Materials and methods for punctal plugs

Abstract

The punctal plug or insert is constructed of a monolithic material and is configured to turn approximately 90° when inserted into the canaliculus of the eye. The punctal plug or insert can include high molecular weight polysaccharides and an added plasticizer.

Description

[Technical field]

[0001] CROSS-REFERENCE TO PRIORITY AND RELATED APPLICATIONS This application claims priority to and benefit of U.S. Provisional Patent Application No. 63 / 188,733, entitled "MATERIALS AND METHODS FOR PUNCTAL PLUGS," filed May 14, 2021, the entire contents of which are incorporated by reference herein, including all tables, figures, and claims. [Background technology]

[0002] Field The present disclosure relates to medical and / or drug delivery devices structured to provide tear retention and / or sustained release of drugs or inert molecules to desired target ocular tissues, and related methods of using such devices for the treatment of ocular diseases and disorders. In certain embodiments, the present disclosure relates to devices for insertion into the canaliculus via the lacrimal punctum, and devices for delivering therapeutic agents to the eye in a controlled manner via these devices.

[0003] 2. Description of Related Art The mammalian eye is a specialized sensory organ that can receive light and visual images. The retina of the eye consists of photoreceptors that detect different levels of light and interneurons that relay signals from the photoreceptors to retinal ganglion cells, which transmit the light-induced signal to the brain. The iris is the inner lining of the eye responsible for controlling the amount of light that reaches the retina. The iris consists of two layers (arranged from anterior to posterior): pigmented fibrovascular tissue known as the stroma and pigmented epithelial cells. The stroma connects a sphincter muscle that constricts the pupil (sphincter pupillae) and a set of dilator muscles that open the pupil (dilator pupillae). The pigmented epithelial cells block light from passing through the iris, thereby limiting the passage of light to the pupil.

[0004] Within the eyelids are drainage ducts for tears produced by the lacrimal gland. The portion of the drainage duct immediately following the opening of the lacrimal duct is the lacrimal punctum. There is one punctum on each of the upper and lower eyelids. Each punctum consists of an L-shaped opening approximately 0.5 mm in diameter lined with non-keratinized squamous epithelium surrounded by fibrous tissue.

[0005] A number of conditions, including eye trauma, infection, degeneration, vascular abnormalities and inflammatory problems, can impair or completely eliminate an individual's ability to perceive visual images. The central portion of the retina is known as the macula. The macula, which is responsible for central vision, fine visualization and color differentiation, can be affected by age-related macular degeneration (wet or dry), diabetic macular edema, idiopathic choroidal neovascularization or high myopic macular degeneration, among other conditions.

[0006] The cornea, lacrimal gland, mucous cells and meibomian glands are all densely innervated. Parasympathetic, sympathetic and sensory innervation play complex stimulatory or inhibitory roles, and neural pathways interact through a complex surface-effect cascade. Abnormalities at any point in these pathways can lead to a global dysregulation of lacrimal gland function. These abnormalities can lead to a condition known as dry eye, keratoconjunctivitis sicca or keratitis sicca, characterized by discomfort, visual disturbances and tear film instability (with potential damage to the ocular surface). Allergic conjunctivitis is another condition affected by the interaction of ocular tissues, usually resulting from histamine release by mast cells, and characterized by redness, conjunctival swelling, itching and increased tear production.

[0007] Other medical conditions, such as abnormalities in intraocular pressure, can also affect vision. Aqueous humor is a clear liquid that fills at least the area between the cornea and the lens at the front of the eye and is responsible for generating pressure within the ocular cavity. Normal intraocular pressure is maintained by draining aqueous humor from the anterior chamber through the trabecular meshwork located in the anterior chamber angle between the iris and the cornea, or through the "uveoscleral outflow pathway." The "uveoscleral outflow pathway" is the space or passageway through which aqueous humor leaves the eye through the ciliary muscle bundle located in the anterior chamber angle and enters the tissue plane between the choroid and sclera that extends posterior to the optic nerve. In the United States, approximately 2% of the population suffers from glaucoma. Glaucoma is a group of eye diseases that encompass a wide range of clinical symptoms and etiologies, but are united by elevated intraocular pressure. Glaucoma produces pathological changes in the optic nerve (seen on the optic disc) that produce corresponding visual field loss, which can lead to blindness if not treated. Elevated intraocular pressure is the only risk factor associated with glaucoma that can be treated; therefore, lowering intraocular pressure is the primary therapeutic goal in all cases of glaucoma, which can be achieved by medical therapy, surgical treatment, or a combination thereof.

[0008] Many eye conditions progress due to the difficulty in administering therapeutic agents to the eye in sufficient amounts and / or duration required to improve symptoms. In many cases, the uptake and processing of the therapeutic agent's drug components occurs before the drug reaches the target site in the eye. Due to this metabolism, systemic administration may require undesirably high concentrations of the drug to reach therapeutic levels at the target site in the eye. This may not only be impractical or expensive, but may also result in a higher incidence of side effects. Local administration is potentially limited by limited diffusion across the cornea, i.e., dilution of the topically applied drug by lacrimal action. Even drugs that penetrate the cornea may be unacceptably flushed out of the eye by ocular fluid flow and migrate into the systemic circulation. Thus, a means for administering therapeutic agents intraocularly in a controlled and targeted manner would address the challenges of other delivery routes.

[0009] Current treatments for ocular conditions include many therapies or combinations thereof, including but not limited to artificial tears, medications (such as mast cell stabilizers, immunosuppressants, corticosteroids, etc.), meibomian gland expression, hot compresses, or punctal plugs. Problematically, existing punctal plugs are short (e.g., 2-2.5 mm) to avoid anatomical "bends" or "turns" in the canaliculus. Furthermore, existing punctal plugs are permanent devices that can cause clogging and require subsequent removal. Topical medications, particularly antihistamines, NASIDs, and corticosteroids, can also be used to treat allergic conjunctivitis. These treatments require frequent application of medications to the eye by the patient, which can increase the medication burden and other life limitations for the patient. A long-term drug delivery solution would alleviate this burden. Summary of the Invention [Problem to be solved by the invention]

[0010] In some embodiments, the devices disclosed herein act to provide a therapeutic effect to the eye of a subject. The devices include punctal plugs or punctal inserts that provide tear retention and / or controlled delivery of drugs or other non-active molecules to the tear film. Advantageously, the devices disclosed herein are long and flexible so that they can be inserted through anatomical "bends" or "turns" in the canaliculus. In addition, the devices disclosed herein are completely erodible. [Means for solving the problem]

[0011] In a first embodiment of the present disclosure, which may be combined with other embodiments set forth herein unless otherwise specified in light of the disclosure herein and without limiting the scope of the present invention in any manner, the punctal plug is constructed of a monolithic material and is configured to turn approximately 90° when inserted into the canaliculus of the eye.

[0012] In a second embodiment of the present disclosure, which may be combined with other embodiments listed herein unless otherwise specified, the length of the punctal plug is greater than 5 mm.

[0013] In a third embodiment of the present disclosure, which may be combined with other embodiments listed herein unless otherwise specified, the diameter of the punctal plug is greater than 0.2 mm and less than 1.0 mm.

[0014] In a fourth aspect of the present disclosure, which may be combined with other aspects listed herein unless otherwise specified, the monolithic material is disintegratable in water.

[0015] In a fifth aspect of the present disclosure, which may be combined with other aspects listed herein unless otherwise specified, the monolithic material is disintegrable and configured to be washed out of the nasal passages for removal.

[0016] In a sixth embodiment of the present disclosure, which may be combined with other embodiments listed herein unless otherwise specified, the punctal plug comprises at least 50% by weight of high molecular weight polysaccharide.

[0017] In a seventh aspect of the present disclosure, which may be combined with other aspects recited herein unless otherwise specified, the punctal plug is constructed of high molecular weight polysaccharides and an added plasticizer.

[0018] In an eighth embodiment of the present disclosure, which may be combined with any other embodiment listed herein unless otherwise specified, the high molecular weight polysaccharide is hydroxypropyl methylcellulose.

[0019] In a ninth aspect of the present disclosure, which may be combined with other aspects listed herein unless otherwise specified, the high molecular weight polysaccharide is carboxymethylcellulose.

[0020] In a tenth embodiment of the present disclosure, which may be combined with other embodiments listed herein unless otherwise specified, the high molecular weight polysaccharide is hyaluronic acid.

[0021] In an eleventh embodiment of the present disclosure, which may be combined with other embodiments recited herein unless otherwise specified, the added plasticizer comprises one or more of glycerin, polyethylene glycol 6000, stearic acid, lauric acid, and dimyristoyl phosphatidylglycerol.

[0022] In a twelfth embodiment of the present disclosure, which may be combined with other embodiments listed herein unless otherwise specified, the punctal plug comprises a fluorescent moiety for improving visibility of the punctal plug during insertion.

[0023] In a thirteenth embodiment of the present disclosure, which may be combined with other embodiments recited herein unless otherwise specified, the punctal plug comprises a fluorescent moiety to allow in situ visualization of the punctal plug for the duration of the plug.

[0024] In a fourteenth aspect of the present disclosure, which may be combined with any other aspect set forth herein unless otherwise specified, the punctal plug is configured to maintain a tear film in the eye, the punctal plug is entirely composed of a material suitable for incorporation into a lubricating eye drop, and the material disintegrates slowly into the tear film.

[0025] In a fifteenth aspect of the present disclosure, which may be combined with other aspects recited in this specification unless otherwise specified, the punctal plug is constructed of a collapsible monolithic material and configured to be inserted into the canaliculus of the eye.

[0026] In a sixteenth embodiment of the present disclosure, which may be combined with other embodiments listed herein unless otherwise specified, the length of the punctal plug is greater than 5 mm.

[0027] In a seventeenth embodiment of the present disclosure, which may be combined with other embodiments listed herein unless otherwise specified, the diameter of the punctal plug is greater than 0.2 mm and less than 1.0 mm.

[0028] In an eighteenth embodiment of the present disclosure, which may be combined with other embodiments recited herein unless otherwise specified, the monolithic material is disintegrable and configured to be washed out of the nasal passages for removal.

[0029] In a nineteenth embodiment of the present disclosure, which may be combined with other embodiments listed herein unless otherwise specified, the punctal plug comprises at least 50% by weight of high molecular weight polysaccharide.

[0030] In a twentieth embodiment of the present disclosure, which may be combined with any other embodiment set forth herein unless otherwise specified, the punctal plug is constructed of high molecular weight polysaccharides and an added plasticizer, the high molecular weight polysaccharides being one of hydroxypropylmethylcellulose, carboxymethylcellulose, and hyaluronic acid.

[0031] Further features and advantages of the disclosed devices, systems and methods will be described and will be apparent from the following detailed description and drawings. The features and advantages described herein are not all-inclusive, and in particular, numerous additional features and advantages will be apparent to those skilled in the art in view of the drawings and detailed description. Also, a particular embodiment does not necessarily have all of the advantages listed herein. Moreover, it should be noted that the language used in this specification has been selected for readability and instructional purposes, and not to limit the scope of the subject matter of the present invention.

[0032] These and other features, aspects, and advantages of the present disclosure are described below with reference to drawings of embodiments, which are intended to illustrate, but not to limit, the present disclosure. Those skilled in the art will readily appreciate that features shown in the exemplary embodiments may be combined in ways not explicitly shown herein but envisioned and disclosed. [Brief description of the drawings]

[0033] [Figure 1] 1 illustrates an exemplary ocular environment, according to embodiments disclosed herein. [Figure 1A] 1 illustrates an exemplary ocular environment, according to embodiments disclosed herein. [Diagram 2] 1A-1D show straight and curved cylindrical punctal plugs before and after insertion into an eye according to embodiments disclosed herein. [Figure 2A] 1A-1D show straight and curved cylindrical punctal plugs before and after insertion into an eye according to embodiments disclosed herein. [Diagram 3] 1 shows a knotted cylindrical punctal plug having a colored portion according to an embodiment disclosed herein. [Figure 4] 1 illustrates the insertion of a cylindrical punctal plug into a curved passageway, according to embodiments disclosed herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] Detailed Description Achieving local intraocular administration of a drug may require direct injection or application, but may also involve the use of a drug release device, some of which may be placed in the immediate vicinity of the target site of action in the eye, or in the ocular chamber where the target site is located, for example, in the anterior chamber, posterior chamber, or both (simultaneously). The use of a drug release device may also allow targeted delivery of a drug to a specific ocular tissue, such as the macula, retina, ciliary body, optic nerve, or the vascular supply to a specific region of the eye. The use of a drug release device may also provide the opportunity to administer a controlled amount of drug for a desired period of time, depending on the medical condition.

[0035] As used herein, "patient" shall be given its ordinary meaning and shall refer to mammals in general. The term "mammal" as such includes, but is not limited to, humans, dogs, cats, rabbits, rodents, pigs, sheep, and primates, among others. In addition, throughout this specification, numerical ranges are given along with a list of numerical values ​​for a particular parameter. In such cases, it should be noted that such disclosure includes not only the recited numerical values, but also numerical ranges including integer and fractional values ​​between any two of the recited numerical values.

[0036] As used herein, "drug" generally refers to one or more drugs that can be administered alone or mixed and / or formulated with one or more pharma- ceutically acceptable excipients, such as binders, disintegrants, fillers, diluents, lubricants, drug release-controlling polymers, or other agents, such as those that can be contained within the devices described herein. The term "drug" is a broad term that can be used interchangeably with "therapeutic agent" and "medicinal drug" or "pharmacologic agent," and includes so-called small molecule drugs, as well as macromolecular drugs and biological agents, such as proteins, nucleic acids, antibodies, and the like, whether such drugs are natural, synthetic, or recombinant. Drug may refer to the drug alone or in combination with the excipients described above. "Drug" may also refer to an active drug or a prodrug or salt of an active drug. When a drug is in the device, it may be referred to as a "drug load" or "drug," and it should be understood that these terms are interchangeable.

[0037] Dry Eye Disease Treatment Referring now to the drawings, Figures 1 and 1A show a typical ocular environment, i.e., the anatomical features of the ocular environment include an upper eyelid 1 and a lower eyelid 2. The eye further includes upper and lower lacrimal puncta 3 and upper and lower lacrimal ducts 4 which communicate with the respective puncta 3. The lower lacrimal duct 4 (also commonly referred to as a duct) is typically formed as a 2 mm long proximal duct 4a descending from the lower punctum 3. This duct 4 makes a right angle turn and continues as a distal duct 4b of approximately 8 mm which connects the duct to the nasolacrimal duct 5.

[0038] One such condition associated with the lacrimal ducts4 and associated anatomical structures is called dry eye disease (DED). DED is an ocular condition that is recognized as a disorder of the lacrimal system, including the lacrimal gland, lacrimal duct, cornea, conjunctiva, and meibomian glands. Symptoms of DED include redness, burning, reflex tearing, itching, and foreign body sensation. The severity of DED is usually classified into categories 1-4 (1 being mild, 2 being moderate, 3 being severe, and 4 being dysfunctional or permanent).

[0039] For mild to moderate DED, symptoms can be alleviated by the use of over-the-counter lubricating eye drops applied as needed. These solutions are usually composed of high molecular weight (HMW) polysaccharides, such as hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC) or hyaluronic acid (HA). These HMW cellulosic materials bind to the mucin-containing corneal surface. Over-the-counter (OTC) lubricating eye drops also usually contain emollient or moisturizing ingredients, such as glycerin. Finally, lubricating eye drops can also contain lipid-mimetic compounds, such as dimyristoyl phosphatidylglycerol. These molecules can act as tear surface modifiers and help prevent tear film evaporation. OTC eye drops are useful, but must be reapplied frequently to improve moderate dry eye symptoms.

[0040] In addition to lubricating eye drops, punctal plug devices can also be used for mild to moderate dry eye symptoms. Exemplary devices are shown in Figures 2 and 2A. These devices are inserted into the punctum 3 and positioned at the edge of the lower eyelid 2. The device is inserted partway into the upper part 4a of the canaliculus. Once in place, the device blocks naturally occurring tears from exiting the canaliculus into the nasolacrimal duct 5. Punctal plugs are also indicated for use to enhance retention and potentiation of eye drop medications.

[0041] In a preferred embodiment, a device such as plug 6 treats mild to moderate dry eye symptoms by maintaining the tear film while simultaneously releasing ingredients such as mucin-binding polymers, emollients and lipid-mimetic biomolecules to alleviate the associated symptoms of dry eye disease.

[0042] Specifically, the device described herein and shown in FIG. 2 is a cylindrical punctal plug 6 with a diameter of about 0.5 mm and a length of 6 mm. However, it should be understood that alternative diameters and lengths are contemplated herein. For example, the punctal plug can have a length of up to about 1 mm, up to about 2 mm, up to about 3 mm, up to about 4 mm, up to about 5 mm, up to about 6 mm, up to about 7 mm, up to about 8 mm, up to about 9 mm, or up to 10 mm, or more. As will be appreciated, longer plugs can contain larger amounts of drugs and related ingredients due to their larger total volume. Furthermore, although the disclosure herein primarily refers to punctal plugs (e.g., punctal plugs 6), it should be understood that these devices may additionally or alternatively be referred to as lacrimal inserts.

[0043] In some embodiments, the size of the plug 6 can be optionally varied depending on the patient. In other embodiments, the plug 6 is designed as a "one size fits all" device that can more easily fit into various sizes of puncta. For example, the swellable plug 6 disclosed herein can be easily inserted into a variety of different puncta 3. In some embodiments, the plug 6 is designed to fit into either the left or right eye.

[0044] It should be appreciated that the plug 6 is configured to be inserted into the tear duct 4 of the eye via the lacrimal punctum 3 as shown in FIG. 2A. In certain embodiments, the plug 6 can be placed in the patient by a non-surgical procedure. This delivery scheme also easily replicates drug release kinetics known to be useful from eye drops. In particular, the plug 6 is an ideal platform for delivering therapeutic agents to the eye under chronic conditions such as dry eye. It may also be useful for long-term treatments such as atropine for the treatment of myopia progression in children due to its ease of replacement and relatively large size compared to other ocular delivery platforms. FIG. 2A thus illustrates a close-up schematic diagram of the patient's ocular anatomy and the insertion of the plug 6 into the tear duct 4 of the patient's eye. As shown, the plug 6 is configured to make an approximately 90° turn or bend once inserted into the tear duct 4 of the eye.

[0045] Device configuration and construction Generally, the plug 6 is constructed by a hot melt extrusion method. Specifically, the plug 6 is a homogenous monolithic filament that remains flexible at room temperature. Once the plug 6 undergoes hydration with the tear film, the flexibility changes and the plug 6 disintegrates. Generally, by being disintegrable, the plug 6 is configured for one-time use, thus avoiding certain risks associated with permanent plugs, such as infection, granuloma, and related safety issues, such as overinsertion and subsequent surgical removal. In certain embodiments, the plug 6 comprises a monolithic material that is disintegrable in water. In a related embodiment, the water is tear fluid. The plug 6 may also be configured to be washed out of the nasal passages (after disintegration) for removal from the canaliculus.

[0046] In one embodiment, the plug 6 has sufficient strength and flexibility to maintain the knot, as shown in Figure 3. As shown in Figure 3, the plug 6 has flexibility such that the entire knot has a dimension of about 2 mm; this knot dimension demonstrates that the plug 6 has the necessary flexibility and strength in the anatomical dimensions required to pass from the proximal portion of the canaliculus 4a to the distal portion of the canaliculus 4b. For example, the plug 6 makes a turn or bend of about 90° as it passes from the proximal portion of the canaliculus 4a to the distal portion of the canaliculus 4b.

[0047] In certain embodiments, the bulk material for hot melt extrusion is a water soluble polymer, such as, for example, a family of high molecular weight polysaccharides, hi a particular embodiment, the high molecular weight polysaccharide is hydroxypropyl methylcellulose.

[0048] Generally, disintegration is imparted by absorbing polysaccharides and plasticizing them to make them flexible. These water-soluble polymers are mixed with low molecular weight wetting and non-wetting agents, which conveniently impart plasticity during hot melt extrusion. In some embodiments, the monolithic material includes an added plasticizer. In a related embodiment, the added plasticizer includes one or more of glycerin, polyethylene glycol 6000, stearic acid, lauric acid, and dimyristoyl phosphatidylglycerol.

[0049] These additives can also modify the rate of disintegration of the plug 6. For example, the addition of a lipophilic waxy additive slows the rate of water uptake into the plug 6, which changes the behavior and lifespan of the plug 6 in the tubule.

[0050] In one embodiment, the materials used to construct the plug 6 are first blended and mixed, for example by hand or using commercially available equipment, until a homogenous mixture is obtained. This homogenous mixture is added to an extrusion apparatus that can heat the homogenous mixture to about 160-220°C. Upon heating, the materials are homogenously combined and the plasticizer component wets and combines with the bulk polymer component. Also, during extrusion, the additives melt into the mixture. In certain embodiments, a D&C Green No. 6 component or dye is added at a concentration of up to 0.05% to improve visualization of insertion into the eye. This component gives the plug 6 a blue appearance as shown in the knot of FIG. 3. In another related embodiment, a D&C Violet No. 20 component is added to give the plug 6 a purple appearance.

[0051] In some embodiments, the fluorescent moiety improves visibility of the punctal plug during insertion. In some embodiments, the fluorescent moiety allows for in situ visualization of the punctal plug during its duration. It should be understood that the fluorescent moiety can also take the form of a small molecule that is added to the formulation during processing. Additionally or alternatively, the moiety can take the form of a pendant group attached, for example, to a larger polysaccharide.

[0052] The material is then extruded into cylindrical filament-like rods or other relevant shapes.

[0053] After extrusion, the material is allowed to return to room temperature, resulting in a long, flexible, filament-like rod. The filament has a diameter that can range from 0.2 to 0.8 millimeters. The filament is cut to a length that can range from 2 to 10 mm to form a plug 6. The plug 6 is packaged and finally sterilized by common sterilization methods, such as gamma irradiation, ETO gas, autoclaving, or other relevant sterilization methods.

[0054] Once packaged and sterilized, the plug 6 is ready for insertion.

[0055] Device Insertion and Use Specifically, once the plug 6 is constructed, the resulting extruded material is flexible at room temperature, even before hydration; this flexibility allows the plug 6 to bend and flex as it is forced through the anatomical angle in the canaliculus (as shown in FIG. 2A). At the same time, the plug 6 maintains sufficient tensile strength and rigidity to be inserted with slotted forceps, a common insertion method, or by hand. In certain embodiments, the plug 6 is longer than 5 mm and can form a 90° turn or bend once inserted into the canaliculus of the eye. In general, longer plugs provide improved retention due to the larger surface area that accompanies the larger length. Longer plugs also provide improved duration of action due to the larger length of material that must disintegrate.

[0056] The transition of the plug 6 from a straight line to an anatomical turn is further illustrated by FIG. 4. That is, in slide 1 of FIG. 4, the plug 6 is grasped with a slotted forceps and introduced into the inferior punctum 3. Alternatively, the plug 6 can be introduced into the inferior punctum 3 by hand. In slides 2 and 3, the plug 6 advances into the proximal portion 4a of the canaliculus. In slide 4, the plug 6 begins to make an anatomical turn into the distal portion 4b of the canaliculus. In slide 5, the plug 6 advances further. In slide 6, the plug 6 is inserted completely past the punctum.

[0057] For example, in one embodiment, the plug 6 is approximately 10 mm in length. In this embodiment, when inserted, the proximal end of the plug 6 (e.g., 2 mm of the 10 mm plug 6) is located at the proximal portion 4a of the tubule; similarly, when inserted, the distal end of the plug 6 (e.g., 8 mm of the 10 mm plug 6) is located at the distal portion 4b of the tubule.

[0058] Upon hydration, the plug 6 becomes a gelatinous mass that swells slightly to ensure retention within the canaliculus. This gelatinous mass is also conformable, which provides better comfort for the patient. Advantageously, the plug 6 swells, allowing for a one-size-fits-all approach. A swollen plug simplifies sizing requirements for the patient and does not require the use of a retention mechanism to ensure the plug 6 stays in place after insertion. The gelatinous mass is fully disintegrable and can be washed away once fully hydrated, ensuring ease and safety of removal by irrigation from the nasal cavity, for example with a saline irrigation.

[0059] In the experimental results, to demonstrate that the plugs 6 completely disintegrate in aqueous solution, three plugs 6 were placed in individual vials of saline buffer and placed in a 37° C. water bath. The plugs 6 were observed to swell and completely disintegrate after a few days. The buffer in each vial was then tested for percent HPMC composition by gel permeation chromatography using a refractive index detector. Samples were recovered at 92%, 105%, and 88%, with an average recovery of 95%. This demonstrates that the bulk polymer HPMC was dissolved in the buffer.

[0060] It should be understood that the plug 6 is generally biodegradable or bioerodible, and may comprise any suitable material, including poly(lactic acid), polyethylene-vinyl acetate, poly(lactic acid-co-glycolic acid), poly(D,L-lactide), poly(D,L-lactide-co-trimethylene carbonate), collagen, heparinized collagen, poly(caprolactone), poly(glycolic acid), and / or other polymers or copolymers.

[0061] In some embodiments, the plug 6 comprises a polymer having a drug distributed or dispersed throughout. Detailed methods for incorporating drugs or prodrugs into a polymer matrix are disclosed in US8,628,792, WO2009 / 035565 and US2016 / 0172268, the disclosures of which are incorporated herein by reference in their entirety. The distribution of the drug within the polymer can be homogenous, such as by stirring a powdered or liquid drug with a thermoplastic polymer in soft or flowable form (such as polyurethane); or by stirring a powdered or liquid drug with a thermosetting polymer (such as polydimethylsiloxane or other silicone) or hydrogel (such as polyacrylamide) in prepolymer form.

[0062] In some embodiments, the drug loading associated with plug 6 provides an initial elution range of 1 μg / day, 2 μg / day, 3 μg / day, 4 μg / day, 5 μg / day, 6 μg / day, 7 μg / day, 8 μg / day, 9 μg / day, 10 μg / day. In some examples, the drug loading can include a drug elution rate of at least 1 μg to about 5 μg / day, about 5 μg to about 10 μg / day, about 2 μg to about 4 μg / day, about 4 μg to about 6 μg / day, about 6 μg to about 8 μg / day, about 8 μg to about 10 μg / day, or about 3 μg to about 8 μg / day. In some embodiments, the drug loading is 0.2 μg / day, 0.3 μg / day, 0.4 μg / day, 0.5 μg / day, 0.6 μg / day, 0.7 μg / day, 0.8 μg / day, 1.0 μg / day, 1.1 μg / day, 1.2 μg / day, 1.3 μg / day, 1.4 μg / day, 1.5 μg / day, 1.6 μg / day, 1.7 μg / day, 1.8 μg / day, 1.9 ... μg / day, 1.8μg / day, 1.9μg / day, 2.0μg / day, 2.1μg / day, 2.2μg / day, 2.3μg / day, 2.4μg / day, 2.5μg / day, 2.6μg / day, 2.7μg / day, 2.8μg / day, 2.9μg / day, 3.0μg / day, 3.1μg / day, 3.2μg / day, 3.3μg / day, 3 0.4μg / day, 3.5μg / day, 3.6μg / day, 3.7μg / day, 3.8μg / day, 3.9μg / day, 4.0μg / day, 4.1μg / day, 4.2μg / day, 4.3μg / day, 4.4μg / day, 4.5μg / day and about 0.2μg / day to about 0.8μg / day, about 0.8μg / day to about 1.0μg / day to about These may include drug elution rates in the ranges of 1.5 μg / day, about 1.5 μg / day to about 2.0 μg / day, about 2.0 μg / day to about 2.5 μg / day, about 2.5 μg / day to about 3.0 μg / day, about 3.0 μg / day to about 3.5 μg / day, about 3.5 μg / day to about 4.0 μg / day, and about 4.0 μg / day to about 4.5 μg / day.

[0063] It will be understood that the embodiments described herein may include drugs (sometimes referred to herein as formulations or drug formulations or drug loading) that are mixed or compounded with biodegradable materials, excipients, polymers, or other agents that modify the release characteristics of the drug to form a solid or soft solid, e.g., a paste, gel, etc. Drug formulations or other forms of drugs can be loaded directly into the device.

[0064] In some embodiments, the plug 6 can contain multiple active pharmaceutical ingredients ("APIs"). In some examples, the lacrimal insert 6 can be configured to contain two pharmaceuticals that provide an initial release of a corticosteroid, such as loteprednol etabonate, and a sustained release of an immunosuppressant, such as cyclosporine A.

[0065] In some embodiments, such materials include biodegradable or bioerodible copolymers of lactic acid and glycolic acid, also known as poly(lactic-co-glycolic acid) or PLGA. Although some disclosures herein specifically describe the use of PLGA, those of skill in the art will understand that other suitable biodegradable materials may be used in place of or in combination with PLGA in such embodiments.

[0066] In some embodiments, it may be desirable to provide a particular release rate of a drug from a PLGA copolymer, other polymeric material, or other excipient. Because the release rate of a drug from a polymer correlates with the degradation rate of that polymer, controlling the degradation rate provides a means for controlling the delivery rate of a drug contained within a therapeutic agent. Altering the average molecular weight of the polymer or copolymer chains that make up a PLGA copolymer or other polymer can be used to control the degradation rate of the copolymer, thereby achieving a desired duration or other release profile of therapeutic agent delivery to the eye.

[0067] In certain other embodiments using PLGA copolymers, the biodegradation rate of the PLGA copolymer can also be controlled by altering the ratio of lactic acid units to glycolic acid units in the copolymer.

[0068] Yet other embodiments may utilize a combination of varying the average molecular weight of the constituent components of the copolymer and varying the ratio of lactic acid to glycolic acid in the copolymer to achieve a desired biodegradation rate.

[0069] In some embodiments, the drug is compounded with one or more polymers to form a gel or paste that aids in determining the elution rate of the drug. Certain preferred formulations have one or more of three properties: high drug component density and high overall material density; the ability to flow freely to facilitate filling of the device and prevent air gaps or other dead spaces in the device, which may include thixotropic materials; a flexible or malleable drug final form once placed in the device, if designed to be flexible during use or insertion; and the ability to remain effective in drug delivery even if the encapsulating polymer is ruptured, broken or otherwise damaged.

[0070] In some embodiments, the therapeutic agent is a protein, and in such embodiments, drying and / or tableting should be completed under specific temperature, acid / base, etc. conditions that do not adversely affect the biological activity of the therapeutic agent. To help maintain the biological activity of the micropelleted therapeutic agent, in some embodiments, protein therapeutic agents are formulated with stabilizing agents such as mannitol, trehalose, starch or other polyhydroxypolymers to maintain the structure (and thus activity) of the therapeutic protein.

[0071] As mentioned above, depending on the embodiment, the drug administered via the drug delivery device may be in the form of a nanodispersion, which is particularly advantageous when the drug to be administered is poorly soluble or insoluble in aqueous solutions, which may lead to instability and / or reduced bioavailability.

[0072] The term "nanodispersion" as used herein shall be given its ordinary meaning and shall refer to a composition comprising nanoparticles that include a drug and / or an aqueous vehicle. In some embodiments, the aqueous vehicle comprises a water-miscible solvent and water. In some embodiments, the nanoparticles may comprise a drug, a polymer, and a surfactant, which in some embodiments comprises a mixture of a fatty acid or a salt thereof and a sterol or a derivative thereof or a salt thereof.

[0073] The term "nanoparticle" as used herein shall be given its ordinary meaning and shall also refer to particles having controlled dimensions on the order of nanometers. For example, the nanoparticles, in some embodiments, include polymeric nanoparticles (polymer formulations that entrap a drug) and / or polymeric nanovesicles (polymer-stabilized nano-sized vesicles that encapsulate a drug) and / or polymeric nanocapsules (polymeric membranes surrounding a drug core) and / or surfactant-stabilized nano-sized particles of drugs, and have an average particle size of less than about 300 nm, e.g., in the range of about 10 nm to about 275 nm or in the range of about 10 nm to about 200 nm.

[0074] In some embodiments, the water-miscible solvent used in the nanodispersion includes one or more of alcohols, glycols and their derivatives, polyalkylene glycols and their derivatives, glycerol, glycofurol, and combinations thereof. Further non-limiting examples include, but are not limited to, alcohols, such as ethanol, n-propanol, isopropanol; glycols, such as ethylene glycol, propylene glycol, butylene glycol and their derivatives; polyethylene glycols, such as PEG400 or PEG3350; polypropylene glycols and their derivatives, such as PPG-10 butanediol, PPG-10 methyl glucose ether, PPG-20 methyl glucose ether, PPG-15 stearyl ether; glycerol; glycofurol, and the like, and mixtures thereof. In yet further embodiments, the non-aqueous solvent is selected from the group consisting of alcohols, polyethylene glycols, and / or mixtures thereof, such as a mixture of ethanol and PEG (polyethylene glycol). In some embodiments where ethanol is used in the nanodispersion, ethanol is present in an amount ranging from about 0.001% w / v to about 5% w / v, more preferably from about 0.05% w / v to about 0.5% w / v, and most preferably from about 0.1% w / v to about 0.25% w / v. Polyethylene glycols preferably used include PEG-400 and PEG-3350. PEG-400 is used in an amount ranging from about 0.01% w / v to about 20.0% w / v, more preferably from about 0.05% w / v to about 5.0% w / v, and most preferably from about 1.0% w / v to about 2.5% w / v, depending on the embodiment. PEG-3350 is used in an amount ranging from about 0.001% w / v to about 10.0% w / v, more preferably from about 0.05% w / v to about 5.0% w / v, and most preferably from about 0.1% w / v to about 3% w / v, depending on the embodiment.

[0075] In some embodiments, the nanoparticles include one or more polymers. The polymers used in some embodiments are preferably water-soluble. One such water-soluble polymer used in some embodiments, polyvinylpyrrolidone, is a tertiary amide polymer having monomer units of 1-vinyl-2-pyrrolidone arranged in a linear chain. It has an average molecular weight in the range of about 10,000 to about 700,000. In some embodiments, other grades of polyvinylpyrrolidone are used having molecular weights in the range of about 2000 to about 3000, about 7000 to about 11,000, about 28,000 to about 34,000, or about 1,000,000 to about 1,500,000. In still further embodiments, the polyvinylpyrrolidone used in the polymer has a molecular weight in the range of about 1,000 to about 45,000, preferably about 4,000 to about 30,000. According to some embodiments, the amount of polymer used in the nanodispersion ranges from about 0.001% w / v to about 20% w / v, preferably from about 0.01% w / v to about 5.0% w / v and from about 0.01% w / v to about 1.0% w / v.

[0076] In some embodiments, polyethylene glycol is used in addition to or instead of polyvinylpyrrolidone. In some embodiments, the amount of polymer used in the nanodispersion ranges from about 0.001% w / v to about 20% w / v, such as from about 0.01% w / v to about 5.0% w / v, and in some embodiments, from about 0.01% w / v to about 1.0% w / v.

[0077] In some embodiments of the nanodispersion for the drug, a surfactant is used, hi some embodiments, the surfactant comprises a mixture of a fatty acid or a salt thereof and a sterol or a derivative thereof or a salt thereof.

[0078] The term "fatty acid" as used herein shall be given its ordinary meaning and shall include aliphatic (saturated or unsaturated) monocarboxylic acids derived from or contained in esterified form in animal or vegetable fats, oils or waxes. Non-limiting examples of fatty acids (or salts thereof) that may be used in some embodiments include, but are not limited to, fatty acids having "n" carbon atoms (where "n" ranges from about 4 to about 28) or salts thereof. The fatty acids may be saturated or unsaturated fatty acids and their salts and combinations thereof. Depending on the embodiment, the saturated fatty acids and their salts may be selected from butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, sodium caprylate, sodium laurate, sodium myristate, sodium palmitate, and the like, and / or mixtures thereof. The unsaturated fatty acids and their salts may be selected from myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, alpha-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, sodium oleate, sodium arachidonate, and the like, and / or mixtures thereof.

[0079] In addition, non-limiting examples of sterols or their derivatives or salts that can be used in the nanodispersion or nanoparticles can be sterol acid esters.Sterols that can be suitable include, but are not limited to, cholesterol, plant sterols, ergosterol, bile salts, and mixtures thereof.Cholesterol acid salts that can be used include cholesteryl sulfate, cholesterol acetate, cholesterol chloroacetate, cholesterol benzoate, cholesterol myristate, cholesterol hemisuccinate, cholesterol phosphate, cholesterol phosphate, phosphonate, borate, nitrate, cholesterol cinnamate, cholesterol crotanate, cholesterol butyrate, cholesterol heptanoate, cholesterol hexanoate, cholesterol octanoate, cholesterol nonanoate, cholesterol decanoate, cholesterol oleate, cholesterol propionate, cholesterol valerate, dicholesteryl carbonate, and the like, and mixtures thereof.Plant sterols that can be used in the composition include sitosterol, campesterol, stigmasterol, brassicasterol, and its derivatives, salts, and mixtures thereof. For example, phytosterols marketed by Sigma, USA, including β-sitosterol, campesterol and dihydrobrassicasterol. Bile acids include cholic acid, chenodeoxycholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, ursodeoxycholic acid and their derivatives, salts and mixtures thereof. Sterols can also be esters of cholesterol, such as cholesterol hemisuccinate, salts of cholesterol, such as cholesterol hydrogen sulfate and cholesterol sulfate, ergosterol, esters of ergosterol, such as ergosterol hemisuccinate, salts of ergosterol, such as ergosterol hydrogen sulfate and ergosterol sulfate, lanosterol, esters of lanosterol, such as lanosterol hemisuccinate, salts of lanosterol, such as lanosterol hydrogen sulfate and lanosterol sulfate.

[0080] According to one embodiment, the nanoparticles comprise a surfactant which is a mixture of a sterol or a derivative or a salt thereof and a fatty acid or a salt thereof. In a further embodiment, the nanoparticles are composed of cholesterol esters or polar acids. In yet a further embodiment, the surfactant used in the nanodispersion is a mixture of caprylic acid and cholesteryl sulfate. Caprylic acid, also known as octanoic acid, can be used in such embodiments in an amount ranging from about 0.001% w / v to about 5.0% w / v, more preferably from about 0.01% w / v to about 1.0% w / v, and most preferably from about 0.01% w / v to about 0.5% w / v. Cholesteryl sulfate is used in certain embodiments in an amount ranging from about 0.001% w / v to about 5.0% w / v, more preferably from about 0.01% w / v to about 1.0% w / v, and most preferably from about 0.01% w / v to about 0.5% w / v. In one embodiment, the surfactant used is selected from oleic acid and cholesteryl sulfate and / or mixtures thereof. In some embodiments, the surfactant used is selected from saturated fatty acids and bile acids or bile salts and / or mixtures thereof. Bile salts, when used according to some embodiments, are present in an amount ranging from about 0.001% w / v to about 5.0% w / v, more preferably from about 0.01% w / v to about 1.0% w / v, and most preferably from about 0.01% w / v to about 0.75% w / v. Other amounts may be used in conjunction with other embodiments disclosed herein. Nanodispersions can be produced by art-recognized methods, such as those disclosed in U.S. Patent No. 8,778,364, which is incorporated herein by reference in its entirety (and the resulting nanodispersions).

[0081] In addition, one or more of the therapeutic agent regions may be formed from a drug-cyclodextrin inclusion complex; liposomal encapsulation; micelles based on polymers such as polysaccharides, poly(ethylene glycol)-poly(lactide), methoxypoly(ethylene glycol)-poly(hexyl lactide), or hydrophobically modified hydroxypropyl cellulose; nanoparticles of amorphous drug formed by antisolvent precipitation and stabilized with a surfactant such as polysorbate 80 or polyoxyl 15 hydroxystearate; one or more drugs, a polymer, and a surfactant (the surfactant may include a mixture of a fatty acid or a salt thereof and a sterol or a derivative thereof or a salt thereof). These may include nanoparticles with an average particle size of less than 500 nm, including drugs co-processed or granulated with excipients such as microcrystalline cellulose, lactose, hydroxypropyl methylcellulose or povidone; polyethylene glycol chains attached to the drug, polymer or surfactant (PEGylation); solid dispersions in polymeric carriers such as hypromellose acetate succinate, copolymers based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate, poly(vinylpyrrolidone-vinyl acetate) or lauroyl macrogol glycerides; or microspheres (e.g. based on PLGA or chitosan).

[0082] The plug 6 can be formed from a composition of materials including, but not limited to, a cellulosic or equivalent high molecular weight polymer, a plasticizer for the high molecular weight polymer, and a lipid-mimetic small molecule.

[0083] Additionally, the plug 6 can be formulated to allow for sustained release. In some embodiments, this sustained release can be by disintegration upon exposure to an aqueous fluid or medium. In some embodiments, the sustained release can be for at least one day, at least one week, at least one month, at least six months, or at least one year.

[0084] The material properties that allow the plug 6 to flex also allow the plug 6 to conform to curved or bent shapes. In some embodiments, the plug 6 can be flexible, yet rigid enough to be pushed into an opening. This combination of flexibility and pushability creates unique material properties that are different from other lacrimal inserts, which start out very stiff, but quickly become too soft to sustain a push of more than a few millimeters. Thus, the plugs described herein can be useful as stand-alone inserts, without the need for a tube or sleeve or other structure required to house them.

[0085] The plug 6 can act as a stand-alone insert, but in some embodiments may be used with an appropriately designed body to hold it in a particular position.

[0086] The material properties of the plug 6 include pushability, flexibility, and ease of removal when disintegration is complete. In one embodiment, the chemistry is such that any substances released upon disintegration can be useful in ameliorating an ocular condition, such as dry eye. In some embodiments, the chemistry is such that any substances released upon disintegration can be useful in ameliorating an ocular condition.

[0087] The composition of materials used to form the plug 6 can be comprised entirely of FDA over-the-counter (OTC) monograph ingredients for ophthalmic compositions, such as OTC eye drops. This use of OTC monograph ingredients is in contrast to typical drug delivery extrusions that use polymers such as PLGA, which are necessary for bulk properties but serve no clinical need.

[0088] In some embodiments, the polymer used to form the plug 6 can be the active ingredient, so there is no wasted polymer used to support and / or release the active ingredient. This polymer, which may or may not be the active ingredient, can be a cellulose derivative such as sodium carboxymethylcellulose, hydroxyethylcellulose, hypromellose (hydroxypropylmethylcellulose), methylcellulose, etc. The polymer can also be polyvinyl alcohol (PVA), povidone (polyvinylpyrrolidone). In some embodiments, the polymer can also be hyaluronic acid, guar gum, or chondroitin sulfate.

[0089] In some embodiments, any number of these polymers can be combined.

[0090] In some embodiments, the drug can be formulated with a viscosity modifier. The viscosity modifier can be used to increase or decrease the viscosity of the formulated drug. Viscosity modifiers can include, but are not limited to, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hyaluronic acid, and combinations thereof.

[0091] The polymers used can be bulk or viscosity modifying polymers that, when combined with the natural aqueous substances of the tear film, can act as a mucin binding layer, soothing the corneal tissue and thus exerting a therapeutic effect as an active ingredient.

[0092] The composition of material used to form the plug 6 can include a plasticizer. The plasticizer can be an OTC monograph component. In some embodiments, the plasticizer can be an OTC demulcent or emollient, such as polyethylene glycol, e.g., polyethylene glycol 300, polyethylene glycol 400, or polyethylene glycol 6000, glycerin, mineral oil, white petrolatum, white wax, paraffin, lanolin, propylene glycol, or combinations thereof.

[0093] The inclusion of a plasticizer can modify the material properties of the polymer to make it more extrudable, conformable, pushable and / or rigid, as desired to make it easier to insert and place the plug 6, for example, in the canaliculus via a punctum.

[0094] In some embodiments, the composition of material used to form the plug 6 can include a phospholipid. The phospholipid can be 1,2-dimyristoyl-sn-glycero-3-phospho-rac-glycerol sodium salt (DMPG-Na) or its related free acid. This phospholipid component can improve some dry eye symptoms by mimicking the natural lipid layer of the tear film. This layer constitutes the outermost portion of the aqueous tear film and slows the evaporation of water.

[0095] In some embodiments, the plug 6 can include polyethylene glycol. The polyethylene glycol can be PEG 6000. In some embodiments, the plug 6 can include hydroxypropyl methylcellulose. In some embodiments, the plug 6 can include a phospholipid. The phospholipid can be 1,2-dimyristoyl-sn-glycero-3-phospho-rac-glycerol.

[0096] In one embodiment, the filaments comprise about 10% hydroxypropyl methylcellulose, 10% polyethylene glycol, and 80% phospholipids. In another embodiment, the filaments comprise about 10% hydroxypropyl methylcellulose, 80% polyethylene glycol, and 10% phospholipids. In another embodiment, the filaments comprise about 80% hydroxypropyl methylcellulose, 10% polyethylene glycol, and 10% phospholipids. In another embodiment, the filaments comprise about 20% hydroxypropyl methylcellulose, 20% polyethylene glycol, and 60% phospholipids. In another embodiment, the filaments comprise about 20% hydroxypropyl methylcellulose, 60% polyethylene glycol, and 20% phospholipids. In another embodiment, the filaments comprise about 60% hydroxypropyl methylcellulose, 20% polyethylene glycol, and 20% phospholipids. In another embodiment, the filaments comprise about 40% hydroxypropyl methylcellulose, 40% polyethylene glycol, and 20% phospholipids. In another embodiment, the filaments comprise about 40% hydroxypropyl methylcellulose, 20% polyethylene glycol, and 40% phospholipids. In another embodiment, the filaments comprise about 20% hydroxypropyl methylcellulose, 40% polyethylene glycol, and 40% phospholipids.

[0097] In one embodiment, the filaments comprise about 10% hydroxypropyl methylcellulose, 10% PEG 6000, and 80% 1,2-dimyristoyl-sn-glycero-3-phospho-rac-glycerol. In another embodiment, the filaments comprise about 10% hydroxypropyl methylcellulose, 80% PEG 6000, and 10% 1,2-dimyristoyl-sn-glycero-3-phospho-rac-glycerol. In another embodiment, the filaments comprise about 80% hydroxypropyl methylcellulose, 10% PEG 6000, and 10% 1,2-dimyristoyl-sn-glycero-3-phospho-rac-glycerol. In another embodiment, the filaments comprise about 20% hydroxypropyl methylcellulose, 20% PEG 6000, and 60% 1,2-dimyristoyl-sn-glycero-3-phospho-rac-glycerol. In another embodiment, the filaments comprise about 20% hydroxypropyl methylcellulose, 60% PEG 6000, and 20% 1,2-dimyristoyl-sn-glycero-3-phospho-rac-glycerol. In another embodiment, the filaments comprise about 60% hydroxypropyl methylcellulose, 20% PEG 6000, and 20% 1,2-dimyristoyl-sn-glycero-3-phospho-rac-glycerol. In another embodiment, the filaments comprise about 40% hydroxypropyl methylcellulose, 40% PEG 6000, and 20% 1,2-dimyristoyl-sn-glycero-3-phospho-rac-glycerol. In another embodiment, the filaments comprise about 40% hydroxypropyl methylcellulose, 20% PEG 6000, and 40% 1,2-dimyristoyl-sn-glycero-3-phospho-rac-glycerol. In another embodiment, the filaments comprise about 20% hydroxypropylmethylcellulose, 40% PEG 6000, and 40% 1,2-dimyristoyl-sn-glycero-3-phospho-rac-glycerol.

[0098] The therapeutic agent utilized may include one or more of the drugs provided below, either alone or in combination. The drug utilized may also be an equivalent, derivative or analog of one or more of the drugs provided below.

[0099] In cases where more than one drug is desired for the treatment of a particular condition, or where a second drug is administered, such as to counteract a side effect of a first drug, some embodiments may utilize the same form of the two drugs. In other embodiments, different forms of the drugs may be used. Similarly, if one or more drugs utilize an auxiliary drug, excipient, or auxiliary compound, for example to enhance stability or tailor the elution profile, the compound may also be in any form that is miscible with the drug and can be reasonably retained with the device. In some embodiments, the treatment of a particular condition with a drug released from the device may not only treat the condition, but may also induce certain undesired side effects.

[0100] Drugs may include, but are not limited to, pharmaceuticals, such as anti-glaucoma drugs, ophthalmic drugs, antimicrobials, such as antibiotics, antivirals, antiparasitics and antifungals, anti-inflammatory drugs (including steroidal or non-steroidal anti-inflammatory drugs), biologicals, such as hormones, enzymes or enzyme-related components, antibodies or antibody-related components, oligonucleotides (including DNA, RNA, small interfering RNA, antisense oligonucleotides, etc.), DNA / RNA vectors, viruses (wild-type or genetically modified) or viral vectors, peptides, proteins, enzymes, extracellular components, and live cells configured to produce one or more biological components. The use of a particular drug is not limited to its primary indication or regulatory approved therapeutic indication or method of use. Drugs also include compounds or other substances that reduce or treat one or more side effects of another drug or therapeutic agent. Because many drugs have more than one mechanism of action, the description of a particular drug within any one therapeutic class below represents only one possible use of the drug and is not intended to limit the scope of its use with an ophthalmic device system.

[0101] As mentioned above, the therapeutic agent may be combined with any number of excipients known in the art. In addition to the biodegradable polymer excipients mentioned above, other excipients may be used, including benzyl alcohol, ethyl cellulose, methyl cellulose, hydroxymethyl cellulose, cetyl alcohol, croscarmellose sodium, dextran, glucose, fructose, gelatin, glycerin, monoglycerides, diglycerides, kaolin, calcium chloride, lactose, lactose monohydrate, maltodextrin, polysorbates, pregelatinized starch, calcium stearate, magnesium stearate, silicon dioxide, corn starch, talc, and the like. One or more excipients may be present in a total amount as low as about 1%, 5%, or 10%, or in other embodiments, in a total amount as high as 50%, 70%, or 90%.

[0102] In some embodiments, the drug can be formulated with an antibacterial agent. The antibacterial agent can include a poloxamer. The poloxamer can be a copolymer of polyoxyethylene and polyoxypropylene. In some embodiments, the poloxamer can be poloxamer 188.

[0103] In other embodiments, antimicrobial activity can be achieved by modifying the surface of the devices described herein to resist microbial adhesion, for example, by adding a hydrophilic or lipophilic surface to the device. The surface of the device can also be modified by a coating of an antimicrobial agent, such as silver or benzalkonium chloride.

[0104] Examples of drugs that may be used with plug 6 include various antisecretory agents; antimitotic agents and other antiproliferative agents, particularly antiangiogenic agents such as angiostatin, anecortave acetate, thrombospondin, VEGF receptor tyrosine kinase inhibitors and anti-vascular endothelial growth factor (anti-VEGF) agents such as ranibizumab (LUCENTIS®) and bevacizumab (AVASTIN®), pegaptanib (MACUGEN®), aflibercept ( EYLEA), sunitinib and sorafenib, and any of a variety of known small molecule and transcription inhibitors with anti-angiogenic effects; known classes of ophthalmic drugs, such as glaucoma medications, for example adrenergic antagonists, for example beta-blockers, such as atenolol, propranolol, metipranolol, betaxolol, carteolol, levobetaxolol, levobunolol and timolol; adrenergic or sympathomimetic agents, such as epinephrine, flucloxin, dipivefrin, clonidine, apclonidine and brimonidine; parasympathomimetics or cholinergic agents such as pilocarpine, carbachol, phosphoryl iodine and physostigmine, salicylates, acetylcholine chloride, eserine, diisopropyl fluorophosphate, demecarium bromide; muscarinics; carbonic anhydrase inhibitors such as topical and / or systemic agents such as acetozolamide, brinzolamide, dorzolamide and methazolamide, escarinic acid; These may include toxolamide, diamox, and dichlorphenamide; mydriatic and cycloplegic agents, such as atropine, cyclopentolate, succinylcholine, homatropine, phenylephrine, scopolamine, and tropicamide; prostaglandins, such as prostaglandin F2α, antiprostaglandins, prostaglandin precursors, or prostaglandin analogues, such as bimatoprost, latanoprost, travoprost, and unoprostone.

[0105] Other examples of drugs useful in the plug 6 also include anti-inflammatory agents, such as glucocorticoids and corticosteroids, such as betamethasone, cortisone, dexamethasone, dexamethasone 21-phosphate, methylprednisolone, prednisolone 21-phosphate, prednisolone acetate, prednisolone, fluorometholone, loteprednol, medrysone, fluocinolone acetonide, triamcinolone acetonide, triamcinolone, triamcinolone acetonide, beclomethasone, budesonide, flunisolide, fluorometholone, fluticasone, hydrocortisone, anti-infective or anti-bacterial agents such as antibiotics, for example tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline, chloramphenicol, rifampicin, cyprusside ... lofloxacin, tobramycin, gentamicin, erythromycin, penicillin, sulfonamides, sulfadiazine, sulfacetamide, sulfamethizole, sulfisoxazole, nitrofurazone, sodium propionate, aminoglycosides such as gentamicin and tobramycin; fluoroquinolones such as ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, norfloxacin, ofloxacin; bacitracin, erythromycin, fusidic acid, neomycin, polymyxin B, gramicidin, trimethoprim, tetracycline ... methoprim and sulfacetamide; antifungal agents such as amphotericin B and miconazole; antiviral agents such as idoxuridine, trifluorothymidine, acyclovir, ganciclovir, interferons; antifungal agents; immunomodulators such as antiallergic agents, for example sodium cromoglycate, antazoline, metapyriline, chlorpheniramine, cetrizine, pyrilamine, profenpyridamine; antihistamines such as azelastine, emedastine and levocabastine; immunological agents (such as vaccines, immunostimulants and / or immunosuppressants);mast cell stabilizers such as cromolyn sodium, ketotifen, lodoxamide, nedocrimil, olopatadine and pemirolast; ciliary body ablatives such as gentimicin and cidofovir; and other ophthalmic medications such as verteporfin, proparacaine, tetracaine, cyclosporine and pilocarpine; inhibitors of cell surface glycoprotein receptors; decongestants such as phenylephrine, naphazoline, tetrahydrazoline; lipids or antihypertensive lipids; dopamine agonists and / or antagonists, e.g. antihypertensives; angiotensin-converting enzyme (ACE) inhibitors; angiotensin-1 receptor antagonists, such as olmesartan; microtubule inhibitors; molecular motor (dynein and / or kinesin) inhibitors; actin cytoskeleton regulators, such as cytochalasins, latrunculins, swinholide A, ethacrynic acid, H-7 and Rho-kinase (ROCK) inhibitors; remodeling inhibitors; extracellular matrix modulators, such as adenosine receptor agonists and / or antagonists, such as N-6-cyclohexyl adenosine and (R)-phenylisopropyl adenosine; serotonergic agents; hormonal agents, such as estrogen, estradiol, progesterone, insulin, calcitonin, parathyroid hormone, peptides and vasopressin hypothalamic releasing factors; growth factor antagonists or growth factors, such as epidermal growth factor, fibroblast growth factor, platelet derived growth factor These may include peptides or antagonists thereof (e.g., those disclosed in U.S. Pat. No. 7,759,472 or U.S. patent application Ser. Nos. 12 / 465,051, 12 / 564,863 or 12 / 641,270, all of which are incorporated herein by reference in their entirety), transforming growth factor beta, somatotropin, fibronectin, connective tissue growth factor, bone morphogenetic protein (BMP); cytokines such as interleukins, CD44, cochlin, and serum amyloids such as serum amyloid A;

[0106] Other therapeutic agents that may be used with the plug 6 include neuroprotectants such as lubesol, nimodipine and related compounds, such as blood flow enhancers such as dorzolamide or betaxolol; compounds that promote blood oxygenation such as erythropoietin; sodium channel blockers; calcium channel blockers such as nilvadipine or lomerizine; glutamate inhibitors such as memantine, nitromemantine, riluzole, dextromethorphan or agmatine; acetylcholinesterase inhibitors such as galantamine; hydroxylamine or its derivatives, for example, the water-soluble hydroxylamine derivative OT-440; synaptic modulators, for example, hydrogen sulfide compounds containing flavonoid glycosides and / or terpenoids, such as ginkgo; neurotrophic factors, for example, glial cell line derived neurotrophic factor, brain derived neurotrophic factor; cytokines of the IL-6 protein family, for example, ciliary neurotrophic factor or leukemia inhibitory factor; compounds or factors that affect nitric oxide levels, for example, nitric oxide, nitroglycerin or nitric oxide synthase inhibitors; cannabinoid receptor agonists, for example, WIN55-212-2; free radical suppressors, Scavengers, such as methoxypolyethylene glycol thioester (MPDTE) or methoxypolyethylene glycol thiol conjugated with EDTA methyl triester (MPSEDE); antioxidants, such as astaxanthin, dithiol thiones, vitamin E or metallocorrols, such as iron, manganese or gallium corrols; compounds or factors involved in oxygen homeostasis, such as neuroglobin or cytoglobin; inhibitors or factors affecting mitochondrial fission, such as Mdivi-1 (selective inhibitor of dynamin-related protein 1 (Drp1)); kinase inhibitors or modulators, such as the Rho kinase inhibitor H-1152 or the tyrosine kinase inhibitor AG1478; compounds or factors affecting integrin function, such as the β1 integrin activating antibody HUTS-21; N-acyl-ethanolamines and their precursors, N-acyl-ethanolamine phospholipids; stimulators of the glucagon-like peptide 1 receptor, such as glucagon-like peptide 1; polyphenol-containing compounds, such as resveratrol; chelating compounds; apoptosis-related protease inhibitors; compounds that reduce de novo protein synthesis;These include radiotherapy agents; agents for photodynamic therapy; gene therapy agents; gene modulators; autoimmune modulators that prevent damage to nerves or parts of nerves, such as demyelination, such as glatimir; myelin inhibitors, such as anti-NgR blocking protein, NgR(310)ecto-Fc; other immune modulators, such as FK506 binding proteins, such as FKBP51; and medications for dry eye, such as cyclosporine, cyclosporine A, demulcents, and sodium hyaluronate;

[0107] Other therapeutic agents that can be used with plug 6 include other beta-blockers, such as acebutolol, atenolol, bisoprolol, carvedilol, asmolol, labetalol, nadolol, penbutolol, and pindolol; other corticosteroids and nonsteroidal anti-inflammatory agents, such as aspirin, betamethasone, cortisone, diflunisal, etodolac, fenoprofen, fludrocortisone, flurbiprofen, hydrocortisone, ibuprofen, indomethacin, ketoprofen, meclofenamate ... Fenamates, meloxicam, methylprednisolone, nabumetone, naproxen, oxaprozin, prednisolone, prioxicam, salsalate, sulindac, and tolmetin; COX-2 inhibitors such as celecoxib, rofecoxib, and valdecoxib; other immunomodulators such as aldesleukin, adalimumab (HUMIRA®), azathioprine, basiliximab, daclizumab, etanercept (ENBREL®), hydroxychloroquine, infliximab (REMICADE®), )), leflunomide, methotrexate, mycophenolate mofetil and sulfasalazine; other antihistamines such as loratadine, desloratadine, cetirizine, diphenhydramine, chlorpheniramine, dexchlorpheniramine, clemastine, cyproheptadine, fexofenadine, hydroxyzine and promethazine; other anti-infectives such as aminoglycosides such as amikacin and streptomycin; anti-fungals such as amphotericin B, caspofungin, clotrimazole, fluconazole , itraconazole, ketoconazole, voriconazole, terbinafine and nystatin; antimalarials such as chloroquine, atovaquone, mefloquine, primaquine, quinidine and quinine; antimycobacterials such as ethambutol, isoniazid, pyrazinamide, rifampin and rifabutin; antiparasitic agents such as albendazole, mebendazole, thiobendazole, metronidazole, pyrantel, atovaquone, iodoquinaol, ivermectin, paromycin, praziquantel and trimetrexate;other antiviral agents, such as anti-CMV agents or anti-herpes agents, such as acyclovir, cidofovir, famciclovir, ganciclovir, valacyclovir, valganciclovir, vidarabine, trifluridine and foscarnet; protease inhibitors, such as ritonavir, saquinavir, lopinavir, indinavir, atazanavir, amprenavir and nelfinavir; nucleotide / nucleoside / non-nucleoside reverse transcriptase inhibitors, such as abacavir, ddI, 3TC, d4T, ddC, tenofovir and emtricitabine , delavirdine, efavirenz and nevirapine; other antivirals such as interferons, ribavirin and trifluridine; other antibacterials such as carbapenems such as ertapenem, imipenem and meropenem; cephalosporins such as cefadroxil, cefazolin, cefdinir, cefditoren, cephalexin, cefaclor, cefepime, cefoperazone, cefotaxime, cefotetan, cefoxitin, cefpodoxime, cefprozil, ceftaxidime, ceftibuten, ceftizoxime, ceftoria. other macrolides and ketolides such as azithromycin, clarithromycin, dirithromycin and telithromycin; penicillins (with or without clavulanic acid) such as amoxicillin, ampicillin, pivampicillin, dicloxacillin, nafcillin, oxacillin, piperacillin and ticarcillin; tetracyclines such as doxycycline, minocycline and tetracycline; other antibacterial agents such as aztreonam, chloramphenicol, clarithromycin, ... alpha blockers such as doxazosin, prazosin and terazosin; calcium channel blockers such as amlodipine, bepridil, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine and verapamil; other antihypertensives such as clonidine, diazoxide, fenoldopan, hydralazine, minoxidil, nitroprusside, phenoxybenzamine, epoprostenol, tolazoline, treprostinil and nitrates;Anticoagulants such as heparin and heparin analogues, such as heparin, dalteparin, enoxaparin, tinzaparin, and fondaparinux; other anticoagulants, such as hirudin, aprotinin, argatroban, bivalirudin, desirudin, lepirudin, warfarin, and ximelagatran; antiplatelet agents, such as abciximab, clopidogrel, dipyridamole, optifibatide, ticlopidine, and tirofiban; prostaglandin PDE-5 inhibitors and other prostaglandin agents, such as alprostadil, carboprost , sildenafil, tadalafil and vardenafil; thrombin inhibitors; antithrombotic agents; platelet aggregation inhibitors; thrombolytic and / or fibrinolytic agents such as alteplase, anistreplase, reteplase, streptokinase, tenecteplase and urokinase; antiproliferative agents such as sirolimus, tacrolimus, everolimus, zotarolimus, paclitaxel and mycophenolic acid; hormone-related agents such as levothyroxine, fluoxymestrol, methyltestosterone, nandrolone, oxandrolone, testosterone, estradiol, estrone, estropipate, clomiphene, gonadotropins, hydroxyprogesterone, levonorgestrel, medroxyprogesterone, megestrol, mifepristone, norethindrone, oxytocin, progesterone, raloxifene and tamoxifen; antitumor agents such as alkylating agents, for example carmustine, lomustine, melphalan, cisplatin, fluorouracil 3 and procarbazine; antibiotic-like agents, for example bleomycin, daunorubicin, doxorubicin, idarubicin, mitomycin and plicamycin; antiproliferative agents (such as 1,3-cis-retinoic acid, 5-fluorouracil, taxol, rapamycin, mitomycin C, and cisplatin); antimetabolites such as cytarabine, fludarabine, hydroxyurea, mercaptopurine, and 5-fluorouracil (5-FU); immunomodulators such as aldesleukin, imatinib, rituximab, and tositumomab; mitotic inhibitors such as docetaxel, etoposide, vinblastine, and vincristine; radioactive agents such as strontium-89;and other antitumor agents such as irinotecan, topotecan, and mitotane.;

[0108] Although specific embodiments of the present disclosure have been described, these embodiments are presented by way of example only and are not intended to limit the scope of the present disclosure. Indeed, the novel methods, systems, and devices described herein may be embodied in a variety of other forms. For example, one illustrated or described device embodiment may be combined with another illustrated or described plug or insert embodiment. Moreover, the devices may be utilized for other purposes. For example, the devices may be placed in other tissues of the body where localized delivery of hyaluronic acid may be beneficial. Moreover, various omissions, substitutions, and changes in the form of the methods, systems, and devices described herein may be made without departing from the spirit of the present disclosure.

Claims

1. The punctal plug is constructed of a monolithic material and configured to turn approximately 90 degrees when inserted into the canaliculus of the eye, The monolithic material comprises a high molecular weight polysaccharide.

2. The punctal plug of claim 1, wherein the length of the punctal plug is greater than 5 mm.

3. A punctal plug as described in claim 2, wherein the diameter of the punctal plug is greater than 0.2 mm and less than 1.0 mm.

4. The punctal plug of claim 1 , wherein the monolithic material is disintegratable in water.

5. The punctal plug of claim 1 , wherein the monolithic material is disintegrable and configured to be washed out of the nasal passages for removal.

6. A punctal plug as described in claim 1, containing at least 50% by weight of the high molecular weight polysaccharide.

7. The punctal plug of claim 1, wherein the monolithic material further comprises an added plasticizer.

8. The punctal plug of claim 7 , wherein the high molecular weight polysaccharide is hydroxypropyl methylcellulose.

9. The punctal plug of claim 7 , wherein the high molecular weight polysaccharide is carboxymethylcellulose.

10. The punctal plug of claim 7 , wherein the high molecular weight polysaccharide is hyaluronic acid.

11. The punctal plug of claim 7 , wherein the added plasticizer comprises one or more of glycerin, polyethylene glycol 6000, stearic acid, lauric acid, and dimyristoyl phosphatidylglycerol.

12. 10. The punctal plug of claim 1, comprising a fluorescent moiety for improving visibility of the punctal plug during insertion.

13. 10. The punctal plug of claim 1, comprising a fluorescent moiety that allows for in situ visualization of the punctal plug for its duration.

14. 10. The punctal plug of claim 1, configured to maintain a tear film in the eye, constructed entirely of a material suitable for incorporation into a lubricating eye drop, said monolithic material disintegrating into the tear film over a period of at least one month.

15. A punctal plug, constructed of a disintegrable monolithic material such that the punctal plug is configured to be inserted into the canaliculus of the eye, the disintegrable monolithic material comprising a high molecular weight polysaccharide.

16. The punctal plug of claim 15, wherein the length of the punctal plug is greater than 5 mm.

17. The punctal plug of claim 16, wherein the diameter of the punctal plug is greater than 0.2 mm and less than 1.0 mm.

18. The punctal plug of claim 15 , wherein the disintegrable monolithic material is configured to be washed out of the nasal passages for removal.

19. The punctal plug described in claim 15, containing at least 50% by weight of the high molecular weight polysaccharide.

20. The punctal plug of claim 15, wherein the monolithic material further comprises an added plasticizer, and the polymeric polysaccharides are one of hydroxypropylmethylcellulose, carboxymethylcellulose and hyaluronic acid.

21. The punctal plug of claim 1, wherein the monolithic material is homogeneous.

22. The punctal plug of claim 15, wherein the disintegratable monolithic material is homogeneous.

23. The punctal plug of claim 1, wherein the monolithic material comprises hydroxypropyl cellulose.

24. The punctal plug of claim 15, wherein the disintegratable monolithic material comprises hydroxypropyl cellulose.

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