U.S. patent number 3,618,604 [Application Number 04/831,761] was granted by the patent office on 1971-11-09 for ocular insert.
This patent grant is currently assigned to Alza Corporation. Invention is credited to Richard A. Ness.
United States Patent |
3,618,604 |
Ness |
November 9, 1971 |
**Please see images for:
( Certificate of Correction ) ** |
OCULAR INSERT
Abstract
Drug-dispensing ocular insert is comprised of a flexible body of
polymeric material that is insoluble in tear liquid and has an
imperforate surface. The polymeric material contains a drug which
is dispensed to the eye in a therapeutically effective amount by
diffusion through the polymeric material. The ocular insert is
adapted for insertion in the cul-de-sac of the conjunctiva between
the sclera of the eyeball and the lower lid, to be held in place
against the eyeball by the pressure of the lid.
Inventors: |
Ness; Richard A. (Fergus Falls,
MN) |
Assignee: |
Alza Corporation (N/A)
|
Family
ID: |
25259803 |
Appl.
No.: |
04/831,761 |
Filed: |
June 9, 1969 |
Current U.S.
Class: |
604/294 |
Current CPC
Class: |
A61K
9/0051 (20130101); A61F 9/0017 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61F 9/00 (20060101); A61m
031/00 () |
Field of
Search: |
;128/260,296,156 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Michell; Robert W.
Assistant Examiner: Dyer; R. P.
Claims
What is claimed is:
1. A medication-dispensing tablet for a human eyeball, said tablet
comprising a reservoir of drug formulation confined within a
flexible, imperforate and continuous-surfaced body of nonallergenic
polymeric material which is insoluble in tear liquid, said body
being formed of a drug-release rate-controlling polymer to
continuously meter the flow of drug by diffusion from the reservoir
to the eye at a controlled, predetermined and reproducible rate
over a prolonged period of time, said body being adapted for
insertion into the cul-de-sac of the conjunctiva between the sclera
of the eyeball and eyelid, to be held in place against the eyeball
by the pressure of the lid, and said body having a marginal outline
and cross section adapted to assume essentially the configuration
of the scleral curvature; said drug being capable of transport
through the unbroken walls of said body by diffusion and said body
being so constructed and arranged that, when applied to the
eyeball, to dispense said drug thereto, drug leaving said body by
diffusion is transported to the eyeball by the flow of tears and by
the blinking action of the eyelids.
2. The medication-dispensing tablet as defined by claim 1, wherein
the reservoir of drug formulation is comprised of a sealed
container with walls of said polymeric material and said drug is
contained in an interior chamber thereof.
3. The medication-dispensing tablet as defined by claim 2, wherein
said polymeric material is selected from the group consisting of
plasticized or unplasticized polyvinyl chloride, plasticized nylon,
unplasticized soft nylon, plasticized polyethylene terephthalate,
silicone rubber, hydrophilic hydrogel of an ester of acrylic or
methacrylic acid, modified collagen, cross-linked hydrophilic
polyether gel, cross-linked polyvinyl alcohol, and cross-linked
partially hydrolyzed polyvinyl acetate.
4. The medication-dispensing tablet as defined by claim 3, wherein
said polymeric material is silicone rubber.
5. The medication-dispensing tablet as defined by claim 3, wherein
said polymeric material is a hydrophilic hydrogel of an ester of
acrylic or methacrylic acid.
6. The medication-dispensing tablet as defined by claim 1, wherein
the reservoir of drug formulation is comprised of a matrix of the
drug-release rate-controlling polymeric material, said matrix
having the drug distributed therethrough.
7. The medication-dispensing tablet as defined by claim 1, wherein
said polymeric material is selected from the group consisting of
plasticized unplasticized polyvinyl chloride, plasticized nylon,
unplasticized soft nylon, plasticized polyethylene terephthalate,
silicone rubber, hydrophilic hydrogel of an ester of acrylic or
methacrylic acid, modified collagen, cross-linked hydrophilic
polyether gel, cross-linked polyvinyl alcohol, and cross-linked
partially hydrolyzed polyvinyl acetate.
8. The medication-dispensing tablet as defined by claim 7, wherein
said polymeric material is silicone rubber.
9. The medication-dispensing tablet as defined by claim 7, wherein
said polymeric material is a hydrophilic hydrogel of an ester of
acrylic or methacrylic acid.
10. The medication-dispensing tablet as defined by claim 1, wherein
said drug is an ophthalmic drug.
11. The medication-dispensing tablet as defined by claim 1, wherein
said drug is a systemically active drug which will pass through the
eye to the bloodstream and produce a pharmacologic response at a
site remote from the eye.
12. The medication-dispensing tablet as defined by claim 1, wherein
said drug is a systemically active drug which will pass through the
tissue surrounding the eye to the bloodstream and produce a
pharmacologic response at a site remote from the eye.
13. The medication-dispensing tablet as defined by claim 1, wherein
from 1 microgram to 1 milligram of drug is incorporated in said
tablet.
14. The medication-dispensing tablet as defined by claim 1, wherein
same is circular in cross section and tapered at its ends.
15. The medication-dispensing tablet as defined by claim 1, wherein
same is ellipsoidal in cross section and tapered at its ends.
16. The medication-dispensing tablet as defined by claim 1, wherein
same ranges from 4 to 20 millimeters in length, 1 to 12 millimeters
in width, and 0.1 to 1 millimeter in thickness.
17. The medication-dispensing tablet as defined by claim 1, wherein
the drug is chloramphenicol and the polymeric material is
polyethylene terephthalate.
18. The medication-dispensing tablet as defined by claim 1, wherein
the drug is promethazine trichloroacetate and the polymeric
material is polyvinyl chloride. 19The medication-dispensing tablet
as defined by claim 1, wherein the drug is chloramphenicol and the
polymeric material is
polydimethylsiloxane rubber. 20. The medication-dispensing tablet
as defined by claim 1, wherein the drug is a member selected from
the group consisting of pilocarpine and pilocarpine
perfluorobutyrate and the
polymeric material is polyvinyl chloride. 21. The
medication-dispensing tablet as defined by claim 1, wherein the
drug is dexamethasone and the polymeric material is nylon-66.
Description
BACKGROUND OF THE INVENTION
This invention relates to an ocular insert for dispensing drugs to
the eye over a prolonged period of time.
At the present time, diseases of the eye are treated by applying
ophthalmic drugs in liquid or ointment form. To be effective in
many cases, the application of drug should be substantially
continuous. Such continuous delivery of drug is not obtained
through the use of liquid or ointment dosage forms, even though
they be applied at intervals during the day and night. Periodic
application of these dosage forms results in the eye receiving a
massive, but unpredictable, amount of drug at the time of
application but the drug is washed away rapidly by tears, leaving
the eye without medication until the next application. Ointment
dosage forms are presently available only in unsterilized form and
this too presents a problem.
At a very early time, drugs were dissolved or dispersed in a
water-soluble gel of glycerinated gelatin that was shaped to the
form of a lamella or eye disk. These lamellae were applied to the
inner surface of the eyelid to supply drug to the eye. In use, the
glycerinated gelatin vehicle dissolved rapidly in tear liquid,
producing the same type of effect as liquid dosage forms. Lamellae
were not a sustained-release dosage form. To my knowledge, they are
not used in this country, although they may be used to a small
extent in Europe. Further information on these water-soluble dosage
forms can be found in Remington's Pharmaceutical Sciences, XIII,
pages 547-8 (Mack Publishing Co., Easton, Pa. 1965); Fishburn, An
Introduction to Pharmaceutical Formulation, page 116 (Pergamon
Press Ltd., New York City, N.Y. 1965); and U.S. Pat. No. 273,410,
Mar. 6, 1883.
U.S. Pat. No. 3,416,530, granted Dec. 17, 1968, and assigned to the
assignee of this invention, is directed to my invention of a
drug-dispensing ocular insert that truly acts as a depot or drug
reservoir, retaining and slowly releasing drug to the eye for
prolonged periods of time. Such ocular inserts are fabricated of
flexible polymeric materials that are biologically inert,
nonallergenic, and insoluble in tear liquid. To initiate the
therapeutic program, the ocular insert is placed in the cul-de-sac
of the conjunctiva between the sclera of the eyeball and the lid.
Since the polymeric material from which the ocular insert is formed
is insoluble in tear liquid it retains its integrity and remains
intact during the course of therapy, acting as a reservoir to
continuously release drug to the eye and surrounding tissues at a
rate which is not affected by dissolution or erosion of the
polymeric material. On termination of the therapeutic program, the
ocular insert is removed from the cul-de-sac. Thus, a single such
ocular insert provides the complete ophthalmic dosage regime for a
particular time period, on the order of 24 hours or longer.
Frequent repeated applications, as is necessary with liquids,
ointments, or water-soluble lamellae, often requiring awakening the
patient during the night, are avoided.
To provide for release of ophthalmic drug from the polymeric body
of the ocular insert, U.S. Pat. No. 3,416,530 describes using
polymeric materials which are perforated with capillary openings.
While these capillary openings are effective to release drug to the
eye, they add considerable complexity to the manufacture of ocular
inserts; for it is difficult to control the size of these openings
in large-scale manufacturing using various polymers.
The best mode contemplated for practicing the invention of U.S.
Pat. 3,416,530, was, at the time the patent application maturing to
that patent was filed, to place the ocular insert under the upper
eyelid in generally radially spaced relation to the cornea of the
eyeball and in the path of flow of tears from the associated
lachrymal gland. However, the eye has a tendency to roll upwardly
during sleeping a process known as Bell's Phenomenon, which may
cause discomfort to some persons if the ocular insert is under the
upper lid.
SUMMARY OF THE INVENTION
It is one object of this invention to provide an improved
drug-dispensing ocular insert which acts as a reservoir for the
continuous and prolonged release of drugs to the eye.
Aother object of this invention is to provide a drug-dispensing
ocular insert which delivers drugs to the eye at a controlled rate,
that is not dependent upon the size and number of perforations or
pores in the polymeric body of the ocular insert.
Still another object of this invention is to provide a
drug-dispensing ocular insert which is comfortable to wear for long
periods and does not cause discomfort during sleeping and normal
daily wear.
In accomplishing these objects, one feature of this invention
resides in a drug-dispensing ocular insert to deliver drug to the
eye over a prolonged period of time, comprising a flexible body of
polymeric material insoluble in tear liquid and having an
imperforate surface, the body containing a drug which is dispensed
to the eye in a therapeutically effective amount by diffusion
through the polymeric material. The ocular insert of this invention
is adapted for insertion in the cul-de-sac of the conjunctiva
between the sclera of the eyeball and the lower lid, to be held in
place against the eyeball by the pressure of the lid.
Other objects features and advantages of the invention will become
more apparent from the following description of the invention and
from the claims.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with this invention, a drug-dispensing ocular insert
is designed for placement and retention under the lower eyelid and
is fabricated of a polymeric material, having an imperforate
surface, that will release drug by diffusion therethrough.
Polymeric materials used in forming the ocular insert are flexible,
biologically inert, insoluble in tear liquid, and nonallergenic. It
is important that the polymeric material be capable of transferring
the drug through its unbroken walls by the diffusion of drug or
drug solution therethrough. By utilizing the mechanism of diffusion
to dispense drug to the eye, the rate of drug release can be
controlled with precision and reproducibility. In each case,
selection of the polymeric material is dependent on the particular
drug and drug form to be used in the device. Exemplary materials
for fabricating the ocular insert include hydrophobic polymers such
as plasticized or unplasticized polyvinylchloride, plasticized
nylon, unplasticized soft nylon, plasticized polyethylene
terephthalate, and silicone rubber; and hydrophilic polymers such
as the hydrophilic hydrogels of esters of acrylic and methacrylic
acid (as described in U.S. Pat. Nos. 2,976,576 and 3,220,960 and
Belgian Pat. No. 701,813), modified collagen, cross-linked
hydrophilic polyether gels (as described in U.S. Pat. No.
3,419,006), cross-linked polyvinylalcohol, and cross-linked
partially hydrolyzed polyvinylacetate. When plasticizers are used
to impart flexibility to the polymer, various plasticizers known to
the art can be employed, such as long-chain fatty amides, higher
alcohols, and dioctyl phthalate.
Those skilled in the art will appreciate that many of the
hydrophilic polymers suitable for use in this invention absorb tear
liquid, forming a hydrogel therewith. Tear liquid entering the
polymeric structure to form the swollen hydrogel molecules
dissolves the drug within the polymeric body, and the resulting
drug solution then diffuses outwardly from the the hydrogel
structure. Therefore, as used in this specification and the
appended claims, the term "diffusion" refers to the movement of a
drug through an imperforate polymeric body, as well as to the
movement of a drug solution through an imperforate body. Use of the
expression "insoluble in tear liquid" to refer to suitable
polymeric materials, means that the polymeric materials do not
dissolve and erode as a result of the action of tear liquid, but
may absorb tear liquid, forming a swollen hydrogel.
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 that enter circulation in the bloodstream
and produce a pharmacologic response at a site remote from the
point of application of the ocular insert. Thus, drugs which will
pass through the eye or the tissue surrounding the eye to the
bloodstream, 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
include, without limitation: Anti-infectives: such as antibiotics,
including tetracycline, chlortetracycline, bacitracin, neomycin,
polymyxin, gramicidin, oxytetracycline, chloramphenicol, and
erythromycin; sulfonamides, including sulfacetamide,
sulfamethizole, and sulfisoxazole; antivirals, including
idoxuridine; and other anti-infectives including nitrofurazone and
sodium propionate; Antiallergenics such as antazoline,
methapyrilene, chlorpheniramine, pyrilamine and prophenpyridamine;
Anti-inflammatories such as hydrocortisone, hydrocortisone acetate,
dexamethasone, dexamethasone 21-phosphate, fluocinolone, medrysone,
prednisolone, prednisolone 21-phosphate and prednisolone acetate;
Decongestants such as phenylephrine, naphazoline, and
tetrahydrazoline; Miotics and anticholinesterases such as
pilocarpine, eserine salicylate, carbachol, diisopropyl
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 in various
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. 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 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. Since the ocular insert is intended to provide the
complete dosage regime for eye therapy for but a particular time
span, such as 24 hours, there is no critical upper limit on the
amount of drug incorporated in the device. For when the device is
removed and disposed of it makes little difference whether any drug
remains in the device. The lower limit will depend on the activity
of the drug and its capability of being released from the device.
Thus it is not practical to define a range for the therapeutically
effective amount of drug incorporated into the device. However,
typically, from 1 microgram to 1 milligram of drug is incorporated
in the ocular insert.
In each case, the polymeric material used to form the ocular insert
is chosen for its compatibility with a particular drug and its
capability of releasing that drug by diffusion at an appropriate
rate over a prolonged period of time. Specific, but nonlimiting,
examples of combinations of drugs and polymers for use in forming
the ocular insert are: (1) chloramphenicol incorporated into
polyethylene terephthalate plasticized with higher alcohols; (2)
promethazine trichloroacetate incorporated into polyvinylchloride
plasticized with dioctylphthalate; (3) chloramphenicol dispersed
throughout polydimethylsiloxane rubber; (4) pilocarpine or
pilocarpine perfluorobutyrate incorporated into polyvinylchloride
plasticized with dioctylsebecate; and (5) dexamethasone
incorporated into nylon-66 plasticized with higher alcohols.
The ocular insert can be fabricated in any convenient shape for
comfortable retention in the cul-de-sac. It is important, however,
that the device have no sharp, jagged, or rough edges which can
irritate the sensitive tissues of the eye. Thus the marginal
outline of the ocular insert can be ellipsoid, bean-shaped,
rectangular, etc. In cross section, it can be concavo-convex,
rectangular, etc. As the ocular insert is flexible and, in use,
will assume essentially the configuration of the scleral curvature,
the original 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 applied 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 and removed from the eye.
The upper limit on the size of the device is governed by the
limited space within the cul-de-sac that conveniently and
comfortably can be filled with an ocular insert. Typically, the
ocular insert is 4 to 20 millimeters in length, 1 to 12 millimeters
in width, and 0.1 to 1 millimeter in thickness. Preferably it is
ellipsoidal in shape and about 6 .times. 4 .times. 0.5 millimeters
in size.
The ocular insert can be a polymeric matrix with the drug dispersed
therethrough or can be a sealed container with walls of polymeric
material and having the drug in an interior chamber thereof. One
such container has a circular or ellipsoidal cross section and is
tapered at the ends. Drug can be incorporated in the ocular insert
in many ways. When the ocular insert is in the form of a container,
any of the encapsulation, bonding, and coating techniques
conventionally used in the art can be employed. When the ocular
insert is a solid matrix with the drug dispersed therethrough, it
can be fabricated by adding the drugs to the monomers prior to
polymerization; adding the drug to the polymer in liquid form,
molding and curing; or by impregnating the polymeric material,
either before or after shaping to the form of the ocular insert,
with the drug.
Referring particularly to FIGS. 1 and 2, to use the ocular insert
10 (shown by dot and dash lines in FIG. 1), it is placed in the
cul-de-sac 11 of the conjunctiva 12 between sclera 13 of the
eyeball 14 and the lower lid 15. The pressure of the lower lid 15
maintains the ocular insert 10 in place. With the ocular insert 10
under the lower lid 15, the device is comfortable to the wearer and
does not contact the cornea 16 during sleeping nor during normal
ocular motion. Once in place, the ocular insert 10 functions as a
drug reservoir gradually releasing drug to the eye and surrounding
tissue. Drug 17 leaving the ocular insert by diffusion is
transported to the eyeball 14 by the flow of tear liquid and by the
blinking action of the eyelids. By use of the ocular insert, the
eye is continuously bathed with drug 17 over a particular time
span. Normally, the ocular insert 10 will be retained in place for
a period of 24 hours, thereby supplying the complete dosage regime
for eye therapy over that period of time. During the course of use,
the polymeric body 18 of the ocular insert does not dissolve or
erode in tear liquid and a predictable and reproducible dosage
regime is provided.
In a specific example of the manufacture of an ocular insert of the
invention, liquid polydimethylsiloxane (Dow Corning Silastic 382)
is mixed with chloramphenicol antibiotic. After uniformly mixing
the antibiotic with the unvulcanized silicone rubber, stannous
octoate catalyst (0.5 percent by weight) is added and the mixture
is poured into a mold having an ellipsoidal cavity 6 millimeters by
4 millimeters by 0.5 millimeter to cure the silicone rubber at room
temperature. The resulting ocular insert formed of silicone rubber
contains 0.5 milligram of chloramphenicol. When inserted in the
cul-de-sac of the conjunctiva between the sclera of the eyeball and
the lower lid, the ocular insert is effective to deliver to the eye
the dose of chloramphenicol antibiotic required for 24 hours of
treatment of infection. After that period of time, the ocular
insert, with its dimensions unchanged, is removed from the
cul-de-sac and an identical insert placed in its stead to continue
the therapeutic program for an additional 24 -hour period.
Thus, the improved ocular insert of this invention offers many
advantages. As it is formed of a polymeric material, insoluble in
tear liquid, the ocular insert does not dissolve or erode in tear
liquid during the course of therapeutic program. This permits the
therapeutic program to be precisely controlled and the release of
drug predicted with accuracy. That the ocular insert releases drug
by diffusion is most important, since this too provides for close
control over the rate of drug release from the polymer.
While there have been described and pointed out the fundamental
novel features of the invention as applied to the preferred
embodiment, those skilled in the art will appreciate that various
modifications, changes, and omissions in the ocular insert
illustrated and described can be made without departing from the
spirit of the invention. It is the intention, therefore, to be
limited only by the scope of the following claims.
* * * * *