Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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LUBRICANT FOR THE OCULAR SURFACE
Cross Reference to Related Applications
Priority is claimed to U.S. Provisional Application Serial No.
60/552,577 filed March 12, 2004 and U.S. Provisional Application Serial
No. 60/562,63 filed April 15, 2004.
Background of the Invention
This invention is generally in the field of ocular lubricants, and in
particular relates to a formulation for treatment of the symptoms of dry eye.
The surface of the eye requires constant lubrication for proper
function. This includes quality of vision as well as comfort. The eye
becomes irritated and vision blurs when inadequately lubricated. This
condition is frequently referred to as dry eye. Inadequately treated severe
dry eye can lead to cornea scarring, blindness and even loss of the eye. Dry
eye is a common condition and many over-the-counter and even prescription
therapies are available to mitigate this at times difficult and annoying
condition. Many patients are unable to find relief with present therapies.
It is well recognized that the meibomian gland secretions of the
eyelid provide the lipid layer of the tear film. The major component of the
meibomian gland lipid secretions are wax esters (Driver and Lemp,
Meibomian Gland Dysfunction, Surv Ophthahnol 40:343-367,1996). It is
also known that the natural product jojoba is comprised of over 97% wax
esters of the long chain variety similar to that of the lipid tear film.
It is therefore an object of the present invention to provide a
formulation for alleviating the symptoms of dry eye.
It is a further object of the present invention to provide an over the
counter formulation for alleviating the symptoms of dry eye.
Summary of the Invention
A formulation has been developed for treatment of the symptoms of
dry eye which incorporates the natural product jojoba wax, or components
thereof, to enhance the spreading of the artificial tear as well as stabilize
the
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tear film. The jojoba wax tear relieves irritation and discomfort as well as
sharpens the blurred vision.
Detailed Description of the Invention
A jojoba liquid wax formulation providing comfort and clarity of
vision to patients with dry eye has been developed. The wax esters of the
jojoba improve and enhance the spreading, stability and lubricating effect of
the artificial tear on the tear film.
I. Formulation
A. Wax
In the preferred embodiment, the formulation contains jojoba wax in
an emulsion. The jojoba wax performs as lubricant and evaporation
retardant for the tear film. Jojoba wax is a liquid wax composed of long
chain wax esters. The components of the jojoba wax esters include long
chain alcohols esterified with long chain fatty acids with a total of 3 ~ to
44
carbon atoms. Exemplary long chain fatty acids include gadoleic, palmitic,
palmitoleic, stearic, oleic, linoleic, arachidic, linolenic, eicosenoic,
behenic,
erucic, lignoceric, lactic, decate, acetic and myristic fatty acids. The fatty
acids typically have carbon chains of C12 to C30, with or without various
degrees of saturation or unsaturation. The alcohol components of the wax
ester contain carbon chains between C16 and C32 with or without various
degrees of saturation or unsaturation. The alcohol component may be eicos-
11-enol, docos-13-enol, tetracos-15-enol, myristyl alcohol, octyldodecyl
stearoyl alcohol or cetyl alcohol.
Jojoba's melting point is about 6°C. It is extracted from seeds
and
leaves of the jojoba tree (Simmondsia chi~censis) cultivated in the desert
conditions of Arizona and California as well as Northern Mexico and other
locations. The chemical structure does not vary with plant type, growing
location, soil type, rainfall or altitude. The oil produced by jojoba lacks
triglycerides. It does not contain glycerol combined with fatty acids. Rather
the jojoba combines fatty alcohols with fatty acids to produce a vegetable oil
which is actually a liquid wax, having its own type of molecular size and
shape with unusual anti-evaporative properties which protect the shrub from
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its severe arid natural habitat. Jojoba wax or the wax esters therein keep the
shrub well lubricated and moisturized yet it is non occlusive. The non-
occlusive property is related to its porosity. In the shrubs and trees it is
derived from, the porosity allows for evaporative exchange of vapors thus
cooling the jojoba tree in its hot native climate.
The natural jojoba is 97% wax esters with few impurities. There are no
resins, tars, or alkaloids and only a trace amount of saturated wax, alcohols,
fatty acids, and hydrocarbons. Jojoba wax is non toxic and biodegradable
and is pasteurized to kill microorganisms (National Research Council. 1985.
Jojoba: New Crop for Arid Lauds, New Material for Ihdustt~. National
Academy Press, Washington, D.C.). The liquid wax commercially available
does not include those solid components of the seed which have toxic
effects; the glycosides simmondsin and simmondsin-2-ferulate.
The wax esters are comprised of alcohols esterified with long chain fatty
acids with a total of 38 to 44 carbon atoms. The fatty alcohols are
predominantly 20 and 22 carbon atoms with one double bond. Its fatty acids
are mostly 20:1 (70%), with some 22:1 (20%) and the remainder 18:1 (10%).
All double bonds have a cis configuration and are spaced widely apart
equidistant from the ester linkage creating an especially stable molecule
resistant to oxidation. The cis double bond configuration is also felt to give
the jojoba its porosity.
Oils having similar properties to jojoba wax, or its components, may
be substituted for the jojoba oil. Jojoba has been identified as chemically
similar to sperm whale oil, an unsaturated wax. Sperm whales were sought
for their oil throughout the 20th century since it is considered a fine
lubricant
oil. Due to the near extinction of the sperm whale, alternative lubricants
were sought. Although jojoba was known to similar to sperm whale oil since
the 1930's, the advanced study of its chemistry was not available until the
1970's and 1980's due to advances in technology. Both are fme lubricants
as they are stable at high temperatures and high pressures. However, jojoba
is now felt to be a superior lubricant to sperm whale oil (National Academy
of Sciences. 1975. Products from Jojoba: A Promising New Crop for Arid
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Lands. National Research Council Washington D.C.). Another similar oil
to sperm whale oil is from the fish Orange Roughy. This oil and other fish
oils may be used in place of or in combination with the jojoba.
Jojoba wax is approved by the Food and Drug Administration
("FDA") for use in cosmetics and other formulations for application around
the eyes, although not for direct application to the eye. Jojoba wax is used
extensively in the cosmetic industry in up to at least a 10% in water
emulsion, in eye makeup remover, as well as for skin and hair products. It is
also used in therapeutic massage. Primary eye irritation studies have been
performed in rabbits using undiluted refined jojoba liquid wax. Slight
irritation was noted which resolved within 24 hours. A 20% natural jojoba
wax dropped in rabbit eyes was concluded a nonirritant (Final Report on the
Safety Assessment of Jojoba Oil and Jojoba Wax, J Amer College
Toxicology, 11 (1),1992,57-74.) The Environmental Protection Agency
(EPA) in the Federal Register 40 CFR Part 180, 1995 acknowledged the
wide distribution of Jojoba in commerce and availability to the general
public throughout the United States without any evidence of significant
adverse effects to humans or the environment. The Cosmetic Ingredient
Review lists Jojoba as safe to use.
Jojoba wax has also been shown to help break down sebum in
plugged up sebaceous pores of the skin. It may prove to also be able to break
down and unplug the modified sebaceous (meibomian) glands of the lid
when applied as a drop or an ointment or other topical therapy.
Jojoba wax also has intrinsic antimicrobial properties which include
activity against envelope viruses, mold, fungus and bacteria. U.S. Patent
Nos. 4,585,656 and 6,559,182 describe the efficacy oftreating envelope
viruses with jojoba wax esters. In vitro experiments in the literature showed
jojoba has an intense inhibiting effect on Mycobacterium tubercle bacilli. It
may be useful as a prophylactic as well as therapeutic agent to prevent and
treat ocular or periocular infections. It may be used as therapy for infection
of any part of the eye or adnexal structure.
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Other jojoba derivatives which may be incorporated into an
ophthalmic delivery system include jojoba esters, jojoba alcohols, and the
hydrogenated jojoba solid wax. Jojoba esters are the result of an inter-
esterification of various ratios of jojoba liquid wax and hydrogenated jojoba
solid wax. The physical consistency ranges from liquid to semi-solid paste
or creams. Jojoba solid wax is derived from the hydrogenation and complete
reduction of the unsaturated wax esters. It is a hard crystalline wax
comparable to beeswax with a melting point of 69°C and can be prepared
in
a wax in water emulsion. This wax-in-water emulsion emulsifies easily and
may also be used in an ophthalmic preparation. Possible emulsifying agents
for the ophthalmic preparation include stearic acid (4%) and triethanolamine
(2%). Jojoba alcohols are generated from a sodium reduction of jojoba
liquid wax and hydrogenated jojoba solid wax with subsequent additional
refinement. Jojobutter-51 is an isomorphous mixture of jojoba liquid wax,
partially isomerized jojoba liquid wax and hydrogenated jojoba solid wax (J
Amer College Toxicology, 11 (1),1992). Sulfurization of jojoba results in
enhanced lubricant properties which is further enhanced with phosphorus,
bromine or chlorine. (Wisniak J The Chemistry and Technology of Jojoba
Oil, Am Oil Chemist Society, 1987) and may optimize the lubrication of an
ophthalmic tear supplement.
B. Artificial Tears
The wax is mixed with an aqueous solution for application to the eye.
Typically the aqueous solution may be sterile water or hypotonic or isotonic
saline and will contain buffer to physiological pH, in the range of about 7-
7.5. It may also be cell culture media such as Dulbecco's Media (DMEM). It
will also contain a surfactant/lubricant/demulcent such as polysorbate 80.
Ancillary ingredients to establish the desired tonicity with tears may include
electrolytes. Preservatives such as sodium bisulfate, ascorbic acid, alpha-
tocopherol, benzalkonium chloride, ethylenediaminetetraacetic acid (EDTA)
and chlorhexidine can be used as well as chlorbutanol, sodium perborate and
stabilized oxy-chloro complex. Other preservatives include polyquad,
polyhexamethyl biguanide, chlorhexidine, propylparabens and
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methylparabens and others. Other additives may include humectants such as
propylene glycol and sorbitol. Representative pH buffers include sodium
borate or mono and di-sodium phosphate or other phosphate, carbonate or
acetate salts.
The jojoba wax concentration in an aqueous carrier will typically be
between 0.001 % to 50%. The jojoba in aqueous emulsion may include a
second emollient such as mineral or light mineral oil. Other emollients may
be used in the emulsion such as white petrolatum, white ointment, paraffin,
and beeswax or other wax. These emollients may be used to increase the
viscosity of the emulsion. The ratio of jojoba to the second emollient is from
greater than 1:5 to 500:1. Jojoba is also available as a clear, water colored
refined liquid wax which may also be used as a second emollient in the
above ratios.
The formulation may further include a sterol, hydroxycarotenoid or
Vitamin A optionally esterified with fatty acids of various chain lengths
between C10 and C30. The formulation may also include polar lipids
including glycolipids,sphingolipids and/or phospholipids including
phosphatidylinositol, phosphatidylethanolamine, sphingomyelin,
phosphatidylglycerol, and diphosphatidylglycerol, Triglycerides may also be
included.
Suitable lubricants used with the wax ester in a concentration
between 0.01 % to 20% include cellulose derivatives. Examples of cellulose
derivatives include carboxymethylcellulose sodium 0.2 to 2.5%,
hydroxyethyl cellulose 0.2% to 2.5%, hydroxypropyl methylcellulose 0.2%
to 2.5%, and methylcellulose 0.2% to 2.5%. Other examples of lubricants
include Dextran 70, (0.1 %), gelatin, 0.01 %, glycerin, 0.2 to 1 %,
polyethylene
glycol 300, 0.2 to 1%, polyethylene glycol 400, 0.2 to 1%, polysorbate 80,
0.2 to 5%, propylene glycol, 0.2 to 5%, polyvinyl alcohol 0.1 to 5%, and
povidone 0.1 to 5%. These lubricants can increase viscosity of the artificial
tear as a mucomimetic and may be added to the formulation. The
formulation can be thought of as a tear replacement therapy. Additional
mucomimetics include carbomer and hyaluronic acid.
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Ophthalmic astringents may also be included. One example is zinc
sulfate, 0.25%. A hypertonicity agent may be used such as sodium chloride
2 to 5 %. An ophthalmic vasoconstrictor may be used including ephedrine
hydrochloride, 0.123%, naphazoline hydrochloride, 0.01 to 0.03%,
phenylephrine hydrochloride, 0.08 to 0.2% and tetrahydrozoline
hydrochloride, 0.01 to 0.05%.
The eye drop can also include a fiu ther emulsifier.
Proteins normally found in the tear may be included in the
formulation to further increase stability. These may include amongst others,
prealbumin, albumin, lyzozyme, lactoferrin,beta lactoglobulin,IgA as well as
lipocalins.
Suitable electrolytes include sodium chloride, potassium chloride,
sodium phosphate, potassium phosphate, sodium and potassium sulfates and
sodium and potassium bicarbonates. Suitable non electrolytes such as
glycerin and sugars such as urea, sorbitol, glucose and sucrose can also be
added.
In another embodiment, the jojoba wax ,up to 70%, is formulated as
an ointment emollient. A suitable carrier includes a mixture of mineral oil
and petrolatum in a ratio of about 70% to 30%, paraffin up to 5%, white
ointment up to 100%, white petrolatum up to 100%, petrolatum up to 100%,
white wax up to 5%, yellow wax up to 5%, colorless jojoba wax up to 50%,
lanolin 1 to 10% and anhydrous lanolin 1 to 10%.
The formulation can also be used as a platform to deliver other active
agents. Other active ingredients that could be used include anti-glaucoma
therapies, antibiotics, antimicrobial peptides, antivirals, antiparasitics,
antifungals, antiinflammatories, antihistamines, anti-allergy therapies,
hormones such as androgens and others, vitamins,growth factors,cytokines,
mucins,surface stimulating drugs, immunomodulators, immune response
modifiers, cytokine modifying agents, immunosuppressive agents,
antineoplastic agents,eyelash growth stimulators and other medicaments.
Additional classes of additives include lubricants, preservatives,
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stabilizers, wetting agents, emulsifiers, buffers, and different salts to
alter
osmotic pressure, as well as solubilizing agents, dispersants, and detergents.
The wax can also be added to artificial tears obtained over the
counter ("OTC"). Examples include VISINETM marketed by Pfizer,
REFRESH TEARSTM product line marketed by Allergan, SYSTANETM
marketed by Alcon, GENTEALTM marketed by Novartis, and OCUCOATTM
marketed by Bausch and Lomb.
II. Methods of Use
In the preferred embodiment, the formulation is administered once to
four times a day directly to the eyes of the individual in need thereof. The
frequency will vary depending on the severity of symptoms. The
formulation may be applied as a drop in the form of an emulsion or
suspension, liposome, lotion, ointment, cream, gel, salve or powder and
sustained or slow release, as well as eyelid lotion. It may also be used as an
I 5 eye wash or rinse to irrigate the eye. The formulation may also be applied
in
a sprayable form. This lubricant will be extremely helpful in eradicating the
symptoms of dry eye in the various settings it occurs. This includes the most
common settings of age related so called dry eye syndrome, computer related
dry eye, dry eye after Lasik, and dry eye associated with reading, driving or
watching a movie or television. Patients with contact lens intolerance or who
use an ocular prosthesis will also greatly benefit from the enhanced
lubrication. Other examples include patients with a history of eye surgery
and dry eye. This includes cataract surgery, cornea surgery and cornea
transplants. Patients with neurologic disorders such as Bell's Palsy or other
neuroparalytic as well as neurotrophic disease will also benefit.
Lagophthalmous characterized by an exposed ocular surface which can occur
while sleeping or even during waking hours will be improved with the
ointment, and/or gel form of this lubricant. Devastating although rare
mucous membrane blistering diseases as Stevens Johnson Syndrome are also
associated with both a watery and lipid dry eye due to fibrotic changes
associated with glandular tissues. The jojoba formulation should be
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especially helpful to replace lipid and aqueous deficiencies and help relieve
suffering to comfort an otherwise extremely painful eye.
Other types of dry eye characterized by plugged, inflamed and/or
dysfunctional sebaceous glands of the lid known as meibomian gland
dysfunction should also be mproved with use of this formulation applied to
the eyelids.
Patients with eye infections of the lid, conjunctiva, cornea and tear
apparatus and lacrimal gland should also benefit with application of this
formulation in one or more forms to the eyelids, conjunctiva, and cornea as
well as tear film and other adnexal structures including lacrimal gland, and
tear outflow system including puncta, canaliculi, and lacrimal sac.
In preliminary studies on skin, Jojoba wax has been shoran to relieve
pain and reduce swelling from superficial thermal and chemical burns.
There may also be a therapeutic effect on ocular burns.
The formulation can also be used to prevent, treat or alleviate the
symptoms of envelope viruses including herpes simplex keratitis, and
varicella zoster keratitis which causes chicken pox and shingles. Other viral
infections of the eye that may be treated include human herpes virus 8 (HSV
8), I~aposi sarcoma as well as Epstein-Barr virus, cytomegalic inclusion
virus (CMV) and Human Immunodeficiency Virus (HIV).
Non-ocular uses of the formulation include use to treat or prevent
accumulation of ear canal wax, treatment of vaginal dryness or other
symptoms of perimenopausal dryness, moisturizing dry nasal mucosa or
where the patient has a sinus condition, including inflammation or infection.
Examules
In a preferred embodiment, the formulation contains 0.5-5% jojoba
wax, most preferably 0.5 to 2% jojoba, 1% polysorbate 80 in an aqueous
buffered saline based liquid wax emulsion.
The 2% jojoba formulation was administered to a total of 16
volunteer individuals with different types of irritated eyes. The drop was
reported to be extremely comfortable for all individuals without causing
visual blur.
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Three volunteers had painful dry eye after Lasik. None of the
conventional therapies had helped them thus far. For PC, AS, and IAA, relief
was immediate and lasted about 8-10 hours.
For TB who said his irritation was allergic in nature, none of the
presently available OTC drops had helped relieve his severe symptoms. One
drop of the jojoba wax formulation applied to each eye relieved all
symptoms for the entire day.
For JR who said his eyes are always irritated in the morning, get red
and stay red for hours and who has yet to find a comfortable and effective
OTC eyedrop, one drop of the jojoba wax formulation applied to each eye
eliminated the red eyes and comforted his eyes for the entire day.
Two individuals (RD and AM) used the jojoba wax formulation in
the setting of soft contact lens wear and found its comforting properties to
be
truly unique. They enjoyed instant relief of eye discomfort which lasted the
entire day.
One individual (ST) used the jojoba wax formulation in the setting of
rigid contact lens wear and also had instant relief of eye irritation lasting
the
whole day.
In summary, the volunteers were extremely pleased by the comfort,
immediate and lasting relief of the jojoba wax formulation.
Three additional patients (HK, LF, and IM) with cornea erosions
were placed on this formulation using 1% jojoba wax. The drop was used
four times per day. The drop was well tolerated, and was found to be
soothing and very comfortable. Within one to two weeks the erosions were
markedly and almost completely resolved.
A formulation consisting of 5% jojoba in aqueous with additional
0.05% white petrolatum USP was created using a heating stir plate and was
placed in the right eye of 6 volunteers. For MB, MH, DN, HL, AM, and SM
the drop was well tolerated, comfortable and felt thicker than 5% jojoba in
aqueous emulsion without the petrolatum.
The formulation was also evaluated on two volunteers using lipid tear
interferometry. A drop of the formulation was placed in one eye and an
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artificial aqueous tear in the other. The interferometry pattern showed thick
blue waves of liquid wax quickly mixing with the volunteer's own lipid tear
within seconds. The resultant lipid tear pattern showed a healthy enhanced
film at least three hours later. Breakup times were also prolonged
therapeutically in the eye receiving the emulsion compared to the fellow eye.
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