U.S. patent number 3,867,519 [Application Number 05/248,168] was granted by the patent office on 1975-02-18 for bioerodible drug delivery device.
This patent grant is currently assigned to Alza Corporation. Invention is credited to Alan S. Michaels.
United States Patent |
3,867,519 |
Michaels |
February 18, 1975 |
Bioerodible drug delivery device
Abstract
A drug delivery device for the continuous and controlled
administration of a predetermined therapeutically effective dosage
of drug to a mamallian patient over a prolonged period of time. The
device meters the flow of drug by means of a drug release rate
controlling material comprised of an anionic polyvalent metal
cation cross-linked polyelectrolyte. The device bioerodes in the
biological environment of the patient concurrently with the
dispensing or at a point in time after the dispensing of the
therapeutically desired amount of drug.
Inventors: |
Michaels; Alan S. (Atherton,
CA) |
Assignee: |
Alza Corporation (N/A)
|
Family
ID: |
22937990 |
Appl.
No.: |
05/248,168 |
Filed: |
April 27, 1972 |
Current U.S.
Class: |
424/473; 424/480;
424/469; 424/481 |
Current CPC
Class: |
A61K
9/0051 (20130101); A61F 9/0017 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61F 9/00 (20060101); A61k
027/12 () |
Field of
Search: |
;128/260 ;424/19-22 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Voropaeva et al. OFTAL, ZH.24:543-544(1969) "The Use of Pilocarpine
in a Polyvinyl Membrane for the Treatment of Patients with Acute
Attacks of Glaucoma" .
Loucas et al. J. Pharm. Sci. 61(6):985-986 (June 1972) "Solid-state
Ophthalmic Dosage Systems in Effecting Prolonged Release of
Pilocarpine in the Cul-de-sac" .
Dohlman et al. Annals of Ophthalmology (Oct. 1972) pp. 823-832 "A
New Ocular Insert Device for Continuous Constant-rate Delivery of
Medication to the Eye".
|
Primary Examiner: Rose; Shep K.
Attorney, Agent or Firm: Sabatine; Paul L. Benz; William H.
Mandell; Edward L.
Claims
1. An ocular delivery device for the sustained administration of a
predetermined dosage regimen of ophthalmic drug to the eye of a
mammalian patient comprising (1) an inner reservoir comprised of a
biodegradable material containing a drug formulation for the eye
confined therein and permeable to the passage of drug, and (2) an
outer membrane surrounding the inner reservoir, the membrane
permeable to the passage of drug, but at a lower rate than through
the inner reservoir, the membrane formed from drug release rate
controlling bioerodible material comprising a polyvalent ion
cross-linked anionic polyelectrolyte with the polyvalent ion a
member selected from the group consisting of aluminum, barium,
cadmium, calcium, copper, iron and zinc and the anionic
polyelectrolyte, a member selected from the group consisting of
pharmaceutically acceptable agar, algin, alginic acid, carrageenan,
cellulose, gum arabic, gum ghatti, pectic acid, pectin, pectinic
acid, and polysaccharide, with the polyelectrolyte cross-linked
from two-tenths to three equivalents cross-linking agent selected
solely from said polyvalent cation for each equivalent of
polyelectrolyte, which material bioerodes in the eye of the patient
in from four hours to thirty days into innocuous products in
response to the biological environment therein by a process of
polyvalent ion displacement with noncross-linking ions present in
the eye with said displacement rate corresponding to the extent of
polyvalent ion cross-linked, and wherein the membrane material
continuously meters the flow of a therapeutically effective amount
of said drug from the reservoir to the eye of the patient
2. An ocular delivery device for the sustained administration of a
predetermined dosage of an ophthalmic drug selected from the group
consisting of pilocarpine and hydrocortisone when placed in the sac
of a mammalian eye bounded by the surface of the bulbar conjunctiva
of the sclera of the eyeball and the palpebral conjunctiva of the
lid, comprising a body of a biocompatible bioerodible drug release
rate controlling material containing said drug therein, said
material comprising a polyvalent ion cross-linked anionic
polyelectrolyte, with said polyelectrolyte cross-linked solely with
a polvalent cation selected from the group consisting of aluminum,
barium, cadmium, calcium, copper, iron and zinc, said anionic
polyelectrolyte a water-soluble member selected from the group
consisting of agar, algin, alginic acid, carrageenan, cellulose,
gum arabic, gum ghatti, pectic acid, pectin, pectinic acid and
polysaccharide, which cross-linked material bioerodes to nontoxic
materials when placed in the eye in response to the biological eye
environment by a process of polyvalent ion displacement of the
cross-linked cation with noncross-linking ions present in the
environment, with the bioerosion rate corresponding to the extent
of polyvalent ion cross-linked, and wherein the ocular device
continuously meters a flow of a therapeutically effective amount of
said drug from the device at a
3. An ocular delivery device in accordance with claim 2 for the
sustained administration of a predetermined dosage of an ocular
drug selected from the group consisting of pilocarpine and
hydrocortisone when placed in the sac of a mammalian eye bounded by
the surface of the bulbar conjunctiva of the sclera of the eyeball
and the palpebral conjunctiva of the lid comprising a body of
biocompatible bioerodible drug release rate controlling material
containing from 5 percent to 90 percent of ocular drug based on the
weight of the material with from one-tenth percent to 35 percent of
drug dissolved in the material, said material comprising a
polyvalent ion cross-linked anionic polyelectrolyte, with said
polyelectrolyte cross-linked with from two-tenths to three
equivalents of a cross-linking agent selected from the group
consisting of aluminum, barium, cadmium, calcium, copper, iron and
zinc for each equivalent of polyelectrolyte, with said
polyelectrolyte selected from the group consisting of agar, algin,
alginic acid, carrageenan, cellulose, gum arabic, gum ghatti,
pectic acid, pectin, pectinic acid and polysaccharide, which
material bioerodes to physiologically acceptable materials when
placed in an eye in response to the biological environment of the
eye by a process of polyvalent ion displacement of the cross-linked
ion with noncross-linking ions in situ, and wherein the device
concurrent with the displacement continuously meters the flow of a
therapeutically effective amount of said drug from the device to
the eye at a controlled rate over a
4. An ocular delivery device for the sustained administration of a
predetermined dosage of an ophthalmic drug when placed in a
mammalian eye comprising a body shaped and adapted for insertion
and comfortable retention in the eye, the device made of a
biocompatible bioerodible drug release rate controlling material
containing an ocular drug formulation of from 5 percent to 90
percent of drug based on the weight of the material with from
one-tenth percent to 35 percent of drug dissolved in the material
with the drug a member selected from the ophthalmic drug group
consisting of antibiotic, antibacterial, antiviral, antiallergenic,
anti-inflammatory, miotic, anticholinesterase, decongestant, and
sympathomimetic, said material comprising a polyvalent ion
cross-linked anionic polyelectrolyte with the polyelectrolyte
cross-linked with from two-tenths to three equivalents of a
cross-linking agent selected from the group consisting of
polyvalent cations aluminum, barium, cadmium, calcium, copper, iron
and zinc for each equivalent of a member selected from the group
consisting of agar, algin, alginic acid, carrageenan, cellulose,
gum arabic, gum ghatti, pectic acid, pectin, pectinic acid and
polysaccharide polyelectrolyte which cross-linked polyelectrolyte
material is hydrophilic insoluble in the cross-linked form,
initially imperforate, when placed in the eye absorbs fluid, swells
and forms a fluid impregnated microporous structure and bioerodes
in from 4 hours to 30 days into innocuous products in response to
the biological environment by a process of polvyalent ion
displacement with noncross-linking ions in the eye, and wherein the
body concurrent with the displacement continuously meters the flow
of a therapeutically effective amount of said ophthalmic drug from
the device
5. An ocular bioerodible delivery device for the sustained
administration of a predetermined dosage of ophthalmic drug to the
eye of a mammalian patient comprising a matrix of a polyvalent
cation cross-linked anionic polyelectrolyte material with the
polyelectrolyte cross-linked with from two-tenths to three
equivalents cross-linking agents selected solely from the
polyvalent cations aluminum, barium, cadmium, calcium, copper, iron
and zinc for each equivalent of a physiologically acceptable
anionic polyelectrolyte selected from the group consisting of agar,
algin, alginic acid, carrageenan, cellulose, gum arabic, gum
ghatti, pectic acid, pectin, pectinic acid and polysaccharide, with
the meterial having distributed throughout a plurality of
reservoirs, with each of the reservoirs comprised of an eye
formulation confined within a release rate controlling material,
the reservoir characterized by being (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 biodegradable material, the matrix
material permeable to the passage of drug at a higher rate than
through the drug release rate controlling material with the matrix
material bioeroding to essentially nontoxic material in response to
the biological environment of the eye by a process of polyvalent
ion displacement with noncross-linking ions present in the eye,
with the release rate controlling material metering a
therapeutically effective amount of drug from the reservoir to the
eye of the patient at a controlled rate over a prolonged period of
time.
Description
CROSS REFERENCE TO OTHER APPLICATION
This application is related to pending U.S. application Ser. No.
179,129 filed Sept. 9, 1971 which discloses the subject matter of
this application in accord with Rule 79 of the Rules of Practice of
the U.S. Patent Office in Patent Cases, 1970.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a method and device for the controlled
administration of drug to a patient. More particularly, this
invention relates to a drug dispensing device which bioerodes in
the biological environment of such patient. In preferred
embodiments, the invention relates to a bioerodible device for the
controlled and continuous administration of drug to a mammalian
patient, especially to the eye of such patient, over a prolonged
period of time. In aother aspect the invention relates to a method
for preparing these devices.
2. Description of the Prior Art
Many and varied compositions, products, appliances, depositors,
applicators, dispensers and injectors are well known in the art in
which the timing or spacing of administration or absorption of drug
is regulated by the structure or physical arrangement of elements
so that a single administration provides a gradual but sustained
feeding of the drug to a patient by slow or differential release.
The advantages of such devices are that they enable the physician
to more carefully regulate the level of drug administration to the
patient. A further advantage of sustained release devices is the
fact that the number of times that the drug need be administered is
reduced.
Where oral administration is desired, one means for obtaining the
above objective is to employ capsules or tablets which release the
drug at a uniform rate during the capsule's passage through the
gastrointestinal tract. In the past this object has been achieved
by admixing one or more inert ingredients with the drug in such a
manner that these inactive materials interfere with the
disintegration of the tablet or the dissolution of the drug. An
obvious form of such a tablet is one wherein tablets can be
composed of several alternate layers of medicament and inert
material. In this manner, as each alternate protective layer
disintegrates the patient receives a further dose of medicament.
However, tablets of this type suffer from the disadvantage of not
providing a uniform and constant drug release. Furthermore, such
tablets are difficult to prepare with precision so that in many
instances the desired dosage level cannot be assured. Moreover, it
has not been possible to provide for prolonged release of a drug by
these tablets because of their rapid rate of degradation or
dissolution. Still further, degradable carriers of this type have
not generally found wide acceptance because of the undesirable side
effects which they often produce, for example, foreign body
reaction and scar formation.
Recognizing these disadvantages, more recently there have been
developed certain synthetic polymeric carriers, most notably the
polysiloxane rubbers, which are designed to deliver a drug to the
patient without concomitant degradation of the delivery device.
Instead, the polymeric drug delivery systems are based upon the
phenomenon of diffusion in which drug migrates through a polymer
wall at a relatively low rate. In such a system, the drug is
disposed throughout the polymeric carrier manufactured from the
polymeric material.
In this regard, a significant advance has recently been made in the
field of ophthalmic drug delivery systems. Thus, U.S. Pat. No.
3,416,530, granted Dec. 17, 1968 to Ness, entitled "Eyeball
Medication Dispensing Tablet," and U.S. Pat. No. 3,618,604 issued
Nov. 9 1971 to Ness, entitled "Ocular Insert," disclose a drug
dispensing ocular insert which releases controlled amounts of drug
to the eye. These devices have the added advantage of permitting
slow release of drug over prolonged periods of time. Such ocular
inserts are fabricated of materials that are biologically inert,
non-allergenic, and non-bioerodible 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 not erodible by tear liquid, it
retains its integrity during the course of therapy, acting as a
reservoir to continuously release drug to the eye and surrounding
tissues at a controlled rate. A single such ocular insert can
provide 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. On termination of the
therapeutic program the ocular insert is removed from the eye.
While the drug dispensing ocular inserts described above, which
deliver precise amounts of drug to the eye continuously and in a
controlled manner of 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 remains
intact during the course of therapy and on termination of the
therapy program must be removed, which may present difficulty and
discomfort to some patients. In rare instances, the removal is made
more difficult by unwanted migration of the insert to the upper
fornix. Further, in ophthalmic practice physician-patient contact
is often not of a sufficient degree to insure that instructions
from the doctor are accurately carried out by the patient. Thus,
when a non-erodible ocular insert is used, there is no certainty
that the insert will be removed by the patient at the completion of
treatment. This is particularly true with elderly patients who
often forget or are simply unable to remove the device due to
failing memory or eyesight.
Disadvantages of the same nature exist with drug delivery devices
which are non-bioerodible employed in areas of the anatomy other
than the eye in that at some point in time the device must be
surgically or otherwise removed from the body of the patient.
OBJECTS OF THE INVENTION
Therefore, it is a primary object of this invention to provide a
drug delivery device which does not suffer from the disadvantages
associated with heretofore known sustained release drug delivery
devices.
Another object of the invention resides in the provision of a
sustained release drug delivery device which is capable of
completely bioeroding within the body of the patient, re, mammals,
including humans, animals, e.g., farm animals, domestic animals and
the like, with no undesirable side effects.
Still another object of this invention is to provide an improved
drug dispensing device for the controlled continuous and prolonged
administration of drugs.
A further object of this invention is to provide an improved drug
dispensing ocular insert for the controlled administration of drugs
to the eye.
A still further object of this invention is to provide an improved
drug dispensing ocular device for delivering drugs to the eye with
increased efficacy.
Still another object of this invention is to provide an improved
drug dispensing ocular device 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 drug
dispensing ocular device for the controlled continuous
administration of drugs to the eye over a prolonged period of time
which bioerodes into innocuous products concurrently with the
dispensing or at a point in time after the dispensing of the
drug.
Yet another object of this invention is to provide a method for
producing these improved devices.
Another object of this invention is to provide an improved method
for treating a patient employing the drug delivery devices of this
invention.
These objects, as well as other objects, features and advantages
will become more readily apparent from the following detailed
description, the drawings and the accompanying claims.
SUMMARY OF THE INVENTION
In accomplishing these objects, a primary aspect of this invention
resides in a bioerodible device for the sustained administration of
a therapeutically effective predetermined dosage of drug to a
patient comprising one or more reservoirs each of which comprises a
drug formulation confined within a polyvalent metal ion
cross-linked anionic polyelectrolyte which bioerodes in the body in
response to the biological environment therein by a process of
polyvalent metal ion displacement.
In one preferred aspect, this invention is directed to an ocular
device and resides in a bioerodible ocular insert for the
controlled continuous administration of a predetermined dosage of
drug to the eye. The invention shall be described in major part, by
way of illustration of preferred embodiments, with application to
such ocular inserts although it will be appreciated by those
skilled in the art that the methods and devices described herein
are not so limited in application. These latter considerations are
treated hereinafter.
One embodiment of the 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 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 eye
comprising a polyvalent metal ion cross-linked anionic
polyelectrolyte wherein the body continuously meters the flow of a
therapeutically effective amount of drug to the eye at a controlled
rate over a prolonged period of time.
Another embodiment of the 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 comprised of
a "biodegradable" material containing a drug formulation confined
therein, and (2) an outer membrane surrounding the inner reservoir
and formed from drug release rate controlling "bioerodible"
material comprising a polyvalent metal ion cross-linked anionic
polyelectrolyte which continuously meters 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, the
insert being adapted for insertion and retention in the eye.
In yet another embodiment the invention resides in a bioerodible
ocular insert for the controlled continuous administration of a
predetermined dosage of drug to the eye over a prolonged period of
time, comprisng a matrix material of a polyvalent cation
cross-linked anionic polyelectrolyte having distributed throughout
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 "biodegradable" material;
the matrix material being permeable to the passage of drug at a
higher rate than through the drug release rate controlling
material, the latter material metering a therpeutically 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 eye and
wherein the materials comprising the insert are eliminated from the
ocular cavity by bioeroding or biodegrading in the environment of
the eye or the reservoir material eliminated by passage through the
punctum, the eliminations taking place concurrently with the
dispensing or at a point in time after the dispensing of the
therapeutically desired amount of drug.
In another aspect the invention resides in a process for preparing
polyvalent metal ion cross-linked anionic polyelectrolyte
structures to be employed in drug delivery devices which comprises
the sequential steps of:
a. forming the desired structures from a water soluble anionic
polyelectrolyte,
b. contacting the structures with a solution of polyvalent metal
cations to cross-link the anionic polyelectrolyte, and
c. recovering the polyvalent metal ion cross-linked anionic
polyelectrlyte structure.
In yet another aspect, the invention resides in another process for
preparing polyvalent metal ion cross-linked anionic polyelectrolyte
structures to be employed as drug release rate controlling
materials which comprises the sequential steps of:
a. preparing an aqueous solution containing an initially water
soluble anionic polyelectrolyte,
b. adding to the aqueous solution a polyvalent metal cation capable
of reacting with the anionic polyelectrolyte to form a water
insoluble cross-linked precipitate in an amount sufficient to form
such a cross-linked precipitate,
c. recovering the cross-linked precipitate and ading to it water
and a sufficient amount of a complexing reagent to render the
precipitate water soluble by forming a coordination complex
therewith,
d. forming the solution into the desired structures, and
e. removing at least substantially the complexing reagent from the
solution, thereby causing the polyvalent metal cation cross-linked
anionic polyelectrolyte to precipitate in the form of the desired
shaped structures, and
f. recovering the thus prepared shaped structure.
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 in
an operative position 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 and 6 are diagrammatic cross-sectional views of
several embodiments of ocular inserts of this invention.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with preferred embodiments of the present invention,
polyvalent metal ion cross-linked anionic polyelectrolytes are
employed in bioerodible ocular inserts for the controlled
dispensing of predetermined dosages of drug to the eye. Polyvalent
metal ion cross-linked anionic polyelectrolyte materials are
hydrophilic, water insoluble in their cross-linked state,
compatible with the tissues of the eye and bioerodible therein.
The term "reservoir" is used herein to define the drug-containing
portion of the delivery device and is intended to connote a broad
class of structures capable of fulfilling the 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.
The term "water soluble" is defined to mean materials which are
soluble in water to a degree which exceeds approximately 50 parts
per million.
The term "biodegradable" or "biodegrade," as used in this
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
biological environment in the patent 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
body and surrounding tissues, or otherwise dissipated thereby.
The term "patient" or "mammal" as used herein denotes any
prospective situs for the delivery device of this invention
providing a biological environment having materials therein which
are co-reactive with the polyvalent cation cross-linked
polyelectrolyte defined herein so as to cause bioerosion thereof
over a prolonged period of time.
The term "bioerode" or "bioerodible" as used in this specification
and claims is intended to define a process wherein the polyvalent
cation cross-linked polyelectrolytes employed and characterized in
the present invention innocuously disintegrate or break down as a
unit structure or entity over a prolonged period of time when
placed in contact with bio-fluids by virtue of the gradual
displacement of polyvalent metal ion cross-links by
non-cross-linking monovalent ions, especially sodium ions, present
in the saline body fluids, with resulting solubilization of the
non-cross-linked polymer. This bioerosion mechanism is especially
fortuitous for erodible devices designed for the controlled release
of drugs to the eye over a prolonged period of time since the
conditions prevalent in the environment of the eye, e.g., tear
salinity, tear flow rates, and the degree of mixing in the eye,
produce polyvalent ion displacement rates, which yield erosion
times for devices of a size suitable for placement in the
environment of the eye from about 4 hours to about 30 days. These
erosion times are perfectly suited for prolonged release ocular
inserts. The erosion rate may be easily and accurately controlled
within this range by varying the extent of polyvalent metal ion
cross-linking, an increase in the number of polyvalent metal ion
cross-links slowing the rate of bioerosion.
Another advantage of drug dispensing ocular inserts prepared from
polyvalent metal ion cross-linked anionic polyelectrolytes which
contain one or more drug reservoirs is their ability to
advantageously administer a metered amount of drug from these
reservoirs to the eye and surrounding tissues when placed in the
environment of the eye. It has been found that such mode of
administration surprisingly operates to significantly improve the
therapeutic efficacy when compared with conventional treatment
which consists of periodically applying the ophthalmic drugs in
liquid or ointment form.
In preferred embodiments, the polyvalent metal ion cross-linked
anionic polyelectrolyte functions in these devices or inserts as a
drug release rate controlling material, controlling the
administration of a metered amount of drug to the eye and
surrounding tissues over a prolonged period of time when the device
is placed in the environment of the eye. The polyvalent metal
cation cross-linked polyelectrolytes, when used to control the rate
of drug release, do so through the drug transfer mechanisms of: (1)
"Permeation Control Release," i.e., the controlled release of the
drug by the processes of diffusive transfer by controlled flow of
drugs through the polyvalent metal ion cross-linked material,
and/or "Erosion Control Release," i.e., the metered release of
entrapped drug contained in the polyvalent metal ion cross-linked
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 of the eye.
The actual control mechanism of drug release is dependent upon the
design of the insert with particular regard to the combination
selection of drug and release rate controlling material. In a
system comprising a drug confined within a bioerodible material,
two processes occur side by side: the release of drug from the
material and bioerosion of the material. These two processes need
not necessarily be coupled as indicated by consideration of the
drug transfer mechanism above.
The following are generalized considerations to be made in order to
properly design an ocular insert or for that matter any device of
the types disclosed herein.
In the inventive release system herein described, a primary factor
which determines the rate of drug release is the solubility of the
particular drug itself in the tear fluid impregnated microporous
insert structure as later explained. Therefore, it has been found
that it is not preferred to deliver water soluble drugs using the
highly water permeable and hydrophilic release rate controlling
polyelectrolyte materials of this invention over prolonged periods
of time because the rate of release of drug is governed by that of
simple rapid dissolution of the drug in tear fluid which is
unsatisfactory for the reasons that the release of drug from the
device is both uncontrolled and usually exceeds the desired
therapeutic dosage. It is thus preferred in these cases that
certain modifications be made to insolubilize or decrease the water
solubility of the drug to a level at or below 50 parts per million
in water so as to effect the drug release by a Permeation Control
Mechanism (1), e.g., by controlled diffusive transfer. The water
solubility of drug can be decreased in a number of ways, among
which include the forming of pharmaceutically acceptable
derivatives of the drug which have the desired solubility
characteristics. These derivatives can be prepared by art known
techniques and then used in the paractice of the invention. Of
course, the drug derivatives should be such as to convert to the
active drug within the body through the action of body enzymes,
assisted transformation, pH, specific organ activities, and the
like. Alternatively, insolubilization of the drug can be effected
by coating the drug, such as by microencapsulating the drug, with a
material to decrease the rate of release of drug by simple and
rapid dissolution in tear fluid. Therefore, devices of the type
illustrated in FIG. 3 are preferably made, in cases where the drug
is water soluble by decreasing the water solubility of the drug.
Methods and materials for microencapsulating the drug in order to
decrease the drug solubility in water are described hereinafter
with regard to the reservoirs in FIG. 6.
The rate of drug release can also be uniquely modified by varying
the nature of the polyvalent metal ion cross-linked
polyelectrolyte. When placed in the environment of use, e.g., the
eye, the cross-linked polyelectrolytes of this invention are
initially imperforate but being hydrophilic absorb tear fluid and
swell to an extent governed by their polyvalent metal cation
cross-linking content to achieve fluid impregnated microporous
structures. Drug can then diffuse from the internal reservoirs out
through the tear fluid-filled micropores to the eye and surrounding
tissues, including the corneal epithalum, by the flow of tear fluid
and the blinking action of the eyelids. With "Permeation Control
Release," the rate of diffusion of drug through the fluid in the
microporous polymeric structure controls the rate of drug release.
Since by this mechanism of release the rate of drug release from
the device is controlled, in addition to the solubility of the drug
in tear fluid and tear layer thickness, by the porosity and
swelling of the rate-controlling material, and this porosity and
swelling are related to the extent of the polyvalent metal ion
cross-linking the rate-controlling material, accurate and
reproducible control can be achieved by varying the degree of metal
ion cross-linking.
Anionic polyelectrolyte polymeric materials which may be interacted
with polyvalent cations to produce the polyvalent metal ion
cross-linked structures which are employed in the present invention
contain a plurality of functional groups which react with
polyvalent metal cations to form water insoluble salts.
These functional groups can be characterized as being dissociable
anionic groups which are chemically bonded to the polymeric chain.
Suitable functional groups include carboxylic acid groups and
sulfur- and phosphorous-containing acid groups and their
dissociable salts with monovalent cations. The anionic
polyelectrolyte polymers thus include polymer chains having
attached thereto a plurality of, for example, carboxylate groups,
sulfonate groups, sulfate groups, phosphate groups or phosphite
groups in either their acid form or monovalent cation (ammonia or
alkali metal ion) form. Other noninterferring functional groups,
such as hydroxyl groups, either linkages, or olefinic
unsaturations, may be attached to or incorporated into the polymer
chains if desired.
Exemplary anionic polyelectrolytes include modified natural and
synthetic polymers such as carboxymethylcellulose, carboxymethyl
starch, polystyrene sulfonic acid, polyvinyl sulfuric acid, the
sodium, ammonium and potassium salts of polyvinyl sulfuric acid,
polyvinyl sulfonic acid, polyvinyl methylol sulfonic acid,
polyacrylic acid, polymethacrylic acid and copolymers thereof with
acrylic or methacrylic esters, polyvinyl acetate, polyvinyl
alcohol, polyvinyl chloride, styrene, and as a generally preferred
class of anionic polymers, the carboxyl group containing anionic
polysaccharides or glycans. The polysaccharides which comprises
this preferred class may contain as their dissociable anionic
components, the acids D-glucuronic acid, pyruvic acid, D-mannuronic
acid, D-mannopyranosyl uronic acid, D-glucopyranosyl uronic acid,
D-galacturonic acid, D-guluronic acid, and L-iduronic acid; and
thier alkali metal or ammonium salts.
Preferred anionic polysaccharides are the naturally occurring water
soluble vegetable-derived anionic polysaccharides. These include,
for example, pectin, pectinic acid, pectic acid and the monovalent
cation salts; the anionic exudate gums such as gum arabic, gum
ghatti; the seaweed gums such as algin, alginic acid, the
carrageenans and agar in acid and salt forms as well as the
hemicelluloses. The anionic microbial polysaccharides such as are
formed from carbon-containing substrates by the action of the
microorganisms Xanthomonas campestrix (NRRL Strain B-1459),
Arthrobacter viscosus (NRRL Strain B 1973) or Cryptococcus
laurentii (NRRL Strain Y 1401) may also be employed to
advantage.
The naturally-occurring vegetable-derived water-soluble
polysaccharides are preferred as they are essentially devoid of
human or animal toxicity and undergo enzymatic cleavage in the body
to easily absorbed simple sugars.
The initially water soluble anionic polyelectrolytes are
cross-linked with polyvalent metal cations to yield the drug
release controlling materials of this invention. In general, any
polyvalent metal cation which is non-toxic to the mammalian patient
being treated may be used. Preferred cations includes the non-toxic
polyvalent cations of elements of atomic number 13 through 56
inclusive which are found in groups IIa through IIIa inclusive of
the Periodic Table of the Elements such as barium II, copper II,
iron II and III, zinc II, aluminum III and cadium II. A preferred
group of these metals comprises calcium II, barium II, zinc II and
aluminum III.
The amount of polyvalent ion cross-linking should be controlled
since it can determine to a major extent the drug permeability and
hence drug release characteristics of the polyelectrolyte product.
As a rule, increasing the amount of metal ion increases the amount
of cross-linking and lowers the drug release rate. It is generally
suitable to employ from about 0.2 to 3 equivalents of polyvalent
cation for each equialvent of polyelectrolyte anionic groups
capable of cross-linking. It is preferred to employ from about 0.4
to about 1.5 equivalents of polyvalent metal cation for each
equivalent of polyelectrolyte anionic groups. The exact proportions
of polyvalent cation employed should be controlled to tailor the
precise drug release rate desired.
Polyvalent metal cation cross-linked anionic polyelectrolytes for
use as drug release controlling materials can be prepared by
several alternative methods. As a general rule, these materials are
not easily shaped or formed when in their cross-linked
configuration, so it is desirable to form or shape the
polyelectrolyte in a non-cross-linked form and carry out the
cross-linking.
One very suitable method for preparing the polyvalent metal ion
cross-linked product comprises: (a) In a first step preparing an
aqueous first solution containing an initially water-soluble
anionic polyelectrolyte and adding thereto a polyvalent metal
cation, to form a water insoluble metal cross-linked precipitate.
The concentration of the anionic polyelectrolyte in the first
solution prior to precipitate is not critical and may vary from
about 0.01 percent by weight to its solubility limit. The
cross-linked precipitate should be washed free of monovalent
cations. For example if the initial soluble polyelectrolyte was
sodium alginate and it was treated with calcium ions to yield a
calcium cross-linked alginate precipitate, the sodium ion should be
wahsed from the precipitate. If this is not done, the rate of
bioerosion, which is in part controlled by the displacement of
polyvalent cross-linking ions with monovalent non-cross-linking
ions from tear fluids, may be irreproducible because of the
availability of residual monovalent ions in the precipitate itself.
The amount of polyvalent metal ion containing precipitate should be
closely controlled since any polyvalent metal ion introduced into
the system during this precipitation, unless in such excess as to
be rinsed out in the washing steps, will appear in the final
product as cross-linking. As already noted, the rate of drug
release is a function of the extent of polyvalent metal ion
polyelectrolyte cross-linking. (b) In a second step, adding to the
water-insoluble cross-linked precipitate a sufficient amount of a
complexing reagent to render the precipitate water-soluble by
forming a water soluble coordination complex with the polyvalent
metal cations. Suitable complexing reagents are any of those
materials which are capable of solubilizing or maintaining the
polyelectrolyte-polyvalent cationic reaction product in solution so
as to enable fabrication of the solution into the desired shape.
Electron donating complexing reagents are generally preferred.
Exemplary of electron donating materials are primary, secondary and
tertiary amines such as mono, di, or trimethyl amine, mono, di, or
tri-ethanolamine, morpholine, pyridine, piperidine, piperazine,
aniline, 2-methyl imidazole, ethylene diamine and higher
polyethylene polyamines, and amonia.
The complexing reagent must be present in solution in an amount
sufficient to prevent precipitation of the reactive components.
This amount will usually be from about 0.5 to 10 moles of
complexing reagent per gram atom of polyvalent metal ion, and
preferably is from 1 to 5 moles of complexing reagent per gram atom
of polyvalent metal. Although amounts as great as 50% or more
weight of the total solution may be used, it is unnecessary and
frequently undesirable to employ any more than the minimum amount
of complexing reagent required to prevent precipitation of the
polyelectrolytes. In general, the concentration of the
polyelectrolyte in the resulting solution must be at least 0.5
percent by weight and preferably above 1 percent by weight, based
on the solution in order to obtain continuous solids in the
supsequent processing.
In a third step, the aqueous solution is formed into the dsired
shapes and configurations. This formation may be carried out by
casting, extruding, coating and like techniques. If desired, drugs
may be dispersed or dissolved in the solution at this point.
In a fourth step, the solution thus formed is then casused to gel
by changing conditions so as to permit precipitation to occur by
breaking down the coordinate complex so as to cross-link the
polymer with metal. Gelation of the polymeric complex solute can be
effected by reducing the effective concentration of the complexing
reagent by neutralization thereof with acid, or removal in the case
of volatile reagents by evaporation in the presence of heated moist
air. The formed structure of polyvalent metal ion cross-linked
polyelectrolyte is then recovered.
In an alternative method of production, the complexing reagent can
be added to the solution of anionic polyelectrolyte prior to the
addition of the polyvalent cation to maintain the reaction product
in solution in lieu of resolubilizing the precipitate. This method
comprises teh sequential steps of: fabricating a solution of an
initially water-soluble anionic polyelectrolyte and optionally
drugs into the desired shape. in a second step dipping the thus
formed shape into an aqueous solution of a polyvalent metal cation
to cross-link the anionic polyelectrolyte; and finally recovering
the thus prepared water insoluble cross-linked structure. Undesired
monovalent cations of present are then removed by washing during
the recovery step.
It is often desired to incorporate plasticizers in the polyvalent
metal ion cross-linked polyelectrolyte materials to improve or vary
their physical properties, such as to make them more flexible.
Exemplary plasticizers suitable for employment for the present
purpose are the pharmaceutically acceptable plasticizers
conventionally used, such as diethyl adipate, di-isobutyl, adipate,
di-n-hexyl adipate, di-isooctyl adipate, di-n-hexyl azelate,
di-2-ethyl-hexylazelate, ethylene glycol dibenzoate, acetyl
tri-n-butyl citrate, epoxidized soy bean oil, glycerol monoacetate,
diethylene glycol dipelargonate, propylene glycol diluarate,
isooctyl palmitate, triphenyl phosphte, and the like. In addition,
binding agents or distintegrating agents to regulate or to
facilitate the bioerosion of the device can be employed. Exemplary
of these materials are glycerin, dextrose, sorbitol, mannitol,
sucrose, poly (ethylene glycol), monoglyceryl esters of fatty
acids, methylcellulose, starch, and the like. The proportion of
agent used will vary within broad limits depending upon the rate of
disintegration desired, as well as upon the characteristics of the
medicament and metal ion cross-linked polyelectrolyte involved. In
general, about 0.01 parts to about 5 parts by weight for each part
by weight of the polyelectrolyte can be used, depending on the
agent.
Enzymes can be incorporated into the release rate controlling
materials in order to further control their rate of bioerosion.
When plasticizers, enzymes, etc. are included in the metal ion
cross-linked polymers they are most suitably added prior to shaping
the final formed structure, such as by dissolving or dispensing
them in the solution from which the body is gelled.
The metal ion cross-linked anionic polyelectrolytes may be employed
in all types of devices for delivering drugs to the eye. While not
intending to restrict the scope of this invention certain
embodiments of bioerodible drug releasing devices employing these
memtal ion cross-linked polyelectrolytes and their use in
dispensing drug to the eye ar exemplified in the drawings which are
exaggerated in size for purposes of illustration.
Referring particularly to FIGS. 1 and 2, a human eye is shown in
each figure, more or less diagrammatically, 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 palperbral conjunctiva. The
sclera 4 is lined with the bulbar conjunctiva which covers the
exposed portion of the eyeball. The cornea 5 is covered with an
epithelial layer which is transparent. That portion of the
palpebral conjunctiva which lines the upper eyelids 2 and the
underlying portion of the bulbar conjuncativa defines 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
defines the lower sac 11. Upper and lower eyelashes are indicated
at 8 and 9, respectively.
A bioerodible ocular insert 12 in accord with this invention 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, it is inserted
in the eye, preferably within the upper sac 7 or lower sac 11,
bounded by the surfaces of the sclera of the eyeball and the
conjunctiva of the lid. Insertion of the insert 12 into the eye can
be satisfactorily accomplished by mounting or grasping the device
by means of a suitable holder, which optionally may include a
minute suction cup for engaging the outer surface of the insert.
The holder may be one of the several types commonly used to insert
and remove corneal contact lenses, artificial eyes, and the like.
Once in place, the ocular insert functions to administer a metered
amount of drug from thr reservoir to the eye and surrounding
tissues, in preferred embodiments, continuously over a prolonged
period of time.
FIGS. 3 to 6 inclusive, illustrate, in diagrammatic cross-sectional
views, exemplary types of drug dispensing ocular inserts wich
employ polyvalent metal ion cross-linked anioic polyelectrolytes.
FIG. 3 illustrates generally, by reference numeral 20, an
embodiment of this invention wherein the bioerodible ocular insert
is comprised of a continuous matrix 22 formed of polyvalent metal
ion cross-linekd anionic polyelectrolytes that have particles of
drug 21 dispersed therethrough. The matrix 22 functions both as a
drug reservoir and a rate-controlling material. When ocular device
20 is placed in the environment of the eye it absorbs tear liquid
and swells, achieving a microporous structure which is permeable to
drug. Drug 21 can continuously diffusively transfer through these
micropores in a permeation control mode of release, the rate of
drug release being primarily dependent upon the extent of
polyvalent metal ion cross-linking in the matetial of matrix 22 and
the solubility of drug in the eye fluids impregnated in the
structure. If the drug is water soluble, this mode of release is
not preferred and other embodiments of this invention, to be set
forth hereinafter, are generally better suited for delivery by the
water soluble drugs.
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, retangular,
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.
FIG. 4 illustrates generally, by reference numeral 30, an
embodiment of this invention which finds its most general
application for the release of water insoluble drugs. The
bioerodible ocular insert is comprised of an inner reservoir 31
which is formed of a biodegradable matrix material having drug 21
dispersed therethrough. Surrounding matrix 20 is bioerodible rate
controlling membrane 22 constructed of the polyvalent metal ion
cross-linked polyelectrolyte in accord with the invention. 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 31 so that
release of drug through membrane 22 is the drug release rate
controlling step from the ocular insert. The inner matrix 31 serves
as a depot or reservoir source for the drug and can be a porous,
solid or gel material. When ocular insert 19 is placed in the eye,
drug is continuously metered through and removed from the outer
surface of bioerodible membrane 22 where it is made available to
the eye fluids and tissues.
An advantage of the insert of the type illustrated in FIG. 4 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
controll release mechanism" and includes a sequence of steps
characterized by controlled drug diffusion through the pore filled
medium of the metal ion cross-linked polyelectrolyte 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 pore
filled medium of the cross-linked polyelectrolyte membrane 22, the
thickness of this membrane. 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. 4.
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
cross-linked polyelectrolyte membrane of the insert. It is
preferred, although not essential, that drug 21 essentially be
depleted or consumed from the reservoir 31 before release rate
controlling membrane 22 completely bioerodes. However, if it is
desired to obtain a constant rate of drug release rate over the
active releasing period of the insert, prior depletion of drug is
an essential requirement. Upon the erosion of membrane 22,
reservoir 31 will erode as well, leaving no residual parts in the
eye to be removed.
The reservoir 31 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 achievement of a constant rate of release that the
membrane 22 have a lower permeability to the drug by diffusion than
does the matrix material 31. The initial ratio of permeability
rates for drug for the matrix material 31 to membrane material 22
should be approximately between 1.5:1 and 100:1, and preferably
between 2:1 and 10:1. 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 the range of from
0.1 to 35 percent 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 polyvalent metal ion
cross-linked polyelectrolyte membrane 22, which can be
controlled.
As discussed 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.
In general, to design a device of the type shown in FIG. 4 it is
first necessary to select the drug to be used, its doage, and the
period of therapy. This establishes the required drug release rate
and amount of drug to be incorporated in the device. Materials for
both the reservoir and rate controlling polyvalent metal ion
cross-linked polyelectrolyte membrane which have the appropriate
permeability characteristic and erosion and degration rates can
then be correlated with thickness and effective surface release
area to fabricate a device which meters the desired amount of drug
to the eye over the established period of time and thereafter
completely erodes in the eye.
FIG. 5 illustrates generally, by reference numeral 40, another
bioerodible ocular insert of this invention having a hollow
interior reservoir 41 containing drug formulation 21 in the
reservoir 41. Polyvalent metal ion cross-linked anionic
polyelectrolyte rate controlling bioerodible membrane 22 surrounds
the reservoir 40 and controls the flow of drug from the reservoir
41 to the eye. This embodiment differs from that illustrated in
FIG. 4, mainly in that therein the reservoir 31 is formed of a
matrix material with the drug dispersed therethrough, whereas in
the embodiment of FIG. 5 the drug 21 is confined in the hollow
reservoir container 41. The insert shown in FIG. 5 operates in a
manner similar to the device illustrated in FIG. 4, as described
above. It is imperative that the drug 21 be depleted from the
reservoir 41 prior to the complete erosion of rate controlling
membrane 22 in order to avoid a sudden and unwanted release of drug
from the reservoir 41 to the eye.
When the drug being released to the eye is water soluble, it is
often difficult to control its rate of release with the hydrophilic
polyvalent metal ion cross-linked anionic polyelectrolytes of the
present invention. In such cases the rate of drug release may be
provided by simple rapid dissolution of the drug in tear fluids
which is unsatisfactory for the reasons that the release of drug is
both uncontrolled and usually exceeds the desired therapeutic
dosage. It is therefore preferred in these cases when employing the
embodiment of FIG. 4 that certain modifications be made to
insolubilize or decrease the water solubility of the drug so as to
effect the drug release by a Permeation Control mechanism, e.g., by
controlled viscous fluid diffusive transfer as hereinbefore
discussed.
FIG. 6 illustrates an ocular insert 50 of this invention
particularly suited for administering a water soluble drug. The
drug delivery device 50 is comprised of a bioerodible matrix 22 of
polyvalent cation cross-linked anionic polyelectrolyte material
having dispersed therethrough a plurality of drug reservoirs 51.
The reservoirs 51 are microcapsules comprised of a water soluble
drug whether in solid form, liquid form or in admixture with a
carrier, confined within a drug release rate controlling material.
Drug molecules released from the reservoirs 51 pass into the matrix
22 and then migrate through the matrix 22 for administration of
drug to the eye. Release of drug from the reservoir is the rate
controlling step for release of drug from the device. In
construction, the device can be viewed as a single unit device
comprising two structures acting in concert for effective drug
administration to the eye. One structure pertains to the reservoirs
51 which are microcapsules comprising a microbody of drug release
rate controlling material having drug 21 confined therein, and the
other structure relates to the bioerodible matrix 22 housing the
reservoirs and is formed of a material permeable to the passage of
drug.
The reservoirs 51 can be formed as a hollow container having a drug
therein formed from drug release rate controlling material.
Additionally, the reservoir 51 can be a solid particle having a
drug distributed therethrough and formed of a drug release rate
controlling material. Alternatively, the reservoir 51 can be a
porous structure formed of a material possessing drug release rate
controlling properties. Reservoir 51 can have the conventional
aggregate structure and particulate structure of conventional
geometric shape. By controlling the structure of the reservoirs of
the drug delivery device, the invention makes possible a drug time
pattern of release, including a zero order drug release. Thus, in
the presently preferred embodiments for obtaining a constant rate
of release, the reservoir is formed as a capsule containing the
drug therein and surrounded by a rate controlling membrane, or the
reservoir is a solid matrix with a limited number of discrete
particles of drug contained therein.
The materials suitable for fabricating the reservoir 51, whether of
hollow, solid, porous, semi-porous or the like structures, are
generally those materials capable of forming membranes with or
without pores or voids, or coating through which the drug can pass
at a controlled rate by the process of diffusion. Suitable
materials for forming the reservoirs are naturally-occurring or
synthetic materials that are non-toxic and which preferably have a
slow solubility and/or low diffusivity to water. In general, these
qualities will be possessed by rate release controlling materials
that are hydrophobic in nature. The rate controlling materials used
for the reservoir 51 can be biodegradable, biodegration in the
environment of the eye taking place concurrently with the
dispensing or at a point in time after the dispensing of the
therapeutically desired amount of drug. Alternatively, when the
reservoir 51 is of an initial size and configuration such as to be
capable of being eliminated from the ocular cavity through the
punctum with tear fluid can be made of non-biodegradable material.
Microcapsules, preferably of approximately 100 micron size or less,
will be of suitable dimension for proper punctum passage.
Exemplary non-biodegradable materials suitable for fabricating the
microcapsules when of an initial size such as to pass through the
punctum are drug release rate controlling materials such as
hydrophobic polymers, e.g., polyvinylchloride, nylon, silicone
rubber, cholesterol; substituted alkyl celluloses such as
hydroxypropyl methyl cellulose, methyl celluloe, ethyl cellulose,
cellulose acetate; waxes, e.g., paraffin, ethylene wax,
hydrogenated castor oil; C.sub.10 to C.sub.20 fatty acids, e.g.,
stearic acid, palmitic acid; hydrophilic polymers, e.g.,
polymerized esters of methacrylic acid (Hydron), and the like.
Biodegradable materials suitable for preparing the microcapsule
reservoirs are disclosed hereinafter. The actual material selected
for fabricating the microcapsule reservoir is one that can slow
down the rate of release of the water soluble drug to the desired
level. Preferred are the hydrophobic materials. Although
hydrophilic type materials can sometimes be employed for
fabricating the reservoir in cases where the water soluble drug is
not too highly permeable therein, in most cases thicker coatings of
microcapsule material and larger microcapsule diameters will be
required than for hydrophobic type microcapsule materials. In this
regard, among other factors which must be considered, in addition
to the nature of the reservoir rate controlling material, and which
affect the rate of release of drug from the microcapsule, are the
microcapsule size, the density of drug and the thickness of the
reservoir wall. Qualitative guides in this regard are that the rate
of release of drug will decrease with corresponding increasing
values for each of these parameters as will be appreciated by those
skilled in the art.
Any of the standard encapsulation or impregnation techniques known
in the art can be used to prepare the microcapsules 51 to be
incorporated into the matrix material 22, of FIG. 6, in accord with
this invention. Thus, the drug, admixture of drug, or drug solution
can be added to the encapsulating material in liquid form and
uniformly distributed therethrough by mixing; or solid
encapsulating material can be impregnated with the drug by
immersion in a bath of the drug to cause the drug to diffuse into
the material. Subsequently, the solid material can be reduced to
fine microcapsules by grinding, each of the microcapsules
comprising drug coated with and distributed throughout the
encapsulated material. Alternatively, fine particles or solutions
of the drug can be encapsulated with a coating. One suitable
technique comprises suspending dry particles of the drug in an air
stream and contacting that stream with a stream containing the
encapsulating material that coats the drug with a membrane
permeable to drug.
Another standard method of microencapsulation suitable for the
prupose of the invention is the coacervation technique. The
coacervation technique of fabrication as conventionally employed
consists essentially of the formation of three immiscible phases, a
liquid manufacturing phase, a core material phase and a coating
phase with deposition of the liquid polymer coating on the core
material and rigidizing the coating, usually by thermal,
cross-linking or desolvation techniques to form microcapsules.
Techniques for preparing microcapsules, such as the classic
Bungenberg de Jong and Kaas method are reported in Biochem. Z.,
Vol. 232, pp. 338-345, 1971; Colloid Science, Vol. 11, "Reversible
System," edited by H. R. Kruyt, 1949, Elsevier Publishing Company,
Inc., New York; J. Pharm. Sci., Vol. 59, No. 10 (1970), pp.
1,367-1,376; and, Remington's Pharmaceutical Science, Vol. XIV,
Mack Publishing Company, Easton, Pa., 1970, pp. 1,676-1,677. Other
procedures for preparing microcapsules are set forth in West German
Patent No. DT-1939-066; and the like.
Although the device of the type illustrated in FIG. 6 is
particularly well suited to the administration of water soluble
drug and so described above, it will be appreciated that it is
equally well adapted to the administration of drugs as hereinafter
set forth which are not water soluble.
Devices of the type shown in FIG. 6 can be designed by first
selecting the drug to be used, its dosage, and the period of
therapy. This establishes the required drug release rate and amount
of drug to be incorporated in the device. Materials having the
appropriate drug release rate characteristics and erosion rates can
then be correlated with the effective surface release area to
fabricate a device which meters the desired rate of the drug to the
eye over the established period of time. A particular added
advantage of a device of the type as illustrated in FIG. 6 is the
fact that the number of reservoirs employed can be varied in order
to achieve the desired drug release rate from the device.
Any of the drugs used to treat the eye and surrounding tissues can
be incorporated in the ocular insert of this invention. Also, it is
practical to use the eye and surrounding tissues as a point of
entry for systemic drugs or antigens that ultimately enter
circulation in the blood stream, or enter the nasopharyngeal area
by normal routes, and produce a pharmacologic response at a site
remote from the point of application of the ocular insert. Thus,
drugs or antigens which will pass through the eye or the tissue
surrounding the eye to the blood stream or to the nasalpharyngeal,
esophageal or gastrointestinal areas, but which are not used in
therapy of the eye itself, can be incorporated in the ocular
insert.
Suitable drugs for use in therapy of the eye with the ocular insert
of this invention consistent with their known dosages and uses are
without limitation: antibiotics such as tetracycline,
chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin,
oxytetracycline, chloramphenicol, gentamycin, and erythromycin;
antibacterials such as sulfonamides, sulfacetamide, sulfamethizole
and sulfisoxazole; antivirals, including idoxuridine; and other
antibacterial agents such as nitrofurazone and sodium propionate;
antiallergenics such as antazoline, methapyriline,
chlorpheniramine, pyrilamine and prophenpyridamine;
anti-inflammatories such as hydrocortisone, hydrocortisone acetate,
dexamethasone, dexamethasone 21-phosphate, fluocinolone, medrysone,
prednisolone, methylpredenisolone, predisolone 21-phosphate,
prednisolone acetate, fluoromethalone, betamethasone and
triamcinolone; decongestants such as phenylephrine, naphazoline,
and tetrahydrazoline; miotics and anticholinesterases such as
pilocarpine, eserine salicylate, carbachol, di-isopropyl
fluorophosphate, phospholine iodide, and demecarium bromide;
mydriatics such as atropine sulfate, cyclopentolate, homatropine,
scopolamine, tropicamide, eucatropine, and hydroxyamphetamine; and
sympathomimetics such as epinephrine.
Drugs can be invarious forms, such as uncharged molecules,
components of molecular complexes, or nonirritating,
pharmacologicaly acceptable salts such as hydrochloride,
hydrobromide, sulfate, phosphate, nitrate, borate, acetate,
maleate, tartrate, salicylate, etc. For acidic drugs, salts of
metals, amines, or organic cations (e.g., quaternary ammonium) can
be employed. Furthermore, simple derivatives of the drugs such as
ethers, esters, amides, etc., which have desirable retention,
release or solubility characteristics, but which are easily
hydrolized by body pH, enzymes, etc., can be employed. The amount
of drug incorporated in the ocular insert varies widely depending
on the particular drug, the desired therapeutic effect, and the
time span for which the ocular insert will be used.
The above drugs and other drugs can be present in the reservoir
alone or in combination form with pharmaceutical carriers. The
pharmaceutical carriers acceptable for the purpose of this
invention are the art-known carriers that do not adversely affect
the drug, the host, or the material comprising the drug delivery
device. Suitable pharmaceutical carriers include sterile water;
saline; dextrose; dextrose in water or saline; condensation
products of castor oil and ethylene oxide combining about 30 to
about 35 moles of ethylene oxide per mole of castor oil; liquid
glyceryl triester of a lower molecular weight fatty acid; lower
alkanols; oils such as corn oil; peanut oil; sesame oil, and the
like, with emulsifiers such as mono- or di-glyceride of a fatty
acid, or a phosphatide, e.g., lecithin, and the like; glycols;
polyalkylene glycols; aqueous media in the presence of a suspending
agent, for example, sodium carboxymethylcellulose; sodium alginate;
poly(vinylpyrrolidone); and the like, alone, or with suitable
dispensing agents such as lecithin; polyoxyethylene stearate; and
the like. The carrier may also contain adjuvants such as
preserving, stabilizing, wetting, emulsifying agents, and the
like.
To provide compatibility with the eye and surrounding tissues, at
least for the initial period after insertion, the surface of the
ocular insert in contact with the eye can be coated with a thin
layer, e.g., from 1 to 2 microns thick, biodegradable hydrophilic
material. Exemplary of the suitable materials for this purpose are
the water soluble hydrophilic polymers of uncross-linked
hydroxyalkyl acrylates and methacrylates, as disclosed in U.S. Pat.
No. 3,576,760, gelatin, non-cross-linked polysaccharides, e.g.,
agar, gum arabic, and the like.
In preferred embodiments, the ocular insert is intended to provide
a complete dosage regimen for eye therapy over this prolonged
period. Therefore, the amount of drug to be incorporated in the
device is determined by the fact that sufficient amounts of drug
must be present to maintain the desired dosage level over the
therapeutic treatment period. Typically, from 1 microgram to 1 gram
or larger of drug is incorporated in the ocular insert, the exact
amount, of course, depending upon the drug used and treatment
period. Illustratively, in order to treat glaucoma in an adult
human, the daily release dosage should be in the range of between
25 micrograms to 1,000 micrograms of pilocarpine per day. Thus, for
example, using pilocarpine with a device intended to remain in
place for 7 days, and with a release rate of 500 micrograms of drug
per day, 3.5 milligrams of pilocarpine will be incorporated in the
device. Other devices containing different amounts of drug for use
for different time periods and releasing drug at higher or lower
controlled rates are also readily made by the invention.
Further, in practicing this invention one can employ any of the
aforementioned listed drugs, consistent with their known dosages
and uses, to establish a release rate, e.b., micrograms/insert/day.
Exemplary of the dosages to be used are:
Antibiotics, such as polymixin: 250 micrograms/insert/day
Sulfonamides, such as sulfacetamide: 500 micrograms/insert/day
Antivirals, such as idoxuridine: 5 micrograms/insert/day
Anti-inflammatories, such as hydrocorti- sone acetate or
prednisolone: 500 micrograms/insert/day
The ocular inserts are suitably packaged using a drug and moisture
impermeable packaging material such as the foil-polylaminates, e.g,
aluminum foil-polyethylene laminate or aluminum foil-polyester
(Mylar)-laminate. While the inserts can be packaged either wet or
dry, the latter becomes mandatory when certain bioerosion processes
are involved. More specifically, when the bioerosion process is
effected by dissolution or hydrolysis, dry packing, e.g., vacuum
packing, is required.
The ocular devices are preferably sterilized prior to insertion in
the eye. The sterilization can be effected prior to packaging or
after packaging. Suitable sterilization methods such as the use of
radiation or ethylene oxide can be satisfactorily employed. Details
for these methods and others are set forth in Remington's
Pharmaceutical Sciences, Vol. XIV, 1970, pp. 1,501-1,518.
Essential to this invention is the use of polyvalent metal ion
cross-linked anionic polyelectrolyte materials for the controlled
administration of drug to a patient. Although the use of polyvalent
metal ion cross-linked anionic polyelectrolytes in drug delivery
devices has principally been described with regard to erodible
ocular devices for the controlled administration of drugs to the
eye, these materials may be employed as well in a wide variety of
bioerodible devices for administering drugs at controlled rates to
other areas of the body which offer a saline environment as is
required to effect bioerosion. Thus various other forms of the
invention are intended to be included herein. Thus, the metal ion
cross-linked polyelectrolytes may be employed to advantage in
external and internal erodible drug delivery devices such as, for
example, buccal patches, sublingual or bucal tablets, peroral
dosage forms which bioerode by the action of the saline in saliva;
subcutaneous implantates for releasing a drug to the tissues of a
patient; artificial glands, which are eroded by salinity of blood;
vaginal suppositories; drug dispensing intrauterine devices; and
rectal suppositories which are eroded by the action of vaginal and
intestinal fluids respectively. In each instance, the device
employs polyvalent metal ion cross-linked anionic polyelectrolytes
and is of a shape or form appropriate for implementation or
insertion in the described body tissues or cavities, respectively
or for application to a particular body area.
Therefore in practicing the invention, one can employ any drug used
to treat the body in addition to those ophthalmic drugs previously
listed, which is capable of being dispersed in or confined by the
polymer in accordance with its known usage. The term "drug" as used
herein is intended to be interpreted in its broadest sense as
including any composition or substance that will produce a
pharmacologic response either at the site of application or at a
site remote therefrom. Suitable drugs for use in therapy with the
drug delivery system of the invention include, without
limitation:
1. Protein drugs such as insulin;
2. Desensitizing agents such as ragweed pollen antigens, hay fever
pollen antigens, dust antigen and milk antigen;
3. Vaccines such as small pox, yellow fever, distemper, hog
cholera, fowl pox, anti-venom, scarlet fever, diphtheria toxoid,
tetanus toxoid, pigeon pox, whooping cough, influenzae, rabies,
mumps, measles, poliomyelitis, Newcastle disease, etc.;
4. Anti-infectives, such as antibiotics, including penicillin,
tetracycline, chlortetracycline, bacitracin, nystatin,
streptomycin, neomycin, polymyxin, gramicidin, oxytetracycline,
chloramphenicol, and erythromycin; sulfonamides, including
sulfacetamide, sulfamethizole, sulfamethazine, sulfadiazine,
sulfamerazine, and sulfisoxazole; anti-virals including
idoxuridine; and other anti-infectives including nitrofurazone and
sodium propionate;
5. Anti-allergenics such as antazoline, methapyrilene,
chlorpheniramine, pyrilamine and prophenpyridamine;
6. Anti-inflammatories such as hydrocortisone, cortisone,
hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate,
fluocinolone, triamcinolone, medrysone, prednisolone, prednisolone
21-phosphate, and prednisolone acetate;
7. Decongestants such as phenylephrine, naphazoline, and
tetrahydrozoline;
8. Sympathomimetics such as epinephrine;
9. Sedatives and Hypnotics such as pentobarbital sodium,
phenobarbital, secobarbital sodium, codeine,
(.alpha.-bromoisovaleryl) urea, carbromal;
10. Psychic Energizers such as 3-(2-aminopropyl) indole acetate and
3-(2-aminobutyl) Indole acetate;
11. Tranquilizers such as reserpine, chlorpromazine, and
thiopropazate;
12. Androgenic steroids such as methyltestosterone and
fluoxymesterone;
13. Estrogens such as estrone, 17 .beta.-estradiol, ethinyl
estradiol, and diethyl stilbesterol;
14. Progestational agents such as progesterone, megestrol,
melengestrol, chlormadinone, ethisterone, norethynodrel,
19-nor-progesterone, norethindrone, medroxyprogesterone and 17
.alpha.-hydroxyprogesterone;
15. Homoral agents such as the prostaglandins, for example,
PGE.sub.1, PGE.sub.2, and PGF.sub.2 ;
16. Antipyretics such as aspirin, sodium salicylate, and
salicylamide;
17. Antispasmodics such as atropine, methantheline, papaverine, and
methscopolamine bromide;
18. Anti-malarials such as the 4-amino-quinolines,
8-aminoquinolines, chloroquine, and pyrimethamine;
19. Antihistamines such as diphenhydramide, dimenhydrinate,
tripelennamine, perphenazine, and carphenazine;
20. Cardioactive agents such as hydrochlorothiazide flumethiazide,
chlorothiazide, and aminotrate;
21. Nutritional agents such as vitamins, essential amino acids and
essential fats;
22. Anti-Parkinsonism agents such as L-dopa,
(L-3,4-dihydroxyphenylalanine);
23. Investigative antihypotensive agents such as dopamine,
4-(2-aminoethyl) pyrocatechol.
Other drugs having the same or different physiological activity as
those recited above can be employed in drug delivery systems within
the scope of the present invention. Suitable mixtures of drugs can,
of course, be dispensed with equal facility as with single
component systems.
Drugs can be in different forms, such as uncharged molecules,
components of molecular complexes, or nonirritating,
pharmacologically acceptable salts such as hydrochloride,
hydrobromide, sulfate, phosphate, nitrate, borate, acetate,
maleate, tartrate, salicylate, etc. For acidic drugs, salts of
metals, amines, or organic cations (e.g., quaternary ammonium) can
be employed. Furthermore, simple derivatives of the drugs (such as
ethers, esters, amides, etc.) which have desirable retention and
release characteristics but which are easily hydrolyzed by body pH,
enzymes, etc. can be employed.
The amount of drug employed in devices in accord with this
invention may vary over a wide range, depending upon the type of
drug and the dosage desired and the size and type of device in
which the drug is employed. The amount may vary from the minimum
effective single dosage of the drug employed to a maximum number of
effective doses limited by the size and/or erosion characteristics
of the devices. In general, drug is usually present in an amount
equivalent to from about 5 to 90 percent of the weight of the
polyvalent metal ion cross-linked polyelectrolyte, although larger
or smaller amounts consistant with the above noted general limits
may be employed if desired.
The rate of bioerosion or biodegradation of materials employed in
the invention can be determined experimentally by placing them
under simulated environmental conditions. For example, the rate of
bioerosion of a material in the eye may be measured by placing a
small weighed sample of the material in a 0.9 percent by weight
sodium chloride solution (simulated tear fluids) at body
temperature (37.degree.C), agitating for a timed interval, renewing
the sodium chloride solution if material solubility considerations
make it necessary, and then weighing the sample to determine the
weight loss and hence the rate of erosion.
As previously discussed, devices of this invention are designed to
dispense a metered amount of drug from the reservoir to the patient
over a prolonged period of time, primarily through diffusion or
erosion control drug release transfer mechanisms. Moreover, as
heretofore indicated, in order to design these devices, it is
necessary to correlate drug dosage with permeability
characteristics and erosion rates. Methods of determining the rate
of passage of drugs by diffusion through drug permeable polymeric
material which can readily be adapted to the materials employed in
this invention are exemplified in: Dziuk, P. J. and Cook, B.,
Passage of Steroids Through Silicone Rubbers, Endocrinology,
78:208, 1966; U.S. Pat. No. 3,279,996; Folkman and Edmonds,
Circulation Research, 10:632, 1962, Folkman and Long, J. Surg.
Res., 43:139, 1964; Powers, J., Parasitology, 51:53 (April 1965),
No. 2 Section 2; and copending application Ser. No. 42,786 filed
June 2, 1970, of Alejandro Zaffaroni. This application is
incorporated herein by reference.
Overall rates of drug release by erosion control mechanism or by
combinations of both erosion control and diffusion control
mechanisms can be determined directly by placing drug-containing
devices under simulated environment conditions and periodically
measuring the amount of drug released.
For a more complete understanding of the nature of this invention,
reference should be made to the following examples which are given
merely as further illustrations of the invention, and are not to be
construed in a limiting sense. All parts are given by weight,
unless stated to the contrary.
EXAMPLE 1
A bioerodible ocular insert employing a polyvalent metal ion
cross-linked polyelectrolyte and containing hydrocortisone is
prepared in the following manner:
A. Preparation of zinc alginate
1. Seven grams of sodium alginate (Keltone, Kelco Co., KT-9529-21)
is dissolved in 350 ml of distilled water by means of efficient
stirring, to yield a slightly viscous solution.
2. In a separate preparation, 10 grams of zinc chloride is
dissolved in 600 ml of distilled water and the pH is adjusted to 3
by drop-wise addition of concentrated hydrochloric acid.
3. The zinc chloride is transferred into a gallon-size Waring
blender and to this solution is added in small proportions the
sodium alginate solution under moderate agitation. After the
addition is complete, the mixture is vigorously stirred for 10-15
minutes, transferred to a glass container and allowed to stand
overnight.
4. The precipitate is then transferred to a large size
chromatographic column and washed continuously with distilled water
to a negative silver chloride test (or to the same conductivity
reading as distilled water). The aqueous suspension of the sodium
chloride-free zinc alginate is isolated by lyophilization and
vacuum-dried at 40.degree.C overnight.
B. Preparation of hydrocortisone ocular insert
1. The mixture containing 1.5 grams of micronized hydrocortisone in
3.5 grams of glycerine is homogenized by means of a suitable
colloid mill or by simple grinding of the mixture with mortar and
pestle.
2. The resulting white paste is slowly poured into a Waring blender
containing 100 ml of 1.2% ammonium hydroxide solution under
vigorous agitation. To this suspension is then added 5 grams of
zinc alginate previously prepared, and the vigorous agitation is
continued until the complete dissolution of the zinc alginate
results; if marked thickening occurs, more ammonia solution can be
added.
3. The viscous dispersion of (2) is drawn on a glass plate with a
wet thickness of ca. 10 mils. The cast plate is placed in a
circulating stream of warm, moisturized air at 40.degree.C, and
allowed to dry thoroughly.
4. The resulting film is removed from the plate by stripping, and
is punch-cut into desired shape and size. For example, the circular
insert device of 6.1 mm diameter and 3 mil thickness contains about
0.45 mg of hydrocortisone. When inserted in a monkey's eye, the
resulting insert releases the drug over a 2-day period at the
termination of which the insert has totally eroded in the eye.
EXAMPLE 2
Plasticized zinc alginate-hydrocortisone acetate and aluminum
alginate-hydrocortisone acetate bioerodible ocular inserts are
prepared in the following manner:
A. Preparation of sodium alginate-hydrocortisone acetate base
1. A paste containing 3.2 grams of micronized hydrocortisone
acetate and 5.6 gm glycerine is prepared by grinding the mixture
with mortar and pestle (or with colloid mill).
2. The paste is transferred into a Waring blender containing 0.03
gram Tween 80 (Atlas Chemical Industries) and 150 ml distilled
water. To this fine particle suspension is added 7.5 grams of
sodium alginate under vigorous stirring. Alternatively, the
Premier-Dispersator (Premier Mill Corp.) may be used for this
purpose. If necessary, the whole content may be transferred by a
wide-mouth bottle and placed on a variable speed jar mill (Norton
Co.) for 12 hours or to complete sodium alginate dissolution.
3. The film is then prepared by casting the mixture on a clean
glass plate, and drying it at 40.degree.C for 16 hours. A 125 mil
cast of this solution gives about 10 mil thick dry film.
B. Insolubilization
1. A portion of the plasticized sodium alginate-hydrocortisone
acetate film is dipped into 5.5% zinc chloride solution (pH
adjusted to 4.5) for 5 hours. The film is then washed twice by
immersion in a stirred 50 percent glycerine bath or until the final
washing gives a negative silver chloride test. The film is then air
dried at room temperature, and punch-cut into circular discs 6 mm
in diameter.
2. An aluminum alginate-hydrocortisone acetate film can also be
prepared from the plasticized sodium alginate film by a method
analogous to that of zinc alginate film described above using 10
percent alum (KAL(SO.sub.4).sbsb.2) solution (pH 3.1).
When inserted in the sac of a human eye, the above prepared devices
release the drug at a controlled rate. The inserts completely
bioerode in the eye at the termination of the therapeutic program.
Table I, which follows, characterizes the devices prepared.
TABLE I ______________________________________ CHARACTERISTICS OF
HYDROCORTISONE ACETATE CONTAINING METAL-ALGINATE COMPLEXES
______________________________________ Zn-Alginate Al-Alginate
Hydrocortisone Hydrocortisone Acetate Acetate
______________________________________ 1. Hydrocortisone 30/70
30/70 acetate content (H.C.Ac./Alg.) 2. Cross-linking conditions
5.5% ZnCl.sub.2 10% Alum pH 4.5 pH 3.1 5 hrs. 5 hrs. 3. Tackiness
non-tack non-tack 4. Color, appearance, etc. white, smooth white,
smooth 5. Cohesiveness (or intact- fair good ness on swelling,
after 3-4 hrs.) 6. Time to erosion (days) 6 days >10 days 7.
Hydrocortisone acetate 7 1.5 release .mu.g/hr
______________________________________
EXAMPLE 3
Five polyvalent metal ion cross-linked polyelectrolytes (zinc
alginates) having varying ratios of polyelectrolyte to polyvalent
ion are prepared and tested as follows:
A. The apparatus, materials and preparative technique described in
Part A of Example 1 are used. The amount of zinc chloride employed
is varied as follows:
Preparation Equivalents Alginate Number Equivalents Zn II 2 1 3 1.5
4 2 5 2.5 6 3
B. Preparation of films
Four-gram portions of the products of part A are each added to 100
ml of 1.2 percent ammonium hydroxide solution and vigorously
stirred to yield viscous solutions. These solutions are drawn on
glass plates with wet thickness of about 60 mil and the cast plates
thoroughly dried at 40.degree.C in a circulating stream of moist
air. This passage of moist air removes the added ammonium hydroxide
as well.
C. Testing of films
1. Erosion Rates
Seven to 11 mg samples of the resulting films are shaken in 10 cc
of 0.9 % NaCl solution (saline) at 37.degree.C. Fresh saline is
substituted every 30 minutes. The erosion of the samples is
monitored and it is observed that the rate of erosion of the
samples is related to the ratio of polyelectrolyte to metal ion.
Preparation 6, having the least metal ion cross-linking, is the
fastest eroding, dissolving in less than 1 hour. Preparations 5 and
4 require from 1 to 2 hours to dissolve. Preparations 3 and 2
require about 5 and 10 hours, respectively, to dissolve.
The erosion rate study is repeated with one change. Instead of
saline, deionized water is employed as the erosion environment.
After 60 hours, little or no erosion is noted with any of the
films, indicating, by comparison with the erosion observed with
saline, that the rate controlling mechanism for bioerosion is the
gradual displacement of the cross-linking polyvalent metal ions
with non-cross-linking monovalent ions of the saline.
2. Liquid Uptake
Samples of the products denoted Preparation Number 2 (1 equivalent
of alginate for each equivalent of zinc) and Preparation Number 3
(1.5 equivalent of alginate for each equivalent of zinc) weighing
0.2052 gram and 0.2901 gram, respectively, are each placed in 100
ml of saline at room temperatures. After 1 hours, the samples are
removed, liquid adhering to the surface is removed, and the samples
are weighed. The sample of Preparation 2, the more heavily
cross-linked material, has absorbed 40 % of its original weight of
saline. The sample of Preparation 3, being less tightly
cross-linked, has absorbed 111% of its original weight of
saline.
Comparison of the liquid uptakes of the two samples shows that the
sample of the less thoroughly cross-linked material has achieved a
structure having more liquid-filled pores through which drug might
more easily and more rapidly diffuse, while the more thoroughly
cross-linked material would give a slower rate of drug
diffusion.
EXAMPLE 4
A. Zinc II cross-linked alginate containing one equivalent of zinc
per equivalent of alginate is prepared in accord with the procedure
described in part A of Example 1. 4.15 grams of this cross-linked
alginate is dissolved with vigorous stirring in 4.67 ml of 28%
NH.sub.4 OH and 95 ml and deionized water. Separately, a slurry of
0.32 gm of hydrocortisone acetate (Cal Biochem -- Lot 100298) is
slurried in a minimum amount of water. The slurry is added to the
alginate solution and vigorously agitated for 5 to 10 minutes to
yield a viscous dispersion which is cast in a film on glass. The
film is air dried, subjected to steam treatment to remove residual
ammonia, and finally oven dried for 5 minutes at 80.degree.C. Based
on the initial weight of dry zinc II cross-linked polyelectrolyte,
this product contains about 8% by weight hydrocortisone
acetate.
B. This preparation is repeated, varying the amount of drug added,
to prepare a film containing 29% of hydrocortisone.
C. Samples of the films of part A and part B are placed in 0.9%
saline to determine water uptake. When equilibrium water uptake is
reached, the film of part A absorbs 103% of its initial weight of
saline, while the film of part B absorbs 95% of its initial weight
of saline. Samples of similar film containing no hydrocortisone
shows water uptakes of 95-100% of their initial weight. These
essentially identical water uptakes indicate that porosity of these
films in constant when cross-linking is constant and is essentially
independent of drug loading. With constant porosity it would be
expected that these materials would have similar rates of drug
release of diffusion, irrespective of drug loadings. Six mm
diameter discs are punch-cut from a 30 mil thickness film of the
material produced in part A (8% drug) and of a 60 mil thickness
film of the material produced in part B (29% drug). These discs are
inserted in rabbits' eyes, and sequentially removed and weighed to
determine erosion rates. The 30 mil film completely erodes in less
than 30 hours, while the 60 mil film requires about 40 hours to
erode. The devices are compatible with rabbit eyes, causing no
untoward irritation.
EXAMPLE 5
Bioerodible ocular inserts are prepared from other representative
anionic polyelectrolytes:
A. Preparation of polyelectrolyte drug bases
1. Pectin
A solution containing 6 grams (12%) of pectin (Matheson Coleman and
Bell Low methoxy grade citrus pectin) and 12% of glycerin in
deionized water is prepared in a Waring blender. In a second Waring
blender, 1.5 grams of micronized hydrocortisone in 3.5 grams of
glycerine is thoroughly homogenized. With vigorous stirring, the
contents of the two blenders are combined. An 80 mil wet thickness
film is prepared by casting the resulting mixture on a glass plate.
The film is air dried at room temperature and then dried at a
pressure of less than 1 mm and 40.degree.C for 6 hours to give a
8-10 mil thick dry film.
2. Pectin -- Alginate Mixture
The preparation described in subsection (1) of this part of this
Example is repeated with the following changes. Instead of 6 grams
of pectin, 3 grams of pectin and 3 grams of sodium alginate are
employed; and the amount of hydrocortisone is raised from 1.5 grams
to 2.6 grams.
3. Carboxymethyl Cellulose
The preparation described in subsection (1) of this part of this
Example is repeated with the following changes. Instead of 6 grams
of pectin, 6 grams of sodium carboxymethyl cellulose powder
(Hercules 7 MF Grade) is employed; and the glycerine plasticizer is
omitted and replaced with equivalent volume of deionized water.
4. Agar
Ten grams of agar (Schwartz-Mann Lot No. W 3435) is suspended in
100 ml of deionized water and heated for 12 minutes in a pressure
cooker to yield a clear solution. A paste of 4.28 grams of
hydrocortisone acetate and 7.5 grams of glycerine is prepared and
added to 20 ml of deionized water. At about 100.degree.C, the paste
and solution are combined and stirred to give a homogeneous
mixture. A film is prepared from this mixture and dried in accord
with subsection (1) of this part of this example.
B. Insolubilization
Portions of the four films prepared in part A are insolubilized by
being dipped into polyvalent metal ion containing solutions, washed
to remove monovalent cations, air dried, and punch-cut into samples
for testing. The following polyvalent metal ion polyelectrolyte
combinations are made:
1. Pectin Films
a. With Zn II -- The pectin film is dipped in a 40% zinc chloride
solution (pH 4.5) for 5 hours.
b. With Al III -- The pectin film is dipped in a 40% aluminum
chloride solution (pH 1.55) for 5 hours.
c. With Ba II -- The pectin film is dipped in a 9.77% barium
chloride solution (pH 5.8) for 5 hours.
d. With Ca II -- The Pectin film is dipped in a 5.88% calcium
chloride solution (pH 6.1) for 5 hours.
2. Pectin-alginate
a. With Zn II -- The pectin-alginate film is dipped in a 40% zinc
chloride solution (pH 4.5) for 12 hours.
b. With Al III -- The pectin-alginate film is dipped in a 10%
aluminum chloride solution (pH 3.1) for 12 hours.
3. Carboxymethyl Cellulose
a. With Zn II -- The carboxymethyl cellulose film is dipped in a
40% zinc chloride solution (pH 4.5) for 5 hours.
b. With Al III -- The film is dipped in a 4% aluminum chloride
solution (pH 3.3) for 5 hours.
4. Agar
a. With Zn II -- The agar film is dipped in a 51.5% zinc chloride
solution (pH 4.8) for 12 hours.
b. With Al III -- The agar film is dipped in a 4% aluminum chloride
solution (pH 3.3) for 12 hours.
c. With Ba II -- The agar film is dipped in a 9.77% barium chloride
solution (pH 5.8) for 12 hours.
d. With Ca II -- The agar film is dipped in a 5.88% calcium
chloride solution (pH 6.1) for 12 hours.
5. Alginate
Portions of sodium alginate film containing 30% hydrocortisone
acetate, as prepared in Example 2, are dipped into 30.9% barium
chloride solution (pH 4.5) for 12 hours, a 30.0% calcium chloride
solution (pH 6.7) for 12 hours, a 20% ferric chloride solution (pH
4) for 12 hours, and a 20% cadmium nitrate solution (pH 4) for 12
hours.
If cut into suitable shapes and inserted into the sac of an eye,
the above prepared metal ion cross-linked materials would release
the drug at a controlled rate and completely bioerode in the
environment of the sac of the eye at the termination of the
therapeutic program. Table II, which follows, characterizes the
materials prepared.
TABLE II
__________________________________________________________________________
Characteristics of hydrocortisone acetate containing polyvalent
metal ion linked polyelectrolytes.
__________________________________________________________________________
PECTIN CHARACTERISTIC Zn II Al III Ba II Ca II
__________________________________________________________________________
1. Hydrocortisone 20/80 20/80 20/80 20/80 acetate content (H.C.
Ac/Alg.) 2. Tackiness non-tack. non-tack. non-tack. non-tack. 3.
Flexibility soft, brittle flex. flex. flex. 4. Color, Appear-
white, white, white, white, ance, etc. smooth smooth smooth smooth
5. Cohesiveness (or poor fair- fair- fair intactness) on good good
swelling (after 3-4 hrs) 6. Time to Erosion 1 110+ 60+ 0.5-1 (hr)
(in 0.9% - NaCl) for 9-12 mil Film 7. Hydrocortisone 100+ 4 7 100+
acetate release .mu.g/hr. CARBOXYMETHYL CELLULOSE CHARACTERISTIC Zn
II Al III
__________________________________________________________________________
1. Hydrocortisone 30/70 30/70 acetate content (H.C. Ac/Alg.) 2.
Tackiness non-tack. non-tack. 3. Flexibility sl. flex. sl. flex. 4.
Color, Appear- white, white, ance, etc. rough rough 5. Cohesiveness
(or poor poor intactness) on swelling (after 3-4 hrs) 6. Time to
Erosion -- >300 (hr) (in 0.9% - NaCl) for 9-12 mil Film 7.
Hydrocortisone -- 7 acetate release .mu.g/hr. PECTIN-ALGINATE
CHARACTERISTIC Zn II Al III
__________________________________________________________________________
1. Hydrocortisone 30/70 30/70 acetate content (H.C. Ac/Alg.) 2.
Tackiness non-tack. non-tack. 3. Flexibility sl. flex. brittle 4.
Color, Appear- white, white, ance, etc. smooth smooth 5.
Cohesiveness (or poor fair intactness) on swelling (after 3-4 hrs)
6. Time to Erosion 24 24 (hr) (in 0.9% - NaCl) for 9-12 mil Film 7.
Hydrocortisone 10 4 acetate release .mu.g/hr. AGAR CHARACTERISTIC
Zn II Al III Ba II Ca II
__________________________________________________________________________
1. Hydrocortisone 30/70 30/70 30/70 30/70 acetate content (H.C.
Ac/Alg.) 2. Tackiness sl. tack. non-tack. non-tack. sl. tack. 3.
Flexibility brittle brittle brittle brittle 4. Color, Appear- sl.
tan, sl. tan, sl. tan, sl. tan, ance, etc. smooth smooth smooth
smooth 5. Cohesiveness (or fair-poor fair-poor fair-poor fair-poor
intactness) on swelling (after 3-4 hrs) 6. Time to Erosion 100+
180+ 180+ 100+ (hr) (in 0.9% - NaCl) for 9-12 mil Film 7.
Hydrocortisone 6-8 6-8 6-8 5 acetate release .mu.g/hr. ALGINATE
CHARACTERISTIC Ba II Ca II Fe III Cd II
__________________________________________________________________________
1. Hydrocortisone 30/70 30/70 30/70 30/70 acetate content (H.C.
Ac/Alg.) 2. Tackiness non-tack. non-tack. non-tack. non-tack. 3.
Flexibility flex. flex. sl. flex. sl. flex. 4. Color, Appear-
white, white, brown, sl. yel. ance, etc. smooth smooth smooth
smooth 5. Cohesiveness (or good-fair fair fair fair intactness) on
swelling (after 3-4 hrs) 6. Time to Erosion 50+ 20+ 30+ 30+ (hr)
(in 0.9% - NaCl) for 9-12 mil Film 7. Hydrocortisone 4 6 5 4-6
acetate release .mu.g/hr.
__________________________________________________________________________
EXAMPLE 6
Five hundred grams of chloramphenicol of a particle size of 50
microns is encapsulated with polylactic acid polymer of molecular
weight 50,000, according to the following procedure. Two hundred
and fifty grams of the polylactic acid is dissolved into 2 liters
of chloroform. The chloramphenicol particles are coated by
polylactic acid using Wurster air suspension technique. The coat
thickness is determined to be 30 microns thick.
Separately, in a Waring blender, 10 grams of sodium alginate is
vigorously stirred with 300 ml of deionized water to yield a
slightly viscous solution.
Stirring is stopped and 3 grams of the chloramphenicol
microcrystals are thoroughly dispersed in the sodium alginate
solution. The final mixture is then cast on a clean glass plate
leveled with a doctor's blade to a thickness of 80 mils, and dried
for 24 hours in a stream of circulating 35.degree.C air. The
resulting film is removed from the glass plate by stripping, and
immersed in a 6% by weight zinc chloride solution (pH 5.0) for 12
hours. The film is then repeatedly washed until a washing gives a
negative chloride test. The film is then air dried at room
temperature and punch-cut into elliptically shaped ovals 8 mm in
major axis and 5 mm in minor axis. When these ovals are placed in
the sacs of eyes, they release chloramphenicol for a prolonged
period of time at a rate controlled by the polylactic acid
microencapsulation polymer. The metal ion linked polyelectrolyte
which functions as a matrix for the microcapsules, completely
bioerodes in the environment of the eye at the termination of the
therapeutic program.
EXAMPLE 7
Ten grams of sodium alginate, 20 grams of glycerine and 180 grams
of deionized water are combined with vigorous stirring to give a
clear viscous solution. To this solution is added 0.5 grams of
micronized progesterone crystals and the mixture is vigorously
agitated to achieve a uniform suspension. The suspension is then
cast on a glass plate and drawn to a wet thickness of 150 mils. The
cast plate is placed in a circulating stream of 40.degree.C air and
allowed to dry.
The resulting film is stripped from the plate and immersed in a 10%
solution of aluminum chloride at pH 3.1 for 12 hours. The film is
then washed in a 10% by weight glycerine solution until a negative
chloride test results. The film is then removed, dried in air and
cut into 40 mg pieces. These pieces are then implanted in female
Holtzman rats where they produce an estrogenic response lasting for
about 2 weeks.
EXAMPLE 8
Ocular inserts of the type set forth in FIGS. 4 and 5 include
devices comprising the following combinations of drug, inner
reservoir and outer rate controlling membrane:
1. An inner reservoir of hydrocortisone acetate dispersed in a
poly(vinyl alcohol) matrix with the outer rate controlling membrane
material being an aluminum ion cross-linked plasticized pectin.
2. An inner reservoir of hydrocortisone acetate surrounded by a
membrane of zinc II cross-linked plasticized alginate.
* * * * *