CN101505683A

CN101505683A - Drug delivery methods, structures, and compositions for nasolacrimal system

Info

Publication number: CN101505683A
Application number: CNA2007800171662A
Authority: CN
Inventors: 小尤金·德朱昂; 卡里·赖希; 斯蒂芬·博伊德; 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: 2009-08-12
Anticipated expiration: 2027-04-02
Also published as: CN101505683B; CN101505681B; CN101505681A

Abstract

An implant which is provided by the invention for being inserted into the lacrimal punctum of patient comprises a main body. The main body comprises a distant end, a near end and a shaft between the distant end and the near end. The distant end of main body can be inserted into the inner cavity of lacrimal duct to the distant end through the lacrimal punctum. The main body comprises a therapeutic agent included in the flux core of pharmaceutical base. The exposing of pharmaceutical base to the tear causes that the effective therapeutic agent is released into the tear in duration. The main body is provided with a sheath which is configured on the pharmaceutical base for inhibiting the releasing of agent from the near end. The body is also provided with an outer surface which is combined with the tissue of inner cavity wall that restricts the discharging of tissue of inner cavity wall. In a specific execution mode, the pharmaceutical base comprises a non-biological absorptive polymer, such as the silicone in the non-homogeneous phase compound comprising the agent.

Description

The medicine release method, structure and the compositions that are used for nose tear system

Cross reference to related application

The application requires the U.S. Provisional Application No.60/787 that submits on March 31st, 2006 according to 35 USC 1 19 (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 the implant that is used 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 of treatment (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 recommendation.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 the 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 being left, 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 on eye drop, some potential problems of this method may comprise: implant the implantation of required tissue site, implant in a period of time that the 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 released, 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 the implanting device, the system and method that are used for discharging therapeutic agent from the lacrimal point of patient's part tissue of eye.

In first scheme, embodiments of the present invention provide a kind of implant that is used for being inserted into patient's lacrimal point.Described lacrimal point provides flow path from eye to the lacrimal ductule inner chamber to tear.Described implant comprises main body.Described main body has far-end, near-end and axle between the two.The described far-end of described main body can distad be inserted in the described lacrimal ductule inner chamber by described lacrimal point.Described main body is included in the therapeutic agent that the pharmaceutical base medicated core contains.Described pharmaceutical base is exposed to described tear makes effective therapeutic agent continue to be discharged in the described tear in period one.Described main body has the sheath that is arranged on the described pharmaceutical base and discharges from described near-end to suppress described preparation.Described main body also has and forms the discharge that the outer surface that engages with the internal chamber wall tissue suppresses main body with in being arranged in inner chamber the time.

In some embodiments, described pharmaceutical base comprises the examples of non-bioabsorbable polymer, for example, is included in the silicone in the non-homogeneous mixture of described preparation.Described non-homogeneous mixture can comprise by the saturated silicone substrate portion of described therapeutic agent and the inclusion body of described therapeutic agent.

In many embodiments, the outer surface of described main body can be disposed on the described sheath, and described outer surface can limit and suppress the body shape that described main body is discharged from described lacrimal point.Described main body may further include the supporting construction on described pharmaceutical base.Described supporting construction can limit described outer surface and form and suppress the shape that described main body is discharged from described lacrimal point.In the specific embodiment, described supporting construction within it portion accept described sheath and pharmaceutical base medicated core and when suppressing to use the non-of described pharmaceutical base have a mind to discharge.Described supporting construction can comprise spiral winding.Described supporting construction can have accepter therein, and described accepter is adapted at wherein accepting described sheath and pharmaceutical base and freely transmits fluid when allowing to use between described near-end and described tear film.When in described lacrimal point, discharging, the radial expansion of described outer surface, described radial expansion can suppress the discharge from described lacrimal point.

In the specific embodiment, described preparation comprises prostaglandin analogue, and comprise at least 3 months described lasting period.

In many embodiments, provide a kind of implant that is used for being inserted into the patient.Described patient has the tear path relevant with eye, and described implant comprises main body.Described main body can comprise therapeutic agent and supporting construction.Described main body can form when implanting destination locations along described tear path, some days slow release in period every day a certain amount of described therapeutic agent is discharged in the described tear.Described amount significantly is lower than the amount that gives described therapeutic agent every day with eye drop of recommendation.For example, described amount can be lower than recommendation with 10% of eye drop dosage.In the specific embodiment, described amount can be lower than described recommendation with 5% of eye drop dosage.

In many embodiments, comprised at least 3 weeks described period and can comprise at least 3 months.Described therapeutic agent can comprise timolol maleate.Described main body can comprise the described therapeutic agent of about 270 μ g～about 1350 μ g.The amount that discharge described every day can be about 20 μ g～about 135 μ g.

In many embodiments, described therapeutic agent can comprise prostaglandin analogue, for example latanoprost and/or bimatoprost, and described main body can comprise the therapeutic agent of about 3 μ g～about 135 μ g.Described amount can be about 5ng～about 500ng.In the specific embodiment, described main body can comprise the therapeutic agent of about 5 μ g～about 30 μ g, and described amount can be about 10ng～about 150ng.

In another program, embodiments of the present invention provide a kind of method that is used for therapeutic agent is discharged into the eye with relevant tear.Described method comprises medicated core is placed in the lacrimal ductule of described eye.Described medicated core comprises substrate and at the inclusion body of described intramatrical described therapeutic agent.The part of described medicated core is exposed to described tear.Described therapeutic agent is discharged in the described tear of described eye.Described therapeutic agent is dissolved in the described substrate, so when described therapeutic agent when one continues in period to discharge by described exposure portion with treatment level, described substrate maintenance is saturated by described therapeutic agent substantially.

In many embodiments, rate of release is substantially by the dissolubility of the described preparation in the described medicated core, the area decision of the dissolubility of the described preparation in the described tear and described exposure portion.Described medicine can be in about 90 days discharges by described exposure portion with treatment level.Described therapeutic agent can comprise prostaglandin analogue, and the described inclusion body of described therapeutic agent comprises oil.Described therapeutic agent can be encapsulated in described substrate, and described substrate can comprise the examples of non-bioabsorbable polymer.

In many embodiments, described therapeutic agent has by weight the dissolubility less than about 0.03% in water.Described therapeutic agent can discharge with treatment level in response to the surfactant of described tear.Sheath can be configured on the described medicated core limiting described exposure portion, and described exposure portion is orientated towards described eye at the near-end of described medicated core.

In many embodiments, provide a kind of treatment glaucomatous tear stains plug.Described plug comprises the wide main body of about at the most 2.0mm.35 days the time, described 35 days every day, described main body discharged the therapeutic agent of therapeutic dose at least in being inserted into described lacrimal point.In some embodiments, when being inserted among the described patient, the wide described main body of about at the most 2.0mm comprises the wide sectional dimension of about at the most 1.0mm.In the specific embodiment, described main body comprises medicated core and the described therapeutic agent that discharges from described medicated core.Described medicated core can be wide up to about 1mm, and described main body can be about 2mm at the most on length.

In many embodiments, provide a kind of and treat glaucomatous method with the tear stains plug, described method is included in 90 days from described tear stains plug with 10ng/ days stripping therapeutic agents at least at least.In the specific embodiment, described therapeutic agent comprises at least a in bimatoprost or the latanoprost.Described therapeutic agent can have about at the most 0.03% dissolubility by weight in water.

In many embodiments, a kind of glaucomatous tear stains plug that is used for the treatment of is provided, described plug comprises cock body.Described cock body comprises therapeutic agent, and described cock body is suitable for discharging described therapeutic agent in response to the surfactant of eye with treatment level.In the specific embodiment, described therapeutic agent has about at the most 0.03% dissolubility by weight in water.Described therapeutic agent can comprise cyclosporin.

In many embodiments, provide a kind of glaucomatous tear stains plug that is used for the treatment of.Described plug comprises cock body.Described cock body comprises therapeutic agent.Described cock body is suitable at least about 20 days the described therapeutic agent of about 80～120ng is discharged in the tear of described eye.In the specific embodiment, described therapeutic agent can comprise at least a in bimatoprost or the latanoprost.

In some embodiments, provide a kind of glaucomatous tear stains plug that is used for the treatment of.Described tear stains plug comprises cock body.Described cock body is included in about at the most 0.02cm ³The therapeutic agent of storage in the volume.Described cock body is suitable for discharging the described therapeutic agent of treatment level at least about 1 month.In the specific embodiment, described cock body is suitable for discharging described therapeutic agent with treatment level at least about 3 months.Described cock body can be suitable at least 1 month discharging described therapeutic agent with zero order release rate in fact.

In some embodiments, provide a kind of compositions that is used for the treatment of the glaucomatous material of eye with relevant tear.Described compositions comprises inclusion body.Described inclusion body comprises the therapeutic agent of conc forms.Described therapeutic agent has about at the most 0.03% dissolubility by weight in water.Silicone substrate encapsulation has described inclusion body.Described therapeutic agent is dissolved in the described silicone substrate, with treatment level described therapeutic agent is discharged into the described tear from described silicone substrate.In the specific embodiment, described therapeutic agent inclusion body is encapsulated in the described silicon matrix, comprises the non-homogeneous mixture that is encapsulated in the intramatrical described inclusion body of described silicone.Described inclusion body can comprise latanoprost oil.

Description of drawings

Fig. 1-1 and Fig. 1-2 represent the anatomical tissue structure of eye that is suitable for using implant treatment according to embodiment of the present invention;

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 keeps the schematic illustration of the slow release implant of structure, core and sheath for the current limliting that comprises according to an embodiment of the present invention;

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 the 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 is used to increase the perspective view of slow release implant of the core of the passage that medicine moves for expression having according to an embodiment of the present invention comprises;

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 is the side view of the slow release implant of the medicated core on the expression surface with the recessed indentation (concave indented) that comprises the exposed surface area that is used to increase core according to an embodiment of the present invention;

Fig. 2 M is the expression side view of the 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 of the exposed surface area that is used to increase 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～Fig. 5 C be according to an embodiment of the present invention the replacement medicated core and the schematic illustration of sheath body;

Fig. 6 A～Fig. 6 C represents the configuration of slow release implant according to an embodiment of the present invention; With

Fig. 7 A and Fig. 7 B represent the three kinds of concentration for the three kinds of cores and the latanoprost about 5%, 11% and 18% of 0.006,0.012 and 0.025 inch of diameter according to embodiment of the present invention respectively, the stripping data of the 1st day and the 14th day latanoprost;

Fig. 7 C represents according to the latanoprost of embodiment of the present invention from the 0.32mm diameter of the drug weight that has 5,10 and 20% concentration and 3.5,7,14 μ g respectively, the stripping data of 0.95mm length medicated core;

Fig. 7 D and Fig. 7 E represent according to embodiment of the present invention for respectively as Fig. 7 A and Fig. 7 B latanoprost in three kinds of core diameters and the three kinds of concentration shown in the 1st day and the 14th day, dissolution rate is to the dependency of the exposed surface area of medicated core;

Fig. 8 A represents to enter stripping figure the buffer that does not have surfactant and have surfactant according to the cyclosporin of embodiment of the present invention from medicated core;

Fig. 9 A represent according to embodiment of the present invention for silicone gross sample with 1% bimatoprost, in 100 days with the standard stripping figure of ng/ device/sky expression;

Figure 10 A represents according to the latanoprost of four kinds of latanoprost preparations of the embodiment of the present invention stripping figure from core.

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 disposed 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 on fovea centralis 7F and retina 7.The optical power of cornea 4 and crystalline lens 5 helps to form image on 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 so that the good near vision of near-eye side object to be provided 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 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 inlet 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 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 around these microgranules of encapsulation in the solid matrix, for example silicone, and substrate 170 is saturated substantially by described therapeutic agent when core discharges at therapeutic agent like this.

Medicated core 110 is surrounded by sheath body 120.Sheath body 120 is impermeable to therapeutic agent 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.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 benign tissue bond surface is provided.Sheath body 120 comprises with keeping structure 130 and being connected to keep the sheath body 150 of sheath body 120 and medicated core 110.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 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 with utensil for example the protuberance that engages of the utensil of hook, circle, stitching thread or ring 124R etc. can stretch out from sheath body 124, so that medicated core and sheath body can be removed the replacement that promotes 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.Medicated core 116 is covered most of medicated core 116 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.Medicated core 118 is covered most of medicated core 118 by sheath body 128.Medicated core discharges therapeutic agent by exposed distal ends as mentioned above, 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 strongly and relevant substantially 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, near the diameter on the exposure medicated core surface for example 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 exposed surface of the physical characteristic of described medicated core, for example by reducing therapeutic agent described herein dissolved concentration in drug matrices with the increase of compensation medicated core.

Fig. 1 G keeps the schematic illustration of the slow release implant 180 of structure 186, core 182 and sheath 184 for the current limliting that comprises according to an embodiment of the present invention.Sheath body 184 can cover medicated core 182 to small part.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 the release therapeutic agent of increase.Inaccessible unit 188 can be configured in and keep wearing lacrimal ductule with blocking-up tear stream 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.At a lot of cores and the sheath of this explanation, especially, can be used as the tear stains plug and implant separately with reference to the structure of Fig. 2 A～Fig. 2 J explanation.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 proximate diameter of maximum cross-section diameter with 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 have with the proximate external diameter of maximum cross-section diameter of core 210 and with the proximate internal diameter of 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 on 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 the 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 cutaway view of the expression slow release implant 206 with medicated core 216 according to an embodiment of the present invention, and this medicated core 216 comprises the increase exposed surface area 216A that has from the battlements of exposed surface area 216A extension.Described battlements comprises the surface area of a plurality of isolated finger piece 216F with 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 an end openings so that exposed surface 216A to be provided on 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 has the permission medicine and moves to the tear on every side or the exposed surface 260A of tear film liquid on the end of core.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 moving from core 260 to tear or tear film liquid and the targeted treatment area.Form fold 260F and in core 260, form passage 260C.The end of passage 260C and core is connected to become the opening in exposed surface 260A, and prepares for the mobile of therapeutic agent.Like this, whole exposed surface area of core 260 comprise.Directly be 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 has the permission medicine and moves to the tear on every side or the exposed surface 260A of tear film liquid on the end of core.Core 262 also comprises passage 262C.Passage 262C increases the surface area of passage by the inner surperficial 262P of the porous that forms to SMIS 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 moving from core 262 to tear or 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 used to increase the perspective view of slow release implant 254 of the core 264 of the passage that medicine moves for expression having according to an embodiment of the present invention comprises.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 moving from core 264 to tear or 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 to small part covers medicated core 266 and extends 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 on sheath body 276.Protuberance 276P can be extruded inward so 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 to small part covers medicated core 268 and extends 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.Parts 268F such as soft brush also are soft, elasticity 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 that is used to make 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 a 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 to small part covers medicated core 269 and extends to limit 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 is the side view of the slow release implant 230 of the medicated core 232 of the expression surperficial 232A with the recessed indentation that comprises the exposed surface area that is used to increase core according to an embodiment of the present invention.Sheath body 234 to small part covers medicated core 232 and extends.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 expression vertical view of the 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 of the exposed surface area that is used to increase core.Sheath body 244 to small part covers medicated core 242 and extends.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 provides 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 sheath body 320 core is remained near the lacrimal point.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 to small part covers medicated core 410 and limits 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 holding unit 430 from the small bore contour shape when the heavy in section contour shape expands, inaccessible unit 440 can be with keeping structure 430 to move.In a lot of embodiments, keep structure and inaccessible unitary size corresponding to dacryocanalicular diameter, for example be complementary 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 with dacryocanalicular diameter.

Shown in Fig. 4 A, keep structure 430 and inaccessible unit 440 in the low profile shape.This low profile shape can occur when inaccessible unit and holding unit are configured in the top of insertion instrument and be capped configuration.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 and change over the diameter that is fit to be contained in or to slip into the size in the lacrimal ductule, and in second largest contour shape, described holding unit and inaccessible unitary size 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, the length of inaccessible unit 440 and maintenance structure 430 is than low profile shape short-distance and medium-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 on sheath body 420, to slide, 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 is than medicated core 410 short distances 450, 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 can be used to insert the execution of instrument mode 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 with implant 520 to keep implant.Along with expanding lacrimal point in advance, can implant 520 be inserted in the lacrimal point with instrument 500 with dilator 510.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.

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 that is used to expand 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 implant 570 is advanced to far-end when far-end advances at plunger 580 with plunger 580.When lacrimal point during with dilator 560 expansion, plunger 580 can advance implant 570 is disposed near the lacrimal ductule inner chamber the lacrimal point to far-end.In a lot of embodiments, can press the button so 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 often comprise that the surface that is similar to is with the expansion lacrimal point.Implant 620, sheath 610 and circulus 615 can be inserted in the lacrimal point so that implant is disposed in the lacrimal ductule inner chamber to small part.Circulus 615 is configured on the sheath 610, and so sheath 610 can be retracted and slide under circulus 615.When sheath 610 was retracted near-end with exposure implant 620, stop 625 can link to each other with main body 605 and with intracavity in lacrimal ductule implant 620 be remained on desired depth.

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 with the exposure of the desired location in lacrimal ductule inner chamber implant in the contraction on the proximal direction on the proximal direction 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 of expanding lacrimal point before the implant, and as mentioned above, and dilator can be configured on the terminal opposite end that this insertion tool coating is loaded with implant.

Fig. 5 A～Fig. 5 C be according to an embodiment of the present invention replacement medicated core 510 and the schematic illustration of sheath body 520.Implant 700 comprises medicated core 510, sheath body 520 and keeps structure 530.Implant 500 can comprise and is held that structure 530 supports and can be with its inaccessible unit that moves.Usually keep structure 530 before implanting, to show as first contour shape---the low profile shape, and show as second contour shape after implanting---big contour shape.Maintenance structure 530 is shown in the big contour shape and is implanted in the lacrimal ductule inner chamber.Sheath body 520 comprises extension 525A and extension 525B so that sheath body and medicated core are attached on the maintenance structure 530, and said sheath body and medicated core are held structure 530 and keep.Medicated core 510 and sheath body 520 can be by pulling to near-end with medicated core 510 and being removed together shown in arrow 540.Shown in Fig. 5 B, keep structure 530 after medicated core 510 and sheath body 520 are removed, still to be implanted in the lacrimal ductule tissue.Shown in Fig. 5 C, replace medicated core 560 and replace sheath body 570 and can be inserted into together.Preferably discharged the effective dose of therapeutic agent at medicated core 510, the supply of the therapeutic agent in medicated core reduces, and the therapeutic agent rate of release is carried out this replacement near behind the minimum effect level.Replace sheath body 570 and comprise extension 575A and extension 575B.Replacement medicated core 560 and replacement sheath body 570 can be pushed into far-end and be inserted in the maintenance structure 530 will replace medicated core 560 and to replace sheath body 570 shown in arrow 590.When replacement medicated core 560 is inserted in the elastomeric element 530 with replacement sheath body 570, keep structure 530 substantially still on same position.

Fig. 6 A～Fig. 6 C represents the configuration of slow release implant according to an embodiment of the present invention.As shown in Figure 6A, configuration tool 610 is inserted in the lacrimal ductule 600 by lacrimal point 600A.Top and sheath 612 that slow release implant 620 is loaded onto configuration tool 610 cover slow release implant 620.When sheath 612 is configured on the maintenance structure 630, keep structure 630 to show as the low profile shape.Shown in Fig. 6 B, the outer sheath 612 of drawing back configuration tool 610 is to expose the maintenance structure 630 of slow release implant 620.Holding unit 630 exposed portions show as big contour shape.Shown in Fig. 6 C, configuration tool 610 has been removed and slow release implant 620 is implanted in the lacrimal ductule 600.Medicated core 640 is attached on the maintenance structure 630 and is maintained in the lacrimal ductule.Outer body sheath 650 covers the part of medicated core 640 at least, and medicated core 640 is discharged into therapeutic agent near the lacrimal point 600A of lacrimal ductule 600 the tear or tear film liquid 660.

The sheath body

Described sheath body comprises that suitable shape and material move from described medicated core with the control therapeutic agent.The sheath body accommodates core and can closely be fit to core.Described sheath body is by making for the impervious material of therapeutic agent substantially, and so the transfer rate of therapeutic agent can be mainly be controlled by the exposed surface area of the medicated core that is not covered by the sheath body.In a lot of embodiments, therapeutic agent by moving of sheath body can be about the exposed surface of therapeutic agent by medicated core move 1/10th or still less, be generally one of percentage or still less.In other words, therapeutic agent moves the moving less than the exposed surface of therapeutic agent by medicated core of approximate number magnitude at least by the sheath body.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, is for example injected and/or be 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 medicated 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 keep structure can have the feature of difference for example is used to represent the color of the difference of arranging, 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 the labelling of the degree of depth of the layout that at least one is used for being illustrated in lacrimal ductule, and 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 the 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 on sheath body and medicated core.Preferably have this slip ability at an end, this is because when keeping structure to expand on width when showing as required transversal width, described maintenance structure might shorten on 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.

Inaccessible unit

Described inaccessible unit comprises and forms shape so that implant can suppress even block fluid stream is worn the hollow tissue structure to small part 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 the isolating light wall pipe that slides as mentioned above and be anchored on the material of an end that keeps structure on maintenance structure end.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.Inaccessible unitary thickness can be in the relative broad range of about 0.0.1mm～about 0.15mm, usually in the scope of about 0.05mm～0.1mm.

Therapeutic agent

" therapeutic agent " can comprise can be the equivalent of following substances any one or they, 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 of treatment includes but not limited to glaucoma, before the art and aftertreatment, 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 (tetracycline for example, 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; The reconstruct 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) (salicylic acid for example, indomethacin, ibuprofen, diclofenac, fluorine be than Lip river branch, the piroxicam indomethacin, ibuprofen, naphthalene can general (naxopren), 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 (sodiumchromoglycate), 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 (pilocarpine for example, Salicylate, carbachol, acetylcholine chloride, physostigmine is with color woods, diisopropylfluorophosphonate, ecothiopate iodide, demecarium bromide); Antineoplastic agent (carmustine for example, 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 prostaglandin for example, antiprostaglandin, the prostaglandin precursor comprises 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 for example, dorzolamide, brinzolamide, methazolamide, diclofenamide (dichlorphenamide), Acetazolamide; Neuroprotective is lubeluzole for example, nimodipine and related compound; And parasympathomimetic agent pilocarpine for example, carbachol, physostigmine etc.

The amount of the medicine relevant with doser can be depending in 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 in the specified disease or the discomfort of desire treatment, and desire obtains the 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 providing drug conveying, thereby the wide therapeutic domain with wide margin of safety is provided to be lower than the day speed for the treatment of the eye drop mode that goes up effective treatment in fact.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 of treatment, 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 3 months example, 0.25% timolol changes the timolol, the particularly timolol of 2.5mg/1000 μ L of carrying 2.5～5mg/1000 μ L into.The timolol eye drop that is used for topical is generally 40～60 μ L, particularly 50 μ L.Therefore, in eye drop, has the timolol of 0.08～0.15mg, particularly 0.125mg.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, and this refers to 1.5～7.5 μ g, 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 can change from the slow release amount that device discharges every day, 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, and the drug residue that causes only about 50ng (8%) after 5 minutes is 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, gives 1 every day usually at the commercial latanoprost pharmaceutical solutions that obtains.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,, 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 for bimatoprost and analog and derivant thereof, 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 the little device of device than the required β of being used for-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, 2.7～13.5 μ g for example, 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, low rate of release, rapid release (bolus release), prominent release or it makes up administration to be also contained in the scope of the present invention.The rapid 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 discharged 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 the 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 alternatively, 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 relevant with the concentration of therapeutic agent in being dissolved in substrate.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 liquid that therapeutic agent in the core can comprise this therapeutic agent, solid, solid gel, solid crystal, solid amorphous, solid particle, and/or dissolved mode.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 substantially 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 silicone, acrylate, and polyethylene, polyurethane, polyurethane, hydrogel, polyester (for example obtains 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 is extruded 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 (for example, obtains 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), poly-(L-lactic acid) are (PLLA), gather (L-glycolic) (PLGA), polyglycolide, poly--the L-lactide, poly--the D-lactide, poly-(aminoacid) 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 relevant with the concentration of therapeutic agent in being dissolved in medicated core.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 the release dynamics of additive with the 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 the dissolubility of lysed therapeutic agent to substrate.Might be relevant by the lysed dissolubility of this therapeutic agent with the hydrophobic and/or hydrophilic nmature of substrate and 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 than the big exposure surface area from medicated core to the purpose position, 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 connects with tear or tear symphysis, the groove of exposed surface, any one of the protuberance of exposed surface.Exposed surface can form porous by adding dissolved salt, in case salt dissolving then residual the porous cavity arranged.Also can use hydrogel, swelling is to provide bigger exposed surface area dimensionally.This hydrogel also can be made into the rate travel of porous with further raising therapeutic agent.

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

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, for example so-called " self discharges medicine " or polymer drug (the Polymerix company of New Jersey Piscataway) are designed to only be degraded into treatment and go up useful chemical compound and physiology's inertia link molecule, further in U.S. Patent Publication No. 2005/0048121 (East), specify, by reference it all is herein incorporated.This release polymers 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 release polymers can be used as the device coating or be used for injectable prolonged drug preparation (storage for example of the present invention) with the form of microsphere.Further the polymer release tech also goes for device of the present invention, for example the technology of putting down in writing and obtaining from Medivas (Santiago, California) in U.S. Patent Publication No. 2004/0170685 (Carpenter).

In the specific embodiment, medicated core substrate comprises solid material, for example the silicone of encapsulation medicine inclusion body.This medicine be included in the water extremely insoluble and in encapsulation medicated core substrate dissolved a little molecule.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, the saturated drug matrices of essential drug thing, and 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 essential drug thing is saturated, in many embodiments, the rate-limiting step of drug release is the surface transhipment of the medicated core substrate of medicine from be exposed to the tear film.Because medicated core substrate essential drug thing is saturated, intramatrical drug level gradient minimum can significantly not promote rate of drug release.Because it is approaching constant to be exposed to the surface area of the medicated core in the tear film, 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 by weight 0.03%～by weight is about 0.002%, and molecular weight is about 400 gram/moles (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 by weight 0.005% water solubility, 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 the surfactant of medicated core with 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 compound and latent active nano fiber composition (the Innovative Surface Technologies company limited in Sao Paulo, the Minnesota State) the 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 Nusil 6385 (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 Loctite 4305 pharmaceutical grade binding agents.This medicine insert can be configured in the hole of tear stains plug, and these Loctite 4305 binding agents 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 was fit to discharge medicine 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 telescopic medicine insert of polyimides 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-level 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 in initial release period, device can discharge about 100ng every day.Every day the extra 20ng that discharges be lower than treatment level, for example 60ng/ sky can have beneficial effect when discharging therapeutic agent.Because the amount of drug release can accurately be controlled, initial high dose might can not cause complication and/or side effect to the patient.

Embodiment 1.1 latanoprost medicated core stripping data

Above-mentioned medicated core be prepared to have 0.006 inch, the different cross section size of 0.012 inch and 0.025 inch, and in silicone substrate, have 5%, 10% and 20% drug level.These medicated core can mix latanoprost with syringe and the preparation of cartridge case device with silicone, this mixture is expelled in the polyimide tube that is cut into Len req and sealing.The length of described medicated core is about 0.80～0.95mm, under the diameter of 0.012 inch (0.32mm), for its concentration that is respectively 5%, 10% and 20%, corresponds respectively to the total latanoprost content that contains in the medicated core of about 3.5 μ g, 7 μ g and 14 μ g.

Syringe and cartridge case device.1. get three kinds of different-diameters: the polyimide tube of 0.006 inch, 0.0125 inch and 0.025 inch.2. the polyimide tube with different-diameter cuts into～15cm length.3. polyimide tube is inserted in the syringe adapter.4. with binding agent polyimide tube is adhered in the bodkin joint (Loctite, low viscosity UV solidifies).5. trimming device end.6. use methanol wash cartridge case device then with distilled water, in 60 ℃ of baking ovens, be dried.

Latanoprost is mixed with silicone.The preparation latanoprost.Form with 1% methyl acetate solution provides latanoprost.An amount of solvent is placed vessel, with vaporized nitrogen solution until residual latanoprost only.The vessel that will have latanoprost oil were placed 30 minutes in a vacuum.Latanoprost is mixed with silicone.The latanoprost (5%, 10% and 20%) of three kinds of variable concentrations among preparation silicon (ketone) Nusil 6385 also is expelled in the pipe (0.006 inch, 0.012 inch and 0.025 inch) of different-diameter it to form 3 * 3 substrate.The percentage rate of latanoprost in silicone is by the gross weight decision of drug matrices.Computing formula: the weight of latanoprost/(weight of the weight+silicone of latanoprost) * 100=medicine percentage rate.

Syringe.1. cartridge case and polyimides pipe unit are inserted in the 1ml syringe.2. in syringe, add 1 catalyst (MED-6385 firming agent).3. with pure air excessive catalyst is discharged polyimide tube.4. with silicone drug matrices filled syringe.5. drug matrices is expelled in the pipe until this pipe and is filled or syringe plunger becomes very that difficulty pushes away.6. seal the far-end of this polyimide tube, and keep-up pressure and begin to solidify until silicone.7. at room temperature solidified 12 hours.8. placed in a vacuum 30 minutes.9. pipe is placed in the appropriate size finishing fixture (being formed in its inner pipe that keeps different size) and and cuts into length (0.80～0.95mm) the medicine insert.

Test.Stripping research (external).1. the plunger with 10 same sizes and same concentrations is placed in each centrifuge tube, and is 7.4 buffer 1.5ml to wherein adding pH.2. behind the appropriate time be 7.4 buffer replacement solvent with new pH.3. use PDA detector 2996 under 210nm, SunfireC18,3mm * 10mm chromatographic column (Massachusetts Penelope Milford's Waters company) is carried out the HPLC of eluent.Use the mixture of acetonitrile and water to carry out gradient elution.Mark in using with the concentration of the latanoprost of accurate weighing carried out inside demarcation before or after each is analyzed.4. for the pipe of the different size of latanoprost, calculate the amount that each device discharges medicine every day with variable concentrations.5. draw the figure of the dissolution rate of the 1st day and the 14th day to area and concentration.

Fig. 7 A and Fig. 7 B represent three kinds of concentration for the three kinds of cores and the latanoprost about 5%, 11% and 18% of 0.006,0.012 and 0.025 inch of diameter respectively, the stripping data of the 1st day and the 14th day latanoprost.Drafting is with the dissolution rate of the latanoprost of nanogram (the ng)/sky expression figure for percentage concentration.These data show that in the same time, the little concentration that depends on of dissolution rate depends on exposed surface area strongly in phase.At the 1st day, the core of described 0.006 inch, 0.012 inch and 0.025 inch diameter discharged the latanoprost of about 200ng, 400ng and 1200ng respectively, shows the increase along with medicated core exposed surface area size, and the amount of the latanoprost of release increases.For each pipe diameter, the amount of the latanoprost of release and the concentration of medicated core Chinese medicine are compared with the least square regression line.For 0.006,0.012 and 0.025 inch medicated core, the slope of the regression line is respectively 11.8,7.4 and 23.4.As mentioned above, these values show, the doubling concentration and can not cause that latanoprost doubles from the dissolution rate of described core of latanoprost medicine in the core, consistent with latanoprost drop and the saturated substantially medicated core substrate of the dissolved therein latanoprost of above-mentioned usefulness in being suspended in medicated core substrate.

At the 14th day, the core of described 0.006 inch, 0.012 inch (0.32mm) and 0.025 inch diameter discharges the latanoprost of about 25ng, 100ng and 300ng respectively, show increase along with medicated core exposed surface area size in the period that prolongs, the amount of the latanoprost that discharges increases, and the little concentration that depends on therapeutic agent in the core of amount of latanoprost release.For each pipe diameter, the amount of the latanoprost of release and the concentration of medicated core Chinese medicine are compared with the least square regression line.For 0.006,0.012 and 0.025 inch medicated core, the slope of the regression line is respectively 3.0,4.3 and 2.2.As mentioned above, medicated core for 0.012 and 0.025 inch, these values show, the doubling concentration and can not cause that latanoprost doubles from the dissolution rate of described core of latanoprost medicine in the core, be suspended in medicated core substrate in the latanoprost drop and with the saturated substantially medicated core substrate of dissolved latanoprost is consistent therein.Yet, for the core of 0.006 inch diameter, there is approximate one-level relation in the core between the amount of initial amount and the 14th day drug release, this may be because the loss of latanoprost medicine drop in core causes.

Fig. 7 D and Fig. 7 E represent according to embodiment of the present invention for respectively as Fig. 7 A and Fig. 7 B latanoprost in three kinds of core diameters and the three kinds of concentration shown in the 1st day and the 14th day, dissolution rate is to the dependency of the exposed surface area of medicated core.Drafting with the dissolution rate of the latanoprost of nanogram (ng)/sky expression for mm ²The figure of the exposed surface area of the medicated core that passes through the decision of medicated core diameter of expression.These data show that in the 1st day and the 14th day, the little drug level that depends in the core of dissolution rate depends on exposed surface area strongly.The exposed surface area of the core of described 0.006 inch, 0.012 inch and 0.025 inch diameter is about 0.02,0.07 and 0.32mm respectively ²At the 1st day, described 0.02,0.07 and 0.32mm ²Core discharge the latanoprost of about 200ng, 400ng and 1200ng respectively, show increase along with medicated core exposed surface area size, the amount of the latanoprost of release increases.For the concentration of therapeutic agent in each medicated core, the amount of the latanoprost of release and the exposed surface area of medicated core are compared with the least square regression line.Medicated core for 5.1%, 11.2% and 17.9%, the slope of the regression line is respectively 2837.8,3286.1 and 3411.6, has 0.9925,0.9701 and 1 R respectively ²Coefficient.At the 14th day, described 0.02,0.07 and 0.32mm ²Core discharge the latanoprost of about 25ng, 100ng and 300ng respectively, show increase along with medicated core exposed surface area size, the amount of the latanoprost of release increases.For 5.1%, 11.2% and 17.9% medicated core, the slope of the regression line is respectively 812.19,1060.1 and 764.35, has 0.9904,0.9924 and 0.9663 R respectively ²Coefficient.As mentioned above, these values show that latanoprost is from the linear increase of surface area of the dissolution rate and the medicated core of core, and is consistent with the medicine sheath that can control exposed surface area.The latanoprost stripping to the weak dependency of the concentration in the medicated core be suspended in medicated core substrate in the latanoprost drop and with the saturated substantially medicated core substrate of dissolved latanoprost is consistent therein.

Fig. 7 C represents according to the latanoprost of embodiment of the present invention from the 0.32mm diameter of the drug weight that has 5,10 and 20% concentration and 3.5,7,14 μ g respectively, the stripping data of 0.95mm length medicated core.Prepare medicated core as mentioned above.To draw dissolution rate figure in ng/ days from 0～40 day.14 μ g cores showed about 100ng/ days speed from about 10～40 days.7 μ g cores showed suitable speed from about 10～20 days.As mentioned above, these data be suspended in medicated core substrate in the latanoprost drop and with the saturated substantially medicated core substrate of dissolved latanoprost is consistent therein.

Table 2 expression is to the desired parameters of each drug level.Shown in Fig. 1 C, the in vitro results in the buffer saline digestion series shows, depends on initial drug level, and the about 500ng latanoprost of the initial stripping of described tear stains plug/sky was reduced to rapidly in 7～14 days 100ng/ days.

Table 2. medicament elution character

Total latanoprost amount	14μg	7μg	3.5μg
Total latanoprost amount	14μg	7μg	3.5μg	Dissolution rate in vitro	See Fig. 1 C	See Fig. 1 C	See Fig. 1 C
Persistent period	～100 days	～45 days	～25 days	Dissolution rate in vitro	See Fig. 1 C	See Fig. 1 C	See Fig. 1 C

In many embodiments, the persistent period of medicated core can based on medicine remain on original vol in the medicine insert～decide computation time of 10% o'clock dissolution rate horizontal exceeding or to keep substantially constant be about 100ng/ days for example.

Embodiment 2 cyclosporin medicated core stripping data

Prepare medicated core in the foregoing description 1 with cyclosporin with 21.2% concentration.Fig. 8 A represents to enter stripping figure the buffer that does not have surfactant and have surfactant according to the cyclosporin of embodiment of the present invention from medicated core.Described buffer prepares as mentioned above.Solution with surfactant comprises 95% buffer agent and 5% surfactant, and UP-1005 Ultra Pure Fluid obtains from the Dow Corning of Michigan week Midland.Embodiment of the present invention is carried out correlational study to be shown, in at least some cases, surfactant can be used to external with the original position stripping of simulation from eye, and this is because described eye can comprise natural surfactant in the tear film, for example the surfactant protein D.The cyclosporin stripping figure that enters into surfactant was about 50～100ng/ days from 30～60 days.The patient's number for example empirical data of 10 patients' tear can be determined and be used to improve the external model with proper amount of surfactant.Described medicated core substrate can be modified according to people's tear surfactant, and this can decide with the external model of modifying.Medicated core can be modified with corresponding people's surface of tear-film activating agent by many methods, for example as mentioned above by exposed surface area that increases and/or the additive that increases the amount of cyclosporin medicine dissolution in core, thereby if suitably then increase stripping from core to treatment level.

The total stripping data of embodiment 3 bimatoprosts

Preparation has the 1% bimatoprost gross sample of known diameter 0.076cm (0.76mm).The height of determining each sample by the weight and the known diameter of sample.

Table 2 gross sample size

Sample	wt(mg)	Diameter (cm)	Computed altitude (cm)	Exposed surface area (cm^2)
Sample	wt(mg)	Diameter (cm)	Computed altitude (cm)	Exposed surface area (cm^2)	14-2-10	1.9	0.076	0.42	0.109
14-2-11	1.5	0.076	0.33	0.088	14-2-10	1.9	0.076	0.42	0.109
14-2-11	1.5	0.076	0.33	0.088	14-2-12	1.9	0.076	0.42	0.109

This computed altitude is 0.33cm～0.42cm.For 0.42 and the 0.33cm sample if be respectively 0.019cm ³And 0.015cm ³Volume, then each ends exposed surface area of each gross sample is 0.045cm ²Exposed surface area by the sample of height and the exposure that does not have the medicine sheath that calculates of diameter is about 0.1cm ²Estimate three kinds of preparations: 1) silicone 4011,0.1% bimatoprosts, 0% surfactant; 2) silicone 4011,1% bimatoprosts, about 11% surfactant; With 3) silicone 4011,1% bimatoprosts, about 33% surfactant.The surface area of supposing overall apparatus is 0.1cm ², the surface area of clinical device is 0.00078cm ²(0.3mm diameter), the stripping data that the gross sample with preparation 1,2 and 3 is measured are standardized as the every device of ng every day (ng/ device/sky).When Fig. 9 A represents according to the 0.3mm exposed surface diameter of the suppose device end of embodiment of the present invention, for silicone gross sample with 1% bimatoprost, the standardized stripping figure that in 100 days, represents with ng/ device/sky.This standardized stripping figure is about 10ng/ days.These data show, are about the zero level release dynamics from about 10 days～about 90 days for each preparation.As mentioned above, these data be suspended in medicated core substrate in the bimatoprost granule and with the saturated substantially medicated core substrate of dissolved bimatoprost is consistent therein.As mentioned above, can use the similar preparation of moulding exposed surface,, and in prolonging period, discharge medicine with therapeutic dose with the increase exposed surface area with medicated core sheath and the core that is exposed to tear.

In some embodiments, core can comprise have with exposed surface area be 0.0045cm ²The core of the 0.76mm diameter of suitable exposed surface diameter 0.76mm.As mentioned above, described core can be covered to limit the exposed surface of core by sheath.6 times of (0.0045cm that are about the stripping figure of device based on the standardized stripping figure of this device of above-mentioned gross sample data with 0.3mm diameter exposed surface area ²/ 0.00078cm ²).Therefore, can in about 90 days period, obtain having the zero level release stripping figure of about 60ng/ days dissolution rate.If exposed surface area increases to 0.0078cm ², for example having a lot of exposed surface shapes as mentioned above, described zero level discharged dissolution rate and be about 100ng/ days in about 90 days period.Described concentration also can increase from 1%.Also can obtain identical stripping figure with latanoprost.

Embodiment 4 latanoprost stripping data

Preparation has latanoprost, the medicated core of silicone 4011,6385 and/or NaCl as mentioned above.Be prepared as follows four kinds of preparations: A) silicone 4011, about 20% latanoprost and about 20% NaCl; B) silicone 4011, about 20% latanoprost and about 10% NaCl; C) silicone 4011, about 10% latanoprost and about 10% NaCl; And D) silicone 6385, about 20% latanoprost.Figure 10 A represents according to the latanoprost of four kinds of latanoprost preparations of the embodiment of the present invention stripping figure from core.The result shows, through 3 weeks (21 days) being reduced to about 100ng/ device/sky from the about 300ng/ device of initial rate/sky.Described result is about the medicated core of not sterilizing.The aseptic medicated core of latanoprost has obtained same result.As mentioned above, these data be suspended in medicated core substrate in the latanoprost drop and with the saturated substantially medicated core substrate of dissolved latanoprost is consistent therein.

In order more clearly to understand, exemplary embodiment is specified by embodiment, those skilled in the art will recognize that and can carry out multiple modification, modification, change.For example, can adopt multiple releasing mechanism, each device embodiments can be adapted to comprise further feature or material, further, can adopt various features or multiple material in a device.Therefore, scope of the present invention is only limited by appended claim.

Claims

1, a kind of implant that is used for being inserted into patient's lacrimal point, described lacrimal point provides flow path from eye to the lacrimal ductule inner chamber to tear, described implant comprises: have far-end, the main body of near-end and the axle between the two, the described far-end of described main body can be inserted in the described lacrimal ductule inner chamber by described lacrimal point, described main body is included in the therapeutic agent that the pharmaceutical base medicated core contains, described pharmaceutical base is exposed to described tear makes effective therapeutic agent continue to be discharged in the described tear in period one, described main body also has the sheath that is arranged on the described pharmaceutical base, with suppress described preparation from described near-end discharge and form the outer surface that engages with internal chamber wall tissue be arranged into inner chamber wherein the time inhibition main body be discharged from.

2, implant according to claim 1, wherein, described pharmaceutical base comprises the examples of non-bioabsorbable polymer.

3, implant according to claim 2, wherein, described pharmaceutical base is included in the silicone in the non-homogeneous mixture of described preparation.

4, implant according to claim 3, wherein, described non-homogeneous mixture comprise by the saturated silicone substrate portion of described therapeutic agent and comprise described therapeutic agent inclusion body forgive body.

5, implant according to claim 1, wherein, described outer surface is disposed on the described sheath, and described outer surface limits and suppresses the body shape that described main body is discharged from described lacrimal point.

6, implant according to claim 1, wherein, described main body further is included in the supporting construction on the described pharmaceutical base, and described supporting construction limits described outer surface and forms and suppresses the shape that described main body is discharged from described lacrimal point.

7, implant according to claim 6, wherein, described supporting construction within it portion accept described sheath and pharmaceutical base medicated core and when suppressing to use the non-of described pharmaceutical base have a mind to discharge.

8, implant according to claim 6, wherein, described supporting construction comprises spiral winding.

9, implant according to claim 6, wherein, described supporting construction has accepter therein, and described accepter is adapted at wherein accepting described sheath and pharmaceutical base and freely transmits fluid when allowing to use between described near-end and described tear film.

10, implant according to claim 1, wherein, when in described lacrimal point, discharging, the radial expansion of described outer surface, and described radial expansion suppresses the discharge from described lacrimal point.

11, implant according to claim 1, wherein, described preparation comprises prostaglandin analogue, comprise at least 3 months described lasting period.

12, a kind of implant that is used for being inserted into the patient, described patient has the tear path relevant with eye, and described implant comprises:

The main body that comprises therapeutic agent and supporting construction, described main body forms when implanting destination locations along described tear path, some days slow release in period every day a certain amount of described therapeutic agent is discharged in the described tear, described amount significantly be lower than recommendation the amount that gives described therapeutic agent every day with eye drop 10%.

13, implant according to claim 12, wherein, described amount be lower than described recommendation with 5% of eye drop dosage.

14, implant according to claim 12 wherein, comprised at least 3 weeks described period.

15, implant according to claim 12, wherein, comprise at least 3 months described period.

16, implant according to claim 12, wherein, described therapeutic agent comprises timolol maleate.

17, implant according to claim 12, wherein, described therapeutic agent comprises latanoprost or other prostaglandin analogue.

18, implant according to claim 12, wherein, described main body comprises the described therapeutic agent of about 270 μ g～about 1350 μ g.

19, therapeutic agent according to claim 12, wherein, described amount is about 20 μ g～about 135 μ g.

20, implant according to claim 12, wherein, described main body comprises the therapeutic agent of about 3 μ g～about 135 μ g.

21, implant according to claim 20, wherein, described therapeutic agent comprises prostaglandin analogue.

22, implant according to claim 20, wherein, described therapeutic agent comprises latanoprost.

23, implant according to claim 20, wherein, described therapeutic agent comprises bimatoprost.

24, implant according to claim 12, wherein, described amount is about 5ng～about 500ng.

25, implant according to claim 12, wherein, described main body comprises the therapeutic agent of about 5 μ g～about 30 μ g.

26, implant according to claim 12, wherein, described amount is about 10ng～about 150ng.

27, a kind of method that is used for therapeutic agent is discharged into eye with relevant tear, described method comprises:

Medicated core is placed in the lacrimal ductule of described eye, described medicated core comprises substrate and at the inclusion body of described intramatrical described therapeutic agent, wherein, the part of described medicated core is exposed to described tear;

Described therapeutic agent is discharged in the described tear of described eye, wherein, described therapeutic agent is dissolved in the described substrate, when described therapeutic agent when one continues in period to discharge by described exposure portion with treatment level, described substrate maintenance is saturated by described therapeutic agent substantially.

28, method according to claim 27, wherein, rate of release is substantially by the dissolubility of the described preparation in the described medicated core, the area decision of the dissolubility of the described preparation in the described tear and described exposure portion.

29, method according to claim 27, wherein, described medicine discharged by described exposure portion with treatment level in about 90 days.

30, method according to claim 27, wherein, described therapeutic agent comprises prostaglandin analogue.

31, method according to claim 27, wherein, the described inclusion body of described therapeutic agent comprises oil.

32, method according to claim 27, wherein, described therapeutic agent is encapsulated in described substrate, and described substrate comprises the examples of non-bioabsorbable polymer.

33, method according to claim 27, wherein, described therapeutic agent has by weight the dissolubility less than about 0.03% in water.

34, method according to claim 27, wherein, described therapeutic agent discharges with treatment level in response to the surfactant of tear.

35, method according to claim 27, wherein, sheath is disposed on the described medicated core limiting described exposure portion, and described exposure portion is orientated towards described eye at the near-end of described medicated core.

36, the glaucomatous tear stains plug of a kind of treatment, described plug comprises:

The wide main body of about at the most 2.0mm 35 days the time, discharges the therapeutic agent of therapeutic dose at least described 35 days every day in being inserted into described lacrimal point.

37, tear stains plug according to claim 36, wherein, when being inserted among the described patient, the wide described main body of described about at the most 2.0mm comprises the wide sectional dimension of about at the most 1.0mm.

38, tear stains plug according to claim 36, wherein, described main body comprises medicated core and the described therapeutic agent of carrying from described medicated core, and described medicated core is wide up to about 1mm.

39, tear stains plug according to claim 36, wherein, described main body is about 2mm at the most on length.

40, a kind ofly treat glaucomatous method with the tear stains plug, described method comprises:

In at least 90 days from described tear stains plug 10ng/ days stripping therapeutic agents at least.

41, according to the described method of claim 40, wherein, described therapeutic agent comprises at least a in bimatoprost or the latanoprost.

42, according to the described method of claim 40, wherein, described therapeutic agent has about at the most 0.03% dissolubility by weight in water.

43, a kind ofly be used for the treatment of glaucomatous tear stains plug, described plug comprises:

Cock body, described cock body comprises therapeutic agent, wherein said cock body is suitable for discharging described therapeutic agent in response to the treatment level of the surfactant of eye.

44, according to the described plug of claim 43, wherein, described therapeutic agent has about at the most 0.03% dissolubility by weight in water.

45, according to the described plug of claim 43, wherein, described therapeutic agent comprises cyclosporin.

46, a kind ofly be used for the treatment of glaucomatous tear stains plug, described plug comprises:

Cock body, described cock body comprises therapeutic agent, wherein, described cock body is suitable at least about 20 days the described therapeutic agent of about 80～120ng is discharged in the tear of described eye.

47, according to the described tear stains plug of claim 46, wherein, described therapeutic agent comprises at least a in bimatoprost or the latanoprost.

48, a kind ofly be used for the treatment of glaucomatous tear stains plug, described tear stains plug comprises:

Be included in about at the most 0.02cm ³The cock body of the therapeutic agent of storage in the volume, wherein, described cock body is suitable for the described therapeutic agent of delivery of therapeutic levels at least about 1 month.

49, according to the described tear stains plug of claim 48, wherein, described cock body is suitable for carrying described therapeutic agent with treatment level at least about 3 months.

50, according to the described tear stains plug of claim 48, wherein, described cock body was suitable for discharging described therapeutic agent with zero order release rate substantially at least 1 month.

51, a kind of compositions that is used for the treatment of the glaucomatous material of eye with relevant tear, described compositions comprises:

The therapeutic agent inclusion body that comprises conc forms, wherein, described therapeutic agent has about at the most 0.03% dissolubility by weight in water; With

Encapsulation has the silicone substrate of described inclusion body, and wherein, described therapeutic agent is dissolved in the described silicone substrate, with treatment level described therapeutic agent is discharged into the described tear from described silicone substrate.

52,, wherein, be encapsulated in the intramatrical therapeutic agent inclusion body of described silicone and comprise the non-homogeneous mixture that is encapsulated in the intramatrical described inclusion body of described silicone according to the described compositions of claim 51.

53, according to the described compositions of claim 51, wherein, described inclusion body comprises latanoprost oil.