Note: Descriptions are shown in the official language in which they were submitted.
WO 2010/117733 PCT/US2010/029085
METHODS AND APPARATUS FOR
DISPENSING MEDICAMENTS INTO A PUNCTAL PLUG
RELATED APPLICATIONS
This application claims priority to U.S. Patent Application Serial
No. 12/414,815, filed March 31, 2009.
FIELD OF USE
This invention describes methods and apparatus for dispensing one or more
materials, such as a medicament, into a punctal plug reservoir and, more
specifically,
in some embodiments, dispensing a drug component including excipients into a
cavity
of a punctal plug.
BACKGROUND
Medicaments frequently are administered to the eye for the treatment of ocular
diseases and disorders. Conventional means for delivering medicaments to the
eye
involve topical application to the surface of the eye. The eye is uniquely
suited to
topical administration because, when properly constituted, topically applied
medicaments can penetrate through the cornea and rise to therapeutic
concentration
levels inside the eye. Medicaments for ocular diseases and disorders may be
administered orally or by injection, but such administration routes are
disadvantageous
in that, in oral administration, the active agent may reach the eye in too low
a
concentration to have the desired pharmacological effect and their use is
complicated
by significant, systemic side effects and injections pose the risk of
infection.
The majority of ocular medicaments are currently delivered topically using eye
drops which, though effective for some applications, are inefficient. When a
drop of
liquid is added to the eye, it overfills the conjunctival sac, the pocket
between the eye
and the lids, causing a substantial portion of the drop to be lost due to
overflow of the
lid margin onto the cheek. In addition, a substantial portion of the drop that
remains on
the ocular surface is drained into the lacrimal puncta, diluting the
concentration of the
drug.
Accordingly, alternative methods and devices for delivering medicaments to an
ophthalmic area may be beneficial.
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SUMMARY
The present invention relates to devices for administering a medicament via a
punctal plug, and includes methods and apparatus for deposition of a
medicament in a
punctal plug cavity wherein the medicament can subsequently be delivered to a
patient
with the punctal plug inserted into a punctum.
DESCRIPTION OF THE DRAWINGS
FIGS. IA-1C illustrate a punctal plug and method for deposition into a punctal
plug
according to some embodiments of the present invention.
FIG. 2 illustrates apparatus for punctal plug deposition according to some
embodiments of the present invention.
FIG. 3 illustrates additional aspects of apparatus for punctal plug deposition
according
to some embodiments of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention includes apparatus and methods for forming punctal
plugs that may be used to deliver active agents to one or both of the
nasolacrimal duct
and to the tear fluid of the eye. In some embodiments, a location for
dissemination of
an active agent is positioned to release the active agent into tear fluid and
preferably
with minimal release into the nasolacrimal duct. Some embodiments include
apparatus
and methods for forming a punctal plug comprising, consisting essentially of,
and
consisting of. a punctal plug body having a first end and a second end; a
surface
extending between the two ends; a reservoir contained within the punctal plug
body
wherein the reservoir comprises, consists essentially of and consists of an
active agent-
containing material and an active agent, wherein the active agent is present
in a
continuous or discontinuous concentration gradient within the active agent-
containing
material. The punctal plug may additionally comprise a defined area, such as
an
opening in the punctal plug, which is more conducive to elution or other
dissemination
of the active agent from the punctal plug cavity to an area proximate to the
punctal
plug. Some preferred embodiments include an area conducive to dissemination of
the
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active agent comprising an opening with a diameter which is smaller than a
diameter of
the cavity containing the active ingredient.
The present invention additionally provides devices, and methods for their use
and manufacture, that can be used to deliver active agents into a cavity in a
punctal
plug in a controlled manner.
It has been known to fill a cavity in a punctal plug via insertion of a rod,
or
other rigid or semi rigid article. The rod can include a pharmaceutical or
other
medicament. However, the physical conditions of a punctum may include physical
manipulation and the presence of moisture. Insertion of a rod of medicament
into a
plug can be difficult.
Definitions:
As used herein, the term "active agent" refers to an agent capable of
treating,
inhibiting, or preventing a disorder or a disease. Exemplary active agents
include,
without limitation, pharmaceuticals and nutraceuticals. Preferred active
agents are
capable of treating, inhibiting, or preventing a disorder or a disease of one
or more of
the eye, nose and throat.
As used herein, the term "punctal plug" refers to a device of a size and shape
suitable for insertion into the inferior or superior lacrimal canaliculus of
the eye
through, respectively, the inferior or superior lacrimal punctum.
As used herein, the term "opening" refers to an opening in the punctal plug
body of a device of the invention of a size and shape through which the active
agent
can pass. Preferably, only the active agent can pass through the opening. The
opening
may be covered with a membrane, mesh, grid or it may be uncovered. The
membrane,
mesh, or grid may be one or more of porous, semi-porous, permeable, semi-
permeable,
and biodegradable.
Referring now to Fig. 1, at Fig. 1A a punctal plug device 101 is illustrated
with
an opening 102 which fluidly communicates with a cavity 105 formed in the
punctal
plug body. At Fig. 1B, a dispenser tip 103 is positioned proximate to the
opening 102
and dispenses a material 104 through the opening 102 and into the cavity 105.
At
Fig. 1C, the cavity 105 is shown filled by the dispenser tip 103 with a
material 104
containing an active agent. Examples of active agents can include one or more
of-
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bimatoprost; bimatoprost with an ethyleneoxynalacetate ("EVA") membrane in
amounts greater than 0 and less than 25%.
In various embodiments of the present invention, the material 104 containing
one or more active agents-and an active agent therein is deposited in the
cavity 105 of
a punctal plug device in small doses and at high viscosity. For example, in
some
embodiments, the material 104 can have a viscosity of between 1 (one)
centipoise to
over 1,000,000 (one million) centipoise. In addition, some embodiments include
deposition of small doses of the material 104, such as between 10 (ten)
picoliters and
10,000 (ten thousand) picoliters. The material 104 may also include one or
more
excipients. The excipients may be the portion of the material 104 which
provides the
high viscous properties.
The cavity may be any size and/or shape that a punctal plug design may
support. In some embodiments, the volume of the cavity 105 will be about
between 10
and 100 nanoliters. Some specific embodiments include a cavity volume of about
between 40 nanoliters and 50 nanoliters. An opening 102 to a cavity into which
a
dispenser tip may be inserted, may be, for example, include a diameter of
between
about 0.1 mm to 0.4mm and a cavity 105 may include a depth of between about
0.5mm
to about 2.0 mm. In some preferred embodiments, the opening 102 will be about
0.2
mm and the depth of the cavity will be about 1.5mm. Additional preferred
aspects of
embodiments can include a design with a 0.385 diameter and 1.5 mm length with
a
cavity volume of 175nL.
The active agent may be dispersed throughout the active agent-containing
material 104 or dissolved within the material 104. Alternatively, the active
agent may
be contained in inclusions, particulates, droplets, or micro-encapsulated
within the
material 104. Still as another alternative, the active agent may be covalently
bonded to
the material 104 and released by hydrolysis, enzymatic degradation and the
like. Yet
as another alternative, the active agent may be in a reservoir within the
material 104.
According to some embodiments of the present invention the active agent may
be released from the punctal plug device 101 in a controlled manner, meaning
over a
period of time by using an active agent-containing material 104 in which the
agent is
present in a continuous concentration gradient throughout the material 104 or
by using
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a discontinuous concentration gradient. Additional embodiments include a
device that
exhibits a "burst" or immediate release upon insertion of an amount of active
agent that
is greater than the average release rate over time.
Referring now to Fig. 2, an example of some embodiments of the present
invention which include a punctal plug active agent pump 200 for depositing
the
material with an active ingredient 104 into a cavity 105 of a punctal plug
device 101
(illustrated in Fig. 1). Generally, the pump 200 includes a reservoir, such as
a cartridge
201, mounted in a pump body 207 and attached to provide fluid communication to
a
dispenser tip 203. The cartridge 201 can include, for example, a removable
syringe.
The cartridge 201 can be formed from a polycarbonate, stainless steel or other
rigid or semi-rigid material. In some preferred embodiments, the cartridge is
formed
from a material that can be sterilized and also withstand heating during the
deposition
process. Additionally, in some embodiments, the cartridge 201 will have an end
proximate to the dispenser tip 203 and an end distal to the dispenser tip,
wherein the
end proximate to the dispenser tip can include a lure lock mechanism for
securing the
cartridge 201 to a dispenser body 202. Other locking or fastening mechanisms
may
also be used to secured the cartridge 201 in a position proximate to and in
fluid
communication with the dispenser tip 203. Some embodiments may therefore
include
designs of a polycarbonate or stainless steel syringe.
Some embodiments can include a "smart pump" such as a positive pressure
pump with a computer controlled needle valve, which control starts and stops
and
material flow for a range of viscosities. A computer controlled needle valve
provides
active valving to control flow characteristics, such as, for example: opening,
closing
and suck-back associated with the pumping of the active agent-containing
material
104. A dead volume inside the pump can range in some embodiments from between
about 0.025 cc to 0.3 cc. Such degrees of control, allow the present invention
to
dispense very small volumes of an active agent-containing material 104. Some
embodiments can include dispensing volumes of 50 picoliters or less and in
some
preferred embodiments, volumes of between 20 picoliters to 60 picoliters. In
another
aspect, a range of viscosities of an active agent-containing material 104 from
1
centipoise to over 1,000,000 centipoise. Other embodiments include a range of
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viscosities of between 500,000 centipoise to 3,500,000 centipoise. One
exemplary
pump mechanism can include a high pressure positive displacement pump, such as
those offered for commercial use by nScript, Inc.
Some preferred embodiments will include one or more heating sources 204-206
for heating the material with an active ingredient 104 while it is in one or
more of: a)
the cartridge 201; b) the dispenser body 202; and c) the dispenser tip 203.
The heat
source can include, for example, one or more of. electrically resistive
elements;
thermoelectric devices and heated fluid paths. As illustrated, in some
embodiments, a
heating source 205 may be located along side the cartridge 201 and allow the
material
with an active ingredient 104 to be kept at an elevated temperature while in
the
cartridge 201. Some embodiments can also include a heater element 204 in or
proximate to the pump body 207. Some embodiments may also include temperature
requirements that may be adjusted according to material properties excipients
to be
deposited.
In another aspect, some embodiments of the present invention include a
temperature probe 206. The temperature probe can include a transducer for
providing
a digital or analog output indicating a temperature of a designated portion of
the
punctal plug active agent pump 200. Embodiments can include an electronic
feedback
circuit (not shown), which allows control of an amount of heat applied to the
active
ingredient 104. In some embodiments, the feedback constitutes a closed loop
feedback
design.
Additionally, in some embodiments, an amount of heat applied to the material
containing an active ingredient 104 can be used to control a viscosity of the
material
containing an active ingredient 104. Typically, a higher amount of heat
applied will
lower the viscosity of the material containing an active ingredient 104 and
allow for
less pressure to be applied to move the material containing an active
ingredient 104
through the punctal plug active agent pump 200. By way of example, a material
containing an active ingredient 104 can be dispensed through the dispenser tip
203 at a
temperature of between 40 C and 80 C and in some preferred embodiments at a
temperature of between 60 C and 70 C. In some particular embodiments, a
punctal
plug 101 into which the material containing the active material 104 is
dispensed is also
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heated to a temperature of between 40 C and 80 C. In some embodiments, the
application of heat to the punctal plug 101 can provide additionally
elasticity to the
plug during the deposition allowing the cavity 105 to expand and more easily
accept
the material containing an active ingredient 104. In various embodiments, a
preferred
temperature may be based upon one or more of. an active ingredient used; an
excipient
included in the material containing an active ingredient 104; and
Referring now to Fig. 3, a perspective view illustrates a pump 200 with a
dispenser tip 301 and a quick change tip base 302. The quick change tip base
facilitates removal/replacement of a tip by an operator. As illustrated in
Fig. 3, in
some embodiments, pump body 304 can be mounted on a track 304, or other
mechanical or robotic device which allows motion in one, two or three
dimensions.
The motion may be controlled in some embodiments, motion is controlled via
automation and allows for the alignment of the dispenser tip 301 with a
punctal plug
(not illustrated in Fig. 3). In still another aspect, some embodiments may
include a
automated vision system to facilitate automated alignment and filling of
plugs.
Without being bound to any particular theory, it is believed that an active
agent-containing material 104 that does not undergo significant chemical
degradation
during the time desired for the release of active agent will release the agent
by
diffusion through the matrix to a device's release surfaces, meaning surfaces
of the
active agent-containing material 104 in contact with a person's body fluid.
According
to Fick's Law, the diffusive transport or flux, J, of the agent through the
active agent-
containing material 104 is governed at each point and each time by the local
concentration gradient, the diffusivity of the active agent with the material
D, and the
spatial variation of the cross-sectional geometry of the device.
Some exemplary embodiments can include a material with a mix of excipients
and active agents. Pre-mixing apparatus and processes may include twin-screw
compounding, chaotic mixing, solvent mixing, or spray drying, or other mixing
mechanisms. An exemplary compound can include: 25% bimatoprost as an active
agent; 37.5% ethylene vinyl acetate, EVA as a first excipient and 37.5%
polycaprolactone, PCL as a second excipient.
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The pre-mixed material can be loaded into the heated or non-heated syringe
200 as pellets. Pellets are not a requirement; the material 104 can be in the
form of one
or more of. a powder, fluff and other mediums. Additionally, in some
embodiments,
such as those in which it is desired to avoid multiple thermal cycle exposure
of an
active agent and/or to minimize air bubbles, the heated syringe may be
directly
attached to the micro-compounder so that the pre-mixed material is directly
supplied
into a nano-dosing dispensing system, such as those described above, without
having
to cool it to room temperature or lower. As such, in some embodiments the
material
containing an active agent may be supplied to the nano-dispensing system in a
melt
form.
In another aspect of the present invention, a local gradient of a
concentration of
active agent may be controlled by placing more active agent at one location in
the
material containing an active agent 104 relative to another location.
Alternatively, the
matrix may be have a gradient, meaning that one section of the material 104
has a first
concentration and the concentration abruptly changes to a second, different
concentration in an adjacent section of the matrix. The diffusivity for the
active agent
may also be spatially controlled by varying one or more of the chemical
composition,
porosity, and crystallinity of the active agent-containing material 104.
Additionally, the spatial variation of the material's cross-sectional geometry
may be used to control diffusivity. For example, if the material 104 was in
the form of
a straight rod that has a uniform active agent concentration, diffusivity will
be reduced
when the area at the open end of the material 104 is significantly smaller
than the
average of the entire material 104. Preferably, the material 104 area at the
open end of
the device is no more than one-half of the average cross sectional area of the
material,
meaning the cross section determined perpendicular to the primary dimension of
active
agent transport use.
One of ordinary skill in the art will recognize that, depending on how one
varies one or more of the local concentration gradient, the diffusivity of the
active
agent from the material D, and the spatial variation of the cross-sectional
geometry of
the device, a variety of release profiles may be obtained including, without
limitation
first order, second order, biphasic, pulsatile and the like. For example,
either or both of
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the active agent concentration and diffusivity may increase from the surface
to the
center of the active agent-containing material in order to achieve more
initial release.
Alternatively, either or both may be increased or decreased and then increased
again
within the material to achieve a pulsatile release profile. The ability to
achieve a
variety of release profiles by varying local concentration gradient, the
diffusivity of the
active agent, and the spatial variation of the cross-sectional geometry may
eliminate
the need for rate- limiting membranes in the device.
Devices formed according to the present invention may contain a reservoir or
cavity 104 within the punctal plug body, and the cavity 104 has at least at
least one
active agent-containing material deposited therein. in some embodiments, the
punctal
plug body is preferably impermeable to the active agent, meaning only an
insubstantial
amount of active agent can pass there through, and the punctal plug body has
at least
one opening through which the active agent is released. The opening may have a
membrane or permeable material covering through which the active agent may
pass in
therapeutic amounts.
The active agent-containing material useful in the devices of the invention is
any material that is capable of containing the active agent, does not alter
the chemical
characteristics of the active agent, and does not significantly chemically
degrade or
physically dissolve when placed in contact with ocular fluids. Preferably, the
active
agent-containing material is non-biodegradable, meaning that it does not
degrade to a
substantial degree upon exposure to biologically active substances typically
present in
mammals. Additionally, the active agent-containing material is capable of
releasing
the active agent by one or more of diffusion, degradation, or hydrolyzation.
Preferably, the active agent-containing material is a polymeric material,
meaning that it
is a material made of one or more types of polymers.
When the active agent-containing material is combined with the active agent,
the material may also contain one or more materials that are insoluble in
water and
non-biodegradable, but from which the active agent can diffuse. For example,
if the
active agent-containing material is a polymeric material, the material may be
composed of one or more polymers that are insoluble in water and non-
biodegradable.
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Suitable polymeric materials for the active agent-containing material include,
without limitation, hydrophobic and hydrophilic absorbable and non-absorbable
polymers. Suitable hydrophobic, non-absorbable polymers include, without
limitation,
ethylene vinyl alcohol ("EVA"), fluorinated polymers including without
limitation,
polytetrafluoroethylene ("PTFE") and polyvinylidene fluoride (" PVDF"),
polypropylene, polyethylene, polyisobutylene, nylon, polyurethanes,
polyacrylates and
methacrylates, polyvinyl palmitate, polyvinyl stearates, polyvinyl myristate,
cyanoacrylates, epoxies, silicones, copolymers thereof with hydrophobic or
hydrophilic monomers, and blends thereof with hydrophilic or hydrophobic
polymers
and excipients.
Hydrophilic, non-absorbable polymers useful in the invention include, without
limitation, cross-linked poly(ethylene glycol), poly(ethylene oxide),
poly(propylene
glycol), poly(vinyl alcohol), poly(hydroxyethyl acrylate or methacrylate),
poly(vinylpyrrolidone), polyacrylic acid, poly(ethyloxazoline), and
poly(dimethyl
acrylamide), copolymers thereof with hydrophobic or hydrophilic monomers, and
blends thereof with hydrophilic or hydrophobic polymers and excipients.
Hydrophobic, absorbable polymers that may be used include, without
limitation, aliphatic polyesters, polyesters derived from fatty acids,
poly(amino acids),
poly(ether-esters), poly(ester amides), polyalkylene oxalates, polyamides,
poly(iminocarbonates), polycarbonates, polyorthoesteres, polyoxaesters,
polyamidoesters, polyoxaesters containing amine groups, phosphoesters,
poly)anhydrides), polypropylene fumarates, polyphosphazenes, and blends
thereof.
Examples of useful hydrophilic, absorbable polymers include, without
limitation,
polysaccharides and carbohydrates including, without limitation, crosslinked
alginate,
hyaluronic acid, dextran, pectin, hydroxyethyl cellulose, hydroxy propyl
cellulose,
gellan gum, guar gum, keratin sulfate, chondroitin sulfate, dermatan sulfate,
proteins
including, without limitation, collagen, gelatin, fibrin, albumin and
ovalbumin, and
phospholipids including, without limitation, phosphoryl choline derivatives
and
polysulfobetains.
More preferably, the active agent-containing material is a polymeric material
that is polycaprolactone. Still more preferably, the material is poly(epsilon-
WO 2010/117733 PCT/US2010/029085
caprolactone), and ethylene vinyl acetate of molecular weights between about
10,000
and 80,0000. About 0 to about 100 weight percent polycaprolactone and about
100 to
about 0 weight percent of the ethylene vinyl acetate are used based on the
total weight
of the polymeric material and, preferably, about 50 % each of polycaprolactone
and
ethylene vinyl acetate is used.
The polymeric material used is preferably greater than about 99 % pure and the
active agents are preferably greater than about 97 % pure. One of ordinary
skill in the
art will recognize that in compounding, the conditions under which compounding
is
carried out will need to take into account the characteristics of the active
agent to
ensure that the active agents do not become degraded by the process. The
polycaprolactone and ethylene vinyl acetate preferably are combined with the
desired
active agent or agents, micro-compounded, and then extruded.
In a preferred embodiment, the active agent-containing material is a polymeric
material that is combined with at least one active agent to form a highly
viscous
material, such as, for example with a viscosity of between 500,000 cP and
4,000,000
cP. Preferably the viscosity of the active agent containing material can be
decreased
by heating the active agent containing material while it is contained in, or
passing
through a dispensing pump according to the present invention.
Conclusion
The present invention, as described above and as further defined by the claims
below, provides methods of processing punctal plugs and apparatus for
implementing
such methods, as well as punctal plugs formed thereby.
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