JP2008049129A - Lacrimal punctum plug for delivery of active agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide lacrimal punctum plugs for the delivery of at least a kind of active agent. <P>SOLUTION: The invention provides lacrimal punctum plugs for the delivery of active agents. The plugs have a body (50) throughout which at least one active agent is dispersed or that is coated with a polymeric material containing at least one active agent. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

Disclosure details

(Field of the Invention)
The present invention relates to a device suitable for administering a substance to one or more of the eye, nose and throat. In particular, the present invention relates to a punctal plug for administration of at least one active agent.

[Related applications]
This application claims priority from US Provisional Patent Application No. 60 / 805,380, filed June 21, 2006.

BACKGROUND OF THE INVENTION
Human tears are secreted by the lacrimal gland and flow across the surface of the eye to a shallow pool (called the lacrimal lake), where the eyelids are located together at the inner ends of these eyelids. From here, tears flow out through small openings in each eyelid. These openings are called the superior lacrimal puncta and the inferior lacrimal puncta. From these upper and lower punctums, tears flow into the upper and lower tubules, respectively. These lacrimal tubules are tubular passages leading to the lacrimal sac. The lacrimal sac is the upper dilated portion of the nasolacrimal duct, which drains tears into the nasal organ system. Thus, the active agent can be administered to the nose and throat via the lacrimal canal leading to the nasolacrimal duct.

  Active agents are often administered to the eye for the treatment of eye diseases and disorders. Conventional means of administering active agents to the eye include topical application to the surface of the eye. The eye is uniquely suited for topical administration. This is because when properly configured, the topical active agent enters through the cornea and rises to a therapeutic concentration level inside the eye. Active agents for ophthalmic diseases and disorders may be administered orally or by infusion, but such routes of administration are desirable for oral administration because the active agent reaches the eye at too low concentrations. No effect can be obtained and their use is complicated by significant systemic side effects and infusion is inconvenient because it poses a risk of infection.

  Most of the ophthalmic active agents are currently administered locally using eye drops, which are effective depending on the application but are inefficient. When a droplet is added to the eye, the droplet overflows from the conjunctival sac, which is a sac-like cavity (pocket) between the eye and the eyelid, so that a substantial portion of the droplet is placed on the cheek Lost due to eyelid margin overflow. In addition, a substantial portion of the droplet that remains on the ocular surface is drained into the punctum, diluting the concentration of the drug.

Detailed Description of Invention and Exemplary Embodiments
The present invention provides a punctal plug that can be used to administer an active agent to one or both of the nasolacrimal duct and ocular tears. The punctal plug includes: (a) a body having a first end, a second end, and a side 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 a cap adjacent to both the first and second ends of the body, and consists essentially of (a) and (b). Or (a) and (b), and the cap is made of an active agent-containing material containing at least one active agent.

  In some punctal plugs, as shown in FIGS. 1, 2, and 3, the active agent is dispersed throughout the body of the plug, and the active agent is released, for example, when the body dissolves or degrades. Alternatively, the active agent diffuses from the body depending on the material of construction of the body. Alternatively, as illustrated in FIGS. 4, 5, 6, and 10, the active agent is distributed throughout the body of the plug, but all but at least a portion of the punctal plug The surface of the part is covered with a membrane that is impermeable to the active agent. The active agent is released through one or more uncoated portions of the body.

  Yet another punctal plug is coated with a polymeric material containing an active agent. In one such embodiment, referring to FIG. 9, a punctal plug is provided in the body 90 and has one or more, preferably at least two recesses 95 that increase its surface area. Depending on the polymeric material comprising the coating, the active agent is released from the coating 98 when the coating dissolves or decomposes, or the active agent diffuses out of the coating.

  In order to administer the active agent into the eye tear fluid, a punctal plug is inserted into the lacrimal canal and the active agent is released into the eye tear fluid. Referring to FIG. 2, for administration into lacrimal fluid, a collar 34 is preferably connected to the body of the punctal plug, and when the punctal plug is inserted into the punctum canal, Administration into the liquid is performed. The collar 34 is placed outside the punctum. For administration of the active agent into the nasolacrimal duct, the punctal plug is preferably inserted deeply into the lacrimal canal and the active agent is released into the nasolacrimal duct. In certain embodiments of the present invention, the body expands to secure the punctal plug within the lacrimal canal, as shown, for example, in FIGS. 2, 3, 5, 6, 7, 8, and 9. It has segments 22, 32, 52, 62, 72, 82, and 92, respectively.

  As used herein, the term “punctum plug” means a device of a size and shape suitable for insertion through the lower punctum or upper punctum into the lower tubule or upper tubule of the eye. ing.

  The term “active agent” as used herein refers to an agent that can treat, suppress, or prevent a disorder or disease. Exemplary agents include, but are not limited to, pharmaceuticals and nutraceuticals. Preferred active agents can treat, inhibit or prevent one or more disorders or diseases of the eye, nose and throat.

  As used herein, the expression “material (or substance) that is at least partially water soluble” refers to a level of water sufficient to cause detectable dissolution of the substance when exposed to an aqueous environment. Means a material (or substance) that exhibits solubility in

  As used herein, the expression “material that is biodegradable” generally degrades to a detectable extent when exposed to biologically active substances present in mammals. It means a material (or substance).

  As used herein, the expression “material (or substance) insoluble in water” means a material (or substance) that does not substantially dissolve upon exposure to water.

  As used herein, the expression “material (or substance) that is non-biodegradable” does not substantially degrade upon exposure to biologically active substances that are generally present in mammals. It means a material (or substance).

  As used herein, the expression “membrane that is impermeable to the active agent” means a membrane that allows only a trace amount of the active agent to pass through.

  As used herein, the expression “water permeable membrane” means a membrane that is capable of passing a detectable level of water.

  As used herein, “(one) recess”, “(plural) recesses”, and all variants thereof are provided on the body of the punctal plug to effectively increase the surface area of the body. It means a dent of any size or shape.

  The present invention includes a number of punctal plugs that administer the active agent to the eye lacrimal fluid or nasolacrimal duct. The punctal plug is preferably inserted into the lower lacrimal tubule, the upper lacrimal tubule, or both the lower and upper lacrimal tubules. Where a punctal plug is used to administer the active agent to the eye lacrimal fluid, the punctal plug preferably has a collar at one end of the body. The collar is a part of the punctal plug, which is located after at least a part of the collar extends beyond the tubule and is located outside the tubule after insertion of the punctal plug into the tubule. To a sufficient extent, it extends radially outward from one end of the body. A portion of the punctal plug without a collar is inserted into one of the lower or upper lacrimal tubule, which is the opening of the tubule at the edge of each eyelid. Referring to FIG. 3, the enlarged segment 32 and the body 30 are inserted into one of the lacrimal tubules, the collar 34 is positioned or resting on the outside of the lacrimal tubule, and the punctal plug slides down into the lacrimal tubule. So that contact between the punctal plug and the eye lacrimal fluid is maintained. The collar may be of any size and shape sufficient to at least partially secure the punctal plug within the lacrimal tubule.

  If a punctal plug is used to administer the active agent to the nasolacrimal duct, the punctal plug is preferably not provided with a collar so that the punctal plug can be applied to one or both tears. The tubules can be inserted deep enough to release the active agent into the lacrimal sac. 1, 2, and 4 show examples of punctal plugs useful for administering an active agent to the nasolacrimal duct.

  Many punctal plugs of the present invention each have various features and advantages. For example, a punctal plug has a body with a first end, a second end, and a side surface extending between the two ends. The side preferably has an outer diameter that is substantially circular in shape. A portion of the side surface of a punctal plug has an outer diameter that is greater than the outer diameter of the remainder of the side surface. Referring to FIG. 5, the lateral enlarged portion 52 secures or secures the punctal plug within the lacrimal canal. The enlarged portion may be of any size or shape and may be present on any portion of the side as long as the enlarged portion at least partially secures the punctal plug within the lacrimal canal. Advantageously, the enlarged portion may be in the form of an inverted triangle with flattened vertices.

  In some punctal plugs, at least one active agent is provided substantially throughout the body of the punctal plug, dispersed throughout, or otherwise contained throughout the body, As such, it is intended to serve as a carrier for the active agent. In certain embodiments of the present invention, preferably in embodiments where the punctal plug comprises a collar, the active agent is released from the body into the tears of the eye. The active agent can also be released from the body into the nasolacrimal duct. In a particular feature of the invention, the active agent is released from the body into both the eye lacrimal fluid and the nasolacrimal duct.

  Depending on the active agent-containing material comprising the body, the active agent may be released from the body almost immediately or the active agent may be released continuously over a desired period of time. For example, the body may be composed of a polymeric material that is at least partially soluble in water. When such a body is exposed to an aqueous environment of lacrimal tubules or lacrimal fluid, such body preferably dissolves and releases the active agent as it dissolves. The water solubility of the polymeric material of the body is typically directly proportional to its dissolution rate. Suitable polymeric materials that are at least partially soluble in water are, for example, poly (ethylene glycol), poly (ethylene oxide), poly (propylene glycol), poly (vinyl alcohol), poly (hydroxyethyl methacrylate), poly (vinyl pyrrolidone) , Polyacrylic acid, poly (ethyloxazoline), poly (dimethylacrylamide), phosphorylcholine derivatives (including but not limited to) phospholipids, polysulfobetaines, polysaccharides and carbohydrates such as hyaluronic acid, dextran , Hydroxyethyl cellulose, hydroxylpropyl cellulose, gellan gum, guar gum, heparan sulfate, chondroitin sulfate, heparin, and alginic acid, gelatin, collagen, albumin , And ovalbumin (but not limited to) proteins, as well as the polyamino acids. The polymeric materials in this list may be copolymerized or mixed with hydrophobic polymers and monomers.

  As a variant, the punctal plug, where the body serves as a carrier for the active agent, the chemical body of the punctal plug, for example when exposed to biologically active substances typically present in mammals. It may be composed of a biodegradable polymer material that decomposes into The biodegradable polymeric material is preferably hydrolyzed under in vivo conditions. Biodegradation typically occurs more slowly than dissolution, and the body of the plug may be made of a biodegradable material if a slower and sustained release of the active agent is desired. Suitable biodegradable polymeric materials include glycolide, lactide, epsilon-caprolactone and other hydroxy acid polymers and oligomers, and other biologicals that produce substances that are non-toxic or present as normal metabolites in the body. Include, but are not limited to, degradable polymers. Preferred poly (alpha-hydroxy acids) are poly (glycolic acid), poly (2-dioxanone), poly (DL-lactic acid) and poly (L-lactic acid). Other useful materials include poly (amino acids), polycarbonates, poly (anhydrides), poly (orthoesters), poly (phosphazine) and poly (phosphate esters). Polylactones such as poly (epsilon-caprolactone), poly (delta-caprolactone), poly (delta-valerolactone) and poly (gamma-butyrolactone) are also useful, as are chitosan, alginic acid, collagen, and gelatin. In particular features of the invention, the polymeric material comprising the body may be one or a mixture of two or more soluble and biodegradable polymers.

  Alternatively, the body of the punctal plug, which serves as a carrier for the active agent, may be composed of a water insoluble and non-biodegradable material from which the active agent can diffuse. . Suitable polymeric materials of this type are cross-linked polymers such as cross-linked poly (ethylene glycol), poly (ethylene oxide), poly (propylene glycol), poly (vinyl alcohol), poly (hydroxyethyl methacrylate), poly (vinyl pyrrolidone) , Polyacrylic acid, poly (ethyloxazoline), poly (dimethylacrylamide), but are not limited thereto. These polymers may be copolymerized or mixed with one or both of the hydrophobic polymer and the monomer. Further examples of suitable polymers that are insoluble in water and non-biodegradable include silicones, silicone blends, silicone copolymers, eg, hydrophilic monomers of pHEMA (polyhydroxyethyl methacrylate), polyethylene glycol, polyvinyl pyrrolidone, and glycerol, For example, 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, including (but not limited to) silicone hydrogel polymers, phosphorylcholine derivatives. Phospholipid (phospholipid), polysulfobetaine, polysaccharide (Polysaccharides), carbohydrates such as hyaluronic acid, dextran, hydroxyethyl cellulose, hydroxylpropyl cellulose, gellan gum, guar gum, heparan sulfate, chondritin sulfate, heparin, and alginic acid, 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"). Additional examples of suitable polymers that are insoluble in water and / or non-biodegradable include silicone, polyurethane, cyanoacrylate, polyacrylic acid, fibrin, and cross-linked proteins such as albumin and collagen-gelatin, It is not limited to these.

  The amount of active agent used in the plugs of the present invention can be selected from one or more selected active agents, the desired dose to be administered via the punctal plug, the desired release rate, the melting point of the active agent, And the material used to form the cap. Preferably, the amount used is a therapeutically effective amount, which means an amount effective to achieve the desired therapeutic, suppressive, or prophylactic effect. Typically, an active agent in an amount of about 0.05 to about 20,000 micrograms may be used. The ratio of active agent to polymeric material is about 10% to about 90%, preferably about 20% to about 50%.

  The punctal plug, where the body serves as a carrier for at least one active agent, can be, for example, solution casting, extrusion molding, chemical crosslinking by forming covalent or ionic bonds, lathe processing, compression molding, injection molding, liquid injection molding, It can be manufactured using methods including techniques such as blow molding and polymerization, and such polymerizations include photopolymerization, thermal polymerization, ion-initiated polymerization, and redox-initiated polymerization. The active agent may be incorporated into the cap by adding it to the material that makes up the body during manufacture of the body, or the active agent may be, for example, a solution of the active agent following manufacture of the punctal plug cap. The activator may be added to the body of the punctal plug by immersing in a pre-shaped body.

  The surface of all parts of the body of the punctal plug, where the body serves as a carrier for the active agent, may be coated with a membrane that is impermeable to the active agent, so that the active agent is It will be released only from the uncoated part of the body. The uncoated portion may be anywhere on the body (including the collar if present), depending on the desired release location of the active agent. In certain embodiments of the invention, when the punctal plug is inserted into the lacrimal tubule, the uncoated portion of the body is directed to the eye and the active agent is released into the eye's tears. In another aspect of the invention, when the punctal plug is inserted into the lacrimal canal, the uncoated portion of the body is directed to the nasolacrimal duct and the active agent is released into the nasolacrimal duct. In yet another embodiment of the invention, when the punctal plug is inserted into the lacrimal canal, the uncoated portion of the body is directed to the eye and nasolacrimal duct, and the active agent is the ocular tear and nose. Released into both lacrimal ducts.

  The coating is preferably made of a material that is impermeable to the active agent, such materials including ethylene vinyl alcohol, ethylene vinyl acetate, cellulose derivatives such as cellulose acetate, polydimethylenesiloxane derivatives, and polyurethane. However, it is not limited to these. In some punctal plugs, the membrane is impermeable to water and the active agent is passively diffused through the uncoated portion of the body. Such membranes may be made from the materials listed in the paragraph above.

  In another punctal plug, the membrane is permeable to water but the active agent is impermeable. Following insertion into the lacrimal tubule, water diffuses through the membrane and into the body creating an osmotic gradient. This is described, for example, in US Pat. Nos. 6,923,880 and 5,817,335, which are incorporated herein by reference in their entirety. Be incorporated. The active agent is then passed through the uncoated portion of the body by an osmotic gradient. Membranes that allow water to pass but are impervious to the active agent are made from materials including, for example, HYTREL® polybutylene terephthalate elastomers, cellulose ethers, cellulose esters, moisture flow promoting polyvinyl acetate copolymers, and ethylene vinyl alcohol. May be.

  With reference to FIGS. 7 and 8, in one embodiment, the active agent is not contained within the body, and the bodies 70 and 80 are respectively coated with polymeric materials 78 and 88, respectively. Containing at least one active agent, the body being impermeable to the active agent. The thickness of the coating may be increased and the body dimensions may be reduced proportionally, thereby increasing the amount of active agent that the punctal plug can hold. Thus, the coating may be of any thickness sufficient to hold the desired amount of active agent. Some of the punctal plugs may further include a recess provided in the body and increasing the surface area of the body. The recess may be of any size or shape.

  The coating may be composed of a polymeric material that is at least partially soluble in water. When such a coating is exposed to an aqueous environment of lacrimal tubules or tears, such coating dissolves and releases the active agent as it dissolves. The water solubility of the polymeric material comprising the coating is typically directly proportional to its dissolution rate. Suitable polymeric materials that are at least partially soluble in water include poly (ethylene glycol), poly (ethylene oxide), poly (propylene glycol), poly (vinyl alcohol), poly (hydroxyethyl methacrylate), poly (vinyl pyrrolidone), poly Phospholipids, including but not limited to acrylic acid, poly (ethyloxazoline), poly (dimethylacrylamide), phosphorylcholine derivatives, polysulfobetaines such as hyaluronic acid, dextran, hydroxyethylcellulose, hydroxylpropylcellulose, gellan gum, guar gum , Polysaccharides and carbohydrates such as, but not limited to, heparan sulfate, chondroitin sulfate, heparin and alginic acid Gen, albumin, and including ovalbumin, protein are not limited to, as well as polyamino acids, including but not limited to. The polymeric materials in this list may be copolymerized or mixed with hydrophobic polymers, monomers, or both.

  Alternatively, the coating may be composed of a biodegradable polymeric material that chemically degrades, for example, when exposed to biologically active substances typically present in mammals. The biodegradable polymeric material is preferably hydrolyzed under in vivo conditions. Biodegradation typically occurs more slowly than dissolution, and thus the coating may be made of a biodegradable material if a slower and sustained release of the active agent is desired. Suitable biodegradable polymeric materials include glycolide, lactide, epsilon-caprolactone and other hydroxy acid polymers and oligomers, and others that produce substances that are non-toxic or exist as normal metabolites in the body. Including but not limited to biologically degradable polymers. Preferred poly (alpha-hydroxy acids) are poly (glycolic acid), poly (2-dioxanone), poly (DL-lactic acid) and poly (L-lactic acid). Other useful materials include poly (amino acids), polycarbonates, poly (anhydrides), poly (orthoesters), poly (phosphazine) and poly (phosphate esters). Polylactones such as poly (epsilon-caprolactone), poly (delta-caprolactone), poly (delta-valerolactone) and poly (gamma-butyrolactone) are also useful, as are chitosan, alginic acid, collagen, and gelatin. In particular features of the invention, the polymeric material comprising the cap may be comprised of one or a mixture of two or more soluble and biodegradable polymers.

  Alternatively, the coating may be composed of a water-insoluble and non-biodegradable polymeric material from which the active agent can diffuse. Suitable polymeric materials of this type typically include, but are not limited to, crosslinked polymers, which are crosslinked poly (ethylene glycol), poly (ethylene oxide), poly (propylene glycol), poly (vinyl). Alcohol), poly (hydroxyethyl methacrylate), poly (vinyl pyrrolidone), polyacrylic acid, poly (ethyl oxazoline), poly (dimethylacrylamide), but are not limited thereto. These polymers may be copolymerized or mixed with one or both of the hydrophobic polymer and the monomer. Suitable further polymers that are insoluble in water and non-biodegradable are silicones, silicone mixtures, silicone copolymers, eg hydrophilic monomers of pHEMA (polyhydroxyethyl methacrylate), polyethylene glycol, polyvinylpyrrolidone, and glycerol, U.S. Pat. Nos. 5,962,548, 6,020,445, 6,099,852, 6,367,929, and 6, 822,016 (these US patents are incorporated herein by reference in their entirety), including but not limited to silicone hydrogel polymers, phosphorylcholine derivatives But not limited to phospholipids (phospholipids), polysulfones Ins, polysaccharides (polysaccharides), carbohydrates such as hyaluronic acid, dextran, hydroxyethyl cellulose, hydroxylpropyl cellulose, gellan gum, guar gum, heparan sulfate, chondritin sulfate, heparin and alginic acid, gelatin, collagen, albumin, and ovalbumin Including, but not limited to, proteins, polyamino acids, fluorinated polymers such as PTFE, PVDF and Teflon, polypropylene, polyethylene, nylon, and EVA (ie, ethylene-vinyl acetate copolymers) ), But is not limited thereto. Further examples of suitable polymers having one or both of water insoluble and non-biodegradable include silicones, polyurethanes, cyanoacrylates, polyacrylic acid, fibrin, and cross-linked proteins such as albumin and collagen-gelatin, It is not limited to these.

  In the case of punctal plugs where the body is coated with a polymeric material made of at least one active agent, the body is first subjected to chemical cross-linking, lathes, for example by solution casting, extrusion, formation of covalent or ionic bonds Manufactured using any suitable process that may include lathing, compression molding, injection molding, liquid injection molding, blow molding and polymerization, such polymerization is photopolymerization, thermal polymerization, ion initiated polymerization, and redox initiation. Including polymerization. The body is then coated with the polymeric material containing the active agent using any of a variety of processes, such as dip coating, spin coating, vapor deposition coating, adsorption, laminate assembly, Including, but not limited to, pre-formed film deposition, plasma coating, powder coating, spray coating including electrical spraying. The coating is polymerized onto the surface of the punctal plug, adsorbed via mechanical interlock, deposited via evaporation of the solvent carrier, deposited or solidified upon cooling, and chemically bonded using a crosslinker Alternatively, they may be bonded via an adhesive. Alternatively, the coating may be in the form of an unbonded sleeve provided around one or both of the plug body and collar.

  The amount of active agent used in the plugs of the present invention can be selected from one or more selected active agents, the desired dose to be administered via the punctal plug, the desired release rate, the melting point of the active agent, And the material used to form the cap. Preferably, the amount used is a therapeutically effective amount, which means an amount effective to achieve the desired therapeutic, suppressive, or prophylactic effect. Typically, an active agent in an amount of about 0.05 to about 8,000 micrograms may be used.

  The punctal plugs described herein can be used to administer various active agents for one or more of the treatment, suppression, and prevention of many diseases and disorders. With each punctal plug, at least one active agent can be administered, and different types of active agents can be administered. For example, the punctal plug can be azelastine HCl, emadastine difumerate, epinastine HCl, ketotifen fume for one or more of allergy treatment, suppression, and prevention. It can be used to administer ketotifen fumerate, levocabastine HCl, olopatadine HCl, pheniramine maleate, and antazoline phosphate. With punctal plugs, administer mast cell stabilizers such as sodium cromolyn, lodoxamide tromethamine, nedocromil sodium, and permirolast potassium be able to.

  With punctal plugs, mydriatics and ciliary muscle palsy, such as henylephrine, atropine sulfate, homatropine, scopolamine HBr, cyclopentrate HCl, tropicamide, and phenylephrine HCl can be administered. With punctal plugs, eye drops such as rose begal, sissamine green, indocyanine green, fluorexon, and fluorescein (but not limited to) can be administered .

  With punctal plugs, corticosteroids (corticosteroids) such as dexamethasone sodium phosphate, dexamethasone, fluoromethalone, fluoromethalone acetate, loteprednol etabonate Prednisone acetate, sodium prednisolone phosphate, medrizone, rimexolone, and fluocinolone acetonide can be administered. With punctal plugs, non-steroidal anti-inflammatory drugs such as flurbiprofen sodium, suprofen, diclofenac sodium, ketorolac tromethamine, cyclosporine, rapamycin methotrexate, azathioprine, and bromocriptine can be administered .

  With punctal plugs, anti-infective drugs such as tobramycin, moxifloxacin, ofloxacin, gatifloxacin, ciprofloxacin, gentamicin, sulfisoxazole diolamine, sulfa Cetamide sodium, vancomycin, polymyxin B, amikacin, norfloxacin, levofloxacin, sulfisoxazole diolamine, sulfacetamide sodium tetracycline, doxycycline, dicloxacillin, ceferexin, amoxiline / clavulanic acid, ceftriaxone, cefixime, erythromycin, Ofloxacin, azithromycin, gentamicin, sulfadiazine, and pyrimethamine can be administered without limitation.

  The punctal plug can be used to administer drugs for one or more of the treatment, suppression, and prevention of glaucoma, such as epinephrine, including dipivefrin, such as aproclonidine. ) And brimonidine and alpha blockers including betaxolol, betaxolol, carteolol, levobunolol, metipranolol, and timolol, for example Direct miotics including carbachol and pilocarpine, such as cholinesterase inhibitors including physostigmine and ecothiophosphate, such as acetazolamide, brinzolamide, dorzolamide, and metazo Carbonic anhydrase inhibitors including amides such as prostoglandin, including but not limited to latanoprost, bimatoprost, uravoprost, and unoprostone cidofovir ) And prostamid.

  With punctal plugs, antiviral drugs can be administered, such as fomivirsen sodium, foscarnet sodium, ganciclovir sodium, valganciclovir HCl, trifluridine, Including but not limited to acyclovir and famiciclovir. With a punctal plug, local anesthetics can be administered, such local anesthetics include tetracaine HCl, proparacaine HCl, and fluorescein sodium, benoxinate and fluorescein sodium, benoxinate and fluorexon disodium However, it is not limited to these. With a punctal plug, an antifungal agent can be administered, and such antifungal agents include, for example, fluconazole, flucytosine, amphotericin B, itraconazole, and ketoconazole.

  With punctal plugs, analgesics can be administered and such analgesics include acetaminophen and codeine, acetaminophen and hydrocodone, acetaminophen, ketorolac, ibuprofen, and tramadol, It is not limited to these. With punctal plugs, vasoconstrictors can be administered and include, but are not limited to, ephedrine hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, tetrahydrozoline hydrochloride, and oxymetazoline. . Finally, punctal plugs can be used to administer vitamins, antioxidants, and dietary supplements, including vitamin A, vitamin D, vitamin E, lutein, taurine, glutathione, zeaxanthin, fatty acids, etc. However, it is not limited to these.

  Active agents administered by punctal plugs may be formulated to include excipients, such excipients include, but are not limited to, synthetic and natural polymers such as, for example, Polyvinyl alcohol, polyethylene glycol, polyacrylic acid, hydroxymethyl cellulose, glycerin, hypromelos, polyvinyl pyrrolidone, carbopol, propylene glycol, hydroxypropyl guar, glucam-20 (glucam-20), hydroxypropyl cellulose, sorbitol , Dextrose (glucose), polysorbate, mannitol, dextran, modified polysaccharides and gums, phosolipid, and sulphobetain.

Embodiment
Specific embodiments of the present invention are as follows.
(1) In the punctum plug,
A punctal plug having a body with a first end, a second end, and two sides extending between the two ends, and at least one active agent contained throughout the body. .
(2) In the punctal plug according to the embodiment (1),
A punctal plug, wherein the body is composed of a polymeric material that is at least partially water soluble and dissolves over time, the body releasing the active agent as the polymeric material dissolves.
(3) In the punctal plug according to the embodiment (1),
The punctal plug, wherein the body is composed of a biodegradable polymer material, and the body releases the active agent as the polymer material degrades.
(4) In the punctal plug according to the embodiment (1),
A punctal plug, wherein the body is composed of a polymeric material that is insoluble in water and non-biodegradable, and the active agent passively diffuses from the cap.
(5) In the punctal plug according to the embodiment (1),
The portion of the side surface having an outer diameter greater than the outer diameter of the remaining portion of the side surface fixes the punctum plug in the punctum tubule when the punctum plug is inserted into the tubule. plug.
(6) In the punctal plug according to the embodiment (1),
A punctal plug, wherein the active agent is released into the tears of the eye.
(7) In the punctal plug according to the embodiment (1),
A punctal plug, wherein the active agent is released into the nasolacrimal duct.
(8) In the punctal plug according to the embodiment (1),
A punctal plug, wherein the active agent is released into both the eye lacrimal fluid and the nasolacrimal duct.
(9) In the punctal plug according to the embodiment (1),
A collar provided at the first end of the body;
In addition, a punctal plug.
(10) In the punctum plug,
A body with a first end, a second end, and a side surface extending between the two ends;
Have
At least one active agent is placed throughout the body;
A punctal plug, wherein the surface of all parts except at least a part of the body is covered with a membrane that is impermeable to the active agent.

(11) In the punctal plug according to the embodiment (10),
The punctal plug, wherein the side surface has an outer periphery that is substantially circular in shape.
(12) In the punctal plug according to the embodiment (10) or (11),
The body is composed of a polymeric material that is at least partially water soluble and dissolves over time, and the body passes through the uncoated portion of the body as the polymeric material dissolves. A punctal plug that releases the agent.
(13) In the punctal plug according to the embodiment (10) or (11),
The body is composed of a polymer material that is biodegradable and degrades over time, and the body releases the active agent through an uncoated portion of the body as the polymer material degrades. To do, punctal plug.
(14) In the punctal plug according to the embodiment (10) or (11),
A punctal plug, wherein the body is composed of a polymeric material that is insoluble in water and non-biodegradable.
(15) In the punctal plug according to the embodiment (14),
A punctal plug, wherein the active agent passively diffuses through an uncoated portion of the body.
(16) In the punctal plug according to the embodiment (14),
The membrane passes water,
Water diffuses through the membrane and into the body, creating an osmotic gradient,
The punctum plug, wherein the active agent is passed through the uncoated portion of the body by the osmotic gradient.
(17) In the punctal plug according to the embodiment (10) or (11),
A portion of the side surface has an outer diameter greater than the outer diameter of the remainder of the side surface;
This enlarged portion of the side is a punctal plug that secures the punctal plug within the tubule when the punctal plug is inserted into the tubule.
(18) In the punctal plug according to the embodiment (10) or (11),
When the punctal plug is inserted into the lacrimal tubule, the uncovered portion of the body faces the eye,
A punctal plug, wherein the active agent is released into the lacrimal fluid of the eye.
(19) In the punctal plug according to the embodiment (10) or (11),
When the punctal plug is inserted into the lacrimal canal, the uncovered portion of the body faces the nasolacrimal duct,
A punctal plug, wherein the active agent is released into the nasolacrimal duct.
(20) In the punctal plug according to the embodiment (10) or (11),
When the punctal plug is inserted into the lacrimal canal, an uncoated part of the body faces the eye, another uncoated part of the body faces the nasolacrimal duct,
A punctal plug, in which the active agent is released into both the lacrimal fluid and the nasolacrimal duct.
(21) In the punctal plug according to the embodiment (10) or (11),
A collar provided on the first portion of the body;
In addition, a punctal plug.

(22) In the punctum plug,
A body with a first end, a second end, and a side surface extending between the two ends;
Have
A portion of the side surface has a dimension that is greater than the dimension of the remainder of the side surface;
The body is coated with a polymeric material comprising at least one active agent;
A punctal plug, wherein the body is impermeable to the active agent.
(23) In the punctal plug according to the embodiment (22),
The punctal plug, wherein the side surface has an outer periphery that is substantially circular in shape.
(24) In the punctal plug according to the embodiment (22) or (23),
A punctal plug, wherein the body is composed of a polymeric material that is at least partially water soluble and dissolves over time, the body releasing the active agent as the polymeric material dissolves.
(25) In the punctal plug of the embodiment (22) or (23),
A punctal plug, wherein the body is composed of a polymeric material that is biodegradable and degrades over time, the body releasing the active agent as the polymeric material degrades.
(26) In the punctal plug according to the embodiment (22) or (23),
The body is composed of a polymeric material that is insoluble in water and non-biodegradable;
The punctal plug, wherein the active agent diffuses passively from the cap.
(27) In the punctal plug according to the embodiment (22) or (23),
The portion of the side surface having an outer diameter greater than the outer diameter of the remaining portion of the side surface fixes the punctum plug in the punctum tubule when the punctum plug is inserted into the tubule. plug.
(28) In the punctal plug of the embodiment (22) or (23),
The punctal plug, wherein the body has one or more recesses that increase the surface area of the body.
(29) In the punctal plug of the embodiment (22) or (23),
A punctal plug, wherein the active agent is released into the tears of the eye.
(30) In the punctal plug of the embodiment (22) or (23),
A punctal plug, wherein the active agent is released into the nasolacrimal duct.

(31) In the punctal plug according to the embodiment (22) or (23),
A punctal plug, wherein the active agent is released into both the eye lacrimal fluid and the nasolacrimal duct.
(32) In the punctal plug of the embodiment (22) or (23),
A collar provided at the first end of the body;
In addition, a punctal plug.
(33) In the method:
Inserting the punctal plug of embodiment (1) into the lacrimal canal;
Having a method.
(34) In the method:
Inserting the punctal plug of embodiment (10) or (11) into a lacrimal canal;
Having a method.
(35) In the method:
Inserting the punctal plug of embodiment (22) or (23) into the lacrimal tubule;
Having a method.

FIG. 3 is a cross-sectional view of a punctal plug having a body 10 and shows a state in which an active agent 18 is dispersed throughout the body. FIG. 4 is a cross-sectional view of a punctal plug having a body 20 with an enlarged segment 22 and showing the active agent 28 being dispersed throughout the body. FIG. 3 is a cross-sectional view of a punctal plug having a body 30 with an enlarged segment 32 and a collar 34, showing the active agent 38 being dispersed throughout the body 30. FIG. 4 is a cross-sectional view of a punctal plug having a main body 40, in which an active agent 48 is dispersed throughout the main body 40 and all but a part of the main body 41 is covered with a membrane 43. FIG. 5 is a cross-sectional view of a punctal plug having a body 50 with an enlarged segment 52, with active agent 58 distributed throughout the body 50, all but a portion of the body 51 being covered by a membrane 53. FIG. FIG. 3 is a cross-sectional view of a punctal plug having a body 60 with an enlarged segment 62 and a collar 64, with an active agent 68 distributed throughout the body 60, except for a portion of the body 61, all of which is a membrane 63. It is a figure which shows the state currently coat | covered with. FIG. 6 is a cross-sectional view of a punctal plug having a body 70 with an enlarged segment 72, showing the body 70 covered with a polymeric material 78 containing an active agent. FIG. 7 is a cross-sectional view of a punctal plug having a body 80 with an enlarged segment 82 and a collar 84, showing the body and collar covered with a polymeric material 88 containing an active agent. FIG. 9 is a cross-sectional view of a punctal plug having a body 90 with an enlarged segment 92 and a collar 94, the body having a recess 95 that increases the surface area of the body, and the body and collar are polymers containing an active agent. It is a figure which shows the state coat | covered with the material 98. FIG. FIG. 7 is a three-dimensional view of the punctal plug shown two-dimensionally in FIG. 6, where the punctal plug has a body 100 and a collar 104 with an enlarged segment 102 and the active agent is dispersed throughout the body. FIG. 2 is a diagram illustrating a state in which all except a part of a main body 101 is covered with a membrane 103.

Claims (16)

In the punctum plug,
A body with a first end, a second end, and a side surface extending between the two ends;
At least one active agent included throughout the body;
Having a punctal plug. The punctal plug of claim 1,
A punctal plug, wherein the body is composed of a polymeric material that is at least partially water soluble and dissolves over time, the body releasing the active agent as the polymeric material dissolves. The punctal plug of claim 1,
The punctal plug, wherein the body is composed of a biodegradable polymer material, and the body releases the active agent as the polymer material degrades. The punctal plug of claim 1,
The body is composed of a polymeric material that is insoluble in water and non-biodegradable;
The punctal plug, wherein the active agent diffuses passively from the cap. In the punctum plug,
A body with a first end, a second end, and a side surface extending between the two ends;
Have
At least one active agent is included throughout the body;
A punctal plug, wherein the surface of all parts except at least a part of the body is covered with a membrane that is impermeable to the active agent. The punctal plug of claim 5,
The punctal plug, wherein the side surface has an outer periphery that is substantially circular in shape. In the punctal plug according to claim 5 or 6,
The body is composed of a polymeric material that is at least partially water soluble and dissolves over time, and the body passes through the uncoated portion of the body as the polymeric material dissolves. A punctal plug that releases the agent. In the punctal plug according to claim 5 or 6,
The body is composed of a polymer material that is biodegradable and degrades over time, and the body releases the active agent through an uncoated portion of the body as the polymer material degrades. To do, punctal plug. In the punctal plug according to claim 5 or 6,
A punctal plug, wherein the body is composed of a polymeric material that is insoluble in water and non-biodegradable. The punctal plug of claim 9,
A punctal plug, wherein the active agent diffuses passively through an uncoated portion of the body. The punctal plug of claim 9,
The membrane passes water,
Water diffuses through the membrane and into the body, creating an osmotic gradient,
The punctal plug, wherein the active agent is allowed to pass through an uncoated portion of the body by the osmotic gradient. In the punctum plug,
A body with a first end, a second end, and a side surface extending between the two ends;
Have
A portion of the side surface has a dimension that is greater than the dimension of the remainder of the side surface;
The body is coated with a polymeric material comprising at least one active agent;
A punctal plug, wherein the body is impermeable to the active agent. The punctal plug of claim 12,
The punctal plug, wherein the side surface has an outer periphery that is substantially circular in shape. The punctal plug of claim 12 or 13,
A punctal plug, wherein the body is composed of a polymeric material that is at least partially water soluble and dissolves over time, the body releasing the active agent as the polymeric material dissolves. The punctal plug of claim 12 or 13,
The punctal plug, wherein the body is composed of a polymeric material that is biodegradable and degrades over time, the body releasing the active agent as the polymeric material degrades. The punctal plug of claim 12 or 13,
The body is composed of a polymeric material that is insoluble in water and non-biodegradable;
The punctal plug, wherein the active agent diffuses passively from the cap.

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