CN101505694B - Punctal plugs for the delivery of active agents - Google Patents

Abstract

The present invention provides a punctal plug for delivering an active reagent to one or both of the tear fluid and nasolacrimal duct of the eye, comprising a body, at least one cap and optionally a circumferential ring.

Description

Punctal Plugs for Delivery of Active Agents

field of invention

The present invention relates to devices suitable for delivering 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.

related application

This application claims priority to US Provisional Application Serial No. 60/805,383, filed June 21,2006.

Background of the invention

Human tears are secreted by the lacrimal glands and flow across the surface of the eye to a shallow pool called the tear pool, which is located where the eyelids gather at their inner ends. From there, tears drain through tiny openings in each eyelid called the upper and lower puncta. From the upper and lower puncta, tears enter the upper and lower canaliculus, respectively, which are duct-like passages that lead to the lacrimal sac. The lacrimal sac is the swollen portion of the upper part of the nasolacrimal duct that drains tears into the nasal system. The active agent can thus be delivered to the nose and throat through said canaliculus leading to the nasolacrimal duct.

Active agents are often administered to the eye to treat ocular diseases and disorders. Traditional methods of delivering active agents to the eye include topical application to the surface of the eye. The eye is particularly well suited for topical administration because, when properly composed, topically applied active agents can penetrate the cornea and rise to therapeutic concentration levels inside the eye. Active agents for ocular diseases and disorders can be administered orally or by injection, but such routes of administration have the disadvantage that the attainable ocular concentrations of the active agent in oral administration are too low to have the desired pharmacology effects and their use is accompanied by significant systemic side effects, whereas injections pose a risk of infection.

Most ophthalmically active agents are currently delivered topically using eye drops, which, while effective for some applications, are inefficient. When a drop of liquid is added to the eye, it fills the conjunctival sac (the pouch between the eye and eyelid), causing a significant portion of the drop to be lost by spilling over the eyelid edge onto the cheek. In addition, a significant portion of the drop remaining on the ocular surface is expelled into the punctum, diluting the concentration of the drug.

Brief description of the drawings

1A is a cross-sectional view of a punctal plug having a body 10 with an enlarged section 12 and a cap 6 containing an active agent 8 .

FIG. 1B is a cross-sectional view of a punctal plug having a body 10 with an enlarged section 12 and a cap 6 containing an active agent 8 .

1C is a cross-sectional view of a punctal plug having a body 10 having an enlarged section 12, a first cap 6 containing an active agent 8, and a second cap 6' containing an active agent 8'.

2A is a cross-sectional view of a punctal plug having a body 20 with an enlarged section 22 and a cap 26 comprising a stem 27 and containing an active agent 28 . The stem portion 27 of the cap is disposed within the body 20 of the punctal plug.

2B is a cross-sectional view of a punctal plug having a body 20 having an enlarged section 22 and a cap 26 comprising a stem 27 and containing an active agent 28 . The stem portion 27 of the cap is disposed within the body 20 of the punctal plug.

2C is a cross-sectional view of a punctal plug having a body 20 having an enlarged section 22, a first cap 26 comprising a stem 27 and containing an active agent 28, and a cap 26'. Two caps 26' contain active agent 28'. The stem portion 27 of the first cap is disposed within the body 20 of the punctal plug.

3A is a cross-sectional view of a punctal plug having a body 30 having an enlarged section 32 and a cap 36 comprising a stem 37 and containing an active agent 38 . The stem portion 37 of the cap is screwed into the body 30 of the punctal plug.

3B is a cross-sectional view of a punctal plug having a body 30 having an enlarged section 32 and a cap 36 comprising a stem 37 and containing an active agent 38 . The stem portion 37 of the cap is screwed into the body 30 of the punctal plug.

3C is a cross-sectional view of a punctal plug having a body 30 having an enlarged section 32, a first cap 36 comprising a stem 37 and containing an active agent 38, and a second cap 36', and The second cap 36' includes an active agent 38'. The stem portion 37 of the first cap is screwed into the body 30 of the punctal plug.

4A is a cross-sectional view of a punctal plug having a body 40 having an enlarged section 42 and a cap 46 including a stem 47 and containing an active agent 48 . The stem portion 47 of the cap snaps into the body 40 of the punctal plug.

4B is a cross-sectional view of a punctal plug having a body 40 having an enlarged section 42 and a cap 46 including a stem 47 and containing an active agent 48 . The stem portion 47 of the cap snaps into the body 40 of the punctal plug.

4C is a cross-sectional view of a punctal plug having a body 40 having an enlarged section 42, a first cap 46 comprising an active agent 48, and a second cap 46' comprising a stem 47 and a second cap 46'. The second cap 46' includes an active agent 48'. The stem portion 47 of the first cap snaps into the body 40 of the punctal plug.

5A is a cross-sectional view of a punctal plug having a body 50 with an enlarged section 52 , a collar 54 containing an active agent 58 , and a cap 56 .

5B is a cross-sectional view of a punctal plug having a body 50 having an enlarged section 52, a surround 54, a first cap 56 containing an active agent 58, and a second cap 56' containing an active agent 58'.

6A is a cross-sectional view of a punctal plug having a body 60 having an enlarged section 62 , a collar 64 , and a cap 66 including a stem 67 and containing an active agent 68 . The stem portion 67 of the cap is disposed within the body 60 of the punctal plug.

6B is a cross-sectional view of a punctal plug having a body 60 having an enlarged section 62, a collar 64, a first cap 66 comprising a stem 67 and a second cap 66', the first cap 66 comprising a stem 67 and containing an active Reagent 68, said second cap 66' contains an active reagent 68'. The stem portion 67 of the first cap is disposed within the body 60 of the punctal plug.

7A is a cross-sectional view of a punctal plug having a body 70 with an enlarged section 72 , a collar 74 and a cap 76 that includes a stem 77 and contains an active agent 78 . The stem portion 77 of the cap is screwed into the body 70 of the punctal plug.

7B is a cross-sectional view of a punctal plug having a body 70 having an enlarged section 72, a collar 74, a first cap 76 including a stem 77 and a second cap 76', the first cap 76 including a stem 77 and containing an active Reagent 78, said second cap 76' comprises an active reagent 78'. The stem portion 77 of the first cap is screwed into the body 70 of the punctal plug.

Figure 8A is a cross-sectional view of a punctal plug having a body 80 having an enlarged section 82, a collar 84, and a cap 86 comprising a stem 87 and containing an active agent. The stem portion 87 of the cap snaps into the body 80 of the punctal plug.

8B is a cross-sectional view of a punctal plug having a body 80 having an enlarged section 82, a collar 84, a first cap 86 including a stem 87 and a second cap 86', the first cap 86 including a stem 87 and containing an active Reagent 88, said second cap 86' comprises an active reagent 88'. The stem portion 87 of the first cap snaps into the body 80 of the punctal plug.

9A is a cross-sectional view of a punctal plug having a body 90 with an enlarged section 92 , a collar 94 and a cap 96 that includes a stem 97 and contains an active agent 98 . The stem portion 97 of the cap is disposed within the body 90 of the punctal plug, and a portion 99 of the cap extends beyond the collar 94 .

9B is a cross-sectional view of a punctal plug having a body 90 having an enlarged section 92, a collar 94, a first cap 96 including a stem 97 and a second cap 96', the first cap 96 comprising a stem 97 and containing an active Reagent 98, said second cap 96' contains an active reagent 98'. The stem portion 97 of the first cap is disposed within the body 90 of the punctal plug, and a portion 99 of the first cap extends beyond the collar 94 .

FIG. 10 is a perspective view of the punctal plug described two-dimensionally in FIG. 8 . The punctal plug has a body 100 having an enlarged section 102 , a collar 104 and a cap 106 comprising a stem 107 and containing an active agent 108 . The stem portion 107 of the cap snaps into the body 100 of the punctal plug.

Detailed Description and Illustrative Embodiments of the Invention

The present invention provides punctal plugs useful for delivering an active agent to either or both the nasolacrimal duct and the tear fluid of the eye. The punctal plug comprises, consists essentially of, and consists of: (a) a body having a first end, a second end, and a transverse surface extending between the two ends; and (b) a cap adjacent to the first end of the body, a cap adjacent to the second end of the body, or each cap adjacent to both the first and second ends of the body, wherein the cap includes a cap that accommodates at least An active agent containing material for the active agent.

Embodiments of punctal plugs of the present invention having bodies 10 and 20 are depicted in FIGS. 1A-C and 2A-C . For example, when the cap dissolves or degrades, or the active agent simply diffuses from the cap, the active agent shown as 8, 8', 28 and 28' in the figure is released from the caps 6 and 26, respectively, depending on Said active agent-containing material used in the preparation of the cap. The cap may be adhered to the end of the body. Alternatively, as depicted in Figures 2A-C, the cap 26 may have a stem portion 27 extending into the body 20 of the plug. In another embodiment and as shown in Figures 3A-C, the stem portion can be screwed into it. Alternatively and as shown in Figures 4A-C, the rod may be snapped into the body. Yet alternatively and as shown in Figures 5A and B, the punctal plug may have a collar at the first end of the body. When such a punctal plug is inserted into a canaliculus, the surrounding ring preferably remains outside the punctum and at least a portion of said cap is adjacent to said surrounding ring. As shown in Figures 9A and B, certain punctal plugs having a surrounding ring 94 may have a cap 99 made of a flexible material, and at least a portion of the cap of such punctal plugs being elongated and extending beyond the surrounding ring, This increases the amount of active reagent 98 that the cap can hold.

In order to deliver the active agent into the tear fluid of the eye, when the punctal plug is inserted into the canaliculus, preferably the cap is positioned adjacent the end of the punctal plug towards the eye and the active agent is released into the tear fluid of the eye. In order to deliver the active agent into the nasolacrimal duct, when the punctal plug is inserted into the canaliculus, preferably the cap is positioned adjacent to the end of the punctal plug towards the nasolacrimal duct and the active agent is released into the nasolacrimal duct. In a particular embodiment of the invention, and for example as illustrated in FIGS. 1A-C , the body comprises an enlarged segment 12 that secures the punctal plug in the canaliculus. In other aspects of the invention and such as depicted in FIGS. 2C and 5B , when the punctal plug is inserted into the canaliculus, one cap is positioned adjacent to the end of the punctal plug toward the eye and a second cap is positioned adjacent to the end toward the nose. The punctal plug end of the lacrimal duct, and the active agent can be released into both the tear fluid of the eye and the nasolacrimal duct.

As used herein, the term "punctal plug" means a device sized and shaped for insertion into the lower or upper canaliculus of the eye through the lower or upper punctum.

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

As used herein, the term "polymeric material" means a material made of one or more types of polymers capable of holding at least one active agent and releasing the active agent, for example, when the polymer dissolves or degrades, when the active agent When diffusing from the polymer, or when using prodrugs (where the active agent is attached to the polymer and subsequently released by detachment from the material).

As used herein, the phrase "at least partially water-soluble material" means that the material exhibits a level of solubility in water sufficient to cause the material to dissolve when exposed to an aqueous environment.

As used herein, the phrase "biodegradable material" means a material that degrades to a detectable extent upon exposure to biologically active substances normally present in mammals.

As used herein, the phrase "water-insoluble material" means a material that does not dissolve to a significant extent when exposed to water.

As used herein, the phrase "non-biodegradable material" means a material that does not degrade to a significant extent when exposed to biologically active substances normally present in mammals.

As used herein, the phrase "cap is removable," "removable cap," and variations thereof mean that the cap of certain punctal plugs of the present invention can be removed before, after, or before and after insertion of the punctal plug into the canaliculus. Both are later removed from the plug, wherein removal of the cap does not affect the integrity of the remainder of the plug.

As used herein, the phrase "flexible material" means a material that is non-rigid and conforms to the surface of any object that comes into contact with the material.

The present invention encompasses various punctal plugs for delivering an active agent to the lacrimal fluid or nasolacrimal duct of the eye. The punctal plug is preferably inserted into the lower canaliculus, the upper canaliculus, or both the lower and upper canaliculus. If a punctal plug is used to deliver an active agent to the tear fluid of the eye, the punctal plug preferably has a ring at one end of the body. The surround is a portion of the punctal plug that extends radially outward from one end of the body to a sufficient extent that at least a portion of the surround will extend beyond the punctum and Outside the punctum. An example of a surrounding ring 54 is depicted in FIG. 5A. The part of the punctal plug without a ring is inserted into one of the lower or upper punctum, which is the opening of the canaliculus on the margin of each eyelid. Referring to FIG. 5A , the enlarged section 52 and body 50 are inserted into one of the punctum while the surrounding ring remains outside the punctum and prevents the punctal plug from slipping into the canaliculus in order to keep the punctal plug and the eye open. contact between tears. The surround may be of any size and shape sufficient to at least partially secure the punctal plug in the punctum.

If punctal plugs are used to deliver the active agent to the nasolacrimal duct, the plugs preferably do not have a ring so that they can be inserted into one or both canaliculi with sufficient depth to allow release of the active agent into the lacrimal sac. Examples of punctal plugs that can be used to deliver active agents into the nasolacrimal duct are depicted in FIGS. 1B, 2B, and 3B.

The various punctal plugs of the present invention each have different features and advantages. For example, some punctal plugs have a body with a first end, a second end, and a transverse surface extending between the two ends. The transverse surface preferably has an outer diameter that is substantially circular in shape. A portion of the lateral surface of certain punctal plugs has a larger outer diameter than the remainder of the lateral surface. Referring to Figure 1A, the enlarged portion 12 of the lateral surface anchors or secures the punctal plug in the canaliculus. The enlarged portion may be of any size or shape and may be present on any portion of the lateral surface so long as the enlarged portion at least partially anchors the punctal plug in the canaliculus. Conveniently, said enlarged portion may assume the shape of an inverted triangle with a flat top.

The body of the punctal plug can be made of any suitable biocompatible material, including but not limited to silicone, silicone blends, silicone copolymers, such as pHEMA ("polyhydroxyethyl methacrylate ”), hydrophilic monomers of polyethylene glycol, polyvinylpyrrolidone, and glycerin, and silicone hydrogel polymers, such as those described in U.S. Patent Nos. They are hereby incorporated by reference in their entirety. Other suitable biocompatible materials include, for example: poly(ethylene glycol); poly(ethylene oxide); poly(propylene glycol); poly(vinyl alcohol); (vinylpyrrolidone); polyacrylic acid; poly(ethyloxazoline); poly(dimethylacrylamide); phospholipids, e.g., phosphorylcholine derivatives; polysulfobetaines; polysaccharides and carbohydrates, For example, hyaluronic acid, dextran, hydroxyethylcellulose, hydroxypropylcellulose, gellangum, guar gum, heparan sulfate, chondroitin sulfate, heparin, and alginate; proteins such as Gelatin, collagen, albumin, and ovalbumin; polyamino acids; fluorinated polymers, such as polytetrafluoroethylene (“PTFE”), polyvinylidene fluoride (“PVDF”), and Teflon; polypropylene; Polyethylene; Nylon; and Ethylene Vinyl Alcohol ("EVA").

The punctal plugs of the present invention have a cap, or material or substance that covers a portion of the body. The cap may be of various shapes and sizes, but is conveniently of a size and shape adapted to be carried on or attached to the end or collar of the plug. The cap is preferably adjacent to the first end of the body, the second end of the body, or both the first and second ends of the body. For those punctal plugs having a surround, preferably a portion of the cap is adjacent to the surround.

The cap may be adhered to the surface of the body, the surround, or a portion of both the body and the surround. The cap is preferably adhered to the end surface and or surrounding ring surface of the body. If the material making up the cap is itself adhesive, the cap may be adhered to the surface of the body or surround. Such materials include, but are not limited to, cyanoacrylates and urethanes. Alternatively, a biocompatible adhesive may be used to adhere the cap to a portion of the body or enclosure surface. Suitable biocompatible adhesives include, but are not limited to, silicones, polyurethanes, cyanoacrylates, polyacrylic acid, fibrin, and cross-linked proteins such as albumin and collagen-gelatin. Suitable reagents that can be used for crosslinking include, but are not limited to, polyfunctional, homobifunctional or heterobifunctional crosslinking agents such as bis-N-succinimidyl-(pentaethylene glycol) ester. The adhesive can function via chemical reaction, or physical or mechanical interlock, and can be initiated by light, heat or laser activation.

At least one active agent is disposed on, dispersed throughout, or otherwise contained within the cap of the punctal plug such that the cap acts as a carrier for the active agent. Depending on the material from which the cap is made to contain the active agent, the active agent may be released from the cap almost immediately, or the active agent may be released in a sustained release manner over a desired period of time. The material may be compatible with one or more active agents to be delivered through the plug and be capable of releasing the active agent(s) in a desired manner (e.g., by dissolution or degradation of the material or diffusion of the active agent from the material). Any material that is an active agent. Any number of materials can be used as the material to hold the active agent, including but not limited to polymeric materials (natural and synthetic), non-polymeric materials (including but not limited to glass and clay), organic materials, inorganic materials (including but not limited to porous ceramics), lipids, waxes, etc., and combinations thereof.

For example, the cap may comprise a polymeric material that is at least partially water soluble. When such a cap is exposed to the aqueous environment of the lacrimal duct or tear fluid, it will preferably dissolve and release the active agent as it dissolves. The solubility in water of the material from which the cap is made is generally proportional to its rate of dissolution. Suitable polymeric materials that are at least partially soluble in water include, for example: poly(ethylene glycol); poly(ethylene oxide); poly(propylene glycol); poly(vinyl alcohol); poly(vinylpyrrolidone); polyacrylic acid; poly(ethyloxazoline); poly(dimethylacrylamide); phoslipids, such as phosphorylcholine derivatives; polysulfobetaines; polysaccharides and Carbohydrates, such as hyaluronic acid, dextran, hydroxyethylcellulose, hydroxypropylcellulose, gellan gum, guar gum, heparan sulfate, chondroitin sulfate, heparin, and alginate; proteins, such as gelatin, collagen, albumin, and ovalbumin; and polyamino acids. The polymeric materials in this list can generally be copolymerized or blended with hydrophobic polymers, monomers, or both.

Alternatively, the cap may comprise a biodegradable polymer that chemically degrades upon exposure to, for example, biologically active substances normally present in mammals. The biodegradable material is preferably hydrolyzable under in vivo conditions. Biodegradation generally occurs more slowly than dissolution, so the cap can therefore be made of a biodegradable material if a slower, more sustained release of the active agent is desired. Suitable biodegradable polymeric materials include, but are not limited to, polymers and oligomers of glycolide, lactide, ε-caprolactone, and other alkyds, and Other biodegradable polymers of metabolite material. Preferred poly(alpha-alkyds) are poly(glycolic acid), poly(2-dioxanone); poly(DL-lactic acid) and poly(L-lactic acid). Other suitable materials include poly(amino acids), polycarbonates, poly(anhydrides), poly(orthoesters), poly(phosphazines), and poly(phosphates). Polylactones such as poly(ε-caprolactone), poly(δ-caprolactone), poly(δ-valerolactone) and poly(γ-butyrolactone) are also suitable, such as chitosan, Alginate, Collagen, and Gel. In certain aspects of the invention, the polymeric material from which the cap is made can be a mixture of one or more soluble and biodegradable polymers.

The cap can also be made of a material that is insoluble in water and not biodegradable, but from which the active agent is able to diffuse. Suitable polymeric materials of this type include, for example, cross-linked polymers such as, but not limited to, cross-linked poly(ethylene glycol), poly(ethylene oxide), poly(propylene glycol), poly(vinyl alcohol), poly(methyl hydroxyethyl acrylate), poly(vinylpyrrolidone), polyacrylic acid, poly(ethyloxazoline), and poly(dimethylacrylamide). These polymers can be copolymerized or blended with either or both hydrophobic polymers and monomers. Other examples of suitable polymers that are water-insoluble and/or non-biodegradable include, but are not limited to, silicones, polyurethanes, cyanoacrylates, polyacrylic acid, fibrin, and cross-linked proteins such as albumin and collagen -gelatin.

In certain embodiments of the punctal plug of the present invention, the cap has a stem portion disposed within the body of the punctal plug. FIG. 10 is a three-dimensional view of a punctal plug body 100 with a cap 106 attached to a surround 104 . The cap 106 has a stem portion 107 that extends down into the body 100 . As shown in Figure 10, the stem may be screwed or snapped into the body of the punctal plug, or simply inserted into a portion of the body. Punctal plugs having a cap with a stem portion may or may not have a collar. The rod may be symmetrical or asymmetrical, depending on the shape of the body part into which it is inserted. The inner wall of the body may be substantially smooth or may include features to help retain the rod within the body, including, but not limited to, grooved, scored, roughened, etc. surfaces in the inner wall. In alternative embodiments, in addition to disposing or dispersing the active agent throughout the cap, the active agent may also be disposed, dispersed, on both the cap and stem portion or on one of the cap or stem portions. be throughout or otherwise housed within both or one of the cap and stem portions.

For those punctal plugs having a ring at the first end of the body, preferably at least a portion of the cap is adjacent to the ring, and the active agent is preferably released into the tear fluid of the eye when the plug is inserted into a canaliculus . Punctal plugs with a cap adjacent to the ring may also have a cap at the second end of the body that faces the nasolacrimal duct when the plug is inserted into the canaliculus, and the active agent is released from such punctal plugs into tear fluid entering the eye and nasal cavity. Both tear ducts.

For certain punctal plugs, such as those with a ring to deliver an active agent to the eye's lacrimal fluid, if the cap is made of a material that dissolves or erodes after insertion into the canaliculus, it can be used, for example After the cap dissolves or erodes, a new cap is added to the punctal plug, the cap containing the same or a different active agent than the previously capped active agent. The new cap may be made of the same or different material from which the previous cap was constructed. The cap of some plugs can be replaced while the plug remains in the canaliculus, while other plugs are removed from the canaliculus to replace the cap and then reinserted into the canaliculus. The cap of the punctal plug can be replaced at any time after insertion into the canaliculus, whether or not the cap has completely dissolved or degraded.

The active agent preferably diffuses passively from the cap of those punctal plugs made of water-insoluble and non-biodegradable P material. Certain such punctal plugs (such as those with a ring to deliver the active agent to the tear fluid of the eye) have the ability to be removed from the punctal plug after, for example, substantially all of the active agent has diffused from the cap. removal of the cap without affecting the integrity of the remainder of the punctal plug. A new cap containing the same or a different active agent than the previously capped one can be added to the punctal plug. The new cap may comprise the same or a different polymeric material than the polymeric material comprising the previous cap. The caps may be removed from some of these punctal plugs and a new cap may be added after the plug has been inserted into the canaliculus and while the plug remains in the canaliculus. Other punctal plugs were removed from the canaliculi to replace the existing caps with new ones.

Certain punctal plugs with a collar may have a cap made of a flexible material adjacent to the collar. One or more portions of such a cap may extend beyond the perimeter to increase the amount of active agent that the cap can hold. Suitable materials for such caps include, for example, low molecular weight polymers or elastomers, such as polyolefins, polyesters, polyurethanes, acrylics and copolymers thereof. In such punctal plugs, a portion of the cap rests on the collar, and at least one portion of the cap preferably extends beyond said portion resting on the collar. In such punctal plugs, the cap may be clear or flesh-coloured.

The punctal plugs of the present invention can be manufactured using methods including, for example, solution casting, extrusion, chemical crosslinking by formation of covalent or ionic bonds, lathing, compression molding, injection molding, liquid injection molding, blow molding, and polymerization , including photopolymerization, thermal polymerization, and ionically and redox-initiated polymerization. Punctal plugs and caps are usually manufactured separately. The caps can be manufactured using methods including, for example, solution casting, extrusion, chemical crosslinking by formation of covalent or ionic bonds, lathing, compression molding, injection molding, liquid injection molding, blow molding and polymerization, including photo Polymerization, thermal polymerization, and ionically and redox-initiated polymerization. The active agent may be incorporated into the cap by adding the active agent to the material comprising the cap during manufacture of the cap, for example by injection molding or dissolving the active agent into the cap material, or the active agent may The punctal plug cap may be added to the cap after it has been made, such as, but not limited to, by dipping a solution of at least one active agent into a pre-formed cap, for example using a solvent containing the medicament, or by incorporating the active agent into a pre-formed cap. Reagents are covalently attached to the material after surface modification.

The amount of active agent used in the plugs of the present invention will depend on the active agent or agents selected, the desired dose to be delivered via the punctal plug, the desired rate of release, and the active agent(s) selected. and the melting point of the material used to form the cap. Preferably, the amount used is a therapeutically effective amount, meaning that amount is effective to achieve the desired therapeutic, inhibitory or prophylactic effect. Generally, amounts of about 0.05 to about 8,000 micrograms of active agent can be used.

斯汀盐酸，依美斯汀二富马酸盐，盐酸依匹斯汀，酮替芬富马酸盐，盐酸左卡巴斯汀，盐酸奥洛他定，马来酸非利拉明，以及磷酸安他唑林以用于变态反应的治疗、抑制和预防中的一种或多种。所述泪点塞可用于递送肥大细胞稳定剂，例如色甘酸钠、洛度沙胺、缓血酸胺、尼多考米钠和吡嘧司特钾。The punctal plugs described herein can be used to deliver various active agents useful in the treatment, inhibition and prevention of one or more of a variety of diseases and conditions. 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 plug can be used to deliver nitrogen

Stine hydrochloride, emedastine difumarate, epinastine hydrochloride, ketotifen fumarate, levocabastine hydrochloride, olopatadine hydrochloride, feliramine maleate, and phosphoric acid Antazoline is used for one or more of treatment, suppression and prevention of allergy. The punctal plug can be used to deliver mast cell stabilizers such as cromolyn sodium, lodoxamide, tromethamine, nidocomib sodium, and pyrazomilast potassium.

The punctal plug can be used to deliver mydriatic and cycloplegic agents such as henylephrine, atropine sulfate, homatropine, scopolamine hydrobromide, cyclopentolate hydrochloride, tropicamide, and phenylephrine hydrochloride. The punctal plugs can be used to deliver ophthalmic dyes such as, but not limited to, rose begal, lissamine green, indocyanine green, calcein, and fluorescein.

The punctal plug can be used to deliver corticosteroids such as dexamethasone sodium phosphate, dexamethasone, fluorometholone, fluorometholone acetate, loteprednol etabonate, prednisolone acetate, prednisolone Sodium phosphate, medroxyprogesterone, dimethionyl, and fluocinolone. The punctal plugs may be used to deliver non-steroidal anti-inflammatory agents such as, but not limited to, flurbiprofen sodium, suprofen, diclofenac, ketorolac tromethamine, cyclosporine, rapamycin pterin, azathioprine, and bromocriptine.

The punctal plug can be used to deliver anti-infective drugs, such as but not limited to, tobramycin, moxifloxacin, ofloxacin, gatifloxacin, ciprofloxacin, gentamicin, sulfisoxazole Ketone (sulfisoxazolone) diolamine, sulfacetamide sodium, vancomycin, polymyxin B, amikacin, norfloxacin, levofloxacin, sulfisoxazole diethanolamine, sulfacetamide sodium tetracycline, doxyl Cyclocycline, dicloxacillin, cephalexin, amoxicillin/clavulanate, ceftriaxone, cefixime, erythromycin, ofloxacin, azithromycin, gentamicin, sulfadiazine, and B Amidine.

The punctal plugs can be used to deliver agents for one or more of glaucoma treatment, inhibition, and prevention, including, but not limited to, epinephrines, including, for example: dipephrine; alpha-2 adrenergic agents, including, for example, aclonidine and brimonidine; beta-blockers, including but not limited to, betaxolol, carteolol, levobunolol, metopolol, and timolol Mirin; direct miotics, including, for example, carbachol and pilocarpine; cholinesterase inhibitors, including but not limited to, physostigmine and diethoxyphosphorylcholine; carbonic anhydrase inhibitors, including, For example, acetazolamide, brinzolamide, dorzolamide, and methazolamide; prostaglandins and prostamides, including but not limited to, latanoprost, bimatoprost, travoprost (uravoprost), and unoprostone cidofovir.

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

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

Active agents delivered through the punctal plug can be formulated with excipients including, but not limited to, synthetic and natural polymers, including, for example, polyvinyl alcohol, polyethylene glycol, polyacrylic acid, methylol Cellulose, glycerin, hypromelos, polyvinylpyrrolidone, carbopol, propylene glycol, hydroxypropyl guar gum, glucam-20, hydroxypropyl cellulose, sorbitol, glucose, poly Sorbates, mannitol, dextran, modified polysaccharides and gums, phospholipids, and sultaines.

Claims (22)

1. Punctal plug comprises:

Main body, the lateral surfaces that it has first end, second end and between said two ends, extends;

Be adjacent to said main body first end block, be adjacent to the block of said main body second end or be adjacent to said main body first and second ends both each block; Wherein said block comprises the material that holds active agent that accommodates at least a active agent, and

The ring that encloses at the said main body first end place.

2. Punctal plug according to claim 1, wherein said lateral surfaces have the part that shape is essentially circular outer diameter and said lateral surfaces and have the external diameter bigger than the external diameter of this lateral surfaces remainder.

3. Punctal plug according to claim 1 and 2, wherein each block comprises the water-soluble polymeric material of part at least; Biodegradable polymeric material; Perhaps water insoluble and non-biodegradable polymeric material and said active agent are from the passive diffusion of said block.

4. according to claim 2 or 3 described Punctal plugs, wherein when Punctal plug inserted lacrimal ductule, the part that the external diameter of lateral surfaces is bigger than the external diameter of said lateral surfaces remainder was fixed on said Punctal plug in the lacrimal ductule.

5. Punctal plug according to claim 1 and 2, wherein the block one of or both adhere to the end of said main body.

6. Punctal plug according to claim 5 further comprises a block of the end that causes adhering to said main body or the biocompatible binding agent that each block adheres to said main body.

7. Punctal plug according to claim 1 and 2, wherein said block further comprise the bar part of block.

8. Punctal plug according to claim 6, the said part that wherein is arranged at the block in the said punctal plug body is screwed in the main body of said Punctal plug.

9. Punctal plug according to claim 6, the said part that wherein is arranged at the block in the said punctal plug body is snapped in the main body of said Punctal plug.

10. Punctal plug according to claim 1 and 2, wherein when said Punctal plug inserted lacrimal ductule, block was set to be adjacent to the end of said Punctal plug towards eyes, and active agent discharges into the tear of eyes.

11. Punctal plug according to claim 1 and 2, wherein when said Punctal plug inserted lacrimal ductule, block was set to be adjacent to the end of said Punctal plug towards nasolacrimal duct, and active agent discharges into nasolacrimal duct.

12. Punctal plug according to claim 1 and 2; Wherein when said Punctal plug inserts lacrimal ductule; A block is set to be adjacent to the end of said Punctal plug towards eyes; Another block is set to be adjacent to the end of said Punctal plug towards nasolacrimal duct, and active agent discharges into the tear and the nasolacrimal duct of eyes.

13. Punctal plug according to claim 1 and 2, wherein at least a portion of block is with to enclose ring contiguous, and active agent discharges into the tear of eyes.

14. Punctal plug according to claim 13, wherein second block is contiguous with second end of said main body, and active agent also discharges into nasolacrimal duct.

15. Punctal plug according to claim 13 wherein is adjacent to the said said block that encloses ring and comprises polymeric material, this polymeric material dissolves in time, and when it dissolves, discharges said active agent for part is water-soluble at least.

16. Punctal plug according to claim 13 wherein is adjacent to the said said block that encloses ring and comprises polymeric material, this polymeric material is biodegradable, degraded in time, and when it is degraded, discharge said active agent.

17. Punctal plug according to claim 13 wherein is adjacent to the said said block that encloses ring and comprises polymeric material, this polymeric material is water insoluble and non-biodegradable, and active agent is from the passive diffusion of said block.

18. Punctal plug according to claim 17, it is removable wherein being adjacent to the said said block that encloses ring.

19. Punctal plug according to claim 13 wherein is adjacent to the said said block that encloses ring and comprises flexible polymeric material, and at least a portion of said block extends across the said ring that encloses.

20. Punctal plug according to claim 13, wherein said block further comprises the bar part.

21. Punctal plug according to claim 20, the bar of wherein said block partly is screwed in the main body of said Punctal plug.

22. Punctal plug according to claim 20, the bar of wherein said block partly is positioned at or snaps in the main body of said Punctal plug.

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