typically sliced into layers, and the slices are
scanned into lines (producing a "2D drawing" used to generate
trajectory as in computer numerical control toolpath), resulting in
a layer-to-layer physical building process.
[0061] The 3D printing process enables the creation of different
sizes and shapes microneedles, as well as the ability to produce
microneedle arrays with more than one benefit agent. The location,
sharpness, cavitation, and material within individual microneedles
can be much more easily controlled with 3D printing than
micromachining or microcasting. Soft materials, hard materials, and
even liquids can be incorporated into individual microneedles. A
change in delivery profile can be designed into the system to make
a smart microneedle array. Incompatible compounds may also be built
into different sections of the microneedle array without cross
contamination fears.
[0062] The microneedles need to deliver active/drug at least 100
microns or deeper, but can be designed to have a variable
penetration at or above 20 microns. Different applications and uses
would need differing levels of penetration, solubility and design
features (size, shape, angle, solubility, etc.). In some cases, the
benefit agent may be dissolved into the microneedle material,
whereas in others it may be stored in a reservoir and delivered
through a microfluidic channel in the microneedle.
[0063] Although shown and described is what is believed to be the
most practical and preferred embodiments, it is apparent that
departures from specific designs and methods described and shown
will suggest themselves to those skilled in the art and may be used
without departing from the spirit and scope of the invention. The
present invention is not restricted to the particular constructions
described and illustrated, but should be constructed to cohere with
all modifications that may fall within the scope of the appended
claims.
* * * * *