Note: Descriptions are shown in the official language in which they were submitted.
CA 02544460 2001-06-18
CONTROLLED-RELEASE BIOCOMPATIBLE OCULAR DRUG DELIVERY
IMPLANT DEVICES AND METHODS
This application is a divisional application of co-pending application Serial
No.
10
2,355,313 filed October 10, 2000.
TECHNICAL FIELD
The present invention relates to biocompatible controlled-release drug
delivery
devices that are~implantable in the eye. Accordingly, the invention transcends
the scientific
disciplines of pharmaceutical delivery, polymer chemistry, and medicine.
BACKGROUND ART
A leading cause of blindness is the inability to introduce drugs or
therapeutic agents
into the eye and maintain these drugs or agents at a therapeutically effective
concentration
therein for the necessary duration. Systemic administration may not be an
ideal solution
because, often, unacceptably high levels of systemic dosing is needed to
achieve effective
intraocuiar concentrations, with the increased incidence of unacceptable side
effects of the
drugs. Simple ocular instillation or application is not an acceptable
alternative in many
cases because the drug may be quickly washed out by tear-action or is depleted
from within
the eye into the general circulation.
A better solution would be to provide a delivery device which can be implanted
into
the eye such that a controlled amount of desired drug can be released
constantly over a
period of several days, or weeks, or even months. Some such devices have been
reported
in the prior art. See, for example, U.S. Pat. No. 4,853,224, which discloses
biocompatible
implants for introduction into an anterior segment or posterior segment of an
eye for the
treatment of an ocular condition. U.S. Pat. No. 5,164,188 discloses a method
of treating an
ocular condition by introduction of a biodegradable implant comprising drugs
of interest
into the suprachoroidal space or pars plans of the eye. See also U.S. Patents
Nos.
5,824,072, 5,476,511, 4,997,652, 4,959,217, 4,668,506, and 4,144,317.
Many of the above-disclosed devices comprise of multiple layers and are
complicated in their design and manufacture. Moreover, some of the devices are
osmotically driven wherein an osmotic gradient is responsible for the drug
efflux from the
device. In some cases, the drug release is controlled by an ionic gradient.
These devices
CA 02544460 2001-06-18
thus must necessarily comprise these additional osmotic or ionic agents, which
may not be
compatible with the ocular environment. Thus, there is a need for a
biocompatible ocular
implantable controlled release drug delivery device that is simple in design,
does not
require an osmotic or ionic agent for drug efflux and yet accomplishes the
objectives of
prolonged and uninterrupted ocular drug delivery. This invention meets this
need.
DISCLOSURE OF THE INVENTION
The invention of the parent application desirably provides a biocompatible
implantable ocular controlled release drug delivery device for continuously
delivering a
drug into the interior of an eye, comprising an element sized for implantation
into the
interior of the eye, the element having a polymeric outer layer that is
substantially
impermeable to the drug and intraocular fluids, the polymeric outer layer
covering a core
which comprises the drug to be delivered, wherein said outer layer has one or
more
orifices through which intraocular fluids may pass to contact the core and
dissolve the
drug, and through which the dissolved drug may pass to the exterior of the
element, and
1 S said orifices in total having an area less than 10 percent of the total
surface area of said device.
The outer layer of the devices of this invention can be made biodegradable.
The devices of the parent application can be used to deliver an antibiotic, an
antiviral agent, an anti-fungal agent, an anticancer agent, an antiglaucoma
agent, an anti-
inflammatory agent, an analgesic, an immunomodulatory agent, a macromolecule
or a
mixture thereof.
The invention of the parent application desirably provides a biocompatible
implantable ocular controlled release drug delivery device as described above
wherein the
outer layer comprises polytetrafluoroethylene, the core comprises gentamicin,
cefazolin,
or a mixture thereof, and the total area of orifices is less than 1 percent of
the total surface
area of the device.
The outer layer of the biocompatible implantable ocular controlled release
drug
delivery device as described above comprises polyfluorinated
ethylenepropylene, and the
core comprises dexamethasone, and the total area of orifices is less than 7
percent of the
total surface area of the device.
The outer layer of the biocompatible implantable ocular controlled release
drug
delivery device described above comprises polytetrafluoroethylene, and the
core
comprises aldose reductase inhibitor, and the total area of orifices is less
than 8 percent of
the total surface area of the device.
2
CA 02544460 2001-06-18
Also provided is a biocompatible implantable ocular controlled release drug
delivery device as described above wherein the outer layer comprises
polytetrafluoro-
ethylene, or silicone or a mixture thereof, the core comprises ganciclovir [9-
[[2-hydroxy-
1-(hydroxymethyl)ethoxy]-methyl]-guanine], and the total area of orifices is
less than 1
percent of the total surface area of the device.
Also provided is a biocompatible implantable ocular controlled release drug
deliver device as described above wherein the outer layer comprises polylactic
acid,
polyglycolic acid, or a mixture thereof, the core comprises ganciclovir [9-[[2-
hydroxy-1-
(hydroxymethyl)ethoxy]-methyl]-guanine], and the total area of orifices is
less than 1
percent of the total surface area of the device.
In a preferred embodiment the rate of release of the drug is determined solely
by
the composition of the core and the total surface area of one or more orifices
relative to the
total surface area of said device.
In a further preferred embodiment the device continuously delivers the drug
within
the eye for a period of at least several weeks.
The invention of this application desirably provides a biodegradable implant
for
placement in an eye of a human, comprising: an extruded element including one
or more
orifices and being sized for implantation into the interior of the human eye
and to directly
communicate with the vitreal chamber of the human eye, the element comprising
a
therapeutic agent and a biodegradable polymer, wherein the implant releases
the
therapeutic agent at a rate determined by the composition of the implant and
the total
surface area of the one or more orifices relative to the total surface area of
the implant, the
total surface area of the one or more orifices being less than 10 percent of
the total surface
area of the device.
Methods are also provided for administering the biocompatible implantable
ocular
controlled release drug delivery device.
BRIEF DESCRIPTION OF THE DRAWINGS
Figures lA-1F are graphical displays of drug release data from cylindrical
devices
made from Teflon~ (polytetrafluoroethylene), wherein the number and
configuration of
orifices varied.
Figure 2 is a graphical display of release data of dexamethasone from
cylindrical
devices made of poly(fluorinated ethylene propylene) (FEP), wherein the
orifice
configuration and number varied.
3
CA 02544460 2001-06-18
Figure 3 is a graphical display of release data of an aldose reductase
inhibitor
(ARn from cylindrical devices made from polytetrafluoroethylene. In this case,
an orifice
was created on each spherical face of the device by leaving the spherical
faces open (i.e.,
unsealed).
Figure 4 is a graphical display of ganciclovir [9-[[2-hydroxy-1-
(hydroxymethyl)-
ethoxy]-methyl]-guanine (DHPG)J release data from cylindrical devices made
from
silicone, wherein each spherical face of the cylindrical device is sealed.
Figure 5 is a graphical display of ganciclovir [9-[[2-hydroxy-1-
(hydroxymethyl)-
ethoxy]-methyl)-guanine (DHPG)] release data from cylindrical devices made
from
polylactic acid, wherein each spherical face of the cylindrical device is open
and one
additional orifice is drilled on the longitudinal surface of the cylindrical
device.
3a
CA 02544460 2001-06-18
MODES FOR CARRYING OUT THE 1NVENTTON
A. General Techniques
One of ordinary skill in the art would readily appreciate that the
pharmaceutical
devices and methods described herein can be prepared and practiced by applying
known
procedures in the pharmaceutical arts. Thus, the practice of the present
invention employs,
unless otherwise indicated, conventional techniques of pharmaceutical sciences
including
pharmaceutical dosage form design, drug development, pharmacology, of organic
chemistry, and polymer sciences. See generally, for example, Remington: The
Science and
Practice of Pharmacy, 19th Ed., Mack Publishing Co., Easton, PA (1995)
(hereinafter
REMINGTON).
B. Definitions
As used herein, certain terms have the following defined meanings.
As used in the description and claims, the singular forms a, an and the
include
plural references unless the context clearly dictates otherwise. For example,
the term a
drug may refer to one or more drugs for use in the presently disclosed
invention.
Controlled release refers to the release of a given drug from a device at a
predeterrriined rate. Such rate of release can be zero order, pseudo-zero
order, first order,
pseudo-first order and the like. Thus, relatively constant or predictably
varying amounts of
the drug can be delivered over a specified period of time.
Delivery refers to the release of a drug from a device comprising that drug
into an
environment surrounding the device. The environment into which the drug so
released may
or may not be the ultimate site of activity for that drug. In some instances,
the released
drug may need to be transported to its ultimate site of activity.
Biocompatible means that the device, polymer or component is substantially non-
immunogenic and leaves no toxic, potentially inflammatory or immunogenic
reaction
products at the tissue site of administration.
The term ocular refers to the eye, including all its muscles, nerves, blood
vessels,
tear ducts, membranes etc., as well as structures that are immediately
connected with the
eye and its physiological. functions. The terms ocular, ocular structures and
eye are used
interchangeably throughout this disclosure.
4
CA 02544460 2001-06-18
Ocular delivery refers to delivery of a desired drug to the eye. Moreover,
ocular
delivery may include systemic delivery through the eye, because, as one of
ordinary skill in
the art recognizes, a localized delivery to a particular site in the eye.may
result, due to the
highly perfused nature of the eye, in the drug being absorbed through the
blood vessels and
carried to a location remote from the eye leading to systemic delivery. Given
this
characteristic, it may be advantageous in some cases to aim for systemic
delivery through
the eye. Such systemic delivery is also within the scope of the present
invention.
The term biodegradable means that the component, carrier or formulation
degrades
in biological media such as body fluids and anatomical structures comprising
or bathed by
body fluids. Alternatively, biodegradation refers to, in the context of a
biodegradable
polymer for example, the situation in which the molecular weight of the
polymer decreases
due to a reduction in the number of monomers with time. Examples of body
fluids include
blood, plasma, saliva, tears, lymph, urine, etc. Examples of anatomical
structures
comprising or bathed by body fluids include the oral cavity, the nasal cavity,
the
genitourinary tract, the respiratory tract, the gastrointestinal tract, ocular
system, etc. Such
erosion in body fluids may be due to factors such as dissolution, dispersion,
friction,
gravity, etc.
The term drug device or delivery device or simply device as used herein refers
to a
composition that contains and or delivers a drug to a subject and is generally
considered to
be otherwise pharmacologically inactive. The devices of this invention
comprise an outer
layer, a core and at least one orifice in the outer layer. The subject can be
a human or any
animal. The term animal includes any known animal as well as fishes, avians,
and reptiles.
Outer layer is a layer of material that covers the entire core of a drug
delivery
device, except for the openings) provided in the outer layer by way of an
orifice.
Depending on the method of manufacture of the device, the outer layer and the
drug core
may or may not be substantially in contact with each other. The outer layer
material can be
made of a polymeric composition and, when in use, is substantially impermeable
to body
fluids and the drug to be delivered, wherein the influx of the body fluids and
the efflux of
the drug occurs substantially or entirely through the orifice(s).
Substantially impermeable, impermeable or non permeable refer to the
permeability
characteristic of the outer layer of the device, wherein the influx and efflux
of water or
body fluids as well as the core composition including the drug across the
outer layer of the
5
CA 02544460 2001-06-18
device is de minimus, i. e., nonsubstantial, except for that occurring through
the orifices
provided in the device. One of ordinary skill in the art may recognize that no
device when
implanted may remain completely impermeable to body fluids over, extended
periods of
time. However, the objective of the present invention is achieved if the
controlled delivery
characteristics of the device are not substantially affected even if the
device is shown to be
or have been permeable to body fluids wherein such permeability occurs or has
occurred
through means other than the orifices provided in the device. For example,
accidental
puncturing of the device during implantation may make the device permeable.
Where the
device is of the refillable type, puncturing of the device may occur during
such refillings.
In these cases, the device may become permeable through such puncturing.
However, the
device should be considered impermeable or substantially impermeable so long
as its
controlled delivery characteristics are not affected.
Core comprises the drug to be delivered and, optionally, mixed with an
adjuvant.
The term drug includes any known pharmacologically active agent as well as its
1 ~ pharmaceutically acceptable salt, prodrug such as an ester or an ether, or
a salt of a
prodrug, or a solvate such as ethanolate, or other derivative of such
pharmacologically
active drug. These salts, prodrugs, salts of prodrugs, solvates and
derivatives are well-
known in the art.
Salts of the pharmacologically active drugs may be derived from inorganic or
organic acids and bases. Examples of inorganic acids include hydrochloric,
hydrobromic,
sulfuric, nitric, perchloric, and phosphoric acids. Examples of bases include
alkali metal
(e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides,
ammonia,
and compounds of formula NW4+, wherein W is C~.~ alkyl.
Examples of organic salts include: acetate, propionate, butyrate, hexanoate,
heptanoate, undecanoate, palmoate, cyclopentanepropionate, adipate, alginate,
aspartate,
benzoate, citrate, oxalate, succinate, tartarate, lactate, maleate, fumarate,
camphorate,
nicotinate, pectinate, picrate, pivalate, tosylate, gluconate, digluconate,
hemisulfate,
methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, dodecylsulfate,
camphorsulfonate, benzenesulfonate, 2-naphthalenesulfonate, thiocyanate,
phosphate,
glycerophosphate, and phenylpropionate. Several of the officially approved
salts are listed
in mvttNGTON, supra, Chapter 83.
6
CA 02544460 2001-06-18
The term derivative of a compound as used herein means a chemically modified
compound wherein the chemical modification takes place at one or more
functional groups
of the compound and /or on an aromatic, alicyclic, or heterocyclic structures,
when present.
The derivative however is expected to retain the pharmacological activity of
the compound
from which it is derived.
The term prodrug refers to a precursor of a pharmacologically active compound
wherein the precursor itself may or may not be pharmacologically active but,
upon
administration, will be converted, either metabolically or otherwise, into the
pharmacologically active drug of interest. Several prodrugs have been prepared
and
disclosed for a variety of pharmaceuticals. See, for example, Bundgaard, H.
and Moss, J., J.
Pharm. Sci. 78: 122-126 (1989). Thus, one of ordinary skill in the art knows
how to
prepare these derivatives and prodrugs with commonly employed techniques of
organic
synthesis.
In addition, polymorphs, isomers (including stereoisomers, geometric isomer
and
optical isomers) and anomers of the pharmaceuticals described herein are
contemplated.
Further, the term drug includes nucleic acid sequences. These nucleic acid
sequences may be delivered as "naked" or as packaged in a vector, wherein the
naked or the
vector-packaged nucleic acid may provide the desired pharmacologic,
physiologic or
immunologic effect by interacting with the cellular membranes of the ocular
tissue. On the
other hand, the nucleic acid may be taken up by the ocular cells wherein the
nucleic acid is
incorporated into the cell and expressed to produce a protein. The protein
thus produced
may have a variety of physiologic, pharmacologic or immunologic functions. For
example,
in one aspect, the protein may act as an immunogen by binding to the ocular
cells, thereby
triggering an immunologic reaction that may result in an attack by killer T-
cells to cause
cell death. Such cell death is desirable when treating for example, cancerous
conditions of
the eye. In another aspect, the protein may stimulate growth of epithelial
cells in an ocular
tissue. Some growth factors deliverable by the devices of this invention
include brain
nerve growth factor (BNGF), celiary nerve growth factor (CNGF), vascular
endothelial
growth factor (VEGF). Several vectors, including viral (such as adenoviral)
and non-viral
(such as liposomal), as well as methods for incorporating nucleic acids in
such vectors are
known in the art.
7
CA 02544460 2001-06-18
The terms drug and pharmaceutical as used herein are identical in meaning and
thus are used interchangeably.
An adjuvant is an agent that may affect any of (1 ) the rate of release of the
drug; (2)
the stability of the drug; (3) the solubility of the drug; or (4)
physicochemical
characteristics of the core itself, including compactness, pH, etc. However,
an adjuvant
does not include those~ingredients that affect the release rate by providing
an osmotic
pressure or ion gradient. In one aspect, adjuvants may include solubilizing
agents,
solubility decreasing agents, and dispersing agents.
A solubilization agent increases the solubility of a pharmaceutical in the
formulation. The solubilization agent preferably comprises between about 0.01
% and
about 20% by weight of the final formulation, and more preferably between
about 0.1%
and 10% by weight of the final formulation.
A solubility decreasing agent can be used in the formulation to achieve the
desired
release characteristics. Solubility of a drug can be decreased by techniques
known in the
1 S art, such as by complexation, etc. Examples of complexation agents
include: 2-
hydroxynicotinic acid, 2-hydroxyphenylacetic acid, cyclodextrans, phthalic
acid,
polyethylene giycols, hydroquinone and derivatives thereof, caffeine, bile
salts and acids.
As used herein, the term solubility refers to the extent to which a solute
dissolves in
a solvent, wherein the solute and "solvent" may be of the same or of different
physical
state. Thus, a solution of a solid or a liquid in any "solvent" such as a
solid, liquid or gas is
within the scope of this term.
Solubility can be expressed in many ways, such as: weight/volume (grams/mL);
molality (number of moles of solute/1000 grams of solvent); mol fraction
(fraction of the
total number of mols present which are mole of one component); mol % (mol
fraction x
100); normality (number of gram equivalent weights of solute dissolved in
1000mL of
solution); % by weight (% w/w); % weight in volume (%w/v); % by volume (%
v/v).
Solubility can also be described by terms such as: very soluble (less than I
part of
solvent per 1 part of solute); freely soluble (from 1 to 10 parts of solvent
per 1 part of
solute); soluble (from 10 to 30 parts of solvent per 1 part of solute);
sparingly soluble (from
30 to 100 parts of solvent for 1 part of solute); slightly soluble (from 100
to 1000 parts of
solvent for 1 part of solute); very slightly soluble (from 1000 to 10,000
parts of solvent for
1 part of solute); and practically insoluble, or insoluble (more than 10,000
parts of solvent
8
CA 02544460 2001-06-18
for 1 part of solute). For further elaboration; see ttEMtt~~GTON, supra,
Chapter 16, which is
incorporated by reference.
A dispersing agent is an agent that facilitates the formation of a dispersion
of one or
more internal phases in a continuous phase. Examples of such dispersions
include
suspensions and emulsions, wherein the continuous phase may be water, for
example, and
the internal phase is a solid or a water-immiscible liquid, respectively.
Thus, dispersing
agents may include suspending agents and emulsifying agents.
Orifice refers to an opening in the outer layer through which, when the device
is in
use, body fluids can enter the device and the dissolved drug in the device can
migrate out
of the device. This expression is synonymous with "passageway" or "aperture"
or "hole" or
"bore" and the like. The orifices can have any shape, for example, spherical,
cubical,
ellipsoidal, cylindrical, conical, inverse-conical, irregular, and the like.
The delivery device
can have more than one orifice. When the device is fabricated with more than
one orifrce,
the orifices can be construed as the functional equivalent of a single
orifice.
The term area of the orifice refers to the area of a surface of a section of
the outer
layer that has been removed to provide the orifice. More specifically, it
refers to either the
outermost surface of the removed section of the outer layer (i. e., that
surface of the outer
layer that is farthest from the drug core) or the innermost surface of the
removed section of
the outer layer (i.e., that surface of the outer layer that is closest to the
drug core),
whichever has the smallest surface area. The surface area is measured as the
area of the
surface in a two-dimensional plane.
Thus, for example, when the orifice is cubical, the surface area of the
orifice is the
area represented by its two-dimensional plane, namely a square. When the
orifice is
cylindrical, the surface area of the orifice is the area of the circular
plane, disregarding the
height (i. e., thickness of the outer layer). When the orifice is spherical,
the surface area of
the orifice is the area of the circular plane. When the orifice is conical,
the surface area of
the orifice is the area of that surface of the orifice that is closest to the
drug core. Vdhen the
orifice is inverse-conical shaped, the surface area of the orifice is the area
of that surface of
the orifice that is farthest from the drug core. When the orifice is formed by
leaving
unsealed an end of an open cylindrical tube, the area of the orifice refers to
the
area of a circle having the radius of the cylindrical device.
9
CA 02544460 2001-06-18
It is appreciated that, in some aspects, as for example when the device is
cylindrical,
a given surface of the removed section may Have curvature, In calculating the
area of that
surface, the effects of curvature are ignored when, as described above, the
surface is
projected in a two-dimensional plane. As a practical matter, since the outer
layer of the
devices of this invention has, in general. a thickness of about 0.6 mm or
less, the effect of
this thickness (or height) has been ignored in calculating the area of the
orifice. Thus, for
example, in calculating the area of a cylindrical or spherical orifice, the
only relevant
measurement is the radius of the orifice.
The term total surface area of the device refers to the entire exterior
surface area of
the device without excluding the surface area of the orifice. For example,
when the device
is cylindrical, with one orifice on its longitudinal face, the total surface
area of the device is
calculated using the formula: (p *2xr) + 2 mz wherein p and r are the length
and radius of
the device.
An effective amount is an amount sufficient to effect beneficial or desired
results.
1 S An effective amount can be administered in one or more administrations,
applications or
dosages. Determination of an effective amount for a given administration is
well within the
ordinary skill in the pharmaceutical arts.
Administration refers to a method of placing a device to a desired site. The
placing
of a device can be by any pharmaceutically accepted means such as by
swallowing,
retaining it within the mouth until the drug has been dispensed, placing it
within the buccal
cavity, inserting, implanting, attaching, etc. These and other methods of
administration are
known in the art.
The term pharmaceutically acceptable is an adjective and means that the
ingredient
that is being qualified is compatible with the other ingredients of the
formulation and not
injtuious to the patient. Several pharmaceutically acceptable ingredients are
known in the
art and official publications such as THE I1NITED STATES PHARMACOEPIA describe
the
analytical criteria to assess the pharmaceutical acceptability of numerous
ingredients of
interest.
Concentrations, amounts, etc., of various components of this invention are
often
presented in a range format throughout this application. The description in
range format is
merely for convenience and brevity and should not be construed as an
inflexible limitation
on the scope of the invention. Accordingly, the description of a range should
be considered
CA 02544460 2001-06-18
to have specifically disclosed all the possible subranges as well as
individual numerical
values within that range. For example, description of a range such as 1 % to
8% should be
considered to have specifically disclosed subranges such as 1 % to7%, 2% to
8%, 2% to
6%, 3% to 6%, 4% to 8%, 3% to 8% etc., as well as individual numbers within
that range,
such as, 2%, S%, 7% etc. This construction applies regardless of the breadth
of the range
and in all contexts throughout this disclosure.
C. The Devices
The present invention provides biocompatible controlled-release ocularly
implantable drug delivery devices and methods for using such devices. The
device
comprises a drug core surrounded by a substantially impermeable polymeric
outer layer
which has one or more orifices through which body fluids may enter to dissolve
the drug
and through which the dissolved drug may efflux at a desired rate for a
desired period. The
present invention is particularly appropriate for drugs that are very active
even in extremely
small quantities and whose sustained long-term administration is sought.
The device can be implanted anywhere in a human or an animal to obtain
localized
or systemic effects of the drug that is released from the device. In some
particular aspects,
the device is implanted in the eye to treat or prevent a variety of conditions
of the eye such
as bacterial and viral infections, inflammation, cancerous growth, ocular
pressure,
haemorrhage, etc. In some aspects, the device can be made biodegradable after
the release
of the drug is completed.
The devices of the present invention may be of any preselected shape, such as
spherical, cylindrical, cubical, conical, ellipsoidical, biconvex,
hemispherical or near-
hemispherical etc. By "near-hemispherical", it is meant that ane face of the
device is
substantially flat, shallow convex or shallow concave, and the opposite face
is deeply
convex (i. e., the deeply convex face has a greater radius of curvature than
the shallow
convex, shallow concave, or substantially flat face).
The devices for ocular implantation are generally small such that the devices
can be
implanted in the fairly small ocular cavity. For example, when the device is
cylindrical, it
may be about 3-7 millimeters in height and about 0.5 to 4 millimeters in
diameter. The
volume of the device is such that the device holds sufficient amount of the
drug to provide
a continuous delivery over the implant's long delivery period, e.g., several
weeks, months,
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CA 02544460 2001-06-18
or even longer, i.e., up to 2 or more years. The volume needed thus depends on
characteristics such as drug solubility, drug delivery rate, period of
delivery, drug's half
life, etc. Once implanted, the device gives a continuous delivery of the drug
to internal
regions of the eye without requiring additional invasive penetrations into
these regions.
The following description provides greater details of the various aspects of
the
devices and the methods.
1. The Polymeric Outer Layer
Various biocompatible substantially impermeable polymeric compositions may be
employed in preparing the outer layer of the devices. Some relevant factors to
be
considered in choosing a polymeric composition include: compatibility of the
polymer with
the biological environment of the implant, compatibility of the drug with the
polymer, ease
of manufacture, a half life in the physiological environment of at least
several days, no
significant enhancement of the viscosity of the vitreous, and the desired rate
of release of
the drug. Depending on the relative importance of these characteristics, the
compositions
can be varied. Several such polymers and their methods of preparation are well-
known in
the art. See, for example, U.S. Pat. Nos. 4,304,765; 4,668,506 4,959,217;
4,144,317, and
5,824,074, Encyclopedia of Polymer Science and Technology, Vol. 3, published
by
Interscience Publishers, Inc., New York, latest edition, and Handbook of
Common
Polymers by Scott, J. R and Roff, W. J., published by CRC Press, Cleveland,
Ohio, latest
edition.
The polymers of interest may be homopolymers, copolymers, straight, branched-
chain, or cross-linked derivatives. Same exemplary polymers include:
polycarbamates or
polyureas, cross-linked polyvinyl acetate) and the like, ethylene-vinyl ester
copolymers
having an ester content of 4 to 80% such as ethylene-vinyl acetate (EVA)
copolymer,
ethylene-vinyl hexanoate copolymer, ethylene-vinyl propionate copolymer,
ethylene-vinyl
butyrate copolymer, ethylene-vinyl pentantoate copolymer, ethylene-vinyl
trimethyl acxtate
copolymer, ethylene-vinyl diethyl acetate copolymer, ethylene-vinyl 3-methyl
butanoate
copolymer, ethylene-vinyl 3-3-dimethyl butanoate copolymer, and ethylene-vinyl
benzoate
copolymer, or a mixture thereof.
Additional examples include polymers such as: poly(methylmethacrylate),
poly(butylmethacrylate), plasticized poly(vinylchloride), plasticized
poly(amides),
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CA 02544460 2001-06-18
plasticized nylon, plasticized soft nylon, plasticized polyethylene
terephthalate), natural
rubber, silicone, poly(isoprene), poly(isobutylene), poly(butaiiiene),
poly(ethylene),
poly(tetrafluoroethylene), poly(vinylidene chloride), poly(acrylonitrile,
cross-linked
poly(vinylpyrrolidone), chlorinated poly(ethylene),
poly(trifluorochloroethylene),
polyethylene chlorotrifluoroethylene), poly(tetrafluoroethylene), polyethylene
tetrafluoroethylene), poly(4,4'-isopropylidene diphenylene carbonate),
polyurethane,
poly(perfluoroalkoxy), poly(vinylidenefluoride), vinylidene chloride-
acrylonitrile
copolymer, vinyl chloride-diethyl fumarate copolymer, silicone, silicone
rubbers (of
medical grade such as SilasticR~ Medical Grade ETR Elastomer Q7-4750 or Dovw
CorningR~ MDX 4-4210 Medical Grade Elastomer); and cross-linked copolymers of
polydimethylsilane silicone polymers.
Some further examples of polymers include: poly(dimethylsiloxanes), ethylene-
propylene rubber, silicone-carbonate copolymers, vinylidene chloride-vinyl
chloride
copolymer, vinyl chloride-acrylonitrile copolymer, vinylidene chloride-
acrylonitrile
copolymer, poly(olefins), polyvinyl-olefins), poly(styrene), poly(halo-
olefins),
poly(vinyls) such as polyvinyl acetate, cross-linked polyvinyl alcohol, cross-
linked
polyvinyl butyrate, ethylene ethylacrylate copolymer, poIyethyl hexylacrylate,
polyvinyl
chloride, polyvinyl acetals, plasiticized ethylene vinylacetate copolymer,
polyvinyl alcohol,
polyvinyl acetate, ethylene vinylchloride copolymer, polyvinyl esters,
polyvinylbutyrate,
polyvinylfortnal, poly(acrylate), poly(methacryIate), poly(oxides),
poly(esters),
poly(amides), and poly(carbonates), or a mixture thereof.
In some aspects, the devices may be biodegradable wherein the outer layer
degrades
after the drug has been released for the desired duration. The biodegradable
polymeric
compositions may comprise organic esters or ethers, which when degraded result
in
physiologically acceptable degradation products, including the monomers.
Anhydrides,
amides, orthoesters or the like, by themselves or in combination with other
monomers, may
find use. The polymers may be addition or condensation polymers, cross-Linked
or non-
cross-linked. For the most part, besides carbon and hydrogen, the polymers
will include
oxygen and nitrogen, particularly oxygen. The oxygen may be present as oxy,
e.g.,
hydroxy or ether, carbonyl, e.g., non-oxo-carbonyl, such as carboxylic acid
ester, and the
like. The nitrogen may be present as amide, cyano and amino. In some aspects,
the
13
CA 02544460 2001-06-18
polymer is polytetrafluoroethylene, (commercially known as Teflon~), ethyl
vinyl alcohol
or ethylene vinyl acetate.
Some examples of biodegradable polymers useful in the present invention
include:
hydroxyaliphatic carboxylic acids, either homo- or copolymers, such as
polylactic acid,
polyglycolic acid, polylactic glycolic acid; polysaccharides such as cellulose
or
cellulose derivatives such as ethyl cellulose, cross-linked or uncross-linked
sodium
carboxymethyl cellulose, sodium carboxymethylcellulose starch, cellulose
ethers, cellulose
esters such as cellulose acetate, cellulose acetate phthallate,
hydroxypropylmethyl cellulose
phthallate and calcium alginate, polypropylene, polybutyrates, polycarbonate,
acrylate
polymers such as polymethacrylates, polyanhydrides, polyvalerates,
polycaprolactones
such as poly-e-caprolactone, polydimethylsiloxane, polyamides,
polyvinylpyrollidone,
polyvinylalcohol phthallate, waxes such as paraffin wax and white beeswax,
natural oils,
shellac, zein, or a mixture thereof.
Suitable biodegradable polymeric compositions can be easily obtained since the
decomposition rate of biodegradable polymers can be varied by chemical
modification
and/or by varying the component ratios and/or by varying the molecular weight.
In case of
certain polymers, isomerism can give rise to polymers with distinct
characteristics. For
example, by using the L-lactate, a slowly eroding polymer is achieved, while
erosion is
substantially enhanced with the lactate racemate.
Z. The Core
The core of the delivery device comprises the drug to be delivered and may
optionally comprise a pharmaceutically acceptable adjuvant. .There is no
critical upper or
lower limit as to the amount of drug that can be incorporated into the core of
the device.
Thus, the ratio of drug to device is dictated by the desired time span, the
release rate, and
the efficacy of the drug. For example, the drug may be from about 1 to 80, and
in some
aspects, from about 20 to 40 weight percent of the device. Generally, devices
of various
sizes can be prepared to house from 0.05 ng to 50 grams of drug or more, with
individual
devices containing, for example, 25 ng, about 1 pg, about 10 fig, about 100
p.g, about 1 mg,
about S mg, about 250 mg, about 500 mg, about 1.5 g, or the like.
The drug can be deposited in the device as a dry powder, particles, granules,
or as a
compressed solid. The drug may also be present as a solution or be dispersed
in a polymer
14
CA 02544460 2001-06-18
matrix. The polymers used in the matrix with the drug are bio-compatible with
body
tissues and body fluids and can be biodegradable or substantially insoluble in
the body
fluids. Any of the above-described biocompatible polymer compositions can be
used to
prepare the matrix. The amount of polymer in the core may be from about 0% to
80 wt
by weight. These polymers are commercially available and methods for preparing
polymer
matrices are well-known in the art. See, for example, U.S. patent No.
x,882,682.
a) Drubs
A wide variety of systemic and ocular conditions such as inflammation,
infection,
cancerous growth, may be prevented or treated using the drug delivery devices
of the
present invention. More specifically, ocular conditions such as glaucoma,
proliferative
vitreoretinopathy, diabetic retinopathy, uveitis, keratitis, cytomegalovirus
retinitis, herpes
simplex viral and adenoviral infections can be treated or prevented.
The following classes of drugs could be delivered using the devices of the
present
invention: anesthetics, analgesics, cell transport/mobility impending agents
such as
colchicine, vincristine, cytochalasin B and related compounds; antiglaucoma
drugs
including beta-blockers such as timolol, betaxolol, atenolol, etc; carbonic
anhydrase
inhibitors such~as acetazolamide, methazolamide, dichlorphenamide, diamox; and
neuroprotectants such as nimodipine and related compounds.
Additional examples include antibiotics such as tetracycline,
chlortetracycline,
hacitracin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol,
gentamycin, and erythromycin; antibacterials such as sulfonamides,
sulfacetamide,
sulfamethizole and sulfisoxazole; anti-fungal agents such as fluconazole,
nitrofurazone,
amphotericine B, ketoconazole, and related compounds; anti-viral agents such
as
trifluorothymidine, acyclovir, ganciclovir, DDI, AZT, foscarnet, vidarabine,
trifluorouridine, idoxuridine, ribavirin, protease inhibitors and anti-
cytomegalovirus agents;
antiallergenics such as methapyriline, chlorpheniramine, pyrilamine and
prophenpyridamine; anti-inflammatories such as hydrocortisone, dexamethasone,
fluocinolone, prednisone, prednisolone, methylprednisolone, fluorometholone,
betamethasone and triamcinolone; decongestants such as phenylephrine,
naphazoline, and
tetrahydrazoline; miotics and anti-cholinesterases such as pilocarpine,
carbachol, di-
isopropyl fluorophosphate, phospholine iodine, and demecarium bromide;
mydriatics such
CA 02544460 2001-06-18
as atropine sulfate, cyclvpentolate, homatropine, scopolamine, tropicamide,
eucatropine;
sympathomimetics such as epinephrine and vasoconstrictors and vasodilators.
Anticlotting
agents such as heparin, antifibrinogen, fibrinolysin, anticlotting activase,
etc., can also be
delivered.
Antidiabetic agents that may be delivered using the present devices include
acetohexamide, chlorpropamide, glipizide, glyburide, tolazamide, tolbutamide,
insulin,
aldose reductase inhibitors, etc. Some examples of anti-cancer agents include
5-
fluorouracil, adriamycin, asparaginase, azacitidine, azathioprine, bleomycin,
busulfan,
carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide,
cyclosporine;
cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin,
estramustine, etoposide,
etretinate, filgrastin, floxuridine, fludarabine, fluorouracil,
fluoxymesterone, flutamide,
goserelin, hydroxyurea, ifosfamide, leuprolide, IevamisoIe, lomustine,
nitrogen mustard,
melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, pentostatin,
pipobroman,
plicamycin, procarbazine, sargramostin, streptozocin, tamoxifen, taxol,
teniposide,
thioguanine, uracil mustard, vinblastine, vincristine and vindesine.
Hormones, peptides, nucleic acids, saccharides, Lipids, glycolipids,
glycoproteins,
and other macromolecules can be delivered using the present devices. Examples
include:
endocrine hormones such as pituitary, insulin, insulin-related growth factor,
thyroid,
growth hormones; heat shock proteins; immunological response modifiers such as
muramyl
dipeptide, cyclosporins, interferons (including a, Vii, and Y interferons),
interleultin-2,
cytokines, FI~506 (an epoxy-pyrido-oxaazcyclotricosine-tetrone, also lc~own as
Tacrolimus), tumor necrosis factor, pentostatin, thymopentin, transforming
factor betaz,
erythropoetin; antineogenesis proteins (e.g.> anit VEGF, Interfurons), among
others and
anticiotting agents including anticlotting activase. Further examples of
macromolecules
that can be delivered include monoclonal antibodies, brain nerve growth factor
(BNGF),
celiary nerve growth factor (CNGF), vascular endothelial growth factor (VEGF),
and
monoclonal antibodies directed against such growth factors. Additional
examples of
immunomodulators include tumor necrosis factor inhibitors such as thalidomide.
In addition, nulceic acids can also be delivered wherein the nucleic acid may
be
expressed to produce a protein that may have a variety of pharmacological,
physiological or
immunological activities. Thus, the above list of drugs is not meant to be
exhaustive.
16
CA 02544460 2001-06-18
Practically any drug may be used in the instant invention, and there are no
particular
restrictions in terms of molecular weight and so forth.
Additional examples of beneficial drugs that may be employed in the present
invention and the specific conditions to be treated or prevented are disclosed
in
IZEMINGTOIV, supra; The Pharmacological Basis of Therapeutics, by Goodman and
Gilman,
19th edition, published by the MacMillan Company, London; and The Merck Index,
13th
Edition, 1998, published by Merck & Co., Rahway, N.J.
b) Adjnvants
In certain aspects, it may be advantageous to include one or more adjuvants in
the
core to alter the release characteristics of the drug from the device, or to
enhance the
stability of the drug or to alter the solubility of the drug in body fluids or
to alter the
physicochemical characteristics of the core itself. Adjuvants may include
swelling agents
to improve the accessibility of the drug to body fluids or, alternatively,
adjuvants may be
used to slow the release of drug from the device. Examples of such solubility
decreasing
agents include complexation agents, hydrophobic materials and insoluble
polymers. A
surfactant or an effervescent base may be helpful in certain cases to overcome
surface
tension effects, etc.
Adjuvants may also include diluents, buffering agents and preservatives.
Examples
of buffering agents include alkali or alkaline earth carbonates, phosphates,
bicarbonates,
citrates, borates, acetates, succinates and the like, such as sodium
phosphate, citrate, borate,
acetate, bicarbonate and carbonate. These agents may be present in amounts
sufficient to
maintain a pH of the system of between 2 to 9 and preferably 4 to 8, during
manufacturing,
storage and delivery conditions. Examples of preservatives include
benzalkonium chloride,
antioxidants, such as ascorbic acid, sodium bisulfite, parabens, benzyl
alcohol. These
agents may be added in amounts of from about 0.001 to about 5%.
Where the implant is positioned such that no portion of the implant is in
direct
contact with the site of action, for example, the vitreous, diffusion of the
drug through
biological membranes to the site of action may be facilitated by permeation
enhancers (e.g.,
DMSO, detergents, ethanol, isopropyl myristate, oleic acid, azome and the
like). The
determination of proper amounts and methods for using permeation enhancers are
within
the ordinary skill in the art. See, for example, 1ZEMINGTON, supra, Chapter
41.
17
CA 02544460 2001-06-18
3. Tire Orifice
When in use, the devices of this invention are substantially impermeable to
both the
body fluids of the environment and to the drug, except through the orifices
provided in their
outer layer. Thus, the influx of body fluids and the efflux of drug solution
occurs
primarily, if not entirely, through the orifice. The desired rate of release
of the drug is
achieved by providing an orifice of proper area relative to the area of the
device and taking
into account parameters such as the solubility properties of the drug and the
optionally
present adjuvants. It is preferred that the orifice extend through the entire
thickness of the
outer layer such that there is immediate exposure of the core to the body
fluids when the
device is implanted.
The number, configuration, shape and size of the orifices are chosen to
provide the
release rate required to suit a treatment regimen. In some aspects, more than
one orifice
may be provided in the device for the release of drug. When more than one
orifice is
provided, the plurality of orifices should be construed to be of functionally
equivalent to a
single orifice. The orifices can be positioned anywhere on the device
including the edges,
on the same face of the device, or on different faces. The number of orifices
in each device
may range from about 1 to about 5 or more.
The orifices are generally spherical but may be of any design, such as
cubical,
pyramidical, ellipsoidical, conical, and the like, so long as the desired
release rate is
achieved. When the orifice is spherical, its diameter may range from about
0.045 mm or
less to about 6 mm. In some aspects, the diameters may range from about 0.001
mm to 0.5
mm.
The orifice has an area which corresponds to less than 10 percent of the area
of the
device. In some aspects, the orifice has an area which is about less than 7
percent of the
area of the device. In some aspects, the orifice has an area which is about
less than 2
percent, or less than 1 percent of the area of the device. When the device is
provided with a
number of orifices, the sum of the areas of all the orifices comprises less
than 10 percent of
the area of the device.
As provided in the Definitions section, the term "orifice" is a broad term
which
represents an aperture, hole, or opening. Thus, when the device is
cylindrical, an orifice
can also be formed by leaving one of the two spherical faces open, i.e.,
unsealed. In some
I8
CA 02544460 2001-06-18
aspects, both the spherical faces of a cylindrical device can be left open,
forming an orifice
at each spherical face. It is appreciated that to form an orifice by this
manner, the spherical
faces need not be completely left open, i.e., partial opening may also lead to
an orifice at
either end of the cylindrical device. In addition, the cylindrical device may
also be
equipped with additional orifices on other surfaces.
4. Additional Aspects
In some aspects, it may be desirable for the device to further comprise a
backing
layer. The backing layer will be in contact with the surfaces of tile device
which are not in
contact with or adjacent the desired site of therapy. The composition of the
backing layer
may vary with.the drug employed, the site of implantation, compatibility with
agents in
addition to the drug which may be employed in the device and the like. The
backing layer
is biocompatible and substantially impermeable to the drug contained within
the device.
Exemplary compositions for the backing layer include polyesters (e.g., mylar),
polyethylene, polypropylene, polyethylene vinyl acetate,
polytetrafluoroethylene, aclar,
silicone, silastic, nylon, and other film material which are well known and/or
commercially
available.
The device may also comprise an adhesive layer or coating for securing the
device
at the desired insertion site, particularly where the device is to be placed
substantially on
the outer surface of the eye over an avascular region. The adhesive layer may
be in the
form of a release liner or peel strip. The adhesive layer may be made of any
suitable
material which is biocompatible. Many such adhesive layer-forming polymers are
known
in the art. See, for example, U.S. Patents Nos. 5,693,335 and 5,006,342.
In some aspects, the device can be operated as a refillable device. For
example,
where the molecular weight of the drug, the desired dosage, the period of
administration (as
in chronic therapy) and the like are such that the size of the device required
to contain the
desired amount of drug is incompatible with the area of implantation, a device
comprising a
refillable reservoir may be used. The device may be refilled with any one or
all of the
components present in the original core. The device may be refilled by, for
example,
injection of the core material directly into the reservoir of the device,
taking particular care
not to compromise the ability of the device to release the. drug at the
desired rate. Thus, in
some aspects, the outer surface of the device may comprise a self sealing
layer made of a
19
CA 02544460 2001-06-18
non-biodegradable material and is capable of resealing. See, for example, U.S.
Pat. No.
4,300,557, for a description of refillable type devices.
While the present invention focuses on ocular implantation of the devices
disclosed
herein, the devices can be easily implanted in other areas of the body. Thus,
the devices of
S the present invention may be adapted for gastrointestinal, buccal, cervical,
rectal, vaginal,
intrauterine, nasal, and dermal implant use and the like. In addition, one or
more of the
devices may be administered at one time and more than one agent may be
included in the
core.
D. Implantation
Methods of implanting a drug delivery device are well-known in the art, and
include
surgical means, injection, trocar, etc. The ocular implant devices of the
present invention
may be implanted at several anatomical regions of the eye. For example, the
devices may
be placed substantially upon the outer surface of the eye and may be anchored
in the
1 S conjunctiva or sclera, or episclerally or intrasclerally over an avascular
region. The devices
may also be implanted substantially within the suprachoroidal space over an
avascular
region such as the pans plans or a surgically-induced avascular region.
Alternatively, the devices may be implanted in an area in direct communication
with the vitreal chamber or vitreous so as to avoid diffusion of the drug into
the
bloodstream. The devices can also be implanted in the anterior chamber. On the
other
hand, diffusion of the drug to the desired site may be facilitated by forming
holes or tunnels
through the layers of the sclera or other tissue which communicate, with the
desired site of
therapy which lie beneath the device. As a result, the tunnels will lie
beneath the implant
and serve to substantially direct the flow of the drug from the device to the
desired site of
therapy. These holes may be formed by surgical procedures which are known in
the art or
through the application of a permeability enhancing agent described above such
as ethanol,
oleic acid, isopropyl myristate and the like.
Alternatively, the device may be inserted so as to directly communicate with
the
vitrea.l chamber. A hole of suitable size may be made through the sclera to
communicate
with the base of the vitreous body through the pars plane. The implant is
positioned over
the hole within the scleral bed and the flap of the trap door is sewn back
into place. Such
CA 02544460 2001-06-18
placement of the implant wil! allow for the ready diffusion of the drug into
the vitreous and
into the intraocular structure.
The devices can be implanted by using an implanter, the operation of which is
described in U.S. Patent Nos. 3,921,632 and 4,451,254. Surgical procedures,
such as those
known in the art, may be necessary to position large implants. For example,
the implants
can be inserted through a sclerotomy into the suprachoroid. In this instance,
the sclera is
cut to expose the suprachoroid. An implant is then inserted on either side of
the incision.
Alternatively, a partial-thickness scleral trap-door can be fashioned over the
suprachoroid
or an avascular region. An implant is then inserted and the scleral flap is
sewn back into
place to secure the implant.
In many aspects, the device per se can be implanted. In some aspects, the
device
can be placed in a "container" which is then implanted. For example, the
device can be
placed in a "container" such as an artifical lens or a limb first and the
artificial lens or limb
is then ocularly implanted, for example in the anterior chamber. Thus, the
devices of this
I S invention are introduced into a body cavity or area in many different
ways.
E. Methods of Makiag~Implants
Several techniques such as solvent evaporation methods, phase separation
methods,
interfacial methods, extrusion methods, molding methods, injection molding
methods, heat
press methods and the like can be used to prepare the outer layer and or the
entire device.
Such techniques are well-known in the art. See, for example, U.S. Patents Nos.
5,164,188
and 5,660,847, and Handbook of Common Polymers, by J. R. Scott and W. J. Rofh,
Section
64, (1971) published by CRC Press, Cleveland, Ohio.
In one particular aspect, a technique known as injection molding is used. For
a
general description of this technique, see for example, U.S. Patents Nos.
3,432,592,
4,801,460, 4,806, 337, 5,004,601, and 5,082,655, and Cuff', G. and Raouf, F.,
Pharmaceutical Technology, 96-106 (1998).
Briefly, the injection molding technique comprises several steps. In the first
step,
the mold is closed and clamped to prevent it from opening. In the second step,
the
polymeric material is injected through a nozzle and into the cavities of the
mold by moving
a screw to a predetermined distance. By adjusting the distance the screw must
be moved,
the amount of material that is injected into the mold is controlled. The screw
may be
21
CA 02544460 2001-06-18
displaced further to facilitate packing of additional material into maid
cavities to fill the
voids that may have been generated when the mold cools after the first
injection. The
various parameters of the injection and packing steps, such as packing time,
packing
pressure, injection rate, injection pressure can be automated. The mold is
cooled and the
S screw is returned to its pre-injection position. The mold is opened and the
molded parts (in
this case, the implants) are ejected. See Cuff and Raouf, supra.
1. Methods of Forming the Outer Layer
The biocompatible, substantially impermeable outer layer can be obtained by
coating the core with a polymeric composition described above. The coat can be
applied
using organic solvents, and the solvents are vacuum stripped from the coat to
leave a dry
coat. The polymer, at a concentration of from about 10 to about 80 weight
percent is
dissolved or suspended in an organic solvent at the appropriate temperature,
for example
for polylactic polymer, between 60° to 90 °C. The resulting
mixture can be cut, molded,
injection molded, extruded, or poured or sprayed onto a pre-formed core into
any shape or
size for implantation. The spraying can be accomplished in a rotating pan
water or in a
fluidized bed water until the desired coating thickness is achieved.
Alternatively, the core may be dip coated or melt coated. This type of coating
is
especially useful with waxes and oils. In another embodiment, the core may be
compression coated, wherein a suitable polymeric composition may be pressed
onto a
preformed core. In another aspect, an adhesive coat such as shellac or
polyvinyl acetate
phthatlate (PVAP) is applied to the core prior to applying the impermeable
coating in order
to improve adhesion of the impermeable coating to the core. These techniques
are well-
known in the art. See, for example, Handbook of Common Polymers, by J. R Scott
and W.
J. Roff, Section 64, (1971) published by CRC Press, Cleveland, Ohio.
When the outer Iayer is injection molded or extruded into the desired shape,
the
cavity formed by the outer layer can be then filled with the drug composition.
Then, the
ends are sealed with an end cap. At least one orifice is drilled in the lead
end of the device.
Optionally, an orifice is drilled, or preformed in the wall, or an orifice is
sealed with a
break-off tab that is broken open, or cut open, or the Like, at the time of
use.
Alternatively, the core-free device may be loaded with drug by, for example,
immersing the device in a solution comprising the drug for a time sufficient
for absorption
22
CA 02544460 2001-06-18
of the drug. The device may be equipped with a hollow fiber and the drug may
be directly
loaded into the fiber and the device subsequently sealed. Where the activity
of the drug
will not be compromised, the drug-filled device may then be dried or partially
dried for
storage until use. This method may find particular application where the
activity of the drug
of choice is sensitive to exposure to solvents, heat or other aspects of the
conventional
solvent-evaporation, molding, extrusion or other methods described above.
Where a backing layer is to be employed, the polymer solution may be layered
directly onto the backing layer material and the solvent evaporated or a
release liner
attached to the underlying structure. Where desired, a release liner may then
be placed on
top of the polymer layer. Where the device is to comprise an adhesive layer,
the adhesive
layer may be applied to the release liner prior to placing the release liner
on the polymer
layer and/or membrane layer. When the release liner is later removed prior to
insertion of
the device, the adhesive layer will substantially remain on the polymer layer.
Where a refillable reservoir device is desired, the device may be molded in
two
separate portions. At least one of these separate portions may be
substantially concave.
The two portions, which comprise the body of the device, tnay then be sealed
together with
a biocompatible adhesive, such as a silicone adhesive, to form a device having
a
substantially hollow center which may serve as a reservoir or depot for the
drug.
Alternatively, devices comprising a reservoir may be produced by conventional
form-fill-
seal techniques. The refillable device may also be manufactured employing
injection
molding techniques wherein the refillable device may be filled with the drug
or drug
suspension after the outer layer is formed. Alternatively, the device may be
co-molded so
that the.outer surface and the drug core are formed substantially
simultaneously by, for
example, co-injection into a mold during injection molding.
The thickness of the outer layer should be selected as a function of the
material
properties and the desired release rate. The outer layer thickness is not
critical as long as
the specified functions of the outer layer are fulfilled. The outer layer
thickness may be, for
example, from about 0.05 mm to 3 mm. The thickness of the coating necessary to
provide
results in accordance with the present invention can be determined by using
techniques that
are well-known in the art. See, for example, Handbook of Common Polymers,
supra.
Devices can be prepared with differing coating thicknesses but without an
orifice, and
dissolution tests on these devices can be performed. The desired coating
thickness can be
23
CA 02544460 2001-06-18
selected by oprimizing the conditions under which the drug is not released
from the device
during the desired duration of controlled release.
2. Making the Core
The core of the device of the present invention may be prepared using
conventional
tablet excipients and formulation methods and compressed into its final stage
using
standard tablet compressing machines. Depending upon the solubility and the
amount of
drug to be included in the core, any generally accepted soluble or insoluble
inert
pharmaceutical filler (diluent) material may be used to bulk up the core or to
solubilize the
drug. These materials include but are not limited to sucrose, dextrose,
lactose, fructose;
xylitol, mannitol, sorbitol, glycerol monostearate, dicalcium phosphate,
calcium sulfate,
calcium carbonate, starches, cellulose, polyethylene glycols,
polyvinylpyrrolidones,
polyvinyl alcohols, sodium or potassium carboxmethylcelluloses, gelatins, or
mixtures of
thereof.
1 S In addition, the drug may be compressed with a small amount of lubricant.
It is
preferred that a lubricant be mixed with the drug and excipients prior to
compression into a
solid core. Any generally accepted pharmaceutical lubricant, including calcium
or
magnesium soaps may be used. Most preferred is magnesium stearate in an amount
of
about 0.25-S percent by weight of the core.
Drugs may also be formulated with a small amount of a binder material such as
gelatin or polyvinylpyrrolidone (i.e., 94-99.75% of the core comprises the
drug). In such
cases, the components of the core may be subjected to wet granulation.
The particular excipient chosen is dependent in part upon the solubility of
the drug
in the bodily fluid. The ratio of drug to excipient is based in part upon
relative solubility of
the drug in the bodily fluid and the desired rate of release. If the drug is
relatively soluble,
it may be desirable to slow down the erosion of the core by using a relatively
insoluble
excipient such as dicalcium phosphate.
The complete mixture of drug, lubricant, excipient, e~c., in an amount
sufficient to
make a uniform batch of cores may be directly used or can be compressed in a
conventional
production scale tableting machine at normal compression pressures, i. e.,
about 2000-
16000 lbs/sq. in.
24
CA 02544460 2001-06-18
3. Making the Orifice
The orifice may be formed using any technique known in the art. For instance,
the
orifice may be made using a needle or other form of boring instrument such as
a
mechanical drill or a laser to remove a section of the impermeable portion of
the device.
Alternatively, a specially designed punch tip may be incorporated into the
compressing
equipment, in order to pierce through the impermeable portion at the point of
compaction.
The orifice may be made by drilling the appropriate size hole through a wall
of the
device using a mechanical or laser-based process. In the preferred embodiment,
a digital
laser marking system is used to drill the holes required. This system allows
for an array of
apertures to be drilled on both faces of a dosage form simultaneously and at
rates suitable
for production of dosage forms.
The process utilizes a digital laser marking system (for example the
DigiMarkT"'
variable marking system, available from Directed Energy, Inc.) to produce an
unlimited
number of holes through the surface or coating of the dosage form, at rates
practically
suitable for production of dosage forms.
The steps involved in this laser drilling process are as follows: a digital
laser
marking system is focused at a laser stage; the dosage form is moved onto the
laser stage of
the digital laser marking system is pulsed to energize those laser tubes
needed to drill the
desired apertures along a linear array on the dosage form, the dosage form is
moved
forward on the laser stage and the digital laser marking system is again
pulsed as needed to
produce an additional linear array of apertures; the dosage form is then
removed from the
laser stage.
Orifices and equipment for forming orifices are disclosed in U.S. Pat. Nos.
3,845,770; 3,916,899; 4,063,064 and 4,008,864. Orifices formed by leaching are
disclosed
in U.S. Pat. Nos. 4,200,098 and 4,285,987. Laser drilling machines equipped
with photo
wave length detecting systems for orienting a device are described in U.S.
Pat. No.
4,063,064 and in U.S. Pat. No. 4,088,864.
F. Methods for Testing the Device
In order to define the potential drug-release behavior of the devices in vivo,
the
device may be maintained in a measured volume of a saline solution. The
mixture is
maintained at 37 °C and agitated or stirred slowly. The appearance of
the dissolved drug as
CA 02544460 2001-06-18
a function of time may be followed spectrophotometrically or by other
analytical means.
While release may not always be uniform, normally the release will-be free of
substantial
fluctuations from some average value which allows for a relatively uniform
release, usually
following a brief initial phase of rapid release of the drug. Additional
methods are known
in the art. See, for example, REMINGTON, szrpra, Chapter 94.
G. Specific Examples
Ocular devices comprising various types of drugs were prepared and tested for
their
controlled release properties and the duration of release was measured.
Cylindrical devices
from polytetrafluoroethylene, polyfluorinated ethylenepropylene (FEP) or
silicone
materials were prepared with varying number and configuration of orifices.
These
characteristics were summarized in Table 1. The release data were summarized
in Table 2
and graphically displayed in Figures IA-1F and 2-4.
In addition to varying the materials used for making the device, the number
and
conf guration of orifices, as well as the drug to be delivered were varied.
Gentamicin is an
example of very soluble low molecular weight drug. Dexamethasone and cefazolin
are
examples of practically insoluble drugs of low molecular weight. DHPG or
ganciclovir
LU-U2-hydi'oxy-1-(hydroxymethyl) ethoxy]-methyl]-guanine)] is a freely soluble
drug of
low molecular weight whereas BSA (bovine serum albumin) is an example of a
freely
soluble macromolecule.
As more fully discussed in the Examples below, the data indicate that the
present
devices having the orifice area/total surface area of less than 10% can be
successfully used
to deliver a variety of drugs in a controlled manner for a duration of several
weeks or even
months. These characteristics are maintained regardless of the number and
configuration
of orifices present in the device. Moreover, unlike the prior art devices, the
present devices
do not require the presence of an osmotic agent, or an ion to propel the drug
from the
device.
While the above described embodiments of the invention are described in terms
of
preferred ranges of the amount of effective agent, these preferences are by no
means meant
to limit the invention. As would be readily understood by one skilled in the
art, the
preferred amounts, materials and dimensions, actual release rates and duration
of release
depend on a variety of factors in addition to the above, such as the disease
state being
26
CA 02544460 2001-06-18
s
treated, the age and condition of the patient, the route of administration, as
well as other
factors. Thus, the following examples should be viewed as mere illustrations
and not
limitations on the scope of the invention disclosed herein.
EXAMPLES
Examples 1-6: Cylindrical Devices with Varied Number and Configuration of
Orifices
A Teflon~ tube obtained from Small Parts, Inc., Florida of 0.97 mm internal
diameter and 1.31 mm outer diameter was used to prepare the cylindrical
devices of
Examples 1-6. In all these Examples, the orifices) in each device is
spherical. In the case
of Examples 1-3 and S, each orifice had an internal diameter of 0.25 mm. The
orifice of
the device in Example 6 had an internal diameter of 0.3 mm. The orifice of the
device in
Example 4 was formed by leaving open (unsealed) one spherical face of the
cylindrical
device. The length of the device varied in each case, and ranged from 3.7 mm
(for
I S Example 6) to 7.2 mm (for Examples 2 and 4). These characteristics were
summarized in
Table I.
27
CA 02544460 2001-06-18
4-;
O
N
N ~ N ~ n n ~ ' ~ \0 N
00 N ~ ~ ~ N d p~f'v ~ ' N
' ~ 1 ~'
O ~' M r1'~ V1~ ~ m..
N
O n
~
00'- v~r1OyO~ Ov 'vtv0 ~G~G N p o
et M M M M o N M N N N N N
...
d'
M
N
V
V ~ ~ N o0vDt~et d etN o0.-~t~ ~tetv0v0et v~N
4
v100o0o0Ov o0 O ~Dd M N M et~OC~V lw0 v0OD
N -~- N etM oo ..-~OvC y0t'~~ O O O ~ ~-N O C
O C O C~1O O -~ 'v?'v'i~D~Ct'~~DC O O O O C 00
4 x
V
.b
O
x
~o
0
~i
er a M ~nM c~N vo ~cooO .-.--.O ............._~..."~n
" M
V ~-~ M ~ tnN Cy N N N ~ N N - .-~.-..-r.-.r.~..
Wit'N ~D C : : t 0 00 t ~C~DvCvG ~Gv
b 7
~ N n .- .-M e o ~ C
N M N M M - M M N N N N N V1V1~1V1 tf1~
~~
a
(~ N
~
A
1:;
NO~ 01Ovp~n ~ O~ M 00et.-~t~ 00V1t~d'~ 00[wM
'~i'~tM etl~ 00 0000~ lw0 t~N M v'100 Ovet
O O ~ -~O ~1 N M ~Go0O ~tO O O O O --
C O C O O o CO .-:.-..-~.~cV .-:p C GOo C C
H .e
H o
~
v0
x
~N
MO
"' ~~ ~'--~~ M -~ M ~tN M ~'~!'tN N M N M N M N
O
.oH
~ N
4i
~ ~
~G
~ V ~ U ~~~ V ~ ~ a ~ ~ ~ ~ ~ ~ 0Ø 4 ~ 0.
N ~
~
A o m ~ ~ ~~ a A A 0.0 ~ 0.A a A x a ~ x '~
~ ~ ~ Q Ca A Ca
w ~
'~
t7t~U C7~U
- N M ~ ~A1D t~ 00Ov "~'~ ~ ~ ~ ~ ~ ~ ~ A
4r
.y N ..
. ,
28
CA 02544460 2001-06-18
In each case, the general procedure for preparing the cylindrical device was
as
follows. The desired number of orifices on the longitudinal surface (except in
the case of
Example 4) of the Teflon~ tube were provided by using a mechanical drill.
Where there
were multiple number of orifices, the orifices were spaced approximately 1-2
mm from
S each other. The Teflon~ tube was cut using a sharp knife, and sealed with
epoxy resin on
one end, about 3-4 mm from the nearest orifice (except in the case of Example
4). The tube
was weighed on a microbalance. The drug to be delivered was packed into the
tube using a
spatula and a small metal plunger. When the desired amount of the drug was
packed, the
tube was cut on the open-end at a distance of about to 0.1-0.2 mm from the
packed drug.
The open end of the tube was sealed. The total orifice area/total surface area
of the device
ranged from 0.152 % (Example 2) to 2.286% (Example 4).
In the case of Example l, the device was 5.2 mm long and comprised 4.1 mg of
fluorescein sodium, obtained from EM Science, NJ. The device in Example 2 was
7.2 mm
long and comprised 3.5 mg of BSA, obtained from Sigma Chemical Co., Milwaukee,
WI.
The device in Example 3 was 5.7 mm long and comprised 3.3 mg of gentamicin.
The
device in Example 4 was 7.2 mm long and comprised 3.9 mg of gentamicin. The
device in
Example 4 was distinct from the devices of Examples 1-3 in that in the latter
case, each of
the devices contained one orifice on its longitudinal surface, whereas, in
Example 4, the
orifice was formed by leaving open (r. e., left unsealed) one spherical face.
The device in Example 5 was 6.7 mm long and comprised 3.9 mg of cefazolin.
Cefazolin sodium powder was obtained from LyphoMed, Inc., and the cefazolin
acid was
precipitated by using an acid. The term cefazolin as used throughout this
application refers
to the cefazolin acid prepared in this manner. The device in Example 6 was 3.7
mm long
and comprised a combination of gentamicin and cefazolin in a mixture that
ranged from 1:3
to 3: l, with the total weight being 0.376 mg.
Release study
In each case, the delivery device was placed in 4~ 10 ml of saline solution in
a vial.
The vial was incubated at 37°C. Saline samples of approximately 1-S ml
were taken at
specified times while adding to the vial an equal amount of fresh saline. The
amount of
fluorescein released was measured using standard analytical procedures that
are well-
known for the assay of the drug in question.
29
CA 02544460 2001-06-18
For example, the release of fluorescein and BSA were measured using a UV
spectrophotometer, Hewlett Packard Vectra X1~~IUV*operating at 280 nm and
ambient
temperature. The release of gentamicin was measured using standard
fluorescense
immunoassay methodology (FPIA) and TDX instrumentation. Cefazolin release was
. monitored using the above-described UV spectrophotometer operating at 272
nm. The
results were summarized in Table 1 (supra) and were displayed graphically in
Figures 1 A-
1F.
The data from the Figures and Table 1 indicate that controlled release
delivery for
extended periods can be achieved by using the devices of this invention that
are
characterized by a ratio of orifice arealtotal surface area of less than 10%,
regardless of the
solubility of the drug and the number and configuration of the orifices of the
device. The
data also indicate that more than one drug can be delivered by the present
devices and that
the release characteristics of each drug can be influenced by the other. See,
Examples 4, 5,
and 6, Figures lA-1F and Table 1.
Examples 7-9: Delivery Device Comprising Dexamethasone (Cylindrical Devices,
Varied
Orifice Number and Configuration)
By following the procedure described in the case of Examples 1-6 above,
cylindrical devices o,~ polyfluorinated ethylenepropylene (FEP) material
comprising
dexamethasone were prepared. In Example 7, the device had three orifices on
the
longitudinal surface of the cylindrical device and both the spherical faces of
the device are
sealed. The device comprised 2.9 mg of dexamethasone. In Example 8, the device
comprised of a total of four orifices, one resulting from a spherical face
which is left open
(i.e., unsealed). Three additional orifices were made on the Longitudinal
surface of the
device as described above. The device comprised of 3.4 mg of dexamethasone. In
the case
of both Examples 7 and 8, the devices were 7.2 mm long.
In Example 9, the device comprised of a total of two orifices, each one
resulting
from the spherical face which is left open (i.e., unsealed). The device was
5.2 mm long and
comprised of 2.6 mg of dexamethasone.
In the case of Examples 7 and 8, each orifice was spherical and had an
internal
diameter of 0,5 mm, with a total orifice areahotal surface area of 1.884% and
4.104%,
*Trade-mark 30
CA 02544460 2001-06-18
respectively. The corresponding figures in the case of Example 9 are 0,94 mm
and
5.962%. See Table 1. In all cases, the tubes had an internal diameter of 0.94
mm and an
outer diameter of 1.27 mm.
S Release Study
The procedure was similar to that as described in Examples 1-6 above. The
amounts of dexamethasone released was measured using HPLC, C 18 column with a
W
detection operating at 280 nm. The data were smnmarized in Table 1 and
displayed
graphically in Figure 2.
The data indicate that regardless of the number and configuration of the
orifices in
each device, as well as the length of the device, all three devices provided
controlled
release delivery over a prolonged period, in these cases, from 365 to 455
days. The data
support the general conclusion that so long as the orifice area/total surface
area of the
device is less than 10%, such devices can be used to deliver drugs in a
controlled release
manner over prolonged periods of time.
Examples 10-13: Delivery Devices Comprising an Aldose Reductase Inhibitor
(ARI)
Cylindrical Devices, Varied Orifice Number and Configuration)
By following the procedure described in Example 4 above, cylindrical devices
of
Teflon~ material comprising ARI were prepared. ARI represents a generic groups
of
compounds known as aldose reductase inhibitors. Such aldose reductase
inhibitors are
well-known in the art. See, for example Sorbinil. Any of the aldose reductase
inhibitors
can be used for delivery with the present devices. In Example 10, the device
comprised of
a total of three orifices, wherein two orifices were created by leaving open
each of the
spherical face of the cylindrical device. The third orifice was created by a
mechanical drill.
The device comprised of 2-3 mg of an ARI.
In Example I I, the same procedure as in Example 10 was followed, to create a
cylindrical device, except that in this case, the device consisted of four
orifices. One orifice
was derived finm each of the two spherical faces which were left unsealed. Two
additional
orifices were created on the longitudinal surface of the cylindrical device as
described
above.
31
CA 02544460 2001-06-18
In Example 12, the procedure as in Example 11 was followed to prepare a
cylindrical device consisting of a total of five orifices, one from each
unsealed spherical
face of the device and three on the longitudinal face.
In Example 13, the procedure as in Example 10 was followed to prepare a
cylindrical device having two orifices only, wherein one orifice resulted from
each of the
spherical face which is left open, l. e., unsealed. No additional orifices
were created on the
longitudinal surface of the cylindrical device.
In all the above Examples (10-13), Teflon~ tubes of 0.97mm internal diameter
and
1.31 mm outer diameter were used. The area of each orifice created from each
spherical
face of the device was 1.48 mmz. Each orifice created on the longitudinal
surface (except
for the case of Example 13) is spherical and has an internal diameter of 0.5
mm. The
length of the tube in case of Examples 10 and 13 was 5.2 mm and in the case of
Examples
11 and 12, it was 6.2 mm. The devices had a combined orifice area/total
surface area
ranging from 6.134% to 7.327%. See Table 1. The amount of drug in each device
ranged
from 2 mg in Example 10 to 2.2 mg in Example 13 to 2.6 mg each in Examples 1 I
and 12.
The release was measured for 579 days.
Release Study
The procedure was similar to that as described in Example 7 above. The amount
of
AR.I released was measured using HPLC methodology, with a C18 column and a W
detector operating at 280 nm. The data were summarized in a table and
graphically
displayed in Figure 3.
These results indicate that controlled release delivery over prolonged
periods, in this
case, several hundreds of days, can be obtained regardless of the number and
configuration
of the orifices in the device.
Examples 14-20: Delivery Device Comprising Ganciclovir (9-~(2-hydroxy-1-
(hydroxymethyl) ethoxy~-methyll-guanine (DHPG)1 (Cylindrical Device with Both
Spherical Ends Sealed, Varied Orifice Number)
Small holes were drilled longitudinally in the wall of a silicone tube
(Examples 14-
19) or a Teflon~ tube (Example 20), using an Excimer laser. The silicone
devices were
32
CA 02544460 2001-06-18
prepared as following: a bead of silicone adhesive was injected approximately
1.5 mm into
one end of a tube. After the adhesive dried and cured, about 5 mg of DHPG (in
case of
Examples I4-19) or 50 mg of DHPG (in case of Example 20) was packed into the
open end
of the tube with a small plunger. The tube was then cut to an appropriate
length, leaving
S 1.5-2.0 mm at the end. A bead of adhesive was injected to seal the open end.
The adhesive
was allowed to dry and cure before the DHPG delivery system was used.
The Teflon~ device for Example 20 was prepared using the procedures described
in
the case of Example 13 above, but using DHPG, instead of ARI as the drug.
The tube in each case was 10 mm in length. The silicone tubes had an outer
diameter of 1.65 mm and an internal diameter of 1.02 mm, whereas the Teflon~
tube had
an outer diameter of 5 mm and an internal diameter of 3.175 mm. All the
silicone tubes
had their both spherical faces sealed and two or three orifices were provided
on their
longitudinal surfaces. The Teflon~ tube device on the other hand had its both
spherical
faces left open, creating the only two orifices of the device.
The diameter of the orifice in the silicone devices varied from 0.125 mm to
0.250
mm. The orifices of the Teflon~ device had an internal diameter identical to
the tube's
internal diameter, namely, 3.175 mm. The ratio of orifice area to the total
surface area of
the silicone device ranged from 0.044 to 0.262, whereas the corresponding
value for the
Teflon~ device was 8.065. See Table 1. The amount of DHPG in all cases was 5
mg per
device, except for in Example 20 where the amount of DHPG was 50 mg.
Release Study _.
The methodology was as described in the case of Example 5. The amount of DHPG
release was measured by HPLC. The data for silicone devices were summarized in
Table 2
and displayed graphically in Figure 4. These data indicate that as the ratio
of orifice area to
total surface area of the device decreased, the duration of release increased,
indicating
further that prolonged release can be obtained by lowering the ratio of
orifice area to total
surface area of the dwice. The fact that the Teflon~ device, having the
greatest ratio under
consideration (8.0625%), released the drug very quickly (in about 24 days)
further supports
this result. Among the silicone devices, the ratio of orifice area/surface
area and the release
duration appears to be strongly correlated, indicating that as the ratio
decreased by half, the
duration of release increased roughly by two-fold.
33
CA 02544460 2001-06-18
The data show that devices with orifice areas less than 10°l0 of the
total surface area
of the device, more preferably, less than 1 % for silicone devices can deliver
drugs for
prolonged time.
Example 21: Biodegradable Delivery Device Comprising Polylactic Acid Polymer
and Ganciclovir [9-((2-hYdmxy-1-(hydroxymethyl) ethoxy]-methyl-guanine~DHPG~
(Cylindrical Device with Both Spherical Ends Open, One Additional Orifice)
Polylactic acid biodegradable delivery devices were prepared by using
injection
molding process, which has been generally described supra. The device was
cylindrical
with both spherical ends open and had one orifice on its longitudinal face
obtained by a
mechanical drill. The total orifice area was less than ten percent of the
total surface area of
the device. The device comprised of 10.8 mg of DHPG. Release of DHPG from the
device
was measured as in the above Example. The release data was shown graphically
in Figure
S. The data indicate that biodegradable polymeric devices can deliver drugs at
a controlled
rate for a prolonged period when the total orifice area is less than ten
percent of the surface
area of the device.
From the foregoing description, one of ordinary skill in the art can easily
ascertain
the essential characteristics of the instant invention, and without departing
from the spirit
and scope~thereof, can make various changes and/or modifications of the
invention to adapt
it to various usages and conditions. As such, these changes and/or
modifications are
intended to be within the full range of equivalence of the following claims.
34
