U.S. patent application number 17/747287 was filed with the patent office on 2022-09-01 for microneedle system for administering liquid formulations.
The applicant listed for this patent is LTS LOHMANN THERAPIE-SYSTEME AG. Invention is credited to Karsten HEUSER, Heiko SPILGIES.
Application Number | 20220273928 17/747287 |
Document ID | / |
Family ID | 1000006344976 |
Filed Date | 2022-09-01 |
United States Patent
Application |
20220273928 |
Kind Code |
A1 |
HEUSER; Karsten ; et
al. |
September 1, 2022 |
MICRONEEDLE SYSTEM FOR ADMINISTERING LIQUID FORMULATIONS
Abstract
The present invention relates to a microneedle system (MNS) for
intradermally delivering solutions or formulations. The invention
relates to a microneedle system, comprising a cover element (1), an
active substance container (2), a frame (3), a microneedle array
(MNA) (4) and a base plate (5), wherein the microneedle array (MNA)
(4) is connected to the frame (3), and the base plate (5) has an
opening for receiving the microneedle array (4), the cover element
(1) and the base plate (5) are movably connected to one another,
the base plate (5) is joined to a surgical tape (6), and the frame
(3) and the base plate (5) can be linearly displaced with respect
to one another. The MNS according to the invention is suitable for
intradermally administering medicinal drugs, active substances,
pharmaceutical or cosmetic compositions or other substances to an
individual, and preferably to a patient, over an extended
period.
Inventors: |
HEUSER; Karsten; (Bad
Breisig, DE) ; SPILGIES; Heiko; (Berlin, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LTS LOHMANN THERAPIE-SYSTEME AG |
Andrenach |
|
DE |
|
|
Family ID: |
1000006344976 |
Appl. No.: |
17/747287 |
Filed: |
May 18, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15565025 |
Oct 6, 2017 |
11344708 |
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PCT/EP2016/057675 |
Apr 7, 2016 |
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17747287 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61M 2037/0061 20130101;
A61M 2037/003 20130101; A61M 2037/0023 20130101; A61M 2037/0053
20130101; A61B 17/205 20130101; A61M 37/0015 20130101 |
International
Class: |
A61M 37/00 20060101
A61M037/00; A61B 17/20 20060101 A61B017/20 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 7, 2015 |
EP |
15162636.3 |
Claims
1.-15. (canceled)
16. A microneedle system for intradermal delivery, comprising: i.)
a cover element over an active substance container, wherein the
active substance container is accommodated in a frame comprising a
microneedle array; and ii.) a base plate, wherein the base plate
has an opening for receiving the microneedle array, and the cover
element and the base plate are movably connected to one another via
a thread; iii.) the base plate is entirely or partially joined to a
surgical tape; and iv.) the frame and the base plate are movably
connected to one another, wherein the frame comprising a
microneedle array can be linearly displaced in the direction of the
opening of the base plate, and the base plate comprises at least
one opening element for opening the active substance container.
17. The microneedle system according to claim 16, wherein the frame
comprises one or more catch hooks, which can engage in recesses in
the base plate.
18. The microneedle system according to claim 16, wherein the base
plate has a peripheral projection, including an opening, which is
inwardly offset with respect to the base plate edge, and on the
outer side of the edge, a thread is provided, which is
complementary to the thread of the cover element.
19. The microneedle system according to claim 16, wherein the
bottom side of the cover element comprises a peripheral thread,
which is complementary to the thread of the base plate.
20. The microneedle system according to claim 16, wherein the cover
element comprises one or more markings, which define how the
microneedle system can be transferred from the storage position
into the delivery position.
21. The microneedle system according to claim 16, wherein the
surgical tape is protected by a protective film.
22. The microneedle system according to claim 16, wherein the
diameter of the microneedle system is at least 10 mm.
23. The microneedle system according to claim 16, wherein the
diameter of the microneedle system is at least 25 mm.
24. The microneedle system according to claim 16, wherein the
diameter of the microneedle system is at least 50 mm.
25. The microneedle system according to claim 16, wherein the
height of the microneedle system is no more than 30 mm.
26. The microneedle system according to claim 16, wherein the
height of the microneedle system is no more than 20 mm.
27. The microneedle system according to claim 16, wherein the
height of the microneedle system is no more than 10 mm.
28. The microneedle system according to claim 24, wherein the
height of the microneedle system is no more than 10 mm.
29. The microneedle system according to claim 16, wherein the
active substance container is a blow-fill-seal container or a
disposable container.
30. The microneedle system according to claim 16, wherein the
active substance container contains one or more substances,
medicinal drugs, active agents, solutions or (liquid)
formulations.
31. A method for producing the microneedle system according to
claim 16, a) an active substance container being provided; b) a
microneedle array being provided; and c) the active substance
container and the microneedle array being combined with the frame,
the base plate and the surgical tape to form the microneedle
system, wherein the cover element and the base plate are movably
connected to one another via a thread and a rotation of the cover
element relative to the base plate causes the active substance
container to be opened by an opening element.
32. The method according to claim 31, wherein the active substance
container being provided is produced by way of a blow-seal
method.
33. A method for intradermal delivery, comprising the following
steps: a) fixing a microneedle system according to claim to the
skin of the individual by way of the surgical tape; and b)
transferring the microneedle system from a storage position into
the delivery position.
34. The microneedle system according to claim 16, comprising the
active substance container, containing active substances in a
liquid formulation for use in the intradermal delivery.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Ser. No.
15/565,025, filed Oct. 6, 2017, which is a national stage
application (under 35 U.S.C. .sctn. 371) of PCT/EP2016/057675,
filed Apr. 7, 2016, which claims benefit of European Application
No. 15162636.3, filed Apr. 7, 2015, all of which are incorporated
herein by reference in their entirety.
[0002] The present invention relates to a microneedle system
(abbreviated as MNS) for intradermally delivering solutions or
formulations. The invention relates to a microneedle system,
comprising a cover element (1), an active substance container (2),
a frame (3), a microneedle array (abbreviated as MNA) (4) and a
base plate (5), wherein the microneedle array (MNA) (4) is
connected to the frame (3), and the base plate (5) has an opening
for receiving the microneedle array (4), the cover element (1) and
the base plate (5) are movably connected to one another, the base
plate (5) is joined to a surgical tape (6), and the frame (3) and
the base plate (5) can be linearly displaced with respect to one
another.
[0003] The MNS according to the invention is suitable for
intradermally administering medicinal drugs, active substances,
pharmaceutical or cosmetic compositions or other substances to an
individual, and preferably to a patient, over an extended
period.
BACKGROUND OF THE INVENTION
[0004] Microneedle systems and devices in which microneedle arrays
are used for the painless intradermal administration of medicinal
drugs are known from the prior art.
[0005] The skin consists of several layers. The outermost layer of
the skin, this being the stratum corneum, has known blocking
properties to prevent foreign substances from penetrating into the
body and the body's own substances from exiting the body. The
stratum corneum, which is a complex structure composed of compacted
horny cell residues having a thickness of approximately 10 to 30
micrometers, forms a watertight membrane for this purpose to
protect the body. The natural impermeability of the stratum corneum
prevents most pharmaceutical agents and other substances from being
administered through the skin as part of an intradermal
delivery.
[0006] As a result, various substances are therefore administered,
for example, by generating micropores or cuts in the stratum
corneum and feeding or delivering a medicinal drug into or beneath
the stratum corneum. In this way, it is also possible to administer
a number of medicinal drugs subcutaneously or intradermally or
intracutaneously, for example.
[0007] For use, microneedle systems (MNS) composed of a microneedle
array (MNA) and possibly further components require an element that
presses the microneedles (also referred to as skin penetration
elements) of the array (MNA) against the delivery site on the skin
so as to penetrate the stratum corneum and thereby establish a
fluid channel between the external medicinal drug reservoir (such
as a container) and the skin by way of the MNA. If a liquid
formulation is selected for the medicinal drug, an element that
opens the active substance container and, depending on the design,
also pushes the medicinal drug out of the active substance
container, is necessary in the MNS. Various embodiments are known
for implementing the former element, which generally employ a
mechanical energy store for opening the active substance container.
A syringe integrated into the MNS or a miniaturized pump, for
example, implements the pushing out of the active substance
container.
[0008] A corresponding simple microneedle system is described in WO
02/05889 A1. This device comprises a housing including an inside
active substance container in the form of a flexible bladder. The
flexible bladder is positioned in a cavity in the housing. The
cavity is covered by a cover member, which can be pressed downward
so as to press the flexible bladder against a microneedle array
situated on the bottom of the housing. This opens the active
substance container, and the liquid contained in the flexible
bladder flows to several microneedles.
[0009] DE 603 05 901 T2 discloses a device composed of a housing
and a cartridge. The cartridge comprises the container for the
active substance-containing solution and, in addition to the bottom
wall, comprises a lower outside wall that is spaced apart from the
bottom wall and includes an integrated needle array. The housing
comprises a base part, a peripheral side wall, and a cover member,
which can be pivoted between an open and a closed position and is
connected to the base part by a hinge, snap fit, interference fit
or friction fit. The microneedle system is assembled by positioning
the cartridge in the housing, wherein the cartridge is aligned in a
defined position in the housing by way of a notch. The microneedle
system is positioned on the patient's skin surface in such a way
that the needle array pierces the surface of the skin before the
cover member of the housing is pivoted into the closed position.
When the cover member is closed, the active substance container is
pierced. The cover member of the housing comprises a spring to
apply pressure to the cartridge and causes the active
substance-containing solution to be dispensed when the cover member
is closed. Furthermore, a wristband is necessary for fixation.
[0010] The devices and methods known from the prior art for
intradermally delivering active substances are only successful to a
limited degree.
[0011] The known microneedle systems have the disadvantage that
they apply a force to the MNA only during the brief use (several
seconds or less), and the MNA during the subsequent usage phase
(several minutes to several days) tends to detach again from the
skin. For many uses, however, it is necessary to ensure a lasting
force fit with the skin during the delivery or over an extended
period.
[0012] Many known microneedle systems moreover have the
disadvantage that applicators are needed, which are not an integral
part of the microneedle system, but must be provided as an
additional separate unit. For the intradermal delivery, an
embodiment that combines the MNS and delivery system in one unit is
desirable, wherein the design of the overall system, and in
particularly the height and the diameter, does not influence
comfortable use or wearing of the MNS.
[0013] All known devices comprising active substance containers
moreover consist of a combination of a microneedle array with a
syringe, a pump or a spring for dispensing the active
substance-containing solution. Due to the design, these devices are
inconvenient to use and complex to produce. A need exists for
devices that are easy to produce and use.
[0014] This object is achieved according to the invention by a
microneedle system (MNS), comprising a cover element (1), an active
substance container (2), a frame (3), a microneedle array (4), a
base plate (5) and a surgical tape (6) according to the
invention.
BRIEF DESCRIPTION OF THE FIGURES
[0015] FIG. 1: shows an exploded view of the integral parts of the
MNS according to the invention. In the illustrated exemplary
embodiment, the overall system has a maximum diameter of 50 mm in
terms of the surgical tape (6) and protective film (7) and a total
height of approximately 7 mm.
[0016] FIG. 2: shows the sectional view of the MNS in the storage
position; and
[0017] FIG. 3: shows the sectional view of the MNS in the delivery
position.
[0018] In the MNS according to the invention, the microneedle array
(4) is connected to the frame (3), preferably on the underside of
the frame (3), and the base plate (5) has an opening for receiving
the microneedle array (4).
[0019] The frame (3) can also be regarded as a mount for the
microneedle array (4) and is used to fix the microneedle array (4)
and to receive an active substance container (2).
[0020] The cover element (1) and the base plate (5) are movably
connected to one another, preferably via a thread. The base plate
(5) is furthermore entirely or partially joined to or provided with
a surgical tape (6), and the frame (3) and the base plate (5) can
be linearly displaced with respect to one another.
[0021] The MNS is preferably protected until use by a protective
film (7), in particular on the surgical tape (6).
[0022] In contrast to the microneedle systems known from the prior
art, the MNS according to the invention is thus substantially
composed of an active substance container, which can be joined to
the skin in one unit by way of a surgical tape. The MNS according
to the invention does not require an additional applicator, no
pump, syringe or spring. It is easy and cost-effective to produce.
The MNS can, but does not have to, be supplemented with further
integral parts. It is suitable for intradermally administering
medicinal drugs, active substances, pharmaceutical or cosmetic
compositions or other substances to an individual, and preferably
to a patient, over an extended period. The MNS according to the
invention is easy to handle and can be carried out directly by the
individual at home or at the point of care, for example as part of
self-medication by the patient or for cosmetic use. In particular,
the piercing of the microneedles into the skin is a routine process
and does not require checkups and monitoring by a physician or
supervision by medical staff. This is in particular advantageous
during extended or repeated deliveries since the patient or the
individual does not require repeated care by the medical staff or
over the extended period. This is possible since the needles of the
MNA can be easily introduced into the stratum corneum, where they
remain over an extended period, even without re-pressing, so that
the delivery of the desired amount of medicinal product, active
substance, pharmaceutical composition or other substances,
including directly by the patient or the individual, is ensured by
way of the MNS according to the invention.
[0023] The invention therefore relates to a microneedle system for
intradermal delivery, comprising:
[0024] i.) a cover element (1) over an active substance container
(2), wherein the active substance container (2) is accommodated in
a frame (3) comprising a microneedle array (4); and
[0025] ii.) a base plate (5), wherein the base plate (5) has an
opening for receiving the microneedle array (4), and the cover
element (1) and the base plate (5) are movably connected to one
another;
[0026] iii.) the base plate (5) is entirely or partially joined to
a surgical tape (6); and
[0027] iv.) the frame (3) and the base plate (5) are movably
connected to one another, wherein the frame (3) comprising a
microneedle array (4) can be linearly displaced in the direction of
the opening of the base plate (5).
[0028] Furthermore, the cover element (1) and the base plate (5)
are preferably movably connected to one another via a thread.
[0029] According to the invention, the term "intradermal delivery"
(synonym: "intracutaneous delivery") describes the administration
of substances via the MNA into the skin and requires the
microneedles to pierce the skin.
[0030] According to the invention, after fixation of the
microneedle system on the skin by way of a surgical tape (6), in a
first step the cover element (1) is rotated on the base plate (5)
via the thread and, in this way, the frame (3) comprising a
microneedle array (4) is moved in the direction of the opening of
the base plate (5).
[0031] In the course of this movement or stroke, the frame (3)
comprising a microneedle array (4) reaches the plane of the opening
of the base plate (5), wherein the protruding microneedles
penetrate into the skin. At the same time, the active substance
container (2), which was entrained, reaches one or more opening
elements (8) (mandrel or the like), so that the container breaks
open, and the solution or formulation is dispensed, and more
particularly into the provided MNA. The opening elements (8) are
provided in such a way that the opening elements (8) make contact
with and open the active substance container (2) as soon as the
microneedle array (4) reaches the plane of the opening of the base
plate (5) (referred to as the delivery position).
[0032] In a preferred embodiment of the invention, the frame (3) of
the microneedle system comprises at least one or more catch hooks
(9), which preferably protrude and can engage in the base plate
(5). The base plate (5) can comprise appropriate recesses (10). The
catch hooks (9) furthermore serve as engagement points for the
stroke out of the above-mentioned rotational movement of the cover
element (1) relate to the base plate (5).
[0033] The catch hooks (9) provide the frame (3) with a defined
position with respect to the base plate (5) and also prevent a
(full) rotation of the frame (3) or on the base plate (5). At the
same time, the catch hooks are formed on the frame (3), and the
recesses (10) are formed in the base plate (5), in such a way that
the frame (3) is movably mounted in the base plate (5).
[0034] Once the frame (3) is situated in the plane of the base
plate (5) or surgical tape (6), the MNA (4) is localized in the
opening of the base plate (5).
[0035] The frame (3) and the base plate (5) are movably connected
to one another, but can be linearly displaced with respect to one
another, wherein the catch hook or hooks (9) is or are to prevent a
rotational movement or a rotation of the frame (3) on the base
plate (5).
[0036] In a particularly preferred embodiment of the microneedle
system, the cover element (1) and the base plate (5) are movably
connected to one another via a thread. In a preferred embodiment of
the microneedle system, the active substance container is opened by
a quarter turn of the thread. The preferred angle of rotation is
90.degree.. Depending on the design, the angle of rotation can be
between 10.degree. and 350.degree.. It may be indicated to the user
when the maximum angle of rotation has been reached, which in the
simplest case takes place, for example, by a position marking at
the stop.
[0037] In a further preferred embodiment of the microneedle system,
the surgical tape (6) is protected by a protective film (7).
[0038] In a further preferred embodiment of the microneedle system,
the diameter of the microneedle system is at least 10 mm,
preferably at least 25 mm, and particularly preferably at least 50
mm.
[0039] In a further preferred embodiment of the microneedle system,
the height of the microneedle system is no more than 30 mm,
preferably no more than 20 mm, and particularly preferably no more
than 10 mm.
[0040] In a further preferred embodiment of the microneedle system,
the active substance container (2) is a blow-fill-seal container or
a disposable container.
[0041] In a further preferred embodiment of the microneedle system,
the active substance container (2) contains one or more substances,
medicinal drugs, active substances, solutions or (liquid)
formulations, in particular pharmaceutical active agents or
pharmaceutical compositions, in particular antibiotics, antiviral
active agents, analgesic drugs, anesthetics, appetite suppressants,
arthritis drugs, antidepressants, antihistamines, anti-inflammatory
agents, antineoplastic agents, vaccines, including DNA vaccines,
and the like, proteins, peptides or fragments thereof, nucleic
acids or parts thereof, as well as cosmetics, nutritional
supplements, sunscreens, insect repellents, radical scavengers,
hydrating agents and dyes.
[0042] The active substance container (2) preferably contains
solutions or (liquid) formulations comprising active agents or
auxiliary agents.
[0043] The term "solution" or "(liquid) formulation" shall mean
that one or more substances are involved, having at least such a
state of aggregation that the substance can be intradermally
delivered by the MNA (4) at room temperature within a predefined
delivery period. Suitable viscosities are values between 0 and 200
mPa*s.
[0044] The invention likewise relates to a method for producing a
microneedle system according to the invention, comprising the
following steps: [0045] a) providing an active substance container
(2), preferably produced by way of a blow-seal method; [0046] b)
providing a microneedle array (4); and [0047] c) combining the
active substance container (2) and the microneedle array (4) with
the frame (3), the base plate (5) and the surgical tape (6) to form
the microneedle system.
[0048] The invention also relates to a method for carrying out an
intradermal delivery, comprising the following steps: [0049] a)
fixing a microneedle system according to the invention to the skin
by way of the surgical tape (6); [0050] b) transferring the
microneedle system from a storage position (first position) into
the delivery position (second position), for example by rotating
the cover element (1) relative to the base plate (5).
[0051] A preferred embodiment of the invention relates to a method
for carrying out an intradermal delivery, comprising the following
steps: [0052] a) fixing a microneedle system, comprising: [0053]
i.) a cover element (1) over an active substance container (2),
wherein the active substance container (2) is accommodated in a
frame (3) comprising a microneedle array (4); and [0054] ii.) a
base plate (5), wherein the base plate (5) has an opening for
receiving the microneedle array (4), and the cover element (1) and
the base plate (5) are movably connected to one another; [0055]
iii.) the base plate (5) is entirely or partially joined to a
surgical tape (6); and [0056] iv.) the frame (3) and the base plate
(5) are movably connected to one another, wherein the frame (3)
comprising a microneedle array (4) can be linearly displaced in the
direction of the opening of the base plate (5), to the skin by way
of the surgical tape (6); and [0057] b) transferring the
microneedle system from a storage position (first position) into
the delivery position (second position), for example by rotating
the cover element (1) relative to the base plate (5), wherein the
active substance container (2) is opened by an opening element
(8).
[0058] The invention also relates to a method for intradermal
delivery, comprising the following steps: [0059] a) fixing a
microneedle system according to the invention to the skin by way of
the surgical tape (6); [0060] b) transferring the microneedle
system according to the invention from a storage position into the
delivery position, for example by turning the thread between the
cover element (1) and the base plate (5); and [0061] c) delivering
one or more substances into the selected region of the skin of an
individual.
[0062] The invention furthermore relates to the preparation of one
or more substances, medicinal drugs, active substances, solutions
or (liquid) formulations for the intradermal delivery in a
microneedle system according to the invention.
[0063] The MNS according to the invention can comprise one or more
MNAs (4) and one or more active substance containers (2). The MNS
according to the invention allows the stratum corneum to be pierced
painlessly and the microneedles to penetrate into the skin with
little force expenditure. The MNS according to the invention
particularly advantageously enables a constant force fit with the
skin, and allows a constant and lasting force fit between the skin
and the MNA (4) to be maintained during the delivery. The MNS
according to the invention is designed so as to first be applied to
the skin during use and fixed. The MNA (4) is in a first position,
this being the storage position. By rotating the cover element (1)
about the base plate (5), the frame (3) is linearly displaced with
respect to the base plate (5) (delivery mechanism). The MNA (4) is
moved from the storage position into the delivery position, while
the active substance container (2) is opened by an opening element
(8). The solution contained in the active substance container (2)
flows out of the active substance container (2) and into the MNA or
into the microneedles. In the delivery position, the microneedles
have pierced the stratum corneum and penetrated into the skin. The
liquid is intradermally delivered through the microneedles. By
actuating the delivery mechanism, constant tension is generated and
maintained between the skin and the MNS. As a result, a lasting
force fit exists between the MNS and the skin during the entire
intradermal delivery, so that the solution can also be administered
over an extended period. The MNA (4) remains in the skin during the
entire delivery, without the needles of the MNA (4) detaching from
the skin.
[0064] The cover element (1) has a shape and dimensions
complementary to those of the base plate (5). The cover element (1)
and the base plate (5) form a housing. The cover element (1)
preferably comprises a thread for locking the cover element (1) in
a closed position and for transferring the MNA from the storage
position into the delivery position.
[0065] The cover element (1) has an upper side and a bottom side,
wherein the bottom side is inwardly directed facing the base plate
(5), and preferably is in contact with the catch hooks (9). The
cover element (1) has the shape of a curved cap, for example. The
upper side of the cover element (1) preferably has a structure that
facilitates the transfer from the storage position into the
delivery position. For example, the upper side of the cover element
(1) has one or more grooves that prevent slipping. Furthermore, the
cover element (1) can comprise one or more markings, which define
how the MNS can be transferred from the storage position into the
delivery position. The bottom side comprises a peripheral thread,
which is complementary to the thread of the base plate (5), so that
the cover element (1) and the base plate (5) can be connected by
turns of the thread. At the same time, the turning of the thread
between the cover element (1) and the base plate (5) effectuates
the transfer of the MNA from the storage position into the delivery
position.
[0066] The cover element (1) and the base plate (5) form a housing,
having an inside cavity suitable for accommodating the frame (3),
the MNA (4) and the active substance container (2).
[0067] The base plate (5) has a peripheral projection, including an
opening, which is inwardly offset with respect to the base plate
edge. This projection serves as a spacer for generating the cavity.
On the outer side of the edge a thread is provided, which is
complementary to the thread of the cover element (1). To create the
cavity, the cover element (1) is placed on the base plate (5), and
the thread is not turned. The cavity delimited by the cover element
(1) and the base plate (5) is reduced by a partial or full turn of
the thread, or by multiple turns of the thread.
[0068] In the storage position, the MNA (4) is located above the
skin, and the microneedles have not penetrated into the stratum
corneum. During the transition into the delivery position, the
cavity is reduced, and the MNA (4) is lowered. In this process, the
microneedles penetrate into the skin, and preferably into the
stratum corneum or through the stratum corneum, and remain in this
position for the duration of the delivery or the duration of the
use of the MNS.
[0069] The frame (3) is dimensioned so as to be able to accommodate
the active substance container (2). The active substance container
(2) is preferably inserted or fixed in the frame (3) in such a way
that it is likewise linearly displaced with respect to the base
plate (5) during the turn of the thread.
[0070] The active substance container (2) is made of a material
that can be opened by at least one opening element (8). In
preferred embodiments of the invention, the active substance
container (2) is produced by way of a blow-fill-seal process.
Appropriate methods are known from the prior art and described, for
example, in Andrew. W. Goll (ISPE (2012) Knowledge Brief,
KB-0025-Jun12). Particularly preferred embodiments of the MNS
according to the invention relate to those in which a
blow-fill-seal container is used.
[0071] The MNS according to the invention furthermore comprises a
surgical tape (6) for attaching the MNS to the skin. The term
surgical tape (6) covers any attachment means suitable for
attaching the MNS to the skin surface. For example, the surgical
tape (6) can comprise a fixed carrier and a chemical or biological
substance, and preferably an adhesive. The surgical tape (6) may
also only comprise or consist of one or more chemical and/or
biological substances, wherein the one or more chemical and/or
biological substances are applied directly to the underside of the
base plate (5) and are suitable for attaching the MNS to the skin
surface. The surgical tape (6) may also comprise or consist of a
structured surface, for example a nanostructure, which is suitable
for attaching the MNS to the skin surface. The crucial aspect is
that the surgical tape (6) generates appropriately strong
attachment and fixation on the skin surface, so that a constant
force fit is created between the skin and the MNA (4), and this
force fit between the skin and the MNA (4) is maintained during the
delivery. The selection of the suitable surgical tape (6) depends
on the tightness of the skin in the particular region (for example
the abdomen or back), the amount of fatty tissue in and beneath the
stratum corneum in the particular region, the body mass index of
the individual, the age of the individual, the eating habits of the
individual (such as the intake of liquids), the lifestyle habits of
the individual (such as the sun exposure of the particular skin
region), and possibly other factors. Accordingly, a person skilled
in the art can select respectively suitable surgical tapes (6) for
different individuals or patients and/or skin regions. The
selection of the surgical tape (6) furthermore depends on the size
of the MNS and the materials used in the MNS and/or the weight of
these materials. Examples of suitable surgical tapes (6) include
customary commercially available (pressure-sensitive) adhesives on
a carrier, and possibly also comprising double-sided coatings.
[0072] The surgical tape (6) is securely joined to the base plate
(5). In a particular embodiment, the surgical tape (6) forms an
integral part of the base plate (5). The surgical tape (6) has one
or more recesses through which the microneedles of the MNA (4) pass
when the delivery position is being set and through which the
microneedles project during the delivery. The recessed region of
the surgical tape (6) may optionally be protected by a protective
film (7) or the like until the delivery or until fixation on the
skin.
[0073] According to the invention, the microneedle array (MNA) (4)
(synonym: microneedle path or microneedle pad) carries one or more
skin penetration elements. In some embodiments, the skin
penetration elements are disposed in an array of rows and columns,
which are spaced apart from one another by a substantially equal
distance. The actual length and spacing of the skin penetrating
elements may depend on the solution to be administered and the
administration site on the body of the individual or patient.
Typically, the skin penetration elements are needles, and
preferably hollow needles, which are fixed on or to a carrier and
protrude from this carrier. The skin penetrating elements are
disposed in an array that is provided for administering an
effective amount of a solution over a defined time period through
the skin of an individual/a patient. Typically, the microneedle
array (4) has a surface area of approximately 1 cm.sup.2 to
approximately 10 cm.sup.2, and preferably of approximately 2 to 5
cm.sup.2.
[0074] The skin penetration elements are preferably hollow needles,
which each have an axial passage and a chamfered, pointed outer tip
for piercing the skin of the individual/patient. The skin
penetration elements are attached in holes in a fixed carrier in
such a way that the solution is able to flow from the active
substance container (2) through the axial passages of the hollow
needles. The skin penetration elements can be attached in the
openings of the fixed carrier by way of a suitable adhesive or
interference fit. In an alternative embodiment, micro skin
penetration elements may be designed in one piece with the fixed
carrier. The skin penetration elements preferably each have one
chamfered, tapered tip and one axial passage, so as to establish a
fluid connection between the active substance container (2) and an
intradermal site in the skin of the patient.
[0075] The skin penetration elements preferably have a length that
is suitable for achieving the desired skin penetration depth. The
length and the thickness of the skin penetration elements are
selected based on the solution to be administered, the thickness of
the skin, and the target region in which the MNS is provided. In
embodiments of the invention, the skin penetration elements can be
microneedles, microtubes, solid or hollow needles, lancets and the
like. In a preferred embodiment, the skin penetration elements are
hollow needles or cannulas made of stainless steel. The size of the
needles is approximately 24 gauge to 50 gauge, and preferably
approximately 30 gauge to approximately 36 gauge, and in the most
preferred variant, the size is approximately 34 gauge. Smaller
needles penetrate the skin surface more easily than large needles
and are generally preferred. The needles are located in the MNS on
the underside of the frame (3) so as to provide an effective length
of approximately 50 micrometers to approximately 5000 micrometers.
In another embodiment, the needles have an effective length of
approximately 500 micrometers to approximately 3000 micrometers. In
further embodiments, the needles can have an effective length in
the range of approximately 1000 micrometers and 2000 micrometers.
Typically, the needles have an effective length of approximately
500 micrometers to approximately 1000 micrometers.
[0076] The integral parts of the MNS, and in particular the cover
element (1), the frame (3), the base plate (5), optionally the
carrier material of the MNA (4) and/or optionally the carrier
material of the surgical tape (6), can be made of a suitable
plastic material. Typically, non-reactive, inert, well-tolerated,
biocompatible, such as dermatologically tested, plastic material is
used for this purpose. Suitable plastic materials include
polyethylene, polypropylene, polyesters, polyamides,
polycarbonates, and copolymers thereof.
[0077] In the MNA (4), the skin penetration elements form an array
(which is to say an arrangement), for example in the form of rows
and columns spaced apart from one another. One, at least 2, more,
or a plurality of skin penetration elements may be provided in the
MNA (4), for example 10 to 1,000,000, preferably 50 to 100,000, and
particularly preferably 100 to 10,000 skin penetration elements.
The MNA (4) can, for example, be produced from a silicon wafer,
which is machined and etched so as to form the individual needles.
In alternative embodiments, the MNA (4) can be produced from
stainless steel, tungsten steel, and alloys of nickel, molybdenum,
chromium, cobalt and titanium. In further embodiments, the MNA (4)
can be produced from ceramic materials, glass, polymers, and other
non-reactive materials.
[0078] The array of skin penetration elements is typically disposed
in rows and columns; however, the skin penetration elements may be
disposed in other suitable patterns. The skin penetration elements
are preferably spaced sufficiently apart from one another, so that
the skin penetration elements are able to penetrate the skin to a
depth that is substantially uniform across the entire array,
without interfering with one another. The preferred penetration
depth of the needles is defined by the stratum corneum, which is
preferably completely or substantially completely pierced. In
preferred embodiments, the skin penetration elements penetrate into
the skin to a uniform depth and/or pierce the skin so as to
administer the solution at the selected skin depth, and reduce the
risk of leakage during the administration of the substance. The
number of skin penetration elements in the array may vary as a
function of the dimensions of the skin penetration elements, the
substance to be administered, and the penetration depth.
[0079] The MNS according to the invention can comprise one or more
active substance containers (2). The active substance containers
(2) can have differing volumes or be designed to be loaded with
differing volumes of solution. The selection of the volume is
dependent on the (active) substance to be administered, or the
agent to be administered, the selected formulation, the dosage, the
treatment regimen, and other factors. The delivery duration depends
on the volume of the active substance container (2), the (active)
substance to be administered, the selected formulation, the dosage,
the treatment regimen, the selected MNA (4) (such as the inside
diameter of the skin penetration elements), the properties of the
skin in the particular region, and other factors. For example, the
MNS is suitable for deliveries of 0.5 minute to 10 days, especially
5 minutes to 1 day, preferably 1 to 5 hours, and particularly
preferably approximately 2 hours. During this time, the MNS
according to the invention ensures a constant force fit between the
skin and the MNA (4), without the needles having to be
re-pressed.
[0080] One embodiment of the MNS according to the invention is
illustrated by way of example by the following figures and
examples.
EXAMPLE 1: COMPOSITION OF AN MNS ACCORDING TO FIG. 1
[0081] The active substance solution is located in a blow-fill-seal
container (2), which is situated in a frame (3). The MNA (4) is
connected to the underside of the frame (3). The frame (3) is
movably mounted in a base plate (5), the frame (3) and the base
plate (5) being linearly displaceable with respect to one another,
and the catch hooks on the frame (3) defining the stroke and
preventing a rotational movement. The base plate (5) is securely
joined to the surgical tape (6) and protected until use by a
protective film (7). The frame or cap (3) and the base plate (5)
are movably connected via a thread.
EXAMPLE 2: USE OF THE DELIVERY MECHANISM
[0082] Proceeding from the sectional view of the MNS in the storage
position according to FIG. 2, first the protective film (7) is
removed, and the MNS is fixed to the skin by way of the surgical
tape (6). A quarter turn of the thread of the cap (3) about the
base plate (5) causes the blow-fill-seal container, the frame (3)
and the MNA (4) to be linearly displaced with respect to the base
plate (5), and the active substance container (2) to be opened by
mandrels (opening elements (8)) on the base plate (5).
KEY
[0083] (1) cover element [0084] (2) active substance container
[0085] (3) frame [0086] (4) microneedle array [0087] (5) base plate
[0088] (6) surgical tape [0089] (7) protective film [0090] (8)
opening elements [0091] (9) catch hooks [0092] (10) base plate
recesses
[0093] Microneedle System for Administering Liquid Formulations
[0094] The present invention relates to a microneedle system
(abbreviated as MNS) for intradermally delivering solutions or
formulations. The invention relates to a microneedle system,
comprising a cover element (1), an active substance container (2),
a frame (3), a microneedle array (abbreviated as MNA) (4) and a
base plate (5), wherein the microneedle array (MNA) (4) is
connected to the frame (3), and the base plate (5) has an opening
for receiving the microneedle array (4), the cover element (1) and
the base plate (5) are movably connected to one another, the base
plate (5) is joined to a surgical tape (6), and the frame (3) and
the base plate (5) can be linearly displaced with respect to one
another.
[0095] The MNS according to the invention is suitable for
intradermally administering medicinal drugs, active substances,
pharmaceutical or cosmetic compositions or other substances to an
individual, and preferably to a patient, over an extended
period.
[0096] Background of the Invention
[0097] Microneedle systems and devices in which microneedle arrays
are used for the painless intradermal administration of medicinal
drugs are known from the prior art.
[0098] The skin consists of several layers. The outermost layer of
the skin, this being the stratum corneum, has known blocking
properties to prevent foreign substances from penetrating into the
body and the body's own substances from exiting the body. The
stratum corneum, which is a complex structure composed of compacted
horny cell residues having a thickness of approximately 10 to 30
micrometers, forms a watertight membrane for this purpose to
protect the body. The natural impermeability of the stratum corneum
prevents most pharmaceutical agents and other substances from being
administered through the skin as part of an intradermal
delivery.
[0099] As a result, various substances are therefore administered,
for example, by generating micropores or cuts in the stratum
corneum and feeding or delivering a medicinal drug into or beneath
the stratum corneum. In this way, it is also possible to administer
a number of medicinal drugs subcutaneously or intradermally or
intracutaneously, for example.
[0100] For use, microneedle systems (MNS) composed of a microneedle
array (NINA) and possibly further components require an element
that presses the microneedles (also referred to as skin penetration
elements) of the array (MNA) against the delivery site on the skin
so as to penetrate the stratum corneum and thereby establish a
fluid channel between the external medicinal drug reservoir (such
as a container) and the skin by way of the MNA, if a liquid
formulation is selected for the medicinal drug, an element that
opens the active substance container and, depending on the design,
also pushes the medicinal drug out of the active substance
container, is necessary in the MNS, Various embodiments are known
for implementing the former element, which generally employ a
mechanical energy store for opening the active substance container,
A syringe integrated into the MNS or a miniaturized pump, for
example, implements the pushing out of the active substance
container.
[0101] A corresponding simple microneedle system is described in WO
02/05889 A1. This device comprises a housing including an inside
active substance container in the form of a flexible bladder. The
flexible bladder is positioned in a cavity in the housing. The
cavity is covered by a cover member, which can be pressed downward
so as to press the flexible bladder against a microneedle array
situated on the bottom of the housing. This opens the active
substance container, and the liquid contained in the flexible
bladder flows to several microneedles.
[0102] DE 603 05 901 T2 discloses a device composed of a housing
and a cartridge. The cartridge comprises the container for the
active substance-containing solution and, in addition to the bottom
wall, comprises a lower outside wall that is spaced apart from the
bottom wall and includes an integrated needle array. The housing
comprises a base part, a peripheral side wall, and a cover member,
which can be pivoted between an open and a closed position and is
connected to the base part by a hinge, snap fit, interference fit
or friction fit. The microneedle system is assembled by positioning
the cartridge in the housing, wherein the cartridge is aligned in a
defined position in the housing by way of a notch. The microneedle
system is positioned on the patient's skin surface in such a way
that the needle array pierces the surface of the skin before the
cover member of the housing is pivoted into the closed position.
When the cover member is closed, the active substance container is
pierced. The cover member of the housing comprises a spring to
apply pressure to the cartridge and causes the active
substance-containing solution to be dispensed when the cover member
is closed. Furthermore, a wristband is necessary for fixation.
[0103] The devices and methods known from the prior art for
intradermally delivering active substances are only successful to a
limited degree.
[0104] The known microneedle systems have the disadvantage that
they apply a force to the NINA only during the brief use (several
seconds or less), and the MNA during the subsequent usage phase
(several minutes to several days) tends to detach again from the
skin. For many uses, however, it is necessary to ensure a lasting
force fit with the skin during the delivery or over an extended
period.
[0105] Many known microneedle systems moreover have the
disadvantage that applicators are needed, which are not an integral
part of the microneedle system, but must be provided as an
additional separate unit. For the intradermal delivery, an
embodiment that combines the MNS and delivery system in one unit is
desirable, wherein the design of the overall system, and in
particularly the height and the diameter, does not influence
comfortable use or wearing of the MNS.
[0106] All known devices comprising active substance containers
moreover consist of a combination of a microneedle array with a
syringe, a pump or a spring for dispensing the active
substance-containing solution. Due to the design, these devices are
inconvenient to use and complex to produce. A need exists for
devices that are easy to produce and use.
[0107] This object is achieved according to the invention by a
microneedle system (MNS), comprising a cover element (1), an active
substance container a frame (3), a microneedle array (4), a base
plate (5) and a surgical tape (6) according to claim 1 and the
dependent claims.
[0108] In the MNS according to the invention, the microneedle array
(4) is connected to the frame (3), preferably on the underside of
the frame (3), and the base plate (5) has an opening for receiving
the microneedle array (4).
[0109] The frame (3) can also be regarded as a mount for the
microneedle array (4) and is used to fix the microneedle array (4)
and to receive an active substance container (2).
[0110] The cover element (1) and the base plate (5) are movably
connected to one another, preferably via a thread. The base plate
(5) is furthermore entirely or partially joined to or provided with
a surgical tape (6), and the frame (3) and the base plate (5) can
be linearly displaced with respect to one another.
[0111] The MNS is preferably protected until use by a protective
film (7), in particular on the surgical tape (6).
[0112] In contrast to the microneedle systems known from the prior
art, the MNS according to the invention is thus substantially
composed of an active substance container, which can be joined to
the skin in one unit by way of a surgical tape. The MNS according
to the invention does not require an additional applicator, no
pump, syringe or spring. It is easy and cost-effective to produce.
The MNS can, but does not have to, be supplemented with further
integral parts. It is suitable for intradermally administering
medicinal drugs, active substances, pharmaceutical or cosmetic
compositions or other substances to an individual, and preferably
to a patient, over an extended period. The MNS according to the
invention is easy to handle and can be carried out directly by the
individual at home or at the point of care, for example as part of
self-medication by the patient or for cosmetic use. In particular,
the piercing of the microneedles into the skin is a routine process
and does not require checkups and monitoring by a physician or
supervision by medical staff. This is in particular advantageous
during extended or repeated deliveries since the patient or the
individual does not require repeated care by the medical staff or
over the extended period. This is possible since the needles of the
NINA can be easily introduced into the stratum corneum, where they
remain over an extended period, even without re-pressing, so that
the delivery of the desired amount of medicinal product, active
substance, pharmaceutical composition or other substances,
including directly by the patient or the individual, is ensured by
way of the MNS according to the invention.
[0113] The invention therefore relates to a microneedle system for
intradermal delivery, comprising:
[0114] i.) a cover element (I) over an active substance container
(2), wherein the active substance container (2) is accommodated in
a frame (3) comprising a microneedle array (4); and
[0115] ii.) a base plate (5), wherein the base plate (5) has an
opening for receiving the microneedle array (4), and the cover
element (I) and the base plate (5) are movably connected to one
another;
[0116] iii.) the base plate (5) is entirely or partially joined to
a surgical tape (6); and
[0117] iv.) the frame (4) and the base plate (6) are movably
connected to one another, wherein the frame (4) comprising a
microneedle array (5) can be linearly displaced in the direction of
the opening of the base plate (6).
[0118] Furthermore, the cover element (1) and the base plate (5)
are preferably movably connected to one another via a thread.
[0119] According to the invention, the term "intradermal delivery"
(synonym: "intracutaneous delivery") describes the administration
of substances via the MNA into the skin and requires the
microneedles to pierce the skin.
[0120] According to the invention, after fixation of the in
microneedle system on the skin by way of a surgical tape (6), in a
first step the cover element (1) is rotated on the base plate (5)
via the thread and, in this way, the frame (4) comprising a
microneedle array (4) is moved in the direction of the opening of
the base plate (5).
[0121] In the course of this movement or stroke, the frame (3)
comprising a microneedle array (4) reaches the plane of the opening
of the base plate (6), wherein the protruding microneedles
penetrate into the skin. At the same time, the active substance
container (2), which was entrained, reaches one or more opening
elements (8) (mandrel or the like), so that the container breaks
open, and the solution or formulation is dispensed, and more
particularly, into the provided MNA. The opening elements (8) are
provided in such a way that the opening elements (8) make contact
with and open the active substance container (2) as soon as the
microneedle array (4) reaches the plane of the opening of the base
plate (6) (referred to as the delivery position).
[0122] In a preferred embodiment of the invention, the frame (3) of
the microneedle system comprises at least one or more catch hooks
(9), which preferably protrude and can engage in the base plate
(5). The base plate (5) can comprise appropriate recesses (10). The
catch hooks (9) furthermore serve as engagement points for the
stroke out of the above-mentioned rotational movement of the cover
element (I) relate to the base plate (5).
[0123] The catch hooks (9) provide the frame (3) with a defined
position with respect to the base plate (5) and also prevent a
(full) rotation of the frame (3) or on the base plate (5). At the
same time, the catch hooks are formed on the frame (3), and the
recesses (10) are formed in the base plate (5), in such a way that
the frame (3) is movably mounted in the base plate (5).
[0124] Once the frame (3) is situated in the plane of the base
plate (5) or surgical tape (6), the NINA (4) is localized in the
opening of the base plate (5).
[0125] The frame (3) and the base plate (5) are movably connected
to one another, but can be linearly displaced with respect to one
another, wherein the catch hook or hooks (9) is or are to prevent a
rotational movement or a rotation of the frame (3) on the base
plate (5).
[0126] In a particularly preferred embodiment of the microneedle
system, the cover element (1) and the base plate (5) are movably
connected to one another via a thread. In a preferred embodiment of
the microneedle system, the active substance container is opened by
a quarter turn of the thread. The preferred angle of rotation is
90.degree.. Depending on the design, the angle of rotation can be
between 10.degree. and 350.degree.. It may be indicated to the user
when the maximum angle of rotation has been reached, which in the
simplest case takes place, for example, by a position marking at
the stop.
[0127] In a further preferred embodiment of the microneedle system,
the surgical tape (6) is protected by a protective film (7).
[0128] In a further preferred embodiment of the microneedle system,
the diameter of the microneedle system is at least 10 mm,
preferably at least 25 mm, and particularly preferably at least 50
mm.
[0129] In a further preferred embodiment of the microneedle system,
the height of the microneedle system is no more than 30 mm,
preferably no more than 20 mm, and particularly preferably no more
than 10 mm.
[0130] In a further preferred embodiment of the microneedle system,
the active substance container (2) is a blow-fill-seal container or
a disposable container.
[0131] In a further preferred embodiment of the microneedle system,
the active substance container (2) contains one or more substances,
medicinal drugs, active substances, solutions or (liquid)
formulations, in particular pharmaceutical active agents or
pharmaceutical compositions, in particular antibiotics, antiviral
active agents, analgesic drugs, anesthetics, appetite suppressants,
arthritis drugs, antidepressants, antihistamines, anti-inflammatory
agents, antineoplastic agents, vaccines, including DNA vaccines,
and the like, proteins, peptides or fragments thereof, nucleic
acids or parts thereof, as well as cosmetics, nutritional
supplements, sunscreens, insect repellents, radical scavengers,
hydrating agents and dyes.
[0132] The active substance container (2) preferably contains
solutions or (liquid) formulations comprising active agents or
auxiliary agents.
[0133] The term "solution" or "(liquid) formulation" shall mean
that one or more substances are involved, having at least such a
state of aggregation that the substance can be intradermally
delivered by the NINA (4) at room temperature within a predefined
delivery period. Suitable viscosities are values between 0 and 200
mPa*s.
[0134] The invention likewise relates to a method for producing a
microneedle system according to the invention, comprising the
following steps: [0135] a) providing an active substance container
(2), preferably produced by way of a blow-seal method; [0136] b)
providing a microneedle array (4); and [0137] c) combining the
active substance container (2) and the microneedle array (4) with
the frame (3), the base plate (5) and the surgical tape (6) to form
the microneedle system.
[0138] The invention also relates to a method for carrying out an
intradermal delivery, comprising the following steps: [0139] a)
fixing a microneedle system according to the invention to the skin
by way of the surgical tape (6); [0140] b) transferring the
microneedle system from a storage position (first position) into
the delivery position (second position), for example by rotating
the cover element (1) relative to the base plate (5).
[0141] A preferred embodiment of the invention relates to a method
for carrying out an intradermal delivery, comprising the following
steps: [0142] a) fixing a microneedle system, comprising: [0143]
i.) a cover element (I) over an active substance container (2),
wherein the active substance container (2) is accommodated in a
frame (3) comprising a microneedle array (4); and [0144] ii.) a
base plate (5), wherein the base plate (5) has an opening for
receiving the microneedle array (4), and the cover element (1) and
the base plate (5) are movably connected to one another; [0145]
iii.) the base plate (5) is entirely or partially joined to a
surgical tape (6); and [0146] iv.) the frame (4) and the base plate
(6) are movably connected to one another, wherein the frame (4)
comprising a microneedle array (5) can be linearly displaced in the
direction of the opening of the base plate (5), [0147] to the skin
by way of the surgical tape (6); and [0148] b) transferring the
microneedle system from a storage position (first position) into
the delivery position (second position), for example by rotating
the cover element (I) relative to the base plate (5), wherein the
active substance container (2) is opened by an opening element
(8).
[0149] The invention also relates to a method for intradermal
delivery, comprising the following steps: [0150] a) fixing a
microneedle system according to the invention to the skin by way of
the surgical tape (6); [0151] b) transferring the microneedle
system according to the invention from a storage position into the
delivery position, for example by turning the thread between the
cover element (1) and the base plate (5); and [0152] c) delivering
one or more substances into the selected region of the skin of an
individual.
[0153] The invention furthermore relates to the preparation of one
or more substances, medicinal drugs, active substances, solutions
or (liquid) formulations for the intradermal delivery in a
microneedle system according to the invention.
[0154] The MNS according to the invention can comprise one or more
MNAs (4) and one or more active substance containers (2). The MNS
according to the invention allows the stratum corneum to be pierced
painlessly and the microneedles to penetrate into the skin with
little force expenditure. The MNS according to the invention
particularly advantageously enables a constant force fit with the
skin, and allows a constant and lasting force fit between the skin
and the NINA (4) to be maintained during the delivery. The MNS
according to the invention is designed so as to first be applied to
the skin during use and fixed. The MNA (4) is in a first position,
this being the storage position. By rotating the cover element (1)
about the base plate (5), the frame (3) is linearly displaced with
respect to the base plate (5) (delivery mechanism). The MNA (4) is
moved from the storage position into the delivery position, while
the active substance container (2) is opened by an opening element
(8). The solution contained in the active substance container (2)
flows out of the active substance container (2) and into the MNA or
into the microneedles. In the delivery position, the microneedles
have pierced the stratum corneum and penetrated into the skin. The
liquid is intradermally delivered through the microneedles. By
actuating the delivery mechanism, constant tension is generated and
maintained between the skin and the MNS. As a result, a lasting
force fit exists between the MNS and the skin during the entire
intradermal delivery, so that the solution can also be administered
over an extended period. The MNA (4) remains in the skin during the
entire delivery, without the needles of the MNA (4) detaching from
the skin.
[0155] The cover element (1) has a shape and dimensions
complementary to those of the base plate (5), The cover element (1)
and the base plate (5) form a housing. The cover element (1)
preferably comprises a thread for locking the cover element (1) in
a closed position and for transferring the MNA from the storage
position into the delivery position.
[0156] The cover element (1) has an upper side and a bottom side,
wherein the bottom side is inwardly directed facing the base plate
(5), and preferably is in contact with the catch hooks (9). The
cover element (I) has the shape of a curved cap, for example. The
upper side of the cover element (1) preferably has a structure that
facilitates the transfer from the storage position into the
delivery position. For example, the upper side of the cover element
(1) has one or more grooves that prevent slipping. Furthermore, the
cover element (1) can comprise one or more markings, which define
how the MNS can be transferred from the storage position into the
delivery position. The bottom side comprises a peripheral thread,
which is complementary to the thread of the base plate (5), so that
the cover element (1) and the base plate (5) can be connected by
turns of the thread. At the same time, the turning of the thread
between the cover element (1) and the base plate (5) effectuates
the transfer of the MNA from the storage position into the delivery
position.
[0157] The cover element (1) and the base plate (5) form a housing,
having an inside cavity suitable for accommodating the frame (3),
the MNA (4) and the active substance container (2).
[0158] The base plate (5) has a peripheral projection, including an
opening, which is inwardly offset with respect to the base plate
edge. This projection serves as a spacer for generating the cavity.
On the outer side of the edge a thread is provided, which is
complementary to the thread of the cover element (1). To create the
cavity, the cover element (1) is placed on the base plate (5), and
the thread is not turned. The cavity delimited by the cover element
(1) and the base plate (5) is reduced by a partial or full turn of
the thread, or by multiple turns of the thread.
[0159] In the storage position, the MNA (4) is located above the
skin, and the microneedles have not penetrated into the stratum
corneum. During the transition into the delivery position, the
cavity is reduced, and the NINA (4) is lowered. In this process,
the microneedles penetrate into the skin, and preferably into the
stratum corneum or through the stratum corneum, and remain in this
position for the duration of the delivery or the duration of the
use of the MNS.
[0160] The frame (3) is dimensioned so as to be able to accommodate
the active substance container (2). The active substance container
(2) is preferably inserted or fixed in the frame (4) in such a way
that it is likewise linearly displaced with respect to the base
plate (6) during the turn of the thread.
[0161] The active substance container (2) is made of a material
that can be opened by at least one opening element (8). In
preferred embodiments of the invention, the active substance
container (2) is produced by way of a blow-fill-seal process.
Appropriate methods are known from the prior art and described, for
example, in Andrew. W. Goll (ISPE (2012) Knowledge Brief,
KB-0025-Jun12). Particularly preferred embodiments of the MNS
according to the invention relate to those in which a
blow-fill-seal container is used.
[0162] The MNS according to the invention furthermore comprises a
surgical tape (6) for attaching the MNS to the skin. The term
surgical tape (6) covers any attachment means suitable for
attaching the MNS to the skin surface. For example, the surgical
tape (6) can comprise a fixed carrier and a chemical or biological
substance, and preferably an adhesive. The surgical tape (6) may
also only comprise or consist of one or more chemical and/or
biological substances, wherein the one or more chemical and/or
biological substances are applied directly to the underside of the
base plate (5) and are suitable for attaching the MNS to the skin
surface. The surgical tape (6) may also comprise or consist of a
structured surface, for example a nanostructure, which is suitable
for attaching the MNS to the skin surface. The crucial aspect is
that the surgical tape (6) generates appropriately strong
attachment and fixation on the skin surface, so that a constant
force fit is created between the skin and the MNA (4), and this
force fit between the skin and the NINA (4) is maintained during
the delivery. The selection of the suitable surgical tape (6)
depends on the tightness of the skin in the particular region (for
example the abdomen or back), the amount of fatty tissue in and
beneath the stratum corneum in the particular region, the body mass
index of the individual, the age of the individual, the eating
habits of the individual (such as the intake of liquids), the
lifestyle habits of the individual (such as the sun exposure of the
particular skin region), and possibly other factors. Accordingly, a
person skilled in the art can select respectively suitable surgical
tapes (6) for different individuals or patients and/or skin
regions. The selection of the surgical tape (6) furthermore depends
on the size of the MNS and the materials used in the MNS and/or the
weight of these materials. Examples of suitable surgical tapes (6)
include customary commercially available (pressure-sensitive)
adhesives on a carrier, and possibly also comprising double-sided
coatings.
[0163] The surgical tape (6) is securely joined to the base plate
(5). In a particular embodiment, the surgical tape (6) forms an
integral part of the base plate (5). The surgical tape (6) has one
or more recesses through which the microneedles of the MNA (4) pass
when the delivery, position is being set and through which the
microneedles project during the delivery. The recessed region of
the surgical tape (6) may optionally be protected by a protective
film (7) or the like until the delivery or until fixation on the
skin.
[0164] According to the invention, the microneedle array (MNA) (4)
(synonym: microneedle path or microneedle pad) carries one or more
skin penetration elements. In some embodiments, the skin
penetration elements are disposed in an array of rows and columns,
which are spaced apart from one another by a substantially equal
distance. The actual length and spacing of the skin penetrating
elements may depend on the solution to be administered and the
administration site on the body of the individual or patient.
Typically, the skin penetration elements are needles, and
preferably hollow needles, which are fixed on or to a carrier and
protrude from this carrier. The skin penetrating elements are
disposed in an array that is provided for administering an
effective amount of a solution over a defined time period through
the skin of an individual/a patient. Typically, the microneedle
array (4) has a surface area of approximately 1 cm.sup.2 to
approximately 10 cm.sup.2, and preferably of approximately 2 to 5
cm.sup.2.
[0165] The skin penetration elements are preferably hollow needles,
which each have an axial passage and a chamfered, pointed outer tip
for piercing the skin of the individual/patient. The skin
penetration elements are attached in holes in a fixed carrier in
such a way that the solution is able to flow from the active
substance container (2) through the axial passages of the hollow
needles. The skin penetration elements can be attached in the
openings of the fixed carrier by way of a suitable adhesive or
interference fit. In an alternative embodiment, micro skin
penetration elements may be designed in one piece with the fixed
carrier. The skin penetration elements preferably each have one
chamfered, tapered tip and one axial passage, so as to establish a
fluid connection between the active substance container (2) and an
intradermal site in the skin of the patient.
[0166] The skin penetration elements preferably have a length that
is suitable for achieving the desired skin penetration depth. The
length and the thickness of the skin penetration elements are
selected based on the solution to be administered, the thickness of
the skin, and the target region in which the MNS is provided. In
embodiments of the invention, the skin penetration elements can be
microneedles, microtubes, solid or hollow needles, lancets and the
like. In a preferred embodiment, the skin penetration elements are
hollow needles or cannulas made of stainless steel. The size of the
needles is approximately 24 gauge to 50 gauge, and preferably
approximately 30 gauge to approximately 36 gauge, and in the most
preferred variant, the size is approximately 34 gauge, Smaller
needles penetrate the skin surface more easily than large needles
and are generally preferred. The needles are located in the MNS on
the underside of the frame (3) so as to provide an effective length
of approximately 50 micrometers to approximately 5000 micrometers.
In another embodiment, the needles have an effective length of
approximately 500 micrometers to approximately 3000 micrometers. In
further embodiments, the needles can have an effective length in
the range of approximately 1000 micrometers and 2000 micrometers.
Typically, the needles have an effective length of approximately
500 micrometers to approximately 1000 micrometers.
[0167] The integral parts of the MNS, and in particular the cover
element (1), the frame (3), the base plate (5), optionally the
carrier material of the MNA (4) and/or optionally the carrier
material of the surgical tape (6), can be made of a suitable
plastic material. Typically, non-reactive, inert, well-tolerated,
biocompatible, such as dermatologically tested, plastic material is
used for this purpose. Suitable plastic materials include
polyethylene, polypropylene, polyesters, polyamides,
polycarbonates, and copolymers thereof.
[0168] In the MNA (4), the skin penetration elements form an array
(which is to say an arrangement), for example in the form of rows
and columns spaced apart from one another, One, at least 2, more,
or a plurality of skin penetration elements may be provided in the
MNA (4), for example 10 to 1,000,000, preferably 50 to 100,000, and
particularly preferably 100 to 10,000 skin penetration elements.
The MNA (4) can, for example, be produced from a silicon wafer,
which is machined and etched so as to form the individual needles.
In alternative embodiments, the MNA (4) can be produced from
stainless steel, tungsten steel, and alloys of nickel, molybdenum,
chromium, cobalt and titanium. In further embodiments, the MNA (4)
can be produced from ceramic materials, glass, polymers, and other
non-reactive materials.
[0169] The array of skin penetration elements is typically disposed
in rows and columns; however, the skin penetration elements may be
disposed in other suitable patterns. The skin penetration elements
are preferably spaced sufficiently apart from one another, so that
the skin penetration elements are able to penetrate the skin to a
depth that is substantially uniform across the entire array,
without interfering with one another. The preferred penetration
depth of the needles is defined by the stratum corneum, which is
preferably completely or substantially completely pierced. In
preferred embodiments, the skin penetration elements penetrate into
the skin to a uniform depth and/or pierce the skin so as to
administer the solution at the selected skin depth, and reduce the
risk of leakage during the administration of the substance. The
number of skin penetration elements in the array may vary as a
function of the dimensions of the skin penetration elements, the
substance to be administered, and the penetration depth.
[0170] The MNS according to the invention can comprise one or more
active substance containers (2). The active substance containers
(2) can have differing volumes or be designed to be loaded with
differing volumes of solution. The selection of the volume is
dependent on the (active) substance to be administered, or the
agent to be administered, the selected formulation, the dosage, the
treatment regimen, and other factors. The delivery duration depends
on the volume of the active substance container (2), the (active)
substance to be administered, the selected formulation, the dosage,
the treatment regimen, the selected MNA (4) (such as the inside
diameter of the skin penetration elements), the properties of the
skin in the particular region, and other factors. For example, the
MNS is suitable for deliveries of 0.5 minute to 10 days, especially
5 minutes to 1 day, preferably 1 to 5 hours, and particularly
preferably approximately 2 hours. During this time, the MNS
according to the invention ensures a constant force fit between the
skin and the MNA (4), without the needles having to be
re-pressed.
[0171] One embodiment of the MNS according to the invention is
illustrated by way of example by the following figures and
examples.
[0172] FIG. 1: shows an exploded view of the integral parts of the
MNS according to the invention. In the illustrated exemplary
embodiment, the overall system has a maximum diameter of 50 mm in
terms of the surgical tape (6) and protective film (7) and a total
height of approximately 7 mm.
[0173] FIG. 2: shows the sectional view of the MNS in the storage
position; and
[0174] FIG. 3: shows the sectional view of the MNS in the delivery
position.
EXAMPLE 1: COMPOSITION OF AN MNS ACCORDING TO FIG. 1
[0175] The active substance solution is located in a blow-fill-seal
container (2), which is situated in a frame (3). The MNA (4) is
connected to the underside of the frame (3). The frame (3) is
movably mounted in a base plate (5), the frame (3) and the base
plate (5) being linearly displaceable with respect to one another,
and the catch hooks on the frame (4) defining the stroke and
preventing a rotational movement. The base plate (5) is securely
joined to the surgical tape (6) and protected until use by a
protective film (7). The cap (3) and the base plate (5) are movably
connected via a thread.
EXAMPLE 2: USE OF THE DELIVERY MECHANISM
[0176] Proceeding from the sectional view of the MNS in the storage
position according to FIG. 2, first the protective film (7) is
removed, and the MNS is fixed to the skin by way of the surgical
tape (6). A quarter turn of the thread of the cap (3) about the
base plate (5) causes the blow-fill-seal container, the frame (3)
and the MNA (4) to be linearly displaced with respect to the base
plate (5), and the active substance container (2) to be opened by
mandrels (opening elements (8)) on the base plate (5).
* * * * *