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BACKGROUND OF THE INVENTION
This invention relates to a method and device for the controlled continuous
administration of drug to the eye over a prolonged period of time. Still
more particularly, this invention relates to an ocular drug device capable
of bioeroding in the environment of the eye concurrently with the
dispensing or at a point in time after the desired amount of drug has been
administered.
Presently, diseases of the eye are still conventionally treated by
periodically applying ophthalmic drugs in liquid or ointment form. While
this method of administration is suitable in certain instances, a serious
shortcoming is the failure of these types of dosage formulations to
dispense the drug in a continuous manner. Periodic application of these
dosage forms, even though they be applied at intervals during the day and
night, results in the eye receiving a massive, but unpredictable, amount
of drug at each time of application. The result of this intermittent
administration is that the level of drug surges to a peak at the time the
drug is applied to the eye, followed by a decline in concentration. Thus,
a plot of drug in the eye and surrounding tissues vs time, after
administration of several dosage forms a day has the appearance of a
series of peaks which may surpass the toxic threshold of the drug and
valleys which fall below the critical point needed to achieve the desired
therapeutic effect. Further, drug administered via an ointment or liquid
form of therapy is washed away rapidly by tear fluid, leaving the eye
without medication until the next application. Moreover, in some ocular
conditions characterized by constant deterioration, i.e. glaucoma,
continuous treatment offers extremely important therapeutic advantages.
Most ointment dosage forms presently available are in unsterilized form,
and are generally difficult to use without impairment of vision.
It was proposed, late last century, to use water soluble drug containing
gels of glycerinated gelatin that are shaped to the form of a lamella or
eye disk. Such lamellae are applied to the eye to supply drug thereto. In
use, the glycerinated gelatin vehicle dissolves almost instantly in tear
liquid, producing the same type of effect as do liquid dosage forms. Thus,
these disks are not suitable for providing for prolonged or sustained
continuous release of a drug because of their rapid rate of dissolution.
Further information on these water soluble dosage forms can be found in
Remington's Pharmaceutical Sciences, XIII, pp. 547-8 (Mack Publishing
Co., Easton, Pa., 1965); Fishburn, An Introduction to Pharmaceutical
Formulation, p. 116 (Pergman Press Ltd., New York City, N.Y., 1965); and
U.S. Pat. No. 273,410, Mar. 6, 1883.
Recognizing these disadvantages, a significant advance has recently been
made in the field of ophthalmic drug delivery systems. In this regard,
U.S. Pat. No. 3,416,530, granted Dec. 17, 1968, entitled "Eyeball
Medication Dispensing Tablet", and Ser. No. 831,761, filed June 9, 1969,
entitled "Ocular Insert", disclose a drug dispensing ocular insert which
slowly releases drug to the eye for prolonged periods of time. Such ocular
inserts are fabricated of materials that are biologically inert,
non-allergenic, and insoluble in tear liquid. To initiate the therapeutic
program, the ocular insert is placed in the upper or lower sac of the eye
bounded by the surfaces of the sclera of the eyeball and conjunctiva of
the lid. Since the material from which the ocular insert is formed is
insoluble in tear liquid, it retains its integrity and remains intact
during the course of therapy, acting as a reservoir to continuously
release drug to the eye and surrounding tissues at a controlled rate. On
termination of the therapeutic program the ocular insert is removed from
the eye. Thus, a single such ocular insert provides the complete
ophthalmic dosage regimen for a particular time period, on the order of 24
hours or longer. More frequent repeated applications which are necessary
with liquids, ointments, or water soluble lamellae are avoided.
While the drug dispensing ocular inserts described above, which deliver
drug to the eye continuously and in a controlled manner over a prolonged
period of time, have proved to be markedly superior to the prior art
ointments and liquids, there remain, however, improvements to be made. The
ocular insert, after insertion in the eye sac, is designed to remain
intact during the course of therapy, and does so since it is formed of
material insoluble in tear liquid. On termination of the therapy program
the insert must be removed, which may present difficulty and discomfort to
some patients. In rare instances, the simple removal if made more
difficult by unwanted migration of the insert to the upper fornix, where
it may remain long after the entire drug supply has been released to the
eye. Further, as is often conventional in ophthalmic practice,
physician-patient contact is not of a sufficient degree so as to insure
that medical instructions from the doctor are accurately carried out by
the patient. Thus, in the case of the use of an insoluble ocular insert,
there is no certainty that the patient will remove the device when
scheduled to do so. This is particularly true with elderly patients who
often forget or are simply unable to remove the device due to failing
memory or eyesight.
SUMMARY OF THE INVENTION
Accordingly, it is an object of this invention to provide an improved drug
dispensing ocular insert for the controlled continuous administration of
drugs to the eye over a prolonged period of time.
Still another object of this invention is to provide an improved drug
dispensing ocular insert which does not have to be removed from the eye
after termination of the therapeutic program.
A further object of this invention is to provide an improved method for
treating diseases of the eye.
Another object of this invention is to provide an improved drug dispensing
ocular insert for delivering drugs to the eye with increased efficacy.
A still further object of this invention is to provide a bioerodible ocular
device which can be adapted to medications having either relatively high
or relatively low solubilities in eye fluids.
In accomplishing these objects, a major aspect of this invention resides in
an ocular insert for the controlled continuous administration of a
predetermined dosage of drug to the eye, comprising one or more
reservoirs, each of the reservoirs comprised of a drug formulation
confined within a bioerodible drug release rate controlling material, the
insert being of an initial shape which is adapted for insertion and
retention in the sac of the eye bounded by the surfaces of the bulbar
conjunctiva of the sclera of the eyeball and the palpebral conjunctiva of
the lid, the material continuously metering the flow of a therapeutically
effective amount of drug from the reservoir to the eye at a controlled
rate over a prolonged period of time, and wherein the insert bioerodes in
the environment of the eye concurrently with the dispensing or at a point
in time after the dispensing of the therapeutically desired amount of
drug.
One embodiment of the invention described above resides in an ocular insert
for the controlled continuous administration of a predetermined dosage of
drug to the eye over a prolonged period of time, comrising a body of
bioerodible drug release rate controlling material containing a drug
formulation confined therein, the body being of an initial shape which is
adapted for insertion and retention in the sac of the eye bounded by the
surfaces of the bulbar conjunctiva of the sclera of the eyeball and the
palpebral conjunctiva of the lid, the body continuously metering the flow
of a therapeutically effective amount of drug to the eye at a controlled
rate over a prolonged period of time, and wherein the body bioerodes in
the environment of the eye concurrently with the dispensing or at a point
in time after the dispensing of the therapeutically desired amount of
drug.
In another aspect, this invention resides in an ocular insert for the
controlled continuous administration of a predetermined dosage of drug to
the eye, comprising (1) an inner reservoir containing a drug formulation
confined therein, and (2) an outer membrane formed from drug release rate
controlling bioerodible material surrounding the inner reservoir, the
membrane being permeable to passage of drug, but at a lower rate than
through the inner reservoir, the insert being of an initial shape which is
adapted for insertion and retention in the sac of the eye bounded by the
surfaces of the bulbar conjunctiva of the sclera of the eyeball and the
palpebral conjunctiva of the lid, the outer membrane material continuously
metering the flow of a therapeutically effective amount of drug from the
reservoir to the eye at a controlled rate over a prolonged period of time,
and wherein the insert bioerodes in the environment of the eye
concurrently with the dispensing or at a point in time after the
dispensing of the therapeutically desired amount of drug.
In still another aspect, this invention resides in an ocular insert for the
controlled continuous administration of a predetermined dosage of drug to
the eye over a prolonged period of time, comprising a plurality of
reservoirs, each of the reservoirs comprised of a drug formulation
confined within a drug release rate controlling material, the reservoirs
characterized by being either:
1. a microcapsule of an initial size and configuration such as to be
capable of being eliminated from the ocular cavity through the punctum
with tear fluid, or
2. a microcapsule of bioerodible material; the reservoirs being distributed
throughout a bioerodible matrix material permeable to the passage of drug
at a higher rate than through the drug release rate controlling material,
the latter material metering a therapeutically effective amount of drug
from the reservoir to the eye at a controlled rate over a prolonged period
of time, the insert being of an initial shape which is adapted for
insertion and retention in the sac of the eye bounded by the surfaces of
the bulbar conjunctiva of the sclera of the eyeball and the palpebral
conjunctiva of the lid, and wherein the reservoir and matrix are
eliminated from the ocular cavity by bioeroding in the environment of the
eye or the reservoir eliminated by passage through the punctum, the
elimination taking place concurrently with the dispensing or at a point in
time after the dispensing of the therapeutically desired amount of drug.
Other objects, features and advantages of the invention will become more
apparent from the following description when taken in conjunction with the
drawings and from the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings:
FIG. 1 is a view partly in front elevation and partly diagrammatic of a
human eye, illustrating an ocular insert of this invention is an operative
position soon after insertion in the eye.
FIG. 2 is a view partly in vertical section and partly diagrammatic of an
eyeball and the upper and lower eyelids associated therewith showing the
ocular insert of this invention in operative position.
FIGS. 3, 4, 5, 6 and 7 are cross-sectional views of several embodiments of
ocular inserts of this invention.
DETAILED DESCRIPTION OF THE INVENTION
The term "bioerodible", as used in the specification and claims, is defined
as the property or characteristic of a body of a microporous, solid or gel
material to innocuously disintegrate or break down as a unit structure or
entity, over a prolonged period of time, in response to the environment in
the eye by one or more physical or chemical degradative processes, for
example by enzymatic action, oxidation or reduction, hydrolysis
(proteolysis), displacement, e.g. ion exchange, or dissolution by
solubilization, emulsion or micelle formation, and which material is
thereafter absorbed by the eye and surrounding tissues, or otherwise
dissipated, such as by elimination from the ocular cavity through the
punctum with tear fluid.
As used in the instant specification and appended claim, the term
"prolonged period of time" is meant to include time intervals of from at
least 8 hours to approximately 30 days or higher and preferably periods of
from 1 to 8 days. It should be noted that this term is applied with
reference to the time interval over which the drug is released and also
with reference to the time interval over which the insert and component
materials bioerode in the environment in the eye, although each of the
aforesaid time periods may not necessarily be concurrently coextensive in
duration.
The term "reservoir", as used herein to define the drug-containing portion
of the ocular insert, is intended to connote a broad class of structures
capable of fulfilling the intended function and, as will be hereinafter
more completely developed, includes a plurality of discrete,
drug-containing microcapsules or a porous, hollow, solid, gel or liquid
drug-containing body of material. The microcapsule can be formed as a
hollow container having the drug therein or be formed as a solid or porous
particle having the drug distributed therethrough.
In accordance with the present invention, there is provided an ocular
insert for the controlled continuous dispensing of a predetermined dosage
of drug to the eye over a prolonged period of time, comprising one or more
reservoirs, each of the reservoirs comprised of a drug formulation
confined within a bioerodible drug release rate controlling material, the
insert being of an initial shape which is adapted for insertion and
retention in the sac of the eye bounded by the surfaces of the bulbar
conjunctiva of the sclera of the eyeball and the palpebral conjunctiva of
the lid, the material continuously metering the flow of a therapeutically
effective amount of drug from the reservoir to the eye at a controlled
rate over a prolonged period of time, and wherein the insert bioerodes in
the environment of the eye concurrently with the dispensing or at a point
in time after the dispensing of the therapeutically desired amount of
drug.
Referring particularly to FIGS. 1 and 2, a human eye is shown, more or less
diagrammatically, as comprising an eyeball 1 and upper and lower eyelids 2
and 3, respectively, the eyeball 1 being covered for the greater parts of
its area by the sclera 4 and at its central portion by the cornea 5. The
eyelids 2 and 3 are lined with an epithelial membrane or palpebral
conjunctiva. The sclera 4 is also lined with an epithelial membrane or
bulbar conjunctiva which covers the exposed portion of the eyeball
including the cornea 5, that portion covering the cornea being
transparent; that portion of the palpebral conjunctiva which lines the
upper eyelids 2 and the underlying portion of the bulbar conjunctiva
defining the upper sac 7 and that portion of the palpebral conjunctiva
which lines the lower eyelid 3 and the underlying portion of the bulbar
conjunctiva defining the lower sac 11. Upper and lower eyelashes are
indicated at 8 and 9, respectively.
An ocular insert 12 is shown in operative position in the lower sac 11 of
the eye. Other details of the eyeball 1 are not directly concerned with
the structure of the instant invention and, therefore, details showing the
description thereof are being omitted in the interest of brevity.
To use the ocular insert of the invention, as illustrated in FIGS. 3, 4, 5
and 6, it is inserted within the upper 7 or lower sac 11. Placement in the
lower sac is preferred due to the tendency of the eye to roll upwardly
during sleeping, known as Bell's phenomenon, which may cause discomfort to
some patients if the insert is located in the upper sac 7. The ocular
device illustrated in FIG. 7 is inserted in the area surrounding the
corneal surface of the eye lying in both the upper and lower sacs 7 and
11.
Once in place, the ocular insert functions to continuously administer a
metered amount of drug from the reservoir to the eye and surrounding
tissues over a prolonged period of time through the primary drug transfer
mechanisms of: (1) "Permeation Control Release", i.e. the controlled
release of the drug by the processes of: (a) diffusive transfer by
controlled flow of drug through the rate controlling material of the
insert, and/or (2) "Erosion Control Release", i.e. the metered release of
entrapped drug contained in the release rate controlling material as the
material bioerodes in a controlled and predetermined manner over a
prolonged period of time in response to the action of the environment in
the eye. It will be understood with regard to mechanism (1) above, i.e.
Permeation Control Release, that the rate controlling material can be
either of an imperforate or microporous nature, and therefore flow of drug
can be effected by molecular diffusion as is the mode in the case of
imperforate rate controlling materials, or by viscous diffusive flow as is
the mode in the case of microporous rate controlling materials which are
impregnated with eye fluids. Both of these modes of drug transfer are
intended to be included herein. It is further intended to include as
microporous material hydrophilic materials which may be initially
imperforate, but which swell and become microporous in structure in the
environment of the eye. In any event, after the drug leaves the ocular
insert, it is transported to the eye and surrounding tissues, including
the corneal epithalium, by the flow of tear liquid and the blinking action
of the eyelids.
Any material having the ability to control the rate of release of drug over
a prolonged period of time by either of these mechanisms, or a combination
of these mechanisms, (1) or (2) above, is herein defined as "drug release
rate controlling material".
Another mechanism for drug release which must be considered in the case of
inserts made from water permeable materials and water soluble drugs is
that of simple dissolution of the drug, as for example by leaching.
Release of drug by this mode is not preferred due to the fact that it is
difficult to control.
Depending upon the particular embodiment, the drug reservoir can be of drug
release rate controlling material or otherwise. However, as is apparent in
the latter case, the drug must first pass through drug release rate
controlling material prior to reaching the eye. It is therefore critical
to the practice of this invention for all embodiments that the drug pass
through the drug release rate controlling material to meter the flow
thereof at some point after or concurrent with the release of drug from
the reservoir and prior to reaching the eye. The drug release rate
controlling material can be of the barrier or membrane type for example as
shown in FIGS. 3 or 4, or of the matrix type for example as shown in FIG.
5.
It has been found that the ocular insert of this invention provides several
important advantages over known devices and methods of administering drugs
to the eye. One important advantage of the claimed insert resides in the
fact that, in addition to the ability to effectively control the amount of
drug dispensed in a continuous manner and over a prolonged time span with
the attendant advantages thereto, it is not necessary for the patient to
remove the device from the eye at the termination of the therapeutic
program as a result of its bioerodible characteristics. Thus, the devices
of this invention lend themselves to the obtainment of the benefits of
continuous administration and also minimize the disadvantages of having to
remove the ocular insert from the eye. This latter aspect is a
particularly important feature since, by the very nature of the anatomy
involved, tasks such as removal of an object from the eye are made
increasingly more difficult. Moreover, risks of patient non-compliance
with medical instructions, a well known factor in ophthalmic practice, are
minimized to a large degree by the inherent drug administration
pre-program dosage and terminating capabilities of the devices of this
invention.
Yet, another important advantage of the devices of this invention resides
in the ability to effectively control the rate of release of drug in a
zero order manner, that is, the rate of release of drug is substantially
independent of time throughout the major portion of the administration
period. This aspect further enhances the therapeutic benefits to be
obtained by insuring that the drug is both continuously available and at
substantially the same dosage rate. Alternatively, drug can be
administered from the device according to other predetermined time release
patterns. One embodiment that is particularly suited to provide drug
release patterns that are for example sinusoidal, parabolic, and the like,
is that illustrated in FIG. 6. As more fully described hereinafter,
varying release patterns can be obtained by appropriate selection of
reservoirs having different drug release rate characteristics for use in a
given ocular insert.
Still another benefit to be derived by use of the instantly claimed insert
is the increased therapeutic efficacy per unit amount of drug
administered.
The ocular insert can be fabricated in any convenient shape for comfortable
retention in the sac of the eye. Thus, the marginal outline of the ocular
insert can be ellipsoid, donut-shape, bean-shape, banana-shape, circular,
rectangular, etc. In cross-section, it can be doubly convex,
concavo-convex, rectangular, etc. as the ocular insert in use will tend to
conform to the configuration of the eye, the original cross-sectional
shape of the device is not of controlling importance. Dimensions of the
device can vary widely. The lower limit on the size of the device is
governed by the amount of the particular drug to be supplied to the eye
and surrounding tissues to elicit the desired pharmacologic response, as
well as by the smallest sized device which conveniently can be inserted in
the eye. The upper limit on the size of the device is governed by the
geometric space limitations in the eye, consistent with comfortable
retention of the ocular insert. Satisfactory results can be obtained with
an ocular device for insertion in the sac of the eye of from 4 to 20
millimeters in length, 1 to 12 millimeters in width, and 0.1 to 2
millimeters in thickness. Several embodiments of these inserts are
exemplified in FIGS. 3 through 7, inclusive.
In one aspect of this invention, as illustrated in FIGS. 3 and 4, the
ocular insert comprises (1) an inner reservoir containing a drug
formulation confined therein, and (2) an outer membrane formed from drug
release rate controlling bioerodible material surrounding the inner
reservoir, the membrane being permeable to passage of drug, but at a lower
rate than through the inner reservoir, the insert being of an initial
shape which is adapted for insertion and retention in the sac of the eye
bounded by the surfaces of the bulbar conjunctiva of the sclera of the
eyeball and the palpebral conjunctiva of the lid, the outer membrane
material continuously metering the flow of a therapeutically effective
amount of drug from the reservoir to the eye at a controlled rate over a
prolonged period of time, and wherein the insert bioerodes in the
environment of the eye concurrently with the dispensing or at a point in
time after the dispensing of the therapeutically desired amount of drug.
FIG. 3 illustrates generally, by reference numeral 19, an embodiment of
this invention wherein the bioerodible ocular insert is comprised of an
inner reservoir 20 which is formed of a bioerodible matrix material having
drug 21 dispersed therethrough. Surrounding matrix 20 is a rate
controlling membrane 22 which is also bioerodible in the eye. Both matrix
20 and membrane 22 are permeable to the passage of drug by diffusion, that
is, molecules of the drug can dissolve in and diffuse through these
materials; however, the permeability of membrane 22 to drug is lower than
from the matrix 20 so that release of drug through membrane 22 is the drug
rate release controlling step from the ocular insert. The inner matrix 20
serves as a depot or reservoir source for the drug and can be a porous,
solid or gel material. Drug molecules move through the inner matrix 20 by
diffusion, thereby uniformly saturating the innermost surface of membrane
22 with drug after equilibrium conditions are reached. Drug is
continuously metered through and removed from the outer surface of
membrane 22 where it is made available to the eye fluids and tissues.
An advantage of the insert of the type illustrated in FIG. 3 is that it can
be adapted to release drug in a zero order manner, that is, at a constant
rate and over a prolonged period of time. By the appropriate design and
selection of materials, drug release from the device is preferably
primarily effected by a "permeation control release mechanism" and
includes a sequence of steps characterized by controlled drug diffusion
through membrane 22 followed by a combination of leaching of drug by the
tear liquid and the blinking action of the eyelids in order to transport
the drug from the outermost surface of membrane 22 to the eye and
surrounding tissues. Release rate is controlled by system variables such
as the diffusivity and solubility of the drug in the membrane material 22
and the thickness of this material. Design of an ocular device, therefore,
necessitates selection of materials and other parameters in order to
provide the proper release rates and dosage regimen, depending upon the
particular drug to be used. The following are generalized considerations
in order to properly design an ocular insert of the type illustrated in
FIG. 3.
The mechanism by which diffusion is achieved may be explained on the basis
of an activity or chemical potential gradient wherein the confined drug
relieves its internal concentration by spreading out into the adjacent
medium. As the drug is removed from the device and absorbed by eye tissues
or carried away by the eye fluids, the diffusive action continues until
the source of drug 21 has been substantially consumed. The drug will have
a definite and characteristic rate of passage through the release rate
controlling material of the insert. It is preferred, although not
essential, that drug 21 essentially be depleted or consumed from the
reservoir 20 before membrane material 22 completely bioerodes. However, if
it is desired to obtain a zero order drug release rate over the active
releasing period of the insert, prior depletion of drug is an essential
requirement. Of course, it will be appreciated that the device of type
shown in FIG. 3 makes possible drug-time patterns of release other than
zero order. Another reason for the depletion of drug from matrix reservoir
20 prior to the complete erosion of membrane material 22 is to eliminate
the possibility of the sudden release of drug from the reservoir to the
eye at the time of total erosion of membrane 22, as a result of the high
permeability of material 20 to drug, as hereinafter described. Therefore,
membrane material 22 should be selected with regard to its erosion rate,
thickness and permeability to drug 21 in respect to the amount of drug in
core material 20. It will, of course, be appreciated that the inner core
material 20 will not begin to erode until free to contact eye fluids,
which time will be subsequent to the substantially complete erosion of
outer membrane 22.
The reservoir 20 primarily functions as a depot for the drug rather than as
a rate control barrier. Therefore, it should be highly permeable to
passage of drug by diffusion. In contrast, membrane 22 which acts as the
rate-limiting barrier to control drug release must be only slowly
permeable to the passage of drug, with the exact value determined by the
desired release rate. Thus, it is important to the successful practice of
this invention that the membrane 22 have a lower permeability to the drug
by diffusion than does the matrix material 20. The initial ratio of
permeability rates for drug for the matrix material 20 to membrane
material 22 should be approximately between 10:1 and 100:1, and preferably
between 2:1 and 10:1. It will be noted that the effective drug release
rate through the membrane 22 may tend to increase somewhat in the case
wherein membrane erodes from its surface, and the effective release rate
through the membrane material 22 will tend to decrease somewhat as the
concentration of drug in the reservoir 20 depletes. These opposite effects
tend to compensate each other to a large degree so as to give an overall
uniform rate throughout most of the drug release period. However, in cases
where the release rate of the device is not overly sensitive to changes in
thickness in the membrane material, or where the change in thickness of
the membrane material are small during the drug releasing period, it is
preferred, in order to obtain zero order drug release, that the drug be
sparingly soluble in the reservoir matrix material so as to retain
substantially the same thermodynamic activity of the drug throughout the
release period. By "sparingly soluble" is meant that the fractional amount
of drug dissolved in the reservoir material should be in range of from
0.1% to 35% by weight of the total amount of drug to be delivered, such
that solid particles of drug are present throughout most of the drug
release period. Moreover, for best results, the rate of passage of drug
through membrane 22 should not exceed the rate of removal or clearance of
drug from the exterior of the membrane by eye tissues. This insures that
the drug delivery rate is controlled by diffusion through the membrane 22,
which can be controlled.
As disclosed above, the selection of appropriate materials for fabricating
the ocular inserts will be dependent upon their erosion rates in the eye.
The erosion rate of outer membrane material 22 in the eye is determined by
the desired ophthalmic dosage regimen, as well as the length of time the
device is to remain in the eye. Under optimum conditions, the erosion rate
should be such that substantially all of the membrane material 22
bioerodes in the eye tissue soon after the drug has been substantially
depleted from the reservoir 20, preferably no later than in a period of
from 24 hours thereafter, if possible.
The erosion rate of inner core material 20 can be the same as, greater
than, or less than the erosion rate of outer membrane material 22,
although it is preferred that it be greater. The preference of the higher
erosion rate for the inner matrix material 20 is predicated on the fact
that the primary function of this material is to serve as a reservoir for
the drug 21. Erosion of this material does not commence until the drug 21
contained therein has been substantially depleted and the erosion of outer
layer 22 essentially completed. At this stage, no purpose is served by
further retention of core material 20 in the eye. It is preferred that the
erosion rate for core material 20 is such that all of the material
bioerodes in the eye tissue in a relatively quick period of time,
preferably within 8 hours after the substantially complete erosion of the
outer membrane 22 has taken place.
It will of course be appreciated that correlation of the optimum desired
material erosion rate and the drug release rate for a given membrane
material 22 may in some cases be difficult under certain design
conditions. In these cases, selection of a material having the desired
optimum drug release rate should be made with the proviso that the erosion
rate be slow enough to ensure that the membrane layer 22 does not totally
erode prior to the depletion of drug from core material 20. If this
procedure is followed, there will be a period of time in which the ocular
insert remains in the eye but dispenses no drug. This, however, is not of
serious consequence, as a fresh ocular device can be inserted concurrent
with the final stages of the erosion of the original drug depleted device.
The thickness of the inner core 20 can vary, consistent with dimensions
resulting in comfortable retention of the device in the eye and physical
capability to incorporate the desired amount of drug. The thickness of
outer membrane 22 can also vary, depending upon overall comfortable
retention of the device in the eye, as well as providing the desired drug
release rates and a sufficient mass of material so as to enable the
substantially complete depletion of drug from core 20 prior to the
complete erosion of the layer 22, thereby insuring, if desired, that drug
21 is advantageously released from the insert in a zero order manner as
heretofore discussed.
In general, to design a device of the type shown in FIG. 3 it is first
necessary to select the drug to be used, its dosa | | |
