U.S. patent application number 17/493972 was filed with the patent office on 2022-01-27 for bi-functional co-polymer use for ophthalmic and other topical and local applications.
The applicant listed for this patent is Calm Water Therapeutics LLC. Invention is credited to Eugene Rex Cooper, David Maxwell Kleinman, Andrew Loxley, Mark Mitchnick.
Application Number | 20220023334 17/493972 |
Document ID | / |
Family ID | 1000005885194 |
Filed Date | 2022-01-27 |
United States Patent
Application |
20220023334 |
Kind Code |
A1 |
Cooper; Eugene Rex ; et
al. |
January 27, 2022 |
BI-FUNCTIONAL CO-POLYMER USE FOR OPHTHALMIC AND OTHER TOPICAL AND
LOCAL APPLICATIONS
Abstract
The invention contemplates a copolymer which is a graft or block
copolymer useful to change the ocular surface temperature and other
characteristics of biological or contact lens surfaces. Methods for
use of these formulations and coatings to increase the temperature
of the skin, mucous membranes, eye or eyelids will help treat many
conditions including blepharitis and non-healing ulcers. Methods to
decrease evaporation, improve wettability and stabilize the tear
film, and lubricate biological surfaces in a subject, for example,
in the treatment of dry eye syndrome, and to improve contact lens
tolerability, are provided.
Inventors: |
Cooper; Eugene Rex; (Berwyn,
PA) ; Kleinman; David Maxwell; (Rochester, NY)
; Loxley; Andrew; (Philadelphia, PA) ; Mitchnick;
Mark; (East Hampton, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Calm Water Therapeutics LLC |
Rochester |
NY |
US |
|
|
Family ID: |
1000005885194 |
Appl. No.: |
17/493972 |
Filed: |
October 5, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16241127 |
Jan 7, 2019 |
11135242 |
|
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17493972 |
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PCT/US2016/041079 |
Jul 6, 2016 |
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16241127 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/34 20130101;
A61K 47/38 20130101; A61L 12/14 20130101; A61P 27/04 20180101; A61K
47/44 20130101; A61K 9/0014 20130101; A61K 9/08 20130101; A61K
47/10 20130101; B82Y 5/00 20130101; A61P 27/00 20180101; A61K 47/18
20130101; A61K 31/785 20130101; A61K 9/0048 20130101 |
International
Class: |
A61K 31/785 20060101
A61K031/785; A61K 9/00 20060101 A61K009/00; A61K 47/10 20060101
A61K047/10; A61K 47/34 20060101 A61K047/34; A61K 47/18 20060101
A61K047/18; A61P 27/00 20060101 A61P027/00; A61K 9/08 20060101
A61K009/08; A61K 47/38 20060101 A61K047/38; A61K 47/44 20060101
A61K047/44; A61L 12/14 20060101 A61L012/14 |
Claims
1. A method to increase the surface temperature on the external
surface of a treated contact lens that is on the eye of a subject
as compared to an untreated contact lens that is on the eye of a
subject, comprising contacting the eye of said subject with said
treated contact lens, wherein said treated contact lens is in
association with a pharmaceutical composition comprising a
copolymer having a positively charged moiety and a hydrophilic
moiety, wherein said contacting is effected in an amount and for a
duration so as to increase the surface temperature on the external
surface of said treated contact lens that is on the eye of said
subject as compared to an untreated contact lens that is on the eye
of said subject, thereby increasing the surface temperature on the
external surface of a treated contact lens that is on the eye of a
subject as compared to an untreated contact lens that is on the eye
of a subject.
2. The method of claim 1, wherein said contacting the eye of said
subject with said treated contact lens increases the temperature of
the ocular surface of the eye of said subject in contact with said
treated contact lens.
3. The method of claim 1, wherein the copolymer is a graft
copolymer.
4. The method of claim 1, wherein the copolymer a block
co-polymer.
5. The method of claim 1, wherein the hydrophilic moiety is one of
non-ionic or anionic.
6. The method of claim 1, wherein the copolymer creates an
electrostatic adhesion between the copolymer and the biological
surface.
7. The method of claim 1, wherein the copolymer creates a covalent
adhesion between the copolymer and the biological surface.
8. The method of claim 1 wherein the copolymer creates an
electrostatic adhesion with the contact lens.
9. The method of claim 1 wherein the copolymer creates a covalent
adhesion with the contact lens.
10. The method of claim 3, wherein the copolymer is a graft
copolymer and comprises a cationic backbone and side chains that
are water soluble and non-ionic.
11. The method of claim 3, wherein the copolymer is a graft
copolymer and comprises a water soluble non-ionic backbone and
cationic side chains.
12. The method of claim 1, wherein the copolymer is a block
copolymer and comprises at least one cationic block and at least
one block which is water soluble and anionic.
13. The method of claim 1, wherein the copolymer comprises 0.001 to
40% of said composition.
14. The method of claim 1, wherein the copolymer comprises 0.001 to
25% of said composition.
15. The method of claim 1, wherein said composition further
comprises a second polymer.
16. The method of claim 1, wherein said composition further
comprises a PLURONIC block copolymer.
17. The method of claim 1, wherein said composition further
comprises one or more of a surfactant, a preservative, and a
pharmaceutical ingredient selected from the group consisting of:
demulcents, emollients, sodium chloride, and vasoconstrictors.
18. The method of claim 1, wherein said treated contact lens has
been stored in said pharmaceutical composition comprising said
copolymer having a positively charged moiety and a hydrophilic
moiety.
19. The method of claim 1, wherein said increase in temperature
ranges from 0.1 degrees Celsius to 0.5 degrees Celsius.
20. The method of claim 2, wherein said increase in the temperature
of said ocular surface of the eye of said subject in contact with
said treated contact lens is at least 0.1 degrees Celsius.
21. The method of claim 20, wherein said increase in the
temperature of said ocular surface of the eye of said subject in
contact with said treated contact lens is measured at the
conjunctiva.
22. The method of claim 1, wherein said increase in temperature is
measured using a method selected from the group consisting of
ocular thermography, infrared thermal imaging, temperature
distribution assessments, dynamic thermography, ocular surface
temperature assessment and ocular thermometry.
23. The method of claim 1, wherein said increase in temperature is
measured with a thermistor or a thermal camera.
24. The method of claim 22, wherein said increase in temperature is
measured over time using a thermal camera, wherein said increase in
temperature is measured in degrees Celsius.
25. A method to treat blepharitis in a patient by increasing the
temperature of the affected contact-lens wearing eye by treating
said contact lens with a copolymer having a positively charged
moiety and a hydrophilic moiety, wherein said contacting is
effected in an amount and for a duration so as to increase the
surface temperature on the external surface of said treated contact
lens that is on the eye of said patient as compared to an untreated
contact lens that is on the eye of said patient, thereby treating
blepharitis in said patient.
26. A method to treat a chalazion in a patient by increasing the
temperature of the affected contact-lens wearing eye by treating
said contact lens with a copolymer having a positively charged
moiety and a hydrophilic moiety, wherein said contacting is
effected in an amount and for a duration so as to increase the
surface temperature on the external surface of said treated contact
lens that is on the eye of said patient as compared to an untreated
contact lens that is on the eye of said patient, thereby treating
chalazion in said patient.
27. A method to treat dry eye syndrome in a patient by increasing
the temperature of the affected contact-lens wearing eye by
treating said contact lens with a copolymer having a positively
charged moiety and a hydrophilic moiety, wherein said contacting is
effected in an amount and for a duration so as to increase the
surface temperature on the external surface of said treated contact
lens that is on the eye of said patient as compared to an untreated
contact lens that is on the eye of said patient, thereby treating
dry eye syndrome in said patient.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/241,147 filed Jan. 7, 2019, which is a
continuation of international application No. PCT/US2016/041079,
filed on Jul. 6, 2016, the entire contents of each of which are
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention provides topical and/or local delivery
pharmaceutical formulations and coatings for extraocular devices,
drug particles, or drug containing particles comprising a
bi-functional polymer or co-polymer and methods for their use in
modifying surface characteristics and/or changing the wettability
of biological surfaces in a subject, or on the aforementioned
devices. Formulations of the present invention are particularly
useful in various applications including increasing the ocular
surface temperature, preventing evaporation, hydration, in
particular treatment of dry eye syndrome and treatment of
ophthalmic discomfort prevention of infection and/or adhesion of
bacteria, viruses, proteins, toxins, and antigens and delivery of
active pharmaceutical ingredients to biological surfaces.
Formulations of the present invention can be used to alter the
tribological properties of biological surfaces. Formulations of the
present invention are also useful when combined with a host of
topically delivered therapeutic agents. The formulations are also
useful for coating extraocular devices, particularly contact
lenses, to improve their biological compatibility.
BACKGROUND OF THE INVENTION
[0003] Poly(L-lysine)-graft-poly(ethylene glycol) (PLL-g-PEG) is a
water soluble co-polymer consisting of a poly(L-lysine) backbone
and poly(ethylene glycol) side chains (Sawhney et al. Biomaterials
1992 13:863-870). The PLL chain, which carries multiple positive
charges, spontaneously adsorbs onto negatively charged surfaces
while PEG is a polynonion which serves as a non-binding domain.
This adsorption is strong and occurs rapidly, and renders surfaces
protein and cell resistant. Furthermore, PLL-g-PEG has been shown
to improve the biocompatibility of materials. (Sawhney et al.
Biomaterials 1992 13:863-870)
[0004] Various applications for the PLL-g-PEG graft co-polymer,
block co-polymers, and dendrimers with similar binding
characteristics have been described.
SUMMARY OF THE INVENTION
[0005] In one aspect, the invention provides a method for
increasing the wettability of a biological surface or treating
biological surface related discomfort in a subject, involving
contacting the surface with a composition containing a copolymer
having a positively charged, or hydrophobic or covalent bonding
moiety and a hydrophilic moiety, where the contacting is effected
in an amount and for a duration so as to increase the wettability
or treat discomfort of the biological surface.
[0006] In one aspect, the invention provides a composition
containing a copolymer having a positively charged, or hydrophobic,
or covalent bonding moiety and a hydrophilic moiety and a
pharmaceutically acceptable carrier.
[0007] In one aspect, the invention provides a pharmaceutical
formulation containing an effective amount of a composition
containing a copolymer having a positively charged, or hydrophobic,
or covalent bonding moiety and a hydrophilic moiety and a
pharmaceutically acceptable carrier.
[0008] In another aspect, the invention provides a method of
storing a contact lens for at least 1 hour, involving providing the
contact lens and a pharmaceutical formulation of the invention.
[0009] In one aspect, the invention provides a kit containing a
contact lens and a pharmaceutical formulation of the invention, in
a container that is unopened subsequent to manufacture.
[0010] In one aspect, the invention provides a kit containing a
sterile pharmaceutical formulation of the invention and packaging
materials therefore which permit use as an artificial tear product
introducible into the eye.
[0011] In one aspect, the invention provides a kit comprising an
extraocular device coated with the composition of the invention,
and packaging materials therefore. In various embodiments, the
packaging materials permit contacting of the extraocular device
through the nozzle of an eye care solution container. In various
embodiments, the extraocular device is an intracorneal inlay.
[0012] In one aspect, the invention provides a method for
manufacture of a contact lens, involving providing a contact lens
and contacting the contact lens with a composition of the
invention.
[0013] In another aspect, the invention provides a kit containing a
contact lens and a pharmaceutical formulation of the invention, in
a container that is reusable.
[0014] In one aspect, the invention provides a copolymer coated
nanoparticle, the surface of the nanoparticle containing a
copolymer having a positively charged, or hydrophobic, or covalent
bonding moiety and a hydrophilic moiety. In various embodiments,
the nanoparticle further contains an active agent.
[0015] An aspect of the present invention relates to a method for
changing wettability of and/or sterically modifying a biological
surface in a subject comprising locally administering to the
biological surface of the subject a pharmaceutical formulation
comprising a bi-functional co-polymer. A copolymer composition can
be contacted with an external body surface (e.g., skin) and/or used
to prevent infection. Of particular interest and focus in this
invention is the external surface of the eye including bulbar and
palpebral conjunctiva and the cornea. Another aspect of the present
invention relates to a method for treating dry eye syndrome
comprising topically administering to an eye of a subject with dry
eye syndrome a pharmaceutical formulation comprising a
bi-functional co-polymer.
[0016] Another aspect of the present invention relates to a method
for protecting a biological surface in a subject against pathogen
or toxin attack, said method comprising topically or locally
administering to the biological surface in the subject a
pharmaceutical formulation comprising a bi-functional
co-polymer.
[0017] Another aspect of the present invention relates to a method
for delivering an active pharmaceutical ingredient to a biological
surface in a subject comprising topically or locally administering
to the biological surface of the subject a pharmaceutical
formulation comprising a bi-functional co-polymer and the active
pharmaceutical ingredient.
[0018] Another aspect of the present invention relates to a
formulation for use in methods of changing wettability of (or
otherwise sterically modifying or stabilizing)a biological surface
in a subject, treating or preventing dry eye syndrome, treating or
preventing discomfort related complications of LASIK surgery,
treating or preventing infectious or inflammatory conditions of the
external eye, protecting a biological surface in a subject against
pathogens (bacteria, fungi, virus, prions, bioadhesive chemical
agents) and/or delivering an active pharmaceutical ingredient to a
biological surface in a subject, said formulation comprising a
bi-functional co-polymer for topical and/or local administration to
the subject.
[0019] Another aspect of the present invention relates to coating
extraocular devices with a bi-functional co-polymer. Another aspect
of the present invention relates to the use of the bi-functional
co-polymers described herein to prevent or treat contact lens
related discomfort and to reduce symptoms of contact lens
intolerance.
[0020] Other aspects of the invention include the coating and thus
protection of biological surfaces, such as the skin, especially
mucous membranes inside the mouth, nose, throat, ear, vagina, for
the purpose of maintaining hydration, and for protecting the
biological surface from infection by pathogens and from toxins.
[0021] Other aspects of the invention include coating drug
particles or particles containing drug to increase their utility by
increasing half-life and/or decreasing interaction with biologic
phenomenon such as an immune response.
[0022] In various embodiments of any of the above aspects, the
copolymer is a graft or a block copolymer. In various embodiments,
the copolymer is a graft copolymer and contains a cationic backbone
and side chains that are water soluble and non-ionic. In various
embodiments, the copolymer is a graft copolymer and contains a
water soluble non-ionic backbone and cationic side chains. In
various embodiments, the copolymer is a block copolymer and
contains at least one cationic block and at least one water soluble
and non-ionic block. In various embodiments, the copolymer is a
block copolymer and contains at least one block which is
hydrophobic and at least one block which is water soluble and
anionic. In various embodiments, the copolymer is a block copolymer
and contains at least one block which is hydrophobic and at least
one block which is water soluble and cationic. In various
embodiments, the graft copolymer is PLL-g-PEG.
[0023] In various embodiments of any of the above aspects, the
copolymer is a dendrimer. In various embodiments of any of the
above aspects, the hydrophilic moiety is one of non-ionic or
anionic. In various embodiments of any of the above aspects, the
copolymer is a block copolymer and contains at least one block
which is hydrophobic and at least one block which is water soluble
and or non-ionic.
[0024] In various embodiments of any of the above aspects, the
copolymer creates a covalent adhesion between the copolymer and the
biological surface. In various embodiments of any of the above
aspects, the contacted biological surface is the surface of an eye,
a mucous membrane, or skin of a subject.
[0025] In various embodiments of any of the above aspects, the
copolymer is 0.001 to 40% of the composition. In various
embodiments of any of the above aspects, the copolymer is 0.001 to
25% of the composition.
[0026] In various embodiments of any of the above aspects, the
composition further contains a second polymer. In various
embodiments of any of the above aspects, the composition further
contains a PLURONIC block copolymer. In various embodiments of any
of the above aspects, the composition further contains one or more
of a surfactant, a preservative, and a pharmaceutical ingredient
including demulcents [Cellulose derivatives (e.g.,
Carboxymethylcellulose sodium, Hydroxyethyl cellulose,
Hydroxypropyl methylcellulose, Methylcellulose), Dextran 70,
Gelatin, Polyols (e.g., Glycerin, Polyethylene glycol 300,
Polyethylene glycol 400, Polysorbate 80, Propylene glycol),
Polyvinyl alcohol, Povidone] emollients (e.g., Lanolin, mineral
oil, paraffin, petrolatum, white ointment, white petrolatum, white
wax, yellow wax), sodium chloride, and vasoconstrictors (e.g.,
Ephedrine hydrochloride, Naphazoline hydrochloride, Phenylephrine
hydrochloride, and Tetrahydrozoline hydrochloride).
[0027] In various embodiments of any of the above aspects, the
composition is contacted to the biological surface in an amount
sufficient to change tribological properties of the biological
surface of the subject. In various embodiments of any of the above
aspects, the composition is contacted topically to an eye of a
subject. In various embodiments of any of the above aspects, the
composition is topically administered to an eye of a subject to
treat dry eye, ophthalmic irritation, or corneal epithelial
disease. In various embodiments, the composition is contacted to
the eye by an eye drop or an eye care solution. In various
embodiments, the method further involves administering to the eye
of the subject a second, different eye drop. In various embodiments
of any of the above aspects, the composition has a low viscosity
artificial tear less than 20 cP, having prolonged tear film break
up time. In various embodiments of any of the above aspects, the
positively charged moiety is sufficient as a preservative in a
topical ophthalmic formulation. In various embodiments of any of
the above aspects, composition is in a volume sufficient for
instillation in the eye, wherein the copolymer is PLL-g-PEG at a
concentration of 0.1 to 3 wt %.
[0028] In various embodiments of any of the above aspects, the
copolymer is immobilized on an extraocular device at the time of
manufacture. In various embodiments, the copolymer is immobilized
on the extraocular device covalently. In various embodiments, the
immobilization is effected via an aldehyde plasma polymer
interlayer and reductive amination. In various embodiments, the
extraocular device is a contact lens.
BRIEF DESCRIPTION OF THE FIGURES
[0029] FIG. 1 shows results from an in vitro assessment of the
ability of exemplary formulations of the present invention
containing PLL-g-PEG to decrease contact angle of water to
polystyrene. Formulations containing 10 mg/ml or 1% (closed
circles), 5 mg/ml or 0.5% (open circles) or 1 mg/ml or 0.1% (closed
triangles) were compared to a control of deionized water (open
triangles).
[0030] FIG. 2 shows results from an in vitro assessment of the
ability of exemplary formulations of the present invention
containing F87 or F127 to decrease contact angle of water to
polystyrene. Formulations contained either 1% F127 (open circles)
or 1% F87 (closed circles) and were compared to the average contact
angle of deionized water (straight line).
[0031] FIG. 3 shows the results of a randomized, controlled, double
masked clinical trial in sixteen subjects where the tear film
break-up time was measured at varying time points after eye drop
instillation. This clinical methodology is a common assessment tool
for dry eye syndrome, as well as to determine the effectiveness of
artificial tears. Fifteen minutes after instillation of sample
formulation and active control, sample formulation showed extension
of noninvasive tear film break-up time from baseline of 14.67 sec
(p=0.05), while active comparator was 7.4 seconds longer than
baseline (p=0.34).
[0032] FIG. 4 shows results from the same randomized, controlled,
double masked clinical trial where the tear film break-up time was
measured at varying time points in subjects. Fluorescein break-up
time was longer than active comparator at 120 minutes; superior by
4.92 sec (p=0.12).
[0033] FIG. 5 shows results of a sub group analysis of the trial
described above. In the main group of 16 subjects in the trial,
there were three subjects that had unexpectedly long
pre-instillation TFBUT. These long initial values distorted the
relative contributions of the artificial tears to NIBUT for the
other subjects. When these three outliers were removed, there was
superiority in extending NIBUT for the sample formulation at every
time point. The data is graphed based on extension by seconds over
baseline in FIG. 5.
[0034] FIG. 6 shows results of a sub group analysis of the trial
described above similar in method to FIG. 5. In the main group of
16 subjects in the trial, there were three subjects that had
unexpectedly long pre-instillation TFBUT. These long initial values
distorted the relative contributions of the artificial tears to
NIBUT for the other subjects. When these three outliers were
removed, there was superiority in extending NIBUT for the sample
formulation at every time point. The data is graphed by percentage
change from baseline in FIG. 6.
[0035] FIG. 7 is an example schematic drawing of the molecular
behavior of the graft copolymer on an epithelial or ophthalmic
device surface. This schematic demonstrates how the surface
modifying polymer can be beneficial in altering the wettability or
tribological properties of a surface and/or sterically modifying
the surface so that the epithelium is protected and stays wet
longer, or how an extra- or intra-ocular device may be made more
biocompatible and less likely to foul with proteins and cellular
debris. 701 represents the negatively charged epithelial surface
(such as the cornea and conjunctiva) or negative charges on a
device (such as a contact lens). 702 represents the positive charge
on the NH3 terminal of lysine. 703 represents the anchoring poly
(L) lysine backbone. 704 represents the flexible polyethylene
glycol (PEG) side chains that form a brush. This brush can impart
protein resistance, and is hydrated (705 is a water molecule), and
thus there is also a change in wettability imparted onto the
surface on which the graft (or block) copolymer electrostatically
(or through hydrophobic interaction in some cases) adheres. 706
represents the entire graft copolymer molecule (PLL-g-PEG in this
example). Steric stabilization is also imparted to exposed surfaces
decreasing contact with proteins and cells, thereby protecting the
epithelial or device surface from protein or cellular adhesion,
inflammation or fouling. This figure is an example of PLL-g-PEG,
but the same concept applies for other graft copolymers, generally,
using either hydrophobic or cationic interaction with a surface
combined with a hydrophilic moiety imparting the protective aspects
of the invention herein described. Furthermore, the bi-functional
co-polymers, block copolymers, and dendrimers may be diagrammed in
a similar fashion, using a repeating moiety adherent to the surface
and a repeating hydrophilic moiety imparting changes in wettability
and protection. Furthermore, in some embodiments, the bi-functional
copolymer may be covalently immobilized on the surface of a device
such as a contact lens.
DETAILED DESCRIPTION OF THE INVENTION
[0036] It has now been found that topical or local administration
of a formulation comprising a graft co-polymer having a positively
charged or hydrophobic moiety and a hydrophilic moiety or a block
co-polymer having a positively charged or hydrophobic moiety and a
hydrophilic moiety to a biological surface alters and increases the
wettability of certain surfaces, including a biological surface
particularly the cornea conjunctiva and external surface of the
eye, and does so for a prolonged period of time. A copolymer
composition of the invention can be contacted with an external body
surface (e.g., skin) and/or used to prevent infection.
[0037] By "moiety" it is meant the required portion of the polymer.
For example, the moiety may be a monomer or one aspect of the
polymer that imparts some characteristic required for activity
and/or result. The PEG moiety imparts hydrophilicity. The PLL
moiety imparts cationic charges. A phenylboronic moiety for example
imparts an ability to form covalent attractions.
[0038] By "covalent" it is meant an interatomic bond charcterised
by the sharing of electrons. The bond can be reversible or
permanent.
[0039] By "electrostatic" it is meant interaction between two
molecules or two polymers or between a molecule or polymer and a
biological or non-biological surface based on charge
attractions--negative charge on one aspect of entity and positive
charge on one aspect of the other.
[0040] By "bioadhesive" is meant a synthetic or natural polymer
which binds to biological substrates such as mucosal membranes.
Binding may be accomplished by electrostatic interaction, covalent
attraction, hydrophobic interaction or other means.
[0041] By "hydrophobic interaction" it is meant an interaction
between lipophilic moieties on polymers and surfaces to form
adhesions or intermolecular aggregates or intramolecular
interactions (particularly in aqueous based environments).
[0042] By "adhesive", it is meant tending to adhere, stick, or not
come easily loose, or tending to persist.
[0043] By "increases the wettability" it is meant an increase in
the relative degree with which an aqueous liquid will spread onto
or coat a surface, including in the presence of other immiscible
liquids. Increased wettability, according to the invention results
in prolonged stability of the tear film keeping the cornea better
coated by natural and artificial tear film components, reduce
adhesion of inflammatory proteins, bacteria and inflammatory
proteins to a biological surface or membrane of the subject.
[0044] Changes in wettability, however, are only part of the
advantages conveyed by this invention. Surface modifications also
include the steric stabilization of biological surfaces and
extra-ocular ophthalmic device surfaces.
[0045] By "biological surface" is meant the surface of a bodily
organ, whether it be exposed to the external environment, or
internal to the body. For example, the surface of the eye includes
the epithelial covered cornea and bulbar and palpebral conjunctiva,
as well as the posterior tenons layer and sclera; the epithelial
layers of the gastrointestinal tract or the skin are included,
membranes such as mucous membranes, including oral, nasal,
respiratory, urinary tract including the bladder, and vaginal
mucous membranes. Other surfaces include the capsules of organs
such as the spleen and liver, and the outermost aspect of bone,
cartilage, and muscle, as well as wounds and areas where there is
unprotected subepithelial biological tissue exposure.
[0046] By "tribological properties" it is meant properties of
interaction of surfaces in relative motion. For example, a contact
lens on the surface of the eye with some movement on the corneal
surface and/or with the act of blinking whereby the palpebral
conjunctival surface moves over the contact lens constitutes a
state of relative motion between two surfaces. Likewise, blinking
whereby the palpebral conjunctival surface moves over the cornea
and bulbar conjunctiva constitutes a state of relative motion
between two surfaces. Tribological properties can include but are
not limited to properties such as lubrication, friction, and
wear.
[0047] By "subject", as used herein it is meant to be inclusive of
all animals and in particular mammals such as, but not limited to,
humans and dogs as well as agricultural animals such as bovine,
ovine, and porcine.
By "prolonged period of time" means that the formulation has an
effect that lasts longer than leading artificial tear products on
the market, which has been shown to be at least two hours with the
sample formulation, but "prolonged period of time" can also mean
longer than 20 minutes, as most ophthalmic topical products are
washed out of the eye in 20 minutes. A "prolonged" period of time
includes 30, 45, 50 minutes, as well as 1, 2, 5, 10, 24 hours, or
1, 2, 5, 10 or 30 days or more.
[0048] By "steric stabilization" or "steric modification" means
that the surface effects of the graft and block co-polymers results
in a hydrophilic moiety projected away from the biological surface,
drug particle or drug containing particle that imparts
characteristics such as low protein adsorption and cell adhesion.
Such an effect can also be called steric repulsion and surface
exclusion effects secondary to the PEG moieties (termed "brushes"
in some descriptions) on the graft copolymers. Other hydrophilic
chains can accomplish the same purpose in some embodiments. High
surface water retaining capacities, osmotic repulsion, and charge
neutrality may also contribute to this "steric stabilization"
effect.
[0049] By "storage" is meant time on the shelf in a container, and
storage time includes 1, 2, 5, 10, 30, 180, or 360 days or
more.
[0050] Accordingly, the present invention provides methods for
changing wettability of (or sterically stabilizing or otherwise
modifying) biological surfaces or membranes in a subject via
topical or local administration of a pharmaceutical formulation
comprising a graft co-polymer having a positively charged or
hydrophobic moiety and a hydrophilic moiety or a block co-polymer
having a positively charged or hydrophobic moiety and a hydrophilic
moiety to a biological surface of a subject, or both.
Pharmaceutical formulations can be administered topically or
locally in accordance with methods of the present invention to
biological surfaces of a subject including, but not limited to,
skin, mucous membranes, hair, and the surface of the eye.
[0051] According to the present invention, through the use of the
block and graft co-polymers described herein, certain drugs and
active biopharmaceutical agents will have improved efficacy and
decreased frequency of dosing needs as formulations using the block
or graft copolymers can bring such active pharmaceutical agents
into contact with epithelial surfaces, such as the cornea and
conjunctiva, for prolonged periods of time.
[0052] According to the present invention, through the use of the
block and graft co-polymers described herein, the tolerability of
extraocular devices such as contact lenses, shunts, retinal
implant/explant materials and devices for scleral buckles, and drug
delivery devices, can be improved. Furthermore, ophthalmic sutures
may be coated with these polymers decreasing tissue reaction and
reducing unwanted particle or bacterial adherence. First, the
devices can be coated (using electrostatic or hydrophobic
interactions or through covalent immobilization), with the said
polymers increasing wettability, modifying surface characteristics,
and/or sterically stabilizing and decreasing the adherence of
unwanted antigens, cells, proteins, and other particles to them.
Second, by protecting the epithelial surface or other ophthalmic
tissues (through turnover and/or exchange of these adherent
polymers with a biological surface and/or through the separation of
the device from the epithelial surface by the "brush"
characteristics of the hydrophilic moieties), the devices may be
more tolerable.
[0053] By "extraocular device" is meant medical devices that do
touch but do not reside entirely inside the eye. A contact lens is
an extraocular device. An intra-corneal inlay is an extraocular
device because it does not breach the intraocular environment. A
glaucoma shunt, is an extraocular device because the vast majority
of the device (except for the distal tip of the tube) resides
outside the eye. A scleral buckle is an extraocular device.
[0054] By "co-polymers" is meant a polymer with two or more
different monomers. Block, graft, and dendrimer co-polymers are the
major, but not only types of co-polymers referenced herein.
[0055] By "bi-functional" is meant the co-polymer has two or more
different functions that derive from the different moieties or
monomers inherent to the co-polymer. For example a hydrophilic
moiety or monomer has the property of wettability and a cationic
backbone has the property of bioadhesiviness. Joined together in a
co-polymer both functions remain. Specifically, bifunctional
co-polymers relates to but is not limited to graft, block, a and
dendrimer co-polymers. Critical to this invention is the novel use
of bi-functional graft copolymers in ophthalmic use.
[0056] By "ophthalmic use" is meant used on or in or adjacent to
the eye. Topical eye drops are included in ophthalmic use as is
subconjunctival, peribulbar and eyelid use. Use on contact lenses
and extraocular devices is included in ophthalmic use.
[0057] By "pluronic" is meant poloxamers or trade name pluronic
copolymers that are composed of nonionic triblock copolymers
composed of a central hydrophobic chain of polyoxypropylene
(poly(propylene oxide)) flanked by two hydrophilic chains of
polyoxyethylene (poly(ethylene oxide))
[0058] By "preserved" it is meant there is a substance or
preparation added to a product to destroy or inhibit the
multiplication of microorganisms.
[0059] According to the present invention, through the use of the
block and graft co-polymers described herein, the tolerability of
extraocular devices (such as contact lenses and intracorneal
optical devices), can be improved. First, the devices can be coated
with the said polymers increasing wettability and decreasing the
adherence of unwanted antigens, cells, proteins, and other
particles to them. Second, by protecting the adjacent tissue
structures, the devices may be more tolerable and may function
better i.e. through less protein or cellular interaction on the
device. In the case of intracorneal inlay technology, such a
coating may improve the clinical performance of such devices in
multiple ways.
[0060] Graft co-polymers used in the methods and formulations of
the present invention are polymers having a linear section of
repeat units called the "backbone", with at least one side chain of
repeat units (called a graft), usually of a different chemistry,
branching from a point along the backbone. In one embodiment, the
graft co-polymer comprises a cationic backbone and side chains that
are water soluble and non-ionic. In another embodiment, the graft
copolymer comprises a water soluble non-ionic backbone and cationic
side chains.
[0061] Block co-polymers used in the methods and formulations of
the present invention are polymers in which linear sections of a
first section of repeat units are connected end-to-end with linear
sections of subsequent repeat units that are chemically dissimilar
to the first.
[0062] Dendrimers comprised of cationic and hydrophilic polymeric
moieties can similarly be used as identified above in the methods
and formulations of the present invention to accomplish similar
structural and steric alterations of the biological surface
(particularly the eye), drug particles or drug containing
particles.
[0063] By "dendrimers" it is meant co-polymer molecules that are
repeatedly branched.
[0064] Also included in the invention is the use of graft, block,
and dendrimeric copolymers with multi-functionality in topical
applications and formulations including ophthalmic applications and
formulations. For example, a polymer where there is a moiety bonded
to one constituent polymer that promotes covalent bond formation
between the copolymer and biological surfaces such as the surface
of the eye or between the copolymer and extraocular devices that
also project a comb or a brush type of hydrophilic moiety, is
claimed. As can be seen to one skilled in the art, the results
accomplished with the use of electrostatic interaction between the
polymer and biological surfaces and the external environment or
extraocular devices can be accomplished using similarly designed
bi- and multi-functional polymers that promote the formation of a
covalent bond instead of or in addition to electrostatic attraction
only. For example, the use of phenylboronic acid (PBA) or other
boron based moieties in the polymer backbone provide a method for
the formation of covalent complexes between copolymers and
biological surfaces and between copolymers and extraocular devices.
Even though not called out continuously throughout this document,
the method of using covalent, electrostatic and hydrophobic
attraction (or any combination or either) in ophthalmic
applications is described. PLL-g=(PEG; PBA) is an example of a
polymeric structure that would impart the described
characteristics.
[0065] Formulations for use in the methods of the present invention
comprise a block or graft co-polymer having one section, either the
backbone, the graft or the block, that adheres to a biological
surface tissue such as, but not limited to, the eye surface by
electrostatic or hydrophobic forces (or covalent), and another,
chemically different section, either the backbone, the graft, or
block, that is hydrophilic and retains moisture (sometimes called a
"brush" or a "PEG brush" in some embodiments), or allows an aqueous
film to readily spread over and thus wet the biological surface.
Sometimes the graft copolymers such as PLL-g-PEG, for example, can
be referred to as comb co-polymers. Furthermore, the "brush" that
is composed of water soluble polymers that are biocompatible can in
aqueous environment, provide oil free lubricity (Drobeck et al.
Langmuir. 24(4):1484-8).
[0066] The surface modifications imparted by graft and block
co-polymers herein described may include, but are not limited to
changes in wettability, steric modification or steric
stabilization, steric repulsion, surface exclusion effects, high
surface water retaining characteristics, charge neutrality, and
osmotic repulsion. These and other effects on the surfaces are
important processes that may convey clinically meaningful benefits
to subjects and to the performance of medical devices. The
tissue-adhesive sections of a bi-functional co-polymer in the
formulations used in the methods of the present invention may be
cationic, in which case the polymer adheres to the biological
surface by electrostatic attraction, or may be hydrophobic in which
case the polymer adheres to the biological surface by hydrophobic
interaction, or may involve a covalent complex. In some cases, the
wettability of the biological surface may result in whole or in
part from modification of a liquid layer adjacent the surface, such
as the mucous layer adjacent the cornea. In some cases the tissue
surface modification may simply impart a lubricious protective
coating over ophthalmic tissue or extraocular devices. It may also
alter the tribological properties of tissues and extraocular
devices.
[0067] Aspects of the invention include copolymer coated
nanoparticles which can encompass active agents, including drugs
(small molecule, chemical, pharmaceutical, biologic) or allergens
(viruses, bacteria, yeast, prions). The nanoparticles have exposed
on their surface (i.e., are coated with) a copolymer, where the
copolymer has a positively charged, or hydrophobic, or covalent
bonding moiety and a hydrophilic moiety. Nanoparticles are not of
sufficient size to encompass cells. Nanoparticles are not
microspheres. Other aspects of the invention include coating drug
particles or particles containing drug to increase their utility by
increasing half-life and/or decreasing interaction with biologic
phenomenon such as an immune response. For intramuscular injection,
the nanoparticle size should be 1mm or smaller diameter; for
inhalation, the nanoparticle size should be 10 microns or smaller
in diameter; for IV injection, the nanoparticle size should be 1
micron or smaller in diameter.
[0068] Aspects of the invention include copolymer coated
nanoparticles which can encompass active agents, including drugs
(small molecule, chemical, pharmaceutical, biologic) or allergens
(viruses, bacteria, yeast, prions). The nanoparticles have exposed
on their surface (i.e., are coated with) a copolymer, where the
copolymer has a positively charged, or hydrophobic, or covalent
bonding moiety and a hydrophilic moiety. Nanoparticles are not of
sufficient size to encompass cells. Nanoparticles are not
microspheres. Other aspects of the invention include coating drug
particles or particles containing drug to increase their utility by
increasing half-life and/or decreasing interaction with biologic
phenomenon such as an immune response.
[0069] Nanoparticles of the invention have an effective average
particle size of less than about 1000 nm (i.e., 1 micron), less
than about 900 nm, less than about 800 nm, less than about 700 nm,
less than about 600 nm, less than about 500 nm, less than about 400
nm, less than about 300 nm, less than about 250 nm, less than about
200 nm, less than about 150 nm, less than about 100 nm, less than
about 75 nm, or less than about 50 nm, as measured by
light-scattering methods, microscopy, or other appropriate methods.
By "an effective average particle size of less than about 2000 nm"
it is meant that at least 50% by weight of the active agent
particles have a particle size less than the effective average,
i.e., less than about 2000 nm, 1900 nm, 1800 nm, etc., when
measured by the above-noted techniques. In other embodiments of the
invention, at least about 70%, at least about 90%, or at least
about 95% of the active agent particles have a particle size less
than the effective average, i.e., less than about 2000 nm, 1900 nm,
1800 nm, etc. For intramuscular injection, the nanoparticle size
should be 1 mm or smaller diameter; for inhalation, the
nanoparticle size should be 10 microns or smaller in diameter; for
IV injection, the nanoparticle size should be 1 micron or smaller
in diameter.
[0070] Nanoparticles of the invention can be made using, for
example, milling, homogenization, or precipitation techniques.
Exemplary methods of making nanoparticulate compositions are
described in the '684 patent. Methods of making nanoparticulate
compositions are also described in U.S. Pat. No. 5,518,187 for
"Method of Grinding Pharmaceutical Substances;" U.S. Pat. No.
5,718,388 for "Continuous Method of Grinding Pharmaceutical
Substances;" U.S. Pat. No. 5,862,999 for "Method of Grinding
Pharmaceutical Substances;" U.S. Pat. No. 5,665,331 for
"Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents
with Crystal Growth Modifiers;" U.S. Pat. No. 5,662,883 for
"Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents
with Crystal Growth Modifiers;" U.S. Pat. No. 5,560,932 for
"Microprecipitation of Nanoparticulate Pharmaceutical Agents;" U.S.
Pat. No. 5,543,133 for "Process of Preparing X-Ray Contrast
Compositions Containing Nanoparticles;" U.S. Pat. No. 5,534,270 for
"Method of Preparing Stable Drug Nanoparticles;" U.S. Pat. No.
5,510,118 for "Process of Preparing Therapeutic Compositions
Containing Nanoparticles;" and U.S. Pat. No. 5,470,583 for "Method
of Preparing Nanoparticle Compositions Containing Charged
Phospholipids to Reduce Aggregation," all of which are herein
incorporated by reference.
[0071] The resultant nanoparticulate active agent compositions can
be utilized in solid or liquid dosage formulations, such as
controlled release formulations, solid dose fast melt formulations,
aerosol formulations, nasal formulations, lyophilized formulations,
tablets, capsules, solid lozenge, powders, creams, ointments,
etc.
[0072] The nanoparticles of the invention can be contacted with a
copolymer having a positively charged, or hydrophobic or covalent
bonding moiety and a hydrophilic moiety after attrition. One or
more secondary surface stabilizers may also be added before or
after attrition. The active agent particles can be reduced in size
in the presence of a copolymer having a positively charged, or
hydrophobic or covalent bonding moiety and a hydrophilic moiety.
Other compounds, such as a diluent, can be added to the copolymer
active agent/surface stabilizer composition during the size
reduction process (e.g., milling). Dispersions can be manufactured
continuously or in a batch mode.
[0073] Another method of forming the copolymer coated nanoparticles
of the invention is by microprecipitation. This is a method of
preparing stable dispersions of copolymers or active agents in the
presence of one or more surface stabilizers and one or more colloid
stability enhancing surface active agents free of any trace toxic
solvents or solubilized heavy metal impurities. Such a method
comprises, for example: (1) dissolving the copolymer or active
agent in a suitable solvent; (2) adding the formulation from step
(1) to a solution containing a copolymer having a positively
charged, or hydrophobic or covalent bonding moiety and a
hydrophilic moiety and/or active agent and optionally one or more
secondary surface stabilizers, to form a clear solution; and (3)
precipitating the formulation from step (2) using an appropriate
non-solvent. The method can be followed by removal of any formed
salt, if present, by dialysis or diafiltration and concentration of
the dispersion by conventional means.
[0074] Exemplary homogenization methods of preparing copolymer
coated nanoparticles are described in U.S. Pat. No. 5,510,118, for
"Process of Preparing Therapeutic Compositions Containing
Nanoparticles." Such a method comprises dispersing nanoparticles in
a liquid dispersion medium in which the copolymer or active agent
is soluble, followed by subjecting the dispersion to homogenization
to reduce the particle size of the active agent to the desired
effective average particle size. The nanoparticles can be reduced
in size in the presence of a copolymer having a positively charged,
or hydrophobic or covalent bonding moiety and a hydrophilic moiety
and/or active agent, and, if desired, one or more additional
surface stabilizers. Alternatively, the nanoparticles can be
contacted with the copolymer and/or active agent and, if desired,
one or more additional surface stabilizers either before or after
attrition. Other compounds, such as a diluent, can be added to the
active agent/copolymer composition either before, during, or after
the size reduction process. Dispersions can be manufactured
continuously or in a batch mode.
[0075] The copolymer coated nanoparticles of the invention may
contain an active agent. The active agent may be contained within
the nanoparticle, on the surface of the nanoparticle, in the
copolymer coating of the nanoparticle, or on the surface of the
copolymer coating of the nanoparticle. Active agents that can be
used with the copolymer coated nanoparticle include without
limitation drugs (small molecule, chemical, pharmaceutical,
biologic) or allergens (viruses, bacteria, yeast, prions). Active
agents may be therapeutic, or diagnostic agent. A therapeutic agent
can be a pharmaceutical agent, including biologics such as
proteins, peptides, and nucleotides, or a diagnostic agent, such as
a contrast agent, including x-ray contrast agents. The active agent
exists either as a discrete, crystalline phase, an amorphous phase,
a semi-amorphous phase, a semi-crystalline phase, or mixtures
thereof. The crystalline phase differs from a non-crystalline or
amorphous phase which results from precipitation techniques, such
as those described in EP Pat. No. 275,796. Two or more active
agents can be used in combination.
[0076] The active agent can be selected from a variety of known
classes of drugs, including, for example, proteins, peptides,
nucleotides, anti-obesity drugs, nutraceuticals, dietary
supplements, carotenoids, corticosteroids, elastase inhibitors,
anti-fungals, oncology therapies, anti-emetics, analgesics,
cardiovascular agents, anti-inflammatory agents, anthelmintics,
anti-arrhythmic agents, antibiotics (including penicillins),
anticoagulants, antidepressants, antidiabetic agents,
antiepileptics, antihistamines, antihypertensive agents,
antimuscarinic agents, antimycobacterial agents, antineoplastic
agents, immunosuppressants, antithyroid agents, antiviral agents,
anxiolytic sedatives (hypnotics and neuroleptics), astringents,
beta-adrenoceptor blocking agents, blood products and substitutes,
cardiac inotropic agents, contrast media, corticosteroids, cough
suppressants (expectorants and mucolytics), diagnostic agents,
diagnostic imaging agents, diuretics, dopaminergics
(antiparkinsonian agents), haemostatics, immunological agents,
lipid regulating agents, muscle relaxants, parasympathomimetics,
parathyroid calcitonin and biphosphonates, prostaglandins,
radio-pharmaceuticals, sex hormones (including steroids),
anti-allergic agents, stimulants and anoretics, sympathomimetics,
thyroid agents, vasodilators, and xanthines.
[0077] Exemplary nutraceuticals and dietary supplements are
disclosed, for example, in Roberts et al., Nutraceuticals: The
Complete Encyclopedia of Supplements, Herbs, Vitamins, and Healing
Foods (American Nutraceutical Association, 2001), which is
specifically incorporated by reference. A nutraceutical or dietary
supplement, also known as phytochemicals or functional foods, is
generally any one of a class of dietary supplements, vitamins,
minerals, herbs, or healing foods that have medical or
pharmaceutical effects on the body. Exemplary nutraceuticals or
dietary supplements include, but are not limited to, lutein, folic
acid, fatty acids (e.g., DHA and ARA), fruit and vegetable
extracts, vitamin and mineral supplements, phosphatidylserine,
lipoic acid, melatonin, glucosamine/chondroitin, Aloe Vera, Guggul,
glutamine, amino acids (e.g., iso-leucine, leucine, lysine,
methionine, phenylanine, threonine, tryptophan, and valine), green
tea, lycopene, whole foods, food additives, herbs, phytonutrients,
antioxidants, flavonoid constituents of fruits, evening primrose
oil, flax seeds, fish and marine animal oils, and probiotics.
Nutraceuticals and dietary supplements also include bio-engineered
foods genetically engineered to have a desired property, also known
as "pharmafoods."
[0078] Active agents to be administered in an aerosol formulation
are preferably selected from the group consisting of proteins,
peptide, bronchodilators, corticosteroids, elastase inhibitors,
analgesics, anti-fungals, cystic-fibrosis therapies, asthma
therapies, emphysema therapies, respiratory distress syndrome
therapies, chronic bronchitis therapies, chronic obstructive
pulmonary disease therapies, organ-transplant rejection therapies,
therapies for tuberculosis and other infections of the lung, fungal
infection therapies, respiratory illness therapies associated with
acquired immune deficiency syndrome, an oncology drug, an
anti-emetic, an analgesic, and a cardiovascular agent.
[0079] A description of these classes of active agents and a
listing of species within each class can be found in Martindale,
The Extra Pharmacopoeia, Twenty-ninth Edition (The Pharmaceutical
Press, London, 1989), specifically incorporated by reference. The
active agents are commercially available and/or can be prepared by
techniques known in the art.
[0080] Exemplary active agents to be applied to mucous include
dental applications, such as oral bioadhesive nanoparticulate
lidocain formulations, bioadhesive nanoparticulate fluoride
treatments, application to the lungs, throat, GIT, application to
wounds, etc. Also included is application to the throat using a
liquid containing a bioadhesive nanoparticulate formulation
containing, for example, menthol or other numbing compound for
treatment of coughs or sore throats. The stomach and GIT can also
be treated using bioadhesive formulations. This is particularly
useful for treatment of diseases associated with the mucous of the
gastrointestinal tract, such as Crohn's Disease. Other
pharmaceutical therapeutic methodologies include oral dosing, nasal
administration, vaginal administration, ocular administration,
colonic, and subcutaneous administration.
[0081] The compositions of the invention also encompass food
products. For example, spice, oleoresin, flavor oil, color, or
chemicals are often added during food processing to produce the
desirable flavors, taste, and appearance. These agents can be
included in a bioadhesive nanoparticulate composition of the
present invention for increased adhesion to biological surfaces.
Bioadhesive nanoparticulate flavoring agents could be used in
products such as gums to produce prolonged flavor.
[0082] Other exemplary uses of the novel bioadhesive formulations
are provided: teeth can be treated with teeth whiteners or fluoride
bioadhesive compositions; bones can be treated with calcium
bioadhesive compositions; nails can be treated with color or
strengthening bioadhesive formulations; insects or pests can be
treated with insecticides or other toxic compositions to the pest.
In sum, the compositions are useful in treating any biological
surface, or a surface derived from a biological material. Feathers
and scales of animals can be treated, as well as other animal
biological surfaces such as chitin.
[0083] For the purpose of this invention, the description that
follows below on the different types of graft and block co-polymers
applies to invention embodiments of formulations for ophthalmic and
medical topical and pharmaceutical use, and to the use of these
graft and block co-polymers in the setting of extra- and
intra-corneal ophthalmic devices as coatings, and for ways of
treating, storing, or manufacturing, or reapplying the coatings to
these devices:
Examples of cationic polymer sections of graft or block co-polymers
of formulations useful in the methods of the present invention
include, but are not limited to: poly(L-lysine) (PLL), polylysine
[including poly-D-lysine (PDL), poly-DL-lysine,
poly-e-CBZ-D-lysine, poly-e-CBZ-DL-lysine, or poly-e-CBZ-L-lysine)
polyornithine (i.e., poly-DL-ornithine, poly-L-ornithine or
poly-S-CBZ-DL-ornithine), and the like)], [note Pub. No.:
WO/1993/018649 International Application No.: PCT/US1993/002609
contains additional descriptions of polycationic water soluble
graft copolymers and is incorporated here by reference],
poly(2-vinyl pyridine, poly(4-vinyl pyridine) and vinyl co-polymers
containing those repeat units, and poly(aminoethyl methacrylate)
homo- and co-polymers containing N,N
dimethylaminoethylmethacrylate) repeat units. In general, polymers
containing acrylates and acrylamides can serve as cationic sections
of the bi-functional co-polymers. Additional exemplary cationic
polymers include, but are not limited to,
poly(trimethylammonioethyl methacrylate chloride),
poly-(2-(dimethylamino) ethyl methacrylate) (pDMAEMA),
poly-(2-(dimethylamino) ethyl methacrylateco-methacrylic acid)
(pDMAEMA-co-MAA) and poly-(2-methyl-acrylic acid
2-[(2-dimethylamino-ethyl)-methylamino]-ethyl ester) (pDAMA), and
cation guar gum. Another cationic polymer section which can be used
is chitosan (a co-polymer of glucosamine and N-acetyl glucosamine
where 5-100% of the repeat units are glucosamine) and synthetic
derivatives thereof. The use of amines and other positively charged
amino acids bound to polymeric configurations to mimic the cationic
polymeric activities so described. In general, molecular structures
that can impart a positive external charge on a block or graft
copolymer or a dendrimer are included in the invention. Examples of
hydrophobic polymer sections of bi-functional co-polymers of
formulations useful in the methods of the present invention
include, but are not limited to, long-chain aliphatic hydrocarbons,
polyethylene, poly(propylene oxide), polystyrene,
poly(methylmethacrylate), poly(butylenes oxide), and the like. In
general, molecular structures that can impart an exposed
hydrophobic domain on a block or graft copolymer are included in
the invention. The hydrophilic section of the polymer may be
non-ionic if the tissue adhering section is cationic, or non ionic
or anionic if the tissue-adhering section is non-ionic (and
hydrophobic). Examples of non-ionic hydrophilic polymer sections of
formulations useful in methods of the present invention include,
but are not limited to, poly(ethyleneglycol) (PEG),
poly(vinylalcohol), poly(vinylpyrrolidinone), dextrans and the
like. Examples of anionic hydrophilic polymer sections include
homopolymers and co-polymers containing, for example, acrylic acid,
methacrylic acid, itaconic acid, maleic acid, styrene sulfonic
acid, carboxymethylcellulose, carboxyethylcellulose, succinylated
chitosan, cellulose sulfate, and the like. Additional exemplary
hydrophilic polymers include, but are not limited to,
poly(dimethylamino)ethyl methacrylate and poly hydroxypropyl
methacrylate (PHPMA). The adsorbing segment could also comprise a
boronate group selected from the group consisting of phenylboronic
acid (PBA), 2-carboxyethaneboronic acid, 1,2-carboxyethaneboronic
acid, .beta.,.beta.'-dicarboxyethaneboronate,
.beta.,.gamma.-dicarboxypropaneboronate, 2-nitro- and
4-nitro-3-succinamidobenzene boronic acids,
3-nitro-4-(6-aminohexylamido)phenyl boronic acid,
{4-[(hexamethylenetetramine)methyl]phenyl}boronic acid,
4-(N-methyl)carboxamidobenzene boronic acid,
2-{[(4-boronphenyl)methyl]ethylammonio}ethyl and
2-{[(4-boronphenyl)methyl]diethylammonio}-ethyl groups,
succinyl-3-aminophenylboronic add,
6-aminocaproyl-3-aminophenylboronic acid,
3-(N-succinimidoxycarbonyl)aminophenylboronate,
p-(.omega.-aminoethyl)phenylboronate, p-vinylbenzeneboronate,
N-(3-dihydroxyborylphenyl)succinamic acid,
N-(4-nitro-3-dihydroxyborylphenyl)succinamic acid,
O-dimethylaminomethylbenzeneboronic acid, 4-carboxybenzeneboronic
acid, 4-(N-octyl)carboxamidobenzeneboronic acid,
3-nitro-4-carboxybenzeneboronic acid,
2-nitro-4-carboxybenzeneboronic acid, 4-bromophenylboronate,
p-vinylbenzene boronate, 4-(.omega.-aminoethyl)phenylboronate,
catechol [2-(diethylamino)carbonyl, 4-bromomethyl]phenyl boronate,
and 5-vinyl-2-dimethylaminomethylbenzeneboronic acid. Adhesion
resistant segments is another way to describe an important
component of the copolymer. Adhesion resistant moieties could
include: polyalkylene oxides, mixed polyalkylene oxides,
polysaccharides, polyvinyl alcohol, poly-N-vinyl pyrrolidone,
noncationic polyacrylates, noncationic polymethacrylates, and
mixtures and copolymers of these constituents.
[0084] In general, the chains and block and graft copolymer
moieties may be any length, size, or molecular weight, and may have
any number of repeat rates of the polymer components. Imparting
beneficial properties is the main variable that will determine
specific size, weights, chain lengths, and repeat specifications
for applications described herein. As an example, PEG of different
molecular weights can be grafted onto the poly-(L-lysine) at
different ratios of PLL:PEG, to optimize the polymer architecture
for wettability, steric stabilization, and protein resistance.
Additionally, other factors, such as cost, process development
requirements, manufacturing, and biologic tolerability will go into
making specific size, weight, chain length, and repeat
characteristic specification decisions. For these polymers,
polydispersity may be acceptable over both wide and narrow ranges,
and product specifications will be made based on this
characteristic as well. However, this invention claims the use of
all sizes, weights, chain lengths, and repeat characteristics of
these graft and block co-polymers for uses and methods described
herein.
[0085] Graft co-polymers may have a cationic (or non-ionic
hydrophobic) backbone made from a polymer chosen from the list,
supra, and hydrophilic grafts, or have a hydrophilic backbone, and
cationic (or non-ionic hydrophobic) grafts chosen from the list,
supra. For graft co-polymers, grafts may arise from every repeat
unit in the backbone or may be intermittently spaced along the
backbone (with uniform or random frequency). For example, a useful
polymer in formulations for use in the methods of the present
invention is PLL-g-PEG where the backbone is the cationic polymer
poly(L-lysine) and the grafts are made from the hydrophilic polymer
poly(ethylene glycol). The PLL backbone may be from 3 repeat units
to several thousand repeat units long, and the PEG grafts may be
from 1 to several thousand repeat units long. The PEG grafts may be
attached to every PLL repeat unit, every other PLL repeat unit,
every third repeat unit or less frequent. In one embodiment, there
is a PEG graft on average at every third PLL repeat unit. Regarding
PLL, the PLL chain length can be any length, and made from PLL
derived from fermentation processes or synthetic polymerization
reactions. The molecular weight of the PLL backbone can be in the
range of several thousand Daltons (3,000 to 5,000) to tens of
thousands of Daltons 15,000 to 30,000, or higher. The chain length
can be as short as ten lysine groups or as long as one to two
hundred (or longer) lysine groups. The polyamino acid chain bonds
may be epsilon or alpha based. By block or graft co-polymers it is
meant to describe the architecture of the polymer.
[0086] An additional exemplary polymer for use in formulations used
in the methods of the present invention is PLL-g-dextran. Similar
detailed analysis and variability descriptions (as in the paragraph
above) can be made for PLL-g-dextran, and for many other graft
co-polymers claimed in this invention. Those skilled in the art
will identify methods to mimic the behavior of the copolymers
herein described using different monomers and moieties, and those
methods and compositions are claimed.
[0087] Block co-polymers or dendrimers comprising at least one
block or moiety that is cationic and at least one block or moiety
that is water soluble and non-ionic are also useful in formulations
for use in methods of the present invention. In one embodiment, the
co-polymer comprises at least one block which is hydrophobic and at
least one block which is water soluble and anionic, cationic or
non-ionic.
[0088] Examples of water soluble non-ionic co-polymer blocks or
moieties include, but are not limited to, poly(ethylene glycol)
(PEG), polyvinyl alcohol (PVA), poly(hydroxyethyl methacrylate)
(pHEMA), poly(acrylamide), poly (vinyl pyrrolidone) (PVP),
poly(ethyl oxazoline) (PEOX), polysaccharides, and copolymers of
any two or more thereof.
[0089] Examples of water soluble anionic co-polymer blocks or
moieties include, but are not limited to, polyacrylic acid (PAA),
polymethacrylic acid, poly(sodium styrene sulfonate), carboxylated
cellulosics such as carboxymethylcellulose (CMC), poly(itaconic
acid), poly(maleic acid), poly(acrylamidopropanesulfonic acid),
anionic natural gums, anionic carbohydrates, carageenan, alginates
and hyaluronic acid.
[0090] Examples of water soluble cationic co-polymer blocks
include, but are not limited to, polymers based on vinyl pyridine,
N,N-dimethylaminoethylacrylate, N,N-dimethylaminoethylmethacrylate,
other acrylate and acrylamide polymeric structures, allyl
tri(alkyl) ammonium halides, poly(amino styrene), certain types of
cation guar gums, chitosan, polyethyleneimine, polyallylamine,
polyetheramine, polyvinylpyridine, polysaccharides having a
positively charged functionality thereon, polyamino acids such as,
but not limited to, poly-L-histidine, poly-im-benzyl-L-histidine,
poly-D-lysine, poly-DL-lysine, poly-L-lysine,
poly-.epsilon.-CBZ-D-lysine, poly-.epsilon.-CBZ-DL-lysine,
poly-.epsilon.-CBZ-L-lysine, poly-DL-ornithine, poly-L-ornithine,
poly-.DELTA.-CBZ-DL-ornithine, poly-L-arginine,
poly-DL-alanine-poly-L-lysine, poly(-L-histidine, L-glutamic
acid)-poly-DL-alanine-poly-L-lysine, poly(L-phenylalanine,
L-glutamic acid)-poly-DL-alanine-poly-L-lysine, and
poly(L-tyrosine, L-glutamic acid)-poly-DL-alanine-poly-L-lysine,
copolymers of L-arginine with tryptophan, tyrosine, or serine,
copolymers of D-glutamic acid with D-lysine, copolymers of
L-glutamic acid with lysine, ornithine, or mixtures of lysine and
ornithine, and poly (L-glutamic acid), and the use of amines and
other positively charged amino acids bound to polymeric
configurations to mimic the cationic polymeric activities so
described.
[0091] Examples of hydrophobic co-polymer blocks include, but are
not limited to, alkanes, alkenes, alkynes, poly(isobutylene),
polyesters such as poly(caprolactone) (PCL), poly(lactic acid)
(PLA), poly(glycolic acid) (PGA), and copolymers therefrom (PLGA),
polyamides such as nylon(6,6) and Nylon(12), polyurethanes,
poly(propylene oxide), poly(tetramethylene oxide), polyethylene,
polypropylene, polystyrene, poly(acrylates) such as polymethyl
acrylate (PMA), poly(methacrylates) such as
poly(methylmethacrylate) (PMMA), poly(sulfones),
poly(etheretherketones) (PEEKs), poly(phosphazines),
poly(carbonates), poly(acetals) and poly(siloxanes).
As described supra, a host of additional adsorbing agents can be
utilized in the polymer construction.
[0092] As will be understood by the skilled artisan upon reading
this disclosure, triblock configurations can be used. An exemplary
block co-polymer comprising a triblock configuration is
PLURONIC.RTM. F127, also referred to as Poloxamer 407, containing a
poly(ethylene oxide) hydrophilic block ("PEO"), a poly(propylene
oxide) hydrophobic block ("PPO") and another PEO block. Other block
co-polymers for use in the present invention may contain only one
hydrophilic block and one hydrophobic block, or may contain several
alternating blocks, for example the PPO-PEO-PPO block co-polymers
(PLURONIC.RTM., block co-polymers based on ethylene oxide and
propylene oxide, BASF, Florham Park, N.J.). Additional exemplary
PLURONIC block co-polymers useful in the present invention include,
but are not limited to, PLURONIC 10R5, PLURONIC 17R2, PLURONIC
17R4, PLURONIC 25R2, PLURONIC 25R4, PLURONIC 31 R1, PLURONIC F 108
Cast Solid Surfacta, PLURONIC F 108 Pastille, PLURONIC F 108 Prill,
PLURONIC F 108NF Prill Polaxamer 338, PLURONIC F 127 Prill,
PLURONIC F 127 NF, PLURONIC F 127 NF 500 BHT Prill, PLURONIC F 127
NF Prill Poloxamer 407, PLURONIC F 38, PLURONIC F 38 Pastille,
PLURONIC F 68, PLURONIC F 68 Pastille, PLURONIC F 68 LF Pastille,
PLURONIC F 68 NF Prill Poloxamer 188, PLURONIC F 68 Prill, PLURONIC
F 77, PLURONIC F 77 Micropastille, PLURONIC F 87, PLURONIC F 87 NF
Prill Poloxamer 237, PLURONIC F 87 Prill, PLURONIC F 88 Pastille,
PLURONIC F 88 Prill, PLURONIC F 98, PLURONIC F 98 Prill, PLURONIC L
10, PLURONIC L 101, PLURONIC L 121, PLURONIC L 31, PLURONIC L 35,
PLURONIC L 43, PLURONIC L 44, PLURONIC L 44 NF Polaxamer 124,
PLURONIC L 61, PLURONIC L 62, PLURONIC L 62 LF, PLURONIC L 62D,
PLURONIC L 64, PLURONIC L 81, PLURONIC L 92, PLURONIC L44 NF INH
surfactant Polaxamer 124, PLURONIC N 3, PLURONIC P 103, PLURONIC P
104, PLURONIC P 105, PLURONIC P 123 Surfactant, PLURONIC P 65,
PLURONIC P 84, and PLURONIC P85. Where applicable, all particle
sizes of the block co-polymers are included, for example PLURONIC
F127 and PLURONIC F87 are available as prill and microprill
products. Non-ionic surfactants, for example, containing a
hydrophobic segment and a PEO block are considered here as block
co-polymers. The use of these commercially available agents
specifically in combination in formulations with bifunctional
copolymers here described including cationic and other adsorbing
moieties coupled with hydrophilic or non reactive elements is
identified.
[0093] Additional exemplary block or graft co-polymers or
dendrimers which can be used in the present invention are disclosed
in U.S. Pat. Nos. 5,578,442 and 5,834,556, as well as patents: U.S.
Pat. Nos. ,462,990; 5,627,233; 5,567,440; 5,849,839; 5,820,882;
5,380,536; 5,232,984; 6,231,892; 6,743,521; 7,316,845; 2,286,590;
6,596,267; 7,029,688; 6,350,527; 6,652,902. Teachings of each of
which are herein incorporated by reference in their entirety.
[0094] By "formulations" it is meant the particular mixture of base
chemicals and additives required for a product.
[0095] As mentioned previously, the examples of multi-functional or
bifunctional copolymers described above can be used in formulations
for topical ophthalmic use and for coating extraocular and
intra-corneal devices. However, the invention is not limited only
to those entities described above, other variations or types of
graft and block co-polymers having properties described herein is
an embodiment of the invention. The invention is not limited only
to those block and graft co-polymers named and described in detail
herein.
[0096] The block or graft co-polymers are included in formulations
for use in the methods of the present invention at weight percent
concentrations ranging between 0.001% and 40%, more typically 0.01%
to 25%, of the formulation. An effective amount is claimed. In the
Examples in which the formulation is described at present, the
amounts of co-polymers are between about 0.1% and 2%. In addition
the amount of bi-functional co-polymer can fall within other
smaller ranges e.g., 0.01% to 3%, 0.1% to 2.5%, or 0.5 to 2%.
[0097] The combinations of different copolymers can be that each is
(weight/weight) between 0.01% and 2% but can have ranges high as
wide as 0.01% and 5%. An effective amount is an amount that
increases the wettability of a given biological surface, or contact
lens surface; or that changes or modifies the surface in a
favorable way; such modification can include but is not limited to
steric stabilization, steric repulsion, high surface water
retaining capacity, charge neutrality, surface exclusion effects,
or osmotic repulsion. The extent of increase in wettability will
vary with the application and with the disease or disease symptom
that is being treated or prevented. An effective amount is an
amount that leads to beneficial biological surface modification
characteristics, as described above.
[0098] The bi-functional copolymers are used in any of these
concentrations to impart favorable characteristics to a product for
use in humans or other mammals either with or without an active
pharmaceutical ingredient. An active pharmaceutical ingredient can
be added to these formulations and the active agent will be used in
weight percent concentrations from between 0.0001% to 40%, more
typically from 0.01% to 10%. The copolymers can be used with a
preservatives such as, but are not limited to, Polixetonium,
polyquaternium-42, Polyquaternium-1, Polyquat, Alkyl-hydroxy
benzoate preservatives, parabens, hydrogen peroxide, benzalkonium
chloride, cetylpyidimine chloride, cetalkonium chloride, sodium
perborate, Purite, disappearing preservatives, Polyhexamethylene
biguanide (PHMB), chlorobutanol, Benzododecinium bromide, "Ionic
buffered system", povidone, silver, silver sulfate, betadine, and
other antiseptics and proprietary and non-proprietary
preservatives. The polymers herein described can be used in
combination with surfactants or emulsifier. Surfactant means a
chemical agent capable of reducing the surface tension of a liquid
in which it is dissolved. Emulsifier means a substance which
stabilizes an emulsion by increasing its kinetic stability.
An important aspect of this invention is formulations combining
bi-functional copolymers with one or more preservatives,
surfactants, and/or emulsifiers.
[0099] Polydispersity in these graft and block co-polymers can be
either minimal or there can be significant amounts of
polydispersity, and the formulations can still be effective.
[0100] Viscosity can important in these formulations. Typically,
with current technology, higher viscosity eye drop formulations
lead to longer surface changes on an eye but are associated with
visual blur and dissatisfaction by the user. There are advantages
to lower viscosity agents, and in certain formulations described
herein a lower viscosity can be beneficial as there will be less
visual blur imparted when an eye drop is applied. In the current
embodiment, the viscosity is approximately 2.7 centipoise (cP),
however, it can be higher or lower. 2.7 cP is lower than the
viscosity of most commercially available artificial tears. In some
embodiments a higher viscosity formulation may be preferred,
however. Viscosity can be adjusted by adjusting concentrations of
the graft and/or block co-polymers, or by adjusting other
excipients to affect viscosity. Useful viscosities are in the range
of 1 cP up to and including 100 cP or higher, but typically the
viscosity would be between 2 and 30 cP.
[0101] Additional exemplary components which can also be
incorporated into pharmaceutical formulations and coatings for use
in the present invention include, but are not limited to PLURONIC
gelling agents such as, but not limited to F127, F108 as well as
additional PLURONIC agents listed supra. Furthermore, in one
embodiment, these components are used at fractions below that
required for gelling activity.
[0102] Other components (either active or inactive ingredients)
which can be included in these pharmaceutical formulations include,
but are not limited to, lipids, oils, surfactants, water,
lubricating polymers, typical surfactants, buffers, salts,
physiologic ions, proteins, topical emollients, excipients
typically used in oral, topical, mucosal, dermatologic and
ophthalmic formulations, lubricants such as PEG 400,
carboxymethylcellose, hydroxypropyl methylcellulose, mineral oil,
propylene glycol, glycerin, hypromellose, white petrolatum,
polyvinyl alcohol, liposomes, mannitol, hydroxypropyl guar, dextran
70, viscoelastics, guar gum, alginates, and hyaluronic acid, as
well as combinations thereof. Specifically, the use of the herein
described copolymers for ophthalmic indications in combination with
active agents described in the OTC Monograph 21CFR349.14 is
claimed. Additional ingredients may include those routinely
included in shampoos, soaps, and conditioners. Such components may
be included in the formulations in varying percentages ranging from
less than 0.1% to 99% w/w %, more preferably less than 1% to 10%
w/w %. These are wt %'s relative to the total formulation.
[0103] Other components which can be included in these
pharmaceutical formulations include preservatives such as, but are
not limited to, Polixetonium, polyquaternium-42, Polyquaternium-1,
Polyquat, Alkyl-hydroxy benzoate preservatives, parabens, hydrogen
peroxide, benzalkonium chloride, cetylpyidimine chloride,
cetalkonium chloride, sodium perborate, Purite, disappearing
preservatives, Polyhexamethylene biguanide (PHMB), chlorobutanol,
Benzododecinium bromide, "Ionic buffered system", povidone, silver,
silver sulfate, betadine, and other antiseptics and proprietary and
non-proprietary preservatives. Also, PLL-g-PEG, or other cationic
components of graft or block co-polymers may act as a preservative.
Included in this invention, also, is the use of cationic moieties
in the graft or block co-polymers to serve as a preservative for a
formulation containing these agents. Poly (L) lysine, alone, not
coupled with a second polymer, as an ophthalmic preservative, for
example, is included as an invention in this filing.
[0104] Further, in some embodiments, the formulations and coatings
may include one or more additional active pharmaceutical
ingredients. Examples include, but are in no way limited to
anesthetics, antibiotics, anti-virals, anti-inflammatory agents,
intraocular pressure lowering agents, artificial tears, lubricating
products, dilating agents, immunosuppressives, anti-angiogenic
agents, proteins, peptides, neuroprotectants, small molecules,
growth factors and antibodies. By active pharmaceutical ingredient
or API it is also meant to be inclusive of genes and/or gene
transfer agents such as adenovirus, AAD and non viral vectors for
which transfer and transfection is enhanced via formulations of the
present invention. Formulations may be used in accordance with the
present invention to deliver an active pharmaceutical ingredient
which acts locally at the surface or in the tissue to which it is
delivered. Alternatively, or in addition, formulations may be used
in accordance with the present invention to deliver an active
pharmaceutical ingredient which is then absorbed through the tissue
and has a systemic or distal effect. In some embodiments, delivery
of the active pharmaceutical ingredient is facilitated by external
energy such as, but not limited to, iontophoresis, sonic energy,
heat, microneedles, micropore creating devices such as lasers or
high pressure gas.
[0105] Pharmaceutical formulations are a composition suitable for
internal, topical, or ocular administration to an animal, including
humans. The carrier is a pharmaceutically acceptable excipient in
which the co-polymer is admixed.
[0106] "Eye lubricant" can be defined as the API included in
artificial tear products based on the FDA OTC monograph 21 CFR
349.14 for ophthalmics.
[0107] pH of formulations of the present invention is in a
physiologic range depending upon the site of administration and the
site of the biological surface or membrane that is to be modified.
Typically, the pH is above 3, e.g., above 5.6 and below 9. The pH
is preferably between 6.5 and 8. Hypertonic and hypotonic
formulations are claimed. Water is well known as an important
excipient in topical ophthalmic formulations.
[0108] The ability of a pharmaceutical formulation comprising a
graft or block co-polymer with a positively charged or hydrophobic
moiety and a hydrophilic moiety to change wettability and adhere to
and lubricate and modify a biological surface was demonstrated.
Thus, the tribological properties of the surface was modified.
Importantly, these formulations may have very low viscosity (lower
than most artificial tear products on the market). For example, the
formulation tested in humans had a viscosity of 2.7 cP. Thus, the
results are not due to a simple mechanical thickening of the tear
film.
[0109] The ability of formulations comprising either the graft
co-polymer PLL-g-PEG or the block co-polymer F127 to change
wettability was demonstrated in vitro via contact angle
experiments, as described in Example 2. FIG. 1 and FIG. 2
demonstrate the ability of exemplary formulations comprising either
1, 0.5 or 0.1% weight/weight PEG-PLL or 1% F87 or F127
weight/weight, respectively, to decrease the contact angle of water
as compared to a control of deionized water. The ability of these
formulations to decrease contact angle is indicative of their
ability to adhere to negatively charged surfaces such as biological
surfaces and/or membranes and change wettability of the biological
surface and/or membrane. Through the understanding of one skilled
in the art, these formulations will thus also impart surface
modifications such as steric stabilization on the tissue to which
the bi-functional co polymers adhere.
[0110] Important to the management of ocular surface conditions is
an approach to protect the cornea and bulbar conjunctiva. These
parts of the eye are exposed to the environment when the eye is
open. When the eye is open, a patient with an unstable tear film
will develop symptoms such as burning, irritation, and/or the
sensation of dryness. Reflexive tearing may or may not be present.
Eventually, dry eye syndrome can develop and a host of signs and
symptoms are associated with dry eye. One aspect to dry eye is the
evaporation rate of the tears. Faster evaporation, physically, from
a surface leads to cooling of that surface. Typically, it is the
lipid layer, or lipid components, of the tear film that resist
evaporation. The lipids are part of a liquid structure (such as
oils) that is typically more resistant to evaporation than water
based solutions, especially low viscosity solutions.
[0111] There exists a host of conditions for which heat therapy is
recommended and effective. Heat can be used to treat eyelid
conditions, meibomian gland dysfunction, lacrimal drainage
conditions, chalazions, styes, infections, and other eye
conditions. Heat is also used to treat skin and mucous membrane
conditions such as infections, abscesses, and inflammatory
conditions.
[0112] Therefore, there is a need in the art for a multi-functional
polymer based solution that can maintain or increase ocular surface
temperature or the surface temperature of the skin and other mucous
membranes. Disclosed herein are multi-functional graft or block
copolymer based solutions that are effective in methods for
increasing surface temperature, particularly ocular surface
temperature. These multi-functional graft or block copolymer based
solutions may encompass many forms, such as a formulation for an
artificial tear, (especially a low viscosity solution), or a
topical ophthalmic polymer-including product including those that
can be used with contact lenses or in the formulations of drug
products for the eye, that could maintain or increase ocular
surface temperature.
[0113] A polymer based solution comprising the multi-functional
graft or block copolymer disclosed herein generates an increase in
ocular surface temperature immediately after instillation as well
as for prolonged periods such as 15 or even 30 minutes following
instillation, and provides an opportunity for clinical treatment
success in patients at risk of or suffering from tear film
abnormalities may exist with such a formulation. There are a more
than one patient subpopulations that would benefit from increasing
ocular surface temperature. For example, patients with blepharitis,
patients who have ocular discomfort, patients who are status post
eye surgery, patients with ocular allergy, patients with ocular
inflammation, and patients with or at risk for ocular infections.
It is important to focus on blepharitis patients in this
application. Blepharitis is inflammation of the eye lid margin.
Blepharitis is a common cause of ocular irritation and discomfort
in all age groups and ethnicities. There remains important unmet
need in the treatment of blepharitis. This condition can lead to
permanent changes of the eyelid margin or vision change from
corneal problems. The inflammation affects the eyelid itself, and
often secondarily the corneal surface as well as tear quality.
Currently, a recommended treatment is warm compresses to the
eyelids and the eyelid margin. The eyelash margin and areas
anatomical close to there are where the Meibomian glands secrete
their lipid component of tears. The lipids in these secretions can
become more viscous, less liquid-like, and even solid (like many
oils and fats) at lower temperatures. A treatment for Meibomian
gland disease is using a formulation containing a multifunctional
graft copolymer on the eye. The topical formulation will
necessarily bathe the eyelid margin as well. Note, the tear lake,
or lacrimal lake, which is essentially the volume of tears in an
eye, is 7 to 10 microliters. The maximum that the tear lake can
hold is about 20 to 30 microliters after which tears leave the tear
lake and wet the eyelids (tearing). The volume of an eye drop is
about 40 microliters. It is obvious that when an eye drop is
applied to the eye, excess tears will wet the eyelid. This approach
is one way that the lid margin or meibomian gland surface will be
wetted with the topical polymer formulation when instilled as an
eye drop. Additionally, however, the eyelid margin is generally
directly opposed to the surface of the eye. Indeed, the opening and
closing of the eyelid force the excess tears nasally through the
lacrimal drainage system. Thus, the lid margin itself, and the
meibomian glands contained within will be coated with tears. The
lid margin is wetted from even a smaller volume of topical
formulation--tearing or instillation of volumes that would cause
the maximum volume of the tear lake to be exceeded are not
necessary to wet the lid margin and meibomian glands. In one
embodiment of the present invention the Meibomian glands and/or the
lid margin have the resting temperature raised by the instillation
of a multifunctional graft copolymer. There will be clinical
benefits for those suffering from meibomian gland dysfunction
and/or blepharitis by raising the temperature of the lid margin.
This approach is a novel and different approach than what is used
clinically which includes warm compresses, and even a device called
"Lipiflow" heats the eyelids to treat blepharitis. This novel
approach of using a topically applied multifunctional graft
copolymer to increase the lid margin temperature should have great
clinical utility.
[0114] Furthermore, the palpebral conjunctiva also directly
contacts the surface of the eye. Since the Meibomian glands reside
within the eye lid, there is also the advantage with this approach
of placing the multifunctional graft copolymer in the eye
irrespective of excess tearing to coat the lid margin. Since the
ocular surface is higher, direct heat transmission will take place
as a transfer of heat from the ocular surface to the palpebral
conjunctiva and the eyelids themselves. A new treatment for
blepharitis is herein described. A new treatment to enhance
meibomian gland secretions or the lipid component of tears, is thus
described. A new treatment for Meibomian gland dysfunction is
described. This new treatment for eyelid margin disease will also
benefit mattering of the eyelid as the build up around the lashes
will be more easily reduced with a change in temperature at the
eyelid margin. Patients with blepharitis can be treated with a form
of eat therapy through the application of a multifunctional graft
copolymer to the eye. Note, multifunctional graft copolymer refers
to PLL-g-PEG and other graft copolymer molecules with a cationic
backbone and hydrophilic side chains. There is enough novelty with
this approach such that a wider range of graft copolymers is also
included as a novel embodiment of this discovery.
[0115] The definition of an increase in temperature is at least 0.1
degrees Celsius. In some embodiments, and increase of 0.5 degrees
Celsius is possible. An increase of 1 degree Celsius is also
possible. Greater increases in temperature may be seen with this
technology. Temperature is a continuous variable, and viscosity of
lipids and oils vary with temperature. Thus, any increase in
temperature, will decrease lipid viscosity and help lipid tear flow
into the eye. For the purposes of being measurable and clinically
significant, an increase in ocular surface temperature, or the
temperature of a mucous membrane (eyelid margin included) is 0.1
degree Celsius. Likewise, heat is a therapy for certain conditions.
Since temperature is a continuous variable, any increase in
temperature to target tissue should have a beneficial effect.
Increasing the eyelid temperature by 0.1 degree Celsius is
considered a temperature increase. Such an increase (and greater)
has been observed directly with the topical application of a
multifunctional graft copolymer.
[0116] Other patients that may benefit from this technology and
various embodiments of this invention include those with bacterial
infections of the eye, conjunctiva, or eyelids, plus the skin and
other mucous membranes. Patients with corneal infections or viral
keratitis or conjunctivitis will benefit from this treatment.
Patients with a condition where increasing the temperature of the
tissue is felt to be therapeutic will benefit from the use of these
multifunctional graft copolymers. Patients with dry skin and dry
mouth will benefit. Patients with non-healing ulcers whether due to
vascular compromise or other will benefit as heat causes
vasodilation and increases blood flow to a region. The use of these
multifunctional graft copolymers can likewise be used to prevent
infection because increased blood flow can help the body naturally
prevent infection in certain circumstances. The treatment for a
stye or chalazion involves heat. Thus, another embodiment is the
application of the graft multifunctional copolymer to the eye and
eyelid is a treatment for stye and chalazion. Patients with orbital
or preseptal cellulitis can be treated with these formulations.
Other patients that may benefit from this method of increasing the
temperature of skin or mucous membranes by contacting the tissue
with a multifunctional graft copolymer include dry eye patients to
enhance lipid flow, glaucoma patients to help reduce the risk of
bleb associated endophthalmitis, corneal transplant subjects to
help reduce the risk of graft infection, keratoprosthetic patients
to help reduce the risk of infection and to enhance healing at the
host/graft/device margin, post-operative pterygium surgeries where
a conjunctival graft was used, limbal graft surgeries, post op
cataract surgical patients where the increased heat will enhance
wound closure, arthritis patients, sore muscles, sore eyes,
post-operative oculoplastic patients who have undergone eyelid
surgery, post-operative plastic surgery patients, patients with
peripheral vascular disease, patients with infectious skin
problems, patients with an abscess, other signs of infection such
as induration, erythema, and pain, and patients with select
auto-immune skin conditions. Blepharitis and infectious conditions
of the eyelid and the eyelid margin remain a key opportunity for
this new therapy. Mucous membrane inflammation and infection remain
a key treatment for other non-ocular indications. The mucous
membranes of the nares can be treated with multifunctional graft
copolymers to enhance the prevention, treatment and clearance of
viruses including the common cold and influenza. Elevated
temperature helps certain types of immune cells work better, so
there is a broad potential for benefit with this new treatment for
certain infectious conditions.
[0117] Toward that end the working examples demonstrate the effect
on ocular surface temperature of the multifunctional graft
co-polymer in a topical ophthalmic formulation in a clinical
setting. See Example 8 in which the surface temperature after
instillation was compared to the pre-exposure or pre-instillation
ocular surface temperature.
[0118] Ocular surface temperature measurement can also be referred
to as ocular thermography or ocular thermometry. Contact methods
using thermistors can be used to measure ocular surface
temperature. Infrared imaging is the preferred methodology. Thermal
cameras also are used to measure ocular surface temperature. One
camera that specifically is useful here is the Thermovision A40
from FLIR system Inc, which has a sensitivity to detect temperature
change of 0.08 C, a frame rate 30 Hz, and image resolution of
320.times.240 pixels across full field view and emissivity set at
0.98. Cameras that have a detection sensitivity of less than 0.1
degree are preferred. The detection, however, should be able to
accurately identify changes of less than 1 degree Celsius. Any
camera that meets these specifications can in some embodiments be
used to test for the change in surface temperature. Other systems
that can identify these changes in ocular surface temperature
include: thermography, infrared thermal imaging, dry eye,
temperature distribution assessments, dynamic thermography, and
ocular surface temperature assessments.
[0119] Similar approaches for temperature measurement can be used
for other biological surfaces. For example, a multi-functional
polymer based solution disclosed herein that can maintain or
increase the surface temperature of the skin is helpful for
treating skin conditions such as with skin grafts and certain
dermatological conditions that are slow to heal and are exposed to
lengthy periods of cooling and drying environments. This treatment
with topically applied multifunctional block copolymers to raise
skin temperature may benefit non-healing ulcers, abscesses,
induration, scar tissue prevention, and bacterial skin
infections.
[0120] For methods of treating ocular or non-ocular skin grafts or
other ocular disorders (such as eyelid infections and blepharitis)
which endure cooling and slow healing conditions, a beneficial
effect can be attained by increasing the temperature of the ocular
surface through the use of a multi-functional graft or block
copolymer based solutions disclosed herein, A thermogram can report
the ocular surface temperature measurements (an ocular thermogram
for the eye). Infrared cameras and sensors are optimally utilized
for measuring ocular surface temperature (or biological surface
temperature) in these situations.
[0121] It was unanticipated, surprising and important that the
novel and proprietary topical formulation comprising a
multi-functional polymer based solution disclosed herein actually
increased the ocular surface temperature, and that the effect of
increasing the ocular temperature grew over time, especially in the
setting of the subject holding their eyes open for prolonged
periods.
[0122] Thus, it is a surprising discovery that a characteristic
property of the multi-functional graft copolymer described herein
is its ability to increase ocular surface temperature when applied.
Furthermore, when the multi-functional graft copolymer described
herein is combined with lipids in an artificial tear formulation or
other topical formulations, the ocular surface temperature raising
characteristic remains.
[0123] Thus, encompassed herein are topical lipid containing
ophthalmic formulations to which are added the multi-functional
graft copolymer described herein, methods of making said ophthalmic
solutions, and methods of using said ophthalmic solutions for the
treatment of ophthalmic diseases, disorders and conditions.
[0124] Not only can the formulation containing the multi-functional
graft copolymer described herein be delivered to the eye directly
by instillation, but a contact lens can serve as a vehicle for
delivering this multifunctional graft co-polymer. In one embodiment
the contact lens can be manufactured with the multi-functional
graft copolymer described herein. In another embodiment or the
contact lens can be soaked after manufacture with the
multi-functional graft copolymer described herein. In either
embodiment, there will be some multi-functional graft copolymer
described herein that leaves the contact lens either from the
solution coating it or from the lens polymer directly via some
elution.
[0125] Thus, described herein is a method to increase the ocular
surface temperature of the contact lens containing the
multi-functional graft copolymer described herein in wearers of
said contact lens as well as increasing the temperature of the
eye's ocular surface. Furthermore, by wearing a contact lens coated
with containing or exposed to a formulation with a multifunctional
graft copolymer, the prescribing physician and patient can treat an
underlying condition, such as blepharitis, chalazion, stye, or
corneal abrasion, to help improve the condition. See example
(Example 9.). Furthermore, the increased temperature of the eye's
ocular surface will remain in place in contact lens wearers because
the ocular surface temperature can also be measured at the
conjunctiva, which is not covered by a contact lens. Thus, the
temperature will be higher at the contact lens itself, and on the
eyeball. The effect is demonstrated as compared to an untreated
lens on the eye of a subject. The presence of said multi-functional
polymers and their variations as discussed in detail elsewhere
herein exert their effect on the ocular surface temperature when
the temperature is compared to a pre-instillation or pre-exposure
baseline.
[0126] Importantly, the instantly disclosed method of increasing
the temperature of the eye's ocular surface comprising contacting
said surface with formulations comprising the graft copolymers and
block copolymers disclosed herein is not limited to the ocular
surface. A formulation for topical use containing said graft
copolymers and block copolymers decreases rates of evaporation from
a biological surface such as the exposed skin or mucosal surface of
a mammal, including but not limited to humans. Included biological
surfaces are the ocular surface, nasal mucosa, oral mucosa (for
example during mouth breathing), external ear, scalp, lips, eyelids
and skin, as well as the bulbar conjunctiva and cornea. Further
biological surfaces include surface of body parts that find
exposure to the external environment following injury or surgery
including but not limited to as open wounds, skin grafts, and
resections, as they will benefit from the temperature increasing
effect of said formulations comprising the graft copolymers and
block copolymers disclosed herein to reduce evaporation and
subsequent tissue cooling and drying. The range of final
concentrations of formulations with a multifunctional block
copolymer are from 0.001% to 50%. Because of the surface adhering
characteristics quite low formulations have an effect. Higher
strength formulations are a potential way to further increase the
effect or to provide longer lasting products.
[0127] Thus, a biological surface includes the ocular surface, the
skin, and mucosal surfaces. Wounds and organ or tissue surfaces are
also included in the definition of biological surfaces. For the
purposes of this application, the relevance is highest when these
biological surfaces have exposure to an environment whereby there
will be or there is the potential for cooling of that surface when
wet by evaporation. A liquid (generally water-based) product to be
applied to such surfaces will necessarily show cooling on that
surface. By including the invention described herein, embodiments
of formulations comprising the multifunctional graft copolymers in
the solution applied to the biological surface will show less
cooling at the contact of said surface.
[0128] Thus the phrase "increase in surface temperature" not only
comprises an increase in surface temperature of up to 0.2, 0.4,
0.5, 0.6, 0.8, 0.9, 1.0, 1.2, 1.4, 1.5, 1.6, 1.8, 2.0, 2.2, 2.4,
2.5, 2.6, 2.8, 3.0, 3.2, 3.4, 3.5, 3.6, 3.8, 4.0, 4.2, 4.4, 4.5,
4.6, 4.8, 5 degrees F. or more, or an increase in surface
temperature of up to 0.2, 0.4, 0.5, 0.6, 0.8, 0.9, 1.0, 1.2, 1.4,
1.5, 1.6, 1.8, 2.0, 2.2, 2.4, 2.5, 2.6, 2.8, 3.0, 3.2, 3.4, 3.5,
3.6, 3.8, 4.0, 4.2, 4.4, 4.5, 4.6, 4.8, 5 degrees C. or more, with
respect to the surface temperature immediately before application
of said graft copolymers and block copolymers disclosed herein, but
the phrase also encompasses a decrease in the amount of cooling of
the biological surface upon contact with said formulations
comprising the graft copolymers and block copolymers disclosed
herein compared to said formulations without the graft copolymers
and block copolymers disclosed herein, i.e., a baseline of cooling,
is part of the invention. The comparison in these situations is the
evaporation rate, or surface temperature, when a formulation
without the copolymer is applied versus a formulation with the
copolymer. The minimal relevant change, or improvement, is 0.1
degree Celsius. The highest change to be seen will 5 degrees
Celsius or less.
[0129] An increase in surface temperature is a change of at least
0.1 degree Fahrenheit from the pre-contact surface temperature to
the post-contact surface temperature. Copolymer concentrations can
range from 0.01% to 50% in pharmaceutical compositions in the
embodied methods. Preferred embodiments of copolymer concentrations
are in the range of 0.01% to 3%. The multiple varieties of this
structural effect--which is a physicochemical finding or
characteristic of the polymer--will be seen regardless of the
specific design or composition of a multi-functional polymer with
positive charges on one moiety and hydrophilic charges on the
other. The preferred embodiment is a multi-functional graft
copolymer with a positively charged backbone and hydrophilic side
chains. The same benefits can be obtained when formulating with
other actives (an active is an agent approved allowed by the FDA or
other regulatory body as a treatment for a specific indication),
for example glaucoma, anti-inflammatory, anti-allergy, and
anti-infective actives for treatment of patients having glaucoma,
allergies, an ocular infection, including a microbial infection, a
bacterial infection, a viral infection, a parasite infection and a
fungal infection. Other conditions have been mentioned elsewhere.
See Example 10. Thus, the decreased temperature effect upon contact
with a biological surface hold true for any of the variations of
multi-functional graft copolymers that mimic the structure and
physicochemical properties described herein.
[0130] Example 11. Shows the utility of using the multi-functional
graft co-polymer in drug products for the eye with other actives
such as those for treating glaucoma. The effect of the actives on
intraocular pressure were maintained in the presence of
multi-functional graft copolymers, and the tear film was
significantly stabilized. The method for adding the polymer simply
to a topical ophthalmic solution will have value in certain
clinical situations. For example, it may be beneficial for a
physician to write an order wherein polymer is added to an already
manufactured formulation. The manufacturing process, as seen, can
be very simple. In one embodiment, the manufacturing process
comprises sterile filtration of the formulation and simply adding
the polymer to form a formulation is safe and effective. Autoclave
formulation is another approach to product sterilization.
[0131] A "meaningful baseline" as mentioned in the claims regarding
biological surface temperature can be considered or is for the
purposes of this application, any one of, but not limited to: A)
the temperature of the biological surface at baseline if it is a
mucous membrane, or B) the temperature of the ocular surface prior
to any eye drops instilled, or C) the temperature of the biological
surface after it is coated or contacted with a solution identical
to the copolymer solution only there is no copolymer component
added, or D) the actual temperature of the biological surface in
some cases, or E) the temperature of the biological surface when it
is wetted with water in a smooth thin layer, or F) the temperature
of the cornea, or G) the temperature of the bulbar conjunctiva.
[0132] As described in Example 3, Ex vivo experiments in porcine
eyes also showed a delay in pre-corneal water evaporation rates of
approximately 2 seconds longer compared to a control of
Systane.RTM. lubricant eye drops (Active Ingredients: Polyethylene
glycol 400 0.4% and propylene glycol 0.3%. Inactive Ingredients:
boric acid, calcium chloride, hydroxypropyl guar, magnesium
chloride, potassium chloride, purified water, sodium chloride, zinc
chloride.
[0133] As described in Example 1, experiments in a rabbit model
also showed lack of toxicity, in other words, safety, for a
formulation comprising 1% glycerin with 1% PLL-g-PEG and 1% F127 as
delivery of such formulation of the present invention to a
sensitive mucosal surface showed no visible irritation in the
Draize test and no histopathological changes (14 day histopathology
study).
[0134] Furthermore, as described in Examples 4 and 5, performance
of these block and graft copolymer formulations was assessed in the
eyes of human volunteers. Initial informal tolerability studies
showed the eye drop was well tolerated. For example, of the
multiple initial human exposures, there was no irritation or
discomfort seen or reported in any subject. Additionally, there
were no reports of blur following instillation of 50 microliters or
less. Actually, the eye drop was described as soothing on several
occasions. As a further safety step, one volunteer received 1
milliliter of solution in the eye, multiple times, and there was no
irritation or discomfort. The ability to treat dry eye was then
assessed using tear film break up time (TFBUT). TFBUT is indicative
of the rate of evaporation of tears from the surface of the eye.
The longer the TFBUT, the wetter the eye between blinks and the
less likely a patient will have dry eye signs and symptoms. The
first assessments were informal and performed in only a couple of
subjects, then a larger masked, randomized controlled study was
carried out. Administration of a formulation comprising 1% glycerin
with 1% PLL-g-PEG and 1% F127 resulted in prolongation of TFBUT. In
the first informal studies, the TFBUT was measured using
fluorescein staining. The TFBUT was prolonged versus active
comparator on one occasion at early time points, and that increase
was maintained for three hours. Subjective observation of the tear
film break up into smaller patches was confirmed via a non-invasive
wavescan of the tear surface. The larger, randomized controlled
trial studied three groups of patients (none/mild dry eye,
mild/moderate dry eye, and moderate/severe dry eye). The total
number of subjects was 18. Sixteen were analyzed with a noninvasive
TFBUT assessment tool called the Tearscope.TM.. In this study,
there was statistically significant prolongation of the TFBUT at
the 15 minute time point and the two hour time point versus active
comparator (a leading OTC dry eye artificial tear). The two
additional subjects underwent wavescan assessments as an
alternative to the Tearscope Plus.TM.; the results in these two
subjects also showed prolongation of the tear film compared to
control. Accordingly, one embodiment of the present invention
relates to use of these pharmaceutical formulations as lubricating
opthalmic eye drops for treatment of, for example, dry eye syndrome
and contact lens intolerance. As will be understood by the skilled
artisan upon reading this disclosure, however, alternative
ophthalmic delivery means including, but not limited to,
intraocular, periocular, conjunctival, subconjunctival,
transconjunctival, peribulbar, retrobulbar, subtenons,
transscleral, topical gel, topical dispersion, intraorbital,
intrascleral, intravitreal, subretinal, transretinal, choroidal,
uveal, intracameral, transcorneal, intracorneal, intralenticular
(including phakia and psuedophakia), and in or adjacent to the
optic nerve, can be used. The invention can be used with polymeric
and other devices for prolonged ophthalmic drug delivery. The
invention can be used with depot formulation to ease the tolerance
of the eye to prolonged drug exposure.
[0135] Dry eye syndrome is a common and irritating problem for
approximately 60 million Americans. Five million Americans suffer
from an advanced form of this condition. Dry eye syndrome can be
due to a deficiency of the aqueous, lipid, or mucin component of
tears. Dry eye syndrome is also related to inflammation on the
surface of the eye and irregularities of the tear film components.
Aging and hormonal changes can play a role. Environment, as well as
contact lenses and refractive surgery, can initiate and/or
exacerbate the problem.
[0136] Dry eye is treated with eye drops, punctual occlusion, and
occasionally systemically administered medicine, although eye drops
are the mainstay of treatment. While most eye drop treatments are
available over-the-counter, there are two prescription eye drops
inclusive of steroids and cyclosporine that help with dry eye. Most
over-the-counter dry eye syndrome products are washed out through
the lacrimal drainage system quite quickly thus rendering relief
minimal. For example, in at least two studies by Alcon, Systane had
a beneficial effect on tear film break up time that lasted up to 30
minutes. These studies demonstrate Systane.TM. is one of the
longest acting over-the-counter dry eye products. The PLL-g-PEG
formulation shows results improving tear film break up time beyond
two hours.
Accordingly, there is need for formulations of the present
invention for treatment of this condition.
[0137] Formulations can also be used in accordance with the present
invention to provide for prolonged coating of the ocular surface
via the multifunctional properties of the graft and/or block
co-polymers. Without being bound to any particular theory, it is
believed that the hydrophilic domain(s) of the block or graft
co-polymer, which keep the eye lubricated and help to retain tears
on the surface, are anchored at the surface of the eye (cornea and
conjunctiva)for an extended period of time through primarily
interaction of positively charged domain(s) on the block, graft, or
backbone of the graft copolymer and secondarily through hydrophobic
domains on the block, graft or backbone of the polymer with the
surface of the eye through either electrostatic attraction with the
negatively charged areas on the surface of the eye or hydrophobic
interactions with the hydrophobic regions of the eye that play a
role in dry eye syndrome. Similarly, these polymers could interact
with natural mucins and be effective in adhering to mucins and/or
keeping soluble mucins in the tear longer, and/or increasing the
effectiveness and natural protections provided by mucins. The
formulations and use of the graft and block copolymers described
herein may also have beneficial effects based on the steric
stabilization of biological surfaces. The protection provided may
help break the vicious cycle of inflammation, cellular injury, and
discomfort.
[0138] Formulations comprising a bi-functional co-polymer and an
anesthetic agent such as proparacaine can be used in accordance
with the present invention to prolong the anesthetic effect and/or
reduce the acute corneal surface changes seen commonly in the
clinic and operating room associated with decreased sensation of
the cornea and a decreased blink rate. Such formulations can be
applied prior to examination and/or pre-operatively, and will help
maintain a more normal corneal epithelial surface. Furthermore, use
of the formulation will help reduce bacterial adherence at sites of
any procedures performed on the eye and will help reduce
post-procedural infection.
[0139] Formulations described herein also provide a safe,
nonirritating excipient for ophthamological formulations with one
or more additional active pharmaceutical ingredients. For example,
one aspect of the invention is the use of the block and graft
copolymers described herein combined with active agents for
treating ophthalmic disease. Their inclusion may reduce the
irritation or tachyphylaxis (associated with some eye drops), or
simply provide an additional lubricating and wettable ocular
surface enhancing the comfort and acceptance of eye drops.
Exemplary additional active pharmaceutical ingredients for
ophthamological uses include, but are not limited to, lubricants
and demulcents, as described supra, antibiotics (fluoroquinolones,
vancomycin, cephalosporin, gentamycin, erythromycin, azithromycin,
sulfa drugs, bacitracin, gatifloxacin, levofloxin, moxifloxacin,
ofoxacin), acetazolamide, antazoline, aspirin, atropine,
azelastine, bacitracin, betaxolol, bimatoprost, botanical drugs
including zeaxanthine lutein, lycopene brimonodine, brinzolamide,
carbachol, carteolol, ciprofloxacin, ofloxacin, cromalyn,
cyclosporine, cyclosporine pro-drugs and cyclosporine derivatives,
other immunomodulators, dapiprazole, dexamethasone, diclofenac,
dipivifren, dorzolamide, epinephrine, erythromycin,
fluoromethalone, flurbiprofen, gentamycin, glaucoma medications
(prostaglandins, carbonic anhydrase inhibitors, epinephrine or
alpha-agonists, beta-blockers), gramicidin, homatropine,
hydrocortisone, hyoscine, keterolac, ibuprofen, ketotifen,
latanaprost, levobunolol, levocabastine, levofloxin, lotepprednol,
medrysone, methazolamide, metipranolol, naphazoline, natamycin,
nedocromil, neomycin, neuroprotective agents, nonsteroidal
anti-inflammatory agents, nepafanec, norfloxacin, ofloxacin
olopatadine, oxymetazoline, pemirolast, pheniramine, phenylephrine,
pilocarpine, povidone, prednisolone, proparacaine, scopolamine,
tetracaine, steroids, sulfacetamide, tetrahydrozoline, hypertonic
tears, timolal, tobramycin, travaprost, trifluridine, trimethiprim,
tropicamide, unoprostone and zinc. Prodrugs and related compounds,
as well as any new active pharmaceutical ingredients can be used
with the block and graft copolymers here described.
[0140] Formulations comprising a graft and/or block co-polymer can
also be used in accordance with the present invention with contact
lens solutions, manufacturing, rewetting drops, or in pre-insertion
contact lens treatments. The graft and/or block co-polymers can be
used with current contact lens care solution and rewetting drop
ingredients, including, but not limited to, water, preservatives,
NaCl and other salts and mineral ingredients, buffers, and other
polymers and osmotic agents. The use of these graft and block
co-polymers in contact lens related consumer products to impart
clinical benefits is claimed. Also claimed is the use of these
graft and block copolymers in the manufacture, coating, finishing,
and storage of contact lenses.
[0141] Formulations comprising a bi-functional co-polymer can also
be used in accordance with the present invention with a second eye
drop, such as a lipid or oil based eye drop, to enhance the
efficacy of the second eye drop. In one embodiment of this use, the
formulation described herein is administered first followed by
administration of the second eye drop.
[0142] Additionally, these formulations with the ability to prevent
or inhibit cell adhesion are useful in preventing or inhibiting the
spread of bacterial or viral infections such as bacterial
(including Chlamydial, gonorrheal, Staphylococcus epidermidis,
Streptococcus pyogenes, Streptococcus pneumonia, Neisseria
meningitidis and Moraxella lacunata, Haemophilus and family
Enterobacteriaceae, Clostridium species, gram-negative anaerobic
bacilli, and Peptostreptococcus species, N gonorrhoeae, C
trachomatis, Staphylococcal species and S pneumonia) or viral
keratitis or conjunctivitis (including herpetic keratitis and
adenovirus conjunctivitis) and in preventing and/or inhibiting
inflammation caused by adherence of inflammatory cells and proteins
to the eye surface. The invention may be useful in treating or
preventing amebic, protozoal, mycobacterial and other types of
keratitis and conjunctivitis. There may be a benefit in treating
sterile ulcers, ectasia, and corneal or scleral melts. The
anti-inflammatory effect may also be due to inciting agents being
kept off the corneal and conjunctival surface decreasing the
inflammatory reaction. Such formulations will be particularly
useful in neonatal, daycare, pediatric or family settings wherein
outbreak of one individual can lead to infection of many
others.
[0143] For the eye, the application of a formulation in accordance
with the present invention is expected to reduce the exposure of
the surface of the eye to bacterial antigens, such as those from
Staphylococcus aureus, and thus may provide an important part of
the treatment for staph marginal disease. There also may be
benefits to patients with allergic conjunctivitis including giant
papillary conjunctivitis (limiting direct tissue exposure to
antigens), and for patients who have had previous filtering surgery
with thin ischemic blebs, as therapy with a formulation in
accordance with the present invention is expected to reduce the
risk of bleb related endophthalmitis. Additionally, after a corneal
abrasion application of a formulation in accordance with the
present invention can decrease the risk of corneal ulcer
development, especially in the setting of injuries sustained from
vegetable matter which predispose a subject to fungal infections.
Other conditions that could be treated with formulations described
with this invention include conjunctivitis and keratitis due to
processes such as Moorens ulcer, Terriens marginal degeneration,
ligneous conjunctivitis, toxic exposures, autoimmune
conjunctivitis, and phlyectenular conjunctivitis. Use in patients
with keratoprostheses is claimed. The eye drops can be used in
mammals, humans, or even dogs, cats, and horses.
[0144] From experiments described herein, it is expected that
formulations of the present invention will also be useful changing
wettability and/or, steric stabilization, tribological properties,
lubricating and/or preventing adherence of unwanted proteins and
cells to other biological surfaces including, but not limited to,
skin, mucous membranes and hair. These formulations can thus also
be applied in accordance with the present invention to epithelial
tissue of the skin, urinary, or gastrointestinal tract, mucous
membrane, exposed wound surfaces, including respiratory tract
mucosa, oral and nasal mucosa, vaginal mucosa, and conjunctival
surfaces, and surgical and traumatic wounds and ulcerations. These
formulations can serve to protect skin and other organs from
foreign protein, viral, and bacterial adherence. Benefits can
include reduction in rate of infection. Without being limited to
any particular mechanism, it is believed that a formulation
comprising a graft polymer as described above, such as PLL-PEG,
adheres to the biological surface via the PLL moiety while the PEG
moiety prevents and/or reduces the adherence of potentially harmful
particles. Decreased adherence can be beneficial by decreasing
pathogen or toxin exposure, thereby decreasing morbidity and
mortality associated with these agents. For example, lower
bacterial loads can decrease the severity of subsequent bacterial
infection and/or exotoxin exposure, and allow the host defenses and
antibiotics better opportunity to work. Decreasing viral exposure
can reduce transmission rates and possibly the severity of viral
infection. These formulations are useful as well against fungals
and exposure to reactive proteins.
[0145] Accordingly, the formulations described herein have a wide
variety of uses in accordance with the present invention.
[0146] For example, these formulations can be used in accordance
with present invention in military applications to reduce soldiers'
and citizens' morbidity associated with biological or biochemical
warfare attacks.
[0147] These formulations can also be used in accordance with the
present invention to reduce rates of methicillin-resistant
Staphylococcus aureus ("MRSA") adherence in hospitalized patients,
children, and the general population. MRSA is a growing concern in
the health care setting. Reducing the adherence to the epithelial
surface thereby reducing MRSA spread and severity and frequency of
MRSA infections is expected to prove very beneficial. Such use is
expandable to school situations, prehospital admission, nursing
homes and chronic care facilities as well. It is not expected that
MSRA, or other pathogens, would develop resistance to formulations
of the invention.
[0148] These formulations can also be used in accordance with the
present invention to reduce transmission of the common cold and
influenza virus via nasal and inhalational applications in settings
including, but in no way limited to, airplanes, preschools and
schools, homes of affected viral individuals, as well as nursing
homes and chronic care facilities. The block or graft co-polymers
can be included in nasal sprays and products formulated for
inhalational delivery, as is known to those skilled in the art. For
example, a nasal spray would include the block or graft co-polymers
and benzalkonium chloride, dextrose anhydrose, edentate disodium,
microcrystalline cellulose and carboxymethylcellulose sodium,
polysorbate 80, and purified water. An aerosol inhaler would
include the block or graft co-polymers as well as ethanol and
propellant such as propellant HFA-134a
(1,1,1,2-tetrafluoroethane).
[0149] Important utilities of the formulations exist for children
and adults with infirmities, such as immunodeficiencies, chronic
disease and other chronic conditions such as cystic fibrosis, which
leave the host more susceptible to routine illness.
[0150] Application of a formulation in accordance with the present
invention to a wound just after injury or surgery, including, but
not limited to corneal abrasions, corneal surgery such as LASIK,
PRK, or other refractive or vision correction procedures, or
intraocular surgery where an incision is made in the eye through
sclera or conjunctiva/sclera, such as for cataract or glaucoma
surgery. The formulation can be used again after cleansing, can
reduce bacterial infection, and infectious wound complications.
Such formulations may be particularly useful in the field in
military medical operations, after an initial irrigation.
[0151] For these uses in humans, the formulation may be in the form
of a lotion, gel, liquid, spray, rinse, dissolvable wafer, or
glycerin bar to which water is added to solubilize the graft
co-polymer or block co-polymer to make it more amenable to
application. Formulations can be provided as individual or single
use products or in volumes for industrial use and/or multiple use
dispensers. In addition to the bi-functional co-polymer, such
formulations may comprise any and all typical binders, excipients,
and components found in cosmetic sprays, lotions, soaps, shampoos,
cleansers, and oral, nasal, vaginal, and eye care products.
[0152] Formulations of the current invention can be delivered by
eye drop bottles with a nozzle on the end (volume generally between
0.2 cc and 50 mL). The container may be single use disposable
containing a volume of approximately 0.3 mL or a multi use vial
containing a volume between 0.3 mL and 50 Ml. The material would be
high density polyethylene or similar, and the container could be up
to 500 mL for multipurpose contact lens solutions, and would have a
nozzle. The solution could be stored in contact lens containers, as
well.
[0153] By "eye care solution container" it is meant a container for
eye care solutions that is made of high density polyethylene or
similar thermoplastic or petroleum based plastics for health care
use. The eye drop bottle is made from a mold or by blow, fill and
seal methodology. The eye drop solution container has a nozzle for
releasing smaller quantities of the solution than the total volume
of the container. Eye care solution container may be single use or
multi-use. The volumes for an eye care solution container range
from 0.1 cc to 500 cc.
[0154] Formulations comprising a bi-functional co-polymer with a
positively charged or hydrophobic moiety and a hydrophilic moiety
can also be used in accordance with the present invention in the
treatment of dry mouth in subjects with, for example, but not
limited to, Sjogrens syndrome, or dry mouth during or post
chemotherapy. Such formulations may further comprise traditional
lubricants for such dry mouth conditions, such as, but not limited
to, xylitol, and glycerin MouthKote.
[0155] The ability of these formulations to lubricate mucous
membranes without irritation makes these formulations useful as
sexual lubricants as well. Reduced transmission of HIV and other
sexually transmitted diseases when a formulation is applied
prophylactically on skin and mucosal surfaces in accordance with
the present invention prior to exposure may be an additional, if
not a primary benefit in this application.
[0156] Formulations can also be used in accordance with the present
invention to protect gums in, for example, periodontal disease by
reducing inflammatory cell and bacterial cell adherence to the
gums. In this embodiment, these formulations may be incorporated
into, for example, but not limited to, a toothpaste or mouthwash
and may be combined with flavorant and/or fluoride. Formulations
which reduce bacterial adherence in the mouth, and in particular
the posterior tongue and throat, are also expected to be useful in
treating bad breath or halitosis.
[0157] Formulations can also be used in accordance with the present
invention as a preoperative shampoo to reduce bacterial adherence
to hair and/or skin before surgery. Since these formulations have
been found to be safe for administration to the eye, they provide a
useful preoperative shampoo to remove any bacteria adhering to the
eyelashes prior to eye surgery.
[0158] The ability to reduce or prevent bacterial adherence to
biological surfaces such as skin and hair is expected to make these
formulations useful in the treatment of chronic blepharitis as
well, with or without concomitant steroids or antibiotics.
Formulations described herein may be used on the eyelids and eye
lashes, for treatment of medical conditions and for prophylaxis.
For these embodiments, the formulation may be combined with an
antiseptic or an antibiotic.
[0159] Further, the ability to reduce bacterial adherence to skin
makes these formulations useful in deodorants to reduce body odor
caused by bacteria that break down sweat.
[0160] Formulations can also be used in accordance with the present
invention on animals, including household pets, to decrease
bacterial adherence to their skin, oral cavity, or coats. In this
embodiment, the formulation can be in the form of a spray, shampoo,
lotion, or beverage.
[0161] Other uses for these formulations will become evident to
those skilled in the art upon reading this disclosure and are such
uses are encompassed by the present invention.
[0162] The present invention also provides coatings comprising a
graft co-polymer with a positively charged or hydrophobic moiety
and a hydrophilic moiety or a block co-polymer with a positively
charged or hydrophobic moiety and a hydrophilic moiety for
extraocular devices such as contact lenses, glaucoma stents and
valves, scleral buckling hardware and external drug delivery
devices. External drug delivery devices can include biodegradable
devices as well as permanent products such as those made of silicon
and other non bioerodible polymers. There is a potential use for
intraocular devices including, but not limited to, intraocular
lenses, intraocular contact lenses, glaucoma stents, tubes and
valves, intracorneal implants that can be used for the correction
of presbyopia, intraocular pressure sensors (including devices for
continuous or microchip measurements with or without telemetry for
intraocular pressure and intracranial pressure monitoring), and
microchips used for retinal vision enhancement. Such coatings
improve wearability and biocompatibility of these extraocular
devices (such as contact lenses) and decrease proteinaceous,
bacterial, fungal, and particulate adhesions to these extra-ocular
devices. These coatings also improve optical performance of the
lenses. Coating intraocular and extraocular devices in accordance
with the present invention also reduces epithelial adhesion and
fibrosis thereto.
[0163] For example, contact lenses are often difficult to tolerate
due to the discomfort caused by the adhesion of proteins such as
lysozyme and denuded protein products and other particles to the
negative charges of the lens surface. Other particles adhering to
the lens surface include bacteria and bacterial proteins,
endotoxins, antibodies, calcium, and lipids. Other uncharged
particles, and even negatively charged particles can build up on
the lens surface once this cascade of protein adhesion, cellular
and/or particulate adhesions to the lens is initiated. Wearing of
contact lenses with these materials adhered to the contact lens can
lead to discomfort, allergic reactions, ocular irritation, foreign
body sensation, epithelial breakdown and dysfunction, and bacterial
keratitis.
[0164] By binding the surface of a contact lens with positively
charged and/or hydrophobic domains of block or graft co-polymers
included in topical formulations of the present invention, the
aggregation of protein deposits during wear time on the lens is and
will be reduced and contact lenses are and will be better
tolerated. The lens surface is also more lubricious, and the steric
stabilization as well as high surface water retaining capacity and
charge neutrality can impart numerous benefits in this clinical
setting. With protection provided by the polymers herein described,
the contact lenses may also be more wettable and feel more
comfortable with the concomitant use of formulations described
herein as well as other ophthalmic products. Formulations can be
provided in accordance with the present invention as eye drops to
improve contact lens wearability, as a finishing rinse after lens
manufacture, in storage solutions, in lens cleaning solutions, in
rewetting drops, as a drop to be used prior to placing the lens in
the eye, and/or as an active preservative in contact lens
preparation and storage. These formulations thus may be used in
accordance with the present invention in the form of a one time
application or repeated application. Contact lenses and intra- and
extra-ocular devices can be made more biocompatible with the
coatings of the graft and block co-polymers as described
herein.
There are well known similarities, and there exists an established
clinical relationship between dry eye syndrome and contact lens
intolerance. In studies described in examples 4 and 5 in this
invention, it has been shown clinically that the formulations and
uses of graft and block copolymers described herein conferred
meaningful and measurable benefit in dry eye subjects. These
results are highly suggestive of a significant opportunity for
clinical benefit in the contact lens use and contact lens
intolerance clinical setting. By way of interpolation, it follows
that there will be similar benefits conferred in the use of these
graft and block copolymers on other extraocular- and intra-corneal
devices. It can be foreseen that some intra-corneal or extra-ocular
devices will have prolonged biological use (for example extended
wear contact lens, and surgically implanted devices). Under
conditions of high stress (such as ionic, salts or other
electrolyte media, enzymatic, pH, or temperature) and likely
prolonged time in aqueous electrolyte media, the electrostatic or
hydrophobic interactions between the graft and block copolymers and
the intra- or extra ocular devices may be reduced to some degree.
Additionally, the tear film, sub-epithelial, or intraocular fluid
will likely not (unless a specific intervention has been undertaken
for that purpose) be a reservoir for replacement graft copolymers
as they naturally degrade over time. The benefit conferred by the
polymers to the device may, therefore, wear off over time. Thus,
there may be advantages to covalently immobilizing the block or
graft copolymers herein described to the intra or extra ocular
device during manufacturing or finishing. It follows, therefore,
that covalently bonding, embedding during manufacture, or
covalently immobilizing these graft and block co polymers to the
devices may be beneficial. It has been shown that covalent
immobilization does not necessarily result in less efficient
packing of a graft co-polymer (Blattler, et al. Langmuir 2006, 22,
5760-5769). An aldehyde plasma polymer interlayer with reductive
amination can be used in such a setting. Other methods for
covalently immobilizing the block or graft copolymers can also
accomplish the same result of developing a more stable and
resistant coating on the surface of the device.
[0165] Use of block or graft co-polymer containing formulations to
coat intracorneal devices also reduces particulate, cellular,
epithelial, and/or fibrocyte adhesion. Intracorneal inlays, may
benefit from the use of these graft and block copolymers.
Reductions in the risk of infection and clotting or blockage by
protein or fibrin debris, cellular proliferation, inflammation
suppression, and steric repulsion are all ways in which these
polymers may confer advantages to extra- or intraocular devices,
including intracranial implants.
[0166] The descriptions provided above are not to
be construed as limitations of the present invention and its
various embodiments described herein, but rather, are described to
fully allow one skilled in the art to make and use the invention
along with modifications, adaptations, and alterations, all being
within the spirit and broad scope of the present invention as fully
defined herein. Similarly, the following nonlimiting examples are
provided to further illustrate the present invention. Percentages
are weight percentages.
EXAMPLES
Example 1
[0167] The following topical formulation was made and tested:
[0168] 1% F127 [0169] 1% PLL-g-PEG [0170] 1% glycerin [0171]
sterile water for injection [0172] sodium phosphate buffer [0173]
mannitol to adjust osmolality; [0174] pH between 6.5 and 7.5 and
osmolality 274-350 mOsm/kg; [0175] Sterile filtration
[0176] This formulation was tested in the Draize test and no ocular
irritation was observed.
[0177] This formulation was also tested in two volunteer humans and
no irritation was reported. Tear film break up time in one
volunteer was extended compared to the control eye for over two
hours after instillation of the eye drops. On close inspection
under microscopy, after instillation, the tear film of the eye
treated with the PLL-g-PEG formulation displayed a more stable tear
film. This stability was present at greater than three hours after
eye drop instillation. Furthermore on analysis using a Tearscope to
evaluate the tear film, compared to an eye that received a
commercially available product, the eye treated with the PLL-g-PEG
polymer showed an increase in tear film break up time by 30 seconds
compared to control, on one occasion, at one hour after
instillation of the eye drops.
[0178] This formulation was also applied to a contact lens and
tested. One drop was placed on each side of a contact lens. The
lens was placed in a human eye and the patient wore the contact
lens comfortably for 8 hours. The treated lens was described as
being more comfortable in the eye than an untreated control lens.
This formulation was also mixed 1:1 with a commercially available
preserved multi-purpose contact lens solution and the lens was
stored in the solution overnight. The lens was worn the next day
comfortably. Again, the treated lens was more comfortable than an
untreated control lens. One embodiment of the copolymers herein
described has thus been used as an eye drop, used in combination
with other polymers, used with contact lenses, and formulated with
a preservative. The subject felt decreased awareness of the contact
lens and less resistance and discomfort when blinking.
Example 2
[0179] An in vitro assessment was made of the ability of 1%, 0.5%.
and 0.1% PLL-g-PEG formulations and 1% formulation of F127 and F87
to decrease contact angle of water on a polystyrene surface. The
contact angle of a drop of these had a much lower contact angle on
a freshly cleaned polystyrene surface compared to a drop of
deionized water. This experiment demonstrates the ability of these
formulations to change wettability and adherence to negatively
charged surfaces such as the eye and epithelium.
Example 3
[0180] An ex vivo assessment in porcine eyes was made of the
ability of a PLL-g-PEG formulation of the present invention to
decrease evaporation. Porcine eyes were obtained fresh and
refrigerated. They were stored in an oil bath, which caused changes
to the epithelial surface and also partially denuded the epithelial
surface allowing for faster evaporation of an aqueous solution. The
evaporation rates of small areas were measured and Systane was
applied with no change in evaporation rate after a single rinse. A
single rinse with the PLL-g-PEG formulation showed a reduction in
evaporation time by a mean of two seconds. Five eyes were tested.
The formulation was: 1% F127, 1% PLL-g-PEG, 1% glycerin, sterile
water for injection, sodium phosphate buffer, mannitol to adjust
osmolality.
Example 4
[0181] Two tests were performed in human eyes with a PLL-g-PEG
formulation of the present invention.
The formulation was: 1% F127, 1% PLL-g-PEG, 1% glycerin, sterile
water for injection, sodium phosphate buffer, mannitol to adjust
osmolality.
[0182] The first involved the time a human eye could be held open
before the need to blink based on discomfort. The longer an eye
could be held open without pain implies a better tear film covering
over time. In this experiment, one eye received a single eye drop
of Optive.TM. while the other eye received a single eye drop of the
PLL-g-PEG formulation eye drop. The control eye could be held open
30 seconds after instillation without discomfort repeatedly at most
time points (every 10 to 15 minutes) from t=5 minutes to t=120
minutes. The eye treated with the PLL-g-PEG formulation could be
held open without discomfort for times ranging from 40 to 60
seconds at most time points.
[0183] The tear film was also assessed by Fluorescein tear film
break up time. At t=200 minutes after instillation, there was a
longer time to TFBUT by at least 5 seconds in the PLL-g-PEG treated
eye. Additionally, the break up occurred with a much smaller area
of change on the surface of the eye. These results were confirmed
subjectively with the wavescan device looking at tear film
reflectance of light and aberrations.
Example 5
[0184] The formulation was: 1% F127, 1% PLL-g-PEG, 1% glycerin,
sterile water for injection, sodium phosphate buffer, mannitol to
adjust osmolality.
[0185] A randomized, masked, active comparator controlled study was
carried out in eighteen subjects. The study endpoints included
subjective response to the eye drops and the tear film break up
time compared to preinstillation values at t=15, 30, 60, and 120
minutes. Noninvasive tear film break up time (NIBUT) was performed
using the Tearscope.TM. in 16 subjects; fluorescein break up time
(FBUT) at 120 minutes was also measured in these sixteen subjects.
Two subjects were tested with wavescan techniques to look at tear
film break up time with that new technology. A questionnaire was
administered to subjectively assess the acceptability of the eye
drops in all subjects. The principal investigator was not
affiliated with the product and is a full professor at an academic
eye institute. The principal investigator was responsible for the
trial. IRB approval was obtained, and the trial was registered at
clinicaltrials.gov, as per FDA requirements. The comparator was a
leading over-the-counter product with the following formulation:
Active Ingredients: Polyethylene glycol 400 0.4% and propylene
glycol 0.3%. Inactive Ingredients: boric acid, calcium chloride,
hydroxypropyl guar, magnesium chloride, potassium chloride,
purified water, sodium chloride, and zinc chloride. In the
Tearscope portion with sixteen subjects, three groups were studied:
the first group of five subjects had none, occasional, or mild dry
eye symptoms. The second group of five subjects had mild to
moderate dry eye symptoms. The third group of six had moderate to
severe dry eye symptoms. RESULTS: Questionnaire: there was no
difference overall between the acceptance of the eye drops. See
Table 1.
TABLE-US-00001 TABLE 1 Preferred at 5 minutes after instillation
Sample formulation 4 Active comparator 5 No difference 7
Vision changes: No change: 100% Eyeon; No change: 87.5% (2 said
vision was blurrier after active comparator was received. Comments
at two hours if any: Equivalent for active comparator and study
formulation. Regarding slit lamp exam, there were no adverse events
in any eyes, and there were no changes in the anterior segment exam
in any eyes. NIBUT results for the entire cohort: 15 minute time
point showed NIBUT time increase from baseline at plus 14.67 sec
(p<0.05) for sample formulation, while active comparator was 7.4
seconds longer than baseline (p=0.3). Thus, the new formulation
essentially doubled the tear film break up time benefit of the
active comparator at 15 minutes. FBUT was significantly longer than
active comparator at 120 minutes; superior by 4.92 sec (p<0.12).
See FIGS. 3 and 4. The two subjects who had wavescan evaluation
showed results that supported the conclusions in the larger study,
for example, the mean TFBUT was longer for the sample formulation
than active comparator at all time points. Furthermore, a sub group
analysis was performed. In the main group of 16 subjects there was
one subject in each group that had unexpectedly long
pre-instillation TFBUT. These long initial values distorted the
relative contributions of the artificial tears to NIBUT for the
other subjects. When these three outliers were removed, there was
superiority in extending NIBUT for the sample formulation at every
time point. The data was evaluated by seconds over baseline, and by
percentage change from baseline. See FIGS. 5 and 6. Thus, this
randomized, controlled, masked trial supports use of the invention
for treatment, including prevention, of dry eye, contact lens
intolerance, ocular irritation, and other disorders of the skin and
mucous membranes.
Example 6
[0186] There is a need for compositions for treating injuries that
can be custom loaded with therapeutic agents based on the suspected
bacterial species in a wound on an external body surface (e.g., the
skin). Non-restrictive loading could potentially reduce bacterial
colonization by orders of magnitude and reduce infection rates in
compromised patients with contaminated wounds. The following
results indicate that compositions containing a copolymer having a
positively charged, or hydrophobic, or covalent bonding moiety and
a hydrophilic moiety are useful as a carrier for antibiotics. Such
compositions may be used alone, as an adjunctive therapy to wound
treatment, or to protect against pathogen or toxin attack (e.g.,
from bacterial infection).
[0187] A composition containing a copolymer having a positively
charged, or hydrophobic, or covalent bonding moiety and a
hydrophilic moiety is formed into a wound management device or
formulated in a pharmaceutical composition. The copolymer
composition is tested on a mouse model of wound healing. Mice
treated with the copolymer composition have faster and/or more
complete wound healing compared to untreated mice. Mice treated
with the copolymer composition also have fewer or less bacterial
infection compared to untreated mice.
[0188] The copolymer composition is loaded with the antibiotic
amikacin. Amikacin release from the copolymer composition is
measured. The open wounds of the mice may be passively or actively
infected with bacteria. Bacterial growth inhibition of P.
aeruginosa is observed for wounds treated with the copolymer
composition. Treatment of wounds with a copolymer composition with
antibiotics results in inhibition of bacterial growth and progress
in wound healing compared to mice treated with the copolymer
composition alone or with no treatment.
[0189] The ability to customize the antibiotic choice is
advantageous because it allows clinicians to tailor treatment
regimens based on known or suspected bacterial species present.
Copolymer compositions of the invention allow for high release
concentrations of antibiotics. These experiments indicate that
incorporation of antibiotics into a copolymer composition provides
a local drug delivery system that can be used alone or in
conjunction with wound treatment therapies.
Example 7
[0190] There is a need for nanoparticle compositions for treating
nasal and inhalational conditions that can be custom loaded with
active or therapeutic agents based on the treatment required.
Nanoparticles coated with a copolymer having a positively charged,
or hydrophobic, or covalent bonding moiety and a hydrophilic moiety
can be used to deliver active or therapeutic agents for
inhalational applications. For inhalation, the nanoparticle size
should be 10 microns or smaller in diameter, about 1 micron or less
in diameter. The copolymer coated nanoparticles are formulated with
a pharmaceutically acceptable carrier. The copolymer coated
nanoparticles can be used in a pharmaceutical composition that is
administered to the oral, nasal, or respiratory surfaces (e.g., in
the throat) using an aerosol or nasal formulation (e.g., a spray).
The copolymer coated nanoparticles contain active or therapeutic
agents, including drugs (e.g., an antibiotic), menthol, or other
numbing compound for treatment of coughs or sore throats. The
copolymer coated nanoparticles deliver the active and therapeutic
agents when contacted to oral, nasal, or respiratory surfaces
(e.g., mucous membranes). Thus, the copolymer coated nanoparticles
are used to deliver active and therapeutic agents.
Example 8
[0191] There is a need for an eye drop that helps the eye retain
heat. An investigation was carried out into the effect of the
multi-functional graft polymer with a positively charged backbone
and hydrophilic side chains on the body's surface temperature at
the cornea. The finding that topical formulations of this the
multi-functional graft polymer increase the ocular surface
temperature forms the basis of the instantly disclosed new method
for treating human eye conditions. Furthermore, the results of the
assays described in this example were demonstrative directly on the
effect on temperature, not indirectly by timing evaporation on an
isolated surface. The in vivo dynamics are complex due to multiple
variables including ocular blood flow, variabilities in air flow on
a biological surface, and natural tear secretion. Thus, it was
decided to independently measure temperature using thermal imaging
of the surface of the eye to determine if the tear could also
affect the surface temperature of the eye. The stabilization of the
tear film using traditional methodology such as fluorescein tear
break up time has been demonstrated above. It had never been shown
that the formulations tested previously could have any measurable
effect on temperature. Toward that end a proof-of-principal study
was undertaken, as described below.
Purpose:
[0192] To demonstrate if the test drop(s) has any effect on thermal
imaging of the cornea by an infrared camera with concurrent
assessment of the tear film using placido disc imaging.
Methodology:
[0193] One eye (left or OS) was measured at baseline placido disc
and thermal camera. Then in that eye, a formulation of 1%
PLL-g-PEG, 1% glycerin, 1% F127, sterile water for injection,
sodium phosphate buffer, mannitol to adjust osmolality was
instilled. That eye was imaged (OS) with the placido disc and
thermal camera. Four different time points were studied--baseline
(before drop instillation), 5 min, 15 min and 30 min after drop
instillation. The airflow and environment was controlled and was
the same for all measurements. The eye was examined prior to eye
drop instillation and at the time points indicated. The placido
images were studied subjectively to assess tear break up time
(TBUT). Thermal images were also analyzed using custom MATLAB
(matrix laboratory) software to compare average ocular surface
temperature in the central 9 mm corneal region.
Results:
TABLE-US-00002 [0194] TABLE 2 Thermal Imaging Placido (Avg temp
.+-. SD).degree. C. Baseline TBU at 8 secs 33.97 .+-. 0.23 5 min
TBU at 20 secs 34.4 .+-. 0.04 15 min No TBU seen until 35 secs,
nice 35.04 .+-. 0.11 placido pattern, relatively easier to hold eye
open 30 min No TBU until 38 secs, nice placido 35.05 .+-. 0.08
pattern, no distortions noticed, relatively easier to hold eye
open
Major Points--
[0195] The tear break up time by non invasive placido imaging
increased "significantly" from baseline to 5 mins. (significant
tear film break up time can be considered greater than 25% increase
in this example). [0196] The break up time from the 5 minute time
point to the 15 minute and 30 minute time points increased
substantially. [0197] The ocular surface temperature at baseline
was 33.97.+-.0.23.degree. C. OST increased from baseline to 5 mins,
and a marked increase is noticed from baseline to 15 mins and 30
mins, by more than 1.degree. C. For this example, significant
temperature increase is 0.34 degrees Celsius (1% increase).
Conclusions:
[0198] The test drop has a positive effect in increasing the ocular
surface temperature. The test drop also increased the stability of
the tear film as demonstrated by the increased tear break up time.
The eye tolerated the test drop well with no symptoms or
hyperemia.
Example 9
[0199] Example in contact lens/multi-functional polymer surface
temperature effects. Based on the results obtained in Example 8,
above, it can be shown that the use of a contact lens manufactured
with or soaked in PLL-g-PEG or alternative (multifunctional graft
copolymers) stabilizes or increase ocular surface temperature. For
the experiment, the polymer is delivered via an eye drop, as a
rewetting drop following the placement of a contact lens. In this
example, the contact lens is placed and after the eye equilibrates
for greater than 5 minutes the ocular surface temperature is
measured on bulbar conjunctiva and on the contact lens external
surface. The graft co-polymer is instilled. The surface temperature
at either the bulbar conjunctive or the exposed surface of the
contact lens is higher following instillation of the graft
co-polymer with the lens in the eye as compared to the
pre-instillation lens in the eye temperature measurements.
Example 10
[0200] Formulations without pluronics or active demulcents. To
further clarify the value of the graft-copolymer effect alone, and
as supportive evidence that the benefits conferred from topical
formulations with the multi-functional polymer do not require other
additives, the stability of the tear film was assessed in a subject
using a composition that included PLL-g-PEG in solution with
neither a demulcent nor a PLURONIC. The composition was: 1%
PLL-g-PEG, sterile water for injection, sodium phosphate buffer,
sodium chloride, and mannitol to adjust osmolality. An expert
examiner objectively evaluated the stability of the tear film using
fluorescein tear film break up time (FTBUT). The left eye of a
subject, directly before instillation of the test eye drop, showed
a nine second FTBUT. Several minutes were allowed to pass so the
fluorescein washed out of the eye. At that point, a single drop (50
microliters) of the topical of ophthalmic solution containing 1%
PLL-g-PEG but without the demulcent or PLURONIC was instilled in
the left eye. Exactly 15 minutes later the FTBUT was measured, and
it was 16 seconds. Clinical success of prolongation of tear
stability was demonstrated.
TABLE-US-00003 TABLE 3 Clinical evaluation of FTBUT with topical
ophthalmic formulation of 1% PLL-g-PEG without a demulcent or
PLURONIC: Pre-instillation baseline Post-instillation FTBUT at 15
FTBUT minutes Increase 9 seconds 16 seconds 78%
Thus, the multi-functional graft copolymer is responsible for the
benefits obtained from contacting the surface of the eye with
solutions that contain other additives, actives, or excipients.
Example 11
[0201] Utilizing the multi-functional graft co-polymer with other
actives in ophthalmology. PLL-g-PEG was added to a commercial
ophthalmic solution known as Combigan.RTM.. The amount of liquid in
a single multi-use eye drop bottle of Combigan.RTM. containing the
active ingredients of brimonidine tartrate 0.2% and timolol 0.5%
was poured out into a sterile vessel and weighed. Using a
calculation to create a 2% weight/weight solution with PLL-g-PEG
polymer, the proper amount of 99% pure PLL-g-PEG was dissolved into
the solution. The new formulation was sterile filtered and returned
into the internally sterile eye drop bottle. The new formulation
created was thus a combination glaucoma product with the addition
of the graft copolymer PLL-g-PEG. Tear break up time of the
PLL-g-PEG formulation was compared with an unchanged brand new
Combigan eye drop: Combigan.RTM. with PLL-gPEG 2% vs. Combigan.RTM.
alone.
TABLE-US-00004 TABLE 4 OD OS Tear film break up time Fluorescein,
no anesthetic Baseline measure 1 9.3 13.6 measure 2 13 12.3 measure
3 12.5 14 average 11.6 13.3 eye drop instillation OD received
Combigan .RTM. with 2% PLL-g-PEG; OS standard Combigan .RTM. 25-30
minutes post instillation, masked observer measure 1 29.94 12.1
measure 2 26.44 9.58 measure 3 29.91 23.11 average 28.76333 14.93
prolongation of tear film break up time OD 17.16333 sec OS 1.63 sec
IOP at 2 hours post instillation OD 8 mmHg OS 8 mmHg Notes per
examining MD: "The tear film OD looked more stable, more uniform,
and the rate of tear break-up, once begun, was less complete and of
smaller diameter."
This experiment thus demonstrated and confirmed several key
results. First, this study re-affirmed that the effect on tear
stability is from the addition of the graft co-polymer only.
Second, the addition of this polymer did not affect the activity of
the drug product actives on reducing the intraocular pressure in
the subject. Third, the simplicity of formulation with the polymer
was demonstrated. Another aspect of this experiment was the use of
the corneal topographer to assess longstanding effect of the
polymer. Eighty minutes after eye drop installation in both eyes,
the Placido % read parameter which was reported out by the
machine's algorithm when the eyes were held open for 30 seconds was
97.50% OD and 87.30% OS. When the eyes were held open for 60
seconds values were 97.80% read OD and 93.20% OS. Thus, the corneal
topographer can be used to show the beneficial effect on the
corneal surface quality imparted by this PLL-g-PEG formulation, and
be inference a multi-functional graft co-polymer with a positively
charged backbone and hydrophilic side chains.
Example 12
[0202] Eyelid margin inflammation is treated with a multifunctional
graft copolymer. The eyelid margin temperature is 34 degrees
Celsius before treatment. After application of an eye drop with a
multifunctional graft copolymer, the eyelid margin temperature
increases to 35 degrees Celsius. After daily treatment for one
week, the eyelid margin inflammation is reduced.
Example 13
[0203] A patient had a non-healing leg ulcer from poor peripheral
perfusion. The temperature on the surface of the ulcer is 34
degrees Celsius. The ulcer is treated topically with a formulation
containing a multifunctional graft copolymer. Post application, the
ulcers temperature increases to 34.5 degrees Celsius. Over several
weeks with daily application, significant improvement has occurred.
This change in temperature helps heal the ulcer faster as more
blood flow and a lower risk of infection lead to better
outcomes.
* * * * *