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Title:
METHODS AND COSMETIC PREPARATIONS FOR THE SUSTAINED DELIVERY OF THERAPEUTIC AGENTS TO THE EYE
Kind Code:
A1
Abstract:
Cosmetic compositions comprising therapeutic agents for the treatment of various eye conditions and methods of use are described. In particular, the invention provides cosmetic compositions comprising ophthalmic therapeutic agents in combination with a muscle fasciculating agent for application to the outer surface of the upper eyelid, perimeter of the eyelid and/or eyelashes thereby causing transfer of the therapeutic agents into the vascular network within the eyelid for delivery into all parts of the eye, including the posterior segments of the eye, the eyelid glands, conjuctiva and periocular tissue.


Inventors:
Nanduri, Padma (La Jolla, CA, US)
Dyer, Aaron T. (La Jolla, CA, US)
Application Number:
12/916136
Publication Date:
05/05/2011
Filing Date:
10/29/2010
Assignee:
INTRATUS, INC.
Primary Class:
Other Classes:
424/725, 514/20.5, 514/263.31, 514/263.34, 514/397, 514/411
International Classes:
A61K31/522; A61K8/00; A61K31/407; A61K31/4178; A61K36/68; A61K38/13; A61P21/00; A61P27/02; A61P29/00; A61P31/00; A61P31/10; A61Q17/04
View Patent Images:
Claims:
What is claimed is:

1. A cosmetic composition for application to the outer surface or perimeter of the eyelids or eyelashes of a human comprising a carrier material or base formulation, a therapeutically effective amount of an agent for treating eye irritation or dry eye, from about 0.001% to 50 wt % of a muscle fasciculating agent and optionally, pigment and/or moisturizer.

2. The cosmetic composition of claim 1 wherein said composition is in the form of a cosmetic cream, lotion, an eye shadow, mascara, gel, make-up formulation, spray, foam, powder, film, liquid, self-tanning cream or lotion or sun-block cream or lotion.

3. The cosmetic composition of claim 1 wherein the muscle fasciculating agent is selected from caffeine, theophylline, pentoxifyline or theobromide.

4. The cosmetic composition of claim 1 further comprising a permeability enhancer.

5. The cosmetic composition of claim 1 wherein the agent for treating eye irritation is an ophthalmic astringent, ophthalmic demulcent, ophthalmic emollient, ophthalmic vasoconstrictor, an anti-inflammatory, antifungal, antibiotic, a cholinergic agent or a combination thereof.

6. The cosmetic composition of claim 1 wherein the composition is formulated as an eyelid stick.

7. The cosmetic composition of claim 6 wherein the outer borders of the eyelid stick are impregnated with a vasodilator that is released as the eyelid stick is applied to the eyelid of the human.

8. The cosmetic composition of claim 7 comprising about 0.001 to 50 wt % of a muscle fasciculating agent, a therapeutically effective agent for treating eye irritation or dry eye and pigment and/or at least one moisturizing agent distributed evenly throughout the composition.

9. The cosmetic composition of claim 1 wherein the eye irritation is caused by a condition selected from the group consisting of epiphora, photophobia, allergic conjunctivitis, nasolacrimal duct obstruction, allergic eye disease, meibomian glandular dysfunction, blepharitis, rosacea, chalazion, and hordeolum.

10. The cosmetic composition of claim 1 wherein the agent is an agent for treating eye irritation is an agent for treating blepharitis, selected from secretogues, pilocarpine, physostigmine and antibiotics, wherein application of the cosmetic composition to the outer surface or perimeter of at least one eyelid or the eyelashes provides delivery of the agent to the lacrimal glands, meibomian glands and conjuctival goblet cells of the human.

11. The cosmetic composition of claim 1 wherein said composition comprises a therapeutically effective amount of a pharmaceutical agent for treating dry eye.

12. The cosmetic composition of claim 11 wherein the pharmaceutical agent is cyclosporine.

13. The cosmetic composition of claim 1 further comprising an ionotropic agent.

14. The composition of claim 13 wherein the ionotropic agent is digitalis.

15. A cosmetic composition for application to the outer surface or perimeter of the eyelids or eyelashes of a human comprising from about 0.001 to 50 wt % caffeine.

16. The composition of claim 15 further comprising from about 0.001 to 50 wt % of an ionotropic agent.

17. A kit comprising two or more cosmetic compositions for application to the outer surface or perimeter of the upper and/or lower eyelids or eyelashes of a human, wherein each cosmetic composition comprises a carrier material or base formulation, a therapeutically effective amount of an agent for treating eye irritation or dry eye, from about 0.001 wt % to 50 wt % of a muscle fasciculating agent and optionally, pigment and/or at least one moisturizer.

18. The kit of claim 15 wherein the two or more cosmetic compositions each contain a different agent for treating dry eye or eye irritation.

19. The kit according to claim 15 wherein the kit comprises an eyeliner comprising a therapeutically effective amount of a vasoconstrictor and a crème, eyelid moisturizer or eye shadow comprising a therapeutically effective amount of an antihistamine.

Description:

CROSS-REFERENCE OF RELATED APPLICATION

This application claims priority to Provisional Application Ser. No. 61/289,471, filed Dec. 23, 2009 and Provisional Application Ser. No. 61/256,614, filed Oct. 30, 2009, both of which are incorporated herein by reference thereto.

TECHNICAL FIELD

The present invention relates generally to cosmetic preparations and their use to deliver therapeutic agents to treat various conditions affecting the eye. More specifically, the present invention relates to methods and compositions for delivery of one or more therapeutic agents to the eye by topical application of a cosmetic composition containing the therapeutic agent(s) to the eyelid, perimeter of the eyelid and/or eyelashes. More specifically, these methods comprise applying a cosmetic preparation containing the desired therapeutic agent or combination of therapeutic agents to the surface of the eyelid, perimeter of the eye and/or eyelashes thereby causing transfer of the therapeutic agent(s) from the eyelid into the eye via the vascular network within the eyelid.

BACKGROUND OF THE INVENTION

It is estimated that about 33 million Americans suffer from red, itchy, irritated dry eyes. There are several over the counter (OTC) products available for the treatment of red eye and other allergic conditions of the eye, but many consumers have difficulty using the available products which are in the form of eye drops, e.g., Visene, Naphcon, Opcon that are difficult to apply and are messy. Eye drops are particularly problematic for individuals who use eye make up, since the drops often drip, causing make up, e.g., mascara, eyeliner, under eye cover, to run or smear.

Certain products such as those for treating dry eye, e.g., lubricating eye drops are particularly problematic because after application of the drops to the eye, the user experiences blurred vision for a period of time ranging from about five to ten minutes. Moreover, these products are of short duration, requiring multiple application throughout the day and since a disproportionate number of people suffering from dry eye are female, application of drops to treat the condition has the added detractor of resulting in smeared makeup. Also, the currently available OTC products for treating dry eye comprise varying amounts of humectant, astringent and the like which only treat the surface area of the tear film.

Thus, there is a need for compositions and methods for treating such conditions of the eye without the use of eye drops and which decrease or eliminate the need for multiple applications of the therapeutic agent.

SUMMARY OF THE INVENTION

In one aspect of the invention there is provided a cosmetic preparation for application to the eyelids, perimeter of the eyelids or eyelashes of a human comprising a carrier material or base formulation, a therapeutically effective amount of an agent for treating an eye condition such as eye irritation or dry eye, optionally, from about 0.001% to 50% of a muscle fasciculating agent and optionally, a pigment and/or moisturizer. In certain embodiments, the cosmetic preparation is in the form of a cream, a lotion, an eye shadow, a mascara, a gel, a make-up formulation, or a self-tanning cream or lotion. In certain embodiments the muscle fasciculating agent may be selected from caffeine, theophylline, pentoxifyline or theobromide. The cosmetic composition may further comprise a permeability enhancer. In certain embodiments, the composition may further comprise from 0.001 to 50 wt % of an ionotropic agent, such as for example, digitalis. The agent for treating eye irritation or dry eye may be any therapeutic agent known to effectively treat such conditions, such as ophthalmic astringents, ophthalmic demulcents, ophthalmic emollients, ophthalmic vasoconstrictors and combinations thereof. In certain embodiments, the therapeutic agent is an FDA approved over-the-counter (“OTC”) drug.

In another aspect of the invention there is provided a method for topical delivery of an agent for treatment of eye irritation or dry eye comprising topically applying to the upper and/or lower eyelids or eyelid perimeter and/or eyelashes a cosmetic preparation comprising a therapeutically effective amount of an agent for treating eye irritation or dry eye, optionally, from about 0.001% to 50 wt % of a muscle fasciculating agent and optionally, a pigment and/or moisturizer. In certain embodiments the composition may include from 0.001 wt % to 50 wt % of an ionotropic agent such as digitalis. In certain embodiments, the cosmetic preparation is in the form of a cream, a lotion, an eye shadow, a mascara, a gel, a make-up formulation, a sun-block cream, a powder, a solid, a liquid or lotion or a self-tanning cream or lotion. In certain embodiments the muscle fasciculating agent may be selected from caffeine, theophylline, pentoxifyline or theobromide. The cosmetic composition may further comprise a permeability enhancer. The agent for treating eye irritation or dry eye may be any therapeutic agent known to effectively treat such conditions, such as ophthalmic astringents, ophthalmic demulcents, ophthalmic emollients, ophthalmic vasoconstrictors and combinations thereof. In those embodiments involving application of the cosmetic preparation to the eyelashes it is essential that the cosmetic preparation also be applied to at least a portion of the eye lids, such as that portion in direct contact with the eyelashes.

In another aspect of the invention there is provided a method of treating dry eye comprising topically applying to the upper eyelids, lower eyelids and/or eyelashes a cosmetic preparation comprising a therapeutically effective amount of a parasympathomimetic cholinergic agent such as Pilocarpine, Cevimeline, Carbachol or extracts and/or tinctures that contain parasympathomimetics such as Pilocarpus extract or, an anticholinesterase such as Echothiophate Iodidide, Isofluorophate, Demecarium Bromide, Physostigmine, Neostigmine, Pyridostigmine, Edrophonium, an androgen, estrogen, B-agonist such as isoproternol, alpha-agonist such as phenylepherine, ephedrine, and the like (alone or in combination) and from 0.001% to 50% of a muscle fasciculating agent, and optionally, from 0.001 to 50 wt % of an ionotropic agent in addition to any cosmetic agents such as pigment, moisturizer and the like. The cosmetic preparation may be in the form of a cream, a lotion, an eye shadow, a mascara, a gel, a make-up formulation, a powder, a liquid, a sun-blockcream or lotion or a self-tanning cream or lotion, for example.

In another aspect of the invention there is provided a method of maintaining the health of the eye and protecting the eye from oxidative damage comprising topically applying to at least one upper eyelid, lower eyelid and/or eyelashes a cosmetic preparation comprising from about 0.001 to 50 wt % caffeine. In certain embodiments the composition further comprises an ionotropic agent in an amount of from about 0.001 to 50 wt %. In certain embodiments the composition is applied to the upper eyelids, lower eyelids and/or eyelashes of an individual suffering from cataracts.

DETAILED DESCRIPTION OF THE INVENTION

The present inventive methods and compositions utilize transport via vascular collaterals or channels within the eyelid to deliver topically applied therapeutic agents to specific target tissues that receive blood supply, such as glands, conjunctiva, periocular tissue, and the eye, including the posterior segments thereof. The inventors have discovered that topical application of the cosmetic compositions of the invention to the outer surface of the upper or lower eyelids of a human patient greatly aids absorption of any therapeutic agent contained within the cosmetic preparation. 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 its 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 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 and compositions can be utilized to achieve uptake of therapeutic agent into or onto the surface of the eye without causing blurring of vision and without the need to apply liquid drops to the eye.

As used herein the term “drug” means any chemical or natural substance used in the treatment, cure, or prevention, of eye conditions causing irritation, itching, dry eye and the like or used to otherwise enhance physical well-being. The term “therapeutic agent” is also used to denote any compound, molecule, or substance used for the therapeutic treatment of such conditions. The terms “drug” and “therapeutic agent” are used interchangeably herein.

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 as the perimeter of the eyelid(s) 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 otherwise specified. In certain embodiments of the present invention, the cosmetic composition is applied primarily to the eyelashes, e.g., mascara. In those embodiments it is understood that application to the eyelashes will necessarily involve application of the cosmetic composition to the area of the upper and/or lower eyelid in contact with the eyelash.

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.

The term “over the counter” (OTC) as used herein applies to drugs or therapeutic agents that are available without a prescription.

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.

Use of the methods and cosmetic compositions of the present invention disregards 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.

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 and compositions as a vehicle for transdermal drug delivery from cosmetic compositions applied to the 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).

The present invention overcomes several insufficiencies of prior methods for the treatment of eye irritation or dry eye, which generally involve application of drops directly to the eyeball. For example, the most commonly used non-invasive method for treating the vast majority of eye 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.

The present inventors have discovered that sustained release and delivery of therapeutic agent to the 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 and/or eyelashes. The inventors have also discovered that cosmetic preparations for the eye, such as an eye shadow or moisturizer which are formulated to contain one or more therapeutic compounds for treatment of eye irritation or red eye provide an effective and sustained release treatment of such eye conditions. 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, thus providing a significantly improved method for treatment of eye irritation and/or dry eye.

The compositions of the invention comprise a therapeutically effective amount of drug appropriate for the eye condition 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 cosmetic preparation suitable for application to the outer surface of the eyelid or rim of the eyelid or eyelashes. 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 dry eye, a cosmetic preparation in the form of a cream, gel, spray, lotion, powder, stick applicator, foam, film or liquid mascara or eyeliner, for example containing a cholinergic agent such as pilocarpine or carbocholin in an amount of about 0.1 to 40 wt % of the composition is applied to the upper eyelid, rims of the eyelid, or eyelashes, as appropriate for the cosmetic application. The inventors have discovered that application of a cholinergic agent to the eyelid via the present cosmetic compositions results in a significant increase in the three layers of tear film: mucous, aqueous and meibomian gland oil layer. This results in a stable tear sandwich which maximizes vision, comfort and health of the eyeball. The number of applications will vary depending upon the condition being treated and the therapeutic agent or drug being applied.

In certain embodiments of the invention a muscle contractility agent (a micro or muscle fasciculating agent) is included in the cosmetic preparations, such as caffeine, theophylline, pentoxifyline, theobromide. The micro fasciculating agent may be included in an amount from about 0.001 to up to about 50 wt % of the composition, such as 1 wt %, 5 wt %, 30 wt % or 50 wt %. In certain embodiments the micro fasciculating agent is an appropriate amount of caffeine, which has the benefit of being a naturally occurring and readily metabolized small molecule.

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. Examples of positive inotropic agents 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.

The therapeutic agent-containing cosmetic preparations of the invention may be formulated for use alone or in combination with a separate cosmetic composition containing a different therapeutic agent, for example. In certain embodiments an eyeliner containing a vasoconstrictor may be used with an eye shadow or eyelid moisturizer containing an antihistamine, for example to treat eye irritation or dry eye. Various cosmetic preparations containing appropriate therapeutic agent(s) can be formulated and packaged as a kit with instructions for use or may be provided separately.

In certain embodiments of the invention the sole active therapeutic agent(s) of the cosmetic preparation is one or more vasoconstrictors. Cosmetic compositions containing vasoconstrictor as the sole therapeutic agent(s) are applied to the eyelid of the patient for the treatment of conditions including, but not limited to, redeye, allergic conjunctivitis, blepharitis, puffy eye lids and any condition that includes as a symptom vasodilation or irritation of the eyelid, anterior segment, posterior segment or orbit of the eye. In some embodiments, such vasoconstrictor-containing cosmetic preparations may also contain from 0.001 to 50 wt % of a micro fasciculating agent, such as for example, caffeine, theophylline, pentoxifyline or theobromide, and optionally from about 0.001 wt % to 50 wt % of an ionotropic agent, such as digitalis and/or a permeation enhancer agent. Further, vasoconstrictors may be combined with other active agents in the base cosmetic preparation, 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®, naphazoline, Visine®, tetrahydrolozine, Op-Thal-Zin/zinc sulfate, Rhindecon, phenylpropanolamine, Sudafed®, pseudoephedrine, Ephed II, ephedrine, Aramine, metaraminol, Epifrin, epinephrine, Levophed, norepinephrinand nicotine. Certain cosmetic preparations containing a vasoconstrictor as the sole active therapeutic agent will contain only ingredients that are approved OTC agents.

For treatment of eye conditions wherein use of a vasoconstrictor and a second active agent is desirable, the vasoconstrictor-containing cosmetic preparation may be applied separately from a second cosmetic preparation containing the second active agent. For example, the vasoconstrictor may be applied to the perimeter of the area of the eyelid as an eye liner, while the second active agent may be applied to the surface of the upper eyelid as an eye shadow, for example. Application to the perimeter region is believed to limit the effects of the vasoconstrictor and thereby limit any unwanted side effects. Application of a vasoconstrictor and active agent in this manner may also 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) and/or permeating agents and/or microfasciculating agent 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 a cosmetic eyelidstick or film cosmetic applicator with active agent(s), and/or microfasciculating agent and/or permeating agent impregnated in the middle of such applicator. Cosmetic ingredients are distributed throughout the entire preparation. Application of the cosmetic preparation to the eyelid results in localized application of the various therapeutic components (e.g., a border of vasoconstrictor) with even distribution of cosmetic components. The skilled practitioner will immediately recognize that such eyelidsticks can be formulated to contain other therapeutic agents arranged throughout the preparation in a manner allowing application of the therapeutic agent to a specific area of the eyelid by simply applying the preparation in a fluid movement across the eyelid.

Caffeine as the sole active component. 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 as the sole active component 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 compositions containing caffeine as the sole active component 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).

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. As with the other aspects of the invention, the compositions containing caffeine as the sole active ingredient may be formulated as a powder, liquid, gel and the like for cosmetic application to the eyelids and/or eyelashes.

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 an 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.

Ophthalmic Compositions in General: Cosmetic preparations 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), photophobia, allergic conjunctivitis or nasolacrimal duct obstruction including pharmaceutically effective amounts of atropine, scopolamine, homoatropine, cyclopentalate, tropicamide and the like and anticholinergic agents. 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, anti-inflammatory drug, or antibiotic. The therapeutic agents that may be included in such compositions 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 wt % of a micro fasciculating agent, such as caffeine, theophyline or theobromine, for example, and optionally up to 50 wt % of an ionotropic agent. 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.

In certain embodiments of the invention where administration of more than one therapeutic agent is desired, the different therapeutic agents can be separately applied to one or both eyelids or the different therapeutic agents or drugs may be applied to different eyelids or to eyelashes and/or eyelid(s). In other embodiments of this aspect of the invention, one cosmetic preparation containing therapeutic agent and up to 50 wt % micro fasciculating agent and optional ingredients such as vasoconstrictor, permeating agent, ionotropic agent and combinations thereof is applied to the first eyelid of a human patient, while the second cosmetic preparation, 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 dry eye where two or more active agents are used to treat the condition may be carried out by applying one therapeutic agent or set of therapeutic agents to one eyelid and another therapeutic agent or combination of therapeutic agents 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.

Traditionally, treatment of dry eye or blepharitis, for example, has included oral administration (systemic delivery) of the appropriate therapeutic agent, such as the secretogues, pilocarpine and physostigmine, which are indicated for dry eye 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.

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.

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 the eye 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., 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 cosmetic preparations, kits and methods of the invention. The skilled practitioner will appreciate that any therapeutic agent (or combination of agents), particularly those having a size range of 6000 Daltons or smaller may be included in the cosmetic preparations and kits of the invention, although larger molecules may also be used and administered according to the methods described herein to achieve therapeutic concentration at the desired target site.

An effective amount of a penetrating agent may also be included in the cosmetic preparations of the invention to aid penetration of the active component into and across the 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 percutaneous 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 cosmetic preparation. 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 cosmetic preparation.

Also optionally, an amount of a hydrating agent such as hyaluronic acid, saline solution, polyvinylpyrrolidone, and the like may be included in the compositions of the invention.

When included in the cosmetic preparations 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.

The cosmetic preparations of the invention may be formulated as a cream, gel, lotion, ointment, stick, spray, foam, film, powder or the like for direct application to the eyelid or as a liquid for application to the eyelashes or perimeter of the eye, e.g., a mascara or eyeliner, respectively. 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; and thosomes, which are liposomes that contain ethanol, which functions as a permeation enhancer.

Because drug delivery through the eyelid is so effective, the cosmetic preparations can be formulated to contain less drug or therapeutic agent than is routinely administered via eye drops to treat the condition. Moreover, because the composition is not applied directly to the eye, the pH of the 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 cosmetic preparation, it is possible to maximize penetration of unbound therapeutic agent through the skin.

In addition to the components discussed above, any component generally used for manufacturing cosmetic preparations in the desired form can be added to the present compositions of the invention. Cosmetics of the type in question, such as loose or pressed powders, eye shadows, eyelidsticks, eyeliners, mascaras, liquid self-tanners, sun screen, moisturizers and the like, are composed of a carrier material or a base formulation and may include color-imparting and effect-imparting means of various types, with the goal to obtain a certain color effect on the skin or to optically cover up skin flaws or screen out harmful effects of the sun, for example. Examples of such components an ointment base, gel base, solvent, oil, crosslinking agent, surfactant, gum, resin, pH adjuster, stabilizer, antioxidant, preservative, ultraviolet absorbent and wetting agent.

Ointment based formulations may include fat and oil bases such as Vaseline®, paraffin, plastibase, silicone, vegetable oil, lard, wax and unguentum simplex; and/or emulsion bases such as hydrophilic ointment (vanishing cream), hydrophilic Vaseline®., absorption ointment, hydrous lanolin, purified lanolin and hydrophilic plastibase (cold cream).

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.

Solvents used in the manufacture of the cosmetic preparations 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.

Oils used in the manufacture of the cosmetic preparations 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.

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.

Surfactant may be included in the cosmetic preparations 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.

If desired, gum and/or resin may be included in the cosmetic preparations 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.

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 or to maximixe the effect of the cosmetic components. 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.

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-α-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.

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-α-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.

The following tables provide non-limiting examples of excipients (and amounts thereof) that may be included in the cosmetic preparations.

Gel Formulations:

ClassExcipients
PolymersMethyl cellulose
Hydroxyethylcellulose
Hydropropylcellulose
Hydroxypropylmethyl
cellulose
Sodium carboxy methyl
cellulose
Carbopol
Chitosan
Poloxamer (Pluronics ®)
Sodium alginate
Polyvinyl alcohol
Xanthan gum

Cream Formulations:

ClassExcipient
Hydrophobic excipientsStearic acid
Palmitic acid
Lauric acid
Capric acid
Mineral oil
Bees wax
Silicone oil
Emulsifiers (HydrophobicStearyl alcohol
and Hydrophilic)Cetyl alcohol
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 excipientsPurified water
Buffers
Polymers (as outlined for gels)
HumectantsGlycerin
Sorbitol
Propylene glycol
Polyethylene glycol (low molecular weight)

Ointment Formulations:

Petrolatum

White wax

Lanolin

Mineral oil

Bees wax

Microcrystalline

wax

Cholesterol

Cetyl alcohol
Stearyl alcohol

Sorbitan

Sesquioleate

Lanolin alcohol

Exemplary Preservatives that May be Included in the Compositions of the Invention:

PreservativesBithional
Butyl p-
hydroxybenzoate
p-chloro-m-xylenol
Dehydroacetic acid
Ethyl paraben
Methyl-p-
hydroxybenzoate
Propyl-p-
hydroxybenzoate
Sorbic acid

Exemplary Hydrating Agents that May be Included in the Compositions of the Invention and Exemplified Amounts Thereof:

ExcipientFDA Maximum Potency
LACTIC ACIDTOPICAL; EMULSION, CREAM: 1.00%
TOPICAL GEL: 6.07%
TOPICAL LOTION: 5.70%
TOPICAL OINTMENT: NOT KNOWN
TOPICAL SUSPENSION: 0.70%
TOPICAL SOLUTION: 18.06%
SORBITOLTOPICAL; EMULSION: 7.00%
TOPICAL; EMULSION, CREAM:
67.52%
TOPICAL; LOTION: NOT KNOWN
GLYCERINTOPICAL; 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 (1,2,6-TOPICAL; EMULSION, CREAM: 7.50%
HEXANETRIOL)
PROPYLENE GLYCOLTRANSDERMAL GEL: 6.0%
TOPICAL OINTMENT: 38%
TOPICAL LOTION: 59%
TOPICAL GEL: 98.09%
TOPICAL EMULSION CREAM: 71.08%
HEXYLENE GLYCOLTOPICAL; EMULSION, CREAM: 12.0%
TOPICAL; GEL: 2.0%
TOPICAL; OINTMENT: 12.0%
TOPICAL; SOLUTION: 12.0%
TOPICAL; SOLUTION: 29.70%
POLYETHYLENE GLYCOLTOPICAL; OINTMENT: 39.0%
200
POLYETHYLENE GLYCOLTOPICAL; OINTMENT: 57.0%
300TOPICAL; SOLUTION: 29.70%
POLYETHYLENE GLYCOLTOPICAL; EMULSION, CREAM: 7.50%
400TOPICAL; GEL: 45.0%
TOPICAL; LOTION: 12.0%
TOPICAL; OINTMENT: 65.0%
TOPICAL; SOLUTION: 69.90%

Examples of Other Useful Hydrating Agents:

Glycolic Acid

Glycolate salts

D-panthenol

Hyaluronic acid

Lactamide

Monoethanolamine

Acetamide

Monoethanolamine

Exemplary Permeation Enhancers for Use in the Cosmetic Preparations of the Invention (and Exemplified Amounts Thereof):

ClassExcipientFDA Maximum Potency
TerpenesMENTHOLTOPICAL LOTION: 0.05%
TOPICAL SOLUTION: 0.08%
LIMONENE, DL-TOPICAL LOTION: 10%
A-TERPINEOLTOPICAL LOTION: 11%
Essential OilsPEPPERMINT OILTOPICAL OINTMENT: NOT
KNOWN
Fatty Acids andISOPROPYL MYRISTATE0.02%-35%
EstersISOPROPYL PALMITATE1.8%-3.9%
OLEIC ACIDTOPICAL SOLUTION: 7.4%
OLEYL OLEATETOPICAL OINTMENT: 2.55%
STEARIC ACIDTOPICAL; CREAM, AUGMENTED:
3.0%
TOPICAL; EMULSION, CREAM:
22.60%
TOPICAL; LOTION: 20.0%
TOPICAL; OINTMENT: 15.0%
TOPICAL; SUSPENSION: 1.75%
ETHYL ACETATETOPICAL; SOLUTION: 31.0%
DIETHYL SEBACATETOPICAL; SOLUTION: 24.0%
Alcohols, GlycolsALCOHOL1.20-97.50%
and glyceridesPROPYLENE GLYCOLTRANSDERMAL 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 ALCOHOLTOPICAL; 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/CAPRICTOPICAL; CREAM, EMULSION,
TRIGLYCERIDESUSTAINED RELEASE: PENDING
(10.0%)
TOPICAL; EMULSION, CREAM:
PENDING (10.80%)
TOPICAL; SOLUTION: PENDING
(50.0%)
CAPRYLIC/CAPRIC/STEARICTOPICAL; OINTMENT: 70.0%
TRIGLYCERIDE
MYRISTYL ALCOHOLTOPICAL; EMULSION, CREAM:
3.0%
TOPICAL; LOTION: 1.0%
TOPICAL; SUSPENSION: 1.05%
CETYL ALCOHOLTOPICAL; 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 ALCOHOLTOPICAL; 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 ALCOHOLTOPICAL; 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 ALCOHOLTOPICAL; EMULSION, CREAM:
10.0%
TOPICAL; OINTMENT: 5.0%
SurfactantsSODIUM LAURYL SULFATETOPICAL; EMULSION, CREAM:
2.50%
TOPICAL; LOTION: 0.50%
TOPICAL; OINTMENT: 1.0%
POLYSORBATE 20TOPICAL; EMULSION: 2.0%
TOPICAL; EMULSION, CREAM:
0.80%
TOPICAL; LOTION: 7.8%
TOPICAL; SOLUTION: 15.0%
POLYSORBATE 60TOPICAL; EMULSION, AEROSOL
FOAM: 0.42%
TOPICAL; EMULSION, CREAM:
8.0%
TOPICAL; LOTION: 5.0%
TOPICAL; SHAMPOO: 15.0%
TOPICAL; SUSPENSION: 2.85%
LECITHINTOPICAL; GEL: 1.0%
TOPICAL; SOLUTION: 1.40%

Other Permeation Enhancers

ClassExcipient
TerpenesEucalyptol: 1,8-cineole
α-pinene
Menthone
Nerolidol
Terpineol
Carvol
Carvone
Pulegone
Cyclohexane oxide
Limonene oxide
Anise
Essential OilsEucalyptus
Turpentine oil
AmidesUrea
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 andLinoleic Acid
EstersSodium 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 andDimethyl sulfoxide (DMSO)
SimilarDecylmethyl sulfoxide (DCMS)
CompoundsVarious N,N-dimethylamides
N,N-dimethylformamide
Dimethylacetamide (DMA)
N,N-dimethyloctanamide
N,N-dimethyldecanamide
Alcohols, Glycolsn-alkanols (1-nonanol, octyl alcohol)
and GlyceridesLauryl 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
Ttriethylene glycol
Dipropylene glycol
Propanediol
Butanediol
Pentanediol
Surfactantssodium 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
Phospholipidsphosphatidyl glycerol
phosphatidyl glycerol derivatives (PGE, PGS,
DMPG, DSPG, DOPG)
phosphatidyl choline derviatives (PCS, PCE,
DOPC, DLPC, HPC)
Cyclodextrinβ-cyclodextrin
Complexesmethyl-β-cyclodextrin
O-carboxymethyl-o-ethyl-B-cyclodextrin (CME-
B-CD)
2-hydroxypropyl-β-cyclodextrin (HPβCD)
2,6-dimethyl-β-cyclodextriin (DIMEB)
Amino AcidN-dodecyl-L-amino acid methyl ester
Derivativesn-pentyl-N-acetyl prolinate
esters of omega amino acids (octyl-6-
aminohexanoate and decyl-6-aminohexanoate)
OthersClofibric Acid (amide and esters of)
Enzymes (phopholipase C, triacylglycerol
hydrolase (TGH, phospholipase A2

Although the inventors do not wish to be bound by any theory, it is proposed that the present methods and cosmetic preparations 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 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 fasciculating agent or optional inotropic 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 eye. As a result of the pumping action achieved through the use of a micro fasciculating agent and optional ionotropic agent, or in various combinations with 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 cosmetic formulations to treat conditions in the eye previously treated by systemic, oral or other topical routes, e.g., eye drops, 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.

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. 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 and/or at different times during the treatment regimen. Kits will also include, when necessary, instructions for the appropriate dosing regimen.