U.S. patent application number 16/723896 was filed with the patent office on 2020-05-07 for delivery system and process.
The applicant listed for this patent is POLYPHARMA PTY LTD. Invention is credited to Craig ANDREWS, David John BULL, Donald MARTIN, Harry UNGER, Mark UNGER.
Application Number | 20200139098 16/723896 |
Document ID | / |
Family ID | 38831334 |
Filed Date | 2020-05-07 |
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United States Patent
Application |
20200139098 |
Kind Code |
A1 |
UNGER; Harry ; et
al. |
May 7, 2020 |
DELIVERY SYSTEM AND PROCESS
Abstract
A delivery system, including a polymeric material for storing
molecules and/or particles wherein the molecules and/or particles
are substantially bound to said polymeric material through: the
polymeric material comprising an electrical charge and the
molecules and/or particles comprising an electrical charge opposite
to the electrical charge of the polymeric material; and/or the
molecules and/or particles being physically trapped within pores of
the polymeric material; and an ultrasonic transducer configured to
apply an ultrasonic signal to the polymeric material to release the
molecules and/or particles and to transport the released molecules
and/or particles through the polymeric material to a surface for
delivery to an entity.
Inventors: |
UNGER; Harry; (Melbourne,
AU) ; UNGER; Mark; (Melbourne, AU) ; MARTIN;
Donald; (Killara, AU) ; BULL; David John;
(Riverview, AU) ; ANDREWS; Craig; (Mosman,
AU) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
POLYPHARMA PTY LTD |
Toorak |
|
AU |
|
|
Family ID: |
38831334 |
Appl. No.: |
16/723896 |
Filed: |
December 20, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14502405 |
Sep 30, 2014 |
10518073 |
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16723896 |
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12304960 |
Apr 29, 2009 |
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PCT/AU2007/000843 |
Jun 15, 2007 |
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14502405 |
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60814093 |
Jun 15, 2006 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61N 1/327 20130101;
A61M 37/0076 20130101; A61K 47/32 20130101; A61F 9/0017 20130101;
A61K 9/0009 20130101; A61N 1/30 20130101; A61M 37/0092
20130101 |
International
Class: |
A61M 37/00 20060101
A61M037/00; A61N 1/32 20060101 A61N001/32; A61K 47/32 20060101
A61K047/32; A61K 9/00 20060101 A61K009/00; A61F 9/00 20060101
A61F009/00 |
Claims
1. A delivery system, comprising: a polymeric material for storing
molecules and/or particles wherein said molecules and/or particles
are substantially bound to said polymeric material through: i) said
polymeric material comprising an electrical charge and said
molecules and/or particles comprising an electrical charge opposite
to said electrical charge of said polymeric material; and/or ii)
said molecules and/or particles being physically trapped within
pores of said polymeric material; and an ultrasonic transducer
configured to apply an ultrasonic signal to said polymeric material
to release said molecules and/or particles and to transport said
released molecules and/or particles through said polymeric material
to a surface for delivery to an entity.
2. A system as claimed in claim 1, said molecules and/or particles
being physically trapped within pores of said polymeric
material.
3. A system as claimed in claim 1, further comprising an electric
field generator configured to apply an electric field to said
polymeric material to enhance the rate and/or amount of release of
said molecules and/or particles from said polymeric material.
4. A system as claimed claim 1 wherein said polymeric material
comprises a cross-linked polymer, an electro-conductive polymer, an
electro-constrictive polymer, agarose or a hydrogel.
5. A system according to claim 4 wherein said polymeric material is
a gel.
6. A system as claimed in claim 5, wherein said polymeric material
comprises agarose.
7. A system as claimed claim 1 wherein said entity is a biological
tissue.
8. A system as claimed in claim 7, wherein said molecules are
molecules of a therapeutic agent for delivery to said biological
tissue, or said particles contain a therapeutic agent for delivery
to said biological tissue.
9. A system as claimed in claim 8, wherein said agent comprises one
or more drugs, hormones, antibodies, liposomes, and/or
peptides.
10. A system as claimed in claim 7, wherein said biological tissue
is mucosal tissue.
11. A system as claimed in claim 10, wherein said biological tissue
is an eye or ocular adnexae, buccal or gingival mucosa and teeth,
anal or vaginal mucosa, or skin.
12. A system as claimed in claim 11, wherein said biological tissue
is an eye, and said molecules and/or particles are delivered to one
or more parts of said eye including cornea, limbus, sclera, retina,
choroid and uveal tract.
13. A system as claimed in claim 1 wherein said molecules comprise
an ink or dye for printing or marking said entity.
14. A system as claimed in claim 13, comprising means for
controlling said ultrasonic signal to determine a depth of said
printing or marking in said entity.
15. A system as claimed in claim 1, wherein the system is
configured so that, when in contact with said entity, said
ultrasonic signal enhances delivery of said molecules and/or
particles into said entity by sonophoresis.
16. A system as claimed in claim 1, wherein said means for applying
an ultrasonic signal includes at least one ultrasonic transducer
coupled to said polymeric material.
17. A system as claimed in claim 1, wherein the system is a
hand-held device.
18. A system as claimed in claim 1, wherein the system comprises a
removable delivery component incorporating said polymeric
material.
19. A system as claimed in claim 18, wherein said delivery
component also comprises one or more ultrasonic transducers.
20. A system as claimed in claim 18, wherein said delivery
component is a single-use disposable component of the system.
Description
FIELD
[0001] The present invention relates to a delivery system and
process, and in particular to a process and device for delivering
nanoparticles and/or molecules such as drugs, peptides, and/or
hormones to biological tissues, or inks or dyes to a variety of
materials, including paper and skin.
BACKGROUND
[0002] The delivery and incorporation of molecules such as drugs,
hormones, peptides or dyes into inert or biological materials can
be achieved by a number of mechanisms. For inert materials, cost
and quality of delivery is required. In biological systems, such as
animals and humans, issues of safety of delivery are also
important. Delivery of drugs into animals or humans can occur
either orally, by injection at the site, or systemically. Many
drugs require injection to achieve the desired therapeutic outcome.
However, for some conditions and diseases, the risks associated
with injection can outweigh the benefits.
[0003] Injection also requires a higher level of skill. Injection
in areas of greater sensitivity and risk, also often require
sterile conditions and more involved patient care. For example, to
deliver a steroid drug to the back of the eye for treatment of
age-related macular degeneration requires injection into the eye
with a high risk of intraocular infection and retinal detachment,
the most common side-effects associated with injecting therapeutic
agents directly into the eye.
[0004] It is desired to provide a delivery process and system and a
delivery component for the system that alleviate one or more of the
above difficulties, or at least provide a useful alternative.
SUMMARY
[0005] In accordance with the present invention, there is provided
a delivery process, including: [0006] applying an electric field to
a material to release molecules and/or particles substantially
bound within said material; and [0007] applying an ultrasonic
signal to said material to transport said molecules and/or
particles through said material to a surface for delivery to an
entity placed in contact with said surface.
[0008] Preferably, said material includes a polymeric material or a
ceramic material.
[0009] Preferably, said polymeric material includes at least one of
an electro-conductive polymer and a cross-linked polymeric gel.
[0010] Advantageously, said cross-linked polymeric gel may be a
hydrogel.
[0011] Advantageously, said molecules may include one or more drugs
for delivery to biological tissues.
[0012] Advantageously, said molecules may be contained within
particles substantially bound within said material.
[0013] Advantageously, said particles may include
nanoparticles.
[0014] Preferably, said biological tissues include mucosal
tissues.
[0015] Advantageously, said biological tissues may include an eye
or ocular adnexae, buccal or gingival mucosa and teeth, anal or
vaginal mucosa, or skin.
[0016] Advantageously, said nanoparticles may incorporate one or
more drugs, hormones, and/or peptides or other molecules for
delivery to biological tissues.
[0017] Advantageously, said molecules may include an ink or dye for
printing or marking said external entity.
[0018] Advantageously, the process may include controlling an
intensity of said ultrasonic signal to determine a depth of said
printing or marking in said entity.
[0019] Advantageously, said entity may include skin.
[0020] Advantageously, the process may include applying said
molecules or nanoparticles to said material to substantially bind
said molecules or nanoparticles within said material prior to the
application of said electric field.
[0021] The present invention also provides a system having
components for executing the steps of any one of the above
processes.
[0022] The present invention also provides a device having
components for executing the steps of any one of the above
processes.
[0023] In accordance with the present invention, there is also
provided a delivery system, including: [0024] a material for
storing molecules and/or nanoparticles by substantially binding
said molecules and/or nanoparticles to said material; [0025] means
for applying an electric field to said material to release said
molecules and/or nanoparticles; and [0026] means for applying an
ultrasonic signal to said material to transport said molecules
and/or nanoparticles through said material to a surface for
delivery to an entity.
[0027] Preferably, said material includes a polymeric material or a
ceramic material.
[0028] Preferably, said polymeric material includes at least one of
an electro-conductive polymer and a cross-linked polymeric gel.
[0029] Advantageously, said cross-linked polymeric gel may include
a hydrogel.
[0030] Preferably, said means for applying an ultrasonic signal
includes at least one ultrasonic transducer attached to said
polymeric material or a ceramic material.
[0031] Advantageously, said polymeric material may include an
electro-conductive polymer and a cross-linked polymeric gel, said
electro-conductive polymer being disposed between said cross-linked
polymeric gel and said ultrasonic transducer; wherein said
molecules or nanoparticles are released from said
electro-conductive polymer and transported to a surface of said
cross-linked polymeric gel for delivery to said entity.
[0032] Advantageously, said molecules may include one or more
drugs, hormones, peptides and/or other molecules for delivery to a
biological tissue.
[0033] Preferably, said biological tissue include a mucosal
tissue.
[0034] Advantageously, said biological tissue may include an eye or
ocular adnexae, buccal or gingival mucosa and teeth, anal or
vaginal mucosa, or skin.
[0035] Preferably, said surface of said cross-linked polymeric gel
is shaped to match a corresponding shape of a biological
tissue.
[0036] Advantageously, said entity may include an eye, and
cross-linked polymeric gel may include an annular skirt for
placement under an eyelid of said eye.
[0037] Preferably, said system includes an annular delivery
component defining an opening, the annular delivery component
including an annular housing attached to said annular skirt, the at
least one ultrasonic transducer including one or more piezoelectric
transducer elements disposed about an opening of said annular
housing, the opening being adapted to expose a portion of an eye
during delivery of said molecules and/or nanoparticles to an
annular portion of said eye disposed about said portion.
[0038] Advantageously, the system may include an optically
transparent membrane that contacts the exposed portion of the eye
during said delivery.
[0039] Preferably, said material is also disposed within said
housing.
[0040] Advantageously, said annular delivery component may be
disposable.
[0041] Advantageously, said nanoparticles may incorporate one or
more drugs, hormones, and/or peptides for delivery to biological
tissues.
[0042] Advantageously, the disposable annular delivery component
may include an electrode to detect drug level.
[0043] Advantageously, the electrode may also be adapted to deliver
electrical energy to said electro-conductive polymer.
[0044] Preferably, the system includes a handle rotatably coupled
to said disposable annular delivery component.
[0045] Preferably, said handle and disposable annular delivery
component are mutually coupled by coupling arms extending from said
handle to corresponding openings located at substantially opposing
sides of said annular delivery component
[0046] Preferably, the system includes a power supply for said at
least one ultrasonic transducer, the power supply being disposed
within said handle.
[0047] Preferably, said power supply is electrically coupled to
said at least one ultrasonic transducer via electrodes of
respective ones of said coupling arms.
[0048] Advantageously, the disposable annular delivery head may
include an electronic circuit for simultaneous delivery of
electrical energy to the one or more ultrasonic transducer elements
and to the electro-conductive polymer.
[0049] Advantageously, the amount of electrophoresis and
sonophoresis can be independently controlled by the DC and AC
components in the applied signal.
[0050] Advantageously, said molecules may include an ink or dye for
printing or marking said external entity.
[0051] Advantageously, the system may include means for controlling
said ultrasonic signal to determine a depth of said printing or
marking.
[0052] Advantageously, said external entity may include skin.
[0053] Advantageously, the system may include means for providing
an electrical signal to said annular delivery component, said
electrical signal having a DC component and an AC component, said
annular delivery component including means for separating said DC
component and said AC component from said electrical signal, for
generating said electric field from said DC component, and for
generating said ultrasonic signal from said AC component.
[0054] In accordance with the present invention, there is also
provided a delivery component for use with a delivery system,
including: [0055] a material for storing molecules and/or
nanoparticles by substantially binding said molecules and/or
nanoparticles to said material; [0056] means for applying an
electric field to said material to release said molecules and/or
nanoparticles; and [0057] means for applying an ultrasonic signal
to said material to transport said molecules and/or nanoparticles
through said material to a surface of said delivery component for
delivery to an entity.
BRIEF DESCRIPTION OF THE DRAWINGS
[0058] Preferred embodiments of the present invention are
hereinafter described, by way of example only, with reference to
the accompanying drawings, wherein:
[0059] FIG. 1 is a schematic diagram of a first preferred
embodiment of a delivery system;
[0060] FIG. 2 is a schematic diagram of a second preferred
embodiment of a delivery system;
[0061] FIG. 3 is a flow diagram of a preferred embodiment of a
delivery process;
[0062] FIG. 4 is a computer-generated image of a third preferred
embodiment of a hand-held delivery system or device comprising a
handle component and a disposable applicator component or head;
[0063] FIG. 5 is a computer-generated image illustrating the
application of the delivery device to a patient's eye in
preparation for eye surgery;
[0064] FIG. 6 is a computer-generated image illustrating an
alternative form of handle component for the delivery system;
[0065] FIG. 7 is an exploded perspective view of the applicator
component of the delivery system;
[0066] FIG. 8 is a perspective view of the assembled disposable
applicator component;
[0067] FIG. 9 is schematic cross-sectional side view of the
applicator component;
[0068] FIG. 10 is an equivalent electrical circuit diagram of the
applicator component;
[0069] FIG. 11 is a schematic diagram of an electrochemical cell
used to measure the delivery of dye molecules from an
electro-conductive polymer;
[0070] FIG. 12 is a graph showing the amount of dye released as a
function of time with and without ultrasonic stimulation;
[0071] FIG. 13 is a graph of the amount of dye released as a
function of time under the influence of an electric field, with and
without simultaneous ultrasonic stimulation;
[0072] FIGS. 14 to 16 are each fluorescence (left-hand panel) and
optical phase-contrast microscopy (right-hand panel) images of
sectioned rabbit eyes following intravitreal injection of Avastin;
the fluorescence images indicating the presence of Avastin;
[0073] FIGS. 17 to 19 are similar to FIGS. 14 to 16, but for
non-invasive delivery of Avastin under ultrasonic stimulation of a
hydrogel;
[0074] FIG. 20 is a schematic diagram of an experimental
arrangement for demonstrating the stimulated release of gold
nanoparticles under ultrasonic stimulation;
[0075] FIG. 21 is a graph of photo diode output as a function of
time, illustrating the enhanced transport of gold nanoparticles
resulting from application of an ultrasonic signal; and
[0076] FIG. 22 is a side view illustrating the application of the
applicator component of FIGS. 4 to 10 to the eye of a patient.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0077] As shown in FIG. 1, a delivery apparatus or system includes
a storage material 102 to which an ultrasonic transducer 104 is
attached via an electrically conductive film 105. A DC voltage
source 106 connected to the electrically conductive film 105 allows
an electric field to be generated in the storage material 102. A
signal generator 108 connected to the ultrasonic transducer 104
controls the ultrasonic signal generated by the ultrasonic
transducer 104 and transmitted into the storage material 102.
[0078] The storage material 102 is preferably an electro-conductive
polymer, but can alternatively be a cross-linked polymeric gel
material. The polymeric gel material may be a hydrogel containing
water, or may not contain water. The storage material 102 can be an
electro-constrictive polymer.
[0079] The delivery system uses a delivery process as shown in FIG.
3 to deliver molecules and/or particles stored within the storage
material 102 to an exposed surface 110 of the storage material 102
for delivery to an entity 112 placed in contact with that surface
110, as described below. The molecules may be drugs, hormones,
and/or peptides or other molecules suitable for delivery to
biological tissue. The molecules may also be coated by lipids, in
which case they are referred to as liposomes. The particles are
preferably of nanoscale dimensions to enhance their transport, and
accordingly are hereinafter referred to as nanoparticles. However,
it should be understood that the delivery process and system can be
applied to larger particles if desired, providing that such
particles have sufficient mobility through the storage material 102
during use of the process, as described below, to provide a useful
flux of those particles to the delivery surface 110. In particular,
the delivery of nanoparticles can be used to deliver drugs, as
described in Takeuchi H, Yamamoto H, Kawashima Y (2001),
Mucoadhesive nanoparticulate systems for peptide drug delivery, Adv
Drug Rev, 47:39-54. Processes for forming polymer-coated
nanoparticles are also described in Cui F, Qian F, Yin C (2006),
Preparation and characterisation of mucoadhesive polymer-coated
nanoparticles, Int J Pharm. 316:154-161.
[0080] As shown in FIG. 3, the delivery process begins at step 302
by storing within the storage material 102 molecules and/or
nanoparticles to be delivered. The molecules and/or nanoparticles
can be introduced into the storage material 102 using a standard
syringe or can be incorporated within the storage material 102
during its formation, although it will be apparent to those skilled
in the art that other methods can alternatively be used. In any
case, the molecules and/or nanoparticles can be stored within the
storage material 102 while it is configured as shown in FIG. 1 or
it may be so configured at a later time, as described below. The
molecules and/or nanoparticles have a net electrical charge which
causes them to be substantially bound within the storage material
102. Whether the net electric charge is positive or negative
depends upon the nature and type of the particular
electro-conductive polymer or polymeric gel used. For example, the
most preferred electro-conductive polymer is polypyrrole, which has
a positively charged polymer matrix that selectively binds
negatively charged molecules and/or nanoparticles. The preferred
polymeric gel is cross-linked hydroxyethyl methacrylate, which is
capable of binding either positively or negatively charged
molecules or nanoparticles, depending on the nature of the
crosslinking agent and the polarity of the polymer gel matrix.
However, in addition to binding based on the charge of the
molecules of nanoparticles, polymer gels are also porous and are
capable of binding by physical entrapment within their pores. If an
electro-constrictive polymer is used as the storage material 102,
the electric field causes a reduction in the volume of the
electro-constrictive polymer, thereby further enhancing the
transport of the molecules and/or nanoparticles from the
electro-constrictive polymer.
[0081] Having stored the molecules and/or nanoparticles within the
storage material 102, the storage material 102 can be stored for
subsequent use and may be provided to another party for use with
that party's delivery system. In either case, when it is desired to
deliver the stored molecules and/or nanoparticles to an entity, the
storage material 102 is configured as shown in FIG. 1 (if it is not
already so configured). At step 304, an electric field is
established within the storage material 102 by way of the voltage
source 106, which typically generates DC voltages up to about +1.5
VDC. A typical distance from the applied DC voltage to the external
entity 112 is about 10 mm, producing an electric field of about
150V/m. In an alternative embodiment, the electric field is pulsed
by an alternating voltage (typically varying between about -0.5V
and +0.6V) to produce pulsatile release of the stored molecules
and/or nanoparticles. The alternating voltage is preferably in the
form of a symmetrical 3-second square wave having a frequency of
about 0.3 Hz. In either embodiment, the electric field releases the
bound molecules and/or nanoparticles stored within the storage
material 102, allowing them to diffuse and/or otherwise be
transported through the storage material 102.
[0082] At step 306, an ultrasonic signal (typically of 40 kHz) is
generated in the storage material 102 by way of the signal
generator 108 typically providing a peak-to-peak voltage of 20 V to
the ultrasonic transducer 104. This provides an acoustic flux of
approximately 200 mW cm.sup.-2. The ultrasonic signal greatly
increases the mobility of the released molecules and/or
nanoparticles (a phenomenon referred to as sonophoresis),
effectively transporting them to the delivery surface 110 of the
storage material 102, thus allowing them to be delivered to an
external entity 112 contacted by the delivery surface 110 of the
storage material 102. Additionally, the ultrasonic signal is
transmitted through the storage material 102 to the surface of the
entity 112, where it can also enhance the permeability of that
surface.
[0083] Although the electric field has been described above as
being applied prior to the application of the ultrasonic signal, it
will be apparent to those skilled in the art that it is not
necessary that the electric field precede the application of the
ultrasonic signal, but may alternatively be applied or otherwise
controlled at the same time as the ultrasonic signal in order to
control the release and/or transport of the stored molecules and/or
nanoparticles.
[0084] In a second preferred embodiment, as shown in FIG. 2, the
storage material 202 is an electro-conductive polymer, and a
cross-linked polymeric gel material 204 is applied to the surface
of the storage material 202 opposite to the ultrasonic transducer
104 to provide a biocompatible surface for delivery to biological
tissues. As with the first preferred embodiment described above,
the polymeric gel material 204 may or may not contain water. In
this second preferred embodiment, the molecules and/or
nanoparticles released from the storage material 202 are
transported through the polymeric gel 204 for delivery to an
external entity 112 placed in contact with the otherwise exposed
surface of the polymeric gel 204 opposite to the storage material
202. The electro-conductive polymer 202 and the polymeric gel 204
can be bonded together by a variety of methods, including use of an
adhesive, treatment of the polymers 202, 204 with a plasma, use of
a chemical reaction to cause cross linking of the polymers 202, 204
together, use of a chemical reaction to bond the polymers together
without causing cross-linking, or the physical proximity and
surface treatments of the polymers causing absorption of the
polymers to each other. It should be understood the representation
of FIG. 2 is schematic, and the polymeric gel material 204 is
typically substantially thinner than shown.
[0085] The delivery process and systems can be used for a wide
variety of applications, including both internal and external drug
delivery, and printing, marking, or otherwise labelling animate or
inanimate entities.
[0086] In a third preferred embodiment, as shown in FIG. 4, the
delivery system is provided in the form of a handheld device 400
for the non-invasive delivery of molecules to the anterior or
posterior segments of the eye. The molecules may include (i)
anaesthetic compounds, (ii) antibiotic compounds, (iii)
non-steroidal anti-inflammatory drugs (NSAIDs), (iv) steroid drugs,
and/or (v) peptides. The delivery device 400 has two major
components: a reusable handle 402, and a disposable applicator head
404. The handle 402 is provided in two forms, only one of which is
capable of being sterilised in an autoclave.
[0087] The disposable applicator head 404 is preferably provided
separately in a sterile form, packaged in a bubble-package 406. The
applicator head 404 is generally annular in shape and includes two
opposed and radially outwardly directed cylindrical openings into
which correspondingly shaped and inwardly directed projections 408
of the handle 402 are inserted to pivotally couple the applicator
head 404 to the handle 402. This arrangement allows the applicator
head 404 to pivot about the securing projections 408 to facilitate
alignment to the eye. However, the applicator head 404 could
alternatively be coupled to the handle by way of an articulated
coupling that provides additional degrees of freedom for mating the
applicator head 404 to the eye. The applicator head 404 contains a
storage material 708 in the form of a polymer gel or an
electro-conductive polymer that stores the desired molecules and/or
nanoparticles for delivery to the eye, as shown in FIG. 5. If the
storage material 708 is an electro-conductive polymer, the voltage
generated by a voltage source located within the handle 402 induces
an electrochemical electrostatic, and/or electro-constrictive-based
release of the stored molecules and/or nanoparticles otherwise
bound to the electro-conductive polymer 708. This release is
further enhanced when return current from the eye itself forms part
of the electrical circuit, thereby driving the released molecules
and/or nanoparticles into the eye by ionophoresis or phonophoresis,
as described in Tyle P, Agrawala P. "Drug Delivery by
Phonophoresis", Pharmaceutical Research, 6(5):355-361, 1989) ("Tyle
and Agrawala"). The ultrasonic energy transmitted from the
applicator head 504 to the eye enhances the diffusion of the
molecules and/or nanoparticles, through the storage material 708
for delivery to the eye. Furthermore, the ultrasound is also
transmitted to the eye itself, thereby enhancing the permeability
of the eye tissues during delivery, a phenomenon known as
sonophoresis. The delivery of the molecules and/or nanoparticles,
to the anterior and posterior segments of the eye is thus assisted
by the ultrasound. The electrically induced release of the stored
molecules and/or nanoparticles from the electro-conductive polymer
708 allows the rate and total amount of the released and hence
delivered molecules and/or nanoparticles to be controlled by
controlling the duration and magnitude of the electric voltage
applied to the storage material 708. For example, in response to
pressing a 412 button on the handle 402, the delivery system 400
can be configured to apply a fixed (or selected) DC or AC voltage
to the storage material 708 for a fixed (or selected) period of
time, corresponding to a fixed (or selected) fluence or dosage of
the delivered molecules and/or nanoparticle.
[0088] As shown in FIGS. 4 to 8, the disposable applicator head 404
is generally annular in shape, defining a central hole 410 of
diameter 11 mm. The applicator head itself 404 is provided in a
range of external diameters from 15 mm to 20 mm to deliver
molecules and/or nanoparticles to targeted sites on the eye. For
example, a 15 mm diameter applicator head is used for delivery only
to the cornea and limbus areas, whereas a 20 mm diameter applicator
head is used to target both the cornea/limbus areas as well as the
insertion of the extraocular muscles. It can be desirable to target
the extraocular muscles to immobilise the eye in addition to
anaesthetising the eye (cornea and limbus).
[0089] As shown in FIG. 5, the delivery device 400 is applied to
the eye 502 of a patient, and can be used to deliver an anaesthetic
compound into the anterior and posterior segments of the eye 502
during eye surgery. The central opening or hole 410 through the
applicator head 404 allows a surgeon to accurately align and
position the applicator head 404 to be centred with respect to the
cornea and the eye-pupil by being able to view the cornea and
eye-pupil through the central opening in the applicator head 404.
Although the central opening 410 is shown as passing right through
the applicator head 404, it is preferred that the opening be closed
at the delivery end by a thin, optically transparent polymer
membrane that contacts the eye 502 during delivery (in a manner
analogous to a contact lens).
[0090] FIGS. 7 and 8 are respectively exploded and assembled views
of the major components of the applicator head 404, omitting (for
reasons of clarity) details such as the electrical contacts to the
power supply located in the device handle 402. As shown in FIG. 7,
the applicator head 404 includes a piezoelectric transducer having
four piezoelectric transducer elements 702 distributed about the
central hole 410. In an alternative embodiment (not shown), only a
single annular-shaped piezoelectric transducer element is used. In
either embodiment, the electrical contact to the piezoelectric
transducer is included within an electrically conductive housing
712, as described below. A part-spherical, annular metal contact
ring 704 provides the support and the electrical contact for the
storage material 708 which is in contact with the surface of the
contact ring 704. Thus the electrical contact for the piezoelectric
transducer is separate and insulated from the electrical contact
for the storage material 708, as described below. The contact ring
704 includes two metal locating arms 706 extending orthogonally
from the contact ring to locate the storage material 708
therebetween. The contact ring 704 is disposed between the
piezoelectric element 702 and the storage material 708, which as
described above can be either a polymeric gel or an
electro-conductive polymer. A moulded polymeric gel skirt 710
provides the biocompatible delivery surface in contact with the
eye, and the peripheral skirt is slid underneath the patient's
eyelid during use, as shown in FIG. 22. By forming the skirt from
an electrically conductive material, or by forming an electrically
conductive surface coating on the skirt, a return path for
electrical current is provided. The bottom face or delivery surface
714 of the moulded gel skirt 710 is generally concave in shape to
fit the anterior eye surface, and as described above preferably
includes a thin, optically transparent membrane of the gel, located
over the central opening 501.
[0091] Finally, an electrically conductive housing 712 is provided
to encase the piezoelectric elements 702, the ring contact 704 and
the electro-conductive polymer 708 to provide an integral
applicator head 504, as shown assembled in FIG. 8. As described
above, the applicator head 504 can be sold or otherwise provided
separately from the remainder of the delivery device, as a
disposable (or possibly rechargeable) component.
[0092] FIG. 8 is a cross-sectional side view of the annular
applicator head 404, showing how the various components are
electrically coupled. The electrical interface between the
disposable annular applicator head and the device handle provided
by two radially directed electrodes 902, 904 of opposite electrical
polarities located within the cylindrical openings of the
applicator head 404, as described above. A first electrode 902 of
these two electrodes 902, 904 is cylindrical in shape and projects
from the outer housing 712, to which it is electrically connected.
A second electrode 904 of these two electrodes 902, 904 includes an
outwardly directed cylindrical portion projecting from the housing
712 and a disc-shaped portion disposed between the piezoelectric
transducers 702 on one side and an annular disc-shaped electrical
insulator 906 on the other. These electrodes 902, 904 form
electrical connections with corresponding mating electrodes at the
ends of the inwardly directed projections 408 of the device handle
402.
[0093] The electrodes 902, 904 simultaneously supply electrical
energy to both the piezoelectric transducers 702 and the storage
material 708 as a DC-biased high-frequency AC signal.
High-frequency acoustic energy is transmitted through the gel into
the eye in the following manner: the electrodes 501, 502 connect
directly across and deliver high-frequency AC energy to the
piezoelectric transducer(s) 702, which convert this electrical
energy into acoustic energy. The resulting acoustic energy is then
coupled through the annular disc-shaped portion of the second
electrode 904, the electrical insulator 906 and an annular
disc-shaped intermediate electrode 908 into the
electro-conductive/nanoparticle polymer 708 and the cross-linked
gel 710 into the patient's eye. As the piezoelectric transducers
702 are electrically insulating, they do not provide any
substantial electrical path for DC current.
[0094] DC electrical energy is transmitted through the gel 710 into
the eye in the following manner: current is conducted through the
second electrode 904, through a resistor 910 into the intermediate
electrode 908. Note the insulator 906 prevents an alternate current
path through the transducer interface. The high frequency AC
component of the applied signal is dramatically reduced by a
low-pass filter formed by the resistor 910 and a capacitor 912
electrically connected between the intermediate electrode 908 and
the grounded housing 712 (electrically coupled to the patient's eye
502), as will be apparent from the equivalent circuit diagram of
FIG. 10. The result of this filtering effect is to substantially
remove the DC or very low frequency AC component of the electrical
signal applied to the second electrode 502. This DC component is
then passed through the electro-conductive/electro-constrictive
polymer 402 and through the cross-linked gel 404 into the patient's
eye 502, transporting nanoparticles with it by iontophoresis, as
described above. The patient return current path is via the housing
712, the current returning via the patient's eyelid.
[0095] In this embodiment, the AC and DC components of the
electrical signal applied to the disposable annular delivery head
can be independently selected or controlled by the power supply
located within the handle 402 to independently control the levels
of electrophoresis/iontophoresis, sonophoresis and
electro-constriction (if an electroconstriction polymer is used as
the storage material) in the electro-conductive gel.
[0096] Another advantage of this arrangement is the ability to
determine the condition of the storage material 708 and the amount
of drugs or other stored species remaining in the storage material
708, because the amount of free ions in suspension can readily be
measured by the resultant current that flows when a low-frequency
AC voltage is applied to the first and second electrodes 902, 904.
The amount of DC across the capacitor 912 can be controlled by a DC
offset or by the values of the R-C network. As the return current
path is via the patient's eyelid, there is no need for additional
electrodes to complete the patient circuit.
[0097] FIG. 6 shows an alternative form of handle 602 for use with
the applicator heads 404, and it will be apparent that a wide
variety of different handle types can be used with the applicator
heads 404. For example, not only can handles be provided in
different shapes and sizes for different types of users and/or
applications, but also different power supplies can be provided
within these different handles. For example, the simplest type of
power supply might include a simple battery with an on-off button
that simply connects and disconnects the battery directly to the
applicator head 404. Conversely, a more complex power supply might
be rechargeable and include selectable and/or programmable DC
and/or AC voltages, allowing sophisticated users to select
different signal magnitudes, frequencies, and waveforms suited to
particular applications. For example, the power supply could be
pre-configured for one or more predetermined types of applicator
head with particular combinations of drugs and polymers so that the
user could select what dosage of drug is to be delivered and the
device could power the applicator head with a suitable signal and
then generate an indication (for example, an audible signal) when
the desired dosage should have been delivered or absorbed by a
particular type of biological tissue.
[0098] The handheld delivery devices described above provide means
for non-invasive drug delivery to the eye that overcome the risks
associated with injection into the eye. It provides a painless,
rapid and accurate means of delivering local anaesthetic,
antibiotic, and/or anti-inflammatories to the eye for surgery. It
facilitates a safe and relatively comfortable delivery of drugs
targeted for the retina that would otherwise require injection into
or around the eye, or delivered systemically, exposing the patient
to potential unwanted side effects,
[0099] Although the handheld delivery device 400 described above is
particularly suited for delivery of drugs and other molecules to
the eye, it will be apparent that the delivery surface 714 of the
device need not be annular and can alternatively be shaped to fit
the contours of other body parts or biological tissues to which it
is desired to deliver drugs and/or other molecules. For example,
the delivery surface 714 could be shaped to fit the teeth and/or
jaw bones for delivery of molecules to the buccal or gingival
mucosa and teeth, or shaped to fit the contours of the anus or
vagina for delivery of molecules to the anal or vaginal mucosa, or
shaped for transdermal delivery of molecules. Additionally, the
delivery component or head may include an electrode to detect drug
levels. That electrode may be the same electrode used to deliver
electrical energy to the storage material, or may be a separate
electrode.
[0100] Alternatively, the delivery systems described above can be
used to deliver one or more electrically charged chemical
compounds, including a dye or ink that carries an electric charge,
or is contained within a particle that carries an electric charge.
The dye or ink can be deposited at a desired depth below the
surface of the entity to which the dye or ink is applied, which may
include almost any material, and in particular may include paper,
plastic, or skin. In this application, the depth of the deposit is
determined by the intensity and/or duration of the ultrasonic
signal, and the release of the ink or dye can be controlled by
controlling the electric field applied to the storage material.
[0101] When applied to skin, the ultrasonic signal also enhances
the permeability of the skin, and hence the transport of the ink or
dye into the skin. For example, a temporary tattoo lasting for a
relatively short period of time can be produced on the skin of an
individual by using a relatively low power ultrasonic signal to
deposit the ink or dye within the outer most epidermal layer of the
cells in the skin. In contrast, a tattoo can be made to last for a
relatively long period of time ("a permanent tattoo") by using an
ultrasonic signal of relatively high power to deposit the ink or
dye in the dermal layer of cells in the skin. Temporary tattoos can
be useful for a variety of applications, including applications in
the cosmetic industry, for example. Permanent tattoos can be used
to provide an efficient and painless means for identifying domestic
or experimental animals. In either case, a significant advantage of
the processes described herein is that the ink or dye can be
deposited within the skin without physically penetrating the skin
by any part of the delivery device or system. This non-invasive
process thus reduces the risk of infection and/or
contamination.
Example 1
[0102] As shown in FIG. 11, an electrochemical cell 1100 was
constructed by filling a plastic UV cuvette 1102 with a PBS buffer.
The PBS buffer (3 ml) is a phosphate buffered saline having a pH of
.about.7.4 at 25.degree. C. and contains 0.01 M phosphate buffer,
0.0027 M potassium chloride and 0.137 M sodium chloride. An Ag/AgCl
(saturated NaCl) reference electrode 1104 was partially inserted
into the PBS buffer. An auxiliary electrode 1106 formed from
stainless steel mesh of dimensions 4.times.0.8 cm.sup.2 was
attached to one side of the cuvette, and a working electrode 1108
was attached to the opposite side of the cuvette 1102. The working
electrode 1108 was prepared by forming a polypyrrole film (of
dimensions 0.8.times.0.8 cm.sup.2) on one end of gold mylar
substrate was prepared from aqueous 0.2 M pyrrole containing 0.1 M
sulforhodamine B dye as the supporting electrolyte. The amount of
polypyrrole was controlled by applying a constant current density
of 1.0 mA/cm.sup.2 to the solution for 6 minutes. This as-prepared
polypyrrole film was then throughout rinsed with Milli-Q water and
then dried in air. A piece of stainless steel mesh was used to make
the electrical contact to the gold mylar at another end. According
to total consumed charge for the growth of polypyrrole, the amount
of dye in the polypyrrole film was estimated at .about.198
.mu.g.
[0103] The working electrode 1108 and an ultrasound transducer 1110
were respectively attached to the inner and outer faces of one of
the walls of the plastic UV cuvette 1102, as shown. The ultrasound
transducer 1110 was supplied with a 15 V (peak to peak at 40 Hz)
square-wave AC voltage by a function generator (not shown). A
magnetic stirrer 1112 at the base of the cuvette 1102 rotated at
.about.90 RPM.
[0104] The cell 1100 was placed in a MultiSpec-1501 UV-VIS
spectrophotometer from Shimadzu Corporation, which was used to
collect UV-VIS spectra from 500 nm to 800 nm with a collection time
interval of 0.1 minutes. The resulting UV-VIS spectra were used to
determine the amount of dye released from the polypyrrole film.
[0105] FIG. 12 is a graph showing the amount of sulforhodamine B
dye in .mu.g as a function of time in minutes under various
conditions. The line 1202 shows the release of dye from polypyrrole
with no electrical or ultrasonic stimulation; i.e., by natural
diffusion. In contrast, the top line 1204 represents the release of
dye with ultrasound stimulation, which clearly increases the rate
of release by about a factor of two. In the initial linear regime
over the first few minutes, the rate of release under natural
diffusion was about 0.2 .mu.g/min, and with ultrasound was 0.33
.mu.g/min. After 180 minutes, the total amount of dye released was
5.2 .mu.g and 9.9 .mu.g. The effect of ultrasound was confirmed by
an intermediate line 1206 in which the dye was initially released
under natural diffusion, and at approximately 50 minutes the
ultrasound transducer 1110 was powered, which dramatically
increased the rate of release, as shown by the arrow 1208 in FIG.
12. However, in all cases the final amount of release dye in each
case was less than 5% of the total amount of dye in the polymer
film.
[0106] The effect of a pulsed electric field on the release of dye
was demonstrated by applying a symmetrical, three second period
square-wave AC signal ranging between -500 mV and +600 mV (vs.
Ag/AgCl). The lower data set 1302 in FIG. 13 shows the rate of
release of the dye during the electrical stimulation as described
above. In comparison with FIG. 12, it is clear that the electrical
stimulation greatly enhances the release of dye from polypyrrole,
with the rate of release in the first five minutes being .about.4.4
.mu.g/min. As shown by the second data set 1304 the rate of release
is also greatly affected when the electrical stimulation is
combined with the ultrasound stimulation. Although the initial rate
of release indicated by the electrical stimulation alone (data set
1302) is greater than when both stimuli are applied, it will be
apparent that this rate of release quickly decreases with time,
whereas under combined electrical and ultrasound stimulation (data
set 1304), the rate of release remains approximately linear over at
least the first 400 minutes, with the rate of release over 8 hours
being 0.19 .mu.g/min, and the final amount of dye released from the
polymer being about 100 .mu.g, being approximately 50% of the total
amount of dye in the polymer.
[0107] Considering that the polypyrrole is a poly cationic matrix
doped with anionic dye molecules, ion exchange would occur between
the dye and the anions in the PBS. Since the dye is relatively big
(Mw: 580.7), most of the dye molecules might be physically
entrapped in the polymer matrix, so that only a small fraction of
them were released (.about.2.5%). Ultrasound may increase the rate
of release by opening up the pores.
[0108] The data shown in FIG. 13 demonstrates that electrical
stimulation significantly enhances the rate and amount of release.
At a reduction potential, the positive charge along the polypyrrole
chain was neutralised, and the anionic dye was released from the
polymer matrix. At an oxidation potential, the polypyrrole became
positively charged and incorporated anions from the supporting
electrolyte. Repetitive potential pulsing promoted anionic exchange
and enhanced the rate of release in a short time period.
Example 2
[0109] As described above, the delivery system or device can be
used to deliver molecules and/or nanoparticles to the eye of a
patient. Once delivered to the surface of the eye, the molecules
and/or nanoparticles can penetrate the outer surface of the eye and
diffuse to the posterior parts of the eye. For example, FIGS. 14 to
19 are optical microscope images of sectioned rabbit eyes imaged by
Differential Interference Contrast (DIC) phase contrast imaging and
fluorescence imaging, illustrating the distribution of the
monoclonal antibody Avastin to various parts of the eye. Each of
these six Figures includes two panels, comprising a left-hand panel
showing a fluorescence image, and a right-hand panel showing a
white light DIC phase contrast image. FIGS. 14 to 16 illustrate the
distribution of Avastin delivered by intravitreal injection,
whereas FIGS. 17 to 19 show the distribution of Avastin delivered
from a hydrogel by sonophoresis of five minute duration. The red
colour in the fluorescence images indicates a secondary antibody
bound to Avastin. Consequently, the red colour indicates the
location of Avastin in the tissues of the eye.
[0110] The sectioning procedure has caused the retina/choroid to
separate from the sclera. In the eye (RE) with the intravitreal
injection, the vitreous is visible with abundant presence (red
staining) of Avastin. The vitreous humor was not visibly stained in
the eye (LE) with the Sonoactuator, which indicated that no Avastin
diffused out of the retina.
[0111] The ciliary body and iris are also heavily stained in the
eye following intravitreal injection. That is not surprising given
the role of the vitreous in providing a source for diffusion of
Avastin. However, the ciliary body does not stain well in the eye
following delivery from the gel with ultrasound. The passage of
Avastin through the outermost layers of cells at the surface of the
eye is believed to occur by the ultrasound energy acting to
increase the permeability of the layers of cells in the cornea and
sclera, especially in the area of the external limbus, by
reversibly altering the lipid structure of the cells of the cornea
and sclera. After permeating the cornea and sclera the Avastin
reached the retina by diffusion in the uveal tract or in the
potential space between the vitreous humor and the inner limiting
membrane of the retina. The precise mechanism in the eye is not
known but, Tyle and Agarwala describe related theories of the
effect of ultrasound on drug permeation in the skin as being due
either to cavitation effects or effects on the lipid structure of
the stratum corneum of the skin.
[0112] The vitreous humor is not visible in the "white-light" DIC
images because the sections are mounted on the slides using a 90%
glycerol solution in order to stabilise the cover slip and the
section during the confocal microscopy. The glycerol has a similar
refractive index to the vitreous humor. The DIC procedure relies on
phase-contrast optics, and hence structures are only visible when
there are differences in refractive index.
[0113] FIGS. 17 to 19 clearly demonstrate that the Avastin has been
non-invasively delivered to the choroid and retina.
Example 3
[0114] As described above, the delivery system can also be used to
deliver nanoparticles to an entity. FIG. 20 illustrates an
experimental arrangement for demonstrating the delivery of gold
nanoparticles into an optically transparent gel 2004 under
ultrasonic stimulation. The storage medium 2002 was formed by
adding the gold nanoparticles to an agarose solution heated to
about 70-90.degree. C. The agarose solution was then allowed to
solidify by cooling in a 4.degree. C. environment. The result was a
solid cylindrical gel 13 mm in diameter and 10 mm high containing a
suspended dispersion of gold nanoparticles. This storage material
2002 was then sandwiched between the transparent gel 2004 and an
ultrasonic transducer 102 driven by 20 v p-p signal @ 40 kHz
provided by a signal generator 108, resulting in an acoustic
stimulation of about 200 mWcm.sup.-2. The beam generated by a HeNe
laser 2006 is directed through the transparent gel 2004 to be
received by a photodetector 2008 in order to measure the optical
transmission of the laser beam through the transparent gel 2004,
and thereby infer the transport of the gold nanoparticles into the
transparent gel 2004. A standard computer system 2010 having an
analog to digital converter (ADC) card processed the analog signal
generated by the photodetector 2008 for subsequent analysis and
display to a user.
[0115] In this particular arrangement, the storage material 2002
and the transparent gel 2004 were both polymeric gels formed by
dissolving 0.5% agarose (w/v) in MilliQ water. Gold nanoparticles
of 15 to 20 nanometre diameter were added to the heated
(70-90.degree. C.) solution of agarose in MilliQ water and the gold
nanoparticles incorporated into the storage material 2002 during
the setting of the agarose to form the polymeric gel.
[0116] FIG. 21 is a graph of the photodiode output 2102 as a
function of time. Initially, the optical transmission of the
transparent gel 2004 was constant. At a time of around 8 minutes
from the start of the experiment, a 40 kHz ultrasonic signal was
generated by the ultrasonic transducer 102 as indicated and
transmitted into the storage material 2002. In this particular
arrangement, the laser beam was positioned at a point 1 mm below
the interface between the clear gel 2004 and the storage material
2002. After a delay of approximately 2 minutes, the transmission of
the laser beam dropped rapidly over a period of about 8 minutes,
and then began to saturate at a fixed level. At a time of around 29
minutes, the ultrasonic signal was switched off, as indicated. This
data clearly demonstrates that the 40 kHz ultrasonic signal was
very effective in transporting the gold nanoparticles into the
clear gel 2004. Scanning electron microscopy of the clear gel 2004
revealed the presence of the gold nanoparticles, confirming that
they had been transported from the storage material 2002. A control
experiment was performed using an identical storage material
without gold nanoparticles showed a constant optical transmission
that was not affected by the presence or absence of the ultrasonic
signal.
[0117] Many modifications will be apparent to those skilled in the
art without departing from the scope of the present invention as
hereinbefore described with reference to the accompanying
drawings.
* * * * *