U.S. patent application number 12/915823 was filed with the patent office on 2011-05-05 for methods and compositions for sustained delivery of drugs.
This patent application is currently assigned to INTRATUS, INC.. Invention is credited to T. Aaron DYER, Padma NANDURI.
Application Number | 20110104206 12/915823 |
Document ID | / |
Family ID | 43923004 |
Filed Date | 2011-05-05 |
United States Patent
Application |
20110104206 |
Kind Code |
A1 |
NANDURI; Padma ; et
al. |
May 5, 2011 |
METHODS AND COMPOSITIONS FOR SUSTAINED DELIVERY OF DRUGS
Abstract
The present disclosure relates to methods and compositions for
the topical sustained delivery of therapeutic agents. Topical
application of compositions containing a muscle fasciculating agent
result in the sustained release of any therapeutic agent contained
within the composition. More particularly, topical application of
such compositions to the outer surface of the eyelid of a patient
results in increased absorption and sustained release of the
therapeutic agent into the eyes or systemically.
Inventors: |
NANDURI; Padma; (La Jolla,
CA) ; DYER; T. Aaron; (La Jolla, CA) |
Assignee: |
INTRATUS, INC.
|
Family ID: |
43923004 |
Appl. No.: |
12/915823 |
Filed: |
October 29, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61256614 |
Oct 30, 2009 |
|
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61289471 |
Dec 23, 2009 |
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Current U.S.
Class: |
424/239.1 ;
424/774; 514/263.34; 514/263.36; 514/530; 514/6.5 |
Current CPC
Class: |
A61P 25/34 20180101;
A61P 27/02 20180101; A61P 29/00 20180101; A61P 31/00 20180101; A61K
31/522 20130101; A61P 9/12 20180101; A61P 5/00 20180101; A61P 31/10
20180101; A61K 9/0014 20130101; A61K 31/519 20130101; A61K 8/4953
20130101; A61P 9/00 20180101; A61P 27/00 20180101; A61K 9/0019
20130101; A61K 9/06 20130101; A61Q 1/10 20130101; A61P 25/00
20180101; A61K 31/52 20130101; A61K 38/28 20130101; A61K 47/38
20130101; A61P 13/12 20180101; A61K 9/0048 20130101; A61P 21/00
20180101; A61P 3/10 20180101; A61P 35/04 20180101 |
Class at
Publication: |
424/239.1 ;
514/263.34; 514/263.36; 514/6.5; 424/774; 514/530 |
International
Class: |
A61K 31/522 20060101
A61K031/522; A61K 38/28 20060101 A61K038/28; A61K 36/185 20060101
A61K036/185; A61K 31/215 20060101 A61K031/215; A61K 39/08 20060101
A61K039/08; A61P 27/02 20060101 A61P027/02; A61P 3/10 20060101
A61P003/10; A61P 13/12 20060101 A61P013/12; A61P 9/12 20060101
A61P009/12; A61P 9/00 20060101 A61P009/00; A61P 25/34 20060101
A61P025/34; A61P 5/00 20060101 A61P005/00; A61P 35/04 20060101
A61P035/04 |
Claims
1. A method for sustained systemic delivery of a therapeutically
effective amount of a therapeutic agent or combination of
therapeutic agents in a human patient comprising topically applying
a composition comprising said therapeutic agent or combination of
therapeutic agents and a muscle fasciculating agent and optionally,
an ionotropic agent to the outer surface of at least one upper
eyelid or to at least one eye such that the composition contacts
the underside of the skin of at least one eyelid of the
patient.
2. The method of claim 1 wherein the muscle fasciculating agent is
selected from the group consisting of caffeine, theophylline,
pentoxifyline and theobromide.
3. The method of claim 1 wherein the muscle fasciculating agent is
caffeine.
4. The method of claim 1 wherein the composition is topically
applied to the outer portion of at least one eyelid of the
patient.
5. The method of claim 1 wherein the muscle fasciculating agent is
present in an amount of from about 1 wt % to about 50 wt % of the
composition.
6. The method of claim 1 further comprising the step of
administering the composition to at least one lower eyelid of the
patient.
7. The method of claim 1 wherein the patient suffers from a
pathologic condition selected from diabetes, systemic infection,
kidney disease, hypertension, heart disease, nicotine withdrawal,
or a hormone deficiency.
8. The method of claim 1 wherein the therapeutic agent is a
hypertensive medication.
9. The method of claim 1 wherein the therapeutic agent is insulin
or recombinant insulin.
10. The method of claim 1 wherein the composition comprises an
ionotropic agent.
11. The method of claim 10 wherein the ionotropic agent is
digitalis.
12. The method of claim 7 wherein the pathologic condition is
glaucoma and the therapeutic agent is latanoprost.
13. A method for treating an ophthalmic condition in a human
patient comprising topically administering a first composition to
the outer surface of at least one upper eyelid of the patient, said
first composition comprising a therapeutically effective amount of
at least one therapeutic agent effective for treatment of the
ophthalmic condition, wherein said therapeutic agent is not
olopatadine, muscarinic receptor agonist or epinastine and wherein
said first composition does not comprise a permeability
enhancer.
14. The method of claim 13 wherein the composition is applied to
one upper eyelid of the patient.
15. The method of claim 13 wherein the therapeutic agent is a
vasoconstrictor.
16. The method of claim 15 wherein the vasoconstrictor is applied
to the perimeter of at least one eyelid of the patient.
17. The method of claim 13 further comprising applying a second
composition comprising a second therapeutic agent effective for
treating the ophthalmic condition to the outer surface of at least
one eyelid of the patient.
18. The method of claim 15 wherein the first composition further
comprises up to 50 wt % of a muscle fasciculating agent.
19. The method of claim 17 wherein the second composition comprises
up to 50 wt % of a muscle fasciculating agent.
20. The method of claim 17 wherein the first and second
compositions are applied to the outer surface of different
eyelids.
21. The method of claim 13 wherein a vasodilator is the sole active
therapeutic agent.
22. The method of claim 20 wherein the first composition comprises
a muscle fasciculating agent.
23. The method of claim 13, wherein the first composition further
comprises a muscle fasciculating agent.
24. The method of claim 17 wherein the first composition comprises
a vasoconstrictor and the second composition comprises a
vasoldilator.
25. The method of claim 24 wherein the first or second composition
or both further comprises a muscle fasciculating agent and/or
penetrating agent.
26. The method of claim 17 wherein the first or second composition
or both further comprises a muscle fasciculating agent.
27. A topical ophthalmic composition comprising a therapeutically
effective amount of at least one therapeutic agent for treating an
ophthalmic condition, from about 0.001 to 50 wt % of a muscle
fasciculating agent and optionally, a penetrating agent and/or a
hydrating agent and/or an ionotropic agent, wherein application of
the composition to the outer surface of an upper or lower eyelid or
to the underside of the eyelid skin of a human suffering from said
ophthalmic condition provides sustained release of the therapeutic
agent to the eye.
28. The composition of claim 27 wherein the muscle fasciculating
agent is selected from the group consisting of caffeine,
theophylline, pentoxifyline and theobromide.
29. The composition of claim 27 wherein the muscle fasciculating
agent is caffeine.
30. The composition of claim 27 wherein said composition is
formulated as a cream, gel, lotion, spray, foam, film, tape,
ointment, plaster, eyelidstick or adhesive for application to the
upper and/or lower eyelid of a human patient.
31. The composition of claim 27, wherein said composition is
formulated as an eyedrop for application to the eye.
32. The composition of claim 27 wherein the ophthalmic condition is
selected from the group consisting of blepharitis, floppy eyelid
syndrome, trachomatous dry eye, retinopathy, retinal degeneration,
nasolacrimal duct obstruction, epiphora, chalazion, hordeolum,
allergic conjunctivitis and keratitis, infectious conjunctivitis
and keratitis, pterygium, pinguiculum, iritis, uveitis, keratitis,
vitritis, vitreous floaters, vitreous detachment, vitreous
hemorrhage, retinal detachment, sub retinal hemorrhage, choridal
neovascular membrane, retinal edema, macular edema, diabetic
retinopathy, choridal malignancy, orbital malignancy, eyelid
tumors, optic neuritis, optic neuropathy, strabismus, refractive
error and glaucoma.
33. A therapeutic composition for topical sustained systemic
delivery of at least one therapeutic agent, said composition
comprising a therapeutically effective dosage amount of said at
least one therapeutic agent and from about 0.001 to 50 wt % of a
muscle fasciculating agent and optionally from about 0.001 to 50 wt
% of an ionotropic agent, wherein application of the therapeutic
composition to an upper or lower eyelid or to the underside of the
eyelid skin of a patient provides sustained systemic release of the
therapeutic agent.
34. The composition of claim 33 wherein said composition is
formulated to treat a condition selected from diabetes, systemic
infection, kidney disease, hypertension, heart disease, nicotine
withdrawal, or a hormone deficiency
35. The composition of claim 33 wherein the muscle fasciculating
agent is selected from the group consisting of caffeine,
theophylline, pentoxifyline and theobromide.
36. The composition of claim 33 wherein the muscle fasciculating
agent is caffeine.
37. The composition of claim 33 wherein the therapeutic agent is
insulin or a recombinant insulin.
38. A method of treating dry eye in a human patient comprising
applying to the outer surface of at least one upper and/or lower
eyelid of the patient a composition comprising cyclosporine and
from about 0.001% to 1 wt % caffeine.
39. A method of treating glaucoma in a human patient comprising
applying to the outer surface of at least one upper and/or lower
eyelid of the patient a composition comprising about 0.005 wt %
latanoprost and from about 0.001 to 1 wt % caffeine.
40. A method for the sustained systemic delivery of a therapeutic
agent into a patient comprising topically applying to an epidermal
area of said patient a composition comprising from about 0.001 to
50 wt % of a muscle fasciculating agent, a therapeutically
effective amount of the therapeutic agent and optionally, from
about 0.001 to 50 wt % of an ionotropic agent.
41. The method of claim 40 wherein the muscle fasciculating agent
is caffeine.
42. The method of claim 41 wherein the therapeutic agent is
botox.
43. A method of treating cataracts in a patient comprising
topically applying to the outer surface of at least one eyelid of
the patient a composition comprising from about 0.001 to 50 wt %
caffeine.
44. The method of claim 43 wherein the composition further
comprises from about 0.001 to 50 wt % of an ionotropic agent.
45. The method of claim 43 wherein the composition comprises 500 mg
caffeine.
46. The method of claim 43 wherein the composition is applied to
the at least one eyelid once daily.
47. A method of reducing oxidative stress in the eyes of a human
patient comprising topically applying to the outer surface of at
least one eyelid of the patient a composition comprising from about
0.001 to 50 wt % caffeine.
Description
CROSS-REFERENCE OF RELATED APPLICATION
[0001] This application claims priority to provisional application,
U.S. Application No. 61/256,614, filed Oct. 30, 2009 and U.S.
Application Ser. No. 61/289,471, filed Dec. 23, 2009, both of which
are incorporated herein by reference thereto.
TECHNICAL FIELD
[0002] The present invention relates generally to methods and
compositions for the controlled topical delivery of drugs. More
specifically, the present invention relates to methods and
compositions for delivery of one or more drugs to the eye, a
specified area of the eye or systemically to a remote target by
topical application to at least one upper eyelid and optionally at
least one lower eyelid. More specifically, these methods comprise
applying a preparation containing the desired drug or combination
of drugs to the surface of at least one upper eyelid and optionally
at least one lower eyelid, thereby causing transfer of the drug or
drugs from the eyelid into the eye or systemic circulation via the
vascular network within the eyelid.
BACKGROUND OF THE INVENTION
[0003] The treatment of human illness may be accomplished by
administering drugs to the human body via various routes, e.g.,
oral, sublingual, rectal, parenteral, topical, inhalation, etc. The
main advantage of topical delivery of drugs is convenience, with
the added benefits that this delivery route avoids bypass
metabolism, the risks and inconveniences of intravenous therapy and
varied absorption rates and/or gastric emptying times. Topical
delivery is generally defined as the application of a
drug-containing formulation to the skin to directly treat cutaneous
disorders, e.g., acne or the cutaneous manifestations of a general
disease, e.g., psoriasis with the intent of containing the
pharmacological or other effect of the drug to the surface of the
skin or within the skin. Semi-solid formulations in all their
diversity dominate the system for topical delivery, but foams,
spray, medicated powders, solution, and even medicated adhesive
systems are in use.
[0004] Topical delivery includes two basic types of product: (1)
external topicals that are spread, sprayed, or otherwise dispersed
on to cutaneous tissues to cover the affected area and (2) internal
topicals that are applied to the mucous membrane orally, vaginally
or on anorectal tissues for local activity. For the most part
topical preparations are used for the localized effects at the site
of their application by virtue of passive drug penetration into the
underlying layers of skin or mucous membranes. Although some
unintended drug absorption may occur, it is in sub-therapeutic
quantities and generally of minor concern.
[0005] Under certain circumstances systemic delivery of drugs via
topical application of drug-containing compositions to the skin is
desirable. However, permeation across the skin first involves
partitioning of the drug into the stratum corneum, a layer of the
epidermis that is highly impermeable, particularly to hydrophilic
molecules like peptides and proteins. For example, small peptides
such as thyrotropin-releasing hormone (362 daltons) and vasopressin
(356-358 daltons) are known to have difficulty in penetrating the
skin barrier. Most substances are believed to diffuse across the
stratum corneum via an intercellular lipoidal route, which is a
tortuous pathway of limited frictional volume and even more limited
productive fractional area in the plane of diffusion. Once through
the stratum corneum, topically applied drugs must pass through the
dermal region through a system of interlocking channels, through
which diffusion is facile and without selectivity. Thus,
transdermal systemic delivery of drugs is limited by the poor
permeability of some drugs through the skin and limitations of size
of drugs that can diffuse through the skin barrier, i.e., less than
500 Daltons. Moreover, because only limited amounts of drugs
actually penetrate the skin layers even when penetration enhancers
are applied, this route of administration can only be used for
drugs that require very small plasma concentration to be effective.
For example, the largest daily dose of drug in transdermal patch
form is that of nicotine, at a dose of only twenty-one
milligrams.
[0006] Topical administration of drugs to the eye for local
delivery has been used successfully for years, e.g., eye drops for
application directly to the eye or percutaneously absorptive
compositions for passive diffusion across the skin or upper and/or
lower eyelid, however, topical drug delivery for treatment of the
posterior segments of the eye poses several problems. The posterior
segments of the eye are exquisitely protected from the external
environment, which poses unique and fairly challenging hurdles for
drug delivery. In particular, the conjunctiva is a unique barrier
within the eye with tight cell junctions which inhibit the passage
of hydrophilic molecules. Even lipophilic molecules applied to the
eye, for example in the form of eye drops, wash over the
conjunctiva quickly, resulting in a true contact time of about
ninety seconds or less, which is not enough time to permit large
quantities to pass through the conjunctiva. It is somewhat dogmatic
that topical ocular delivery is insufficient to achieve therapeutic
drug levels in the posterior segments.
[0007] Topical delivery of drugs to the upper eyelid for local
delivery to the anterior segments of the eye has been accomplished
through inclusion of an amount of a vasoconstrictor in the
topically applied composition or through application of the drug
near or along the lash line, effectively applying the drug to the
surface of the eyeball over time through blinking action. Inclusion
of a vasoconstrictor in certain ophthalmic compositions,
particularly those intended to treat glaucoma, for example, has
significant drawbacks since the vasoconstrictor restricts blood
flow in the immediate area of the eye as well as within the eye,
thereby exacerbating the underlying condition.
[0008] Thus, there exists a need for methods and compositions for
topical administration of drugs for local delivery, such as to the
eye and particularly the posterior segments of the eye, as well as
for systemic delivery.
SUMMARY OF THE INVENTION
[0009] In one aspect of the invention there is provided a method
for topical administration of a drug or combination of drugs for
systemic delivery thereof to a human patient comprising applying to
at least one eyelid of a patient a composition comprising the drug
or combination. In certain embodiments of this aspect of the
invention the composition further comprises an effective amount of
a muscle fasciculation agent, and optionally further comprises an
effective amount of a permeability enhancer. In certain embodiments
of this aspect of the invention, the muscle fasciculation agent is
caffeine, theophylline, pentoxifyline or theobromide, which may be
included in the topical composition in an amount of up to about 1%
and in certain embodiments may be included in an amount of up to
about 30 wt % or in certain other embodiments, up to about 50 wt %
of the composition. In some embodiments the composition may further
comprise in addition to a muscle fasciculating agent, from about
0.001 to 50 wt % of an ionotropic agent, such as digitalis.
[0010] In another aspect of the invention there is provided a
method for topical delivery of a drug or combination of drugs to
the eyeball, eyelid, anterior segments of the eye or posterior
segments of the eye comprising applying to at least one eyelid of a
human patient a composition comprising the drug or combination of
drugs. In certain embodiments of this aspect of the invention the
composition comprises an effective amount of a muscle fasciculation
agent, and may further comprise an effective amount of a
permeability enhancer, vasoconstrictor or a vasodilator or both. In
certain embodiments, the drug or combination of drugs is a drug
used for ophthalmic treatment, a systemic drug, a nutrient, hormone
or other biological agent and in other embodiments each drug in the
composition is 6000 Daltons or less. In other embodiments of this
aspect of the invention, the muscle fasciculation agent is
caffeine, theophylline, pentoxifyline or theobromide, which may be
included in the topical composition in an amount of up to about 1%
or in certain embodiments up to about 50 wt %. In addition to a
muscle fasciculating agent, the compositions may include from 0.001
to 50 wt % of an ionotropic agent, such as digitalis.
[0011] In certain embodiments of this aspect of the invention, two
different drugs are administered by application of a first drug to
one eyelid and application of a second drug to the other eyelid. In
other embodiments of the invention, uptake of the composition
through the eyelid is manipulated by the applications of the
compositions to different areas of the eyelid, e.g., application of
a composition containing the active drug or combination of drugs to
the middle portion of the eyelid, followed or preceded by
application of a composition comprising a vasoconstrictor agent to
the border of the eyelid.
[0012] In another aspect of the invention there is provided a
method of treating glaucoma comprising topically applying a
composition comprising a therapeutically effective amount of a
.beta.-antagonist, .alpha.-antagonist, prostaglandin analog,
alpha-adrenergic agonist, carbonic anhydrase inhibitor,
anti-cholinergic agent, vasodilator, or neuroprotective agent a
combination thereof to one or both upper and optionally, lower,
eyelids of a patient. In certain embodiments, the composition
further comprises an amount of a muscle fasciculation agent, such
as caffeine, theophylline, pentoxifyline or theobromide effective
to facilitate delivery of the drug to the posterior segment of the
eye, and optionally an effective amount of a permeability enhancer.
In some embodiments the composition may further comprise in
addition to a muscle fasciculating agent, from about 0.001 to 50 wt
% of an ionotropic agent, such as digitalis.
[0013] In another aspect of the invention there is provided a
method of treating dry eye comprising topically applying a
composition comprising a therapeutically effective amount of a
parasympathomimetic cholinergic agent (e.g., Pilocarpine,
Cevimeline, Carbachol), anticholinesterase (e.g., Echothiophate
Iodidide, Isofluorophate, Demecarium Bromide, Physostigmine,
Neostigmine, Pyridostigmine, Edrophonium), androgen, estrogen,
B-agonist (e.g., isoproternol), alpha-agonist (e.g.,
phenylepherine, ephedrine, and the like (alone or in combination)
and from 0.001% to 50 wt % of a muscle fasciculating agent to one
or both upper and optionally lower eyelids of a human patient. In
certain embodiments, the muscle fasciculation agent is caffeine,
theophylline, pentoxifyline or theobromide effective and in another
embodiment, the composition further comprises an effective amount
of a permeability enhancer. In some embodiments the composition may
further comprise in addition to a muscle fasciculating agent, from
about 0.001 to 50 wt % of an ionotropic agent, such as
digitalis.
[0014] In other aspects of the invention, the present method and
composition comprising the appropriate drug(s) or therapeutic
agent(s) in therapeutically effective amount(s) and a
therapeutically effective amount of a micro fasciculating agent is
applied for the treatment of an eye disease or condition such as
blepharitis, floppy eyelid syndrome, trachomatous dry eye,
retinopathy, retinal degeneration, nasolacrimal duct obstruction,
epiphora, chalazion, hordeolum, allergic conjunctivitis and
keratitis, keratopathy, corneal degeneration, cataract, infectious
conjunctivitis and keratitis, pterygium, pinguiculum, iritis,
uveitis, keratitis, vitritis, vitreous floaters, vitreous
detachment, vitreous hemorrhage, retinal detachment, sub retinal
hemorrhage, choridal neovascular membrane, retinal edema, macular
edema, diabetic retinopathy, retinal hemorrhage, choridal
malignancy, orbital malignancy, eyelid tumors, optic neuritis,
optic neuropathy, strabismus, refractive error, glaucoma and the
like, lacrimal gland disorders, aging-related ophthalmic
conditions.
[0015] In yet another aspect of the invention, the present method
and compositions comprising an appropriate drug or therapeutic
agent or combinations of drugs or therapeutic agents is applied to
one or more eyelids to achieve a therapeutically sustainable
systemic concentration of therapeutic agent/drug/combination to
treat a condition or disease remotely removed from the site of
application, e.g., diabetes, systemic infection, kidney disease,
hypertension, heart disease, nicotine withdrawal, or for
administration of hormone replacement therapy.
[0016] In another aspect of the invention, a method of treating an
ophthalmic condition is provided in which a composition comprising
therapeutically effective amount of one or more active agents for
the treatment of the ophthalmic condition and a therapeutically
effective amount of a vasodilator and optionally a therapeutically
effective amount of a muscle (or micro) fasciculatinging agent is
topically applied to one or more eyelids of a patient in need
thereof. In certain embodiments of this aspect of the invention the
vasodilator is a phosphodiesterase inhibitor. In some embodiments
the composition may further comprise in addition to a muscle
fasciculating agent, from about 0.001 to 50 wt % of an ionotropic
agent, such as digitalis.
[0017] In another aspect of the invention there is provided a
method and composition for treating cataracts and/or maintaining
the health of the idea. The methods and compositions of this aspect
of the invention comprise topically applying to the outer surface
of at least one eyelid of a human patient an ophthalmic composition
comprising from about 0.001 to 50 wt % caffeine as the sole active
agent. In certain embodiments, the composition is applied to at
least one eye one time per day. In certain embodiments, the
composition comprises from 10 to 500 mg caffeine. In other
embodiments of this aspect of the invention, the composition
further comprises from about 0.001 to 50 wt % of an ionotropic
agent.
[0018] In another aspect of the invention there is provided a kit
for percutaneous eyelid administration of one or more therapeutic
agents comprising an applicator and a topical composition or
compositions comprising one or more therapeutic agents. In certain
embodiments of this aspect of the invention the applicator is a
patch containing a composition of the invention on the surface to
be applied to the eyelid; a rollerball applicator integrally
connected to a container in which the composition is contained; an
applicator strip comprising a composition of the invention on the
surface to be applied to the eyelid; a pliable finger cot
containing a composition of the invention as a blister positioned
on the tip thereof; or an applicator for dipping into a solution of
a composition of the invention or an eye stick (structurally
similar to lipstick, but for application to the outer surface of
the upper/lower eyelid).
[0019] In another aspect of the invention there is provided a
method and compositions for topical transdermal drug delivery
comprising administering to the outer surface of the epidermis of
an individual a composition comprising the drug and a muscle
fasciculating agent. In certain embodiments the composition further
comprises a permeability enhancer. In certain embodiments of this
aspect of the invention, the muscle fasciculating agent is
caffeine, theophylline, pentoxifyline or theobromide, which may be
included in the topical composition in an amount of up to about 1%
and in certain embodiments may be included in an amount of up to
about 30 wt % or in certain embodiments, up to about 50 wt % of the
composition. In some embodiments the composition may further
comprise in addition to a muscle fasciculating agent, from about
0.001 to 50 wt % of an ionotropic agent, such as digitalis. In
certain embodiments of this aspect of the invention the drug is
fewer than 6000 Daltons in size and in other embodiments the drug
is greater than 6000 Daltons in size.
[0020] In another aspect of the invention there are provided
compositions and methods for enhancing the uptake and providing
sustained release of a therapeutic agent comprising topically
administering to at least one eye of a patient a composition
comprising the therapeutic agent and a muscle fasciculating agent,
wherein the composition contacts the underside of the eyelid of the
at least one eye. In certain embodiments the composition further
comprises a permeability enhancer. In certain embodiments of this
aspect of the invention, the muscle fasciculating agent is
caffeine, theophylline, pentoxifyline or theobromide, which may be
included in the topical composition in an amount of up to about 1%
and in certain embodiments may be included in an amount of up to
about 30 wt % or in certain embodiments, up to about 50 wt % of the
composition. In some embodiments the composition may further
comprise in addition to a muscle fasciculating agent, from about
0.001 to 50 wt % of an ionotropic agent, such as digitalis.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] FIG. 1 is a front view of the left eye, showing (1) the
infratrochlear nerve; (2) ophthalmic (orbital) artery; (3)
nasocilliary nerve; (4) trochlea; (5) tendon of superior oblique
muscle; 96) supratrochlear nerve; (7) superior orbital vein; (8)
supraorbital artery, vein and nerve; (9) levator aponeurosis; (10)
peripheral and marginal arterial arcades of upper lid; (11)
lacrimal artier and nerve terminal branches; (12) orbital lobe of
lacrimal gland; (13) palpebral lobe of lacrimal gland; (14)
zygomaticotemporal nerve; (15) anterior branch of temporal artery;
(16) zygomaticofacial artery and nerve; (17) malar branch of
transverse facial artery; (18) peripheral and marginal arterial
arcades of lower lid; (19) infraorbital artery and nerve; (20)
facial artery and vein; (21) angular artery and vein; (22)
canaliculi; (23) lacrimal sac; (24) medial canthal tendon-anterior
attachment; and (25) dorsal nasal artery.
[0022] FIG. 2 is a graph showing the effect of transdermal
application to an eyelid of a pilocarpine formulation containing
caffeine on human tear production.
[0023] FIG. 3 is a graph showing the comfort level of subjects
after transdermal upper eyelid application of a pilocarpine
formulation with caffeine applied to one upper eyelid.
[0024] FIG. 4 is a graph showing the effect of transdermal upper
eyelid application of a timolol plus caffeine formulation on
intraocular pressure.
[0025] FIG. 5 is a graph showing the percentage change to human
systolic blood pressure and pulse after application to one eyelid
of a timolol plus caffeine.
[0026] FIG. 6 is a graph showing the change in Schirmers score
after upper eyelid application of a transdermaml physostigmine plus
caffeine formulation.
[0027] FIG. 7 is a graph showing the effects of upper eyelid
application of a formulation containing physostigmine plus caffeine
on intraocular pressure in the human eye.
[0028] FIG. 8 is a graph showing change in pupil size after
transdermal upper eyelid application of a physostigmine plus
caffeine formulation.
[0029] FIG. 9 is a graph showing the effect of upper eyelid
transdermal monocular application of a physostigmine plus caffeine
formulation on heart rate.
[0030] FIG. 10 is a graph showing the effect of transdemal
application to an upper eyelid of a physostigmine plus caffeine
formulation on human systolic blood pressure.
[0031] FIG. 11 is a graph showing the effect of upper eyelid
transdermal monocular latanoprost application on human intraocular
pressure.
[0032] FIG. 12 is a graph showing the effect of topical application
to an upper eyelid of a composition containing brimonidine (without
caffeine) on human intraocular pressure.
[0033] FIG. 13 is a graph showing the effect of topical application
to an upper eyelid of a composition containing brimonidine plus
caffeine on human intraocular pressure.
[0034] FIG. 14 is a graph showing the effect on a subject's blood
glucose level of a single topical application of insulin/humulin to
the upper eyelid of a normal subject.
[0035] FIG. 15 is a graph showing the effects on the blood glucose
levels of three diabetic human subjects of transdermal application
to both upper eyelids of a composition containing
insulin/humulin.
[0036] FIG. 16 is a graph showing the effect of application to one
upper eyelid of a composition comprising lisinopril and caffeine on
an untreated hypertensive humansubject's blood pressure.
[0037] FIG. 17 is a graph showing the effect on tear production in
the treated and untreated eye after topical application to one
upper eyelid of a human of a composition comprising pilocarpine
(without caffeine)
[0038] FIG. 18 is a graph showing the effect on comfort level in
the treated and untreated eye of a human after application to one
upper eyelid of a composition comprising pilocarpine (without
caffeine).
DETAILED DESCRIPTION OF THE INVENTION
[0039] The present inventive methods, kits and compositions utilize
transport via vascular collaterals or channels within the eyelid to
deliver therapeutic agents to specific target tissues that receive
blood supply, such as glands, conjunctiva, periocular tissue, the
eye including the posterior segments thereof, and even remote
target sites via the systemic circulation. The inventors have
discovered that topical application of the therapeutic compositions
of the invention to the outer surface of the upper eyelid or
eyelids and optionally to at least one lower eyelid of a human
patient greatly aids absorption of any therapeutic agent. The
eyelid is unique in having scant stratum corneum, the epidermis
surface layer that retards drug absorption, a very thin epidermis
(approximately 40 microns), and no subcutaneous fat. Muscle fibers
of the Orbicularis muscle that cause the eyelid to blink shut are
directly beneath the dermis and these muscle fibers can assist drug
delivery by in-pumping drugs through the muscle and it's vascular
system. The inventors have discovered that these four factors
coupled with a rich circulatory network within the eyelid that can
be accessed by the applied drug via the vascular dermis allow
percutaneous absorption of a wider variety of drugs to therapeutic
levels compared to application of drugs via other routes. Thus,
drugs and other therapeutic agents can be applied to the outer skin
surface of the eyelid (or the skin of the underside of the eyelid
by way of applying an eye drop directly to the eye) to specifically
target the eyelid glands (accessory lacrimal, lacrimal, meibomian,
glands of zeiss and moll); conjunctival goblet cells, which secrete
the mucinous layer of the tear film; the sub-conjunctival space and
conjunctival epithelium; or periocular tissues for drug delivery to
these tissues or to the entire eyeball itself. Moreover, the
present methods, kits and compositions can be utilized to achieve
systemic uptake of therapeutic agent while bypassing the
gastrointestinal (GI) tract and first pass hepatic metabolism.
[0040] As used herein the term "drug" means any chemical substance
used in the treatment, cure, prevention, or diagnosis of disease or
used to otherwise enhance physical or mental well-being. The term
"therapeutic agent" is also used to denote any compound, molecule,
or substance used for the medical treatment of a disease or
condition.
[0041] The term "eyelid" as used herein means particularly the
upper eyelid(s) of a human subject, but may include the lower
eyelid(s) as well. It is understood that in each embodiment of the
present methods the appropriate therapeutic agent is applied to the
outer skin surface of at least one upper eyelid and optionally to
at least one lower eyelid unless expressly stated otherwise.
[0042] The term "muscle fasciculating agent" or "micro
fasciculating agent" as used herein means any agent that causes a
small, local involuntary muscle contraction (a muscle twitch) such
as caffeine, theophylline, pentoxifyline or theobromide.
[0043] The term "sustained release" is used herein in its ordinary
sense to mean that the compositions of the invention are designed
to release a drug slowly over an extended period of time.
[0044] In certain aspects, the present methods and compositions
take advantage of the unique human upper eyelid anatomy to target
drug delivery. The major anatomic landmark and demarcation of the
upper eyelid is the anteroposterior fascial fusion of the orbital
septum and levator aponeurosis (collagen and elastic fiber
extension of the levator muscle that elevates the eyelid) in the
superior aspect of the eyelid. This tissue fuses inferiorly with
the connective tissue "backbone" of the upper eyelid called the
tarsus. Therefore, the upper eyelid is classified as having two
compartments: one that is "preseptal and post-septal" in the
superior aspect of the upper eyelid and "pretarsal and post-tarsal"
in the inferior aspect of the upper eyelid. These separate anatomic
and physiologic compartments are not only basic anatomical dogma,
but form the critical landmarks used in surgery. Our understanding
of physiological functions of the essential function of the upper
eyelid in maintaining secretory tear function and mechanical
protection are based upon these well understood anatomical
barriers.
[0045] Transdermal eyelid drug delivery systems to date have relied
almost exclusively on the principle of passive diffusion to
transport highly lipid-soluble hormones such as the androgens and
estrogens/progestins or small molecules, i.e., less than 500
Daltons to permeate in an untargeted manner throughout the eyelid
tissue or have included amounts of vasoconstrictors to facilitate
drug absorption in an untargeted manner. Due to the rigid
anatomical barriers that exist within the upper eyelid and to a
lesser degree in the lower eyelid, prior methods of topical drug
delivery via the outer surface of the upper (or lower) eyelid have
not been satisfactory in regards to targeted drug delivery to
certain segments of the eye (thus have not successfully targeted
the entire eyeball) and have not achieved successful systemic
delivery of therapeutic amounts of drug or other therapeutic
agents.
[0046] In contrast, the methods, kits and compositions of the
present invention disregard the preconceived dogma regarding
anatomical barriers and compartments of the eyelids, particularly
of the upper eyelid. Although these compartments and barriers
clearly exist, they are connected by the vascular supply between
the two main circulatory systems of the eyelid. These two systems
in a broadest sense derive from the internal carotid artery and the
external carotid artery system. The vascular branches from these
two main arteries provide the eyelid a rich dual blood supply. The
internal carotid branches supply the inner posterior "post-septal
and post-tarsal" compartment and the external carotid branches
serve the outer anterior "preseptal and pretarsal" compartment.
[0047] The present inventors discovered that these two circulatory
systems, which are extensively linked in the upper eyelid via rich
vascular anastomoses can be utilized in the present methods,
compositions and kits as a vehicle for transdermal drug delivery
from the upper eyelid to specifically target the accessory lacrimal
glands, conjunctival mucosal secretory apparatus, meibomian glands,
the sub-conjunctival space of the palpebral conjunctiva that
reflects into the sub-bulbar conjunctival space and to access the
periocular and transscleral pathways for targeting with certain
therapeutic drugs. Furthermore, gravity, which moves drugs applied
to the eyelid inferiorly, is an advantage to the present invention
in regards to drug delivery to periocular tissue and conjunctiva.
Application of the compositions of the present invention to the
upper eyelid results in greater bioavailability of the therapeutic
agent(s) with a large surface area in this setting of gravatitional
advantage. Once the therapeutic agent(s) is secreted into the
peri-conjunctival space, the upper eyelid provides a unique
mechanical spreading action to the agent(s). Finally, the present
drug delivery method reaches any area of the body that is supported
by the vasculatory network.
[0048] The present invention overcomes several insufficiencies of
prior methods for subcutaneous or topical delivery of therapeutic
agents. For example, the most commonly used non-invasive method for
treating the vast majority of eye diseases and conditions is
through the use of eye drops, which are difficult for most people
to apply accurately and are washed out or diluted by the tear
reflex, reducing the drug's ability to remain in contact with and
penetrate the eye. In fact, eye drops are eliminated from the
precorneal area in 90 seconds or less, which is so short an
exposure period, especially for hydrophilic drugs, that the
naturally occurring spaces between epithelial cells (e.g., the
paracellular route of drug delivery) are too widespread and
coincidental to rely on for drug delivery therethrough. Thus, eye
drops generally result in delivery of only about 1-5% of the
topically administered therapeutic agent. Consequently, most eye
drops contain an amount of preservative which functions to punch
holes in the corneal epithelium to improve absorption. Such agents
are inherently toxic to the richly enervated epithelium and cause
pain and discomfort to patients. Moreover, eye drops must be
manufactured within a very narrow pH range, which limits the types
of drugs that can be delivered via this non-invasive route.
[0049] Topical delivery of ophthalmic drugs to the eyelid of a
patient has been used previously with limited success. Application
of olapatadine, epinastine and muscarinic receptor agonists, small
molecules of less than 500 Daltons to the surface of the eyelid has
been reported to achieve sustained delivery of the drug to the
anterior segment of the treated rabbit eye (US 2009/0209632, US
20090143359 and US 2007/0053964, respectively). It is disclosed in
each of these patent applications that the amount of release of
olapatadine, epinastine or muscarinic receptor agonist to the
anterior segment of the eye is controlled by manipulation of the
amount of the drug and/or skin permeability through the use of
known permeability enhancers for application directly to the
anterior segment of the eye, rather than through systemic blood
flow. Systemic absorption was not observed by these prior methods
and hence, delivery to systemic tissues, the contralateral
untreated eye, and the entire treated eyeball including the
posterior segments of the eye was not achieved.
[0050] WO 2008/026756 discloses an ophthalmic percutaneous
absorption composition for administration to the eyelids which
contains a vasoconstrictor as an essential component necessary to
achieve delivery of therapeutic agent to the anterior segments of
the eye. It is specifically disclosed that the vasoconstrictor need
only have blood vessel contracting activity in order to effect
delivery of the drug into the anterior segment of the eye. The
necessity for inclusion of a vasoconstrictor is disadvantageous for
treatment of the eye since these agents decrease blood flow, which
in turn causes visual damage from diseases where ischemia (poor
oxygenation and blood flow) plays a role such as glaucoma, diabetic
retinopathy, retinal degeneration, or vascular disease for
example.
[0051] In contrast, the present inventors have discovered that
sustained release and delivery of therapeutic agent to the systemic
blood flow and/or all regions of the eye, including the heretofore
inaccessible posterior sections of the eye, can be achieved by
topical application of the therapeutic agent(s) to the outer
surface of one or both upper eyelids and optionally, one or both
lower eyelids. The inventors have discovered that application of a
therapeutic compound or drug to one eye (the treated eye) results
in drug delivery to the untreated contralateral eye as well, via
the systemic circulatory system. Moreover, any drug or therapeutic
agent having a molecular weight up to and exceeding 6000 Daltons
can be administered in this manner and achieve therapeutic
concentration at the target site, even when the target site is
remote from the eyelid, i.e., via the systemic circulatory system
or located within the posterior segments of the eye.
[0052] The compositions of the invention comprise a therapeutically
effective amount of drug appropriate for the condition or disease
to be treated. In general, the compositions of the invention
comprise therapeutic agent in amounts of from about 0.01 to about
40 wt % of the composition in a pharmaceutically acceptable carrier
suitable for application to the outer skin surface of the eyelid.
The dose and treatment regimen, including administration period of
the compositions of the invention vary depending on the target
disease, symptom, patient, administration route and the like. The
therapeutic agents useful for the present invention may be
synthetic drugs or may be naturally derived or derivatized. For
example, tinctures and natural extracts containing therapeutic
agents may be employed in the compositions and methods of the
invention. For example, for the treatment of glaucoma, a cream,
gel, spray, lotion, ointment, stick applicator, foam, film, or an
adhesive formulation for example containing latanoprost in an
amount of about 0.1 to 40 wt % of the composition is applied to the
upper eyelid. The inventors have discovered that application of
latanoprost to the upper eyelid (and optionally lower eyelid)
results in a significant and semi-permanent decline in intraocular
pressure in both the treated and untreated eye (although a somewhat
greater decline in the treated eye was observed), indicating that
the number of applications of latanoprost to achieve the target
intraocular pressure can be decreased, e.g., from once per day to
once every two to four days or longer. The treatment period will
vary depending upon the condition being treated and the therapeutic
agent or drug being applied, but in general will range from about
one day to three months.
[0053] In certain embodiments of the invention a muscle
contractility agent (a muscle or micro fasciculating agent) is
included in the therapeutic compositions, such as caffeine,
theophylline, pentoxifyline, theobromide. The micro fasciculating
agent may be included in an amount up to about 50 wt % and this
amount will vary depending on the target site for drug delivery,
e.g. higher amounts of the micro fasciculating agent may be
included when the target is remote (and delivery is achieved
systemically) or if the target site is the posterior segment of the
eye or for sustained delivery. For example, for systemic delivery
of drug via application to one or both upper eyelids an amount of
about 1% by weight or more of a micro fasciculating agent may be
included in the composition, while for those embodiments where
delivery of therapeutic agent to the posterior segment of the eye
is desired, an amount of about 0.5 to 50 wt %, such as for example
5 wt % of a micro fasciculating agent may be included in the
composition. In certain embodiments, particularly those in which
the delivery of therapeutic agent to the anterior portion of the
eye is desired, the amount of micro fasciculating agent in the
composition is in the range of from 0 to 5%, and in other
embodiments from 0.001 to 5%. In certain embodiments, particularly
when sustained release of the therapeutic agent is desired, the
composition may contain up to about 50 wt % of a muscle
fasciculating agent. In certain embodiments the muscle
fasciculating agent is an appropriate amount of caffeine, which has
the benefit of being a naturally occurring and readily metabolized
small molecule.
[0054] In certain embodiments of the invention, an ionotropic agent
may be included in the compositions in addition to a muscle
fasciculating agent. Ionotropic agents include any of a class of
agents affecting the force of muscle contraction. Positive
inotropic agents increase, and negative inotropic agents decrease
the force of skeletal muscle contraction. The ionotropic agent may
be added in an amount of from about 0.001 to 50% and the selection
of the particular ionotropic agent is made on the basis if the
desired effect on muscle contraction. Non-limiting examples of
positive inotropic agents that may be included in the compositions
of the invention include Berberine, Bipyridine derivatives,
Inaminone, Milrinone, Calcium, Calcium sensitisers, Levosimendan,
Cardiac glycosides, Digoxin, Catecholamines, Dopamine, Dobutamine,
Dopexamine, Epinephrine (adrenaline), Isoprenaline (isoproterenol),
Norepinephrine (noradrenaline), Eicosanoids, Prostaglandins,
Phosphodiesterase inhibitors, Enoximone, Milrinone, Theophylline,
and Glucagon. In certain embodiments of the invention, digitalis is
included in the compositions as an ionotropic agent.
[0055] The ophthalmic therapeutic compositions of the invention
that do not include a micro fasciculation agent may contain one or
more of a vast array of ophthalmic therapeutic agents, alone or in
combination, but such therapeutic agents do not include
olopatadine, muscarinic receptor agonists or epinastine, unless
such compositions also include a vasodilator and/or
vasoconstrictor.
[0056] In those aspects of the invention described above, the
methods and compositions take advantage of the extensively linked
circulatory systems in the upper eyelids through application of the
therapeutic composition to the outer surface of the eyelid(s).
However, the inventors have discovered that inclusion of a muscle
fasciculating agent in any ophthalmic composition for direct
topical delivery to the eye that upon application to the eye comes
into contact with the underside of the eyelid skin enhances uptake
and sustained release of the drug(s) included in the ophthalmic
composition. Thus, typical eye drop formulations and gels, for
example, that are formulated for direct application to the eye, are
improved by addition of an amount of from about 0.01 to up to 50 wt
% of a muscle fasciculating agent and optionally, an ionotropic
agent. Such eye drop formulations are encompassed by the present
invention.
[0057] Vasoconstrictor as an active drug: In certain embodiments of
the invention the sole therapeutic agent(s) of the topical
composition is one or more vasoconstrictors. Compositions
containing vasoconstrictor as the sole therapeutic agent(s) are
applied to at least one upper eyelid and optionally at least one
lower eyelid of the patient for the treatment of conditions
including, but not limited to, redeye, allergic conjunctivitis,
blepharitis, puffy eye lids and any disease state or condition that
includes as a symptom edema, vasodilation and/or bleeding in the
eyelid, anterior segment, posterior segment or orbit of the eye. In
some embodiments, such vasoconstrictor-containing compositions may
also contain from 0 to 1% or more as required of a micro
fasciculating agent, such as for example, caffeine, theophylline,
pentoxifyline or theobromide and/or a permeation enhancer agent.
Further, vasoconstrictors may be combined with other active agents,
and/or micro fasciculating agent, permeation agent, and the like.
Although any vasoconstrictor may be used in the compositions and
methods of the present invention, certain embodiments employ a
therapeutically effective amount of ephedrine. Other embodiments of
this aspect of the invention include use of a vasoconstrictor such
as for example methoxamine, phenylyephrine, oxymetazoline, cocaine,
Allerest.RTM., naphazoline, Visine.RTM., tetrahydrolozine,
Op-Thal-Zin/zinc sulfate, Rhindecon, phenylpropanolamine,
Sudafed.RTM., pseudoephedrine, Ephed II, ephedrine, Aramine,
metaraminol, Epifrin, epinephrine, Levophed, norepinephrinand
nicotine.
[0058] In those embodiments of the invention in which a
vasoconstrictor is included in the topical treatment regimen, the
vasoconstrictor may be applied to the eyelid separate from a second
topical composition comprising other active agents,
microfascilitating agent, optional permeating agent and optional
ionotropic agent. The vasoconstrictor containing composition may be
applied to the same area of the eyelid as the second topical
composition or may instead be applied to the perimeter of the area
of the eyelid onto which the second topical composition was
applied. Application to the perimeter region is believed to limit
the effects of the vasoconstrictor and thereby limit any unwanted
side effects, while limiting systemic flow of the active agent.
Application of a vasoconstrictor and active agent in this manner
may be achieved through use of separate applicators or through
application of a composition formulated as a stick applicator (an
"eyelidstick") in which the active ingredients (other than
vasoconstrictor), any permeating agents, muscle fasciculating agent
and/or ionotropic agnet comprise the middle of the eyelidstick and
the perimeter of the eyelidstick comprises the vasoconstrictor,
resulting in application of a small amount of vasoconstrictor on
the perimeter of the application area. In another embodiment, the
vasoconstrictor is impregnated on the border of an eyestrip or film
applicator with active agent(s), and/or micro fasciculating agent,
ionotropic agent and/or permeating agent impregnated in the middle
of or throughout the entire applicator. Application of the strip to
the eyelid and subsequent removal results in localized application
of the various components (e.g., a border of vasoconstrictor).
[0059] Vasodilator as the active drug: Classes of vasodilator
agents that may be included in the compositions as the sole
therapeutic agent(s) or in combination with a vasoconstrictor or
other therapeutically active agent include alpha-blockers
(alpha-adrenoreceptor antagonists), ACE inhibitors (angiotensin
converting enzymes), angiotensin receptor blockers, .beta.2
agonists (.beta.2-adrenoceptor agonists, calcium channel blockers,
centrally acting sympatholytics, direct acting vasodilators,
endothelin receptor antagonists, ganglionic blockers,
nitrodilators, phosphohodiesterase inhibitors, potassium channel
openers, and rennin inhibitors. Specific examples of vasodilators
that may be used in the methods and compositions of the invention
include, but are not limited to: arginine, bencyclane fumarate,
benzyl nicotinate, buphenine hydrochloride, ciclonicate,
cyclandelate, ethyl nicotinate, hepronicate, hexyl nicotinate,
hydralazine, inositol nicotinate, isoxsuprine hydrochloride, methyl
nicotinate, minoxidol, naftidrofuryl oxalate, nicametate citrate,
niceritrol, nicoboxil, nicofuranose, nicotinyl alcohol, nicotinyl
alcohol tartrate, nitric oxide, nitroglycerin, nonivamide,
oxpentifylline, papaverine, papaveroline, pentifylline,
peroxynitrite, pinacidil, sodium nitroprusside, suloctidil,
teasuprine, thymoxamine hydrochloride, tolazoline, vitamin E
nicotinate, and xanthinol nicotinate. Centrally acting
vasomodulatory agents include clonidine, quanaberz, and methyl
dopa. Alpha-adrenoceptor blocking agents include indoramin,
phenoxybenzamine, phentolamine, and prazosin. Adrenergic neuron
blocking agents include bedmidine, debrisoquine, and guanethidine.
ACE inhibitors include benazepril, captopril, cilazapril,
enalapril, fosinopril, lisinopril, perindopril, quinapril, and
ramipril. Ganglion-blocking agents include pentolinium and
trimetaphan. Calcium channel blockers include amlodipine,
diltiazem, felodipine, isradipine, nicardipine, nifedipine,
nimodipine, and verapamil. Prostaglandins including: prostacyclin,
thrombuxane A2, leukotrienes, PGA, PGA1, PGA2, PGE1, PGE2, PGD,
PGG, and PGH. Angiotensin II analogs include saralasin. Such
compounds may be applied to the eyelid as the sole active component
of a topical composition with or without any of a micro
fasciculating agent, permeating agent or ionotropic agent for
therapeutic treatment of the posterior segment of the eye, to treat
the optic nerve or retina, for example or to treat conditions such
as glaucoma, ischemic retinopathy (diabetic, hypertensive,
degenerative) and the like.
[0060] Compositions containing a therapeutically affective amount
of a vasodilator, as the sole active agent or in combination with
other therapeutically active agents, and optional micro
fasciculating agent, ionotropic agent and/or permeating agent may
be used in the treatment of a variety of ophthalmic conditions by
application to at least one eyelid of a patient in need thereof.
The vasodilator species and concentration within the transdermal
drug delivery formulation may be different for each drug and for
each delivery requirement. There may be one or more vasodilator,
acting in a similar or different mechanism within the same
formulation. There may also be vasodilators that are added in
tandem temporally or simultaneously to induce the optimal reaction
and to create a tissue concentration profile of the vasodilators
that optimizes the transdermal transportation of the drug into the
tissue or the bloodstream. The vasodilator may serve exclusively as
the vasodilation agent or it may also, in addition, serve other
functions to the delivery complex such as to assist in the
penetration of the active drug molecule or the penetration of the
other components of the delivery vehicle. The vasodilator may also
co-function by definition and by action as the active drug agent,
or to a serve another undefined function to create the optimal
chemistry of the delivery vehicle formulation.
[0061] In another embodiment of this aspect of the invention, a
vasodilator and vasoconstrictor may be used in combination in the
compositions and methods of the invention. For example, an active
drug, vasodilator, and vasoconstrictor in a formulation, optionally
with a penetrating, ionotropic agent and/or micro fasciculating
agents can be applied to the eyelid. The time release aspect of the
vasodilator and vasoconstrictor affects both drug delivery
destination and activation. In another embodiment, a fast acting
vasodilator is employed in the compositions and methods to
immediately increase blood flow and, therefore, increase drug
absorption immediately upon drug application. This may be followed
by topical application to the same eyelid(s) of a delayed acting
vasoconstrictor which acts to sequester the drug at the treated
site/eyeball thereby preventing systemic absorption and increasing
local activity of drug. In yet another embodiment, a short acting
vasoconstrictor is applied to at least one upper eyelid to prevent
systemic blood flow followed by application to the eyelid of a
delayed acting vasodilator, which then causes increased delivery
systemically. Additionally, since vasoconstrictor use decreases
blood flow locally to the eye and often results in worsening of
ischemic eye diseases such as glaucoma or diabetic retinopathy, the
use of a vasodilator in combination therewith serves to diminish
this negative effect while enabling the use of the least amount of
vasoconstrictor necessary.
[0062] Caffeine as the active drug. Caffeine has been shown to have
certain anti-oxidant properties and to provide protection against
cataract formation and reduce cataracts in test animals when
applied directly to the eye in the form of eye drops. Application
of caffeine to the outer surface of at least one eyelid of a human
patient via the methods and compositions of the invention
eliminates the unpleasant effects of eye drops and results in
delivery of higher concentrations of caffeine to the target site
within the eye than is attainable with eye drops, which are
primarily washed away by blinking. Moreover, because caffeine
causes micro fasciculation in the eyelid muscle, sustained release
of caffeine is attained by application of the composition directly
to one or both eyelids. Consequently, the caffeine composition need
only be applied once per day in many instances, although multiple
applications per day are also contemplated depending on the
physical condition of the treated eye(s).
[0063] The caffeine containing compositions of this aspect of the
invention can be formulated to contain from 0.001 wt % to 50 wt %
caffeine. In certain embodiments, the compositions are formulated
to contain from about 0.001 to 500 mg caffeine, although the
compositions may be formulated to deliver any desired amount of
caffeine. The compositions may also include an inotropic agent to
enhance muscle twitching, such as from 0.001 to 50 wt % of the
composition. Permeation enhancers may also be included in the
compositions.
[0064] Application of caffeine to at least one eyelid serves to
reduce the oxidative stress within the treated and untreated eye,
thus helping to maintain the health of the eye and prevent
oxidative damage. In particular, application of caffeine to at
least one eyelid aids in inhibiting the formation of cataracts.
Moreover, application of caffeine to at least one eyelid of a
individual suffering from cataract(s) reduces the growth of and/or
slows the further growth of the cataract(s). Typically the
caffeine-containing composition is applied to the eyelid of the
affected eye(s), but because caffeine reaches both the treated and
untreated eye, it is not necessary to apply directly to the eyelid
of the affected eye.
[0065] Ophthalmic Compositions in General: Ophthalmic compositions
of the invention can be formulated to contain therapeutic agent or
drug(s) for the treatment of watery eyes or epiphora, that can, for
example, be due to overactive tearing reflex (from dry eye, for
example), keratitis, photophobia, allergic conjunctivitis or
nasolacrimal duct obstruction including pharmaceutically effective
amounts of atropine, scopolamine, homoatropine, cyclopentalate,
tropicamide and the like and anticholinergic agents such as
combinations thereof. Allergic eye disease generally involves an
allergic reaction of the ocular mucosa and the conjuntiva. Seasonal
keratoconjucntivitis, perennial allergic conjunctivitis, vernal
keratoconjuntivitis and atopic conjunctivitis are successfully
treated with the compositions, kits and methods of the invention.
Meibomian glandular dysfunction, blepharitis, rosacea, chalazion,
and hordeolum may be treated according to the methods of the
invention by topical application to at least one eyelid of a
composition of the invention containing one or more cholinergic
agents, antiinflammatory drug, or antibiotic. The therapeutic
agents that may be included include pilocarpine, cyclosporine A,
carbachol, echothiophate iodide, diisopropyl fluorophosphates,
physostigmine, neostigmine, dipivefrin, apraclonodine,
isoproternol, bromocriptine or phenylepherine, and antibiotics such
as the tetracycline class, aminoglycosides, cephalosporins,
antifungals (e.g., Neomycin and Polymixin) and the like appropriate
for the condition to be treated, and optionally, up to about 50% of
a micro fasciculating agent, such as caffeine, theophyline or
theobromine, for example. Generally, the drug targets the meibomian
glands to improve the lipid layer of the tear film, which improves
tear stability, decreases evaporation and improves tear spread.
[0066] Traditionally, treatment of dry eye, dry mouth (Sjogren's
Syndrome) or blepharitis, for example, has included oral
administration (systemic delivery) of the appropriate therapeutic
agent, such as the secretogues, pilocarpine, pilocarpine extract or
tincture and physostigmine, which are indicated for dry eye and dry
mouth and antibiotics such as oxytetracycline have been orally
administered for the treatment of blepharitis. Unfortunately,
systemic cholinergic stimulation is accompanied by numerous
unwanted side effects including sweating, bracycardia, hypotension,
nausea, vomiting and increased urination, while antibiotics are
simply not tolerated by many people.
[0067] The compositions and methods of the present invention enable
topical administration of drugs such as secretogues, e.g.,
pilocarpine (which is a muscarinic receptor agonist as well as a
cholinergic agent) and physostigmine, alone or in combination with
a micro fasciculating agent, directly to the eyelid (one or both
eyelids) with or without the use of vasoconstrictors, for delivery
to the target site, e.g., the lacrimal glands, meibomian glands,
conjuctival goblet cells, resulting in secretions from all three
layers of tear film. Similarly, anti-inflammatories, such as
cyclosporine (molecular weight 1202 Daltons), which is typically
applied to dry eye via eye drops that cause a stinging sensation in
up to 20 to 30% of patients and require months to achieve varying
degrees of efficacy, may be applied via the present methods, thus
avoiding unpleasant side effects and resulting in delivery of the
drug through the eyelid to the accessory lacrimal, lacrimal, and
conjuntival mucosa and meibomian glands, thus achieving therapeutic
effect in less time than previously observed.
[0068] The methods and compositions of the present invention may be
applied to the treatment of various ophthalmic conditions and
diseases including blepharitis, floppy eyelid syndrome,
trachomatous dry eye, retinopathy, retinal degeneration,
nasolacrimal duct obstruction, epiphora, chalazion, hordeolum,
allergic conjunctivitis and keratitis, infectious conjunctivitis
and keratitis, pterygium, pinguiculum, iritis, uveitis, keratitis,
vitritis, vitreous floaters, vitreous detachment, vitreous
hemorrhage, retinal detachment, sub retinal hemorrhage, choridal
neovascular membrane, retinal edema, macular edema, diabetic
retinopathy, choridal malignancy, orbital malignancy, eyelid
tumors, optic neuritis, optic neuropathy, strabismus, refractive
error, and glaucoma. The ophthalmic compositions of the invention
used to treat these various conditions and diseases comprise the
appropriate active ingredient for treatment, such as
anti-inflammatory agents (steroidal anti-inflammatory agents such
as prednisone, triamcinolone, dexamethasone, Durezol,
Fluoromethalone, loteprendol, and the like; non-steroidal
anti-inflammatory drugs (NSAIDs) such as ketorolac, bromphenac,
nephenac, and the like, and immunosuppressive agents, such as:
cyclosporine, tacrilimus, sirolimus, and the like); Dry Eye
Syndrome Agents such as cholinergics which include (a) muscarinic
receptor agonists (Pilocarpine, Cevimeline, Carbachol), (b)
anticholinesterase agents: physostigmine, neostigmine,
echothiophate iodide, pyridostigmine, edrophonium; Beta-agonists
such as Isoproternol; Alpha-agonists (e.g., brimonidine, iopidine,
epinepherine, phenylepherine, all vasoconstrictors; tetracycline
class antibiotics (e.g., for Rosecea) such as doxycycline,
tetracycline; estrogens and androgens; and immunosupressives such
as cyclosporine, and the like; Antiglaucoma agents such as
Betaantagonists, Alpha-antagonists, carbonic anhydrase inhibitors,
prostaglandin analogs (e.g., in certain embodiments, a skin
bleaching agent or anti melanocytic agent may be added to the
compositions to prevent skin darkening (e.g., hydroquinone),
anticholinergic compounds (including muscarinic receptor agonists),
vasodilators. Possible glaucoma drug combinations include
B-antagonist and alpha-antagonist, B-antagonist and carbonic
anhydrase inhibitor, B-antagonist and prostaglandin analog,
anticholinergic (including muscarinic agonists) and alpha-agonist,
any Intraocular pressure lowering agent and vasodilator, any
intraocular pressure lowering agent and neuroprotective agent;
antibiotics such as Cephalosporins, Fluoroquinolone(ciprofloxacin,
moxifloxacin, gatifloxacin), Macrolide(erythromycin, azithromycin,
etc), Tetracycline class, Aminoglycosides(Tobramycin, gentamycin),
Trimethoprim, Sulfonamides, and the like; Antihistamines such as
emedastine, levocabastine, antazoline, pheniramine, azelastine, and
the like; mast cell stabilizers such as lodoxamide, olopatadine,
Ketotifen, Cromolyn Sodium and the like; ocular decongestants such
as Naphazoline, Phenylepherine, Tetrahydrozoline, Oxymetazoline,
and the like; Anti-VEGF (vascular endothelial growth factorsuch as
Lucentis ranibizumab and Avastin (bevacizumab); Anti EGFI
(epidermal growth factor inhibitor) Erlotinib(Tarceva),
Gefitinib(Iressa); Neuroprotective agents such as
Memantine(Namenda), Cholesterol lowering Medications including
statins, IOP lowering agents that are also
neuroprotective(Brimonidine(Alphagan), Betaxolol(Betoptic); herbal
agents, including various extracts, ginko biloba, and the like;
vitamins, minerals, and the like; and oligonucleotides.
[0069] In another aspect of the invention, compositions comprising
a therapeutically effective amount of a desired therapeutic agent
or combination of therapeutic agents and from about 0.001 to 50 wt
% muscle fasciculating agent are formulated for topical transdermal
administration. In this aspect of the invention, the composition is
administered to any outer skin surface of a patient. Any drug or
therapeutic agent that can be applied transdermally can be used in
combination with a muscle fasciculating agent and optional
ionotropic agent as described herein and formulated in any
convenient form for topical administrations, such as a lotion,
creme, patch, and the like. In certain embodiments the composition
further comprises a permeability enhancer. In certain embodiments
of this aspect of the invention, the muscle fasciculating agent is
caffeine, theophylline, pentoxifyline or theobromide, which may be
included in the topical composition in an amount of up to about 1%
and in certain embodiments may be included in an amount of up to
about 30 wt % or in certain other embodiments, up to about 50 wt %
of the composition. In certain embodiments of this aspect of the
invention the drug(s) is less than 6000 Daltons in size, while in
other embodiments the drug may be larger than 6000 Daltons in size.
Non-limiting examples of drugs that may be included in the
compositions for topical transdermal delivery include insulin,
recombinant insulin, botox, myobloc, antihypertensive agents,
nicotine, antibiotics, hormones, recombinant hormones, and
anti-arrhythmic agents. The muscle fasciculating agent serves to
stimulate subcutaneous muscle, which serves to increase absorption
of the active agent into muscle. An optional ionotropic agent
serves to enhance the muscle contractions, further enhancing
absorption of the drug. Since muscle is highly vascular, increasing
absorption into muscle results in increased absorption of the drug
into the body.
[0070] Optionally, an amount of a penetrating agent may also be
included in any of the compositions of the invention to aid
penetration of the active component into and across the skin or
eyelid skin such as for example, aliphatic alcohol, fatty acid and
a salt thereof, fatty acid ester, polyalcohol alkyl ether,
polyoxyethylene alkyl ether, glyceride, polyalcohol medium chain
fatty acid ester, polyoxyethylene sorbitan fatty acid ester, alkyl
lactate ester, terpenes and organic amine. More specifically, the
percutaeous penetrating agent may be ethanol, glycerol, diethylene
glycol, propylene glycol, polyethylene glycol and higher aliphatic
alcohols (saturated or unsaturated higher aliphatic alcohol having
12 to 22 carbon atoms such as oleyl alcohol, lauryl alcohol and
stearyl alcohol), capric acid, myristic acid, palmitic acid, lauric
acid, stearic acid, isostearic acid, oleic acid, linoleic acid and
linolenic acid, and a salt thereof (for example, sodium salt,
potassium salt, magnesium salt, calcium salt and aluminium salt),
include an ester of a fatty acid such as myristic acid, palmitic
acid, lauric acid, stearic acid, isostearic acid, oleic acid,
linoleic acid, linolenic acid, propionic acid, butyric acid,
isobutyric acid, valeric acid, pivalic acid, caproic acid,
heptanoic acid, malonic acid, succinic acid, glutaric acid, adipic
acid, pimelic acid, crotonic acid, sorbic acid, maleic acid,
fumaric acid and sebacic acid with a lower aliphatic alcohol such
as methanol, ethanol, propanol, isopropanol, butanol, pentanol,
hexanol, heptanol and octanol, isopropyl myristate, isopropyl
palmitate, diisopropyl adipate and diethyl sebacate, an ether of a
polyalcohol such as glycerol, ethylene glycol, propylene glycol,
1,3-butylene glycol, diglycerol, polyglycerol, diethylene glycol,
polyethylene glycol, dipropylene glycol, polypropylene glycol,
sorbitan, sorbitol, methyl glucoside, oligosaccharide and reduced
oligosaccharide with alkyl alcohol, polyoxyethylene lauryl ether,
polyoxyethylene cetyl ether, polyoxyethylene stearyl ether and
polyoxyethylene oleyl ether, glycerol ester of fatty acid having 6
to 18 carbon atoms (e.g;, monoglyceride, diglyceride, triglyceride
and a mixture thereof), glyceryl monolaurate, glyceryl
monomyristate, glyceryl monostearate, glyceryl monooleate, glyceryl
dilaurate, glyceryl dimyristate, glyceryl distearate, glyceryl
trilaurate, glyceryl trimyristate and glyceryl tristearate,
ethylene glycol monocaprylate, propylene glycol monocaprylate,
glycerin monocaprylate, mono 2-ethylene glycol ethylhexanoate, mono
2-propylene glycol ethylhexanoate, di(2-propylene)glycol
ethylhexanoate, propylene glycol, dicaprylate, polyoxyethylene
sorbitan monolaurate, polyoxyethylene sorbitan monostearate and
polyoxyethylene sorbitan monooleate, methyl lactate, ethyl lactate,
methyl 2-methoxy propionate and ethyl 2-methoxypropionate,
monoethanolamine, triethanolamine, creatinine and meglumine. In
certain embodiments of the invention one or more of fatty acid
ester, polyoxyethylene, isopropyl myristate and polyoxyethylene
oleyl ether is included in the composition. In other embodiments of
the invention a penetrating agent or combination of agents such as
1-acyl-azacycloheptan-2-one (azone), 1-acyl-glucoside,
1-acyl-poly(oxyethylene), 1-acyl-saccharide,
2-(n-acyl)-cyclohexanone, 1-alkanol, 1-alkanoic acid,
2-(n-acyl)-1,3-doxolane (SEPA), 1,2,3-triacylglyceride,
1-alkylacetate, alkyl-sulfate, dialkyl sulfate, and
phenyl-alkyl-amine may be added to the composition.
[0071] Also optionally, an amount of a hydrating agent such as
hyaluronic acid, saline solution, polyvinylpyrrolidone, may be
included in any of the compositions of the invention. Ophthalmic
compositions of the invention that are intended to penetrate the
stratum corneum generally, although not necessarily, include an
amount of a hydrating agent to facilitate penetration of the
therapeutic agent through the cell junctions of the stratum
corneum.
[0072] When included in the compositions of the invention,
penetrating agents are generally in the amount of from 0.01% to 50%
by weight of the composition and in some embodiments from 0.1% to
about 40% by weight of the composition, 1% to about 35% and in
other embodiments from about 5% to about 30% by weight of the
composition and the amount of hydrating agent is in the range of
from 0.001% to 30% by weight of the composition, in other
embodiments from 0.01 to 25% by weight of the composition and in
still other embodiments, from 0.1% to 10% by weight of the
composition.
[0073] The compositions of the invention may be formulated as a
cream, gel, lotion, ointment, stick, spray, foam, film, strip,
tape, poultice, plaster, adhesive preparation or the like for
direct application to the skin or to the outer surface of the upper
eyelid or may be adhered to a patch, strip, tape, poultice, plaster
and the like that is suitable for application to the skin or to the
outer surface of the upper eyelid. Because drug delivery through
the eyelid is so effective, the compositions for application to the
eyelid can be formulated to contain less drug or therapeutic agent
than is routinely administered via eye drops or for systemic
delivery (e.g., via injection, oral dosage, and the like) to treat
the condition via topical application. Moreover, because the
composition for application to the outer surface of the eyelid is
not applied directly to the eye, the pH of these formulations of
the invention can range from 0 to 14, enabling the use of a wide
range of therapeutic agents that ordinarily cannot be formulated
for topical application to the eye. Also, because there is little
or no limitation on the pH of the compositions of the invention, pH
can be manipulated to maximize penetration of drug through the
eyelid. By manipulating pH of the composition, it is possible to
maximize penetration of unbound therapeutic agent through the
skin.
[0074] In addition to the components discussed above, any component
generally used for manufacturing medicine in the desired form can
be added to the present compositions of the invention, if desired.
Examples of such components include a base matrix for adhesive
preparations, an ointment base, gel base, solvent, oil,
crosslinking agent, surfactant, gum, resin, pH adjuster,
stabilizer, antioxidant, preservative, ultraviolet absorbent and
wetting agent. A percutaneous absorption enhancer can be added, if
desired.
[0075] The base matrix for an adhesive preparation may include an
acrylic pressure sensitive adhesive, a silicone pressure sensitive
adhesive and/or rubber pressure sensitive adhesive, for example.
The matrix can be retained on one surface of a support generally
used in a preparation to be applied to the skin surface such as
tape, patch, cataplasma and plaster, or on one surface of a support
composed of any material having no adverse effect on the present
invention.
[0076] An acrylic pressure sensitive adhesive may include acrylic
acid-octyl acrylate copolymer, acrylate-vinyl acetate copolymer,
2-ethylhexyl acrylate-vinyl pyrrolidone copolymer and/or
methacrylic acid-butyl acrylate copolymer. Silicone pressure
sensitive adhesives useful in certain embodiments of the invention
include polymethylphenylsiloxane copolymer and/or acrylic
acid-dimethylsiloxane copolymer, for example. Rubber pressure
sensitive adhesives that may be used in certain embodiments of the
invention include for example styrene-isoprene-styrene copolymer,
natural rubber, polyisobutylene, polybutene and/or ethylene-vinyl
acetate copolymer (EVA), to which tackifier resin, softener and the
like can be added, if desired.
[0077] Ointment based formulations may include fat and oil bases
such as Vaseline.RTM., paraffin, plastibase, silicone, vegetable
oil, lard, wax and unguentum simplex; and/or emulsion bases such as
hydrophilic ointment (vanishing cream), hydrophilic Vaseline.RTM.,
absorption ointment, hydrous lanolin, purified lanolin and
hydrophilic plastibase (cold cream).
[0078] Gel based formulations may include thickening polymers such
as carboxyvinyl polymer, polyacrylic acid, sodium polyacrylate,
methylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone,
polyethylene oxide, polyacrylamide, gelatine, acacia gum,
tragacanth, guar gum, xanthan gum, agar, chitosan and carageenan;
fatty acid esters such as isopropyl myristate, isopropyl palmitate
and propylene glycol oleate; fatty acids such as lactic acid,
lauric acid, oleic acid, linoleic acid and linolenic acid;
aliphatic alcohols such as lauryl alcohol and oleyl alcohol; and
hydrocarbons such as squalene and squalane.
[0079] Solvents used in the manufacture of the compositions of the
invention may include purified water, methanol, ethanol,
1-propanol, lower alcohol, ethyl acetate, diethyl ether,
tert-butylmethyl ether, pyrrolidone, acetic acid, acetonitrile,
N,N-dimethylformamide, acetone, methyl ethyl ketone, methyl
isobutyl ketone, tetrahydrofuran, chloroform, toluene and xylene,
and the like.
[0080] Oils used in the manufacture of the compositions of the
invention may include volatile or involatile oil, solvent and
resin. Oil is generally used in an external preparation for skin
and may be in a liquid, paste or solid form at room temperature.
Specifically, for example, higher alcohols such as cetyl alcohol
and isostearyl alcohol; fatty acids such as isostearic acid and
oleic acid; polyalcohols such as glycerol, sorbitol, ethylene
glycol, propylene glycol and polyethylene glycol; and esters such
as myristyl myristate, hexyl laurate, decyl oleate, isopropyl
myristate and glyceryl monostearate can be mentioned.
[0081] When included, a crosslinking agent may be for example a
polyisocyanate, organic peroxide, organometallic salt, alkoxide and
metal chelate, examples of which are well known in the art of
manufacturing topical medications for use in humans.
[0082] Surfactant may be included in the compositions of the
invention to facilitate dissolution of formulation components
and/or absorption, including anionic surfactant, cationic
surfactant, nonionic surfactant and amphoteric surfactant. Useful
surfactants include fatty acid salt, alkyl sulfate, polyoxyethylene
alkyl sulfate, alkyl sulfo carboxylate, alkyl ether carboxylate,
amine salt, quanternary ammonium salt, polysorbate 80,
polyoxyethylene hydrogenated castor oil, polyoxyethylene fatty acid
ester, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty
acid ester, alkyl betaine, dimethylalkylglycine and lecithin.
[0083] If desired, gum and/or resin may be included in the
compositions of the invention, including for example, sodium
polyacrylate, cellulose ether, calcium alginate, carboxyvinyl
polymer, ethylene-acrylic acid copolymer, vinyl pyrrolidone
polymer, vinyl alcohol-vinyl pyrrolidone copolymer,
nitrogen-substituted acrylamide polymer, polyacrylamide, cationic
polymer such as cationic guar gum, dimethylacrylic ammonium
polymer, acrylic acid-methacrylic acid copolymer,
polyoxyethylene-polypropylene copolymer, polyvinyl alcohol,
pullulan, agar, gelatine, chitosan, polysaccharide from tamarindo
seed, xanthan gum, carageenan, high-methoxyl pectin, low-methoxyl
pectin, guar gum, acacia gum, microcrystalline cellulose,
arabinogalactan, karaya gum, tragacanth gum, alginate, albumin,
casein, curdlan, gellan gum, dextran, cellulose, polyethyleneimine,
high polymerized polyethylene glycol, cationic silicone polymer,
synthetic latex, acrylic silicone, trimethylsiloxysilicate and
fluorinated silicone resin.
[0084] A pH adjuster may be used in the compositions to adjust pH
of the composition to a desired range, such as pH 4-10, or pH 5-8,
for example or any range that maximizes the penetration through the
skin of the particular drug in the composition. pH adjustment can
be achieved through use of various chemicals such as hydrochloric
acid, citric acid, sodium citrate, acetic acid, sodium acetate,
ammonium acetate, succinic acid, tartaric acid, L-sodium tartrate,
sodium hydrate, potassium hydrate, sodium carbonate, sodium
hydrogencarbonate, lactic acid, calcium lactate, sodium lactate,
sodium fumarate, sodium propionate, boric acid, ammonium borate,
maleic acid, phosphoric acid, sodium hydrogenphosphate, dl-malic
acid, adipic acid, triethanolamine, diisopropanolamine, meglumine,
monoethanolamine, sulfuric acid and aluminum potassium sulfate and
the like.
[0085] Stabilizers may optionally be included in the compositions
of the invention. Useful stabilizers include for example sodium
bisulfite, sodium sulfite, sodium pyrosulfite, sodium formaldehyde
sulfoxylate, L-ascorbic acid, erythorbic acid, L-cysteine,
thioglycerol, butylated hydroxyanisole (BHA), butylated
hydroxytoluene (BHT), propyl gallate, ascorbyl palmitate,
dl-.alpha.-tocopherol, nordihydroguaiaretic acid,
1-hydroxyethylidene-1,1-diphosphonic acid, disodium edetate,
tetrasodium edetate dehydrate, sodium citrate, sodium
polyphosphate, sodium metaphosphate, gluconic acid, phosphoric
acid, citric acid, ascorbic acid and/or succinic acid.
[0086] Other optional components of the compositions include
wetting agents such as glycerol, polyethylene glycol, sorbitol,
maltitol, propylene-glycol, 1,3-butanediol and hydrogenated maltose
syrup; antioxidants such as sodium bisulfite, sodium sulfite,
sodium pyrosulfite, sodium formaldehyde sulfoxylate, L-ascorbic
acid, erythorbic acid, L-cysteine, thioglycerol, butylated
hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl
gallate, ascorbyl, palmitate, dl-.alpha.-tocopherol and
nordihydroguaiaretic acid; preservatives such as methylparaben,
propylparaben, chlorobutanol, benzyl alcohol, phenylethyl alcohol,
benzalkonium chloride, phenol, cresol, thimerosal, dehydroacetic
acid and sorbic acid; ultraviolet absorbent such as octyl
methoxycinnamate, glyceryl monooctanoate di-para-methoxy cinnamate,
2-hydroxy-4-methoxybenzophenone, para-aminobenzoic acid,
para-aminobenzoic acid glycerol ester,
N,N-dipropoxy-para-aminobenzoic acid ethyl ester,
N,N-diethoxy-para-aminobenzoic acid ethyl ester,
N,N-dimethyl-para-aminobenzoic aid ethyl ester,
N,N-dimethyl-para-aminobenzoic acid butyl ester, homomethyl
N-acetylanthranilate, amyl salicylate, menthyl salicylate,
homomethyl salicylate, octyl salicylate, phenyl salicylate, benzyl
salicylate and p-isopropyl phenyl salicylate.
[0087] The formulations of the invention may be in any form, e.g.,
gels, creams, lotions, and the like. The formulations are not
limited in form and may include for example liposomes and other
vesicles, such as transfersomes, which include surface active
agents and are particularly useful for the transdermal delivery of
large molecules such as peptide and proteins; and thosomes, which
are liposomes that contain ethanol, which functions as a permeation
enhancer.
[0088] The following tables provide non-limiting examples of
excipients (and amounts thereof) that may be included in the
inventive compositions.
Gel Formulations:
TABLE-US-00001 [0089] Class Excipients Polymers Methyl cellulose
Hydroxyethylcellulose Hydropropylcellulose Hydroxypropylmethyl
cellulose Sodium carboxy methyl cellulose Carbopol Chitosan
Poloxamer (Pluronics .RTM.) Sodium alginate Polyvinyl alcohol
Xanthan gum
Cream Formulations:
TABLE-US-00002 [0090] Class Excipient Hydrophobic Stearic acid
excipients Palmitic acid Lauric acid Capric acid Mineral oil Bees
wax Silicone oil Emulsifiers Stearyl alcohol (Hydrophobic and Cetyl
alcohol Hydrophilic) Glyceryl monostearate Polyethylene glycol
monostearate Sorbitan monostearate Sorbitan monolaurate Sorbitan
monopalmitate Sorbitan monostearate Sorbitan monoleate Sorbitan
sesquiolate Sorbitan trioleate Cetaryl alcohol Cetereth 20
(ethoxylated derivative of cetaryl alcohol) Sodium
stearoyl-2-lactylate Calcium stearoyl-2 lactylate Polysorbate
Sodium lauryl sulfate Stearyl colamino formyl methyl pyridinium
chloride Sodium borate Polyoxyethylene lauryl alcohol Polyoxylated
oleyl alcohol Polyoxyethylene stearate Polyoxyethylene sorbitan
monostearate Polyoxyethylene glycol monostearate Propylene glycol
monostearate Ethoxylated lanolin Ethoxylated cholesterol
Hydrophilic Purified water excipients Buffers Polymers (as outlined
for gels) Humectants Glycerin Sorbitol Propylene glycol
Polyethylene glycol (low molecular weight)
[0091] Ointment Formulations:
Petrolatum
White wax
Lanolin
Mineral oil
Bees wax
Microcrystalline
[0092] wax
Cholesterol
[0093] Cetyl alcohol Stearyl alcohol
Sorbitan
[0094] sesquioleate Lanolin alcohol
[0095] Exemplary Preservatives that May be Included in the
Compositions of the Invention:
TABLE-US-00003 Preservatives Bithional Butyl p- hydroxybenzoate
p-chloro-m-xylenol Dehydroacetic acid Ethyl paraben Methyl-p-
hydroxybenzoate Propyl-p- hydroxybenzoate Sorbic acid
[0096] Exemplary Hydrating Agents that May be Included in the
Compositions of the Invention and Exemplified Amounts Thereof:
TABLE-US-00004 Excipient FDA Maximum Potency LACTIC ACID TOPICAL;
EMULSION, CREAM: 1.00% TOPICAL GEL: 6.07% TOPICAL LOTION: 5.70%
TOPICAL OINTMENT: NOT KNOWN TOPICAL SUSPENSION: 0.70% TOPICAL
SOLUTION: 18.06% SORBITOL TOPICAL; EMULSION: 7.00% TOPICAL;
EMULSION, CREAM: 67.52% TOPICAL; LOTION: NOT KNOWN GLYCERIN
TOPICAL; CREAM: 4.0% TOPICAL; CREAM, EMULSION,: 2.0% TOPICAL;
EMULSION, CREAM: 20.0% TOPICAL; GEL: 20.0% TOPICAL; LOTION: 50.0%
TOPICAL; OINTMENT: NOT KNOWN TOPICAL; SOLUTION: 50.0% TRANSDERMAL;
GEL: 5.0% HEXANETRIOL TOPICAL; EMULSION, CREAM: 7.50% (1,2,6-
HEXANETRIOL) PROPYLENE TRANSDERMAL GEL: 6.0% GLYCOL TOPICAL
OINTMENT: 38% TOPICAL LOTION: 59% TOPICAL GEL: 98.09% TOPICAL
EMULSION CREAM: 71.08% HEXYLENE TOPICAL; EMULSION, CREAM: 12.0%
GLYCOL TOPICAL; GEL: 2.0% TOPICAL; OINTMENT: 12.0% TOPICAL;
SOLUTION: 12.0% TOPICAL; SOLUTION: 29.70% POLYETHYLENE TOPICAL;
OINTMENT: 39.0% GLYCOL 200 POLYETHYLENE TOPICAL; OINTMENT: 57.0%
GLYCOL 300 TOPICAL; SOLUTION: 29.70% POLYETHYLENE TOPICAL;
EMULSION, CREAM: 7.50% GLYCOL 400 TOPICAL; GEL: 45.0% TOPICAL;
LOTION: 12.0% TOPICAL; OINTMENT: 65.0% TOPICAL; SOLUTION:
69.90%
[0097] Examples of Other Useful Hydrating Agents:
Glycolic Acid
[0098] Glycolate salts
D-panthenol
[0099] Hyaluronic acid
Lactamide
[0100] monoethanolamine
Acetamide
[0101] monoethanolamine
[0102] Exemplary Permeation Enhancers for Use in the Compositions
of the Invention (and Exemplified Amounts Thereof):
TABLE-US-00005 Class Excipient FDA Maximum Potency Terpenes MENTHOL
TOPICAL LOTION: 0.05% LIMONENE, DL- TOPICAL SOLUTION: 0.08%
A-TERPINEOL TOPICAL LOTION: 10% TOPICAL LOTION: 11% Essential Oils
PEPPERMINT OIL TOPICAL OINTMENT: NOT KNOWN Fatty Acids and
ISOPROPYL MYRISTATE 0.02%-35% Esters ISOPROPYL PALMITATE 1.8%-3.9%
OLEIC ACID TOPICAL SOLUTION: 7.4% OLEYL OLEATE TOPICAL OINTMENT:
2.55% STEARIC ACID TOPICAL; CREAM, AUGMENTED: 3.0% TOPICAL;
EMULSION, CREAM: 22.60% TOPICAL; LOTION: 20.0% TOPICAL; OINTMENT:
15.0% TOPICAL; SUSPENSION: 1.75% ETHYL ACETATE TOPICAL; SOLUTION:
31.0% DIETHYL SEBACATE TOPICAL; SOLUTION: 24.0% Alcohols, Glycols
ALCOHOL 1.20-97.50% and glycerides PROPYLENE GLYCOL TRANSDERMAL
GEL: 6.0% TOPICAL OINTMENT: 38% TOPICAL OINTMENT AUGMENTED: 65.0%
TOPICAL LOTION: 59% TOPICAL LOTION AUGMENTED: 30.0% TOPICAL GEL:
98.09% TOPICAL EMULSION CREAM: 71.08% TOPICAL EMULSION LOTION:
47.50% BENZYL ALCOHOL TOPICAL; CREAM, AUGMENTED: 1.00% TOPICAL;
CREAM, EMULSION, SUSTAINED RELEASE: 1.0% TOPICAL; EMULSION, CREAM:
2.70% TOPICAL; GEL: 50.0% TOPICAL; LOTION: 1.30% TOPICAL; OINTMENT:
2.20% TOPICAL; SOLUTION: 2.0% TOPICAL; SUSPENSION: 1.0%
CAPRYLIC/CAPRIC TOPICAL; CREAM, EMULSION, TRIGLYCERIDE SUSTAINED
RELEASE: PENDING (10.0%) TOPICAL; EMULSION, CREAM: PENDING (10.80%)
TOPICAL; SOLUTION: PENDING (50.0%) CAPRYLIC/CAPRIC/STEARIC TOPICAL;
OINTMENT: 70.0% TRIGLYCERIDE MYRISTYL ALCOHOL TOPICAL; EMULSION,
CREAM: 3.0% TOPICAL; LOTION: 1.0% TOPICAL; SUSPENSION: 1.05% CETYL
ALCOHOL TOPICAL; CREAM, AUGMENTED: 4.0% TOPICAL; CREAM, EMULSION,
SUSTAINED RELEASE: 6.0% TOPICAL; EMULSION, AEROSOL FOAM: 3.22%
TOPICAL; EMULSION, CREAM: 12.0% TOPICAL; LOTION: 68.40% TOPICAL;
OINTMENT: 7.0% TOPICAL; SUSPENSION: 2.01% CETOSTEARYL ALCOHOL
TOPICAL; CREAM, AUGMENTED: 8.0% TOPICAL; EMULSION, CREAM: 12.0%
TOPICAL; EMULSION, LOTION: 5.0% TOPICAL; LOTION: 4.0% TOPICAL;
OINTMENT: 1.20% TOPICAL; SUSPENSION: 2.50% STEARYL ALCOHOL TOPICAL;
AEROSOL: 0.53% TOPICAL; CREAM, AUGMENTED: 4.0% TOPICAL; CREAM,
EMULSION, SUSTAINED RELEASE: 3.0% TOPICAL; EMULSION, AEROSOL FOAM:
0.53% TOPICAL; EMULSION, CREAM: 30.0% TOPICAL; LOTION: 12.0%
TOPICAL; OINTMENT: 8.0% TOPICAL; SUSPENSION: 2.01% VAGINAL;
EMULSION, CREAM: 42.50% TOPICAL; OINTMENT: PENDING (0.75%) OLEYL
ALCOHOL TOPICAL; EMULSION, CREAM: 10.0% TOPICAL; OINTMENT: 5.0%
Surfactants SODIUM LAURYL SULFATE TOPICAL; EMULSION, CREAM: 2.50%
TOPICAL; LOTION: 0.50% TOPICAL; OINTMENT: 1.0% POLYSORBATE 20
TOPICAL; EMULSION: 2.0% TOPICAL; EMULSION, CREAM: 0.80% TOPICAL;
LOTION: 7.8% TOPICAL; SOLUTION: 15.0% POLYSORBATE 60 TOPICAL;
EMULSION, AEROSOL FOAM: 0.42% TOPICAL; EMULSION, CREAM: 8.0%
TOPICAL; LOTION: 5.0% TOPICAL; SHAMPOO: 15.0% TOPICAL; SUSPENSION:
2.85% LECITHIN TOPICAL; GEL: 1.0% TOPICAL; SOLUTION: 1.40%
[0103] Other Permeation Enhancers
TABLE-US-00006 Class Excipient Terpenes Eucalyptol: 1,8-cineole
.alpha.-pinene Menthone Nerolidol Terpineol Carvol Carvone Pulegone
cyclohexane oxide limonene oxide Anise Essential Oils Eucalyptus
turpentine oil Amides Urea Dimethylacetamide (DMA) Diethyltoluamide
dimethylformamide (DMF) Dimethyloctamide Dimethyldecamide
N-methyl-2-pyrrolidone (NMP) 2-pyrrolidone N-dodceyl-2-pyrrolidone
(2-pyrrolidone derivative) Fatty acid esters of
N-(2-hydroxyethyl)-2- pyrrolidone (HEP)
1-butyl-3-dodecyl-2-pyrrolidone 1-ethyl-2-pyrrolidone
1-butyl-2-pyrrolidone 1-hexyl-2-pyrrolidone 1-octyl-2-pyrrolidone
1-lauryl-2-pyrrolidone 1-methyl-4-carboxy-2-pyrrolidone
1-hexyl-4-carboxy-2-pyrrolidone 1-lauryl-4-carboxy-2-pyrrolidone
1-methyl-4-methoxycarbonyl-2-pyrrolidone
1-hexyl-4-methoxycarbonyl-2-pyrrolidone
1-lauryl-4-methoxycarbonyl-2-pyrrolidone N-cyclohexylpyrrolidone
N-dimethylaminopropyl-pyrrolidone N-cocoalkypyrrolidone
n-tallowalkylpyrrolidone Fatty Acids and Linoleic Acid Esters
Sodium Oleate Lauric Acid Capric Acid Neodecanoic acid Fatty acid
extract of cod liver oil Valeric Heptanoic Pelagonic caproic capric
caprylic palmitoleic acid Isovaleric Neopentanoic Neoheptanoic
Neononanoic trimethyl hexanoic Neodecanoic Isostearic isopropyl
n-butyrate isopropyl n-hexanoate isopropyl n-decanoate isopropyl
myristate isopropyl palmitate octyldodecyl myristate ethyl acetate
butyl acetate methyl acetate Methylvalerate Methylpropionate
diethyl sebacate ethyl oleate Sulfoxides and Dimethyl sulfoxide
(DMSO) Similar Decylmethyl sulfoxide (DCMS) Compounds Various
N,N-dimethylamides N,N-dimethylformamide Dimethylacetamide (DMA)
N,N-dimethyloctanamide N,N-dimethyldecanamide Alcohols, Glycols
n-alkanols (1-nonanol, octyl alcohol) and Glycerides Lauryl alcohol
Propanol Butanol 2-butanol Pentanol 2-pentanol Hexanol Octanol
Nonanol Decanol glycerol monocaprylate decyl alcohol Lauryl alcohol
Linoleyl alcohol linolenyl alcohol ethylene glycol diethylene
glycol triethylene glycol dipropylene glycol Propanediol Butanediol
Pentanediol Surfactants Sodium laurate sodium octyl sulfate
cetyltrimethylammonium bromide tetradecyltrimethylammonium bromide
octyltrimethyl ammonium bromide benzalkonium chloride
cetylpyridinium chloride dodecyltrimethylammonium chloride
hexadecyltrimethylammonium chloride hexadecyl trimethyl
ammoniopropane sulfonate oleyl betaine Cocamidopropyl
Hydroxysultaine cocamidopropyl betaine Brij (30, 93, 96, 99) Span
(20, 40, 60, 80, 85) Tween (20, 40, 60, 80) Myrj (45, 51, 52)
Miglyol 840 sodium cholate sodium salts of taurocholic (TC)
Glycolic desoxycholic acids Phospholipids phosphatidyl glycerol
phosphatidyl glycerol derivatives (PGE, PGS, DMPG, DSPG, DOPG)
phosphatidyl choline derviatives (PCS, PCE, DOPC, DLPC, HPC)
Cyclodextrin .beta.-cyclodextrin Complexes
methyl-.beta.-cyclodextrin O-carboxymethyl-o-ethyl-B-cyclodextrin
(CME- B-CD) 2-hydroxypropyl-.beta.-cyclodextrin (HP.beta.CD)
2,6-dimethyl-.beta.-cyclodextriin (DIMEB) Amino Acid
N-dodecyl-L-amino acid methyl ester Derivatives n-pentyl-N-acetyl
prolinate esters of omega amino acids (octyl-6- aminohexanoate and
decyl-6-aminohexanoate) Others Clofibric Acid (amide and esters of)
Enzymes (phopholipase C, triacylglycerol hydrolase (TGH,
phospholipase A2
[0104] In certain embodiments of the invention where administration
of more than one therapeutic agent or drug is desired, the
different therapeutic agents or drugs can be separately applied to
one or both upper eyelids (or to the same region of the skin in the
case of transdedrmal application or to the same eye in the case of
eye drops and the like for application to the underside of the
eyelid(s)) or the different therapeutic agents or drugs may be
applied to different eyelids (or different regions of the skin in
the case of topical transdermal application or different eyes in
the case of eye drops and the like for application to the underside
of the eyelid(s)). In other embodiments of this aspect of the
invention, one composition containing therapeutic agent or drug and
up to 1 wt % or more of a muscle fasciculating agent and optional
ingredients such as vasodilator, vasoconstrictor, permeating agent
and combinations thereof is applied to the first eyelid of a human
patient, while the second composition, which is applied to the
other eyelid, does not contain a micro fasciculating agent and/or
one or more optional component. For example, combination therapy
for glaucoma or dry eye where two or more active agents are used to
treat the condition may be carried out by applying one drug or set
of drugs to one eyelid and another drug or combination of drugs to
the other eyelid. Similarly, one therapeutic component such as a
vasodilator may be applied to one eyelid and other active
components and other components may be applied to the other eyelid.
It is understood that the same treatments apply to eyedrops and the
like that are applied to the eye and which have contact with the
underside of the eyelid(s).
[0105] For delivery of certain drugs or therapeutic agents or for
treatment of certain conditions or diseases it may be desirable to
administer the composition of the invention via injection of a
solution containing the desired drug or therapeutic agent directly
into the underside of any portion of the eyelid, such as that
portion of the eyelid in direct contact with the eye although
contact with the eye is not necessary, rather than by topical
application to the upper eyelid. This method of drug delivery is
most useful for accessing the periocular space and tissues to (a)
achieve a high loading dose of drug; and (b) overcome drug
permeability due to drug characteristics such as high molecular
weight, ionization, etc. and is less invasive to the patient than
injecting under the conjunctiva around the eyeball. For example, a
high dose of Triamcinolone (Kenalog) MW 434 Daltons, a long acting
steroid, or Avastin, a large charged molecule MW 149,000 Daltons
can be injected via this method in order to achieve high drug
concentrations without the invasive injection into or adjacent to
the eyeball which most patients find unappealing and traumatic.
Also, a therapy regiment may be applied when warranted, which
includes an initial injection of a composition of the invention
into the underside of the eyelid, followed by application of a
topical composition containing a therapeutically effective amount
of the therapeutic agent(s) to at least one eyelid at appropriate
time intervals, e.g., within 1 to 24 hours following the injection
and once per day thereafter until the condition is effectively
treated or controlled. Conditions that can be treated in this
manner include but are not limited to keratitis inflammation such
as iritis, bleeding conditions such as hyphema, vascular
occlusions, retinal edema, age related macular degeneration, and
diabetic retinopathy. This method can be also be used to deliver
steroids or antibiotics to the eye for example.
[0106] In another embodiment of the invention, iontophoresis is
employed to ensure faster and possibly more effective uptake of
drug or therapeutic agent into the eyelid or skin and hence
circulatory system. Use of iontophoresis to deliver a composition
optionally containing a micro fasciculating agent and drug or
therapeutic agent can result in faster uptake and sustained release
of drug or therapeutic agent. In this aspect of the invention, the
drug that is applied to the skin or upper eyelid surface via
iontophoresis is charged, e.g., Avastin (bevacizumab) which is a
large charged molecule of MW 149,000 which ensures that it can be
driven across the eyelid skin via the low electrical current
provided by the iontophoresis electrode.
[0107] Although the inventors do not wish to be bound by any
theory, it is proposed that the present methods and compositions
achieve sustained release of therapeutic agent from the discovery
of the uniquely permeable and vascular skin of the human eyelid
into the systemic blood flow as long as the therapeutic agent
remains unbound within the skin layer of the upper eyelid. Further,
in those compositions of the invention containing a muscle
fasciculating agent, it is believed that continual
microcontractions in the blink muscle of the eyelid and muscle
surrounding the eyeball caused by the muscle fasciculating agent
result in a continual pumping action moving the drug into the
surrounding muscle and the vascular system, which in humans flows
towards the eyeball rather than away (as in other mammals), which
in turn, facilitates penetration of the drug into the posterior
segments of the eye (e.g., lens, vitreous, cilliary body, pars
plana and plicata, retina, optic nerve, choroid and sclera as well
as into the vascular system in general. As a result of the pumping
action achieved through the use of a muscle fasciculating agent, or
in various combinations with vasodilators, vasoconstrictors, and/or
manipulation of the pH of the compositions of the present
invention, the present methods enable the use of lower
concentrations of therapeutic agent in topical formulations to
treat conditions in the eye previously treated by systemic, oral or
other topical routes using higher concentrations of drug or
therapeutic agent than required by the present methods. The present
invention also enables reduced frequency of treatment, improved
drug targeting, continuous drug delivery, patient convenience and
ease of treatment and potentially enhanced therapeutic effects.
[0108] Similarly, when the composition is applied to the skin
rather than to the outer surface or underside of the eyelid(s),
continual microcontractions in the muscle surrounding the area to
which the composition is applied caused by the muscle fasciculating
agent result in a continual pumping action moving the drug into the
surrounding muscle and the vascular system. By manipulating the
amount of a micro fasciculating agent in the compositions of the
invention, it is possible to direct the drug in therapeutically
effective amounts to its proper target and in some cases to a
target that previously has not been accessible by non-invasive
means or in concentrations not previously obtained via topical
administration. By utilizing the unique vascular and dermal
characteristics of the upper eyelid and optionally, inclusion of a
micro fasciculating agent in the compositions, it is possible to
specifically target and deliver drugs that heretofore could not be
topically administered to achieve therapeutic concentrations of
drug at the target site, such as large molecules, e.g. certain
anti-inflammatories and antibiotics, lipophilic molecules,
hormones, immunosuppressive agents, chemotherapeutic agents,
non-steroidal anti-inflammatory agents, and anti-allergy agents.
Antibiotics such as tetracyclines and other drugs such as
demarcarium bromide, physiostigmine, neostigmine, pyridostigimine,
isofluorophate, diisopropylfluorophosphate, carbachol, dipivefrin,
apraclonodne, isoproternol, bromocriptine, phenylephrine, and
echothiophate iodide, are non-limiting examples of drugs that can
be delivered via the compositions, kits and methods of the
invention. The skilled practitioner will appreciate that any
therapeutic agent or drug (or combination of agents/drugs),
particularly those having a size range of 6000 Daltons or smaller
may be included in the compositions and kits of the invention,
although larger molecules may also be used, e.g., cyclosporine,
botox and other large organic molecules, and administered according
to the methods described herein to achieve therapeutic
concentration at the desired target site. Nonlimiting examples of
active agents that may be delivered by the methods and compositions
of the invention include glaucoma agents such as Ophthalmic
Beta-Blockers, Carbonic Anhydrase Inhibitors, Alpha-Agonists,
Miotics, Prostaglandin analogs, Latanoprost; Brimatoprosost;
Acetazolamide; Apralonidine; Betaxolol; Brimonidine; Brinzolamide;
Carbachol; Carteolol; Dorzolamide; Dipivefrin; Epinephrine;
Levobunolol; Metipranolol; Methazolamide; Pilocarpine; Timolol; and
Travaprost; Dry Eye agents such as Cyclosporine; Allergy Agents;
Antihistamines; Antihistamine/decongestants; Antihistamine/mast
cell stabilizers; Corticosteroids; Decongestants; Homeopathics;
Mast cell stabilizers; Non-steroidal anti-inflammatory drug such as
Optivar/Azelastine; aphazoline; Oxymetazoline; Phenylephrine;
Tetrahydrozoline; Emandine/Emedastine; Elestat/Epinastine; Pataday,
Patanol/Olopatadine; Levocabastine; Alomide/Lodoxamide; Cromolyn;
Alaway/Zaditor/Ketotifen; Alocril/Nedocromil; Alamast/Pemirolast;
Loratadine and Pseudoephedrine; antibiotics such as Ciprofloxacin;
Gatifloxacin; Gentamicin; Levofloxacin; Moxifloxacin; Ofloxacin;
Sulfacetamide; Tobramycin; steroids such as Dexamethasone;
Fluorometholone; Loteprednol; Medrysone; Prednisolone; Rimexolone;
andnon-steroidal anti-inflammatory agents such as Bromfenac;
Diclofenac; Flurbiprofen; Ketorolac; and Nepafenac.
[0109] Topical administration of the compositions of the invention
to the upper eyelid can be achieved by any known means such as for
example, through the use of an applicator such as a patch
containing the composition on its surface intended for contact with
the upper eyelid; a rollerball applicator integrally connected to a
container in which the invention composition is contained; an
applicator strip or plaster comprising a composition of the
invention on the surface to be applied to the eyelid; a pliable
finger cot containing a composition of the invention as a blister
positioned on the tip thereof; or an applicator for dipping into a
solution of a composition of the invention, any of which may be
provided in a kit for a patients' or physician's or other medical
personnel's use.
[0110] Topical administration of the compositions of the invention
to any region of the skin is achieved by any known means, for
example, by application of a patch containing the composition on a
portion of its surface that is applied to the skin, a cream or
lotion, strip, roller ball and the like.
[0111] Kits containing a composition(s) of the invention may
include single use dosage forms of the invention composition, or
may include a vial containing multiple doses that are to be metered
out by the patient or via the applicator itself. Further, kits may
include formulations of different therapeutic agents for treatment
of the applicable condition or disease, intended to be applied to
different eyelids or areas of the skin and/or at different times
during the treatment regimen. Kits will also include, when
necessary, instructions for the appropriate dosing regimen.
EXAMPLES
Example 1
Treatment of Severe Dry Eye
[0112] Two human patients with preexisting symptomatic severe dry
eye were treated as follows. The dry eye condition was assessed by
the Schirmers tear test and corneal observations. Each subject
received a single application of a lotion containing 1% of
pilocarpine and 0.16% caffeine applied to the upper eyelid of the
more severely affected eye by direct application of the lotion to
the upper eyelid. The effect of treatment was then measured over
six hours in regards to tear production and comfort level of the
patient.
[0113] There was a rapid increase in tear production in both
affected eyes in both subjects. There was an exponential increase
in tear production in both patients within one hour of application
that was sustained for six hours, as can be seen in FIG. 2.
[0114] Prior to treatment both patients ranked their comfort level
of the affected eye as 0 on a scale of 0 to 4 with 0 being the most
irritated and 4 being the most comfortable. After application of
pilocarpine, both patients reported a "cooling" feeling in the
affected eye within thirty minutes of treatment, which was
sustained for six to eight hours and a comfort level of 4 was
achieved and maintained within two hours of treatment. A plot of
the patients' comfort level is shown in FIG. 3.
Example 2
Intraocular Pressure
[0115] A normal human subject was selected to determine the effects
of a single application of percutaneous upper eyelid application of
a cream/lotion containing 0.2% timolol and 0.16% caffeine to the
outer surface skin of one upper eyelid. The intraocular pressure
was recorded in both the treated and untreated eye both before and
after application of the composition. Additionally, the subject's
vital signs, including pulse rate and blood pressure were recorded
at the same time intervals as eye pressure was recorded. The effect
of treatment was measured for over fifty two hours.
[0116] After a single application of timolol to one eyelid there
was a rapid decline in intraocular pressure in both eyes as shown
in FIG. 4. The treated eye showed a 73% drop in intraocular
pressure within four hours of treatment, which returned to baseline
eye pressure within 52 hours. The untreated eye rapidly dropped
intraocular pressure by 50% within the same time frame as the
treated eye, demonstrating the systemic absorption of timolol. The
intraocular pressure of the untreated eye remained depressed for 52
hours, just as with the treated eye.
[0117] Although the timolol was absorbed systemically to reach the
untreated eye, the subject's vital signs showed stability within
0.04% for heart rate and 0.5% change for systolic pressure, as
shown in FIG. 5.
Example 3
Effects of Topical Application of Physostigmine to One Eyelid
[0118] A normal human subject was selected to determine the effects
of a single application of percutaneous upper eyelid application of
a cream/lotion containing 5% physostigmine, a parasympathetic
agonist, 0.16% caffeine to the outer surface skin of one upper
eyelid. The effects on tear production, intraocular pressure and
pupilary constriction were measured in both the treated and
untreated eye both before and after application of the composition.
Additionally, the subject's vital signs, including pulse rate and
blood pressure were recorded at the same time intervals as eye
pressure was recorded. The effect of treatment was measured for
over twelve hours. Prior to treatment, the treated eye showed a
dryness level of 0, while the untreated eye had a dryness level of
2 mm by Schirmers measurement.
[0119] After a single application of physostigmine to one eyelid
there was a rapid increase in tear production from 0 to 5 mm in the
treated eye by Schirmers measurement which declined over a period
of 12 hours, as shown in FIG. 6. Tear production in the untreated
eye remained unchanged over the same time period. The treated eye
showed a 50% drop in intraocular pressure within an hour of
treatment, which returned to baseline level within 12 hours. The
intraocular pressure of the untreated eye remained unchanged over
the testing period. These results are shown in FIG. 7.
[0120] The pupil of the treated eye rapidly became miotic (pinpoint
pupil), while the pupil of the untreated eye increased in size, as
shown in FIG. 8. The increase in pupil size in the untreated eye is
the result of a systemic reaction--due to the systemic
parasympathetic stimulation by a single physostigmine application,
there was an increased sympathetic response to maintain the vital
signs and normal cardiac output, resulting in pupilary dilation in
the untreated eye.
[0121] The systemic effects of application of physostigmine to one
eyelid included an initial rapid decline in heart rate of 16%
compared to baseline in the same time frame as the ocular effects.
Physostigmine induced bradycaria in the subject, which was matched
by a 15.7% increase in systolic blood pressure. The systemic
effects are shown in FIGS. 9 and 10.
Example 4
Effect of Topical Application of Latanoprost to One Eyelid
[0122] A normal human subject was selected to determine the effects
of a single percutaneous application to one upper eyelid of a
cream/lotion containing 0.025% latanoprost, and 0.16% caffeine
(applied to the outer surface skin of the upper eyelid). The
effects on intraocular pressure were measured in both the treated
and untreated eye both before and after application of the
composition and were measured at intervals for three months. The
results are shown in FIG. 11.
[0123] FIG. 11 shows the decline in human intraocular pressure
after a single application with transdermal latanoprost on the skin
of one eyelid only. The treated eye showed a 53.8% drop in
intraocular pressure in 10 hours and had not returned to
pre-treatment levels over the three month observation period. The
subject's intraocular pressure remained at 9 or below in the
treated eye.
[0124] The untreated eye also dropped intraocular pressure by 36.3%
within the same time frame and had not returned to baseline level
after three months of observation. The subject's intraocular
pressure remained at 10 or below in the untreated eye. The
mechanism for this rapid decline in pressure in the untreated
contralateral eye is by the pharmacological activity of latanoprost
via systemic absorption.
[0125] Latanoprost is known to increase uveoscleral outflow by
increasing scleral permability. These results demonstrate a
significant sustained intraocular pressure reduction after a single
transdermal application to one eyelid that is unknown in
ophthalmology even with regular daily eye drop therapy and is
probably due to a long lasting increase in scleral permability
bilaterally. These results demonstrate that the present invention
can be applied to treatment of the entire sclera of the eye as
opposed to traditional treatment which treats only a small portion
of the sclera which is accessible via the anterior segment of the
eye.
[0126] The treated eye demonstrates a greater sustained drop in
intraocular pressure than the untreated eye. The probable mechanism
for this effect is the direct penetration of latanoprost to the
posterior segment of the treated eye to change the outflow of the
sclera in addition to the systemic blood flow carrying the drug to
the treated eye and the untreated eye. The untreated eye
demonstrates the effect achieved solely by systemic transport of
latanoprost to the eyeball.
Example 5
Effect of Topical Application of Brimonidine to One Eyelid
[0127] A normal human subject was selected to demonstrate the
effect of a single application of transdermal 0.05% Brimonidine
lotion/cream without caffeine to the unaltered, untreated skin of
the upper eyelid of one eye. The results are shown in FIG. 12. The
intraocular pressure in both the treated and untreated eyes remains
virtually unchanged over a period of seven hours and actually
increased in the treated eye by one point.
[0128] The same treatment was then repeated in the same subject
using transdermal application to a single eyelid of a lotion/cream
composition comprising 0.05% Brimonidine and 0.16% caffeine. The
results are shown in FIG. 13. The intraocular pressure decreased
symmetrically in both eyes by 25% within one hour after application
and by 37.5% in the treated eye and 31.3% in the untreated eye in
two hours. The effect of a single application to one eyelid was
sustained in both eyes 28 hours later and was 31.3% less than
baseline in both eyes. The effect lasted for two weeks and
gradually wore off in 4 weeks. The graph shows the first 48 hours
of this period.
[0129] Brimonidine is routinely administered as an eye drop which
is typically dosed at least two times a day and produces about a
24% drop in intraocular pressure, with numerous well known
side-effects per FDA data including itching, redness, and
intolerance in up to 20% of patients necessitating stoppage of the
drug. Additionally, according to FDA clinical data, 30% more
patients had to discontinue the Brimonidine 0.2% eye drop use due
to lack of clinical effect. In contrast, the results herein show a
dramatic clinical effect without any side effects using only 25% of
the concentration of the drug that the FDA tested.
Example 6
Topical Eyelid Application of Insulin/Humulin to a Non-Diabetic
Subject
[0130] A normal non-diabetic human subject was selected to
demonstrate the effect of a single transdermal application of a
lotion/cream containing 4 units of Insulin/Humulin and 0.16%
caffeine to the unaltered, untreated normal skin of both upper
eyelids. The results are shown in FIG. 14.
[0131] The subject's starting glucose level dropped by 12.5% in 45
minutes, and 15.6% in 1 hour and 15 minutes. The subject's blood
sugar remained low at 81 and the subject reported hypoglycemic
symptoms of sweating, tachycardia, dizziness, and headache.
Consequently, the study was aborted and glucose was
administered.
Example 7
Topical Eyelid Application of Insulin/Humulin to a Diabetic
Subject
[0132] A non-insulin dependent diabetic human subject was selected
to demonstrate the effect of a single transdermal application of a
lotion/cream comprising 4 units Insulin/Humulin and 0.16% caffeine
to the unaltered, untreated normal skin of a both upper eyelids of
both eyes. All diabetic medications had been discontinued for 3
days prior to achieve systemic washout of oral medications. The
results are shown in FIG. 15.
[0133] FIG. 15 shows the results of three trials: one trial was
conducted with 4 units of Humulin and two trials were conducted
with 4 units of Humulog. Humulog is insulin lispro which is a rapid
and intermediate acting insulin of MW 5808 Daltons while Humulin is
MW 5807.72 Daltons and is short acting.
[0134] In Trial I (Humulin) the subject's blood sugar dropped by
18.1% in 2 hours, 44.6% in 3.5 hours, and 49% in 5.5 hours to a
normal range of blood glucose level.
[0135] In Trial II (Humulog), the subject's blood sugar response
showed a more precipitous response with blood sugar decline of
45.4% in a 3.5 hour period despite a higher starting blood glucose
level compared to Trial 1 of Humulin. Finally, Trial I of Humulog
was also conducted to demonstrate the effect of Humulog at an even
higher starting blood glucose level of 351 mg/dl. The subject's
blood sugar dropped by 57.8% in 2.5 hours, and by 65.6% to a normal
level of 121 in 4.5 hours.
[0136] These results demonstrate clinical effectiveness of the
present invention at three different levels of diabetic range blood
glucose levels in a human diabetic patient.
Example 8
Topical Eyelid Application of Lisinopril
[0137] An uncontrolled hypertensive human subject was selected to
demonstrate the effect of a single transdermal application of a
cream/lotion composition comprising 8 mg lisinopril and 0.16%
caffeine to the unaltered, untreated normal skin of the upper
eyelids of both eyes of the subject. All hypertensive medication
(Telmisartan) had been discontinued for 10 days prior to achieve
systemic washout. The patient's baseline blood pressures off all
hypertensive medications were checked a total of 10 times on
different days and times of the day. The blood pressure averaged a
systolic of 145 and a diastolic of 85.
[0138] The subject's blood pressure was re-measured immediately
prior to applying the lisinopril/caffeine transdermal cream and was
140 systolic and 80 diastolic. The systolic blood pressure
sustained a 15.7% drop in the first hour post application with the
diastolic pressure remaining stable. Within two hours the systolic
blood pressure declined further to 17.8% lower than baseline and
the diastolic blood pressure for the first time, now declined by
12.5%. For the next 26 hours, the systolic blood pressure ranged
from a drop of 11.4% to 17.1% less than baseline. The diastolic
blood pressure also remained less than baseline and ranged from 5%
to 12.5% less than baseline pre treatment diastolic blood pressure.
Even 52 hours after application, the subject's blood pressure was
115 systolic and 73 diastolic, which represents a 17.8% drop in
systolic blood pressure and an 8.75% drop in diastolic blood
pressure compared to pretreatment blood pressure. These results are
shown in FIG. 16.
[0139] The subject's heart rate during the trial showed a 16.6%
increase during the first two hours of the trial during which time
both the systolic and diastolic blood pressure declined by 17.8%
and 12.5%, respectively. The percentage rise in heart rate nearly
matches the percentage decline in systolic blood pressure,
demonstrating the human body's ability to maintain perfusion by
compensating for a pharmacologically induced decline in blood
pressure (hypotension) by increasing heart rate via endogenous
sympathetic compensatory mechanisms. This increase in heart rate is
not sustained, since the patient's endogenous mechanisms to
increase vascular resistance were probably activated leading to a
subsequent increase in systolic blood pressure to 14.3% less than
baseline and the heart rate went back to baseline. The diastolic
blood pressure remained stable, but did not affect the heart rate
as did the systolic blood pressure.
Example 9
Topical Eyelid Application of Pilocarpine
[0140] A human subject with preexisting symptomatic severe dry eye
was selected for testing. The dry eye was quantified by Schirmer's
tear testing and corneal findings. The subject received treatment
with a single application of a cream/lotion comprising 1%
pilocarpine without caffeine to the normal untreated, unaltered
skin of one upper eyelid. The effect of treatment was then measured
over six hours in tear production and comfort. The results are
presented in FIGS. 17 and 18 and are described below.
[0141] FIG. 17 demonstrates the rapid increase in human tear
production in the setting of severe dry eye in a subject who was
treated with a single transdermal application of pilocarpine lotion
as described above. The treatment had been applied to the upper
eyelid skin of the eye with a baseline tear production of zero. The
subject showed an exponential increase in natural tear production
within an hour; the increase was self sustained for six hours.
Although the tear production was significant, it is somewhat less
than that generated by the application of a combination of
pilocarpine and caffeine (shown in FIG. 2).
[0142] There was also an increase in tear production in the
untreated eye, which though severely dry also was not as bad as the
baseline in the treated eye. The level of tear production in this
eye approached normal after treatment.
[0143] FIG. 18 shows the subjective comfort level of the severe dry
eye subject for the treated and untreated eye both before and after
application of pilocarpine lotion/cream. Prior to treatment, the
comfort level of the dry eye was ranked on a scale of 0 to 4; 0
being the most irritated and 4 being the most comfortable. After
application of Pilocarpine lotion/cream, the subject reported an
increase in comfort level to a constant score of three. However,
the subject noted the absence of the "cooling" feeling with this
treatment.
Example 9
Formulations
[0144] Each of the following formulations were made by the same
basic formulation procedure:
1) In the main tank, added water, and BG Glycerin. Mixer was turned
on and brought to medium speed. 2) Carbopol 940 was slowly
sprinkled into the vortex. Continued mixing for 15-20 minutes until
free of clumps. 3) Heated the mixture to 65 C and added phase C
(preservatives) 4) In a separate mixing hot tank, the oil phase
(Phase D) was combined and heated to 65.degree. C. 5) When the main
tank and premix tank reached 65.degree. C., the oil phase was added
to the main tank. 6) PEG 8 and optionally caffeine were added with
continued mixing it until coos down to 50.degree. C. 7) In separate
bucket, a 25% sodium hydroxidesolution was prepared with deionized
water, mixing until sodium hydroxide dissolved. (Cautious: Be sure
to wear sleeve, lab coat and safety goggles when preparing this
solution) 8) The sodium hydroide solution was poured into the main
batch. Mixing speed was turned to high speed until a slight vortex
was achieved. 9) The batch was cooled to 40-50.degree. C. and then
Tetrasodium EDTA was added and mixed for 5-10 minutes. 10) Add
Saccharide Isomerate and mix until the batch is homogenous. 11) A
top and bottom sample were obtained for analysis. 12) Mixed in the
listed drug or therapeutic agent, partially dehydrated into 0.005
gm of the formulation. The following are representative examples of
gel, cream, ointment and vesicle based topical bases used in the
examples set forth above.
A. Gel
TABLE-US-00007 [0145] Excipient Use Hydroxyethylcellulose Viscosity
modifier Ethanol Permeation enhancer Methyl paraben Preservative
Propyl paraben Preservative Water/Buffer
B. Cream
TABLE-US-00008 [0146] Excipient Use Stearic acid Oily phase
Propylene glycol monostearate Emulsifier Propylene glycol Humectant
Isopropyl palmitate/Isopropyl myristate Permeation enhancer
Polysorbate 60 Emulsifier Methyl paraben Preservative Propyl
paraben Preservative Water/Buffer
C. Ointment
TABLE-US-00009 [0147] Excipient Use White petrolatum Oily phase
White wax Oily phase Stearyl alcohol Emulsifier Cholesterol
Emulsifier Isopropyl palmitate/Isopropyl myristate Permeation
enhancer
D. Ethosomes (Vesicular Technology)
TABLE-US-00010 [0148] Excipient Use Distearyl phosohotidyl choline
Vesicle forming agent Ethanol Skin permeation enhancer Cholesterol
Vesicle membrane stabilizer Carbopol Gel forming agent Water
Formulations Used in the Examples:
Pilocarpine 1% Formulation Without Caffeine
TABLE-US-00011 [0149] Phase Ingredients % by WT A Water (Deionized)
65.7000 D Caprylic/capric Triglyceride 15.6500 D C12-20 Acid PEG-8
Ester 5.0000 A Butylene Glycol 4.4400 A Glycerin 3.2500 H
Saccharide Isomerate 2.0000 E PEG-8 1.75 D Cetyl Alcohol 1 B
Carbomer 940 0.3 G Tetrasodium EDTA 0.2 F Sodium Hydroxide (25% 0.3
Solution) C Methylparaben 0.2 C Propylparben 0.05
Pilocarpine 1% Formulation with 0.16% Caffeine
TABLE-US-00012 Phase Ingredients % by WT A Water (Deionized)
65.7000 D Caprylic/capric Triglyceride 15.6500 D C12-20 Acid PEG-8
Ester 5.0000 A Butylene Glycol 4.4400 A Glycerin 3.2500 H
Saccharide Isomerate 2.0000 E PEG-8 1.75 D Cetyl Alcohol 1 B
Carbomer 940 0.3 G Tetrasodium EDTA 0.2 F Sodium Hydroxide (25% 0.3
Solution) C Methylparaben 0.2 C Propylparben 0.05 E Caffeine
0.16
TABLE-US-00013 PROPOSED TEST SPECIFICATION Appearance White Viscous
Solution Color White Viscous Solution Order Fragrance Free Clarity
Opaque pH 5.7-6.7 % solids 25.7-28.5 Viscosity 57,000-96,000
cps
Physostigmine (5%) Formulation with Caffeine
TABLE-US-00014 Phase Ingredients % by WT A Water (Deionized) 657000
D Caprylic/capric Triglyceride 156500 D C12-20 Acid PEG-8 Ester
50000 A Butylene Glycol 44400 A Glycerin 32500 H Saccharide
Isomerate 20000 E PEG-8 1.75 D Cetyl Alcohol 1 B Carbomer 940 0.3 G
Tetrasodium EDTA 0.2 F Sodium Hydroxide (25% 0.3 Solution) C
Methylparaben 0.2 C Propylparben 0.05 E Caffeine 0.16
TABLE-US-00015 PROPOSED TEST SPECIFICATION Appearance White Viscous
Solution Color White Viscous Solution Order Fragrance Free Clarity
Opaque pH 5.7-6.7 % solids 25.7-28.5 Viscosity 57,000-96,000
cps
Timolol (0.25%) Formulation with Caffeine
TABLE-US-00016 Phase Ingredients % by WT A Water (Deionized) 657000
D Caprylic/capric Triglyceride 156500 D C12-20 Acid PEG-8 Ester
50000 A Butylene Glycol 44400 A Glycerin 32500 H Saccharide
Isomerate 20000 E PEG-8 1.75 D Cetyl Alcohol 1 B Carbomer 940 0.3 G
Tetrasodium EDTA 0.2 F Sodium Hydroxide (25% 0.3 Solution) C
Methylparaben 0.2 C Propylparben 0.05 E Caffeine 0.16
TABLE-US-00017 PROPOSED TEST SPECIFICATION Appearance White Viscous
Solution Color White Viscous Solution Order Fragrance Free Clarity
Opaque pH 5.7-6.7 % solids 25.7-28.5 Viscosity 57,000-96,000
cps
Lisinopril Formulation
TABLE-US-00018 [0150] Phase Ingredients % by WT A Water (Deionized)
657000 D Caprylic/capric Triglyceride 156500 D C12-20 Acid PEG-8
Ester 50000 A Butylene Glycol 44400 A Glycerin 32500 H Saccharide
Isomerate 20000 E PEG-8 1.75 D Cetyl Alcohol 1 B Carbomer 940 0.3 G
Tetrasodium EDTA 0.2 F Sodium Hydroxide (25% 0.3 Solution) C
Methylparaben 0.2 C Propylparben 0.05 E Caffeine 0.16
TABLE-US-00019 PROPOSED TEST SPECIFICATION Appearance White Viscous
Solution Color White Viscous Solution Order Fragrance Free Clarity
Opaque pH 5.7-6.7 % solids 25.7-28.5 Viscosity 57,000-96,000
cps
Latanoprost Formulation without Caffeine
TABLE-US-00020 Phase Ingredients % by WT A Water (Deionized) 657000
D Caprylic/capric Triglyceride 156500 D C12-20 Acid PEG-8 Ester
50000 A Butylene Glycol 44400 A Glycerin 32500 H Saccharide
Isomerate 20000 E PEG-8 1.75 D Cetyl Alcohol 1 B Carbomer 940 0.3 G
Tetrasodium EDTA 0.2 F Sodium Hydroxide (25% 0.3 Solution) C
Methylparaben 0.2 C Propylparben 0.05
TABLE-US-00021 PROPOSED TEST SPECIFICATION Appearance White Viscous
Solution Color White Viscous Solution Order Fragrance Free Clarity
Opaque pH 5.7-6.7 % solids 25.7-28.5 Viscosity 57,000-96,000
cps
Latanoprost Formulation with Caffeine
TABLE-US-00022 Phase Ingredients % by WT A Water (Deionized) 657000
D Caprylic/capric Triglyceride 156500 D C12-20 Acid PEG-8 Ester
50000 A Butylene Glycol 44400 A Glycerin 32500 H Saccharide
Isomerate 20000 E PEG-8 1.75 D Cetyl Alcohol 1 B Carbomer 940 0.3 G
Tetrasodium EDTA 0.2 F Sodium Hydroxide (25% 0.3 Solution) C
Methylparaben 0.2 C Propylparben 0.05 E Caffeine 0.16
TABLE-US-00023 PROPOSED TEST SPECIFICATION Appearance White Viscous
Solution Color White Viscous Solution Order Fragrance Free Clarity
Opaque pH 5.7-6.7 % solids 25.7-28.5 Viscosity 57,000-96,000
cps
TABLE-US-00024 Brmonidine (Alphagan P) Formulation With
CaffeinePhase Ingredients % by WT A Water (Deionized) 657000 D
Caprylic/capric Triglyceride 156500 D C12-20 Acid PEG-8 Ester 50000
A Butylene Glycol 44400 A Glycerin 32500 H Saccharide Isomerate
20000 E PEG-8 1.75 D Cetyl Alcohol 1 B Carbomer 940 0.3 G
Tetrasodium EDTA 0.2 F Sodium Hydroxide (25% 0.3 Solution) C
Methylparaben 0.2 C Propylparben 0.05 E Caffeine 0.16
TABLE-US-00025 PROPOSED TEST SPECIFICATION Appearance White Viscous
Solution Color White Viscous Solution Order Fragrance Free Clarity
Opaque pH 5.7-6.7 % solids 25.7-28.5 Viscosity 57,000-96,000
cps
Brimonidine (Alphagan P) Formulation without Caffeine
TABLE-US-00026 Phase Ingredients % by WT A Water (Deionized) 657000
D Caprylic/capric Triglyceride 156500 D C12-20 Acid PEG-8 Ester
50000 A Butylene Glycol 44400 A Glycerin 32500 H Saccharide
Isomerate 20000 E PEG-8 1.75 D Cetyl Alcohol 1 B Carbomer 940 0.3 G
Tetrasodium EDTA 0.2 F Sodium Hydroxide (25% 0.3 Solution) C
Methylparaben 0.2 C Propylparben 0.05
TABLE-US-00027 PROPOSED TEST SPECIFICATION Appearance White Viscous
Solution Color White Viscous Solution Order Fragrance Free Clarity
Opaque pH 5.7-6.7 % solids 25.7-28.5 Viscosity 57,000-96,000
cps
* * * * *