HK1168269A - Punctal plugs - Google Patents

Description

Punctal plug

Background

The present invention relates to devices adapted to deliver substances to one or more of the eye, nose and throat. In particular, the present invention relates to punctal plugs for the delivery of at least one active agent.

Human tears are secreted by the lacrimal gland and flow across the ocular surface to a shallow pool, known as the lacrimal lake, where the eyelids meet at the inner extremities. From there, the tears drain through small holes in each of the upper and lower eyelids (referred to as the superior and inferior puncta, respectively), from the superior and inferior puncta and into the respective superior and inferior canaliculi, respectively, which are tubular passages leading to the lacrimal sac. The lacrimal sac is the upper, enlarged portion of the nasolacrimal duct, which drains tears into the nasal system. The active agent can thus be delivered to the nose and throat via the lacrimal canaliculus that leads to the nasolacrimal duct.

Active agents are often administered to the eye to treat ocular diseases. Conventional methods for delivering active agents to the eye involve topical application to the ocular surface. When properly formulated, topically applied active agents can penetrate the cornea, conjunctiva or sclera and rise to therapeutic concentration levels in the eye, and thus the eye is particularly suited to receiving topical administration. Active agents for ocular diseases can be administered orally or by injection, but these routes of administration have the disadvantage that: for oral administration, the concentration of active agents that can reach the eye is too low to achieve the desired pharmacological effect, and their use is associated with significant systemic side effects, whereas injection poses the risk of infection, discomfort, bleeding or puncture of the eye.

Most ophthalmic active agents are typically delivered topically using eye drops, which, while effective in some applications, are inefficient. When a drop of eye drop is applied to the eye, it fills the conjunctival sac (the sac between the eye and the eyelid) such that a significant portion of the drop is lost as it spills over the eyelid margin to the cheek. In addition, a significant portion of the eye drop remaining on the ocular surface can enter the punctum, thereby diluting the drug concentration.

Disclosure of Invention

In one aspect of the invention, a punctal plug has: a first end, a second end, and a side surface extending between the ends; a reservoir contained within the body, wherein the reservoir has at least one opening and contains an active agent-containing material having at least one active agent, and the second end of the punctal plug is an anchor having a conical shape.

In another aspect of the invention, the punctal plug has a conical anchor that is offset from the central axis of the body of the punctal plug.

In another aspect of the invention, the conical portion of the anchor of the punctal plug has the following dimensions: a base of 1.0 to 1.5mm, a height of 0.3 to 1.0mm, a radius of 0.4 to 0.85mm, and an axis of 0 to 0.50 mm.

In another aspect of the invention, the punctal plugs contain an active agent.

Drawings

Fig. 1 is a cross-sectional view of a punctal plug according to the invention having a body 1 and a reservoir 2 in the body 1, the body 1 having an enlarged portion 4, the reservoir 2 containing a polymeric material (not shown) that contains an active agent (not shown). The reservoir 2 has an opening 3 through which the active agent is released.

Fig. 2 is a three-dimensional view of a punctal plug shown in two dimensions, with: a body 90, the body 90 having an enlarged portion 92; a reservoir 95 in the body 90, the reservoir 95 containing a polymeric material 91, the polymeric material 91 containing an active agent 98; and a shroud 94. The reservoir 95 has an opening 93 through which the active agent 98 is released.

Detailed Description

The punctal plugs described in this specification can be used to deliver active agents to one or both of the nasolacrimal duct and the tear fluid of the eye. In one embodiment, the invention provides a punctal plug that comprises, consists essentially of, and consists of: a body having a first end and a second end; a side surface extending between the ends; a reservoir contained within the body, wherein the reservoir comprises, consists essentially of, and consists of at least one opening, and contains a material comprising, consisting essentially of, and consisting of at least one active agent; and wherein the body is impermeable to the active agent.

Referring to fig. 1, punctal plug body 1 has a reservoir 2 that includes at least one opening 3, and the active agent (not shown) is released through opening 3, for example, when the active agent-containing material (preferably a polymeric material) dissolves, degrades, or the active agent is merely diffused or released from the material with which it is associated, absorbed, or otherwise associated (depending on the nature of the material). The opening through which the active agent is released from the punctal plug can be located at the first end and/or the second end of the punctal plug body, or along a lateral surface of the punctal plug. Preferably, the opening is located at the first end and/or the second end. In a particular embodiment of the invention, such as shown in fig. 1, the punctal plug includes an enlarged portion of body 1 or anchor 4 that is sized and shaped to secure the punctal plug in the lacrimal canaliculus.

For delivery of an active agent to the tear fluid of the eye, a punctal plug is inserted into the lacrimal canaliculus and the active agent is released into the tear fluid of the eye. Referring to fig. 2, for delivery into the tear fluid, a collarette 94 is preferably provided on the body 90 of the punctal plug, and when the punctal plug is inserted into the lacrimal canaliculus, the collarette 94 remains outside the punctum. For delivery of the active agent to the nasolacrimal duct, it is preferred to insert the punctal plug deep into the lacrimal canaliculus and release the active agent into the nasolacrimal duct.

As used herein, the term "punctal plug" refers to a device that: it is of a suitable size and shape for insertion through the lower or upper punctum into the lower or upper canaliculus of the eye.

As used herein, the term "active agent" refers to an agent capable of treating, inhibiting, or preventing a disease. Exemplary active agents include, but are not limited to, drugs and nutrients. Preferred agents are capable of treating, inhibiting or preventing a disease of one or more of the eye, nose and throat.

As used herein, the phrase "at least partially water soluble material" refers to a material that exhibits a level of water solubility sufficient to produce a measurable amount of dissolution upon exposure to an aqueous environment.

As used herein, the phrase "biodegradable material" refers to a material that degrades to a measurable degree upon exposure to a biologically active substance typically present in mammals.

As used herein, the phrase "water-insoluble material" refers to a material that does not dissolve to a significant extent upon exposure to water.

As used herein, the phrase "non-biodegradable material" refers to a material that does not degrade to a significant extent upon exposure to biologically active substances typically present in mammals.

As used herein, the phrase "body impermeable to the active agent" refers to a body through which only a very small amount of the active agent can pass.

As used herein, the term "polymeric material" refers to a material made of one or more types of polymers capable of containing at least one active agent and releasing the active agent when: for example, when the polymer is dissolved or degraded, when the active agent diffuses from the polymer, or when a prodrug is used (wherein the active agent is attached to the polymer and then released by cleavage from the material).

As used herein, the term "opening" refers to an opening in the body of the punctal plug that is of a size and shape that is capable of passing an active agent. Preferably, only the active agent can pass through the opening. The opening may be, for example, a hole covered by a membrane, mesh, grid, or it may be uncovered. The film, mesh or grid may have one or more of the following characteristics: porous, semi-porous, permeable, semi-permeable, and biodegradable.

As used herein, the phrase "flexible material" refers to a material that is not rigid and that substantially conforms to the surface of the object regardless of the object with which the material contacts.

As used herein, the phrase "the reservoir and the body are connected" means that the reservoir is substantially all of the body. When the reservoir and body are connected, the collarette may be attached to the body, but the collarette cannot be considered part of the body.

As used herein, the phrase "refilled with active agent" refers to adding any detectable amount of active agent to the reservoir of the punctal plug.

The present invention encompasses punctal plugs for the delivery of active agents to one or both of the tear fluid of the eye and the nasolacrimal duct. Punctal plugs are preferably inserted into the inferior and/or superior lacrimal canaliculus. If the punctal plug is used to deliver an active agent to the tear fluid of the eye, the punctal plug preferably has a collarette at one end of the body. The collarette is a portion of the punctal plug that extends radially outward from one end of the body sufficiently and is of a suitable size and shape such that at least a portion of the collarette extends outward and is positioned beyond the punctum after insertion of the punctal plug into the lacrimal canaliculus. The collarette typically extends about 0.2 to about 1mm beyond the body of the punctal plug. The non-collarette punctal plug is inserted partially into one of the inferior or superior punctum. Referring to fig. 2, enlarged portion 92 and body 90 are inserted into one of the punctum with collarette 94 abutting the exterior of the punctum and preventing the punctal plug from sliding into the lacrimal canaliculus so that contact between the punctal plug and the tear fluid of the eye is maintained.

If punctal plugs are used to deliver active agents to the nasolacrimal duct, the punctal plugs may not have a collarette such that they can be inserted into one or both of the lacrimal canaliculi to a sufficient depth such that the active agent is released into the lacrimal sac.

The punctal plugs of the invention all have various features and advantages. For example, some punctal plugs include a body having a first end, a second end, and a side surface extending between the ends. The side surface preferably has an outer diameter that is generally circular in shape, and thus the body preferably has a cylindrical shape. Referring again to fig. 1, anchors 4 are secured to the end of the body opposite the collarette 5. The anchor provides one or more surfaces that contact the tissue into which it is inserted, thereby increasing the likelihood that the punctal plug will remain in place after insertion. The anchor 4 is a cone, just a right circular cone with its apex pointing away from the body 1. It may also take the shape of an oblique cone or a right or oblique elliptical cone. Preferably, the anchor 4 extends from 0 to 0.4mm, most preferably from 0 to 0.1mm, from the end of the body. The anchor 4 may be formed as a combined geometry of a cone and another shape, such as a washer on top of the cone. When this configuration is used, the washer portion (the section of the cylinder with a diameter greater than the diameter of the body) atop the conical portion of the anchor can extend 0.26mm to 1.09mm beyond the base of the conical portion. The anchor may be secured by glue, welding, adhesive or any other convenient method, although it may be formed by co-molding or over-molding, but is most preferably formed as part of the molding process. Preferred dimensions for preparing a portion of the anchor (in terms of modular geometry) or the conical portion of the anchor as a whole are as follows: a base of 1.0 to 1.5mm, a height of 0.3 to 1.0mm, a radius of 0.4 to 0.85mm, and an axis of 0 to 0.50 mm. It is most preferred that the anchor is offset from the transverse axis of the body by 0.20 mm. Preferably, the offset is 0.085 to 0.130mm from the center of the base of the cone of the anchor (or up to 58% from the center of the circumference of the base of the cone). The shroud 6 may also be offset from the centre of the shaft. The outer diameter of a portion of the lateral surface of some punctal plugs is preferably greater than the outer diameter of the remainder of the lateral surface. Referring to fig. 2, enlarged portion 92 of the lateral surface anchors or secures the punctal plug in the lacrimal canaliculus. The enlarged portion can be of any size or shape, and can be present on any portion of the lateral surface, so long as the enlarged portion at least partially anchors the punctal plug in the lacrimal canaliculus. Preferably, the enlarged portion is at one end of the punctal plug. For convenience, the enlarged portion may take the form of an inverted triangle with a flat apex (as shown in fig. 2), may have a non-tapered body with a rounded end, or may have a tapered shape with an inverted dot at one end. One of ordinary skill in the art will recognize that any of a variety of shapes are possible.

The body 90 of the punctal plugs of the invention can take any shape and size. Preferably, the body has the shape of an elongated cylinder. The body length is about 0.8 to about 5mm, preferably about 1.2 to about 2.5 mm. The body width is from about 0.2 to about 3mm, preferably from 0.3 to about 1.5 mm.

The punctal plug body can be wholly or partially transparent or opaque. Optionally, the body may include a coloring agent or pigment to facilitate visualization of the punctal plugs when placed in the punctum.

The body of the punctal plug can be made of any suitable biocompatible material, including, but not limited to, silicones, silicone blends, silicone copolymers (e.g., hydrophilic monomers of polyhydroxyethylmethyl methacrylate ("pHEMA"), polyethylene glycol, polyvinylpyrrolidone, and glycerol), and silicone hydrogel polymers (e.g., those described in U.S. patent nos. 5,962,548, 6,020,445, 6,099,852, 6,367,929, and 6,822,016, which are incorporated herein by reference in their entirety). Other suitable biocompatible materials include, for example: polyurethanes, polymethylmethacrylate, poly (ethylene glycol), poly (ethylene oxide), poly (propylene glycol), poly (vinyl alcohol), poly (hydroxyethyl methacrylate), poly (vinylpyrrolidone) ("PVP"), polyacrylic acid, poly (ethyl) sOxazolines), poly (dimethylacrylamide), phospholipids (e.g., phosphorylcholine derivatives), polysulfonic betaines, acrylates, polysaccharides and carbohydrates (e.g., hyaluronic acid, dextran, hydroxyethylcellulose, hydroxypropylcellulose, gellan gum, guar gum, heparan sulfate, chondroitin sulfate, heparin and alginates), proteins (e.g., gelatin, collagen, albumin and ovalbumin, polyamino acids), fluorinated polymers (e.g., polytetrafluoroethylene ("PTFE"), polyvinylidene fluoride ("PVDF"), and teflon), polypropylene, polyethylene, nylon, ethylene-vinyl acetate copolymer ("EVA"), polycaprolactone, and ethylene-vinyl alcohol copolymer ("EVOH").

The surface of the body of the punctal plug can be coated in whole or in part. The coating may provide one or more of the following characteristics: smoothness to aid insertion, mucoadhesiveness to aid in tissue compatibility, and texture to aid in anchoring the punctal plug in the punctum. Examples of suitable coatings include, but are not limited to, gelatin, collagen, hydroxyethyl methacrylate, PVP, PEG, heparin, chondroitin sulfate, hyaluronic acid, synthetic and natural proteins, polysaccharides, thiol polymers, thiolated derivatives of polyacrylic and chitosan, polyacrylic acid, carboxymethylcellulose, and the like, and combinations thereof.

Certain embodiments of the punctal plugs of the invention have a body made of a flexible material that conforms to the shape contacted. Optionally, the punctal plugs can have a collarette formed of a less flexible material than the body material or of a material that also conforms to the shape contacted. When a punctal plug having a flexible body and a less flexible collarette is inserted into the lacrimal canaliculus, the collarette remains outside the lacrimal punctum and the punctal plug body conforms to the shape of the lacrimal canaliculus. The reservoir and body of such punctal plugs are preferably contiguous. That is, the reservoir of such punctal plugs preferably constitutes the entire body, except for the collarette.

In embodiments using one or both of a flexible body and a collar, the flexible body and the flexible collar may be made of materials including, but not limited to, nylon, polyethylene terephthalate ("PET"), polybutylene terephthalate ("PBT"), polyethylene, polyurethane, silicone, PTFE, PVDF, and polyolefins. Punctal plugs made of nylon, PET, PBT, polyethylene, PVDF, or polyolefin are typically manufactured by, for example, but not limited to, extrusion, injection molding, or thermoforming. Punctal plugs made of latex, polyurethane, silicone or PTFE are typically made using a solution casting process.

The punctal plugs of the invention include a reservoir within the body that contains a material that contains an active agent. The material can be any material that is compatible with the active agent or agents delivered by the punctal plug and that is capable of releasing the active agent in a desired manner, such as by dissolution or degradation of the material or diffusion of the active agent from the material. A variety of materials may be used as the active agent-containing material, including, but not limited to, naturally occurring and synthetic polymeric materials, non-polymeric materials (including, but not limited to, glasses and clays), organic materials, inorganic materials (including, but not limited to, porous ceramics), lipids, waxes, and the like, and combinations thereof. Preferably, the active agent-containing material is a polymeric material, wherein at least one active agent is disposed on, dispersed throughout, or otherwise contained within the material. The body is preferably impermeable to the active agent and the reservoir has at least one opening through which the active agent is released.

The body has one or more openings in communication with the reservoir at a first end (as shown in fig. 2), a second end (not shown), or another location on the body. In particular embodiments of the invention, when such punctal plugs are inserted into the lacrimal canaliculus and have an opening at the end of the body facing the eye, the active agent is released into the tear fluid of the eye. Alternatively, if the punctal plug has an opening in the end of the body facing the nasolacrimal duct, the active agent is released into the nasolacrimal duct. In those embodiments in which the punctal plug has an opening at the end of the body facing the eye and another opening at the end of the body facing the nasolacrimal duct, the active agent is released into both the tear fluid of the eye and the nasolacrimal duct. For those punctal plugs that have a collarette, the opening for such punctal plugs is preferably located within the collarette, preferably in the middle of the collarette. When such punctal plugs are inserted into the lacrimal canaliculus, the opening faces the eye and the active agent is released into the tear fluid of the eye.

The opening size will be from about 0.05nm to about 2.5mm, preferably from about 0.15mm to about 0.8 mm. Multiple smaller openings may be employed as opposed to a single larger opening at any one location.

Methods of making punctal plugs that can be used in the present invention are well known. Typically, punctal plugs are manufactured by injection molding, cast molding, transfer molding, and the like. Preferably, after manufacture of the punctal plug, the reservoir is filled with one or both of at least one active agent and an active agent-containing material. In addition, one or more excipients may be combined with the active agent alone or in combination with the polymeric material.

Depending on the active agent-containing material selected, the active agent may be released from the material almost immediately, or the active agent may be released in a sustained manner over a desired period of time. For example, polymeric materials consisting of one or more at least partially water soluble polymers may be used. When such a polymeric material is exposed to the aqueous environment of the lacrimal canaliculus or to tear fluid, the material preferably dissolves and releases the active agent as it dissolves. The solubility in water of one or more polymers from which the polymeric material is made is generally proportional to its rate of dissolution. Suitable polymers that are at least partially water soluble include, but are not limited to, poly (ethylene glycol), poly (ethylene oxide), poly (propylene glycol), poly (vinyl alcohol), poly (hydroxyethyl methacrylate), poly (vinyl pyrrolidone), polyacrylic acid, poly (ethyl oxazoline), poly (dimethyl acrylamide), phospholipids (e.g., derivatives of phosphorylcholine), polysulfonated betaines, polysaccharides, and carbohydrates (including, but not limited to, hyaluronic acid, dextran, hydroxyethyl cellulose, hydroxypropyl cellulose, gellan gum, guar gum, heparan sulfate, chondroitin sulfate, heparin and alginate), proteins (e.g., gelatin, collagen, albumin, and ovalbumin, and polyamino acids). The polymeric materials in this list can typically be copolymerized or blended with one or both of the hydrophobic polymer and the monomer.

Alternatively, non-polymeric materials including, but not limited to, lipids, waxes, or inorganic materials may be used. Suitable non-polymeric materials include, but are not limited to, lanolin, paraffin, sorbate, lecithin, vitamins A, D and E, glycerin, sorbitol, mannitol, stearate, fatty acids, lutein, zeaxanthin, taurine, glutathione, and the like.

Alternatively, the active agent-containing material may be one or more biodegradable polymers that chemically degrade, partially or wholly, upon exposure to, for example, biologically active substances typically present in mammals. The biodegradable material is preferably hydrolysable under in vivo conditions. Biodegradation may proceed more slowly than dissolution, and thus the material may be comprised of one or more biodegradable polymers if slower, more sustained release of the active agent is desired.

Suitable biodegradable polymers include, but are not limited to, polymers and oligomers of glycolide, lactide, lactones and other hydroxy acids, as well as other biodegradable polymers that produce non-toxic substances or that exist as normal metabolites in the body. Preferred poly (alpha-hydroxy acids) are poly (glycolic acid), poly (2-dioxanone), poly (DL-lactic acid) and poly (L-lactic acid). Other useful polymers include poly (amino acids), polycarbonates, poly (anhydrides), poly (orthoesters), poly (phosphazines), and poly (phosphoesters). Polylactones including, but not limited to, poly (epsilon-caprolactone), poly (delta-valerolactone), and poly (gamma-butyrolactone), such as chitosan, alginate, collagen, and gelatin, are also useful. In particular aspects of the invention, the active agent-containing polymeric material can comprise a mixture of one or more soluble and biodegradable polymers.

In a preferred embodiment, the active agent-containing material is a polymeric material that is combined with at least one active agent to form one or more fibers or fibrous structures, which may be approximately the size of the reservoir or smaller than that, and the one or more fibers or fibrous structures are inserted into the reservoir through an opening in the body of the punctal plug. The fibers or fiber-like structures may have a size and shape suitable for insertion into the opening, and may be about 0.5 to about 5mm in length and 0.05 to about 2mm in diameter. If only one fiber or fibrous structure is used, it is preferred that the fibers be sized so that when the punctal plug is applied to the punctum of a wearer, the fibers fit snugly and remain in the reservoir. Thus, depending on the shape of the reservoir, the fibers may be symmetrical or asymmetrical. The interior walls of the reservoir may be substantially smooth or may include features that help retain the fibers within the reservoir, including, but not limited to, having surfaces with grooves, indentations, roughness, etc. on the interior walls.

Alternatively, a fiber containing the active agent or agents can be formed and the punctal plugs cast around the fiber. Alternatively, the fiber and active agent can be dosed or nano-dosed in molten form into the punctal plug reservoir and allowed to solidify. Alternatively, the polymer and active agent may be introduced in solution. The solution may comprise monomers, prepolymers, etc. suitable for crosslinking by one or more of radiation, redox and thermal radical polymerization. Alternatively, the fiber may simply be impregnated with the active agent before or after insertion into the punctal plug, or it may be incorporated throughout the silicone or EVA punctal plug.

Preferably, the fibers or fibrous structures are comprised of a polymeric material, and more preferably a polymeric material of polycaprolactone, and even more preferably poly (epsilon-caprolactone) and ethylene vinyl acetate having a molecular weight between about 10,000 and 80,0000. About 0 to about 100 weight percent polycaprolactone and about 100 to about 0 weight percent ethylene vinyl acetate are used, preferably 50 percent each of polycaprolactone and ethylene vinyl acetate are used, based on the total weight of the polymeric material. The purity of the polymeric material used is preferably greater than about 99% and the purity of the active agent is preferably greater than about 97%. One of ordinary skill in the art will recognize that the conditions under which complexation is performed during complexation need to take into account the characteristics of the active agent to ensure that the method does not degrade the active agent. Polycaprolactone and ethylene vinyl acetate are preferably combined with the desired active agent or agents, microcomposited, and then coextruded into fibers. The fiber is then cut to the desired length and inserted into the reservoir through one or more punctal plug openings.

The amount of active agent used in the punctal plugs of the invention depends on the active agent or agents selected, the desired dose to be delivered by the punctal plug, the desired release rate, and the melting points of the active agent and the active agent-containing material. Preferably, the dose used is a therapeutically effective amount, i.e., an amount effective to achieve the desired therapeutic, inhibitory or prophylactic effect. Typically, about 0.05 to about 8,000 micrograms of active agent may be used.

In certain aspects of the invention, the reservoir may be refilled with material after the active agent-containing material has almost completely dissolved or degraded and released the active agent. For example, the material containing the new active agent may be the same or different from the original polymeric material, and may contain at least one active agent that is the same or different from the original active agent. Certain punctal plugs for particular applications may preferably be refilled with material while the punctal plug is still inserted in the lacrimal canaliculus, while other punctal plugs are typically removed from the lacrimal canaliculus, new material added, and the punctal plug reinserted into the lacrimal canaliculus.

When the active agent-containing material is combined with an active agent, the material may also comprise one or more materials that are insoluble in water, non-biodegradable, but from which the active agent can diffuse. For example, when the material is a polymeric material, the material may be composed of one or more polymers that are insoluble in water and non-biodegradable. Suitable polymers of this type include, for example, crosslinked polymers such as crosslinked poly (ethylene glycol), poly (ethylene oxide), poly (propylene glycol), poly (vinyl alcohol), poly (hydroxyethyl methacrylate), poly (vinylpyrrolidone), polyacrylic acid, poly (ethyl oxazoline), and poly (dimethylacrylamide). These polymers may be copolymerized or blended with one or both of the hydrophobic polymer and the monomer. Additional polymers that are water insoluble and non-biodegradable include, but are not limited to, silicones, silicone blends, silicone copolymers (including, but not limited to, hydrophilic monomers of pHEMA, polyethylene glycol, polyvinylpyrrolidone, and glycerol), silicone hydrogel polymers (such as those described in U.S. Pat. nos. 5,962,548, 6,020,445, 6,099,852, 6,367,929, and 6,822,016, which are incorporated herein by reference in their entirety), phospholipids (including, but not limited to, phosphocholine derivatives), polysulfonic betaines, polysaccharides, and carbohydrates (including, but not limited to, hyaluronic acid, dextran, hydroxyethyl cellulose, hydroxypropyl cellulose, gellan gum, guar gum, heparan sulfate, chondroitin sulfate, and heparin), proteins (including, but not limited to, albumin and ovalbumin, polyamino acids), fluorinated polymers (including, but not limited to, PTFE, PVDF, and teflon), polypropylene, and mixtures thereof, Polyethylene, nylon, and EVA. Additional examples of suitable polymers that are insoluble in water and/or non-biodegradable include, but are not limited to, silicones, polyurethanes, cyanoacrylates, and polyacrylic acids.

The punctal plugs described herein can be used to deliver a variety of active agents for one or more of the purposes of treating, inhibiting, and preventing a variety of diseases, allergies, and disorders. Each punctal plug can be used to deliver at least one active agent, and can be used to deliver different types of active agents. For example, the punctal plugs can be used to deliver alcaftadine, azelastine hydrochloride, emedastine difumarate, epinastine hydrochloride, ketotifen fumarate, levocabastine hydrochloride, olopatadine hydrochloride, pheniramine maleate, and antazoline phosphate for one or more of the treatment, inhibition, and prevention of allergy. The punctal plugs can be used to deliver mast cell stabilizers such as cromolyn sodium, lodoxamide tromethamine, nedocromil sodium, and pemirolast potassium.

After the punctal plugs are filled with the active agent, the punctal plugs are sterilized by any convenient method, including, but not limited to, ethylene oxide sterilization, autoclaving, radiation sterilization, and the like, and combinations thereof. Preferably, sterilization is performed by gamma irradiation or using ethylene oxide.

The punctal plugs can be used to deliver mydriatic and cycloplegic drugs including, but not limited to, atropine sulfate, homatropine, scopolamine hydrobromide, cyclopentolate hydrochloride, tropicamide, and phenylephrine hydrochloride. The punctal plugs can be used to deliver ophthalmic dyes including, but not limited to, rose bengal, acid green, indocyanine green, calcein, and fluorescein.

The punctal plugs can be used to deliver corticosteroids including, but not limited to, dexamethasone sodium phosphate, dexamethasone, fluoromethalone acetate, loteprednol etabonate, prednisolone acetate, prednisolone sodium phosphate, medrysone, rematrilone, and fluocinolone acetonide. The punctal plugs can be used to deliver non-steroidal anti-inflammatory agents, including but not limited to flurbiprofen sodium, suprofen, diclofenac sodium, ketorolac tromethamine, cyclosporin, rapamycin, methotrexate, azathioprine, and bromocriptine.

The punctal plugs can be used to deliver anti-infective agents including, but not limited to, tobramycin, moxifloxacin, ofloxacin, gatifloxacin, ciprofloxacin, gentamicin, sulfisoxazolone diethanolamine, sulfacetamide sodium, neomycin, propamidine, chlorhexidine, PHMB, vancomycin, polymyxin B, amikacin, norfloxacin, levofloxacin, sulfisoxazole diethanolamine, sulfacetamide sodium tetracycline, doxycycline, dicloxacillin, cephalexin, amoxicillin/clavulanic acid, ceftriaxone, cefixime, erythromycin, ofloxacin, azithromycin, gentamicin, sulfadiazine, and pyrimidine.

The punctal plugs can be used to deliver agents for one or more of the purposes of treating, inhibiting, and preventing glaucoma, including but not limited to: epinephrine including, for example, dipivefrin; alpha-2 adrenergic receptors including, for example, apraclonidine and brimonidine; beta blockers including, but not limited to, betaxolol, carteolol, levobunolol, metiprolol, and timolol; direct miotics including, for example, carbachol and pilocarpine; cholinesterase inhibitors, including but not limited to physostigmine and fosetyl choline; carbonic anhydrase inhibitors, including, for example, acetazolamide, brinzolamide, dorzolamide, and methazolamide; prostaglandins and prostamides including, but not limited to, latanoprost, bimatoprost, travoprost, and unoprostone cidofovir.

The punctal plugs can be used to deliver antiviral agents including, but not limited to, fomivirsen sodium, foscarnet sodium, ganciclovir sodium, valacyclovir hydrochloride, trifluridine, acyclovir, and famciclovir. The punctal plugs can be used to deliver local anesthetics, including but not limited to tetracaine hydrochloride, proparacaine hydrochloride, and fluorescein sodium, benoxinate and fluorescein sodium, and benoxinate and disodium calcein. The punctal plugs can be used to deliver antifungal agents including, for example, fluconazole, flucytosine, amphotericin B, itraconazole, natamycin, and ketoconazole.

The punctal plugs can be used to deliver analgesics including, but not limited to, acetaminophen and codeine, acetaminophen and hydrocodone, acetaminophen, ketorolac, ibuprofen, and tramadol. The punctal plugs can be used to deliver vasoconstrictors including, but not limited to, ephedrine hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, tetrahydrozoline hydrochloride, and oxymetazoline. Finally, the punctal plugs can be used to deliver vitamins, antioxidants, and nutrients including, but not limited to, vitamins A, D and E, lutein, taurine, glutathione, zeaxanthin, fatty acids, and the like.

The active agents delivered by the punctal plugs can be formulated to contain excipients including, but not limited to, synthetic and natural polymers including, for example, polyvinyl alcohol, polyethylene glycol, PAA (polyacrylic acid), hydroxymethyl cellulose, glycerol, hypromellose (hypromellos), polyvinylpyrrolidone, acrylic acid polymers, propylene glycol, hydroxypropyl guar gum, methyl gluceth-20 (glucam-20), hydroxypropyl cellulose, sorbitol, dextrose, polysorbates, mannitol, dextrans, modified polysaccharides and gums, phospholipids, and sulfobetaines.

The invention can be further illustrated by the following non-limiting examples.

Examples of the invention

Example 1

From 0.35 to 0.75mg of 2 parts of a silicone rubber compound (available from Wacker Silicones, Adrian, Michigan) containing a crosslinking agent and catalyst was injection molded into a punctal plug as shown in FIG. 2. The dimensions of the punctal plugs were as follows: with a total length of 1.85mm, a body length of 1.00mm, a diameter or radius of the flange and arrow of 1.2mm, an offset from the central axis of between 5 and 15 μm, and 2 to 5 threads with an inner diameter of about 0.4 mm.

The insertion and removal forces are summarized in table 1:

TABLE 1：

	Cork stopper	Conical head
			Insertion force (N)	0.22	0.18
Time (seconds)	8	9
			Removal force (N)	0.17	0.12
Time (seconds)	14	17

Claims (17)

1. A punctal plug comprising: a body having a first end, a second end, and a side surface extending between the two ends; a reservoir contained within the body, wherein the reservoir comprises at least one opening and contains an active agent-containing material comprising at least one active agent; and wherein the body is impermeable to the active agent; wherein the second end is comprised of an anchor having a conical shape.

2. The punctal plug of claim 1 wherein the anchor is offset from a central axis of the body.

3. The punctal plug of claim 1 wherein the anchor is a combination of a conical shape and another shape atop a base of the conical portion of the anchor.

4. The punctal plug of claim 3 wherein the other shape is a portion of a cylinder having a diameter greater than the body.

5. The punctal plug of claim 1 wherein the cone is an upright cylindrical cone.

6. The punctal plug of claim 1 wherein the cone is an elliptical cylinder cone.

7. The punctal plug of claim 1 wherein the cone is an oblique cylindrical cone.

8. The punctal plug of claim 1 wherein the cone is an oblique elliptical cylinder cone.

9. The punctal plug of claim 1 wherein the cone has a base of 1.0mm to 1.5 mm.

10. The punctal plug of claim 1 wherein the cone has a height of 0.3mm to 1.0 mm.

11. The punctal plug of claim 1 wherein the cone has a radius of 0.4mm to 0.85 mm.

12. The punctal plug of claim 1 wherein the cone has an axis of 0mm to 0.50 mm.

13. The punctal plug of claim 1 having a base of 1.0mm to 1.5mm, a height of 0.3mm to 1.0mm, a radius of 0.4mm to 0.85mm, and an axis of 0mm to 0.50 mm.

14. The punctal plug of claim 1 wherein the cone is offset from the body.

15. A punctal plug comprising: a body having a first end, a second end, a side surface extending between the two ends, wherein the second end is comprised of an anchor having a conical shape that is offset from a central axis of the body.

16. The punctal plug of claim 15 wherein after insertion into human tissue they exert a frictional force on the tissue of 0.1N to 0.25N.

17. The punctal plug of claim 16, which comprises an active agent.