U.S. patent application number 10/971820 was filed with the patent office on 2005-04-21 for growth factor delivery system for the healing of wounds and the prevention of inflammation and disease.
Invention is credited to Schultz, Clyde L..
Application Number | 20050085758 10/971820 |
Document ID | / |
Family ID | 29272622 |
Filed Date | 2005-04-21 |
United States Patent
Application |
20050085758 |
Kind Code |
A1 |
Schultz, Clyde L. |
April 21, 2005 |
Growth factor delivery system for the healing of wounds and the
prevention of inflammation and disease
Abstract
The present invention features hydrogel drug delivery systems
and methods of producing and using such systems for the treatment
of wounds. The systems are based on a hydrogel into which a low
concentration of growth factor, e.g., epidermal growth factor, is
passively transferred from a dilute aqueous solution. When placed
in contact with a wounded tissue, the growth factor passively
transfers out of the contact lens to provide accelerated healing.
The systems are applicable to ocular and other wound
treatments.
Inventors: |
Schultz, Clyde L.; (Ponte
Vedra, FL) |
Correspondence
Address: |
CLARK & ELBING LLP
101 FEDERAL STREET
BOSTON
MA
02110
US
|
Family ID: |
29272622 |
Appl. No.: |
10/971820 |
Filed: |
October 22, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10971820 |
Oct 22, 2004 |
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10340434 |
Jan 10, 2003 |
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10340434 |
Jan 10, 2003 |
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10132843 |
Apr 25, 2002 |
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Current U.S.
Class: |
602/41 |
Current CPC
Class: |
A61P 11/00 20180101;
A61P 27/02 20180101; A61K 38/1808 20130101; A61K 31/56 20130101;
A61P 29/00 20180101; A61P 1/00 20180101; A61K 47/32 20130101; A61K
9/0051 20130101; A61P 17/02 20180101; A61K 9/0014 20130101 |
Class at
Publication: |
602/041 |
International
Class: |
A61B 018/18 |
Claims
What is claimed is:
1. A method for treating an ocular wound, said method comprising
the steps of: (a) providing a contact lens comprising (i) a
polymeric hydrogel; (ii) a water content of between 37.5% and 75%;
and (iii) substantially pure epidermal growth factor; and (b)
contacting said contact lens with said ocular wound, wherein said
epidermal growth factor is passively released from said contact
lens to treat said ocular wound.
2. The method of claim 1, wherein said contact lens passively
releases at least 0.01, 0.05, 0.5, 1, 10, 15, or 20 .mu.g of said
epidermal growth factor.
3. The method of claim 1, wherein said contact lens is contacted
with said ocular wound for at least 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4,
4.5, 5, 7.5, 10, 15, or 24 hours.
4. The method of claim 1, wherein said contact lens further acts as
a protective shield against mechanical abuse.
5. The method of claim 1, wherein said ocular wound is in
epithelial tissue.
6. The method of claim 1, wherein said ocular wound is in the
sclera or cornea.
7. The method of claim 1, wherein said ocular wound is the result
of vision correcting surgery.
8. The method of claim 7, wherein said vision correcting surgery is
LASIK, PRK, or LASEK.
9. The method of claim 1, wherein said epidermal growth factor
causes a reduction in pain compared to an ocular wound not
contacted with said contact lens.
10. The method of claim 1, wherein said polymeric hydrogel
comprises a tetrapolymer of hydroxymethylmethacrylate, ethylene
glycol, dimethylmethacrylate, and methacrylic acid.
11. The method of claim 1, wherein said polymeric hydrogel
comprises etafilcon A, vifilcon A, polymacon B, lidofilcon A, or
vasurfilcon A.
12. The method of claim 1, wherein said polymeric hydrogel
comprises an ionic polymer.
13. The method of claim 1, wherein said polymeric hydrogel
comprises a non-ionic polymer.
14. The method of claim 1, wherein said contact lens comprises
between 5 and 350 ppb by weight of said epidermal growth
factor.
15. The method of claim 1, wherein said contact lens further
comprises an anti-inflammatory compound
16. The method of claim 15, wherein said anti-inflammatory compound
is dexamethasone, fluorometholone, rimexolone, or prednisolone.
17. The method of claim 1, wherein said contact lens is capable of
correcting vision.
18. The method of claim 17, wherein said contact lens is capable of
correcting vision in the range of +8.0 to -8.0 diopters.
19. The method of claim 17, wherein said contact lens has a base
curve between 8.0 and 9.0.
20. The method of claim 1, wherein said contact lens is a piano
contact lens.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 10/340,434, filed Jan. 10, 2003, which is a
continuation-in-part of U.S. application Ser. No. 10/132,843, filed
Apr. 25, 2002, each of which is hereby incorporated by
reference.
BACKGROUND OF THE INVENTION
[0002] In general, the invention relates to the fields of
hydrogels, drug delivery systems, wound healing, and reduction of
pain and inflammation.
[0003] Corneal wounds caused by injury, disease, or surgery
represent a serious medical condition that may lead to loss of
sight. For example, persistent epithelial defects can lead to
stromal melting, which causes serious visual dysfunction. Wound
healing of corneal mucosal tissue has taken on increased importance
with the advent of laser corrective surgery to re-establish normal
vision for people who do not wish to wear contact lenses or
spectacles. These laser surgical methods are used to correct vision
for nearsightedness (myopia), farsightedness (hyperopia), and
astigmatism. The methods include laser in situ keratomileusis
(LASIK), laser epithelial keratomileusis (LASEK), and
photo-refractive keratectomy (PRK).
[0004] LASIK refers to the use of a laser to reshape the cornea
without invading the adjacent cell layers. During the LASIK
procedure, a microkeratome is used to separate the surface layers
of the cornea and create a corneal flap (160-180 microns deep).
This flap stays attached to the rest of the cornea and is folded
back on one side to expose the stroma of the cornea. The laser
delivers pulses of ultraviolet light onto the inner cornea
(stroma). Each pulse removes a microscopic layer of the inner
cornea to reshape the surface of the cornea. For nearsighted
patients, the procedure flattens the cornea. For farsighted
patients, the procedure increases the curvature of the cornea. For
astigmatism, selected tissues are removed at certain angles to make
the cornea more spherical in shape. After exposure to the laser is
completed, the corneal flap is replaced where it bonds without the
need for stitches. The anterior layers of the cornea (epithelium,
Bowman's Layer) are largely preserved. Once the surgery is
completed, the eye is left to heal normally with the exception of
eye drops, which are used to prevent infection & swelling, with
varying degrees of success. Following the surgery, patients are
able to see clearly without depending on glasses or contacts.
[0005] During PRK, the surgeon removes the epithelium (the anterior
layer of the cornea or Bowman's Layer), which is a thin layer of
protective skin that covers the cornea. This layer can be removed
with an excimer laser or a brush. During the procedure, the patient
stares at a fixation light. In less than a minute, the laser
removes the proper amount of tissue while it reshapes the surface
of the cornea. The excimer laser delivers pulses of ultraviolet
light into the cornea. This exposure to laser radiation reduces or
eliminates nearsightedness by flattening the central cornea and
relocating the focal point of the lens onto the retina rather than
in front of it, which produces sharper vision. Following surgery, a
bandage contact lens is placed on the eye for 2-3 days. Because the
epithelium was removed, patients may experience blurry vision for
three to five days. Eye drops and the contact lens are effective in
reducing postoperative discomfort. The purpose of the contact lens
given to PRK patients post-surgically is to protect the leading
edge of the corneal epithelium that is regenerating along the
surface of the eye, post-surgery. As patients blink, the newer
leading edge of the epithelium may be removed. As a result,
recovery takes longer and there is an increased risk of
infection.
[0006] LASEK is similar to PRK but the epithelium is detached by
using an alcohol solution that weakens the epithelium and allows it
to fold back into a flap. A laser is then used to re-shape the
cornea and correct vision acuity.
[0007] All three procedures can result in corneal epithelial
defects, and inflammation and infection may also occur. These
complications can lead to acuity regression, pain, or other adverse
effects. Corneal defects from injury or other types of surgery,
such as corneal transplants, may also results in these undesirable
outcomes. Wound healing is thus of critical importance for the
outcome of surgery. There exists a need, therefore, for devices and
treatments that promote healing of corneal wounds.
SUMMARY OF THE INVENTION
[0008] The present invention features hydrogel drug delivery
systems and methods of producing and using such systems for the
treatment of wounds. The systems are based on a hydrogel into which
a growth factor, e.g., epidermal growth factor (EGF), is passively
transferred from a dilute aqueous solution. When placed in contact
with a wounded tissue, the growth factor passively transfers out of
the hydrogel to provide accelerated healing and a concomitant
reduction in pain. The amount of growth factor absorbed into the
hydrogel may be .ltoreq.350 ppb, but this amount surprisingly is
effective in producing a therapeutic effect likely because the
delivery system is localized and provides a sustained release of
the factor. Higher concentrations of growth factor may also be
employed. The systems are applicable to ocular wounds, especially
after vision correcting surgery, as well as other wound
treatments.
[0009] Accordingly, in one aspect, the invention features a
polymeric hydrogel that contains a substantially pure growth
factor. Exemplary growth factors include epidermal growth factor,
platelet derived growth factor, hepatocytic growth factor, human
growth hormone, fibroblast growth factor, and combinations thereof.
The concentration of the growth factor is, for example, between
0.005 and 350 ppb. Other exemplary concentrations include at most
1, 10, 25, 50, or 100 ppm. The hydrogel has a water content of, for
example, between 37.5% and 75% by weight. Exemplary hydrogel
materials include a tetrapolymer of hydroxymethylmethacrylate,
ethylene glycol, dimethylmethacrylate, and methacrylic acid. Other
examples of hydrogels include etafilcon A, vifilcon A, lidofilcon
A, vasurfilcon A, and polymacon B. In addition, variations of these
polymers formed by the use of different packing solutions (e.g.,
phosphate-buffered saline and boric acid) in the manufacturing
process are also included. The hydrogel may be ionic or non-ionic.
In various embodiments, the growth factor is capable of being
passively released into an environment, e.g., an ocular
environment, under ambient or existing conditions. In other
embodiments, the hydrogel may be shaped as a contact lens, e.g.,
one capable of correcting vision. Such a contact lens may be
capable of correcting vision in the range of +8.0 to -8.0 diopters,
including plano, and may have a base curve between 8.0 and 9.0.
Hydrogels of the invention may further include other therapeutic
compounds as described herein, e.g., an anti-inflammatory compound,
such as dexamethasone, fluorometholone, rimexolone, or
prednisolone.
[0010] In another aspect, the invention features a polymeric
hydrogel including an anti-inflammatory compound. Exemplary
polymers and anti-inflammatory compounds are as described above.
The concentration of the anti-inflammatory compounds is, for
example, between 0.001 and 100 ppm, e.g., at most 0.01, 0.1, 1, 10,
15, 20, 30, or 50 ppm.
[0011] The invention further features a method for making a
hydrogel drug delivery system by placing the hydrogel, e.g., a
contact lens, in an aqueous solution containing a substantially
pure growth factor as described herein, which is passively
transferred to the hydrogel. This method may further include the
steps of washing the hydrogel in an isotonic saline solution and
partially desiccating the hydrogel prior to placement in the
solution. The aqueous solution has, e.g., a pH between 6.9 and 7.4
and between 0.01 and 10 ng growth factor per .mu.L. The
concentration of growth factor in the hydrogel after soaking (i.e.,
after the medicated hydrogel is manufactured) is, for example,
between 5 and 350 ppb. In one embodiment, the hydrogel is placed in
the solution of growth factor for at least 30 minutes. The aqueous
solution may further include another therapeutic compound as
described herein, e.g., an anti-inflammatory compound, such as
dexamethasone, fluorometholone, rimexolone, or prednisolone.
Hydrogels containing these other therapeutic compounds may also be
obtained by omitting the growth factor in the soaking solution.
[0012] In another aspect, the invention features a method for
treating a wound. The method includes placing a hydrogel, as
described herein, in contact with the wound, wherein the growth
factor or anti-inflammatory compound or both are passively released
from the hydrogel to treat the wound. In one embodiment, the
hydrogel further acts as a protective shield against mechanical
abuse. In various embodiments, the wound is in endothelial tissue,
epithelial tissue, the lung, the skin, or the digestive tract. The
hydrogel may be placed in a body cavity. In another embodiment, the
method causes a reduction in pain compared to a wound not contacted
with the medicated hydrogel. The hydrogel may passively release,
for example, at least 0.01, 0.05, 0.1, 0.5, 1, 10, 15, or 20 .mu.g
of a growth factor, and the hydrogel may be placed in contact with
the wound for at least 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 7.5,
10, 15, or 24 hours. The hydrogel may also passively release at
least 0.01, 0.05, 0.1, 0.5, 1, 10, 15, 20, 50, 100, or 1000 .mu.g
of other compounds, as described herein.
[0013] The invention also features a method of delivering a growth
factor including the steps of placing a polymeric hydrogel of the
invention in contact with a wound that is in contact with a
replenishable bodily fluid; and allowing the growth factor to
release passively from the hydrogel into the replenishable bodily
fluid. In this method, the release of the growth factor from the
hydrogel into the replenishable bodily fluid is accelerated
compared to the release of the growth factor from the hydrogel into
a non-replenishable bodily fluid. An exemplary wound is an ocular
wound, and an exemplary replenishable bodily fluid is tear fluid.
This method may also be used to deliver anti-inflammatory or other
compounds as described herein.
[0014] As used herein, by "ambient conditions" is meant room
temperature and pressure.
[0015] By "existing conditions" is meant in situ, as in the eye or
other body system.
[0016] By "substantially pure" is meant having a purity of greater
than 75% by weight. A growth factor of the invention is, for
example, greater than 85%, 90%, 95%, or even 99% pure. Use of the
term is intended to define purity from other biological compounds,
e.g., proteins, carbohydrates, and lipids that are commonly
associated with the growth factor in vivo.
[0017] By "treating" is meant the medical management of a patient
with the intent that a prevention, cure, stabilization, or
amelioration of the symptoms will result. This term includes active
treatment, that is, treatment directed specifically toward
improvement of the disorder; palliative treatment, that is,
treatment designed for the relief of symptoms rather than the
curing of the disorder; preventive treatment, that is, treatment
directed to prevention of the disorder; and supportive treatment,
that is, treatment employed to supplement another specific therapy
directed toward the improvement of the disorder. The term
"treatment" also includes symptomatic treatment, that is, treatment
directed toward constitutional symptoms of the disorder. The term
further includes the promotion of wound closure or healing.
[0018] By "therapeutically effective amount" is meant an amount of
a compound sufficient to produce a preventative, healing, curative,
stabilizing, or ameliorative effect in the treatment of a
condition, e.g., an eye wound.
[0019] By "wound" is meant an injury to any tissue. Examples of
wounds include burns, lacerations, abrasions, bites, surgical
wounds, puncture wounds, and ulcers.
[0020] By "ocular environment" is meant the tissues of and
surrounding the eye, including, for example, the sclera, cornea,
and other tissues of the ocular cavity.
[0021] By "replenishable bodily fluid" is meant a fluid produced by
a mammal that is periodically replaced with new fluid. Examples of
replenishable bodily fluids include tears, saliva, mucous, gastric
fluids, and urine.
[0022] All percentages described in the present invention are by
weight unless otherwise specified.
[0023] Other features and advantages of the invention will apparent
from the following description and the claims.
BRIEF DESCRIPTION OF THE DRAWING
[0024] FIGS. 1A and 1B are groups of the uptake (A) and release (B)
of EGF from vasurfilcon A contact lenses.
DETAILED DESCRIPTION OF THE INVENTION
[0025] This invention provides a polymeric drug delivery system
including a hydrogel containing a growth factor, e.g., EGF.
Allowing passive transference of the growth factor from a dilute
aqueous solution into the hydrogel produces the delivery system.
The hydrogel, when placed in contact with a wound, delivers a low
concentration of the growth factor. The delivery of the growth
factor is sustained over an extended period of time, which is of
particular utility in environments, e.g., the eye, that are
periodically flushed with bodily fluids, e.g., tears. This
sustained delivery accelerates the wound healing process while
avoiding potential damaging effects of localized delivery of high
concentrations of compounds, e.g., from eye drops.
[0026] Drug Delivery System
[0027] Hydrogels. This invention may employ different polymer
compositions that are useful in the treatment of a variety of
tissues. For example, in the ocular environment, conventional soft
contact lenses can be used and can be either ionic or non-ionic
hydrogels containing between 37.5%-75% water by weight and can have
any base curve, e.g., from 8.0 to 9.0. The contact lenses may also
have the ability to correct vision, for example, over a range of
diopters of +8.0 to -8.0, including plano. Exemplary hydrogel
contact lens materials include etafilcon A, vifilcon A, lidofilcon
A, polymacon B, vasurfilcon A, and a tetrapolymer of
hydroxymethylmethacrylate, ethylene glycol, dimethylmethacrylate,
and methacrylic acid. These materials may also be employed, in
other physical forms, in treating wounds in other tissues. Other
suitable hydrogel materials are known to those skilled in the art.
The hydrogels may be insoluble or may dissolve over time in vivo,
e.g., over one day or one week. The growth factor is passively
delivered, for example, by diffusion out of the hydrogel, by
desorption from the hydrogel, or by release as the hydrogel
dissolves.
[0028] The drug delivery system may be produced from a partially
desiccated hydrogel (or equivalently a partially hydrated
hydrogel). The desiccation step removes, for example, approximately
5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, or 75% of the water in
a hydrogel. Desiccation can occur, for example, by exposure of the
hydrogel to ambient or humidity controlled air, by heating the
hydrogel for a specific period of time, or by blowing dried gas,
such as N.sub.2, over the hydrogel. In one embodiment, the hydrogel
is saturated with physiological (isotonic) saline prior to
desiccation. The partially desiccated hydrogel is then soaked,
e.g., for at least 30 minutes, in a dilute aqueous solution of
growth factor, e.g., at a pH between 6.9 to 7.4. The hydrogels may
also be soaked for at least 1 hour, 6 hours, 12 hours, or 24 hours.
The concentration of growth factor into which the hydrogel is
placed is typically 10 ng/.mu.L or less, e.g., at most 5 ng/.mu.L,
1 ng/.mu.L, 0.1 ng/.mu.L, or 0.01 ng/.mu.L. Higher concentrations
may also be used, for example, to reduce the soaking time. The
growth factor is passively transferred into the hydrogel. This
transfer may occur at least in part by rehydrating the hydrogel.
Diffusion of the growth factor into the water in the hydrogel may
also occur. In alternative embodiments, a fully hydrated or fully
desiccated hydrogel is placed in the soaking solution to produce
the medicated hydrogel.
[0029] Desirably, the concentration of growth factor transferred to
the hydrogel is substantially lower than the solution in which the
hydrogel is soaked. For example, the concentration of growth factor
in the hydrogel is at least 2.times., 5.times., or 10.times. less
than that of the soaking solution. Some growth factors, however,
may have a higher affinity for a hydrogel than aqueous solution,
and such a hydrogel will have a higher concentration of growth
factor than the solution in which it was soaked. The water content
and type of hydrogel, time and conditions, e.g., temperature of
soaking, composition of the soaking solution (e.g., ionic strength
and pH), and type of growth factor employed also may influence the
concentration of growth factor in the drug delivery system. Since
the water content of the hydrogel also helps to determine the total
amount of growth factor present in a hydrogel, it represents a
variable by which to control the amount of growth factor delivered
to a tissue. The production of a hydrogel containing a specified
amount of growth factor can be accomplished by routine
experimentation by one skilled in the art. Exemplary hydrogels
include between 5 and 350 ppb of growth factor, for example,
between 5 and 250 ppb, 5 and 100 ppb, 5 and 50 ppb, or 5 and 10
ppb. The concentration of growth factor in the hydrogel may,
however, be higher, e.g., at most 100, 75, 50, 25, 10, or 1
ppm.
[0030] Growth factors. Growth factors are a heterogeneous group of
proteins capable of stimulating growth and the multiplication of
cells. Exemplary growth factors include epidermal growth factor,
platelet derived growth factor, hepatocytic growth factor, human
growth hormone, fibroblast growth factor, and combinations thereof.
These growth factors may be natural, synthetic, or recombinant
growth factors or growth factor derivatives from any animal, for
example, humans, or any domesticated animal or pet species. Such
growth factors also include biologically active growth factors and
analogs. Peptide growth factors play important biological roles by
regulating many of the processes involved in normal wound healing
including migration, mitosis, and differentiation of cells. Growth
factors are commercially available or may be isolated using methods
known in the art.
[0031] Other compounds. The hydrogels of the invention may also
contain medicaments other than growth factors. These additional
compounds include, without limitation, analgesics,
anti-inflammatory drugs (e.g., dexamethasone, fluorometholone,
rimexolone and prednisolone), antibodies, meganins, self-proteins,
pharmaceutical drugs, and antibiotic compounds. These other
compounds may also be used at reduced concentrations from their
typically prescribed dosages. For example, these chemicals may be
delivered in concentrations of less than 100, 50, 25, 10, 1, 0.1,
0.01, or 0.001 ppm at various sites (e.g., the eye) and under
different conditions (e.g. ambient or existing).
[0032] The use of preservatives is non-ideal as they may transfer
to a hydrogel at a disproportionately high concentration and cause
cytotoxicity.
[0033] Treatment. To treat a wound, a drug delivery system of the
invention may be placed in contact with a damaged tissue. When the
system is shaped as a contact lens, the lens may simply be placed
in the eye normally in order to deliver the growth factor. In order
to effect accelerated healing of other wounds, the hydrogel may be
part of a bandage or may be adhered (e.g., by adhesives or sutures)
to the wounded tissue. If the hydrogel is placed internally in a
patient, the hydrogel is advantageously biodegradable.
[0034] Hydrogels may be considered to be disposable and may be
replaced after a specified period of time, e.g., at least 0.5, 1,
1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 7.5, 10, 15, or 24 hours.
Alternatively, a hydrogel that has a depleted amount of growth
factor may be recycled by desiccating and soaking the hydrogel
again.
[0035] Treatment Approaches
[0036] The invention may be used in conjunction with healing many
types of wounds, including, without limitation, ocular, oral, lung,
digestive tract, skin, large intestine, small intestine, colon, and
other wounds to endothelial, mucosal, or epithelial tissues. As
stated above, the invention provides accelerated healing by
delivering a growth factor to an injured tissue. In certain
embodiments, at least 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, or 20
.mu.g of the growth factor is released from the hydrogel. This
delivery occurs by passive transfer and allows medications to be
released into fluids of the body, e.g., ocular fluid. The growth
factor stimulates proliferation of cells surrounding a wound to
close the wound and replace damaged cells. Because the growth
factor is localized by the hydrogel, which provides greater control
over release of the growth factor or drug, a lesser amount of
growth factor may in many cases be needed to effect wound healing
than if, e.g., topical solutions, such as eye drops are used.
Accelerated healing may also reduce the pain and inflammation
associated with a particular wound and may help prevent infection.
In addition, the hydrogel may also act as a physical barrier to
provide protection from mechanical abuse and to prevent adherence
of the healing tissue to adjacent tissues. The use of hydrogels of
the invention may also allow patients to be treated using fewer
applications than with traditional methods. For example, a patient
treated using the hydrogels of the invention may be able to be
treated only once in a period of at least 48 hours.
[0037] In desirable embodiments, a hydrogel of the invention is
used to treat a wound that is in contact with a replenishable
bodily fluid, e.g., tears. In these embodiments, the growth factor
is released from the hydrogel at a more rapid rate than the release
of the growth factor into a fixed volume of fluid because as the
bodily fluid is replenished, the growth factor released is flushed
away from the site of application causing an increase in the
relative rate of diffusion of the growth factor out of the
hydrogel. The replenishing action of fluids such as tears may also
effectively increase the rate of diffusion of the growth factor
into the fluid and lead to earlier onset of therapeutic activity.
For medicated hydrogels of the invention placed in contact with a
non-replenishable bodily fluid (i.e., one where replacement is very
slow or nonexistent on the time-scale of drug release), lower
concentrations of a drug may be used since the drug is not flushed
from the site as quickly as in a replenishable fluid.
[0038] Ocular Wounds. In one embodiment, the wound is an ocular
wound, e.g., in corneal epithelial, endothelial, or retinal tissue.
The invention is of particular utility after vision correcting
surgery, such as LASIK, PRK, or LASEK. Soft and collagen contact
lenses may be utilized to minimize post-surgical epithelial trauma
and provide a stable healing environment. PRK typically requires a
therapeutic contact lens for 3-4 days, and post-operative
therapeutic drops are often prescribed. In the present invention,
the hydrogel may be shaped as a contact lens that acts as a
reservoir for the growth factor and can serve to protect the
leading edge of wound healing from normal mechanical abuse. The
growth factor gradually delivered in a low concentration from the
hydrogel obviates the need for therapeutic drops. Therapeutic drops
often include high concentrations of drugs because the majority of
the drop is excreted from the eye in a short period of time. These
high concentrations can cause additional damage to a wound, which
is avoided by the use of the present, localized time-release drug
delivery system. A further understanding of the invention may be
obtained from the following non-limiting examples.
EXAMPLE 1
Production of a Drug Delivery System
[0039] An exemplary drug delivery system was prepared as follows.
Contact lenses were removed from their package and rinsed with
saline to remove contact lens packing solution. The hydrogel lens
materials were allowed to desiccate for 10-30 seconds. The hydrogel
lens materials were placed into physiological saline that contained
epidermal growth factor (EGF) at concentrations of 10 ng/.mu.l or
5.0 ng/.mu.l for at least 30 minutes. Lower concentrations may also
be used. Longer passive transference times may also be used.
Untreated or control lenses were placed in physiological saline
without EGF.
EXAMPLE 2
Healing of Ocular Tissue
[0040] Ocular cells were placed into a sterile plastic dish. This
dish contained a 5-mm disk. The purpose of the disk was to prevent
cells from growing in the covered area. When the disk was removed,
a 5-mm "wound" or "hole" was present.
[0041] Contact lenses were then added to these cell sheets with the
wounds. The lenses were left in contact with the cell sheets for a
minimum of 30 minutes. Minimal medium was used to maintain the cell
cultures. Cells were incubated at 35.degree. C..+-.2.degree. C. in
5% CO.sub.2. Contact lenses with or without EGF were produced as in
Example 1. The contact lenses used were polymacon B, vifilcon A,
and lidofilcon A hydrogel polymers.
[0042] The cell sheets were then viewed over time, and the diameter
of the hole was measured.
[0043] The results are expressed in terms of closure of the in
vitro wound over time.
[0044] Epithelial Cells and Tissue. Epithelial (rabbit corneal
epithelial cells) cells were seeded on a dish and contacted with
control and EGF-containing contact lenses. At 48 hours there was a
25% difference in the closure rate between the EGF-treated cells
and the non-EGF treated cells. At 72 hours, there was a 43%
difference in the closure rate between the EGF-treated epithelial
tissue and the controls. The hydrogel material that was used was
vifilcon A, an ionic polymer with a water content of 55%. The
polymer had been incubated with 10 ng/.mu.L EGF for one hour at
4.degree. C. prior to use in the experiments.
[0045] Closure rates were calculated by direct measurement of the
diameter of the wound. Measurements were taken daily.
[0046] In a related series of experiments, a vifilcon A lens was
incubated under the same conditions as above with 5.0 ng/.mu.L of
EGF and then contacted with an epithelial "wound" as above. At 48
hours, there was a 21% closure rate difference between controls and
EGF treated hydrogel materials. At 72 hours, there was also a 21%
difference in the closure rate. These results indicated that over a
72-hour period, the relative healing rates remained essentially the
same for the treated and non-treated epithelial tissue, with the
epithelial tissue treated with EGF always having an accelerated
rate of healing.
[0047] The rate of wound healing increased with increased exposure
of the hydrogel material to the wound. Further, compared to a wound
not contacted with any lens, at 48 hours there was a 31% difference
in the healing rates. Healing for tissue exposed to a lens soaked
in 10 ng/.mu.L of EGF increased from 14% at 48 hours to 25% at 72
hours.
[0048] Endothelial Cells and Tissue. Wounds caused in endothelial
tissue (bovine corneal endothelial cells) were also healed by
release of EGF from a vifilcon A lens. The lens, soaked in 10
ng/.mu.L of EGF as above, showed a 73% difference in healing rates
at 48 hours compared to a control. At 72 hours, the EGF-treated
tissue had completely healed. In the control group, less than half
(43%) of the tissue had healed. The same lens material exposed to 5
ng/.mu.L of EGF showed a 31% difference in closure rate at 48 hours
between the EGF treated group and the controls. At 72 hours, 53% of
the tissue had healed in the EGF treated group, compared to 43% in
the control.
[0049] Lidofilcon A hydrogel (non-ionic, water content=70%)
materials were evaluated for their ability to deliver EGF to
endothelial tissue to close wounds. The concentration of EGF used
in the soaking solution was 10 ng/.mu.L. At 48 hours, the EGF
treated tissue showed a 54% increase in the healing rate (wound
closure rate) as compared to controls. At 72 hours, there was a
difference of 44%.
[0050] A third material, polymacon B, that is non-ionic and has a
water content of 38%, was also evaluated for the ability to deliver
EGF to wounds. The lenses were prepared using a soaking solution of
10 ng/.mu.L of EGF. At 48 hours, the wound was 60% closed in the
treated group and 27% closed in the non-treated group. At 72 hours,
the difference in closure between the treated and untreated groups
was 62%. In the EGF treated group at 72 hours, the wound had closed
by 80%, while in the untreated group, the wound had closed by
46.8%.
EXAMPLE 3
Uptake and Release of EGF
[0051] The amount of uptake and release of EGF from a contact lens
depends on the water content or composition of the lens or both.
Data were collected on the uptake and release of EGF from two types
of lenses, lotrafilcon A (24% water) and vasurfilcon A (74% water).
Both of these lenses are non-ionic. For uptake studies, thirty
lenses of each type were placed in 25 mL of a solution containing
40 ppm of EGF. For release studies, the lenses produced by the
uptake study were placed in 25 mL of solution not containing EGF
after desiccation for 10-30 seconds. For both types of study, the
amount of EGF in the solution was then measured at defined time
intervals. For vasurfilcon A, about 75% of the EGF in solution was
taken up by the lenses after 6 hours (FIG. 1A), at which point the
lenses appeared to be in equilibrium with the solution, and about
37% of the EGF taken up was released after 7 hours (FIG. 1B), at
which point the lenses appeared to be at or near equilibrium. The
release data indicate that contact lenses can deliver a sustained
dosage of EGF over a period of time. For lotrafilcon A,
surprisingly, no measurable amount of EGF was taken up or released
by the lenses. Based on a purely diffusional theory of uptake, at
least some growth factor would have been expected to be taken up in
the water in the lotrafilcon A contact lens. Two possible
explanations for the differential uptake of EGF by the two polymers
studied are 1) a water content higher than 24% is needed for uptake
of EGF and 2) the lotrafilcon A polymer is chemically
(thermodynamically) or structurally (kinetically) unfavorable for
the entry of EGF.
EXAMPLE 4
Animal Tests
[0052] Contact lenses containing EGF, EGF and dexamethasone (an
anti-inflammatory steroid), and human growth hormone (HGH) were
tested in a rabbit model for efficacy and toxicity. New Zealand
white rabbits were anesthetized, and then both eyes were abraded
with a needle. A control contact lens was placed in the left eye,
and a medicated contact lens was placed in the right eye of each
rabbit for up to 4 hours prior to euthanasia. Control contact
lenses (etafilcon A, an ionic lens with 58% water content) were
washed with phosphate-buffered saline (PBS) prior to insertion.
Medicated contact lenses (etafilcon A) were prepared by briefly
drying the lens and then soaking it in 400 ppb, 4 ppm, or 10 ppm
EGF or 400 ppb HGH in PBS for 24 hours. In another experiment,
lenses were soaked in 200 ppb EGF and 12.5 ppm dexamethasone for 25
hours. No toxicity was observed in the rabbits at any concentration
of EGF tested. Rabbits were visually scored on a 0-4 scale (0 being
the best and 4 being the worst) for corneal edema (which is a
measure of wound healing), inflammation, and exudate
production.
[0053] EGF (lenses soaked in 400 ppb EGF) released from hydrogel
contact lenses (right eye) healed wounds at an accelerated rate
when compared to control eyes (left eye) for the first two hours
after treatment. Data from four rabbits are shown in Table 1.
[0054] In another experiment, in addition to being abraded, the
rabbits eyes were treated with a solution of lipopolysaccharide
from E. coli O111:B4 (1 mg/mL) to induce inflammation. Lenses
soaked in 200 ppb EGF and 12.5 ppm (see above) dexamethasone
controlled inflammation and caused increased wound healing (right
eye) compared to control eyes (left eye). EGF controlled healing of
wounds even if there was an increase in inflammation.
[0055] Rabbit eyes (right eye) treated with HGH released from a
contact lens (400 ppb soak) had increased wound healing and
reduction in inflammation compared to control eyes (left eye) in
rabbits. In addition, no toxicity was observed to the ocular
tissue.
1TABLE 1 Wound healing with contact lenses containing EGF Corneal
Time Edema Inflammation Exudate (hours) Left Right Left Right Left
Right Rabbit 1 1 1 1 0 0 0 0 1.5 2 1 1 0 0 0 2 2 1 2 0 1 0 2.5 2 2
1 1 2 1 3 2 2 1 1 2 2 3.5* 2 2 2 2 3 2 Rabbit 2 1 1 1 1 0 0 0 1.5 1
1 0 0 0 0 2 2 2 1 1 2 2 2.5 2 2 1 1 1 3 3 2 1 1 2 2 2 3.5* 2 2 1 2
1 2 Rabbit 3 1 1 1 0 0 0 0 1.5 1 0 0 0 1 0 2* 1 0 0 0 0 0 Rabbit 4
1 1 0 0 0 0 0 1.5 1 0 0 0 0 0 2 1 1 0 0 0 1 2.5 1 1 0 0 0 0 3 1 1 0
0 0 0 3.5 1 1 0 0 0 0 4* 1 1 0 0 0 0 *death of the rabbit
[0056]
2TABLE 2 Wound healing and treatment of inflammation with contact
lenses containing EGF and dexamethasone Corneal Time Edema
Inflammation Exudate (hours) Left Right Left Right Left Right
Rabbit 1 1 1 1 1 0 0 0 1.5 1 1 1 0 0 0 2 1 0 2 0 0 0 2.5 2 0 2 0 0
0 3 2 0 2 0 0 0 3.5* 2 0 1 1 1 1 Rabbit 2 1 1 1 1 0 0 0 1.5 2 1 2 0
0 0 2 2 1 2 0 0 0 2.5 2 1 2 1 1 0 3 2 1 2 0 2 0 3.5 2 1 2 1 1 1
4.0* 2 1 2 2 2 2 Rabbit 3 1 1 1 1 0 0 0 1.5 1 1 1 0 0 0 2 1 1 2 0 1
0 2.5 1 1 1 0 0 0 3.0* 1 0 1 0 0 0 Rabbit 4 1 1 1 1 0 0 0 1.5 1 1 1
0 0 0 2 1 1 1 0 0 0 2.5 1 1 1 0 1 0 3 1 1 1 0 2 0 3.5 1 1 0 0 0 0
4* 1 1 1 0 0 0 *death of the rabbit
[0057]
3TABLE 3 Wound healing with contact lenses containing HGH Corneal
Time Edema Inflammation Exudate (hours) Left Right Left Right Left
Right Rabbit 1 1 1 1 0 0 0 0 1.5 2 0 0 0 0 0 2 2 0 1 0 0 0 2.5 2 0
1 0 0 0 3 2 0 1 1 0 0 3.5* 1 0 1 1 0 0 Rabbit 2 1 1 1 0 0 0 0 1.5 1
1 0 0 0 0 2 1 1 1 0 0 0 2.5 1 0 1 0 0 0 3 1 0 1 0 0 0 3.5* 1 0 0 0
0 1 Rabbit 3 1 1 1 0 0 0 0 1.5 1 0 0 0 0 0 2 1 0 1 0 0 0 2.5 1 0 1
0 0 0 3.0 1 1 1 0 1 0 3.5* 1 1 1 1 0 0 Rabbit 4 1 1 1 0 0 0 0 1.5 1
1 0 0 0 0 2 1 0 1 0 0 1 2.5 1 1 1 0 0 1 3 1 1 1 0 0 1 3.5* 1 1 0 1
0 1 *death of the rabbit
EXAMPLE 5
Human Testing
[0058] A polymacon B lens having 38% water content was soaked in
400 ppb EGF for 24 hours. This lens was placed in a human patient
suffering from a recurring epithelial defect that was not
responsive to traditional medical treatments. Clinical efficacy
(i.e., wound healing) was observed after treatment with the
medicated lens of the invention. Desirably treatment lasts for at
least one hour. This type of injury is normally treated by the
repeated introduction of eye drops, sometimes as often as every 4-5
minutes. A contact lens of the present invention, however, was able
to produce a positive result with only one administration.
[0059] Other Embodiments
[0060] Modifications and variations of the described methods of the
invention will be apparent to those skilled in the art without
departing from the scope and spirit of the invention. Although the
invention has been described in connection with specific desirable
embodiments, it should be understood that the invention as claimed
should not be unduly limited to such specific embodiments. Indeed,
various modifications of the described modes for carrying out the
invention, which are obvious to those skilled in the art, are
intended to be within the scope of the invention.
[0061] All publications, patents, and patent applications mentioned
in this specification are herein incorporated by reference to the
same extent as if each individual publication, patent, or patent
application was specifically and individually to be incorporated by
reference.
[0062] Other embodiments are within the claims.
* * * * *