KR20070121555A - Punctal plugs for the delivery of active agents - Google Patents

Abstract

A punctal plug for delivering an active agent is provided to be fixed to a lacrimal calculus by forming a side expanded portion in the specific size or shape. A punctal plug for delivering an active agent(18) is composed of a body(10) comprising a first end portion, a second end portion, and a lateral side extended between two end portions and a storing space(15) formed in the body to store materials containing at least one active agent and provided with at least one aperture(13). The body is impervious to the active agent. The lateral side of the body has a circular outer diameter and a portion of the lateral side has an outer diameter larger than that of the rest part.

Description

Punctal plugs for the delivery of active agents

1 is a cross-sectional view of a punctal plug having a body 10 with an extended portion 12 and a reservoir 15 in the body 10 containing a polymeric material 11 containing an active agent 18. The reservoir 15 has an opening 13 through which the active agent 18 is released.

FIG. 2 is a cross-sectional view of the punctal plug having a body 20 with an extended portion 22 and a reservoir 25 in the body 20 containing a polymeric material 21 containing an active agent 28. The reservoir 25 has an opening 23 through which the active agent 28 is released.

3 is a cross-sectional view of a punctal plug having a body 30 with an extended portion 32 and a reservoir 35 in the body 30 containing a polymeric material 31 containing an active agent 38. The reservoir 35 has two openings 33 and 33 'through which the active agent 38 is released.

4 shows a puncturing having a body 4 with an extension portion 42 and a reservoir 45 and a collart 44 in a body 40 containing a polymeric material 41 containing an active agent 48. The cross section of the plug. The reservoir 45 has an opening 43 through which the active agent 48 is released.

5 shows punctal with a reservoir 50 and a collarette 54 in a body 50 with an extended portion 52 and a body 50 containing a polymeric material 51 containing an active agent 58. The cross section of the plug. The reservoir 55 has an opening 53 through which the active agent 58 is released.

FIG. 6 shows puncta with a body 60 with an extended portion 62 and a reservoir 65 and a collart 64 in a body 60 containing a polymeric material 61 containing an active agent 68. The cross section of the plug. The reservoir 65 has two openings 63 and 63 'through which the activator 68 is released.

FIG. 7 is a cross-sectional view of a punctal plug having a body 70 made of a flexible polymeric material, a reservoir 75 and a collart 74 in the body 70 co-extending with the body 70. The reservoir 75 contains a polymeric material 71 containing the active agent 78, through which the reservoir 75 has an opening 73 through which the active agent 78 is released.

8 is a cross-sectional view of a punctal plug having a body 80 made of a flexible polymeric material, a reservoir 85 and a collart 84 in the body 80 co-extending with the body 80. The reservoir 85 contains a polymeric material 81 containing the active agent 88, which has two openings 83 and 83 ′ through which the active agent 88 is released.

FIG. 9 shows a body 90 with expansion portion 92 and a reservoir 95 and collarette 94 in body 90 containing polymeric material 91 containing active agent 98. A three-dimensional view of the punctal plug shown two-dimensionally at 4. The reservoir 95 has an opening 93 through which the activator 98 is released.

FIG. 10 is a cross-sectional view of the punctal plug having a body 100 with an extended portion 102, a reservoir 105 in the body 100, a collarlet 104 and a tapered rounded end 103. The reservoir 105 contains a polymeric material 101 containing the active agent 108, which has an opening 103 through which the active agent 108 is released.

FIG. 11 is a graph depicting activator release profile for the punctal plug of Example 2. FIG.

12 is a graph depicting activator release profile for the punctal plug of Example 3. FIG.

The present invention relates to a device suitable for delivering a substance to one or more of the eyes, nose and throat. In particular, the present invention relates to punctal plugs for delivering one or more active agents.

This application claims priority to US Provisional Application No. 60 / 805,378, filed June 21, 2006.

Human tears are secreted by the tear glands and flow from the surface of the eye to shallow pools, known as tear nails, located with their eyelids at their inner distal ends. From there, tears flow through small openings in each of the upper and lower eyelids, called upper tear points and lower tear points, respectively. From the upper and lower tear points, tears pass through the upper and lower tear canals, respectively, which are tubular-shaped passages leading to the tear bag. The tear bag is the upper dilated portion of the nasal duct, which causes tears to flow into the nasal system. Thus, the active agent can be delivered to the nose and throat through the tear canal, which leads to the nasal duct.

Active agents are often administered to the eye for the treatment of eye diseases and ailments. Conventional methods for delivering the active agent to the eye include topical application to the eye surface. The eye is uniquely suited for topical administration because, if properly configured, topically administered actives can penetrate through the cornea to create therapeutic concentration levels inside the eye. Active agents for eye diseases and ailments can be administered orally or by injection, but this route of administration can reach the eye at too low a concentration when the oral administration has the desired pharmacological effect, and their use is severe. While complicated with systemic side effects, injection has the disadvantage of causing a risk of infection.

Although most of the ocular active agents are usually effective in some applications, they are topically administered using inefficient ophthalmic solutions. When the droplet is applied to the eye, it fills the conjunctival sac, a pocket between the eye and the eyelid, which loses a substantial portion of the droplet because it overflows from the edge of the eyelid to the cheek. In addition, a substantial portion of the droplets remaining on the ocular surface flow to the tear point, diluting the concentration of the drug.

The present invention provides a punctal plug that can be used to deliver an active agent to one or both of the nasal ducts and to the tear fluid in the eye. In one aspect, the invention provides a body comprising: a body having a first end, a second end, and a side extending between the two ends; Comprising a reservoir contained in the body, consisting essentially of, consisting of, wherein the reservoir comprises one or more openings, consists essentially of this, consists of this, and comprises one or more active agents, This consists essentially of, and contains a material consisting of, the body providing a punctate plug that is impermeable to the active agent.

Referring to FIG. 1, the punctal plug body 10 has a reservoir 15 containing one or more openings 13, and the activator 18 is, for example, an activator containing material 11, preferably The polymeric material is released through the opening 13 when it dissolves and decomposes, or the active agent 18 is simply diffused or released from the material 11, depending on the properties of the material. The opening from which the active agent is released from the plug may be, for example, at the first end as in FIG. 1, for example at the second end as in FIG. 2, or for example as shown in FIG. 3. May be located at or along the sides of the first and second ends of the. Preferably, the opening is located at one or both of the first and second distal ends. For example, as shown in FIG. 3, in a particular aspect of the invention, the punctal plug contains an enlarged portion 32 of the body 30 having a size and shape suitable for securing the punctal plug to the tear canal. do.

Upon delivery of the active agent to tears in the eye, a punctal plug is inserted into the tear canal and the active is released into the tear in the eye. Referring to FIG. 4, for delivery to tear fluid, the collarette 44 is preferably provided in the body 40 of the punctal plug, and when the punctal plug is inserted into the tear canal, the collarette 44 is tear Will remain outside of the point. Upon delivery of the active agent to the nasal canal, the punctal plug is preferably deeply inserted into the tear canal and the active agent is released into the nasal canal.

As used herein, the term "punctal plug" means a device of a size and shape suitable for insertion into the lower or upper tear canal of the eye through the lower or upper tear point.

As used herein, the term "active agent" means an agent capable of treating, inhibiting or preventing a disease or condition. Examples of active agents include, without limitation, pharmaceuticals and nutrients. Preferred actives can treat, inhibit or prevent one or more diseases or disorders of the eyes, nose and throat.

As used herein, the phrase “at least partially water soluble material” means a material that exhibits sufficient water solubility levels to cause a detectable dissolution of the material upon exposure to an aqueous environment.

As used herein, the phrase "biodegradable substance" means a substance that degrades to a detectable degree upon exposure to biologically active substances conventionally present in mammals.

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

As used herein, the phrase “biodegradable material” means a material that does not decompose to a significant extent upon exposure to biologically active materials normally present in mammals.

As used herein, the phrase "body impermeable to active agent" means a body through which only traces of active agent can pass.

As used herein, a "polymeric substance" contains one or more active agents, for example, when the polymer is dissolved or degraded, when the active agent is diffused from the polymer, or after the active agent is bound to the polymer. When a pro-drug is used which is released by decomposing from it is meant a material made in the form of one or more polymers capable of releasing the active agent.

As used herein, the term “opening” means the inlet of the punctal plug body of a size and shape through which the active agent can pass. Preferably, only the active agent can pass through the opening. The opening may be, for example, a hole covered by a film, a mesh, a grid, or may not be covered. The membrane, mesh or grid may be one or more porous, semiporous, permeable, semipermeable and biodegradable.

As used herein, the phrase "flexible material" refers to a material that is not rigid and substantially conforms to its surface, whatever the object is contacted.

As used herein, the phrase "repository and body are extended" indicates that the reservoir is substantially all of the body. The collarlette may be joined to the body if the reservoir and the body are coextended, but the collarlette is not considered part of the body.

As used herein, the phrase “recharged with an active agent” means adding a detectable amount of active agent to the reservoir of the punctal plug.

The present invention includes a plurality of punctal plugs for delivering the active agent to one or both of the tears in the eye and to the nasal duct. The punctal plug is preferably inserted into the lower tear canal, upper tear canal, or both the lower and upper tear canal. If a punctal plug is used to deliver the active agent to the tear fluid of the eye, the punctal plug preferably has a colorette at one end of the body. The collarlet has a size and shape such that at least one portion of the collarlet extends outwardly and can be external to the tear point after insertion of the punctal plug into the tear canal and extends radially outward from one end of the body to a sufficient degree. It is the puncturing plug part. Typically, the collarette extends about 0.2 to about 1 mm away from the plug body. The punctal plug portion without the coloret is inserted into either the lower tear point or the upper tear point. Referring to FIG. 6, the extended portion 62 and the body 60 are inserted into one of the points, and the collarette 64 remains about the outside of the tear point, preventing the punctal plug from sliding down into the tear canal. Thereby maintaining contact between the punctal plug and the tear in the eye.

If a punctal plug is used to deliver the active agent to the nasal canal, the punctal plug does not have a colorette so that they can be inserted at a sufficient depth into one or both of the tear canals so that the active agent can be released into the tear bag. 1-3 illustrate examples of punctal plugs useful for delivering active agents to the nasal conduit.

Many of the punctal plugs of the present invention have various features and advantages. For example, a particular punctal plug has a body having a first end, a second end, and a side extending between the two ends. The sides preferably have an outer diameter that is substantially circular in shape, so that the body is preferably cylindrical. The side portion of a particular punctal plug has an outer diameter that is greater than the outer diameter of the rest of the side. Referring to Figure 2, the lateral extension 22 secures or secures the punctal plug to the tear canal. The enlarged portion may have a certain size or shape and may be present over any portion of the side, as long as the expanded portion secures the punctal plug at least partially in the tear canal. Preferably, the expansion portion is at one end of the plug. For convenience, the extended portion may have an inverted triangle shape with flat vertices as shown in FIG. 1, a non-tapered body with a rounded end, or tapered at one end with a rounded point, as shown in FIG. 10. It can have Those skilled in the art will appreciate that a wide variety of forms are possible.

The body of the punctal plug of the present invention may have a particular shape and size. Preferably, the body is in an elongated cylinder. The body is about 0.8 to about 5 mm in length, preferably about 1.2 to about 2.5 mm in length. The width of the body is about 0.2 to about 3 mm, preferably 0.3 to about 1.5 mm.

The body of the plug may be wholly or partially transparent or opaque. Optionally, the body may include tints or pigments that make the plug easier to see when located at the punctate.

The body of the punctal plug includes, but is not limited to, hydrophilic monomers of silicone, silicone mixtures, silicone copolymers (eg, polyhydroxyethyl methacrylate ("pHEMA"), polyethylene glycol, polyvinylpyrrolidone and glycerol), and Among suitable biocompatible materials including silicone hydrogel polymers, such as those described in, for example, US Pat. Nos. 5,962,548, 6,020,445, 6,099,852, 6,367,929 and 6,822,016, which are incorporated herein by reference. It can be manufactured in one. Other suitable biocompatible materials include, for example, polyurethanes; Polymethyl methacrylate; Poly (ethylene glycol); Poly (ethylene oxide); Poly (propylene glycol); Poly (vinyl alcohol); Poly (hydroxyethyl methacrylate); Poly (vinylpyrrolidone) ("PVP"); Polyacrylic acid; Poly (ethyloxazoline); Poly (dimethyl acrylamide); Phospholipids such as phosphoryl choline derivatives; Polysulfobetaine; Acrylic esters; Polysaccharides and carbohydrates such as hyaluronic acid, dextran, hydroxyethyl cellulose, hydroxypropyl cellulose, gellan gum, guar gum, heparan sulfate, chondroitin sulfate, heparin and alginate); Proteins such as gelatin, collagen, albumin and egg albumin; Polyamino acids; Fluorinated polymers such as polytetrafluoroethylene ("PTFE"), polyvinylidene fluoride ("PVDF") and Teflon]; Polypropylene; Polyethylene; Nylon and ethylene vinyl alcohol (“EVA”).

The surface of the plug body can be wholly or partially covered. The coating may provide one or more of lubricity to aid insertion, adhesion to improve tissue suitability, and texture to aid in securing the plug within the puncture. Examples of suitable coatings include, without limitation, thiolates of gelatin, collagen, hydroxyethyl methacrylate, PVP, PEG, heparin, chondroitin sulfate, hyaluronic acid, synthetic and natural proteins, and polysaccharides, thiomers, polyacrylic acids, and chitosan. Oxidized derivatives, polyacrylic acid, carboxymethyl cellulose and the like and mixtures thereof.

Certain embodiments of the punctal plug of the present invention have a body made of a flexible material that conforms to its form, whatever is contacted. Optionally, the plug may have a collarlet formed of a material that is less flexible than that of the body or material that conforms too well to its form, whatever it is contacted. When a punctal plug having a flexible body and a less flexible collarlet is inserted into the tear canal, the collarette remains outside the tear point and the body of the punctal plug conforms to the shape of the tear canal. The reservoir and body of this punctal plug are preferably elongated. That is, the reservoir of the punctal plug preferably constitutes the entire body except the collarette.

In embodiments in which one or both of the flexible body and the collarette are used, the flexible body and the flexible collarlet may be, without limitation, nylon, polyethylene terephthalate ("PET"), polybutylene terephthalate ("PBT"). ), Polyethylene, polyurethane, silicone, PTFE, PVDF and polyolefin. Tear plugs made of nylon, PET, PBT, polyethylene, PVDF or polyolefin are usually produced by extrusion, injection molding or thermoforming, for example without limitation. Puncture plugs made of latex, polyurethane, silicone or PTFE are typically manufactured using a solution casting process.

The punctal plug of the present invention contains a reservoir in the body, the reservoir containing the active agent containing material. The substance may be a substance that is compatible with the active agent or agents delivered by the plug and capable of releasing the active agent in a desired manner, for example, by dissolution or degradation of the substance or by diffusion of the active agent from the substance. . Many materials include, without limitation, polymeric materials, without limitation, natural and synthetic non-polymeric materials, including glass and clay, organic materials, without limitation, porous ceramics, lipids, waxes, and mixtures thereof It can be used as an activator-containing material, including an inorganic material. Preferably, the active agent containing material is a polymeric material, wherein one or more active agents are disposed thereon, dispersed throughout, or otherwise contained. The body is preferably impermeable to the active agent and the reservoir has one or more openings through which the active agent is released.

The body communicates with the reservoir at the first distal end as shown in FIG. 4, at the second distal end as shown in FIG. 5, at both the first and second distal ends of the body as shown in FIG. 6, or at other locations in the body. It has one or more openings. In a particular embodiment of the invention, when such a punctate plug is inserted into the tear canal and has an opening at the distal end of the body in contact with the eye, the active agent is released into the tear of the eye. In addition, when the plug has an opening at the distal end of the body in contact with the nasal conduit, the active agent is released into the nasal conjunctiva. In embodiments in which the plug has an opening at the distal end of the body in contact with the eye and another opening at the distal end of the body in contact with the nasal duct, the active agent is released into both the tear and the nasal duct in the eye. In the case of a punctal plug having a collarlet, the opening of this punctal plug is preferably located in the collarlet, preferably in the central part of the collarlet. When such a punctal plug is inserted into the tear canal, the opening is in contact with the eye and the active agent is released into the tear of the eye.

The size of the opening is about 1 nm to about 2.5 mm, preferably about 0.15 to about 0.8 mm. Instead of one large opening in one particular location, multiple small openings may be used.

Methods of making punctal plugs useful in the present invention are well known. Usually, the plug is manufactured by injection molding, casting molding, transfer molding, or the like. Preferably, the reservoir is filled with one or both of the one or more active agents and the active agent-containing material, following the manufacture of the plug. In addition, one or more excipients may be mixed with the active agent alone or with the polymeric material.

Depending on the active agent-containing material selected, the active agent can be released from the material almost immediately, or the active agent can be released in a slow release manner for a desired period of time. For example, polymeric materials composed of one or more polymers that are at least partially soluble in water can be used. When such polymeric material is exposed to the aqueous environment of the tear duct or tear fluid, it is preferably dissolved and releases the active agent upon dissolution. The water solubility of one or more polymers from which the polymeric material is prepared is usually directly proportional to its rate of dissolution. Suitable polymers that are at least partially soluble in water include, but are not limited to, poly (ethylene glycol); Poly (ethylene oxide); Poly (propylene glycol); Poly (vinyl alcohol); Poly (hydroxyethyl methacrylate); Poly (vinylpyrrolidone); Polyacrylic acid; Poly (ethyloxazoline); Poly (dimethyl acrylamide); Phospholipids such as phosphoryl choline derivatives; Polysulfobetaine; 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 such as gelatin, collagen, albumin and egg albumin) and polyamino acids. The polymeric material in this list can usually be copolymerized or mixed with one or both of the hydrophobic polymer and the monomer.

Alternatively, without limitation, nonpolymeric materials including lipids, waxes or inorganic materials can be used. Suitable nonpolymeric materials include, without limitation, lanolin, paraffin, sorbate, lecithin, vitamins A, D and E, glycerin, sorbitol, mannitol, stearate, fatty acids, lutein, zeaxanthin, taurine, glutathione, and the like. .

In addition, the active agent-containing material may be one or more biodegradable polymers that partially or completely chemically degrade upon exposure to, for example, a biologically active substance normally present in a mammal. The biodegradable material may preferably be hydrolyzed under in vivo conditions. Since biodegradation may occur more slowly than dissolution, the material may comprise one or more biodegradable polymers if a slower release of the active agent is desired.

Suitable biodegradable polymers include, without limitation, polymers and oligomers of glycolide, lactide, lactone and other hydroxy acids, and other biologically degradable polymers that produce materials that are nontoxic or that exist as normal metabolites in the body. Included. 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). Without limitation, polylactones including poly (epsilon-caprolactone), poly (delta-caprolactone), poly (delta-valerolactone) and poly (gamma-butyrolactone) include chitosan, alginate, collagen and gelatin Also useful as In a particular aspect of the invention, the polymeric material containing the active agent may comprise a mixture of one or more soluble and biodegradable polymers.

In a preferred embodiment, the active agent containing material is a polymeric material mixed with one or more active agents to form one or more fibers or fibrous structures whose dimensions are substantially the dimension of or less than the reservoir, and the one or more fibers or fibers The shaped structure is inserted into the reservoir through the opening of the plug body. The fibrous or fibrous structure may be present in a size and shape suitable for insertion into the opening, and may be about 0.5 to about 5 mm in length and 0.05 to about 2 mm in diameter. If only one fiber or fibrous structure is used, the dimension of the fiber is preferably such that the fiber is securely fixed to the reservoir so that it remains in the reservoir when the plug is used at the tear point of the wearer. Thus, the fibers can be symmetrical or asymmetrical depending on the shape of the reservoir. The inner wall of the reservoir may be substantially smooth or may include features to help maintain the fibers in the reservoir including a surface having grooves, recesses, roughness, etc. in the inner wall.

In addition, fibers containing the active agent or agents may be formed and the plug may be cast around the fibers. As another alternative, the fibers and actives can be added to the plug reservoir as a melt and solidified. As another alternative, the polymer and the active agent can be introduced as a solution. The solution may contain monomers, prepolymers, etc. suitable for crosslinking via one or more irradiation, redox and thermal radical polymerizations. As another alternative, the fibers may simply be immersed in the active agent either before or after insertion into the plug.

Preferably, the fibrous or fibrous structure is made of polymeric material and more preferably of polycaprolactone, even more preferably of poly (epsilon-caprolactone) and ethylene vinyl acetate having a molecular weight of about 10,000 to 800,000. It is composed. Based on the total weight of the polymeric material, from about 0 to about 100% by weight of polycaprolactone and from about 100 to about 0% by weight of ethylene vinyl acetate are used, preferably about polycaprolactone and ethylene vinyl acetate, respectively 50% is used. The polymeric material used preferably has a purity of greater than about 99% and the active agent preferably has a purity of greater than about 97%. Those skilled in the art will appreciate that the conditions under which the compounding takes place upon compounding need to consider the properties of the active agent to ensure that the active agent is not degraded by the process. Polycaprolactone and ethylene vinyl acetate are preferably mixed with the desired active agent or agents and then extruded as fibers. The fibers are then cut to the desired length and inserted into the reservoir through one or more plug openings.

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

In certain embodiments of the present invention, the reservoir may be refilled with material after substantially all of the active agent-containing material is dissolved or decomposed so that the active agent is released. For example, the new active agent containing material may be the same or different from the previous polymeric material and may contain one or more active agents that are the same or different from the previous active material. Certain punctal plugs used for special applications can preferably be refilled with material while the punctal plug is inserted in the tear canal while the other punctual plug is usually removed from the tear canal and added new material, followed by a punctual plug. Is reinserted into the tear canal.

When the active agent containing material is mixed with the active agent, the material may also contain one or more substances which are insoluble in water and cannot be biodegradable but from which the active agent can diffuse. For example, if the material is a polymeric material, the material may consist of one or more polymers that are insoluble in water and cannot be biodegradable. Suitable polymers of this type include, for example, crosslinked poly (ethylene glycol), poly (ethylene oxide), poly (propylene glycol), poly (vinyl alcohol), poly (hydroxyethyl methacrylate), poly Crosslinked polymers such as (vinylpyrrolidone), polyacrylic acid, poly (ethyloxazoline) and poly (dimethyl acrylamide). These polymers may be copolymerized with or mixed with one or both of hydrophobic polymers and monomers. Additional polymers that are insoluble in water and not biodegradable include, but are not limited to, silicones; Silicone mixtures; Without limitation, silicone copolymers comprising hydrophilic monomers of pHEMA, polyethylene glycol, polyvinylpyrrolidone and glycerol; Silicone hydrogel polymers such as those described in, for example, US Pat. Nos. 5,962,548, 6,020,445, 6,099,852, 6,367,929 and 6,822,016, which are incorporated herein by reference; Phospholipids including, without limitation, phosphoryl choline derivatives; Polysulfobetaine; 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; Without limitation, proteins including albumin and egg albumin; Polyamino acids; Fluorinated polymers including, without limitation, PTFE, PVDF, and Teflon; Polypropylene; Polyethylene; Nylon and EVA. Further examples of suitable polymers that are insoluble in water and not biodegradable include, without limitation, silicones, polyurethanes, cyanoacrylates, polyacrylic acids.

The punctal plugs described herein can be used for the delivery of various active agents for one or more of the treatment, inhibition, and prevention of many diseases and disorders. Each punctal plug may be used to deliver one or more active agents, and may be used to deliver different types of active agents. For example, the punctal plug may contain azelastine HCl, emadastin difumerate, epinastine HCl, ketotifen fumerate, levocavastin HCl, olopatadine for one or more of the treatment, inhibition and prevention of allergies. It can be used for the delivery of HCl, pheniramine maleate and antazoline phosphate. The punctal plug can be used to deliver mast cell stabilizers such as, for example, chromoline sodium, rodoxamide tromethamine, nedochromel sodium, and fermyrolast potassium.

After filling the plug with the active agent, the plug is sterilized by conventional methods including, without limitation, ethylene oxide, autoclaving, irradiation, and combinations thereof. Preferably, sterilization is carried out through the use of gamma radiation or ethylene oxide.

The punctal plug can be used to deliver anesthetics and ocular palsy treatments, including, without limitation, atropine sulfate, homatropin, scopolamine HBr, cyclopentolate HCl, trophamide and phenylephrine HCl. The punctal plug can be used to deliver ophthalmic dyes including, without limitation, rose begol, cysamine green, indocyanine green, fluorexone and fluorescein.

The punctal plug is, without limitation, dexamethasone sodium phosphate, dexamethasone, fluorometallon, fluorometallon acetate, loteprednol etabonate, prednisolone acetate, prednisolone sodium phosphate, medridone, rimxolone and fluorinone acetonide Can be used to deliver corticosteroids, including. The punctal plug delivers, without limitation, nonsteroidal anti-inflammatory agents, including flurbiprofen sodium, suprofen, diclofenac sodium, ketorolac tromethamine, cyclosporin, rapamycin methotrexate, azathioprine, and bromocriptine. It can be used to

The punctal plug is without limitation, tobramycin, moxifloxacin, opfloxacin, gatifloxacin, ciprofloxacin, gentamycin, sulfisoxazolone diolamine, sodium sulfacetamide, vancomycin, polymyxin B, amikacin, nord Floxacin, levofloxacin, sulfisoxazole diolamine, sodium sulfacetamide tetracycline, doxycycline, dicloxacillin, cephalexin, amoxicillin / clabulante, ceftriaxone, seppixsim, erythromycin, opfloxacin, azit It can be used to deliver anti-infective agents, including romanic, gentamicin, sulfadiazine and pyrimethamine.

The punctal plug includes, but is not limited to, epinephrine including dipibephrine; Alpha-2 adrenergic agonistic receptors including, for example, aproclonidine and brimonidine; Beta blockers, including but not limited to betaxolol, carteolol, levobunolol, metipranolol and timolol; Direct molarizers including, for example, carbacol and pilocarpine; Cholinesterase inhibitors including, but not limited to, psychostigmine and ecothioate; Carbonic anhydride inhibitors including, for example, acetazolamide, brinzolamide, dorzolamide and metazolamide; Delivery of agents for one or more of the treatment, inhibition and prevention of glaucoma, including, without limitation, prostaglandins and prostamides, including latanoprost, bimatoprost, uraboprost and unoprostone sipofovir Can be used for

The punctal plug can be used to deliver antiviral agents including, without limitation, pomivirsen sodium, poscannet sodium, gancyclovir sodium, gangancyclovir HCl, trifluidine, acyclovir and famcyclovir. The punctal plug includes, without limitation, tetracaine HCl, propparacaine HCl, propparacaine HCl and sodium fluorescein, benoxinate and sodium fluorescein, and benoxate and fluorexone disodium Can be used to deliver The punctal plug can be used to deliver antifungal agents, including, for example, fluconazole, flucitocin, amphotericin B, itraconazole and ketocaonazole.

The punctal plug can be used to deliver analgesics, including but not limited to acetaminophen and codeine, acetaminophen and hydrocodone, acetaminophen, ketorolac, ibuprofen and tramadol. The punctal plug can be used to deliver vasoconstrictors, including, without limitation, ephedrine hydrochloride, napazoline hydrochloride, phenylephrine hydrochloride, tetrahydrozoline hydrochloride and oxymethazolin. Finally, punctal plugs can be used to deliver vitamins, antioxidants, and nutrients, including, without limitation, vitamins A, D and E, lutein, taurine, glutathione, zeaxanthin, fatty acids, and the like.

Active agents delivered by the punctal plug include, but are not limited to, polyvinyl alcohol, polyethylene glycol, PAA (polyacrylic acid), hydroxymethyl cellulose, glycerin, hypromellose, polyvinylpyrrolidone, carbopol, Synthetic and natural, including propylene glycol, hydroxypropyl guar, glucam-20, hydroxypropyl cellulose, sorbitol, dextrose, polysorbate, mannitol, dextran, modified polysaccharides and rubber, phospholipids and sulfobetaines It may be formulated to contain excipients, including polymers.

The invention will be again clarified by considering the following non-limiting examples.

Example

Example 1

1.50 g of epsilon caprolactone (Aldrich) having an average M _w of approximately 14,000 and an average M _n of approximately 10,000, respectively, was determined by GPC to 1.50 g of EVA (EVATANE ^™ , Arkema) having a purity of approximately 97% or more, and bimatoprost (Cayman). Chemicals) and 1.00 g. The mixture was then paired-screw micro-mixer model No. Add to 20000 (DACA Industries, Inc.) and mix at 67 ° C. for 15 minutes at 120 rpm. After mixing, the mixture is extruded into fibers at 75 ° C.

The fibers are cut into pieces approximately 1.5 mm long and inserted into the openings of the Sharpoint ULTRA ^™ (Surgical Specialties) plug. Seventy plugs containing a medicament having a length of 0.6 mm and 30 placebos each were prepared, and 70 plugs containing a medicament having a length of 0.8 mm each and 50 placebos were prepared. To insert the fibers, each plug is placed under a stereo microscope and tweezers are used to insert the fibers into each plug opening. Each plug is then placed in a glass vial and packed into a pouch. Gamma radiation sterilization is then performed at a total dose of 15 Kgy at about 0.2 Kgy / min.

Example 2

The plug prepared according to the method of Example 1 having a length of approximately 0.6 mm and a fiber of approximately 0.2 mm in diameter and containing 25% w / w are placed in a glass vial containing 1 kPa of phosphate buffered saline at pH 7.4. The vial is placed in a thermostat at 37 ° C. and stirred gently. 1 ml of mother liquor is collected at 3, 8 and 24 hour intervals and then analyzed weekly for drug content via HPLC. 11 is a graph showing the analysis results.

Example 3

The plug prepared according to the method of Example 1 having a length of approximately 0.9 mm and a fiber containing approximately 0.6 mm in diameter and containing 25% were placed in a glass vial containing 1 kPa of phosphate buffered saline at pH 7.4. The vial is placed in a thermostat at 37 ° C. and stirred gently. 1 ml of mother liquor is collected at intervals as shown in Example 2 and then analyzed for drug content via HPLC. 12 is a graph showing the analysis results.

In accordance with the present invention, a punctal plug is provided for delivering an active agent to one or both of the tears in the eye and to the nasal duct.

Claims (25)

A body having a first end, a second end, and a side extending between the two ends; and A reservoir containing an active agent-containing material contained within the body, comprising one or more openings, and comprising one or more active agents, Punctal plug in which the body is impermeable to the active agent. A body having a first end, a second end, and a side extending between the two ends; and A reservoir contained within the body, the reservoir containing an active agent-containing material comprising an opening at the first end, the second end, or both the first end and the second end of the body, and comprising at least one active agent; A punctal plug whose body is impermeable to the active agent. The punctal plug of claim 1, wherein the side of the body has an outer diameter that is substantially circular in shape and a portion of the side has a larger outer diameter than the rest of the sides. 3. The punctal plug of claim 2 wherein the side of the body has an outer diameter that is substantially circular in shape and a portion of the side has a larger outer diameter than the rest of the sides. 5. The punctal plug of claim 1, wherein the active agent-containing material is at least partially water soluble, dissolves over time, and upon dissolution releases the active agent through an opening in the reservoir. 5. The punctal plug of claim 1, wherein the active agent-containing material is biodegradable, degrades over time, and releases the active agent through openings in the reservoir upon degradation. 6. 5. The punctal plug of claim 1, wherein the activator containing material is insoluble in water and not biodegradable, and the activator is passively diffused from the material through the opening of the reservoir. 5. The punctal plug of claim 3 or 4, wherein a portion of the side having a larger outer diameter than the rest of the side secures the punctal plug to the tear canal when the punctal plug is inserted into the tear canal. 5. The punctal plug of claim 1, wherein when the punctal plug is inserted into the tear canal of the eye, the opening of the reservoir contacts the eye and the active agent is released into the tear of the eye. 5. The punctal plug of claim 1, wherein when the punctal plug is inserted into the tear canal of the eye, the opening of the reservoir contacts the nasal canal and the activator is released into the nasal canal. 6. The method of claim 1, wherein when the punctal plug is inserted into the tear canal of the eye, the opening of the reservoir contacts the eye, the active agent is released into the tear of the eye, and the other opening of the reservoir is A punctal plug that comes into contact with the tear duct and the active agent is also released into the nasal duct. When the punctal plug is inserted into the tear canal, the body consists of a flexible polymeric material that matches the shape of the tear canal, A reservoir containing an active agent-containing material contained within the body that is impermeable to the active agent, the active agent containing material comprising one or more openings and comprising one or more active agents; A punctal plug for delivering an active agent to the lacrimal and nasal ducts of the eye, comprising a collarette that remains outside the tear point when the punctal plug is inserted into the tear canal. 13. The punctal plug of claim 12, wherein the active agent-containing material is at least partially water soluble, dissolves over time, and upon dissolution releases the active agent through an opening in the reservoir. 14. The punctal plug of claim 13, wherein substantially all of the preceding active agent-containing material is dissolved and then the reservoir is refilled with an active agent-containing material comprising one or more active agents that are the same or different from the preceding active agent. 20. The punctal plug of claim 19, wherein the active agent-containing material is biodegradable, degrades over time, and releases the active agent through openings in the reservoir upon degradation. 14. The punctal plug of claim 13, wherein after substantially all of the preceding material has been degraded, the reservoir is refilled with an active agent containing material comprising at least one active agent that is the same or different from the preceding active agent. 13. The punctal plug of claim 12, wherein the active agent-containing material is insoluble in water and cannot be biodegradable, wherein the active agent is passively diffused from the material through the opening in the reservoir. 13. The punctal plug of claim 12 wherein the reservoir and the body are coextended. 13. The punctal plug of claim 12, wherein when the punctal plug is inserted into the tear canal, the opening of the reservoir contacts the eye and the active agent is released into the tear of the eye. 13. The punctal plug of claim 12, wherein when the punctal plug is inserted into the tear canal, the opening of the reservoir contacts the nasal canal and the active agent is released into the nasal canal. The method of claim 12, wherein when the punctal plug is inserted into the tear canal, the opening of the reservoir is in contact with the eye, the active agent is released into the tear fluid of the eye, the other opening of the reservoir is in contact with the nasal duct and the active agent is also in the nasal tear tube. Comes from the punctate plug. A body having a first end, a second end, and a side extending between the two ends; and A reservoir containing an active agent-containing material that is contained within the body and includes one or more openings and that is a fibrous or fibrous structure comprising one or more active agents, A punctal plug whose body is impermeable to the active agent. 23. The punctal plug of claim 22, wherein the side of the body has an outer diameter that is substantially circular in shape, and a portion of the side has a larger outer diameter than the rest of the sides. 23. The puncture plug of claim 22, wherein the reservoir contains fibers comprising about 0 to about 100 weight percent polycaprolactone and about 100 to about 0 weight percent ethylene vinyl acetate. 23. The puncture plug of claim 22, wherein the reservoir contains fibers comprising about 50% by weight polycaprolactone and about 50% by weight ethylene vinyl acetate.

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