CN101505681B

CN101505681B - Nasolacrimal drainage system implants for drug therapy

Info

Publication number: CN101505681B
Application number: CN2007800171766A
Authority: CN
Inventors: 小尤金·德朱昂; 斯蒂芬·博伊德; 卡里·赖希; 艾伦·拉帕茨基; 汉森·S·吉福德; 马克·迪姆
Original assignee: QLT Plug Delivery Inc
Current assignee: Mati Therapeutics Inc
Priority date: 2006-03-31
Filing date: 2007-04-02
Publication date: 2013-09-04
Anticipated expiration: 2027-04-02
Also published as: CN101505683A; CN101505683B; CN101505681A

Abstract

Implant devices, systems and methods for insertion into a punctum of a patient optionally comprises a drug core and a sheath body disposed over the drug core. The drug core includes a therapeutic agent deliverable into the eye, and the sheath defines at least one exposed surface of the drug core. The exposed surface(s) of the drug core may contact a tear or tear film fluid and release the therapeutic agent at therapeutic levels over a sustained period when the implant is implanted for use. The implant may include a retention element to retain the drug core and sheath body near the punctum, optionally comprising a shape memory alloy that can resiliently expand. An occlusive element may be attached to the retention element to at least partially occlude tear flow through the canalicular lumen.

Description

The nose tear drainage system implants that is used for Drug therapy

Cross reference to related application

The application requires the U.S. Provisional Application No.60/787 that submits on March 31st, 2006 according to 35USC119 (e), and 775 and the U.S. Provisional Application No.60/871 that submitted in 26th in December in 2006,864 rights and interests, it all openly is incorporated herein by reference.

Technical field

The application relates to for the implant in nose tear drainage system or its periphery use, the tear stains plug that lacrimal ductule implant, lachrymal sac implant, tear stains plug specifically is provided and has the administration ability.

Background technology

In the dosing eyes field, patient and doctor are faced with various challenges.Specifically, the repeatability for the treatment of (carry out multiple injection every day, repeatedly eye drop scheme instils), relevant cost and the shortage of patient's compliance may significantly impact possible therapeutic effect, cause visual deterioration, many times can cause losing one's sight.

Accept Drug therapy, when for example instiling eye drop, patient's compliance potentially unstable, in some cases, the patient may not follow the therapeutic scheme of guidance.Compliance lacks the use of the excessive use (causing systemic side effects) can comprise the failure of instillation drop, invalid operation (instiling less than aequum), drop and OTC (over-the-counter) drop or does not follow the therapeutic scheme that requires multiple drop.Most Drug therapys may require the patient to instil their every days four times at the most.

Except compliance, the minimum charge of some eye drop Drug therapys increases, and causes some patients to face with limited income and buys still complete selection of making up a prescription according to their prescription of elementary necessaries.Insurance does not many times cover the full payment of the eye drop Drug therapy of leaving, and perhaps eye drop comprises multiple different Drug therapy under some situation.

Further, under many circumstances, the topical application Drug therapy reached eye effect peak value in about 2 hours, after this should carry out extra Drug therapy and use to keep therapeutic effect.And the discordance in the therapeutic scheme of self-medication or picked-up may cause the treatment of suboptimum.The open WO06/014434 (Lazer) of PCT may be relevant with these and/or the other problem that relate to eye drop, and its full content is incorporated in this by reference.

A kind of method of promising dosing eyes is to place the implant that discharges medicine near eye in the tissue.Though this method can provide some to improve at eye drop, some potential problems of this method may comprise: implant the implantation of required tissue site, implant in a period of time that maintenance and the medicine of required tissue site prolonging with required treatment level slow release.For example, under the situation of glaucoma treatment, fail to pinpoint a disease in diagnosis and the implant premature loss may cause not having medicine and is transferred, the patient may suffer visual deterioration potentially even may lose one's sight.

According to above-mentioned situation, expectation provides a kind of improved administration implant of some above-mentioned shortcoming at least that overcomes.

Summary of the invention

The invention provides improved implant device, system and method for the lacrimal point that is inserted into the patient.In many embodiments, described implant device can remain in the described eye reliably, and said therapeutic agent can be carried in the period that prolongs.

In first scheme, it is a kind of for the implant that is inserted into patient's lacrimal point that embodiments of the present invention provide.Described implant comprises the medicated core with far-end and near-end.The far-end of described medicated core has the cross section that is fit to by the lacrimal point insertion.Described medicated core comprises the therapeutic agent that can be transported in the eye.Arrange that a sheath covers the part of described medicated core, to limit at least one exposed surface of described medicated core.It is neighbouring with contact tear or tear film liquid that described at least one exposed surface of described medicated core can be positioned at described near-end, and continuing to discharge described therapeutic agent in period with treatment level when the implanted use of described implant.

In many embodiments, a kind of maintenance structure is connected described medicated core to be remained near the described lacrimal point and/or in the described lacrimal point with described medicated core.Described maintenance structure can be connected with described medicated core by described sheath.Described maintenance structure can comprise can the adaptability expanded balloon when described maintenance structure is placed in the described lacrimal point.Described maintenance structure can comprise the link with orientation surface.When described hydrogel aquation, the expansion of described hydrogel can keep described hydrogel near described axle orientation surface.Described link comprises outthrust, flange, edge or keeps at least a in the opening of structure by part.

In many embodiments, described maintenance structure is included in and described surface is remained near the described lacrimal point flange near described at least one exposed surface.Described maintenance structure can have suitable at least part of size that is assemblied in intracavity in the described lacrimal ductule.Described maintenance structure can be anchored in the low profile shape that is suitable for inserting with described maintenance structure between the big contour shape in the described inner chamber and expand.Described maintenance structure can be connected near the described far-end of described medicated core.In the specific embodiment, when described maintenance structure expand into described big contour shape from described low profile shape, described maintenance structure can be slided near described near-end along described medicated core.The length along the described maintenance structure of described medicated core when described big contour shape can be shorter than when described low profile shape along the length of the described maintenance structure of described medicated core.

In some embodiments, but the elastic expansion of described maintenance structure.Described low profile shape can have the cross section of about 0.2mm at the most, and described big contour shape can have the cross section of about 2.0mm at the most.Described maintenance structure can comprise the tubular body with the arm that is separated by groove.Inaccessible unit can be installed on the described maintenance structure, and can expand to suppress tear stream along with described maintenance structure.Described maintenance structure can be arranged to the described medicated core of at least part of covering.Inaccessible unit can suppress tear stream and pass described inner chamber, and at least a portion that described inaccessible unit can cover described maintenance structure is not subjected to described maintenance structure influence to protect described inner chamber.

In many embodiments, described sheath body can comprise the layer that is arranged on the described medicated core, discharges by described layer to suppress described therapeutic agent.Described medicated core can discharge therapeutic agent by described exposed surface.When making described surface be exposed to tear or tear film liquid described implant implantation, described medicated core can discharge described therapeutic agent with treatment level in the period at least 1 week.Described medicated core can comprise the inclusion body of described preparation, and described preparation is dissolved in the medicated core, thereby when medicated core is implanted, provides basic rate of release uniformly.

In some embodiments, inaccessible unit can suppress tear stream and wears described lacrimal ductule inner chamber.For example, described inaccessible unit can be shaped as and suppress the shape that tear stream passes described lacrimal ductule inner chamber.

In many embodiments, provide a kind of implant for the lacrimal point that is inserted into the patient.Described implant comprises therapeutic agent and is used for keeping the material of described therapeutic agent.Arrange at least a portion of described material to keep structure that described maintenance structure can outwards expand described material to be remained near the described lacrimal point from described material.

In many embodiments, described material remains on therapeutic agent at least a in storage or the substrate.Inaccessible unit can be by described maintenance support structure.Described maintenance structure can be anchored in the low profile shape that is suitable for inserting with described maintenance structure between the big contour shape in the described inner chamber and expand.Described inaccessible unit can expand with described maintenance structure.

In another program, embodiments of the present invention provide a kind of method with therapeutic agent treatment eye.Described method comprises the maintenance structure of implant and the far-end of medicated core is inserted in the lacrimal point.Delivering therapeutic agents from described medicated core to eye.The exposed surface of described medicated core is positioned at the near-end of the described medicated core with sheath.Described exposed surface can contact with tear or tear film liquid, and in the time of when described medicated core remains on lacrimal point by the maintenance structure near, described therapeutic agent moved to the described eye from described exposed surface in lasting period.

In many embodiments, provide a kind of method with therapeutic agent treatment eye.Described method comprises the far-end that keeps structure and medicated core inserted wears lacrimal point, and said medicated core is maintained near the described lacrimal point.Described medicated core comprises the therapeutic agent that can be transported in the eye, and wherein, the exposed surface of medicated core is positioned near the near-end of described medicated core.Described exposed surface contacts with described tear or tear film liquid.In the time of near described medicated core is maintained at described lacrimal point, described therapeutic agent continues to transfer to the eye from described exposed surface in period one.

In many embodiments, described maintenance structure expand into wide contour shape from the narrow profile shape.Described maintenance structure is being inserted aquation when wearing described lacrimal point, to expand into wide contour shape from the narrow profile shape.

In many embodiments, a kind of method with therapeutic agent treatment eye is provided, described method comprises the maintenance structure is inserted in the lacrimal ductule inner chamber by lacrimal point, so with described maintenance structure medicated core is anchored in the described inner chamber, and the therapeutic agent that discharges effective dose is in the tear or tear film liquid of eye.When described maintenance structure keeps being anchored in the described inner chamber, remove described medicated core from described maintenance structure.When described maintenance structure keeps being anchored in the described inner chamber, will replace medicated core and be attached on the described maintenance structure.At least one exposed surface of described replacement medicated core discharges described therapeutic agent with treatment level certain continuing in period.

In many embodiments, provide a kind of method that is used for the treatment of eye.Described method comprises that the far-end with implant is inserted in the lacrimal point.The maintenance structure of the described implant that expands is to suppress the discharge of described implant.The expansion of described implant helps inaccessible tear stream to pass described lacrimal point.Delivering therapeutic agents from the near-end of described implant near the tear the described eye.Suppressing the described therapeutic agent in distally of described near-end carries.

In many embodiments, described therapeutic agent suppresses to the sheath that the conveying in the described tear is had the part that is exposed to tear.In the specific embodiment, described maintenance structure can comprise super-elasticity or marmem.Described maintenance structure comprises hydrogel and expands in the distally of described medicated core.

In another program, numerous embodiments of the present invention provides a kind of implant that is used for the treatment of eye.Described eye comprises tear and lacrimal point.Described implant comprise have near-end, far-end and be suitable for being inserted into the medicated core of the cross section in the lacrimal point.Sheath is configured on the described medicated core in distally of described near-end.Swellable material is configured in the distally of described near-end.Described swellable material is adapted at being inserted in the described lacrimal point back swelling keeping described medicated core, and inaccessible tear are communicated with the fluid of described medicated core.

In many embodiments, near the sheath the described near-end of described medicated core connects the wing.The size of adjusting the described wing makes it can remain on described lacrimal point outside the described near-end of described medicated core is remained near the described lacrimal point.

In many embodiments, provide a kind of implant that is used for the treatment of eye.Described eye has tear and lacrimal point.Described implant comprise have near-end, far-end and be suitable for being inserted into the medicated core of the cross section in the lacrimal point.Distally at described at least medicated core near-end disposes sleeve pipe.Swellable material is configured in the distally of described near-end and at least part of by described sleeve covers.Described swellable material is suitable in being inserted into described lacrimal point the back swelling keeping described medicated core, and inaccessible tear are communicated with the fluid of described medicated core.

In many embodiments, described sleeve pipe comprises the short and small outthrust that keeps described tear stains plug when the expansion of described swellable material.

In many embodiments, provide a kind of tear stains plug that is used for the treatment of eye.Described eye comprises tear and lacrimal point.Described plug comprises the medicated core in cock body and the described cock body.Described medicated core comprises the mixture of therapeutic agent and substrate.The surface of described core is exposed to described tear to treat described eye.

In the specific embodiment, when described plug is inserted in the lacrimal point of described eye, but described medicated core elastic expansion is to hold insertion spicule wherein.

In many embodiments, provide a kind of tear stains plug that is used for the treatment of eyes.Described eye has tear and lacrimal point.When described plug comprises in being configured in described eye, the expandable holding unit that expands and engage with described lacrimal point.Main body is connected with described expandable holding unit and comprises for the protuberance of removing described holding unit from described lacrimal point.

In many embodiments, described expandable holding unit comprises swellable material, and described main body is suitable for keeping described swellable material when described main body is removed.In the specific embodiment, described swellable material can comprise hydrogel.

Description of drawings

Fig. 1-1 and Fig. 1-2 represent according to embodiment of the present invention be suitable for use implant the eye anatomical tissue structure;

Figure 1A is the vertical view cutaway drawing of the expression slow release implant that is used for the treatment of the optics of the eye defective according to an embodiment of the present invention;

Figure 1B is the side view cutaway drawing of the slow release implant of expression Figure 1A;

Fig. 1 C is the perspective view of the expression slow release implant with coil maintenance structure according to an embodiment of the present invention;

Fig. 1 D is the perspective view of the expression slow release implant with the maintenance structure that comprises pillar according to an embodiment of the present invention;

Fig. 1 E is the perspective view of the expression slow release implant with cage shape maintenance structure according to an embodiment of the present invention;

Fig. 1 F is the perspective view of the expression slow release implant that comprises core and sheath according to an embodiment of the present invention;

Fig. 1 G has schematically illustrated the current limliting that comprises according to an embodiment of the present invention and has kept the slow release implant of structure, core and sheath;

Fig. 2 A is the cutaway view of the slow release implant of the expression core with the exposed surface area that comprises increase according to an embodiment of the present invention;

Fig. 2 B is the cutaway view of the slow release implant of the expression core with the exposed surface area that comprises increase according to an embodiment of the present invention;

Fig. 2 C and Fig. 2 D are for representing perspective view and the cutaway view of the slow release implant with the core that comprises the exposed surface area that reduces according to an embodiment of the present invention respectively;

Fig. 2 E is the cutaway view of the expression slow release implant with core according to an embodiment of the present invention, and this core comprises the exposed surface area of the increase with groove and battlements;

Fig. 2 F is the perspective view of the expression slow release implant that comprises the core with fold according to an embodiment of the present invention;

Fig. 2 G is the perspective view of the expression slow release implant with the core that comprises the passage with the inner surface of porous according to an embodiment of the present invention;

Fig. 2 H comprises that for expression having according to an embodiment of the present invention porous channel is with the perspective view of the slow release implant of the core that increases drug migration;

Fig. 2 I is the perspective view of the slow release implant on expression lobed exposure medicated core surface according to an embodiment of the present invention;

Fig. 2 J is the side view of the expression slow release implant with core according to an embodiment of the present invention, and this core comprises the exposed surface area with a plurality of soft brush sample parts that therefrom stretch out;

Fig. 2 K is the expression side view with the exposed surface that comprises projection and slow release implant of the medicated core that keeps structure according to an embodiment of the present invention;

Fig. 2 L comprises side view for the slow release implant of the medicated core on (concave indented) surface of the recessed indentation of the exposed surface area that increases core for expression having according to an embodiment of the present invention;

Fig. 2 M is the side view of the expression slow release implant with medicated core according to an embodiment of the present invention, and this medicated core comprises the recessed surface that wherein is formed with passage for increasing the exposed surface area of core;

Fig. 3 A is according to an embodiment of the present invention the implant that comprises the sheath body of expression, and described sheath body has sheath body and core are attached to extension on the holding unit;

Fig. 3 B is the expression implant that comprises holding unit according to an embodiment of the present invention, and this holding unit has the extension that keeps sheath body and core;

Fig. 4 A and Fig. 4 B are the cutaway view of the expression implant with maintenance structure that heavy in section contour shape in the longitudinal direction is shorter than the small bore contour shape according to an embodiment of the present invention;

Fig. 5 A represents that plunger that usefulness according to an embodiment of the present invention can be depressed inserts insertion instrument in the lacrimal point with implant;

Fig. 5 B represents that plunger that usefulness according to an embodiment of the present invention can slide is inserted into insertion instrument in the lacrimal point with implant;

Fig. 6 represents that the sheath that near-end shrinks of passing through according to an embodiment of the present invention inserts insertion instrument in the lacrimal point with implant;

Fig. 7 A～Fig. 7 C schematically illustrated according to an embodiment of the present invention medicated core and the replacement of sheath body;

Fig. 8 A～Fig. 8 C represents the configuration of slow release implant according to an embodiment of the present invention;

Fig. 9 A represents the drug-supplying system for the sleeve pipe that keeps medicated core and hydrogel holding unit of having according to embodiment of the present invention;

Fig. 9 B represents the drug-supplying system shown in Fig. 9 A according to the hydrogel holding unit with aquation of embodiment of the present invention;

Fig. 9 C represents the drug-supplying system shown in Fig. 9 A with sleeve pipe according to embodiment of the present invention, and this sleeve pipe comprises the silicone collar of the outside that rests on lacrimal point;

Fig. 9 D represents the sleeve pipe according to the drug-supplying system of embodiment of the present invention, and this sleeve pipe has the flange that help is inserted into the bullet of lacrimal point and is used for resting on the outside of lacrimal point that is used at far-end lacrimal ductule end;

Fig. 9 E represents the sleeve pipe according to the drug-supplying system of embodiment of the present invention, and this sleeve pipe has for the restriction portion that the hydrogel holding unit is remained on sleeve pipe at the far-end lacrimal ductule end of sleeve pipe;

Fig. 9 F represents the drug-supplying system that has the hydrogel holding unit in being inserted into lacrimal ductule inner chamber process according to embodiment of the present invention;

Fig. 9 G represents to be inserted into according to having of embodiment of the present invention the drug-supplying system shown in Fig. 9 F of back expanded balloon holding unit in the lacrimal ductule inner chamber;

Figure 10 A represents the medicated core insert that uses with the tear stains plug according to embodiment of the present invention;

Figure 10 B represents the tear stains plug according to the endoporus that comprises cylindrical shape of embodiment of the present invention;

Figure 10 C represents the tear stains plug shown in Figure 10 B that has wherein inserted the medicated core shown in Figure 10 A according to embodiment of the present invention;

Figure 11 represents to thrust the medicine system according to the tear stains that comprises medicated core and holding device of embodiment of the present invention, and described holding device comprises the sleeve pipe that is formed with the wing thereon;

Figure 12 A represents the maintenance structure according to the sleeve pipe that has short and small outthrust comprising of embodiment of the present invention and hydrogel;

Figure 12 B represents the maintenance structure shown in Figure 12 A according to embodiment of the present invention, and its short and small outthrust is radial because of the aquation of hydrogel material to be stretched out to the outside;

Figure 12 C represents the maintenance structure according to the sleeve pipe that has short and small outthrust comprising of embodiment of the present invention and ring-type hydrogel swelling part;

Figure 12 D represents the maintenance structure shown in Figure 12 C according to the sleeve pipe that has short and small outthrust comprising of embodiment of the present invention and ring-type hydrogel swelling part;

Figure 13 represents the doser that hydrogel keeps structure that has according to embodiment of the present invention, and this hydrogel keeps structure to comprise for the sleeve pipe with crosscut hole and short and small outstanding lock and/or flange that hydrogel is remained on when the expansion of hydrogel the appropriate location;

Figure 14 A represents the tear stains plug with medicated core and maintenance fin according to embodiment of the present invention;

Figure 14 B represents when plug when being inserted into the lacrimal ductule inner chamber, keeps fin to be folded back to keep the lacrimal ductule of filling in shown in Figure 14 A.

The specific embodiment

Fig. 1-1 and Fig. 1-2 represent the anatomical tissue structure of eye 2 that is suitable for using implant treatment according to embodiment of the present invention.Eye 2 comprises cornea 4 and iris 6.Sclera 8 surrounds cornea 4 and sclera 6 and presents white.Conjunctiva layer 9 substantially transparent also are positioned on the sclera 8.Crystalline lens 5 is positioned at ophthalmic.Retina 7 is positioned near the rear portion of eye 2, usually to photaesthesia.Retina 7 comprises provides the fovea centralis of high visual acuity and colour vision 7F.Cornea 4 and crystalline lens 5 refracted lights are to form image at fovea centralis 7F and retina 7.The optical power of cornea 4 and crystalline lens 5 helps to form image at fovea centralis 7F and retina 7.The relative position of cornea 4, crystalline lens 5 and fovea centralis 7F also is important for picture quality.For example, if the eye 2 from cornea 4 to retina 7F axial length greatly then the eye 2 may myopia.In addition, in adjustment process, crystalline lens 5 moves to provide the good near vision of near-eye side object towards cornea 4.

Anatomical tissue structure as Figure 1-1 also comprises the tear system, and described tear system comprises superior canaliculus 10 and lower lacrimal canaliculi 12 (being generically and collectively referred to as lacrimal ductule) and nasolacrimal duct or lachrymal sac 14.Described superior canaliculus and lower lacrimal canaliculi end at lacrimal point 11 and following lacrimal point 13, are also referred to as the tear stains mouth.Described tear stains mouth is positioned at the high slightly position than the terminal central authorities of the margo palpebrae on the connecting portion 15 of near the ciliary part the inner eye corner 17 and tear portion.Described tear stains mouth is be organized that the Colaesce ring surrounds circular or oval opening slightly.Each tear stains

opening

11,13 each dacryocanalicular

vertical component effect

10a, 12a steering horizontal direction with the entrance of lachrymal sac 14 be connected with each dacryocanalicular

vertical component effect

10a, 12a before another lacrimal ductule is connected.Described lacrimal ductule is tubulose and the stratified squamous epithelium that is lined with the Elastic tissue encirclement that is allowed to the lacrimal ductule expansion.

Figure 1A is the vertical view cutaway drawing of expression according to the slow release implant 100 that is used for the treatment of the optics of the eye defective of embodiment of the present invention.Implant 100 comprises medicated core 110.Medicated core 110 is for maintaining the implantable structure of therapeutic agent.Medicated core 110 comprises the substrate 170 that contains therapeutic agent inclusion body 160.Inclusion body 160 generally includes the conc forms of therapeutic agent, for example, the crystal form of therapeutic agent, this therapeutic agent can be dissolved in the substrate 170 of medicated core 110 as time passes.Substrate 170 can comprise silicone substrate etc., and the mixture of the therapeutic agent in the substrate 170 can be for heterogeneous.In a lot of embodiments, described non-homogeneous mixture comprises the body of forgiving of the saturated silicone substrate portion of therapeutic agent and the inclusion body that comprises therapeutic agent, and this non-homogeneous mixture like this comprises heterogeneous non-homogeneous mixture.In some embodiments, inclusion body 160 comprises the oil droplet of therapeutic agent, for example latanoprost oil.In some embodiments, inclusion body 160 can comprise the granule of therapeutic agent, for example the bimatoprost solid particle of crystal form.In a lot of embodiments, substrate 170 encapsulation inclusion bodys 160, inclusion body 160 can comprise the microgranule with about 1 μ m～about 100 μ m sizes.The solubilization of inclusion bodies of this encapsulation is in solid matrix, for example silicone on every side of these microgranules of encapsulation, and substrate 170 is saturated by described therapeutic agent substantially when therapeutic agent discharges from core like this.

Medicated core 110 is surrounded by sheath body 120.120 pairs of therapeutic agents of sheath body are impermeable substantially, so therapeutic agent is never discharged by the surface of the exposure on the end of the medicated core 110 of sheath body 120 coverings usually.Keep structure 130 to be connected with sheath body 120 with medicated core 110.Make to keep structure 130 to be shaped implant is remained in the hollow tissue structure, for example, above-mentioned dacryocanalicular lacrimal point.

Inaccessible unit 140 is configured in and keeps on the structure 130 and surround keeping structure 130.140 pairs of infiltrative and inaccessible these hollow tissue structures of tear stream right and wrong in inaccessible unit can also make organizing of protective tissue structure not be subjected to keep structure 130 to influence by more optimum tissue bond surface is provided.Sheath body 120 comprises the sheath body 150 that is connected to keep sheath body 120 and medicated core 110 with maintenance structure 130.Sheath body 150 can comprise the stop that restriction sheath body 120 and medicated core 110 move.In a lot of embodiments, sheath body 150 can form has spherical top 150B.The dome outside that provides no wound to enter when importing in the lacrimal ductule can be provided bulbous end 150B.In a lot of embodiments, sheath body 150B can form one with inaccessible unit 140.

Figure 1B is the side view cutaway drawing of the slow release implant of expression Figure 1A.Medicated core 110 is for cylindric and show and have circular section.The sheath body comprises the annulus that is disposed on the medicated core 110.Keep structure 130 to comprise a plurality of vertical pillars 131.Vertical pillar 131 links together near the end that keeps structure.Although vertical pillar is shown, also can use circumferential pillar.The vertical pillar 131 that inaccessible unit 140 is held structure 130 supports and is disposed on it, but can comprise the film etc. of expanded radially.

Fig. 1 C is the perspective view of the expression slow release implant 102 with coil maintenance structure 132 according to an embodiment of the present invention.Keep structure 132 to comprise coil and maintenance medicated core 112.For delivering therapeutic agents is applied to nose and whole body with therapeutic agent, for example the inner chamber of passage 112C can extend through medicated core 112 and wear this inner chamber to allow tear stream stream.Except using passage 112C, or use passage 112C by uniting, when holding unit keeps lacrimal ductule tissue away from medicated core, can change keep structure 132 and core 112 size to allow tear mobile around medicated core and sheath body.Medicated core 112 can partly be covered.Described sheath body comprises the first parts 112A that covers medicated core 112 first ends and the second parts 112B that covers medicated core second end.As mentioned above, the inaccessible unit of configuration on the structure can kept, and/or described maintenance structure can be by dip-coating.

Fig. 1 D is the perspective view of the expression slow release implant 104 with the maintenance structure 134 that comprises pillar according to an embodiment of the present invention.Keep structure 134 to comprise vertical pillar and maintenance medicated core 114.The major part of medicated core 114 is covered by sheath body 124.As mentioned above, medicated core discharges therapeutic agent by exposed distal ends, and sheath body 124 ring-types cover most of medicated core.As mentioned above, can keep the inaccessible unit of configuration on the structure, or can the described maintenance structure of dip-coating.Can stretch out from sheath body 124 with the protuberance that for example utensil of hook, circle, stitching thread or ring 124R etc. engages, so that medicated core and sheath body can remove to promote the replacement of sheath body and core together, and keep structure still to stay implanted in the lacrimal ductule simultaneously.In some embodiments, the protuberance that can engage with the utensil that comprises hook, circle, stitching thread or ring can stretch out from keeping structure 134, to keep structure to remove the slow release implant by removing with protuberance, medicated core and sheath body.

Fig. 1 E is the perspective view of the expression slow release implant 106 with cage shape maintenance structure 136 according to an embodiment of the present invention.Keep structure 136 to comprise many strip metals connecting line and maintenance medicated core 116.The major part of medicated core 116 is covered by sheath body 126.As mentioned above, medicated core discharges therapeutic agent by exposed distal ends, and sheath body 126 ring-types cover most of medicated core.As mentioned above, can keep the inaccessible unit of configuration on the structure, or can the described maintenance structure of dip-coating.

Fig. 1 F is the perspective view of the expression slow release implant that comprises core and sheath according to an embodiment of the present invention.The major part of medicated core 118 is covered by sheath body 128.As mentioned above, medicated core discharges therapeutic agent by exposed distal ends, and sheath body 128 ring-types cover most of medicated core.The therapeutic agent rate of release by exposing medicated core surface area and medicated core 118 in the control of material that comprises.In a lot of embodiments, the therapeutic agent dissolution rate is relevant and relevant substantially strongly with the exposed surface area of medicated core, depends on the drug concentrations in the inclusion body that is disposed in the medicated core more weakly.For annular exposed surface, dissolution rate depends on the diameter of exposed surface strongly, for example near the diameter on the exposure medicated core surface the cylindric medicated core end.This implant can be implanted in the part tissue of eye, for example following or scleral tissue's layer 8 of eye conjunctival tissue layer 9 above, shown in Fig. 1 F, or only part in scleral tissue's layer not penetrate scleral tissue.Be to be noted that medicated core 118 can use with any maintenance structure described herein and inaccessible unit.

In one embodiment, the medicated core that does not have a sheath body 128 is implanted between sclera 8 and the conjunctiva 9.Do not have the sheath body in this embodiment, can adjust the physical characteristic of described medicated core with the exposed surface of the increase of compensation medicated core, for example by reducing the concentration of dissolved therapeutic agent in the drug matrices described herein.

Fig. 1 G has schematically illustrated the current limliting that comprises according to an embodiment of the present invention and has kept the slow release implant 180 of structure 186, core 182 and sheath 184.Sheath body 184 can at least part of covering medicated core 182.Medicated core 182 can comprise the inclusion body of the therapeutic agent of the slow release that therapeutic agent is provided therein.Medicated core 182 can comprise exposure convex surface region 182A.Exposing convex surface region 182A can provide the surface area of increase to discharge therapeutic agent.Inaccessible unit 188 can be configured in and keep flowing through lacrimal ductule with blocking-up tear on the structure 186.In a lot of embodiments, keep structure 186 can be positioned at inaccessible structure 188 and form the inaccessible unit of one to provide with keeping structure.Can adjust size that current limliting keeps structure 186 and inaccessible unit 188 blocks tear stream and wears lacrimal ductule.

Core described here and sheath body can be implanted in the multiple tissue by several different methods.A lot of cores and sheath in this explanation carry out, and especially with reference to the structure of Fig. 2 A～Fig. 2 J explanation, can be used as the tear stains plug and implant separately.In addition, a lot of cores described here and sheath body can comprise medicated core, sheath body and/or analog in order to maintenance structure described herein and inaccessible unit with its implantation.

Fig. 2 A is the cutaway view of the slow release implant 200 of the expression core with the exposed surface area that comprises increase according to an embodiment of the present invention.Medicated core 210 is covered by sheath body 220.Sheath body 220 comprises opening 220A.Opening 220 has the diameter approximate with the maximum cross-section diameter of medicated core 210.Medicated core 210 comprises exposed surface 210E (being also referred to as active surface).Exposed surface 210E comprises three surface: annular surface 210A, cylindrical surface 210B and end surfaces 210C.Annular surface 210A has and the approximate external diameter of the maximum cross-section diameter of core 210 and the internal diameter approximate with the external diameter of cylindrical surface 210B.End surfaces 210C has the diameter that the diameter with cylindrical surface 210B is complementary.The surface area of exposed surface 210E is annular surface 210A, the area sum of cylindrical surface 210B and end surfaces 210C.Described surface area can increase by the size along the periphery zone 210B of the axle longitudinal extension of core 210.

Fig. 2 B is the cutaway view of the slow release implant 202 of the expression core with the exposed surface area 212A that comprises increase 212 according to an embodiment of the present invention.Sheath body 222 extends at core 212.Therapeutic agent can discharge from core as mentioned above.Exposed surface area 212A is nearly taper, can be ellipsoid or sphere, stretches out to increase the exposed surface area of medicated core 212 from the sheath body.

Fig. 2 C and Fig. 2 D are respectively perspective view and the cutaway view of the expression slow release implant 204 with the medicated core 214 that comprises the exposed surface area 214A that reduces according to an embodiment of the present invention.Medicated core 214 is sealing in the sheath body 224.Sheath body 224 comprises the 224A of annular termination portion that limits opening, and medicated core 214 extends from above-mentioned opening.Medicated core 214 comprises the exposed surface 214A that discharges therapeutic agent.Exposed surface 214A has the diameter 214D less than the full-size of crosscut medicated core 214, for example maximum gauge.

Fig. 2 E is the expression cutaway view of the slow release implant 206 with medicated core 216 according to an embodiment of the present invention, and this medicated core 216 comprises the exposed surface area 216A of the increase with the battlements that extends from exposed surface area 216A.Described battlements comprises that a plurality of isolated finger piece 216F are with the surface area of exposed surface 216A that increase is provided.Except the surface area of the increase that provides by battlements, medicated core 216 also can comprise groove 216I.Groove 216I can have inverted cone.Core 216 is covered by sheath body 226.Sheath body 226 in a distal opening to provide exposed surface 216A at medicated core 216.Sheath body 226 also comprises finger piece and has the battlements pattern that is complementary with core 216.

Fig. 2 F is the perspective view of the expression slow release implant 250 that comprises the core with fold according to an embodiment of the present invention.Implant 250 comprises core 260 and sheath body 270.Core 260 the end of core have allow medicine around moving to tear or the exposed surface 260A of tear film liquid.Core 260 also comprises fold 260F.Fold 260F has increased the surface area of the core that is exposed to tear on every side or tear film liquid.By the increase of this exposed surface area, fold 260F has increased therapeutic agent from core 260 to tear or the migration tear film liquid and the targeted treatment area.Form fold 260F in core 260, to form passage 260C.The end of passage 260C and core is connected to become the opening in exposed surface 260A, and prepares for the movement of therapeutic agent.Like this, whole exposed surface area of core 260 comprise, directly are exposed to the exposed surface 260A of tear or tear film liquid, and by passage 260C and exposed surface 260A and the surface that is exposed to the fold 260F of tear or tear film liquid being connected of tear or tear film liquid.

Fig. 2 G is the perspective view of the expression slow release implant with the core that comprises the passage with the inner surface of porous according to an embodiment of the present invention.Implant 252 comprises core 262 and sheath body 272.Core 262 the end of core have allow medicine around moving to tear or the exposed surface 260A of tear film liquid.Core 262 also comprises passage 262C.Passage 262C increases the surface area of passage by the inner surperficial 262P of porous that forms towards core in passage.Passage 262C extends near the end of the core the exposed surface 262A of core.The surface area of the tear around being exposed to or the core of tear film liquid can comprise the inside of the core 262 that is exposed to passage 262C.The increase of this exposed surface area can increase therapeutic agent from core 262 to tear or the movement tear film liquid and the targeted treatment area.Like this, whole exposed surface area of core 262 can comprise, directly are exposed to the exposed surface 260A of tear or tear film liquid, and by passage 262C and exposed surface 262A and the inner surperficial 262P of the porous that is exposed to tear or tear film liquid being connected of tear or tear film liquid.

Fig. 2 H is the perspective view of the expression slow release implant 254 with the core 264 that comprises the passage that moves for increasing medicine according to an embodiment of the present invention.Implant 254 comprises core 264 and sheath body 274.Exposed surface 264A is positioned at the end of core 264, but this exposed surface also can be positioned at other position.Exposed surface 264A allows medicine to move to tear or tear film liquid on every side.Core 264 also comprises passage 264C.Passage 264C extends to exposed surface 264A.Passage 264C is enough big so that tear or tear film liquid can enter into passage, thus the surface area of the core 264 that increase contacts with tear or tear film liquid.The surf zone of the tear around being exposed to or the core of tear film liquid comprises surface, the inside 264P of the core 262 that limits passage 264C.By the increase of this exposed surface area, passage 264C has increased therapeutic agent from core 264 to tear or the movement tear film liquid and the targeted treatment area.Like this, whole exposed surface area of core 264 comprise, directly are exposed to the exposed surface 264A of tear or tear film liquid, and by passage 262C and exposed surface 264A and surface, the inside 264P that is exposed to tear or tear film liquid being connected of tear or tear film liquid.

Fig. 2 I is the perspective view of the expression slow release implant 256 with the medicated core 266 that comprises protruding exposed surface 266A according to an embodiment of the present invention.Medicated core 266 is covered by sheath body 276 parts, and sheath body 276 at least part of covering medicated core 266 extend to limit protruding exposed surface 266A.Sheath body 276 comprises axial region 276S.Protruding exposed surface 266A provides the surface area of increase on the sheath body.The sectional area of protruding exposed surface 266A is greater than the sectional area of the axial region 276S of sheath body 276.Except this bigger sectional area, because from the outward extending convex of core, protruding exposed surface 266A has bigger surface area.Sheath body 276 is included in the sheath body and supports medicated core 266 and this medicated core is provided support a plurality of finger piece 276F with the appropriate location that medicated core 266 is remained on sheath body 276.Finger piece 276F separates mutually, to allow medicine from core is transferred to tear or tear film liquid between the finger piece.Protuberance 276P stretches out at sheath body 276.Protuberance 276P can be extruded inward that medicated core 266 is discharged from the sheath body.Medicated core 266 can be behind the reasonable time, for example the medicated core with other be replaced after medicated core 266 has discharged most of therapeutic agent.

Fig. 2 J is the side view of the expression slow release implant 258 with core 268 according to an embodiment of the present invention, and this core 268 comprises the exposed surface area with a plurality of soft brush sample parts 268F.Medicated core 268 is covered by sheath body 278 parts, and sheath body 278 at least part of covering medicated core 268 extend to limit exposed surface 268A.Sheath body 278 comprises axial region 278S.Soft brush sample parts 268F stretches out from medicated core 268, and medicated core 268 is provided the exposed surface area of increase.Soft brush sample parts 268F also is soft, flexible and flexible, and so these parts do not produce stimulation to adjacent organizing.Though medicated core 268 can be with above-mentioned multiple material manufacture, silicone is the suitable material for the manufacture of the medicated core 268 that comprises soft brush sample parts 268F.The exposed surface 268A of medicated core 268 also comprises groove 268I, and exposed surface 268A partly is spill so at least.

Fig. 2 K is the side view of the expression slow release implant 259 with the medicated core 269 that comprises protruding exposed surface 269A according to an embodiment of the present invention.Medicated core 269 is covered by sheath body 279 parts, and sheath body 279 at least part of covering medicated core 269 extend to locate protruding exposed surface 269A.Sheath body 279 comprises axial region 279S.Protruding exposed surface 269 provides the exposed surface area of increase on the sheath body.The sectional area of protruding exposed surface 269A is greater than the sectional area of the axial region 279S of sheath body 279.Except this bigger sectional area, because from the outward extending convex of core, protruding exposed surface 269A has bigger surface area.Keep structure 289 can be attached on the sheath body 279.Maintenance structure 289 can comprise any one of above-mentioned maintenance structure, for example comprises for example Nitinol ^TMCoil Deng super-elastic shape memory alloy.Maintenance structure 289 can be by dip-coating so that keep structure 289 to have biocompatibility.

Fig. 2 L comprises side view for the slow release implant 230 of the medicated core 232 of the surperficial 232A of the recessed indentation of the exposed surface area that increases core for expression having according to an embodiment of the present invention.Sheath body 234 at least part of covering medicated core 232 extend.The exposed distal ends that the surperficial 232A of recessed indentation is formed at medicated core 232 is with the exposed surface area of increase that medicated core is provided.

Fig. 2 M is the side view of the expression slow release implant 240 with medicated core 242 according to an embodiment of the present invention, and this medicated core 242 comprises the recessed surperficial 242A that wherein is formed with passage 242C for increasing the exposed surface area of core.Sheath body 244 at least part of covering medicated core 242 extend.The exposed distal ends that the surperficial 242A of recessed indentation is formed at medicated core 232 is with the exposed surface area of increase that medicated core is provided.Passage 242C is formed in the medicated core 242 exposed surface area with the increase that this medicated core is provided.Passage 242C can extend on the surperficial 242A of recessed indentation, and so passage 242C can provide core to be exposed to the surface area of the increase of tear or tear film liquid.

Fig. 3 A is the expression implant 310 that comprises the sheath body 320 with extension 322 according to an embodiment of the present invention.Extension 322 is attached on the holding unit core to be remained near the lacrimal point with sheath body 320.Sheath body 320 extends covering core 330 to limit the exposed surface 332 of core 330.Extension 322 can be for elastic, and engage holding unit and/or inaccessible unit so that sheath body core is attached on the holding unit, thereby core is remained near the lacrimal point.

Fig. 3 B is the expression implant 350 that comprises the holding unit 380 with extension 382 according to an embodiment of the present invention.Extension 382 keeps sheath body 360 and core 370.Sheath body 360 extends covering core 370 to limit the exposed surface 372 of core 370.Exposed surface 372 is configured near the near-end of core 370.Extension 382 extends with holding core 370 and sheath body 360 downwards.

Fig. 4 A and Fig. 4 B are the cutaway view of the expression implant 400 with maintenance structure 430 that heavy in section contour shape in the longitudinal direction is shorter than the small bore contour shape according to an embodiment of the present invention.Implant 400 comprises far-end 402 and near-end 404.Implant 400 comprises medicated core 410 and sheath body 420.Sheath body 420 at least part of covering medicated core 410 also limit the exposed surface 412 of medicated core 410.Inaccessible unit 440 can be attached on the maintenance structure 430 and be supported by it.For example when holding unit 430 expand into the heavy in section contour shape from the small bore contour shape, inaccessible unit 440 can be with keeping structure 430 mobile.In a lot of embodiments, keep the size of structure and inaccessible unit corresponding to dacryocanalicular diameter, for example be complementary with dacryocanalicular diameter or be a bit larger tham the lacrimal ductule diameter, thereby inaccessible flow of liquid is worn lacrimal ductule and/or is anchored in the lacrimal ductule.

Shown in Fig. 4 A, keep structure 430 and inaccessible unit 440 in the low profile shape.This low profile shape can be configured in the top of insertion instrument and cappedly occurs when preparing to launch at inaccessible unit and holding unit.Holding unit 430 and inaccessible unit 440 extend along the length of sheath body 420 and medicated core 410 fully.Holding unit 430 is attached near the far-end 402 the sheath body 420.In a lot of embodiments, in the time of in the low profile shape, holding unit 430 and inaccessible unit 440 have the diameter that changes over suitable lacrimal ductule inside and slip into the size in the lacrimal ductule, and in second largest contour shape, the size of described holding unit and inaccessible unit can be suitable for being anchored in the lacrimal ductule.

Shown in Fig. 4 B, keep structure 430 and inaccessible unit 440 in big contour shape.This big contour shape can occur when inaccessible unit and holding unit are configured in the lacrimal ductule.In this big contour shape, inaccessible unit 440 and the length that keeps structure 430 than low profile shape short-and-medium length shown in the distance 450.When the sheath body shows as big contour shape with the maintenance structure, keep the near-end of structure 430 and inaccessible unit 440 to slide at sheath body 420, make the near-end of medicated core 410 and sheath body 420 from keep structure and inaccessible unit, stretch out like this.In some embodiments, the sheath body has been lacked the length shown in the distance 450 than medicated core 410, so when keeping structure and inaccessible unit in big contour shape, and keeps structure to compare in the low profile shape time with inaccessible unit exposing more medicated core.In this embodiment, described maintenance structure and inaccessible unit shrink to expose medicated core.

Fig. 5 A～Fig. 6 represents to be used to insert the embodiment of the instrument of multiple implant described herein.

Fig. 5 A represents insertion instrument 500 according to an embodiment of the present invention, with the plunger that can be depressed 530 implant is inserted in the lacrimal point.Insertion instrument 500 comprises and can be inserted into the dilator 510 to expand lacrimal point in advance in the lacrimal point before inserting implant.Implant 520 can be loaded on the instrument 500 before described lacrimal point expansion in advance.Inner wire 540 can link to each other to keep implant with implant 520.Along with expanding lacrimal point in advance with dilator 510, can implant 520 be inserted in the lacrimal point with instrument 500.When implant 520 is positioned in the lacrimal point, can depression of plunger 530 to engage with line 540 and to discharge implants 520 from instrument 500.In some embodiments, line 540 might comprise the sharp needles tip that penetrates implant 520.Implant 520 might comprise having for example medicated core of silicone of elastomeric material, and this medicated core material shrinks when pin is removed like this.

Fig. 5 B represents that plunger that usefulness according to an embodiment of the present invention can slide is inserted into insertion instrument 550 in the lacrimal point with implant 570.Insertion instrument 550 comprises the dilator with tapered cross-section 560 for the expansion lacrimal point.Insertion instrument 550 comprises and can slide the plunger 580 in the implant 570 propelling inner chambers to far-end.Axle 590 is connected when plunger 580 advances to far-end implant 570 to be advanced to far-end with plunger 580.When lacrimal point during with dilator 560 expansion, plunger 580 can advance implant 570 to be positioned near the lacrimal ductule inner chamber the lacrimal point to far-end.In a lot of embodiments, can press the button that implant is advanced in the chamber to far-end, for example the button that links to each other with axle 590 with intermediary agency.

Fig. 6 represents the insertion instrument 600 in the lacrimal point that implant is inserted that implant is positioned at sheath 610 in the lacrimal ductule inner chamber by shrinking that has according to an embodiment of the present invention.At least a portion of sheath 610 is carried out the moulding lacrimal point of expanding.Sheath 610 forms the implant 620 that keeps the low profile shape.Insertion instrument 600 comprises circulus 615, and described circulus can comprise the part of the main body 605 of insertion instrument 600.Sheath 610 and circulus 615 are carried out moulding with the expansion lacrimal point, and it often comprises that approximate surface that tilts is with the expansion lacrimal point.Implant 620, sheath 610 and circulus 615 can at least part ofly be inserted in the lacrimal point so that implant is positioned in the lacrimal ductule inner chamber.Circulus 615 is configured on the sheath 610, and so sheath 610 can be retracted and slide under circulus 615.Stop 625 can link to each other with main body 605 and with intracavity in lacrimal ductule implant 620 be remained on desired depth, and sheath 610 shrinks to expose implant 620 to near-end simultaneously.

In case implant 620 is configured in the lacrimal ductule inner chamber with desired depth for lacrimal point, then sheath 610 shrinks with desired location in the lacrimal ductule inner chamber and exposes implant 620.Can use plunger 630 to shrink sheath 610.Axle 630 is mechanically connected to sheath 610 on the plunger 630.Plunger 630 can shrink sheath 610 at proximal direction in the contraction on the proximal direction and expose implant with the desired location in the lacrimal ductule inner chamber like this.Implant 620 can be any one of said implant.Usually implant 620 is included in the elastomeric element that is expanded to big contour shape when sheath 610 shrinks.In a lot of embodiments, insertion instrument 600 can be included in and insert the dilator that implant is expanded lacrimal point before, and as mentioned above, dilator can be configured in the terminal opposite end that this insertion tool coating is loaded with implant.

Fig. 7 A～Fig. 7 C be according to an embodiment of the present invention replacement medicated core 710 and the schematic illustration of sheath body 720.Implant 700 comprises medicated core 710, sheath body 720 and keeps structure 730.Implant 700 can comprise and is held that structure 730 supports and can be with its inaccessible unit that moves.Usually keep structure 730 before implanting, can show as first contour shape---the low profile shape, and show as second contour shape after implanting---big contour shape.Maintenance structure 730 is shown in the big contour shape and is implanted in the lacrimal ductule inner chamber.Sheath body 720 comprises extension 725A and extension 725B so that sheath body and medicated core are attached on the maintenance structure 730, and said sheath body and medicated core are held structure 730 and keep.Medicated core 710 and sheath body 720 can be by pulling to near-end with medicated core 710 and being removed together shown in arrow 740.Shown in Fig. 7 B, keep structure 730 after medicated core 710 and sheath body 720 are removed, still to be implanted in the lacrimal ductule tissue.Shown in Fig. 7 C, replace medicated core 760 and replace sheath body 770 and can be inserted into together.Preferably discharged the effective dose of therapeutic agent at medicated core 710, the supply of the therapeutic agent in medicated core reduces, and the therapeutic agent rate of release is carried out this replacement after near minimum effect level.Replace sheath body 770 and comprise extension 775A and extension 775B.Replacement medicated core 760 and replacement sheath body 770 can be pushed into far-end and be inserted in the maintenance structure 730 will replace medicated core 760 and to replace sheath body 770 shown in arrow 790.When replacement medicated core 760 is inserted in the elastomeric element 730 with replacement sheath body 770, keep structure 730 basically still on same position.

Fig. 8 A～Fig. 8 C represents the configuration of slow release implant according to an embodiment of the present invention.Shown in Fig. 8 A, configuration tool 810 is inserted in the lacrimal ductule 800 by lacrimal point 800A.Top and sheath 812 that slow release implant 820 is loaded onto configuration tool 810 cover slow release implant 820.When sheath 812 is configured on the maintenance structure 830, keep structure 830 to show as the low profile shape.Shown in Fig. 8 B, draw back the outer sheath 812 of configuration tool 810 to expose the maintenance structure 830 of slow release implant 820.Holding unit 830 exposed portions show as big contour shape.Shown in Fig. 8 C, configuration tool 810 has been removed and slow release implant 820 is implanted in the lacrimal ductule 800.Medicated core 840 is attached on the maintenance structure 830 and is maintained in the lacrimal ductule.Outer body sheath 850 covers the part of medicated core 840 at least, and medicated core 840 is discharged into therapeutic agent near the lacrimal point 800A of lacrimal ductule 800 the tear or tear film liquid 860.

Fig. 9 A represents the drug-supplying system 900 for the sleeve pipe 930 that keeps medicated core 920 and hydrogel holding unit 910 of having according to embodiment of the present invention.In many embodiments, collar comprises silicone.As mentioned above, medicated core comprises the substrate with therapeutic agent and can have sheath.Hydrogel holding unit 910 can be configured in the sleeve pipe 930, and in the time of in being placed on lacrimal point, described hydrogel holding unit 910 expands owing to absorbing liquid.Described holding unit can comprise many swollen materials.The performance of described sleeve pipe stops the hydrogel parts to be broken away from from the drug-supplying system of assembling the effect that described medicated core insert and hydrogel rod keep together.When described hydrogel expands, described silicone collar, when allowing its expansion slightly, be formed on the hydrogel unit around more tight collapse deviate from from described sleeve pipe to stop hydrogel.In Fig. 9 A, expression has the drug-supplying system of the hydrogel holding unit that inserts preceding shape, and the hydrogel holding unit of shape has for the elongated profile that inserts from lacrimal point to lacrimal ductule before this insertion.This hydrogel aquation not substantially in the narrow profile shape has and is lower than about 10%, about 1% water content for example.

Fig. 9 B represents having by the drug-supplying system shown in Fig. 9 A 900 of the hydrogel holding unit 910 of aquation according to embodiment of the present invention.In the shape of inserting, this hydrogel expands by aquation and in lacrimal ductule.Because the wide range of expansion of this hydrogel, this expansion can closely be fit to many patients' size.In many embodiments, described silicone sleeve can be adopted otherwise and be navigated in the lacrimal point with help.In the shape of this expansion, this hydrogel can show as the equilibrium concentration of water, for example about 50%～95% water.

Fig. 9 C represents the drug-supplying system 950 shown in Fig. 9 A with sleeve pipe 954 according to embodiment of the present invention, and this sleeve pipe 954 comprises that silicone collar 952 is to rest on the outside of lacrimal point.Can adjust the size of this collar, so that this device can not join in the lacrimal point too far.For example, this collar can rest on the outside of lacrimal point.

Fig. 9 D represents the sleeve pipe 966 according to the drug-supplying system 960 of embodiment of the present invention, and this sleeve pipe 966 has the flange 964 that help is inserted into the bullet 962 of lacrimal point and is used for resting on the outside of lacrimal point that is used at the far-end lacrimal ductule end of sleeve pipe.This sleeve pipe can comprise can be varying sized with a plurality of flanges of the outside that rests on lacrimal point, for example 2 flanges, 4 flanges, 8 flanges or 16 flanges.

Fig. 9 E represents the sleeve pipe 974 according to the drug-supplying system 970 of embodiment of the present invention, and this sleeve pipe 974 has for the contraction flow region 972 that the hydrogel holding unit is remained on sleeve pipe at the far-end lacrimal ductule end of sleeve pipe.Contraction flow region 972 comprises that flange is to keep hydrogel here when hydrogel expands.When hydrogel during from the axial outside radial propelling of hydrogel holding unit, contraction flow region 972 also can be formed has short and small outstanding nail and other protuberance to keep hydrogel here.

Fig. 9 F represents the drug-supplying system with hydrogel holding unit 982 980 in being inserted into lacrimal ductule inner chamber 984 processes according to embodiment of the present invention.This holding unit inserts by lacrimal point opening 986 with the narrow profile shape.In the narrow profile shape, this holding unit comprises the hydrogel of substantially dry.In many embodiments, as mentioned above, drug-supplying system comprises flange at the end of the sleeve pipe opposite with holding unit, and so flange rests on the outside of lacrimal point when holding unit expands in the lacrimal ductule inner chamber.

Fig. 9 G represents to be inserted into according to having of embodiment of the present invention the drug-supplying system shown in Fig. 9 F 980 of back expanded balloon holding unit 982 in the lacrimal ductule inner chamber.This hydrogel unit expands with the cover pipe joint and make the resilient silicone sleeve pipe produce the micro-elastic distortion.The hydrogel holding unit advances to the outside so that the wall of lacrimal ductule inner chamber 984 produces micro-strain with enough power.

In many embodiments, drug-supplying system comprises the modular system that has the medicine insert and can hold the commercial commercially available Punctal plug of this medicine insert.This medicine insert can be suitable for being configured in the hole of Punctal plug, and can remain on original position by blockage, and this barrier is installed between the external diameter and silicone consent internal diameter of medicine insert.This package system can be packaged with this shape, sterilization and for Yu doctor.

In many embodiments, the tear stains plug that is used for the treatment of xerophthalmia comprises the swellable material that is connected with union body with medicated core, for example multiple swellable material and the union body shown in Fig. 9 A～Fig. 9 G.In some embodiments, can treat xerophthalmia with multiple tear stains plug described herein, the core in the tear stains plug does not comprise the therapeutic agent that contains therein.In many embodiments, can adjust the size of this body and treat xerophthalmia with inaccessible lacrimal point.In some embodiments, this main body might be less than lacrimal point, and so the hydrogel of swelling can inaccessible lacrimal point.This main body can comprise protuberances such as the flange that can be varying sized remains on when being located in the lacrimal point in main body on the lacrimal point outside, edge, the wing, to help when the hydrogel holding unit swelling cock body and to keep structure to remove from lacrimal point.Related to the present invention studies show that, because hydrogel might break, the existing general tear stains that comprises hydrogel is plugged with and may be difficult to remove, and described hereinly keeps the structure of hydrogel can help to remove swelling hydrogel holding unit with main body.

Figure 10 A represents the medicated core insert 1010 that uses with the tear stains plug according to embodiment of the present invention.As mentioned above, the medicated core insert can comprise the medicine sheath 1014 that has for the impervious substantially polyimides of therapeutic agent and/or multiple material.Medicated core comprises above-mentioned multiple shape, for example cylindrical bar.Can use the cyanoacrylate film at an end of medicated core insert.As mentioned above, the opposite end of exposure medicated core insert is diffused in the tear of eye to allow therapeutic agent.In the specific embodiment, described medicated core insert comprises for example cross sectional dimensions of the about 0.3mm of diameter.The length of medicated core insert is about 0.9mm.

Described medicine insert can comprise the thin-walled polyimide tube, and this thin-walled polyimide tube has the medicated core that comprises the latanoprost that is dispersed in Nusil6385 (MAF970) (the pharmaceutical grade solid silicone that is used for the substrate of administration).The far-end of medicine insert can seal with the cured film of solid Loctite4305 pharmaceutical grade binding agent.Because the medicine insert can be configured in the hole of Punctal plug, the Loctite4305 binding agent can not contact with tissue or tear film.The internal diameter of described medicine insert can be 0.32mm, and length can be 0.95mm.In three kinds of embodiments, latanoprost concentration can be tested clinically: medicated core comprises 3.5,7 or 14 μ g latanoprosts.In many embodiments, total dissolution rate is about 100ng/ days, and medicated core can contain 14 μ g latanoprosts, so medicine can be released～120 days.The gross weight that contains the medicated core of latanoprost can be about 70 μ g.The weight that comprises the medicine insert of polyimides sleeve pipe can be about 100 μ g.

General all material is the pharmaceutical grade material that has passed through a cover safety/toxicity test in medicine insert structure.As shown in the table to the biocompatibility test that medicine insert material carries out by the manufacturer.

In many embodiments, medicated core can comprise silicone.Latanoprost can be dispersed in the uncured Nusil6385 silicone with desired concn, is injected in the polyimides sleeve pipe and curing at room temperature.This method can obtain comprising the solid silicone substrate of the latanoprost of desired concn.

In many embodiments, this sleeve pipe can comprise polyimides.Described polyimides sleeve pipe can hold medicated core to provide structural support and for the barrier of side drug diffusion.The internal diameter of described sleeve pipe can be 0.32mm, and wall thickness can be 0.013mm.

Figure 10 B represents the tear stains plug 1020 according to the internal cavities that comprises cylindrical shape 1022 of embodiment of the present invention.Can change the size of cavity 1022 closely to hold medicated core insert 1010.Tear stains plug 1020 can comprise multiple can be at the commercial tear stains plug that obtains, for example, Medtronic Tear Pool tear stains plug, from " the umbrella shape lacrimal point occluder system " that the Odyssey of Memphis, Tennessee State obtains, and/or the Eagle Vision plug that obtains from the Eagle Vision of Memphis, Tennessee State.In some embodiments, described tear stains plug comprises the tear stains plug of customization, for example the customization plug of the appropriate size selected of the size that records according to the patient.In many embodiments, the tear stains plug has about 2mm length and about 1mm width.

Figure 10 C represents the tear stains plug shown in Figure 10 B that inserts medicated core wherein shown in Figure 10 A that has according to embodiment of the present invention.In many embodiments, the insertion of drug-supplying system is with remove can be can realize in the identical mode of the commercial tear stains plug that obtains with other.Described plug can be inserted in the lacrimal point with tweezers or insertion instrument, for example has the above-mentioned instrument of the pin that can be inserted into the size in the core.When being configured in the last lacrimal point (following lacrimal point) of eye, the near-end of medicated core is exposed in the tear.Because tear contacts for example slow stripping of latanoprost of therapeutic agent with the exposure proximal end face of medicated core.Described drug-supplying system can use tweezers to remove.

Figure 11 represents comprising medicated core 1140 and comprising that the tear stains of the holding device of the sleeve pipe 1110 that is formed with the wing 1112 thereon thrusts medicine system 1100 according to embodiment of the present invention.In many embodiments, keep structure also to comprise hydrogel holding unit 1120.The wing 1112 can limit this device penetrating in the lacrimal point, and so when device and hydrogel holding unit 1120 were maintained in the lacrimal ductule inner chamber, the wing rested on the outside of lacrimal point.In many embodiments, the wing 1112 stops the near-end of tear stains plug to be manoeuvred in the lacrimal ductule inner chamber to far-end.The wing 1112 can help to remove device.Can comprise near the device far-end that 1150 cover to limit the far-end expansion of hydrogel.Suture 1130 can be to remain on medicated core and hydrogel holding unit in the sleeve pipe 1110 from the proximal extension to the far-end.

Figure 12 A represents the maintenance structure 1200 according to the sleeve pipe 1210 that has short and small outthrust 1212 comprising of embodiment of the present invention and hydrogel 1220.Keep structure 1200 can with above-mentioned multiple medicated core coupling.Sleeve pipe 1210 comprises the ring-type shell that covers hydrogel 1220.Hydrogel 1220 can have cylindrical shape to be adapted in the sleeve pipe 1210.When hydrogel 1220 dryings, keep structure 1200 to keep the narrow profile shapes.The opening that short and small outthrust 1212 limits in the sleeve pipe 1210, this opening allows water to enter hydrogel 1220 when sleeve pipe 1210 is inserted into lacrimal point.In some embodiments, sleeve pipe also can comprise the hydrogel component in the silicone that is added into sleeve pipe, and so sleeve pipe also can expand to strengthen maintenance.

Figure 12 B is the short and small outthrust 1212 radial maintenance structures 1200 shown in Figure 12 A that advance to the outside when representing according to the aquation of the hydrogel material of embodiment of the present invention.When water entered opening in the sleeve pipe 1210, hydrogel 1220 expanded so that short and small outthrust 1212 is radial advances to the outside.Keep structure to engage that with internal chamber wall the medicine dissolving device is remained in the lacrimal ductule.Because hydrogel advances to the outside, hydrogel expands near the opening of short and small outthrust, and said hydrogel can be maintained in the described sleeve pipe.

Figure 12 C represents the maintenance structure 1250 according to the sleeve pipe 1260 that has short and small outthrust 1262 comprising of embodiment of the present invention and ring-type hydrogel swelling part 1270.When structure 1250 kept dry, described structure kept the narrow profile shape.As mentioned above, medicated core can be included in the ring-shaped sleeve.

Figure 12 D represents the maintenance structure shown in Figure 12 C according to the sleeve pipe that has short and small outthrust comprising of embodiment of the present invention and ring-type hydrogel swelling part.And then ring-type hydrogel swelling part 1270 aquations, described ring-type hydrogel swelling part advances should push described internal chamber wall to by short and small outthrust to the outside to the outside facing to short and small outthrust 1262.

Figure 13 represents the doser 1300 that keeps structure that has according to embodiment of the present invention, this maintenance structure comprises hydrogel holding unit 1330, has the sleeve pipe 1320 in crosscut hole 1322 and short and small outstanding lock 1334 therein and/or is used for when the expansion of hydrogel hydrogel being remained on the flange of appropriate location.Doser 1300 comprises above-mentioned medicated core insert 1310.Crosscut hole 1322 allows water to pass through and water of hydration gel holding unit 1330.The expansion of hydrogel holding unit 1330 is pushed some hydrogels sleeve pipe 1320 to and is passed crosscut hole 1322, and so the hydrogel holding unit is anchored at sleeve pipe 1320 along with the expansion of hydrogel.When the expansion along with the hydrogel holding unit, holding unit expands so that hydrogel holding unit 1330 is anchored on sleeve pipe 1320, and short and small outstanding lock 1334 engages with hydrogel holding unit 1330.

Figure 14 A represents the tear stains plug 1400 with medicated core 1410 and maintenance fin 1420 according to embodiment of the present invention.Keep fin 1420 can comprise elastomeric material, for example silicone.Medicated core 1410 can comprise above-mentioned multiple medicated core, and above-mentioned sheath can be placed on the described medicated core to limit above-mentioned exposed area.

Figure 14 B represents when plug is inserted into lacrimal ductule inner chamber 1450, keeps fin 1420 to be folded back to keep filling in 1400 the tear stains plug 1400 shown in Figure 14 A.Keep fin 1420 to tilt to the lacrimal point near-end.Folding back of fin 1420 can be got into device in the inner chamber to stop movement.In some embodiments, described plug can comprise the sleeve pipe with above-mentioned wing.

The sheath body

Described sheath body comprises that suitable shape and material are with the migration of control therapeutic agent from described medicated core.The sheath body accommodates core and can closely be fit to core.Described sheath body is by making for the impervious substantially material of therapeutic agent, and so the transfer rate of therapeutic agent can be mainly controlled by the exposed surface area of the medicated core that is not covered by the sheath body.In a lot of embodiments, the movement of therapeutic agent by the sheath body can be about the movement of therapeutic agent by the exposed surface of medicated core 1/10th or still less, be generally one of percentage or still less.In other words, the movement of therapeutic agent by the sheath body at least the approximate number magnitude less than the movement of therapeutic agent by the exposed surface of medicated core.Suitable sheath body material comprises polyimides, polyethylene terephthalate (hereinafter referred to as " PET ").Described sheath body has the thickness away from the opposite sheath surface of core of being restricted to from the sheath surface of contiguous core that is about 0.00025 ＂～about 0.0015 ＂.Overall diameter across the sheath of core is about 0.2mm～1.2mm.Core can form by dip-coating core in the sheath material.Select as the another kind that replaces, or combination with it, the sheath body can comprise the core of managing and being inserted in the sheath, for example is injected and/or is squeezed into sheath body pipe as the liquid or solid that can slide.The sheath body also can be by dip-coating around core, and for example dip-coating is around the preformation core.

Described sheath body can be endowed supplementary features to promote the clinical practice of implant.For example, when keeping structure and sheath body still to be implanted among the patient, sheath can be accepted interchangeable medicated core.The sheath body is attached to rigidly as mentioned above usually and keeps on the structure, and described core is replaceable when keeping structure to keep the sheath body.In the specific embodiment, described sheath body can be endowed at the outside protuberance that pushes or be used for the sheath body is applied load when the sheath body is discharged core.Another medicated core can be placed in the sheath body subsequently.In a lot of embodiments, sheath body and/or maintenance structure can have the feature of difference, the color that for example is used for the difference of its layout of expression, so the patient can easily notice the sheath body and/or keep the layout of structure in lacrimal ductule or other bodily tissue structure.Described holding unit and/or sheath body can comprise that at least one is used for being illustrated in the labelling of the degree of depth that lacrimal ductule arranges, said holding unit and/or sheath body can be placed in the lacrimal ductule with desired depth based on described at least one labelling.

Keep structure

Described maintenance structure comprises and is changed size and forms definite shape so that implant can easily be positioned required tissue location, dacryocanalicular suitable material for example.Described maintenance structure mechanically disposes and typically is expanded to required cross sectional shape, for example has to comprise for example Nitinol ^TMMaintenance structure Deng super-elastic shape memory alloy.Also can use Nitinol ^TMOutside other material, for example elastic metallic or polymer, the metal of plastically deformable or polymer, shape-memory polymers etc. are to provide required expansion.In some embodiments, can use can be available from plastic polymer and the coated fiber of the Biogeneral company limited in Santiago, California.Many metals for example rustless steel and non-marmem can be used and provide required expansion.This swelliong power allows implant to be fit to enter in the hollow tissue structure of various sizes, for example the lacrimal ductule of 0.3mm～1.2mm (that is, a kind of size can be fit to whole needs).Though single maintenance structure can be made into to be fit to the wide lacrimal ductule of 0.3mm～1.2mm, but what replace as required can also use selectable a plurality of maintenance structure to be fit to this scope, for example be used for dacryocanalicular first of 0.3～0.9mm and keep structure, be used for dacryocanalicular second of 0.9～1.2mm and keep structure.Described maintenance structure has the length that is suitable for the anatomical structure that this maintenance structure adheres to, the about 3mm of length of the maintenance structure of for example placing near dacryocanalicular lacrimal point.For different anatomical structures, described length can be suitable for providing sufficient retentivity, and for example 1mm～15mm length is suitable.

Though sheath body and medicated core are attached on the end that keeps structure as mentioned above, in a lot of embodiments, keep another end of structure not to be attached on medicated core and the sheath body, so when keeping the structure expansion, the maintenance structure can slide at sheath body and medicated core.Preferably have this slip ability at an end, this is because when keeping structure to expand when showing as required transversal width at width, described maintenance structure might shorten in length.Yet, it should be noted that a lot of embodiments can use the sheath body that does not slide with respect to core.

In a lot of embodiments, described maintenance structure can reclaim from tissue.Protuberance for example hook, circle or ring can expand to promote to keep removing of structure from keeping structure.

In many embodiments, described sheath and maintenance structure can comprise two parts.

Inaccessible unit

Described inaccessible unit comprises and forms shape so that implant can at least part ofly suppress even block fluid stream is worn the hollow tissue structure that for example tear stream is worn dacryocanalicular suitable material varying sized.Here shown occlusive materials is can be along with the thin-walled film of the biocompatible materials that keeps structure to expand and shrink, the thin-walled film of for example silicone.Inaccessible unit forms as mentioned above and to keep the structure end to slide and to be anchored on the light wall pipe of separation of the material of an end that keeps structure.Another selection that replaces is that described inaccessible unit can form by the described maintenance structure of dip-coating in biocompatible polymer, for example silicone polymer.The thickness of inaccessible unit can be in the relative broad range of about 0.01mm～about 0.15mm, usually in the scope of about 0.05mm～0.1mm.

Therapeutic agent

" therapeutic agent " can comprise can be following substances or their equivalent, the medicine of any one in derivant or the analog comprises: anti-glaucoma medicine (for example, 2-adrenergic agonist components, 1 adrenergic antagonists (beta-Blocking agent), carbonic anhydrase inhibitors (CAIs, whole body and part), parasympathomimetic agent, prostaglandin and intraocular pressure lowering lipid and combination thereof), antibacterial (for example, antibiotic, antiviral agents, antiparasitic, antifungal agent etc.), corticosteroid or other antiinflammatory are (for example, NSAID), Decongestant (for example, vasoconstrictor), improve anaphylactoid preventive (for example, hydryllin, cytokine inhibitor, leukotriene inhibitors, IgE inhibitor, immunomodulator), mast cell stabilizers, cycloplegic or its analog.Can with therapeutic agent (etc.) example of situation for the treatment of includes but not limited to glaucoma, before the art and post-operative treatment, xerophthalmia and allergy.In some embodiments, described therapeutic agent can be lubricant or surfactant, for example is used for the treatment of the lubricant of xerophthalmia.

Typical therapeutic agent includes but not limited to: thrombin inhibitor; Antithrombotic agent; Thrombolytic agent; Fibrinolytic agent; The vasospasm inhibitor; Vasodilation; Hypotensive agent; Antibacterial, for example antibiotic (for example tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, Gramicidin, cefalexin, oxytetracycline, chloromycetin, rifampicin, ciprofloxacin, tobramycin, gentamycin, erythromycin, penicillin, sulfonamides, sulfadiazine, sulfacetamide, ayerlucil, sulfafurazole, nitrofural, sodium propionate), antifungal agent (for example amphotericin B and miconazole) and antiviral agents (for example idoxuridine trifluorothymidine, acyclovir, gancyclovir, interferon); The inhibitor of surface glycoprotein receptor; Anti-platelet agents; Antimitotic drug; The microtubule inhibitor; Secretion inhibitor; Activity inhibitor; Reinvent inhibitor; Antisense nucleotide; Antimetabolite; Antiproliferative agents (comprising angiogenesis inhibitor); Anti-cancer chemotherapeutic agents; Antiinflammatory (for example hydrocortisone, hydrocortisone acetate, dexamethasone 21-phosphate, fluocinolone acetonide, medrysone, methylprednisolone, prednisolone 21-phosphate, prednisolone acetate, fluorometholone, betamethasone, triamcinolone, triamcinolone acetonide); Nonsteroidal anti-inflammatory agent (NSAIDs) (for example salicylic acid, indomethacin, ibuprofen, diclofenac, fluorine can general (naxopren) than Lip river branch, piroxicam indomethacin, ibuprofen, naphthalene, piroxicam and nabumetone).For example, this anti-inflammatory steroid that expection is used in the method for the present invention comprises triamcinolone acetonide (common name), and corticosteroid comprises for example triamcinolone, dexamethasone, fluocinolone acetonide, cortisone, prednisolone, 6.alpha.-fluoro-16.alpha.-methylprednisolone (flumetholone) and derivant thereof; Antiallergic agent (for example sodium cromoglicate, antazoline, methapyrilene, chlorphenamine, cetrizine, pyrilamine, pheniramine); Antiproliferative (for example 1,3-cis-retinoic acid, 5-fluorouracil, paclitaxel, rapamycin, ametycin and cisplatin); Decongestant (for example phenylephrine, naphazoline, tetrahydrozoline); Miotic and anticholinesterase drug (for example pilocarpine, Salicylate, carbachol, acetylcholine chloride, physostigmine, with color woods, diisopropylfluorophosphonate, ecothiopate iodide, demecarium bromide); Antineoplastic agent (for example carmustine, cisplatin, fluorouracil 3); Immune drug (for example vaccine and immunostimulant); Hormone (for example estrogen ,-estradiol, progestational agents, progesterone, insulin, calcitonin, parathyroid hormone, peptide and vassopressin hypothalamic releasing factor); Immunosuppressant, growth hormone antagonist, somatomedin (for example epidermal growth factor, fibroblast growth factor, platelet derived growth factor, transforming growth factor, growth hormone, fibronectin); Angiogenesis inhibitor (for example angiostatin, NSC 24345, thrombospondin, VEGF antibody); Dopamine agonist; Radiotherapy dose; Peptide; Protein; Enzyme; Extracellular matrix; Component; ACE inhibitor; Free radical scavenger; Chelating agen; Antioxidant; Anti-polymerase; The photodynamic therapy agent; Gene therapeutic agents; And other therapeutic agent for example prostaglandin, antiprostaglandin, prostaglandin precursor, comprise that Betimol comprises for example for example bimatoprost, travoprost, latanoprost etc. of timolol, betaxolol, levobunolol, atenolol and prostaglandin analogue of beta-Blocking agent; Carbonic anhydrase inhibitors is acetazolamide, dorzolamide, brinzolamide, methazolamide, diclofenamide (dichlorphenamide), Acetazolamide for example; Neuroprotective is lubeluzole, nimodipine and related compound for example; And parasympathomimetic agent for example pilocarpine, carbachol, physostigmine etc.

The amount of the medicine relevant with doser can be depending on particular agent, the time that required therapeutic effect and device are desired to treat.Because apparatus of the present invention have proposed different shape, size and conveying mechanism, the amount of the medicine relevant with device depends on specified disease or the situation of desire treatment, and desire obtains dosage and the persistent period of therapeutic effect.Usually, when one release from device, the amount of medicine is for can effectively obtaining the amount of required physiology or pharmacology part or systemic effect at least.

Can make the embodiment of doser of the present invention be suitable for being lower than in fact treatment and go up effectively that the day speed of the eye drop mode for the treatment of provides drug conveying, thereby the wide therapeutic domain with wide margin of safety is provided.For example, in many embodiments, the period that prolongs to be at most 5～10% treatment level treatment eye of eye drop dosage every day.Thereby in about 1～3 day quick administration or interim when washing out, implant can be to be higher than the slow release level in fact and fully to be lower than the speed stripping therapeutic agent of eye drop mode dosage every day.For example, have the 100ng average slow release level of every day, and the initial rate of release of 1000～1500ng every day the time, the medication amount of initial release is less than the medicine of the 2500ng in the eye drop of the medicine that gives eye.The application of slow release level used herein is lower than the medication amount of a kind of and/or multiple eye drop that gives every day in fact, so allow device to discharge the effective medication amount for the treatment of, thereby under wide margin of safety, realize required therapeutic effect, and avoid deficiency or overdose of medicine thing amount in destination locations or the zone.

Might refer to short relatively period the period that prolongs, for example a few minutes or several hours (for example for narcotic use), several days or a few week (for example before the operation or operation back antibiotic, the use of steroidal or NSAIDs etc.) or longer (for example under the situation of glaucoma treatment) be some months or several years (collection basis of using based on device) for example.

For example, a kind of medicine, for example, and timolol maleate, a kind of β and β 2 (non-selective) adrenoreceptor blocker go in this device, discharge prolonging period for example 3 months.Though install the treatment of the persistent period that can provide longer or shorter, 3 months for carrying out the typical relatively elapsed time in the topical eye drops treatment to glaucoma patient with glaucoma medicine the doctor.In this example of 3 months, 0.25% timolol changes into carries 2.5～5mg/1000 μ L, the particularly timolol of 2.5mg/1000 μ L.The timolol eye drop that is used for topical is generally 40～60 μ L, particularly 50 μ L.The timolol that therefore, 0.08～0.15mg, particularly 0.125mg may be arranged in eye drop.After 5 minutes, the eye drop of might have an appointment 8% (being 6～10% alternatively) remains in the eye, and therefore this moment, about 10 μ g medicines were effective.Timolol can have 30～50% bioavailability, 1.5～7.5 μ g that this refers to, and for example 4 μ g medicines are effective for eye.Usually give timolol twice every day, can reach μ g every days 8 (or 3～15 μ g) for eye like this.Therefore, doser can be included in 90 days or prolong 270～1350 μ g that discharge, 720 μ g medicines for example in 3 middle of the month.Described medicine can comprise in the device, and based on polymer or medicine/hydrogel concentration stripping.For olopatadine hydrochloride (

) and other medicines, also can be included on the device and stripping with the same mode of timolol.

Can have 0.25% and 0.5% preparation at the commercial timolol maleate solution that obtains, initial dose can be every day twice, each 1 0.25% solution.The timolol of 0.25% concentration is equivalent to 2.5mg/1000 μ l.Can be about 3～15 μ g every days from the slow release amount that medicated core discharges timolol every day.Though every day, the slow release amount from the device administration can change, every day about 8 μ g sustained-release administration be equivalent to give 2 0.25% solution timolol 0.250mg about 3.2%.

For example, under the situation of latanoprost (Xalatan), this glaucoma medicine of prostaglandin F2 alpha analog has the concentrate of about timolol 1/10.Therefore, the amount of the medicine on the implantable device depends on bioavailability, for latanoprost and other prostaglandin analogue, will significantly reduce-Yue 20～135 μ g, particularly 50～100 μ g.It also can change into littler or can hold more medicine and be used for the longer release device in period than the device that is used for β-blocking agent administration.

The Xalatan eye drop contains the latanoprost of the 2.5 μ g that have an appointment, shows as 50 μ L eye drop volumes.Therefore, suppose to have 8% of about 2.5 μ g in back 5 minutes in instillation, then only the drug residue of about 200ng in eye.Based on the latanoprost clinical trial, this amount reduced IOP at least 24 hours be effective.Pfizer/Pharmacia is being carried out a plurality of dose response studieses aspect the NDA that supports Xalatan.The dosage of latanoprost is 12.5 μ g/mL～115 μ g/mL.Be administered once every day, and the general dosage 50 μ g/mL that at every turn give latanoprost are proved to be preferred.Yet even 12.5 μ g/mLQD of lowest dose level or 15 μ g/mL BID provide about 60～75% IOP of 50 μ g/mL QD dosage to reduce all the time.Based on above-mentioned hypothesis, 12.5 μ g/mL concentration provide the latanoprost of 0.625 μ g in 50 μ L eye drop, only cause after 5 minutes the drug residue of about 50ng (8%) in eye.

In many embodiments, the concentration of latanoprost is about 1/100 or 1% of timolol, and in the specific embodiment, the concentration of latanoprost might be about 1/50 or 2% of timolol.For example, can there be 0.005% concentration at the commercial latanoprost pharmaceutical solutions that obtains, gives 1 every day usually.In many embodiments, what the treatment valid density of the medicine that discharge every day from device can be for timolol is about 1/100, and about 30～150ng every day, for example about 80ng shows as tear removing and the bioavailability similar to timolol.For example, for latanoprost and other prostaglandin analogue, the amount of the medicine on implantable device can be very low, is about 1%～2% timolol, and for example 2.7～13.5 μ g also can be about 3～20 μ g.Though the slow release amount of the latanoprost that discharges every day can change, every day about 80ng slow release be equivalent to give 1 0.005% solution latanoprost 2.5 μ g about 3.2%.

For example, under the situation of bimatoprost (Lu Meigen), this glaucoma medicine of synthesising prostate amide prostaglandin analog can have timolol 1/20 or following concentration.Therefore, for bimatoprost and analog and derivant thereof, be loaded in the amount that prolongs the medicine that is used for prolongation release in 3～6 months on the releasing device, depend on bioavailability, can very low-Yue 5～30 μ g, particularly 10～20 μ g.In many embodiments, implant can be held more medicine and be used for longer slow release period, for example uses bimatoprost and derivant 20～40 μ g thereof to be used for 6～12 months slow release period.The reduction of this drug level also can change into than the required little device of device for β-blocking agent administration.

Can be by weight 0.03% in the commercial bimatoprost solution concentration that obtains, administration every day is 1 time usually.Though the slow release amount of the bimatoprost that discharges every day can change, every day 300ng slow release be equivalent to give 1 0.03% solution bimatoprost 15 μ g about 2%.Relevant with the present invention studies show that, bimatoprost even lower sustained-release dosage intraocular pressure can be provided at least some reduce, for example the bimatoprost of 20～200ng and every day eye drop dosage 0.2～2% sustained-release dosage every day.

For example, for travoprost (Su Weitan), prostaglandin F2 alpha analog, this glaucoma medicine can have 2% or following concentration of timolol.For example, can be 0.004% in the commercial solution concentration that obtains, administration every day is 1 time usually.In many embodiments, the treatment valid density of the medicine that discharge every day from device can be about 65ng, shows as the tear similar to timolol and removes and bioavailability.Therefore, the amount that depends on the medicine on the implantable device of bioavailability can significantly reduce.It also can change into littler or can hold more medicine and be used for the longer release device in period than the device that is used for β-blocking agent administration.For example, for travoprost, latanoprost and other prostaglandin F2 alpha analog, the amount of the medicine on implantable device is very low, is about 1/100 timolol, for example 2.7～13.5 μ g, particularly about 3～20 μ g.Though the slow release amount of the latanoprost that discharges every day can change, every day 65ng slow release be equivalent to give 1 0.004% solution travoprost 2.0 μ g about 3.2%.

In some embodiments, therapeutic agent might comprise corticosteroid, for example is used for the treatment of the fluocinolone acetonide of target part tissue of eye.In the specific embodiment, fluocinolone acetonide can discharge from lacrimal ductule, and is transported to retina as the therapeutic agent that is used for diabetic macular edema (DME).

Described device is modified or adjusted with high rate of release, and low rate of release discharges (bolus release) fast, prominent release or it makes up administration to be also contained in the scope of the present invention.The quick release of medicine can discharge by forming the erodable cap that is dissolved into rapidly in tear or the tear film.When this cap contacted with tear or tear film, the dissolution properties of described polymer corroded lid, and all medicine is discharged immediately.The prominent polymer that can use based on polymer dissolution loss in tear or tear film of releasing of medicine is realized.In this example, this medicine and polymer can be along the length layerings of device, thereby externally polymeric layer when dissolving medicine is released immediately.The high or low rate of release of medicine can realize by the dissolubility that changes the erodable polymeric layer, so that medicine layer discharges rapidly or slowly.Other method that discharges medicine can be by the perforated membrane based on the drug molecule size, sol gel (for example sol gel in typical collyrium), and microgranule encapsulation or the nanoparticle encapsulation of medicine are realized.

Medicated core

Medicated core comprises therapeutic agent and the material of this therapeutic agent slow release is provided.Therapeutic agent moves to purpose from medicated core and for example organizes the ciliary muscle of eye.Therapeutic agent can only be slightly soluble in the substrate to washability, so that a small amount of therapeutic agent is dissolved in the substrate and is used for effectively discharging from the surface of medicated core 110.When therapeutic agent when the exposed surface of core is diffused into tear or the tear film, from the core to tear or the rate travel of tear film can be dissolved in substrate in the concentration of therapeutic agent relevant.In addition or with it combination, therapeutic agent from the core to tear or the rate travel of tear film can be relevant with the character of the substrate that is dissolved with therapeutic agent.In the specific embodiment, from the medicated core to tear or the rate travel of tear film can be based on silicone formulations.In some embodiments, the concentration of dissolved therapeutic agent can be controlled to provide the required rate of release of therapeutic agent in medicated core.Be included in the mode of liquid that therapeutic agent in the core can comprise this therapeutic agent, solid, solid gel, solid crystal, solid amorphous, solid particle and/or dissolving.In a preferred embodiment, medicated core comprises the silicone substrate that contains therapeutic agent.Described therapeutic agent can comprise the liquid or solid inclusion body, for example is dispersed in liquid latanoprost drop or solid bimatoprost granule in the silicone substrate respectively.

Medicated core can comprise that one or more have the biocompatible materials that slow release treatment agent ability is provided.Though to comprise that the embodiment of the inclusion body of dissolved drug describes medicated core nonbiodegradable in fact silicone substrate with being positioned at wherein, but medicated core can comprise the structure of the slow release that therapeutic agent is provided, for example biodegradable matrix, porous medicated core, liquid medicated core and solid medicated core.The substrate that comprises therapeutic agent can be formed by any one of biodegradable polymers or non-biodegradation polymer.The non-biodegradation medicated core can comprise that silicone, acrylate, polyethylene, polyurethane, polyurethane, hydrogel, polyester (for example obtain from the E.I.Du Pont de Nemours and Company of the Wilmington of the Delaware State

), polypropylene, polytetrafluoroethylene (PTFE), intumescent PTFE (ePTFE), polyether-ether-ketone (PEEK), nylon, extrude collagen, foam of polymers, silicone rubber, polyethylene terephthalate, ultra-high molecular weight polyethylene, Merlon ammonia ester, polyurethane, polyimides, rustless steel, Ni-Ti alloy (for example Nitinol), titanium, rustless steel, cobalt-chromium alloy and (for example, obtain from the Elgin Specialty Metals of Illinois Elgin Obtain from the Carpenter Metals company of Pennsylvanian Wyomissing ).Biodegradable medicated core can comprise one or more biodegradable polymers, protein for example, hydrogel, polyglycolic acid (PGA), polylactic acid (PLA), gather (L-lactic acid) (PLLA), gather (L-glycolic) (PLGA), polyglycolide, poly--the L-lactide, poly--the D-lactide, polyamino acid Ju diethyleno dioxide ketone, polycaprolactone, polyglyconate, polylactic acid-polyethylene oxide copolymer, modified cellulose, collagen, poe, poly butyric ester, polyanhydride, poly phosphate, poly-('alpha '-hydroxy acids) and combination thereof.In some embodiments, medicated core can comprise at least a aquogel polymer.

Therapeutic agent discharges with effect level

The rate of release of therapeutic agent can be dissolved in medicated core in the concentration of therapeutic agent relevant.In many embodiments, medicated core comprises the nontherapeutic agent that is selected to provide the required dissolubility of therapeutic agent in medicated core.The nontherapeutic agent of this medicated core can comprise above-mentioned polymer and additive.The polymer of core can be selected to provide the required dissolubility of therapeutic agent in substrate.For example, described core can comprise the hydrogel of the dissolubility that can improve hydrophilic therapeutic agent.In some embodiments, can in polymer, add functional group so that the required dissolubility of therapeutic agent in substrate to be provided.For example, functional group can be attached on the silicone polymer.

In some embodiments, can use additive with the release dynamics of control therapeutic agent.For example, can use additive by increasing or reduce the concentration that the dissolubility of therapeutic agent in medicated core controlled therapeutic agent, with the release dynamics of control therapeutic agent.Can control dissolubility by suitable molecule and/or material is provided, described molecule and/or material can increase and/or reduce lysed therapeutic agent to the dissolubility of substrate.Might be relevant with the hydrophobic and/or hydrophilic nmature of substrate and therapeutic agent by the lysed dissolubility of this therapeutic agent.For example, surfactant, Ting Nafen, salt and water can be added in the substrate, and might increase the dissolubility of hydrophilic therapeutic agent in substrate.In addition, oil and hydrophobic molecule can be added in the substrate, and might improve the dissolubility of hydrophobic therapeutic agent in substrate.

Except controlling its rate travel based on the concentration that therapeutic agent is dissolved in the substrate, the surface area that also can control medicated core substitutes with the desired rate that obtains medicine and move to the purpose position from medicated core or as additional means.For example, core increase the rate travel of therapeutic agent from medicated core to the purpose position than the big exposure surface area, and the less exposed surface area of medicated core reduces the rate travel of therapeutic agent from medicated core to the purpose position.The exposed surface area of medicated core can increase by many methods, for example by the battlements of exposed surface, has the porous surface of the exposed vias that is connected with tear or tear film, the groove of exposed surface, any one of the protuberance of exposed surface.Exposed surface can form porous by the salt that adds dissolving, and residual in case salt dissolves have a porous cavity.Also can use hydrogel, swelling is to provide bigger exposed surface area dimensionally.This hydrogel also can be made into porous with the rate travel of further raising therapeutic agent.

Further, can use the implant with the two or more medicine abilities of associated release, for example disclosed structure in United States Patent (USP) the 4281654th (Shell).For example, under the situation of glaucoma treatment, with multiple prostaglandin or a kind of prostaglandin and cholinergic agent or 1 adrenergic antagonists (β-blocade) for example be necessary

Perhaps a kind of prostaglandin and carbonic anhydrase inhibitors come the patient is treated.

In addition, for example can use medicines such as the Biostatic polymer floor dipping sieve of in No. the 2002/0055701st, U.S. Patent application disclosed medicine dipping sieve or record in No. the 2005/0129731st, U.S. Patent application.Might use some polymer process medicine is merged in the device of the present invention, useful chemical compound was connected molecule with physiology's inertia on for example so-called " self administration of medication medicine " or polymer drug (the Polymerix company of New Jersey Piscataway) were designed to only be degraded into and treat, further disclose in No. 2005/0048121 (East) at United States Patent (USP) and specify, by reference it all is herein incorporated.This transferring polymer can be configured in the device of the present invention to provide and equate with polymer erodes and degradation rate and be constant rate of release in therapeutic process.This transferring polymer can be used as the device coating or be used for injectable prolonged drug preparation (for example storage of the present invention) with the form of microsphere.Further the polymer transport technology also goes for device of the present invention, for example discloses the technology that No. 2004/0170685 (Carpenter) puts down in writing and obtain from Medivas (Santiago, California) at United States Patent (USP).

In the specific embodiment, medicated core substrate comprises solid material, for example the silicone of encapsulation medicine inclusion body.This medicine is included in molecule extremely insoluble and that dissolve a little in the water in encapsulation medicated core substrate.Inclusion body by the medicated core encapsulation can be for having the microgranule of the wide size of about 1 μ m～about 100 μ m.This medicine inclusion body can comprise crystallization, for example bimatoprost crystallization, and/or oil droplet, for example latanoprost oil.This medicine inclusion body can be dissolved in the solid medicated core substrate, and with the saturated substantially drug matrices of medicine, for example latanoprost oil is dissolved in the solid medicated core substrate.The medicine that is dissolved in the medicated core substrate is transported to the tear film by the exposed surface of diffusion from medicated core usually.Because medicated core substrate uses medicine saturated basically, in many embodiments, the rate-limiting step of administration is the surface transhipment of the medicated core substrate of medicine from be exposed to the tear film.Because medicated core substrate uses medicine saturated basically, intramatrical drug level gradient minimum can significantly not promote the speed of administration.Because the surface area that is exposed to the medicated core in the tear film is near constant, the transport of drug speed substantially constant from medicated core to the tear film.The present invention is carried out correlational study show, dissolubility and the molecular weight of medicine of therapeutic agent in water can be influential to the transhipment during medicine is from the solid matrix to tear.In many embodiments, this therapeutic agent is water-soluble hardly, has dissolubility in about 0.03%～0.002% the water by weight, and molecular weight is about 400g/mol～about 1200g/mol.

In many embodiments, therapeutic agent has extremely low dissolubility in water, and for example about 0.03%～by weight about 0.002% by weight, molecular weight is about 400 grams/mole (g/mol)～about 1200g/mol, and is soluble in the organic solvent.Cyclosporin A (CsA) is that to have under 25 ℃ be 27.67 μ g/mL or 0.0027% water solubility by weight, and molecular weight (M.W.) is the solid of 1202.6g/mol.Latanoprost (Xalatan) is the prostaglandin F2 alpha analog, is liquid oil at room temperature, have under 25 ℃ be 50 μ g/mL in water for or about 0.005% water solubility by weight, and M.W. is 432.6g/mol.Bimatoprost (Lu Meigen) is the synthesising prostate amide analogue, at room temperature is solid, be 300 μ g/mL or by weight 0.03% at 25 ℃ of following water solubilities, and M.W. is 415.6g/mol.

The present invention is carried out correlational study show, the surfactant of natural generation in the tear film, for example surfactant D and phospholipid might be influential to the transhipment of tear film from core to the medicine that is dissolved in the solid matrix.Medicated core can be adapted to provide medicament slow release owing to the surfactant in the tear film in the tear film with treatment level.For example, for the content of surfactant, can be collected and analyzed patient's number from tear, for example 10 patients obtain empirical data.Slightly water-soluble medicine for example the stripping figure of cyclosporin in the tear of collecting can be determined and with stripping figure contrast in buffer and surfactant, thereby set up the external model of tear surfactant.The external solution with surfactant based on this empirical data can be used to adjust medicated core with the surfactant of corresponding tear film.

Medicated core also can be modified in order to the vehicle excipients with for example nanoparticle or microgranule according to the size of the molecule that is transferred; for example be used for the latent active nano fiber composition (the Innovative Surface Technologies company limited in Sao Paulo, the Minnesota State) of compound and nanometer surface of the texture, be called as

The nanostructured porous silicon, comprise micron-scale granule, film, braided fiber or miniature implanting device (pSividia, Limited, UK) and the cell selected of the targeting protein nano cage system (Chimeracore) that carries out administration.

In many embodiments, the medicine insert comprise have contain be dispersed in Nusil6385 (MAF970), as the thin-walled polyimide tube sheath of the medicated core of the latanoprost in the pharmaceutical grade solid silicone of administration substrate.The far-end of medicine insert is sealed by the cured film of solid Loctite4305 pharmaceutical grade binding agent.This medicine insert can be configured in the hole of tear stains plug, and this Loctite4305 binding agent can not contact with any one party of tissue or tear film.The internal diameter of medicine insert can be 0.32mm, and length can be 0.95mm.Three kinds of latanoprost concentration in the finished drug product can be tested clinically: medicated core can comprise that concentration expressed in percentage by weight is respectively 5,10 and 20% 3.5,7 or 14 μ g latanoprosts.Suppose total dissolution rate of about 100ng/ days, the medicated core that then contains 14 μ g latanoprosts is fit to administration at least about 100 days, for example 120 days.The gross weight that contains the medicated core of latanoprost can be～70 μ g.The weight that comprises the medicine insert of polyimides sleeve pipe can be about 100 μ g.

In many embodiments, medicated core can following stripping: initial high-caliber therapeutic agent, carry out the substantially invariable stripping of therapeutic agent subsequently.In many cases, might be lower than treatment level from the therapeutic dose that core discharges every day, but still provide effect to the patient.Can cause the residual quantity of therapeutic agent and/or the residual effect of therapeutic agent with the high-caliber therapeutic agent that is dissolved of the inferior therapeutic dose coupling of the therapeutic agent that alleviates the patient suffering.In embodiment, treatment level is about 80ng/ days, and at initial medicine-feeding period, device every day can the about 100ng of administration.The 20ng of extra administration every day is to be lower than treatment level, can to have beneficial effect when for example 60ng/ sky imposes therapeutic agent.Because the amount of administration can accurately be controlled, initial high dose might can not cause complication and/or side effect to the patient.

Specify by the exemplary embodiment of embodiment, in order more clearly to understand, to those skilled in the art will recognize that and to carry out multiple modification, modification, change.Therefore, scope of the present invention is only chased after attached claim and is limited.

Claims

1. implant that is used for being inserted into patient's lacrimal point, described implant comprises:

Medicated core with far-end and near-end, the far-end of described medicated core have the cross section that is fit to by the lacrimal point insertion, and described medicated core comprises the therapeutic agent in the eye that can be transported to described patient;

Be arranged in the sheath that limits at least one exposed surface of described medicated core on the part of described medicated core, at least one exposed surface of described medicated core is positioned near the near-end of described medicated core with contact tear or tear film liquid, and when described implant is implanted for use, continuing to discharge described therapeutic agent in period with treatment level, wherein said sheath is impermeable substantially to therapeutic agent; With

Comprise the main body that keeps structure, described maintenance structural configuration becomes the described medicated core of at least part of covering, and described maintenance structure has suitable at least part of size of intracavity in the lacrimal ductule that is assemblied in so that implant maintenance implantation position.

2. implant according to claim 1, wherein, described maintenance structure is connected with described medicated core by described sheath.

3. implant according to claim 1, wherein, described maintenance structure is included in the swellable material that is suitable for expanding when described maintenance structure is placed in the described lacrimal point.

4. implant according to claim 3, wherein, described swellable material comprises hydrogel.

5. implant according to claim 1, wherein, described main body is included in and described surface is remained near the described lacrimal point flange near described at least one exposed surface.

6. implant according to claim 1, wherein, described maintenance structure is expandable being suitable for inserting the low profile shape of described lacrimal point and described maintenance structure being anchored between the big contour shape in the described lacrimal ductule inner chamber.

7. implant according to claim 6, wherein, when described maintenance structure expand into described big contour shape from described low profile shape, described maintenance structure was slided near the near-end of described medicated core along described medicated core.

8. implant according to claim 6, wherein, being shorter in length than when the described low profile shape along the length of the described maintenance structure of described medicated core along the described maintenance structure of described medicated core when described big contour shape.

9. implant according to claim 6, wherein, but the elastic expansion of described maintenance structure, and described maintenance structure comprises elastic metallic or marmem.

10. implant according to claim 6, wherein, described low profile has the cross section of 0.2mm at the most, and described big profile has the cross section of 2.0mm at the most.

11. implant according to claim 1, described maintenance structure comprises the tubular body with the arm that is separated by groove.

12. implant according to claim 1 wherein, further comprises being installed in the structural inaccessible unit that can expand to suppress tear stream along with described maintenance structure of described maintenance.

13. implant according to claim 1; further comprise and suppress the inaccessible unit that tear stream passes described lacrimal ductule inner chamber; wherein, the described inaccessible unit part that covers described maintenance structure at least is not subjected to described maintenance structure influence to protect described lacrimal ductule inner chamber.

14. implant according to claim 1, wherein, described sheath comprises the layer that is arranged on the described medicated core, discharges by described layer to suppress described therapeutic agent.

15. implant according to claim 1, wherein, described medicated core discharges described therapeutic agent by described at least one exposed surface.

16. implant according to claim 1, wherein, when making described surface be exposed to described tear or tear film liquid described implant implantation, described medicated core discharges described therapeutic agent with treatment level in the period at least 1 week.

17. according to the described implant of described claim 1, wherein, described medicated core comprises the inclusion body of described therapeutic agent, described therapeutic agent dissolves in the described medicated core, when described medicated core is implanted, provides basic rate of release uniformly.

18. implant according to claim 1 further comprises and suppresses the inaccessible unit that tear stream passes described lacrimal ductule inner chamber.

19. implant according to claim 18, wherein, described inaccessible unit is shaped as and suppresses the shape that tear stream passes described lacrimal ductule inner chamber.