U.S. patent number 3,807,398 [Application Number 05/290,376] was granted by the patent office on 1974-04-30 for ocular implant.
Invention is credited to Bernard J. Grucza.
United States Patent |
3,807,398 |
Grucza |
April 30, 1974 |
OCULAR IMPLANT
Abstract
Improvements in the O'Driscoll et al U. S. Pat. No. 3,700,761
composition consisting of regulating critical proportions of PVP,
HEMA, MA, EDMA, Water and the first and second stage initiators for
producing hydrophilic lens blanks from which reproducible and
predictable hydrated lenses are obtained with ratios of acceptance
of 95 - 98 percent, to dimensional standards between the grinding
dry and hydrated wet states and with ratios of resisting
dimensional change in wet storage of upwards of ninety five
percent. Compositions lying outside of the critical ranges of
proportions provide lenses which are unpredictable (90 percent
rejection) drift in size and do not provide reproducibility between
dry and wet states and thereby create fitting problems. Critical
ratios of MA to EDMA lying between 2.5/3.2 at 15 percent PVP
content down to 1/1 at 28 percent PVP content provide
reproducibility and predictability dry-to-wet and the optimum ratio
is 1.5/0.7 at 20 percent PVP (reagents containing less than 1
percent water). Further improvement is made in the method of
casting and cutting of U. S. Patent No. 3,700,761, in which there
is used a disposable mold of Teflon, high-density polyethylene or
of RTV Silicone material with break-away curved bottom which is
discarded to provide a convex surface requiring no cutting thereby
eliminating many cutting and grinding steps on the conventional
hard-lens lathe. Water-soluble medicaments as in U.S. Pat. No.
3,700,761 can be added to precision-cut eye bandages by dissolving
in H.sub.2 O and adding a total of 5 percent H.sub.2 O to HEMA or
the medicament can be used in eye drops, the bandage with 5 percent
added containing 65 percent H.sub.2 O instead of 60 percent.
Inventors: |
Grucza; Bernard J. (Buffalo,
NY) |
Family
ID: |
23115719 |
Appl.
No.: |
05/290,376 |
Filed: |
September 19, 1972 |
Current U.S.
Class: |
424/429; 524/347;
264/2.6; 524/340; 524/549; 351/159.02 |
Current CPC
Class: |
C08L
51/003 (20130101); G02B 1/043 (20130101); G02B
1/043 (20130101) |
Current International
Class: |
G02B
1/04 (20060101); A61m 007/00 (); A61j 001/00 ();
B29d 011/00 () |
Field of
Search: |
;128/260,249,268X
;264/1 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Medbery; Aldrich F.
Claims
What is claimed is:
1. A shaped ocular implant comprising a composition in dry form for
medicament delivery which is subjected to cutting and thereafter
hydrating in saline to form an implant having from 50 - 65% H.sub.2
O, said implant in dry form consisting essentially of polymerized
random graft copolymer containing 67.2 to 79.3% HEMA, 14.25 to 28%
PVP, 0.1 to f.04% EDMA, 0.1 to 2.5% MA, from about 1.0 up to 5.0%
H.sub.2 O and from 50 - 100 ppm of hydroquinone stabilizer, the
composition having been polymerized with a low temperature
initiator and a high temperature initiator each in concentration of
0.05 to 0.15 percent after an induction period at 15.degree. -
30.degree.C for a period of 2.5 to six hours.
2. An implant as claimed in claim 1 in the form of an optical
bandage containing an ophthalmologically acceptable medicament
incorporated in the dry form of the implant.
3. An implant as claimed in claim 1 in the form of an optical
bandage hydrated to 50 - 65% H.sub.2 O in combination with a
fountain solution of ophthalmologically acceptable medicament
dissolved in saline solution.
Description
BACKGROUND OF THE INVENTION
In O'Driscoll et al, U.S. Pat. No. 3,700,761, compositions
consisting of HEMA (hydroxyethyl methacrylate) or HPMA
(hydroxypropyl methacrylate) with PVP in proportions of 20 - 45
percent, with up to 1% MA and with about 0.2% EDMA were disclosed.
Low and critical ranges of proportions of first stage initiators
are thermally decomposed at 40.degree. - 60.degree. to provide
solid buttons which after second stage curing at 110.degree.C
radiation curing and hydration provide remarkably high water
content of about 50 - 65 percent in lenses which are cut when dry
on both convex and concave surfaces on the conventional hard-lens
lathe after the step of radiation curing.
SUMMARY OF THE INVENTION
The present invention is an improvement of the initial step of the
method of preparing the hygroscopic lens in the dry state and
depends upon the casting of the lens after a critical induction
period in a break-away curved-bottom plastic mold in static
condition from the liquid mixture of ingredients in critical
porportions and under controlled temperature and inhibitor
concentration conditions which prevent heat transfer through the
mold so that an improved anisotropic lens is produced which has
predictable and reproducible characteristics. This anisotropic lens
of the present invention is characterized by different swelling and
expansion between dry and wet states in the lateral direction and
in the vertical direction but these changes are now reproducible
and predictable to match diameters and steepeness of the
cross-section and thereby assure a substantially rigid and accurate
fit to the eye without drift in diameter or slope or stiffness and
to provide longtime and precision correction of the optical
condition.
As a result of the swelling, and uniquely due to the very high
water uptake (50 - 65 percent), the lens made by the method of the
present invention is found to shape itself by evaporation forces,
in an unusual manner to steepen the vault or slope of the lens
closely resting on the cornea and sclera of the eye, shaping being
similar to that of hard-lens memory characteristics. In contrast to
all other types of soft lenses commercially available,
reproducibility and predictability are achieved by the critically
controlled amounts of PVP, HEMA, EDMA, MA, Water and inhibitor
which is used to stabilize the HEMA and which will produce a lens
having 50 - 65 percent in the saline-stored condition.
In the eye, the lens drops in water content from 55 - 65 percent
down to 45 - 55 percent. Surprisingly, the higher amount of water
retained in the lenses in saline drops to the lower value in from
thirty seconds to two minutes after insertion into the eye. This
water content drop-off from about 50 - 65 percent occurs in most
patients to a value of about 45 - 50 percent. The variations
mentioned are found in testing hundreds of patients whose eye
conditions varied from "wet eye" to "dry eye" as it is known in the
art.
It was discovered that this evaporation which occurs provides a
slight difference in the shape of the lens which results in a
natural astigmatic condition which contributes in a new way to
accurate fitting based on the secure adhesion to the limbal area,
or areas of the lens rim which contract and tighten on the corneal
center so that this contraction effects a closer fit, in cantilever
fashion, and prevents dislodging movements of the lens away from
the scleral area. The larger contact rim of the semi-rigid, rubbery
lens water-laden with precise dimensional predictability, is
uniquely aided for fitting of the entire scleral area and based
upon the geometry of the limbal area of the lens, serves to confine
the individual's own tears beneath the lens. This aids in the
interchange of tear fluid, oxygen and carbon dioxide, all essential
to corneal respiration. The steepness of the vault permits accurate
centering on the cornea while the circulation of tear fluid permits
a respiration result comparable to that due to the permeability of
the cornea itself, and this permeability is based upon the high
O.sub.2 & CO.sub.2 permeability of the lens material.
In accordance with the invention, the casting against the curved
shape of a disposable mold permits a range of dry lenses for
fitting eyes of all dimensions and the range is based upon a
simplified manufacturing procedure, using a break-away mold bottom
eliminating the grinding of the cast surface while providing a
simple number of base curves (5) and a simple number of diameters
(5) to true and time-stable dimensions in x,y and z planes.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention is further illustrated in the drawings in which:
FIG. 1 is a sectional view which shows a break-away mold with
curved bottom into which the composition is cast and polymerized
against a curved inner-surface which surface requires no further
grinding or polishing.
FIG. 2 is a sectional view which shows the breaking of the button
from the mold by ram pressure and movement.
FIG. 3 is an exploded view showing separation of the break-away
bottom from the button.
FIG. 4a shows the first stage of cutting on the lathe as shown in
diagramatic form in FIG. 5.
FIG. 4b shows the second stage.
FIG. 4c shows the third stage of cutting.
FIG. 4d shows the finished lense
FIG. 5 shows the mounting of the lense for cutting in stages 4a, 4b
and 4c, with a conventional hard lense lathe of the type shown in
FIG. 6 and 9 of Mullen, U.S. Pat. No. 2,330,837.
FIG. 6 shows the finished lense with the rim cut after the cutting
stage in FIG. 4d, this rim cut being illustrated in FIG. 5. FIG. 6
shows the dimensions of rim cut lenses of the type shown in FIG.
5.
FIG. 7 shows the mounting of the lense of FIG. 5 on the eye with
space between the rim and sclera before evaporation contracts the
lense.
FIG. 8 shows lense of FIG. 7 after contractile evaporation.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The accuracy of manufacture of the present invention is based upon
the discovery that critical proportions are required of PVP, MA,
EDMA, HEMA, Water with the initiator amounts used for first and
second stage initiation in the Driscoll U.S. Pat. No. 3,700,761,
and that initial amounts of hydroquinone stabilizer are required to
assure storage stability and to give predictability and
reproducibility between dry and wet states, these initial amounts
permit economy, safety, and reliability in supply and in fitting.
The example and drawings illustrate an improved method, based upon
the discovery of first stage initiation which must be carried out
in a preliminary induction stage at room temperature and which
requires that the liquid mixture in static condition in the mold of
FIG. 1, subjected to a room temperature stage for the conversion of
mobile liquid to stringy liquid at a temperature between 15.degree.
- 30.degree. C for 21/2 - 6 hours, the longer time being required
at the lower temperatures. This induction period in the static mold
of FIG. 1, must be carried out before the first stage initiation
under thermal decomposition (40.degree. - 60.degree. C) which
decomposes the rest of the initiator and changes the thickened
liquid into a transparent solid button. Only when this first stage
polymerization is broken down into two stages; first, a quiescent
room temperature induction stage at 15.degree. - 30.degree.C and
then a thermal stage at 40.degree. for four hours or longer can the
chain length of the copolymer grafted onto the PVP be brought up in
uniformity, density, etc., up to the necessary length chains which
will provide the necessary balance and semi-rigid, highly
extensible and brittle properties of the rigid dry polymer. This
dry polymer is subjected to further high temperature
polymerization, as taught in the O'Driscoll Patent after the first
stage without removing from the mold and this second stage is
essential to impart hardness and brittleness which creates a button
that can be ground to a tolerance of 0.01 millimeters and will
maintain its shape after hydration regardless of the shape of eye
to which it is applied. In short, the improvement of the present
invention controls opposite properties in the contact lens of
rubberiness, rigidity, hardness for grinding, dimensional stability
and reproducibility in a new and unusual manner by controlling the
time for chain growth during a preliminary induction period prior
to rapid first stage initiation which occurs in at least four hours
at 40.degree.C in the oven and in the mold.
All of the ingredients -- HEMA, EDMA, PVP, HPMA, MA, H.sub.2 O and
inhibitor (HQ or MEHQ) control the chain growth with given
initiators. However, a critical element for the achievement of
storage stability of the lens in the wet state is the requirement
that no more than one hundred parts per million (preferably 60 - 80
parts per million) of hydroquinone-type polymerizing inhibitor,
used exclusively with HEMA, such as hydroquinone (HQ) or
mono-methyl ether of hydroquinone (MEHQ). It was unexpected to
discover that more than 100 parts per million of HQ inhibitor in
HEMA would cause drifting, spreading and an increase in size of the
diameter with decreased steepness of lenses which were placed in
storage in isotonic saline for long periods of time (two weeks to
six months). In short, only those compositions in which the
inhibitor content is controlled within critical limits of less than
one hundred parts per million based upon the HEMA monomer can
provide lenses which can be stored in the wet state for weeks or
for several months or up to a year without increasing the critical
dimensions of diameter and slope.
IMPROVED MANUFACTURING PROCEDURE ILLUSTRATED IN THE DRAWINGS
Reference is made to the manufacturing procedure which was
illustrated and described in O'Driscoll et al, U.S. Pat. No.
3,700,761, wherein hard-lens cutting and polishing technology was
used (see FIGS. 4a, 4b, 4c, & 4d) after the button was pushed
under pressure and moved out of the Teflon cylindrical mold with
the ram 13 in contact with the planar top of the button.
The present disposible mold 11 with break-away curved bottom 11b is
shown in FIG. 1 as being filled with the polymerizable composition
20 which hardens in static condition through the room-temperature
induction stage (2 1/2 - 6 hours) of the present invention (see
examples below), the first stage initiation under thermal break
down of first initiator to assume the solid state in rubbery
condition (40.degree. - 60.degree. C), the second stage under
thermal break-down of second initiator (110.degree.C - 1 1/2 - 4
hours).
Not until the final cut is made in the form shown in FIG. 4 and
rimming is accomplished to provide double-gauged (inner and outer
sphericities inspected) lens 20 as shown in FIG. 4d is the lens
ready for the radiation post curing step. In the present invention
the compositions made by the new method of bottom ejection of the
buttom permit eliminating all cutting operations from the back
(curved concave surface) of the lens 20e and more important,
provide a superior lens which resists breakage since cutting
inherently introduces microscopic scratches which act as stress
points, initiating cracking and tearing. Eliminating all stress
points on the inner-surfaces provides a stronger, longerwearing,
more tear-resistant lens in hydrated condition.
The bottom ejection illustrated in FIGS. 2 and 3, shows break-away
frangible section 11f in annular shape which serves as the means
for permitting movement of dome portion 11d with the concave
surface of the button. The ram 13 is positioned so that its
diameter fits precisely under frangible positions 11f for free
expulsion of the button (see FIGS. 2 and 3).
LENS IMPROVEMENTS BASED UPON ADAPTING HARD-LENS GRINDING TECHNOLOGY
USED FOR GRINDING THE NEW COMPOSITION
As shown in FIGS. 5 and 6, the hard-lens cutting and grinding
technology of Mullen U.S. Pat. No. 2,330,837 permits the hard
guasi-rubbery buttons to be accurately cut and ground and polished
in the dry state by the same experienced personnel who fit hard
contact lens. However, only on optically corrective surface is
present for cutting in accordance with the invention and this
method of cutting only the outer surface provides a superior lens
which requires only an inner rim cut, shown at 20r in FIG. 5 and is
in an area of the lens which is non-correcting.
Obviously the invention comtemplates the use of a modified form of
break-away curved bottom in the mold which will have the rim cut
dimension put in the mold part and for more automated manufactoring
this method of casting and mold contour information is part of the
present invention.
The importance of the rim, which can be prescription ground to meet
the various requirements of scleral slope encountered by precise
examination or which can be molded as explained, can be seen by the
comparison of views in FIGS. 7 and 8. The lens 20e has just been
put back on the mounting chuck 15 which is carried on the lathe
spindle 16 of the conventional machine in the Mullen Patent. This
view illustrates a finishing polish step of the convex surface
after this rim has been made. The terminology herein defining "rim
cut" relates to both the "rim cut" casting or that which has been
trimmed by cutting.
In FIG. 7 the lens 20e is shown in the stage just after removal
from isotonic saline and being placed on the eye. Under the rim 20r
of the lens, the tear fluid flows freely and contractile forces
based upon evaporation of water begin their effect. The exposed
outer surface of the lens 20e loses water from a range of 50 - 65%
H.sub.2 O down to 45 - 50% H.sub.2 O and the rim 20 thereby moves
downwardly and inwardly gripping the sclera and thereby entrapping
a liquid film of tear fluid, thereunder the contracted form is
shown in FIG. 8.
EXAMPLES SHOWING SCOPE OF PROPORTIONS IN TABLES 1 & 2
The following examples illustrate the scope of initial porportions
of the new compositions used for static casting in the
curved-bottom molds of the O'Driscoll Patent as well as in the
disposable break-away bottom molds of the present invention.
This mixing technique is identical with that in the O'Driscoll
Patent, care being taken not to entrap air and to degas the mixture
under vacuum and bleeding nitrogen gas back into the system.
The two tables below summarize the compositions which provide
reproducibility and predictability. Table 1, illustrates the
fomulations which have been completely analyzed, the EDMA, HEMA, MA
all being done by gas-liquid chromatography, (GLC) with HQ and MEHQ
being done by titration and being double checked by GLC. The water
content was determined by Karl Fisher's method. All values in the
tables below are on a weight basis. The PVP in these tables is
Plasdone C, (K=30) and in its place PVP (K=15) or (K=90) can be
used but best results are achieved with Plasdone C, for the reason
that greater uniformity in dryness of the material, supplied by the
manufacturer, is found as a result of testing.
The water content of Table 1 is based upon testing average of about
500 samples of Plasdone C, averaging 3 - 3.5 percent water, since
the Plasdone C content varies from about 15 to about 28 percent
(spread of 2 percent) of the present composition for contact
lenses, the average contribution of water in the mixture is less
than 1 percent and that Table is entitled substantially dry (less
than 1 percent)
Table 2 illustrates the addition of 5 percent of water to HEMA. All
water, in both tables 1 and 2, determinations are made by testing
"dry" and before and after additions of water and all ingredients
added to the mixture are tested in the same way. Suprisingly and
unexpectedly the EDMA content is raised by 1 percent as a result of
the addition of 5 percent of water and thus increase is reflected
in Table 2 and emphasized by the notation (asterisk) after
EDMA.
TABLE 1
SUBSTANTIALLY DRY (LESS THAN 1% H.sub.2 O)
Ingredient Series A Series B Series C HEMA 79.3 77.8 71.8 PVP
(K=30) 15.0 20.0 28.0 EDMA 3.2 0.7 0.1 MA 2.5 1.5 0.1 H.sub.2 O
less than 1 less than 1 less than 1 HQ or MEHQ 50 - 100 ppm 50 -
100 ppm 50 - 100 ppm
TABLE 2
5% H.sub.2 O ADDED TO HEMA
Ingredient Series E Series F Series G HEMA 74.3 72.9 67.2 PVP
(K=30) 14.25 19.0 26.6 EDMA * 4.04 1.67 1.1 MA 2.40 1.43 0.1
H.sub.2 O 5 5 5 HQ or MEHQ 50 - 100 ppm 50 - 100 ppm 50 - 100
ppm
In all of the preparations of Series A, B, C, E, F and G the first
stage initiators were the three mentioned in O'Driscoll U.S. Pat.
No. 3,700,761 and the second stage initiator was benzoyl peroxide.
This invention is limited to these initiators, e.g. the first stage
are: disecondary butyl peroxy dicarbonate, cyclohexanone peroxide
and acetyl peroxide. First and second stage initiators are used at
a concentration of 0.05 to 0.15 percent by weight of the batch.
UTILITY OF DIFFERENT COMPOSITION FOR SPECIAL LENS MANUFACTURE
In Table 1, series B and in Table 2, series F represent the best
groups for simple corrective hydrated lens which meet 90 percent of
the connections in near-sightedness, far sightedness and minor
astigmatigmatism (less than 2.0 diopters). As shown in FIGS. 6 - 8
for a minus lens, the lens extends beyond the cornea, the distance
beyond the limbus being from about 0.5 - 2.0 mm. and the overall
diameter varying from about 13.5 - 15.5 mm. and the inner rim being
beveled in a flat curve in a width of 0.30 - 0.70 mm., preferably
0.35 - 0.40 mm. the same rim is used with the plus lens.
Center thickneses in the minus lens in the dry state vary from 0.30
mm. to about 0.16 mm., depending upon the power. Thinner lenses are
more highly corrected and these are made from Series C and G in
Tables 1 and 2. Center thicknesses in the plus lenses vary from
0.30 mm. up to 0.45 mm., depending upon the power and the thicker
lenses are the highly corrected ones which can be made from Series
A, B, E or F compositions in Tables 1 and 2.
Astigmatic lenses with minus correction can be cast ground by the
hard lens technology of Feinbloom, U.S. Pat. No. 3,227,507, but the
selection of the composition is important since the cylindrical
correction may be cast into the inner or bottom surface and a
special mold may be made and used with Series G and C in accordance
with the elliptical shapes taught in Feinbloom. The result of
cutting the outer surface as the lathe as to provide a very thin
and fragile center of the prescription ground lens which must have
flexibility and rubber-like properties when dry. The strongest thin
lenses which can be made are based uppm the more rubbery
compositions having a higher PVP content, thus the Series C and
Series G compositions would be selected, depending upon whether the
patient had a "dry eye" to fit or the normal "wet eye". Manifestly,
Series G provides better fitting for the dry eye and Series C
provides better fitting for the wet eye.
In production, grinding rates are higher and manufacturing time
schedules are more easily met by Series A and E since these Series
provide harden buttons (highter EDMA content) and for plus lenses
much higher production schedules can be met.
For dispensing of medication, Series E - G are obviously more
effective, the higher water content accommodating greater total
dosages for sparingly soluble eye medicaments.
The water soluble medicaments from O'Driscoll et al, U.S. Pat. No.
3,700,761 can be incorporated in the HEMA by dissolving in H.sub.2
O and by adding 5 percent of H.sub.2 O to the HEMA; especially
useful lenses are made in this manner to provide hydrated lens
which contain 60 - 65% H.sub.2 O, as against 55 - 60% H.sub.2 O
when the 5% H.sub.2 O addition is omitted. With 5 percent added
H.sub.2 O the lens after hydration is more spongy, and can release
medication more efficiently. Uniquely precision reproducibility and
predictability, dry to wet, and resistance to storage creep in long
time saline storage (two weeks to one year) is achieved only with
the narrow range of formulations of the present invention.
The preferred ophthalmologically acceptable medicaments are know
and include corticosteroids, sulfonamide, disinfectants,
antiseptics, penicillin, pilocarpine, belladonna, dibenzyline,
hydergine, methacholine, carbachol, bethanechol and the like.
It should be emphasized that the foregoing examples are the result
of thousands of formulations, tested completely in the laboratory,
and then on patients under the supervision of qualified
ophthalmologists, these results had to be interpreted in the light
of a host of parameters and only experience showed the relationship
which are summarized above, in conjection with HEMA as the major
ingredient. There is not predictability from HEMA to HPMA
(hydroxypropyl analogue) and there is no basis for reproducing
water uptakes at 50 - 65 percent in hydrated lenses with any other
monomer than HEMA. These parameters, in addition to the
composition, include the batch size contents of all ingredients as
listed; time of mixing, induction period, viscosity changes, heat
transfer, presence of convection currents etc.
Although certain preferred emboidments of eye bandage containing
medicaments have been described herein above in terms of hard
polymer formed by adding up to 5 percent water and subjecting the
composition to the stages of induction for 2 1/2 - 6 hours, first
stage initiation at 40.degree.C and second stage initiation at
110.degree.C for 1 1/2 - 4 hours, it is emphasized that changes in
manufacture can be made, for example, cutting down the time at
110.degree.C to 1/2 hour to prevent excessive drug decomposition
and to thereby provide drug dispensing solid precisely cut products
for any type of known medication which are specifically adapted for
topical administration. For example, using the same lathe as in the
Mullen Patent a sheath or a tube may be turned for encircling a
blood vessel to which a slow-release water soluble drug is
administered to reduce blood pressure. A sheath may be encircled
about a nerve bundle or about a bone and medication administered to
aid in repair and bone growth (calciferol for example). Since
hydration occurs in saline, the implant which is at the same
osmotic pressure as body tissues and as blood contains, in the same
electrolyte environment, a very precisely dosed amount of drug
which can be used to produce a degree of precision in dosage not
heretofore obtainable. If the drug is used for the eye where a high
degree of precision of drug dosage is needed, it may be preferable
to set up a fountain solution in saline which drops the saline
solution containing the drug onto the lens to deliver the dosage to
the eye at a constant rate for a controlled time. Obviously,
fountain supplies of this type may be used with other implants.
It is therefore seen that new compositions of the invention create
new articles of commerce which are hygroscopic buttons in hard form
and are cast from new and disposable molds with break-away bottoms.
The buttons can be turned on a lathe to make new shaped products
such as implants and contact lenses which are adapted to be
hydrated in saline for water uptake of 50 - 65 percent. These
disposable molds form hard products whose inner surfaces are free
from fissures and cracks and which resist tearing by crack
propogation from these fissures.
In the foregoing specification and in the following claims, the
abbreviations are as follows:
Hema -- hydroxyethyl Methacrylate
Pvp -- poly-N-Vinyl Pyrrolidone
Edma -- elthylene Glycol Dimethacrylate
Ma -- methacrylic Acid
H.sub.2 o -- water
ppm -- parts per million
Hq -- hydroquinone
Mehq -- methyl Ether of Hydroquinone
* * * * *