CN101327356A - Dacryon plug for conveying promoting agent - Google Patents
Dacryon plug for conveying promoting agent Download PDFInfo
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- CN101327356A CN101327356A CNA200710129269XA CN200710129269A CN101327356A CN 101327356 A CN101327356 A CN 101327356A CN A200710129269X A CNA200710129269X A CN A200710129269XA CN 200710129269 A CN200710129269 A CN 200710129269A CN 101327356 A CN101327356 A CN 101327356A
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Abstract
The present invention provides a smart plug that is used for carrying the active agent to one or both of the tears of the eyes and the nasolacrimal canal, and is provided with a main body, a storage device that is arranged inside the main body and optional rolling ring. The storage device is provided with at least an opening, a polymeric material and at least one active agent.
Description
Invention field
The present invention relates to be suitable for equipment, particularly, the present invention relates to be used to carry the Punctal plug of at least a activating agent to one or more eyes, N﹠T transportation of substances.
Related application
It is 60/805,378 priority that the application requires in the U.S. Provisional Application series number that on June 21st, 2006 submitted to.
Background of invention
People's tear by lacrimal secretion and the surface of flowing through eyes to the on-swimmer's pool that is called as cus lacrimalis that is arranged in the inner junction of eyelid.From here, tear are respectively by being called little opening discharge in the palpebra inferior on each of lacrimal point and following lacrimal point.From lacrimal point up and down, tear are respectively through as the duct-like last lower lacrimal canaliculi that leads to the path of lachrymal sac.Lachrymal sac is the top expansion of nasolacrimal duct, and it enters tear in the nasus system.Activating agent can be transported to N﹠T by lacrimal ductule like this, this lacrimal ductule leads to nasolacrimal duct.
Usually give disease or the discomfort of eyes administering active agents with the treatment eyes.Being used for conventional means to the eyes delivery of active agents comprises to the surface of eyes and carries out drop.Eyes are unique drops that are suitable for, because when making up when suitable, the permeable cornea of drop activating agent also improves the treatment concentration level of ophthalmic.Being used for disease of eye or uncomfortable activating agent also can be oral or by injection, but these administration paths are disadvantageous, because in oral administration, the surfactant concentration of eyes is too low not to have required drug effect and their use to be subjected to significant system side effects and the complexity that becomes to such an extent as to can arrive, and injection has brought the risk that infects.
Most eye activating agent uses eye drop to carry at present, is effectively though use eye drop for some, its inefficiency.When the eye drop of liquid is added in the eyes, it can overflow conjunctival sac, and the capsule bag between eyes and the eyelid causes eye drop greatly to flow on the cheek and lose owing to overflowing eyelid.In addition, a big chunk eye drop that keeps on the eye surface is discharged in the lacrimal point, the concentration of diluent.
Description of drawings
Fig. 1 is the profile of Punctal plug, and it has main body 10 and the reservoir in main body 10 15, and this main body 10 has the part 12 of expansion, and this reservoir 15 contains the polymeric material 11 of activating agent 18.This reservoir 15 has opening 13, by these opening 13 release bioactive agents 18.
Fig. 2 is the profile of Punctal plug, and it has main body 20 and the reservoir in main body 20 25, and this main body 20 has the part 22 of expansion, and this reservoir 25 contains the polymeric material 21 of activating agent 28.This reservoir 25 has opening 23, by these opening 23 release bioactive agents 28.
Fig. 3 is the profile of Punctal plug, and it has main body 30 and the reservoir in main body 30 35, and this main body 30 has the part 32 of expansion, and this reservoir 35 contains the polymeric material 31 of activating agent 38.This reservoir 35 has two openings 33 and 33 ', by above-mentioned opening 33 and 33 ' release bioactive agent 38.
Fig. 4 is the profile of Punctal plug, and it has main body 40, the reservoir in main body 40 45 and eckband 44, and main body 40 has the part 42 of expansion, and this reservoir 45 contains the polymeric material 41 of activating agent 48.This reservoir 45 has opening 43, by these opening 43 release bioactive agents 48.
Fig. 5 is the profile of Punctal plug, and it has main body 50 and the reservoir in main body 50 55, and main body 50 has the part 52 of expansion, and this reservoir 55 contains the polymeric material 51 of activating agent 58.This reservoir 55 has opening 53, by these opening 53 release bioactive agents 58.
Fig. 6 is the profile of Punctal plug, and it has main body 60, the reservoir in main body 60 65 and eckband 64, and main body 60 has the part 62 of expansion, and this reservoir 65 contains the polymeric material 61 of activating agent 68.This reservoir 65 has two openings 63 and 63 ', by above-mentioned opening 63 and 63 ' release bioactive agent 68.
Fig. 7 is the profile of Punctal plug, and it has the main body 70 made by flexible polymer material, links to each other and reservoir 75 in main body 70 and eckband 74 with main body 70.This reservoir 75 contains the polymeric material 71 of activating agent 78, and this reservoir 75 has opening 73, by this opening release bioactive agent 78.
Fig. 8 is the profile of Punctal plug, and it has the main body 80 made by flexible polymer material, links to each other and reservoir 85 in main body 80 and eckband 84 with main body 80.This reservoir 85 contains the polymeric material 81 of activating agent 88, and this reservoir 85 has two openings 83 and 83 ', by these two opening release bioactive agents 88.
Fig. 9 is the 3-D view of the Punctal plug that two dimension is described among Fig. 4, it has main body 90, contains polymeric material 91 and reservoir in main body 90 95 and eckband 94, this main body 90 has the part 92 of expansion, this polymeric material contains activating agent 98, this reservoir 95 has opening 93, by this opening release bioactive agent 98.
Figure 10 is the profile of Punctal plug, and it has main body 100, the reservoir in main body 100 105, at eckband 104 and a taper nose circle 103, and this main body 100 has the part 102 of expansion.Reservoir 105 comprises a polymeric material 101 that contains activating agent 108, and this reservoir 105 has opening 103, by these opening 103 release bioactive agents 108.
Figure 11 is a chart of having described the Punctal plug activating agent release profiles of embodiment 2.
Figure 12 is a chart of having described the Punctal plug activating agent release profiles of embodiment 3.
The specific embodiment
The invention provides the Punctal plug that can be used for active agent delivery is given one or two nasolacrimal duct and eyes tear.In one embodiment, the invention provides Punctal plug, it comprise following, constitute and constitute by following basically by following: the main body with first end, second end; The side surface that between two ends, extends; Be included in main intravital reservoir, that wherein said reservoir comprises is following, substantially by following and be made of following at least one opening, and contain comprise following, substantially by material following and that constitute by following at least a activating agent; And wherein said main body is impermeable to activating agent.
With reference to figure 1, punctal plug body 10 has reservoir 15, it contains at least one opening 13 and activating agent 18 can be released by opening 13, for example, the material 11 when containing activating agent is preferably polymeric material, water-soluble, degraded, perhaps only when material 11 diffused out or discharges, this depended on the person's character of material to activating agent 18.Can be positioned at for example first end shown in Fig. 1 by its opening that activating agent is discharged from plug, second end among Fig. 2 for example, or first and second two ends of the plug main body shown in Fig. 3 for example are perhaps along its side surface.Preferably, this opening is positioned at a place or two places of first and second ends.In certain embodiments of the present invention, for example shown in Fig. 3, Punctal plug contains the enlarged 32 of main body 30, and its size and shape are suitable for this Punctal plug is fixed in the lacrimal ductule.
For with active agent delivery in the tear of eyes, be inserted into Punctal plug in the lacrimal ductule and activating agent be discharged in the tear of eyes.With reference to figure 4, in order to be transported in the tear, preferably eckband 44 is arranged on the main body 40 of Punctal plug, and when Punctal plug being inserted in this lacrimal ductule, eckband 44 is resisted against dacryocanalicular outside.For with active agent delivery in nasolacrimal duct, Punctal plug is inserted, preferably be inserted in the lacrimal ductule dearly, and activating agent be discharged in the nasolacrimal duct.
As used herein, term " Punctal plug " be meant size and shape be suitable for by down or on lacrimal point be inserted into equipment in the following or superior canaliculus of eyes.
As used herein, term " activating agent " refers to energy treatment, inhibition or prevent disease or uncomfortable preparation.Representational activating agent includes but not limited to medicine and nutrient.Preferred activating agent can treat, suppress or prevent one or more, the disease or the discomfort of N﹠T.
As used herein, term " to the water miscible material of small part " thus in case refer to the dissolubility that in water, shows certain enough levels and cause being exposed to and perceive the material that material disintegrates in the water environment.
As used herein, term " Biodegradable material " is in case refer to and be exposed to the material that is degraded to discernable degree when being present in the intravital bioactive substance of mammal usually.
As used herein, term " water-fast material " is in case refer to be exposed in the water and can not dissolve the material that reaches substantial degree.
As used herein, term " not biodegradable material " is in case refer to and be exposed to the material that can not degrade in a large number when being present in the intravital bioactive substance of mammal usually.
As used herein, term " is impermeable main body to activating agent " refers to the main body that the activating agent that only do not have substantial amount can pass through.
As used herein, term " polymeric material " refers to the material of being made by the polymer of one or more types, these polymer can contain at least a activating agent and discharge this activating agent, for example when polymer dissolution or degraded, when activating agent sheds from this polymer, or when using prodrug, wherein activating agent is attached to polymer and then it is discharged by splitting from material.
As used herein, term " opening " refers to that activating agent can pass through has opening on the punctal plug body of a certain size and shape.Preferably, only activating agent can pass through this opening.This opening for example can be that the hole that covers with film, mesh, grid or it can be uncovered.This film, mesh, grid can be porous, half porous, permeable, semi permeable and biodegradable in one or more.
As used herein, " flexible material " do not refer to hard and the material of the object surface of compliant materials contact basically.
As used herein, " reservoir links to each other with main body " refer to reservoir and come down to the whole of this main body.When this reservoir links to each other with main body, eckband can be connected on this main body, but this eckband will not be considered to the part of this main body.
As used herein, " filling " activating agent that refers to any discernable amount once more with activating agent joins in the reservoir of this Punctal plug.
The present invention comprises numerous being used for one or two the Punctal plug of active agent delivery to the tear of eyes or nasolacrimal duct.Preferably be inserted into this Punctal plug in the lower lacrimal canaliculi, in the superior canaliculus or go up in the lower lacrimal canaliculi.If this Punctal plug is used for the tear of active agent delivery to eyes, this Punctal plug preferably has eckband at an end of main body.This eckband is the part of Punctal plug, and its end from main body extends radially outwardly into sufficient degree, and has certain shape and size, makes at least a portion eckband extend beyond and be positioned at the outside of lacrimal point after Punctal plug is inserted into lacrimal ductule.Usually, this eckband will extend beyond this cock body about 0.2 to about 1mm.The Punctal plug of not leading circle partly is inserted into down in one of them of lacrimal point or last lacrimal point.With reference to figure 6, part 62 and the main body 60 that enlarges is inserted into one of them lacrimal point, and eckband 64 is resisted against the outside of lacrimal point and prevents Punctal plug landing from the lacrimal ductule, thereby keep contacting between Punctal plug and eyes tear.
If this Punctal plug is used for active agent delivery is arrived nasolacrimal duct, then this Punctal plug can not have eckband, makes they to be inserted into one or two dacryocanalicular abundant degree of depth, thereby activating agent is discharged in the lachrymal sac.In Fig. 1 to 3, described to be used for the example of active agent delivery to the Punctal plug of nasolacrimal duct.
In the numerous Punctal plugs of the present invention each has various features and advantage.For example, some Punctal plug has the main body of the side surface that has first end and second end and extend between these two ends.This side surface preferably has and is essentially circular outer diameter in shape, thereby this main body preferably has columnar shape.The part of the side surface of certain Punctal plug has the external diameter bigger than the external diameter of the remainder of side surface.With reference to figure 2, the enlarged 22 of side surface is with the Punctal plug anchoring or be fixed in the lacrimal ductule.The part of this expansion can be any size or shape, and can be present on any part of side surface, as long as this enlarged is anchored at Punctal plug to small part in the lacrimal ductule.Preferably, this enlarged is at an end of this plug.Easily, this enlarged can take to have the del shape on flat summit, as shown in Figure 1, can have and cut an end flat, circle, or have the taper of the circle of band at one end point as shown in figure 10.The shape that one skilled in the art will appreciate that any extensive change all is possible.
The main body of Punctal plug of the present invention can be taked Any shape and size.Preferably, this main body is long and narrow cylindric.This main body grows up about 0.8 to about 5mm, preferably grows up about 1.2 to about 2.5mm.Main body roomy about 0.2 to about 3, preferred 0.3 to about 1.5mm.
The main body of this plug can integral body or partially transparent or opaque.Randomly, this main body can comprise color or dyestuff, makes easier watching when plug is placed on the lacrimal point place.
The main body of Punctal plug can be made by any suitable biocompatible materials, include but not limited to silicones, silicone compound, resinous copolymeric siloxane thing, the hydrophilic monomer of all like poly hydroxy ethyl acrylates (pHEMA), Polyethylene Glycol, polyvinylpyrrolidone and glycerol, and silicone hydrogel polymer, all like U.S. Patent numbers 5,962,548,6,020,445,6,099,852,6,367,929 and 6, those materials described in 822,016, these patents all are incorporated into this as a reference.Other suitable biocompatible materialses comprise, for example: polyurethane; Polymethyl methacrylate; Poly-(ethylene glycol); Poly-(ethylene oxide); Poly-(propylene glycol); Poly-(vinyl alcohol); Poly-(methacrylate hydroxyethyl ester); Poly-(vinylpyrrolidone) (" PVP "); Polyacrylic acid; Poly-(ethyl oxazoline); Poly-(DMAA); Phospholipid, all like Phosphorylcholine derivants; Poly-sulfobetaines; Acrylate, polysaccharide and carbohydrate, all like hyaluronic acids, dextran, hydroxyethyl-cellulose, hydroxypropyl cellulose, gelling carbohydrate gum, guar gum, Heparan sulfate, chondroitin sulfate, heparin and alginate; The all like gelatins of protein, collagen, albumin and ovalbumin; Polyamino acid; Fluoropolymer polymer, all like politef (" PTFE "), polyvinylidene fluoride (" PVDF ") and special teflon; Polypropylene; Polyethylene; Nylon; And poly ethylene vinyl alcohol (" EVA ").
The surface of plug main body can be applied by whole or part.This coating can provide one or more textures that helps the smoothing preparation that inserts, the mucus adhesive that histocompatibility is provided and help plug is anchored at the lacrimal point place.The example of suitable coating includes but not limited to gelatin, collagen, hemacol, PVP, PEG, heparin, chondroitin sulfate, hyaluronic acid, synthetic or native protein and polysaccharide, the thiol derivative of thiomers, polyacrylic acid and chitosan, polyacrylic acid, carboxymethyl cellulose etc. and combination thereof.
Some embodiment of Punctal plug of the present invention has the main body of being made by flexible material, and this flexible material is complied with the shape of its contact.Randomly, this plug can have by making than the flexible material of the flexible difference of material of main part or the material of complying with very much its contact shape.When the Punctal plug that will have flexible body and poorer flexible eckband was inserted in this lacrimal ductule, this eckband was resisted against the outside of lacrimal point, and the main body of Punctal plug is complied with dacryocanalicular shape.Preferably the reservoir of this Punctal plug links to each other with main body.That is, the reservoir of this Punctal plug preferably except eckband, has constituted the whole of this main body.
In the embodiment that uses one or two flexible body and eckband, this flexible body and flexible eckband are made by following material, and described material includes but not limited to nylon, polyethylene terephthalate (" PET "), polybutylene terephthalate (PBT) (" PBT "), polyethylene, polyurethane, silicones, PTFE, PVDF and polyolefin.The Punctal plug of being made by nylon, PET, PBT, polyethylene, PVDF or polyolefin is usually by making such as but not limited to extruding, injection molding or thermoformed.The Punctal plug of being made by latex, polyurethane, silicones or PTFE utilizes the processing of solution founding to make usually.
Punctal plug of the present invention contains reservoir in main body, and this reservoir contains the material of activating agent.This material can be with the activating agent of being carried by plug plug or multiple actives is compatible and can be in a desired manner, and for example the mode that sheds from this material of dissolving by material or degraded or activating agent is come any material of release bioactive agent.A lot of materials can be used as the material that this contains activating agent, include but not limited to polymeric material, the non-cohesive material of natural formation or synthetic, include but not limited to glass and clay, organic material, inorganic material, include but not limited to porous ceramics, lipid, wax etc. and combination thereof.Preferably, the material that contains activating agent is a polymeric material, wherein arranges, spreads all over distribution or otherwise contain at least a activating agent.This main body is permeable to activating agent preferably, and this reservoir has at least one opening, but by this opening release bioactive agent.
This main body has at first end as shown in Figure 4, second end and the first and second end places of main body as shown in Figure 6 as shown in Figure 5, or the another position on this main body has the one or more openings that are communicated with reservoir.In certain embodiments of the present invention,, this activating agent is discharged in the tear of eyes when the opening surface that is inserted into this Punctal plug in the lacrimal ductule and makes main body one end during to eyes.Alternatively, if this plug has opening at the main body one end place in the face of nasolacrimal duct, then activating agent is discharged in this nasolacrimal duct., activating agent is discharged in the tear and nasolacrimal duct of eyes having among the embodiment of opening at those plug plugs in the face of eyes one end place with at main body other end place in the face of nasolacrimal duct.For those Punctal plugs with eckband, preferably the opening with this Punctal plug is positioned in the eckband, preferably in the central part office of eckband.When being inserted into this Punctal plug in the lacrimal ductule, opening surface is to eyes, and activating agent is discharged in the tear of eyes.
The big I of opening from about 1nm to about 2.5mm, and preferably approximately 0.15mm to about 0.8mm.Replacement can be used a plurality of little openings at a big opening of any one position.
The method that manufacturing is used for Punctal plug of the present invention is known.Usually, wait by injection molding, mold, transfer moudling and make this plug.Preferably, after producing described plug, fill at least a activating agent and contain in the material of activating agent one or both to reservoir.In addition, one or more excipient can be mixed with this activating agent separately or with polymeric material.
According to the selected material that contains activating agent, this activating agent can almost discharge from material immediately, or this activating agent can discharge in required a period of time in a continuous manner.For example, can use the polymeric material that comprises one or more polymer, these polymer are partially soluble in water at least.When in the water environment that such polymeric material is exposed to lacrimal ductule or tear, it preferably will dissolve and release bioactive agent when it dissolves.Usually will be directly proportional with its rate of dissolution by its water-soluble of making one or more polymer of main body.At least the suitable polymers that is partially soluble in water includes but not limited to gather (ethylene glycol); Poly-(ethylene oxide); Poly-(propylene glycol); Poly-(vinyl alcohol); Poly-(methacrylate hydroxyethyl ester); Poly-(vinylpyrrolidone); Polyacrylic acid; Poly-(ethyl oxazoline); Poly-(DMAA); Phospholipid, all like Phosphorylcholine derivants; Poly-sulfobetaines; Polysaccharide and carbohydrate include but not limited to hyaluronic acid, dextran, hydroxyethyl-cellulose, hydroxypropyl cellulose, gelling carbohydrate gum, guar gum, Heparan sulfate, chondroitin sulfate, heparin and alginate; The all like gelatins of protein, collagen, albumin and ovalbumin; And polyamino acid.Polymeric material in this tabulation usually and a kind of or both copolymerization or blend in hydrophobic polymer and the monomer.
As alternative, non-cohesive material includes but not limited to use lipid, wax or inorganic material.Suitable non-cohesive material includes but not limited to lanoline, paraffin, sorbate, lecithin, Vitamin A, D and E, glycerol, sorbate, mannitol, stearate, fatty acid, phylloxanthin, cryptoxanthin, taurine, glutathion etc.
Alternatively, the material that contains activating agent can be that in a single day one or more be exposed to the biodegradable polymer that can partly or entirely carry out chemical degradation when for example being present in the intravital bioactive substance of mammal usually.This biodegradable polymeric material preferably live organic intravital condition under hydrolysis.The biodegradation meeting takes place slowlyer than dissolving, thus this activating agent of slower if desired or more lasting release ground, and then this material can comprise one or more biodegradable polymer.
Suitable biodegradable polymer includes but not limited to the polymer and the oligomer of glycolipid, lactide, lactone and other hydroxy acid and produces nontoxic or be present in the other biological degradable polymer of intravital material as the homergy thing.Preferred poly-('alpha '-hydroxy acids) is poly-(glycolic), poly-(2-para-dioxane ketone); Poly-(DL-lactic acid) and poly-(L-lactic acid).Other available materials comprise poly-(aminoacid), Merlon, poly-(acid anhydride), poly-(ortho esters), poly-(phosphazine) and poly-(phosphate ester).Including but not limited to gather the polylactone of (6-caprolactone), poly-(δ-Wu Neizhi), poly-(δ-caprolactone) and poly-(gamma-butyrolacton), also is useful as chitosan, alginate, collagen and gelatin for example.The present invention specific aspect, the polymeric material that contains activating agent can be made of the mixture of one or more dissolubilities and Biodegradable polymer.
In a preferred embodiment, the material that contains activating agent is to mix with the polymeric material of at least a activating agent to form the polymeric material of one or more fibers or filamentary structure, its size is exactly the size of reservoir or littler than the size of reservoir basically, and one or more fibers or filamentary structure are inserted in this reservoir by the opening on the plug main body.The size of this fiber or filamentary structure and shape are suitable for being inserted in the opening, and length is about 0.5 to about 5mm, and diameter is about 0.05 to about 2mm.If use a kind of fiber or filamentary structure, preferably, the size of this fiber is such, makes that this fiber is coupled in this reservoir securely, and is retained in this reservoir when this plug is used for wearer's lacrimal point place.Like this, according to the shape of reservoir, this fiber can be symmetric or asymmetric.The inwall of this reservoir is slickly can comprise that maybe help maintains feature in the reservoir with fiber basically, includes but not limited to have groove on inwall, the surface of impression, coarse or analog.
Alternatively, can form the fiber that contains a kind of activating agent or multiple actives, and this plug is cast around fiber.As another alternative, when melting and allowing to solidify, fiber and activating agent can be put into quantitatively the reservoir of plug.As another alternative, polymer and activating agent can be used as solution and are introduced into.This solution can contain and is suitable for carrying out crosslinked and the monomer that produces, prepolymer etc. through one or more radiation, oxidoreduction and heat radiation polymerization.As another alternative, in inserting plug before or after, only fiber is immersed in the activating agent.
Preferred fiber or filamentary structure are made of polymeric material, and more preferably polymeric material is a polycaprolactone, and more excellent is poly-(6-caprolactone) and the polyethylene vinyl acetate base ester of molecular weight between about 1,000 and 80,000.Based on the gross weight of polymeric material, use about 0 to the polycaprolactone of about 100 percentage by weights and about 100 polyethylene vinyl acetate base esters, and preferably to about 0 percentage by weight, use polycaprolactone and polyethylene vinyl acetate base ester each 50%.The preferred purity of used polymeric material is greater than about 99%, and the preferred purity of activating agent is greater than about 97%.Those of ordinary skills will appreciate that in mixing, can not degrade in this process to guarantee activating agent in the feature of carrying out needing under the blended condition to consider activating agent.Polycaprolactone and polyethylene vinyl acetate base ester are preferably mixed with required a kind of activating agent or multiple actives, and little mixing then is squeezed into fiber.Then this fiber is cut into required length and be inserted in the reservoir by one or more plug openings.
In the plug of the present invention the amount of used activating agent will depend on required a kind of activating agent or multiple actives, the required dosage carried through Punctal plug, required rate of release and activating agent and contain the fusing point of activating agent material.Preferably, used amount is a therapeutically effective amount, this means the effective dose that can realize required treatment, inhibition or preventive effect.Usually, use about 0.05 amount to about 8,000 microgram activating agents.
Of the present invention aspect some, after all materials that contain activating agent had basically dissolved or degraded and discharged this activating agent, Available Material was filled this reservoir once more.For example, the new activating agent that contains material can be with polymeric material be identical or different the preceding, and can contain at least a and the identical or different activating agent of pro-activating agent.Some Punctal plug that is used for application-specific is when Punctal plug still inserts in the lacrimal ductule, can preferably fill once more with material, and other Punctal plug is removed from lacrimal ductule usually, adds new material, and then Punctal plug is inserted in the lacrimal ductule again.
When the material that contains activating agent mixed with activating agent, this material also can contain water insoluble and be not biodegradable one or more materials, but activating agent can shed from this material.For example, if this material is a polymeric material, then this material is can be by one or more water insoluble and be that nonbiodegradable polymer constitutes.The suitable polymeric material of this type comprises, for example crosslinked polymer, all like crosslinked poly-(ethylene glycol), poly-(ethylene oxide); Poly-(propylene glycol); Poly-(vinyl alcohol); Poly-(methacrylate hydroxyethyl ester); Poly-(vinylpyrrolidone); Polyacrylic acid; Poly-(ethyl oxazoline); Poly-(DMAA).These polymer can or mix with hydrophobic polymer, monomer or both copolymerization.In addition water insoluble and be that not biodegradable polymer includes but not limited to silicones, silicones blend; The resinous copolymeric siloxane thing includes but not limited to, the hydrophilic monomer of pHEMA, Polyethylene Glycol, polyvinylpyrrolidone and glycerol; And the silicone hydrogel polymer, all like U.S. Patent numbers 5,962,548,6,020,445,6,099,852,6,367,929 and 6,822, those materials described in 016, these patents all are incorporated into this as a reference; Phospholipid includes but not limited to phosphoryl choline derivative; Poly-sulfobetaines; Polysaccharide and carbohydrate include but not limited to hyaluronic acid, dextran, hydroxyethyl-cellulose, hydroxypropyl cellulose, gelling carbohydrate gum, guar gum, Heparan sulfate, chondroitin sulfate heparin and alginate; Protein includes but not limited to gelatin, collagen, albumin and ovalbumin; Poly-amino acid; Fluoropolymer polymer includes but not limited to PTFE, PVDF and special teflon; Polypropylene; Polyethylene; Nylon; And EVA.Other example water insoluble or not biodegradable or that satisfy both suitable polymers includes but not limited to silicones, polyurethane, cyanoacrylate and polyacrylic acid.
Punctal plug described herein can be used for for one or more treatments, inhibition or prevents a lot of diseases and uncomfortable carry various activating agents.Every kind of Punctal plug can be used for carrying at least a activating agent and can be used for carrying dissimilar activating agents.For example, Punctal plug can be used for carrying be used for the treatment of, the hydrochloric acid nitrogen of inhibition and Polyglucan
Si Ting, emedastine two fumarates, epinastine hydrochloride, ketotifen fumarate, hydrochloric acid levocabastine, Olopatadine hydrochloride, pheniramine and antazoline phosphate.This Punctal plug can be used for carrying mast cell stabilizers, and all like sodium cromoglicate, U-42585E, Buddhist nun examine meter sodium and permirolast potassium more.
After filling this plug with activating agent, utilize the method for any routine that this is filled in the row sterilization, these methods include but not limited to, oxirane, autoclaving, radiation etc. and combination thereof.Preferably, carry out disinfection by gamma ray or use oxirane.
This Punctal plug can be used for carrying iridodilator and cycloplegic, all like phenylephrine alkali, atropine sulfate, melyltropeine, scopolamine HBr, cyclopentolate hydrochloric acid, tropicamide and phenylephrine hydrochloride.This Punctal plug can be used for carrying the ophthalmology dyestuff, all like but be not limited to that tiger red (rose begal), sissamine are green, indocyanine green, calcein and fluorescein.
This Punctal plug can be used for carrying corticosteroid, includes but not limited to dexamethasone sodium phosphate, dexamethasone, fluorometholone, fluorometholone acetate, loteprednol etabonate, Inflamase, medroxyprogesterone, rimexolone and fluorometholone ketal.This Punctal plug can be used for carrying the on-steroidal antiinflammatory, includes but not limited to flurbiprofen sodium, suprofen, diclofenac sodium, ketorolac tromethamine, cyclosporin A, rapamycin methotrexate, azathioprine and bromocriptine.
This Punctal plug can be used for carrying anti-infectious preparation, includes but not limited to tobramycin; Moxifloxacin; ofloxacin; Gatifloxacin; ciprofloxacin; gentamicin; the sulfisoxazolone diethanolamine; sulfacetamide sodium; vancomycin; polymyxin B; amikacin; norfloxacin succinil; levofloxacin; sulfisoxazole diolamine; the sulfacetamide sodium tetracycline; doxycycline; dicloxacillin sodium; cephalexine; amoxicillin/clavulanate; ceftriaxone; Cefspan; erythromycin; ofloxacin; azithromycin; gentamicin; sulfadiazine and ethamine pyridine pyridine.
This Punctal plug can be used for conveying and is suitable for the glaucomatous preparation of one or more treatments, inhibition and prevention, includes but not limited to epinephrine, comprises picture: dipivalyl epinephrine, and alpha-2 adrenergic receptor comprises picture apraclonidine and brimonidine; Beta-blocker comprises picture betaxolol, carteolol, levobunolol, metipranolol and timolol; Directly miotic comprises as ear and pilocarpine in many; Acetylcholinesteraseinhibitors inhibitors comprises picture physostigmine and echothiophate; Carbonic anhydrase inhibitors comprises the picture acetazolamide, brinzolamide, dorzolamide and methazolamide; Prostaglandin and prostamides comprise picture latanoprost, bimatoprost, uravoprost and Unoprostone cidofovir.
This Punctal plug can be used for carrying anti-virus formulation, includes but not limited to Fomivirsen sodium, foscarnet sodium, Ganciclovir Sodium, valganciclovir hydrochloride, trifluorothymidine, acyclovir and famciclovir.This Punctal plug can be used for carrying local anesthetic, includes but not limited to tetracaine hydrochloride, proxymetacaine hydrochloride, proxymetacaine hydrochloride and fluorescein sodium, oxybuprocaine and fluorescein sodium (benoxinate and fluorescein sodium), oxybuprocaine and fluorexon disodium (benoxnate and fluorexon disodium).This Punctal plug can be used for carrying antifungal preparation, for example comprises fluconazol, flucytosine, amphotericin B, itraconazole and ketocaonazole.
This Punctal plug can be used for carrying analgesic, includes but not limited to acetaminophen and codeine, acetaminophen and hydrocodone, acetaminophen, ketorolac tromethamine, ibuprofen aluminum and tramadol.This Punctal plug can be used for delivery of vascular and shrinks medicine, includes but not limited to ephedrine hydrochloride, naphcon, hydrochloride phenylephrine, tetrahydrozoline hydrochloride and oxymetazoline.This Punctal plug can be used for carrying vitamin, antioxidant and dietetic product at last, includes but not limited to Vitamin A, D and E, phylloxanthin, taurine, glutathion, zeaxanthin, fatty acid etc.
The activating agent that this Punctal plug is carried can be mixed with and contain excipient, include but not limited to synthetic and natural polymer, for example comprise polysaccharide and glue, phospholipid and the propyl group pyridine of polyvinyl alcohol, Polyethylene Glycol, PAA (polyacrylic acid), hydroxy methocel, glycerol, hypromellose, polyvinylpyrrolidone, card ripple Bo Er, propylene glycol, hydroxypropyl guar, glucam-20, hydroxypropyl cellulose, Sorbitol, glucose, polysorbate, mannitol, glucosan, improvement.
By considering following non-limiting examples, it is more clear that the present invention will become.
Embodiment
Embodiment 1
By GPC (can obtain) having of 1.50g amount is similar to 14,000 average M from Aldrich (Aldrich)
WWith the average M that is similar to 10,000
nε-polycaprolactone and each purity greater than the EVA (EVATANE of about 97% 1.50g
TM, Arkema) and the bimatoprost of 1.00g (cayman Chemical) mix.The model that then this mixture is placed on from DACA industrial group is in the Double helix micro-mixer of No.20000, and this blender is equipped with the die head of 0.25mm and mixed 15 minutes down 120rpm and 67 ℃.After the mixing, this mixture is expressed in the fiber at 75 ℃.
This fiber is cut into the long part of 1.5mm and inserts can be from the Sharpoint ULTRA of Surgical Specialties acquisition
TMIn the opening of plug, make long 70 plugs of every 0.6mm, and make long 70 plugs of every 0.8mm with medicine and 50 kinds of placebo with medicine and 30 kinds of placebo.In order to insert fiber, under stereoscopic microscope, each plug is located and with tweezers fiber is inserted into the opening of each plug.Then be placed on each plug in the vial and be wrapped in the bag.Then carry out the sterilization of gamma ray with about 0.2Kgy/min with accumulated dose 15Kgy.
The plug length of making according to the method for embodiment 1 is that the 0.6mm and the fiber that will have the approximate 0.2mm of diameter and contain 25%w/w are placed on and have in the vial of 1cc of normal saline that the band pH value is 7.4 phosphate-buffered.This bottle be placed in 37 ℃ the couveuse and shake gently.Then with 3,8 and 24 hours interval collect the liquid of 1cc weekly at interval and analyze medicament contg through HPLC.Figure 11 is a diagram of having described analysis result.
Embodiment 3
The plug length of making according to the method for embodiment 1 is 0.9mm and will has the approximate 0.6mm of diameter and contain 25% fiber and be placed on and have in the vial of 1cc of normal saline that the band pH value is 7.4 phosphate-buffered.This bottle be placed in 37 ℃ the couveuse and shake gently.Setting the interval with embodiment 2 collects the liquid of 1cc and analyzes medicament contg through HPLC.Figure 12 is a diagram of having described analysis result.
Claims (25)
1, a kind of Punctal plug comprises:
The main body of the side surface that has first end, second end and between two ends, extend;
Be included in main intravital reservoir, wherein said reservoir comprises at least one opening, and contains the material that contains activating agent that comprises at least a activating agent; And
Wherein said main body is impermeable to this activating agent.
2, a kind of Punctal plug comprises:
The main body of the side surface that has first end, second end and between two ends, extend;
Be included in main intravital reservoir, wherein said reservoir comprises opening at first end, second end or the place, first and second two ends of main body, and contains the material that contains activating agent that comprises at least a activating agent; And
Wherein said main body is impermeable to this activating agent.
3, Punctal plug as claimed in claim 1, wherein the side surface of main body has shape and is essentially circular outer diameter, and the part of side surface has the bigger external diameter of external diameter than the remainder of side surface.
4, Punctal plug as claimed in claim 2, wherein the side surface of main body has shape and is essentially circular outer diameter, and the part of side surface has the bigger external diameter of external diameter than the remainder of side surface.
5, as claim 1,2,3 or 4 Punctal plug, the wherein said material that contains activating agent is that part is water miscible at least, dissolving in time, and when it dissolves, discharge described activating agent by the opening on the reservoir.
6, as claim 1,2,3 or 4 Punctal plug, the wherein said material that contains activating agent is biodegradable, degraded in time, and when it is degraded, discharge this activating agent by opening.
7, as claim 1,2,3 or 4 Punctal plug, the wherein said material that contains activating agent is water insoluble and is nonbiodegradable, and activating agent diffuses out from described material passively by the opening on the reservoir.
8, as the Punctal plug of claim 3 or 4, wherein when inserting Punctal plug in the lacrimal ductule, external diameter is fixed on Punctal plug in the lacrimal ductule greater than that part of of side surface of the external diameter of the remainder of side surface.
9, as claim 1,2,3 or 4 Punctal plug, wherein when in the lacrimal ductule that Punctal plug is inserted into eyes, the opening surface on the reservoir is to eyes and activating agent is discharged in the tear of eyes.
10, as claim 1,2,3 or 4 Punctal plug, wherein when in the lacrimal ductule that Punctal plug is inserted into eyes, the opening surface on the reservoir is discharged in the nasolacrimal duct to nasolacrimal duct and with activating agent.
11, as claim 1,2,3 or 4 Punctal plug, wherein when in the lacrimal ductule that Punctal plug is inserted into eyes, an opening surface on the reservoir is to eyes and activating agent is discharged in the tear of eyes, and another opening surface is discharged in the nasolacrimal duct to nasolacrimal duct and with activating agent on the reservoir.
12, a kind of be used for active agent delivery comprises to the tear of eyes and the Punctal plug of nasolacrimal duct:
By the main body that flexible polymer material constitutes, when being inserted into this Punctal plug in the lacrimal ductule, this flexible polymer material is complied with dacryocanalicular shape;
Be included in main intravital reservoir, wherein said reservoir comprises at least one opening, and contains the material that contains activating agent that comprises at least a activating agent, and this main body is impermeable to this activating agent; And
Eckband, when being inserted into Punctal plug in the lacrimal ductule, this eckband is resisted against the outside of Punctal plug.
13, as the Punctal plug of claim 12, the material that wherein contains activating agent is partially soluble in water at least, dissolving in time, and when it dissolves, discharge described activating agent by the opening on the reservoir.
14, as the Punctal plug of claim 13, wherein fill described reservoir with the activating agent material that contains that comprises at least a activating agent, described activating agent is identical or different with the pro-activating agent after all contain the material dissolves of activating agent the preceding substantially.
15, as the Punctal plug of claim 19, the wherein said material that contains activating agent is biodegradable, degraded in time, and when it is degraded, discharge described activating agent by the opening on the reservoir.
16, as the Punctal plug of claim 13, wherein fill described reservoir with the activating agent material that contains that comprises at least a activating agent, described activating agent is identical or different with the pro-activating agent after all contain the material dissolves of activating agent the preceding substantially.
17, as the Punctal plug of claim 12, the wherein said material that contains activating agent is water-fast and is not biodegradable, and activating agent diffuses out from material passively by the opening on the reservoir.
18, as the Punctal plug of claim 12, wherein said reservoir links to each other with main body.
19, as the Punctal plug of claim 12, wherein when being inserted into this Punctal plug in the lacrimal ductule, the opening surface on the reservoir is to eyes and activating agent is discharged in the tear of eyes.
20, as the Punctal plug of claim 12, wherein when being inserted into this Punctal plug in the lacrimal ductule, the opening surface on the reservoir is discharged in the nasolacrimal duct to nasolacrimal duct and with activating agent.
21, as the Punctal plug of claim 12, wherein when being inserted into this Punctal plug in the lacrimal ductule, an opening surface on the reservoir is to eyes and activating agent is discharged in the tear of eyes, and another opening surface on the reservoir is discharged in the nasolacrimal duct to nasolacrimal duct and with activating agent.
22, a kind of Punctal plug comprises:
The main body of the side surface that has first end, second end and between two ends, extend;
Be included in main intravital reservoir, wherein said reservoir comprises at least one opening, and contain have fibre structure or filamentary structure comprise at least a activating agent contain the activating agent material; And
Wherein said main body is impermeable to activating agent.
23, as the Punctal plug of claim 22, wherein the side surface of main body has shape and is essentially circular outer diameter, and the part of side surface has the bigger external diameter of external diameter than the remainder of side surface.
24, as the Punctal plug of claim 22, wherein said reservoir contains and comprises the fiber that about 0 polycaprolactone and about 100 that arrives about 100 percentage by weights arrives the ethene-vinyl acetate base ester of about 0 percentage by weight.
25, as the Punctal plug of claim 22, wherein said reservoir contains the fiber of the ethene-vinyl acetate base ester of the polycaprolactone that comprises about 50 percentage by weights and about 50 percentage by weights.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200710129269XA CN101327356A (en) | 2007-06-21 | 2007-06-21 | Dacryon plug for conveying promoting agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200710129269XA CN101327356A (en) | 2007-06-21 | 2007-06-21 | Dacryon plug for conveying promoting agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101327356A true CN101327356A (en) | 2008-12-24 |
Family
ID=40203505
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA200710129269XA Pending CN101327356A (en) | 2007-06-21 | 2007-06-21 | Dacryon plug for conveying promoting agent |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101327356A (en) |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102378619A (en) * | 2009-03-31 | 2012-03-14 | 庄臣及庄臣视力保护公司 | Methods and apparatus for dispensing medicaments into a punctal plug |
| CN102448411A (en) * | 2009-03-31 | 2012-05-09 | 庄臣及庄臣视力保护公司 | Punctal plugs |
| CN103209664A (en) * | 2010-08-05 | 2013-07-17 | 弗赛特影像4股份有限公司 | Implantable therapeutic device |
| CN104306103A (en) * | 2009-01-23 | 2015-01-28 | Qlt股份有限公司 | Sustained released delivery of one or more agents |
| US9417238B2 (en) | 2009-01-29 | 2016-08-16 | Forsight Vision4, Inc. | Posterior segment drug delivery |
| US9474756B2 (en) | 2014-08-08 | 2016-10-25 | Forsight Vision4, Inc. | Stable and soluble formulations of receptor tyrosine kinase inhibitors, and methods of preparation thereof |
| US9526654B2 (en) | 2013-03-28 | 2016-12-27 | Forsight Vision4, Inc. | Ophthalmic implant for delivering therapeutic substances |
| US9968603B2 (en) | 2013-03-14 | 2018-05-15 | Forsight Vision4, Inc. | Systems for sustained intraocular delivery of low solubility compounds from a port delivery system implant |
| US10166142B2 (en) | 2010-01-29 | 2019-01-01 | Forsight Vision4, Inc. | Small molecule delivery with implantable therapeutic device |
| US10813788B2 (en) | 2009-01-29 | 2020-10-27 | Forsight Vision4, Inc. | Implantable therapeutic device |
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| CN104306103A (en) * | 2009-01-23 | 2015-01-28 | Qlt股份有限公司 | Sustained released delivery of one or more agents |
| CN104306103B (en) * | 2009-01-23 | 2017-04-19 | 马缇医疗股份有限公司 | Sustained released delivery of one or more agents |
| US9417238B2 (en) | 2009-01-29 | 2016-08-16 | Forsight Vision4, Inc. | Posterior segment drug delivery |
| US9851351B2 (en) | 2009-01-29 | 2017-12-26 | Forsight Vision4, Inc. | Posterior segment drug delivery |
| US10813788B2 (en) | 2009-01-29 | 2020-10-27 | Forsight Vision4, Inc. | Implantable therapeutic device |
| US10656152B2 (en) | 2009-01-29 | 2020-05-19 | Forsight Vision4, Inc. | Posterior segment drug delivery |
| US11642310B2 (en) | 2009-01-29 | 2023-05-09 | Forsight Vision4, Inc. | Posterior segment drug delivery |
| CN102378619A (en) * | 2009-03-31 | 2012-03-14 | 庄臣及庄臣视力保护公司 | Methods and apparatus for dispensing medicaments into a punctal plug |
| CN102448411A (en) * | 2009-03-31 | 2012-05-09 | 庄臣及庄臣视力保护公司 | Punctal plugs |
| US10166142B2 (en) | 2010-01-29 | 2019-01-01 | Forsight Vision4, Inc. | Small molecule delivery with implantable therapeutic device |
| CN103209664A (en) * | 2010-08-05 | 2013-07-17 | 弗赛特影像4股份有限公司 | Implantable therapeutic device |
| US9492315B2 (en) | 2010-08-05 | 2016-11-15 | Forsight Vision4, Inc. | Implantable therapeutic device |
| US11065151B2 (en) | 2010-11-19 | 2021-07-20 | Forsight Vision4, Inc. | Therapeutic agent formulations for implanted devices |
| US10874548B2 (en) | 2010-11-19 | 2020-12-29 | Forsight Vision4, Inc. | Therapeutic agent formulations for implanted devices |
| US9968603B2 (en) | 2013-03-14 | 2018-05-15 | Forsight Vision4, Inc. | Systems for sustained intraocular delivery of low solubility compounds from a port delivery system implant |
| US9526654B2 (en) | 2013-03-28 | 2016-12-27 | Forsight Vision4, Inc. | Ophthalmic implant for delivering therapeutic substances |
| US11510810B2 (en) | 2013-03-28 | 2022-11-29 | Forsight Vision4, Inc. | Ophthalmic implant for delivering therapeutic substances |
| US10398593B2 (en) | 2013-03-28 | 2019-09-03 | Forsight Vision4, Inc. | Ophthalmic implant for delivering therapeutic substances |
| US9474756B2 (en) | 2014-08-08 | 2016-10-25 | Forsight Vision4, Inc. | Stable and soluble formulations of receptor tyrosine kinase inhibitors, and methods of preparation thereof |
| US10765677B2 (en) | 2014-08-08 | 2020-09-08 | Forsight Vision4, Inc. | Stable and soluble formulations of receptor tyrosine kinase inhibitors, and methods of preparation thereof |
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| US9895369B2 (en) | 2014-08-08 | 2018-02-20 | Forsight Vision4, Inc | Stable and soluble formulations of receptor tyrosine kinase inhibitors, and methods of preparation thereof |
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Open date: 20081224 |