HK1190909B

HK1190909B - Drug delivery methods, structures, and compositions for nasolacrimal system

Info

Publication number: HK1190909B
Application number: HK14104157.5A
Authority: HK
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: 玛提治疗有限公司
Priority date: 2006-03-31
Filing date: 2014-04-30
Publication date: 2017-08-04

Description

Drug release method, structure and composition for nasolacrimal system

Description of the cases

The present application is a divisional application of an invention patent application having an application date of 2007, 4/2, application number of 200780017166.2, entitled "method, structure and composition for drug release for nasolachrymal system".

Cross reference to related applications

The present application claims the benefit of U.S. provisional application No.60/787,775 filed on 31.2006 and U.S. provisional application No.60/871,864 filed on 26.2006 under 35USC119 (e), the entire disclosures of which are incorporated herein by reference.

Technical Field

The present application relates to implants for use in or around a nasolachrymal drainage system, and in particular provides lacrimal implants, lacrimal plugs, and lacrimal plugs with drug delivery capabilities.

Background

In the field of ophthalmic drug delivery, patients and physicians face various challenges. In particular, the reproducibility of treatment (multiple injections per day, instillation of multiple eye drop regimens), associated costs, and lack of patient compliance may significantly impact the potential therapeutic effect, resulting in vision loss and, in many cases, blindness.

Patient compliance may be unstable when receiving medication, such as instillation of eye drops, and in some cases, the patient may not follow the recommended treatment regimen. Lack of compliance may include failure to instill drops, ineffective practice (instillation less than the required amount), excessive use of drops (resulting in systemic side effects), and use of over-the-counter drops or non-compliance with treatment regimens requiring multiple drops. Most drug treatments may require patients to instill them up to four times a day.

In addition to compliance, the minimum cost of some eye drop medications has increased, resulting in some patients facing the option of purchasing basic necessities or filling them entirely in their prescription with limited income. Many times insurance does not cover the full cost of the prescribed eye drop medication or, in some cases, eye drops include multiple different medications.

Further, in many cases, topical drug therapy reaches a peak ocular effect within about 2 hours, after which additional drug therapy applications should be performed to maintain therapeutic effect. Furthermore, inconsistencies in self-administered or ingested medication regimens may lead to suboptimal treatment. PCT publication WO06/014434 (Lazer), the entire contents of which are incorporated herein by reference, may be related to these and/or other problems related to eye drops.

One promising approach to ocular administration is the placement of drug-releasing implants in tissues near the eye. While this approach may provide some improvement over eye drops, some potential problems with this approach may include: implantation of the implant at the desired tissue site, retention of the implant at the desired tissue site, and sustained release of the drug at the desired therapeutic level over an extended period of time. For example, in the case of glaucoma treatment, missed diagnosis and premature loss of the implant may result in no drug being released and the patient may potentially suffer from vision loss and even possible blindness.

In light of the foregoing, it would be desirable to provide an improved drug delivery implant that overcomes at least some of the above-described disadvantages.

Disclosure of Invention

The present invention provides implant devices, systems, and methods for releasing a therapeutic agent from a punctum of ocular tissue of a patient.

In a first aspect, embodiments of the present invention provide an implant for insertion into a punctum of a patient. The punctum provides a flow path for tears from the eye to the lumen of the lacrimal canaliculus. The implant includes a body. The body has a distal end, a proximal end and a shaft therebetween. The distal end of the body is insertable distally through the punctum into the canalicular lumen. The body includes a therapeutic agent contained within a drug core of a formulation matrix. Exposing the formulation matrix to the tear fluid releases an effective therapeutic agent into the tear fluid over a sustained period. The body has a sheath disposed over the agent matrix to inhibit release of the agent from the proximal end. The body also has an exterior surface formed to engage lumen wall tissue to inhibit expulsion of the body when disposed in the lumen.

In some embodiments, the formulation matrix comprises a non-bioabsorbable polymer, for example, silicone included in a heterogeneous mixture of the formulation. The heterogeneous mixture can include a silicone matrix portion saturated with the therapeutic agent and inclusion bodies of the therapeutic agent.

In many embodiments, an exterior surface of the body can be disposed on the sheath, the exterior surface can define a body shape that inhibits expulsion of the body from the punctum. The body may further comprise a support structure on the formulation base. The support structure may define the exterior surface and be shaped to inhibit drainage of the body from the punctum. In particular embodiments, the support structure receives the sheath and drug core of the formulation matrix within its interior and inhibits unintended expulsion of the formulation matrix in use. The support structure may comprise a helical coil. The support structure may have a receptacle therein adapted to receive the sheath and agent matrix therein to allow free transfer of fluid between the proximal end and the tear film in use. Upon release within the punctum, the outer surface expands radially, which can inhibit drainage from the punctum.

In a specific embodiment, the formulation comprises a prostaglandin analog and the sustained period comprises at least 3 months.

In many embodiments, an implant for insertion into a patient is provided. The patient has a tear path associated with the eye, and the implant includes a body. The body may include a therapeutic agent and a support structure. The body can be formed to release an amount of the therapeutic agent into the tear fluid daily over a sustained release period of several days when implanted at a location of interest along the tear path. The amount is significantly lower than the recommended daily amount of the therapeutic agent administered in eye drops. For example, the amount may be less than 10% of the recommended amount for administration in eye drops. In particular embodiments, the amount may be less than 5% of the recommended amount to be administered in eye drops.

In many embodiments, the period comprises at least 3 weeks and may comprise at least 3 months. The therapeutic agent may include timolol maleate. The body can include about 270 μ g to about 1350 μ g of the therapeutic agent. The amount released per day may be from about 20 μ g to about 135 μ g.

In many embodiments, the therapeutic agent can include a prostaglandin analog, such as latanoprost and/or bimatoprost, and the body can include from about 3 μ g to about 135 μ g of the therapeutic agent. The amount may be from about 5ng to about 500 ng. In particular embodiments, the subject can include about 5 μ g to about 30 μ g of the therapeutic agent, and the amount can be about 10ng to about 150 ng.

In another aspect, embodiments of the present invention provide a method for delivering a therapeutic agent to an eye having associated tear fluid. The method comprises placing a drug core in the lacrimal canaliculus of the eye. The drug core includes a matrix and inclusions of the therapeutic agent within the matrix. A portion of the drug core is exposed to the tear. Releasing the therapeutic agent into the tear of the eye. The therapeutic agent is dissolved into the matrix such that the matrix remains substantially saturated with the therapeutic agent when the therapeutic agent is released at therapeutic levels through the exposure over a sustained period of time.

In many embodiments, the release rate is substantially determined by the solubility of the agent in the drug core, the solubility of the agent in the tear, and the area of the exposed portion. The drug may be released at therapeutic levels through the exposure within about 90 days. The therapeutic agent may comprise a prostaglandin analog, and the inclusion bodies of the therapeutic agent comprise oil. The therapeutic agent may be encapsulated within the matrix, which may include a non-bioabsorbable polymer.

In many embodiments, the therapeutic agent has a solubility in water of less than about 0.03% by weight. The therapeutic agent may be released at therapeutic levels in response to the surfactant of the tear. A sheath may be disposed over the drug core to define the exposed portion, the exposed portion being oriented toward the eye at a proximal end of the drug core.

In many embodiments, a lacrimal plug for treating glaucoma is provided. The plug includes a body that is at most about 2.0mm wide. When inserted into the punctum for 35 days, the subject releases at least a therapeutic amount of the therapeutic agent on each of the 35 days. In some embodiments, the body up to about 2.0mm wide comprises a cross-sectional dimension up to about 1.0mm wide when inserted into the patient. In a specific embodiment, the body comprises a drug core and the therapeutic agent is released from the drug core. The core may be up to about 1mm wide and the body may be up to about 2mm in length.

In many embodiments, there is provided a method of treating glaucoma with a lacrimal plug, the method comprising dissolving a therapeutic agent from the lacrimal plug for at least 10 ng/day for at least 90 days. In particular embodiments, the therapeutic agent comprises at least one of bimatoprost or latanoprost. The therapeutic agent may have a solubility in water of up to about 0.03% by weight.

In many embodiments, a lacrimal plug for treating glaucoma is provided, the plug including a plug body. The plug body includes a therapeutic agent, the plug body being adapted to release the therapeutic agent at therapeutic levels in response to a surfactant of the eye. In a specific embodiment, the therapeutic agent has a solubility in water of up to about 0.03% by weight. The therapeutic agent may include cyclosporine.

In many embodiments, a lacrimal plug for treating glaucoma is provided. The plug includes a plug body. The plug body includes a therapeutic agent. The plug body is adapted to release about 80-120 ng of the therapeutic agent into a tear of the eye for at least about 20 days. In particular embodiments, the therapeutic agent may include at least one of bimatoprost or latanoprost.

In some embodiments, a lacrimal plug for treating glaucoma is provided. The lacrimal plug includes a plug body. The plug body comprises at most about 0.02cm³A therapeutic agent stored within the volume. The plug body is adapted to release therapeutic levels of the therapeutic agent for at least about 1 month. In particular embodiments, the plug body is adapted to release the therapeutic agent at therapeutic levels for at least about 3 months. The plug body may be adapted to release the therapeutic agent at a substantially zero-order release rate for at least 1 month.

In some embodiments, a composition of matter for treating glaucoma of an eye having associated tears is provided. The composition includes inclusion bodies. The inclusion bodies include the therapeutic agent in concentrated form. The therapeutic agent has a solubility in water of up to about 0.03% by weight. The silicone matrix encapsulates the inclusion bodies. The therapeutic agent is dissolved in the silicone matrix, releasing the therapeutic agent from the silicone matrix into the tear at therapeutic levels. In particular embodiments, the inclusion bodies of therapeutic agent are encapsulated within the silicone matrix, including a heterogeneous mixture of the inclusion bodies encapsulated within the silicone matrix. The inclusion bodies may comprise latanoprost oil.

Drawings

FIGS. 1-1 and 1-2 illustrate an anatomical structure of an eye suitable for treatment with an implant according to an embodiment of the invention;

FIG. 1A is a top cross-sectional view illustrating a sustained release implant for treating an optical defect of the eye according to one embodiment of the present invention;

FIG. 1B is a side cross-sectional view illustrating the sustained release implant of FIG. 1A;

FIG. 1C is a perspective view illustrating a sustained release implant having a coil retaining structure according to an embodiment of the present invention;

FIG. 1D is a perspective view illustrating a sustained release implant having a retention structure including struts, according to one embodiment of the present invention;

FIG. 1E is a perspective view illustrating a sustained release implant having a cage-like retention structure according to an embodiment of the present invention;

FIG. 1F is a perspective view illustrating a sustained release implant including a core and a sheath according to an embodiment of the present invention;

FIG. 1G is a schematic illustration of a sustained release implant including a flow-restricting retention structure, a core and a sheath, according to an embodiment of the present invention;

FIG. 2A is a cross-sectional view illustrating a sustained release implant having a core with an increased exposed surface area in accordance with an embodiment of the present invention;

FIG. 2B is a cross-sectional view illustrating a sustained release implant having a core with an increased exposed surface area according to an embodiment of the present invention;

FIGS. 2C and 2D are perspective and cross-sectional views, respectively, illustrating a sustained release implant having a core with a reduced exposed surface area in accordance with an embodiment of the present invention;

FIG. 2E is a cross-sectional view showing a sustained release implant having a core including an increased exposed surface area with grooves and castellations, according to an embodiment of the invention;

FIG. 2F is a perspective view illustrating a sustained release implant including a core having corrugations in accordance with one embodiment of the present invention;

FIG. 2G is a perspective view illustrating a sustained release implant having a core with channels having a porous interior surface according to one embodiment of the present invention;

FIG. 2H is a perspective view illustrating a sustained release implant having a core including channels for increasing drug migration in accordance with an embodiment of the present invention;

FIG. 2I is a perspective view illustrating a sustained release implant having a raised exposed core surface according to one embodiment of the present invention;

FIG. 2J is a side view illustrating a sustained release implant having a core including an exposed surface area having a plurality of soft brush-like elements extending therefrom, according to one embodiment of the invention;

FIG. 2K is a side view of a sustained release implant having a drug core with a raised exposed surface and a retention structure according to an embodiment of the present invention;

fig. 2L is a side view illustrating a sustained release implant having a drug core with a surface including a concave indented (concave induced) surface for increasing an exposed surface area of the core, according to an embodiment of the present invention;

FIG. 2M is a side view illustrating a sustained release implant having a drug core including a recessed surface having channels formed therein for increasing the exposed surface area of the core in accordance with an embodiment of the present invention;

FIG. 3A shows an implant including a sheath having an extension attaching the sheath and core to a retention unit, according to one embodiment of the invention;

FIG. 3B shows an implant including a retention unit having an extension that retains a sheath and a core according to an embodiment of the present invention;

FIGS. 4A and 4B are cross-sectional views illustrating an implant having a retaining structure with a large cross-sectional profile shape shorter than a small cross-sectional profile shape in a length direction according to an embodiment of the present invention;

FIGS. 5A-5C are schematic illustrations of an alternative core and sheath according to one embodiment of the invention;

FIGS. 6A-6C illustrate the deployment of a sustained release implant according to an embodiment of the present invention; and

FIGS. 7A and 7B show dissolution data for latanoprost at day 1 and day 14 for three cores of 0.006, 0.012, and 0.025 inch diameter and three concentrations of about 5%, 11%, and 18% latanoprost, respectively, according to an embodiment of the invention;

figure 7C shows dissolution data for latanoprost according to an embodiment of the invention from a 0.32mm diameter, 0.95mm length drug core having a concentration of 5, 10, and 20%, and a drug weight of 3.5, 7, 14 μ g, respectively;

figures 7D and 7E show the dependence of dissolution rate on the exposed surface area of the drug core for three core diameters and three concentrations of latanoprost on day 1 and day 14 as shown in figures 7A and 7B, respectively, according to embodiments of the present invention;

FIG. 8A shows a dissolution profile of cyclosporin according to an embodiment of the invention from the drug core into a buffer without and with a surfactant;

FIG. 9A shows a standard dissolution profile in ng/device/day over 100 days for a total sample of silicone with 1% bimatoprost in accordance with an embodiment of the present invention;

fig. 10A shows the elution profile of latanoprost from the core for four latanoprost formulations according to an embodiment of the present invention.

Detailed Description

Figures 1-1 and 1-2 illustrate the anatomical structure of an eye 2 suitable for treatment with an implant according to an embodiment of the present invention. The eye 2 includes a cornea 4 and an iris 6. The sclera 8 surrounds the cornea 4 and sclera 6 and appears white. The conjunctiva layer 9 is substantially transparent and is disposed over the sclera 8. The lens 5 is located in the eye. The retina 7 is located near the back of the eye 2 and is typically sensitive to light. The retina 7 includes a fovea 7F that provides high visual acuity and color vision. The cornea 4 and lens 5 refract light to form an image on the fovea 7F and retina 7. The optical power of the cornea 4 and lens 5 helps to form an image on the fovea 7F and retina 7. The relative positions of the cornea 4, lens 5 and fovea 7F are also important for image quality. For example, if the axis of the eye 2 from the cornea 4 to the retina 7F is large then the eye 2 may be myopic. Furthermore, during accommodation, the lens 5 moves towards the cornea 4 to provide excellent near vision of near-to-eye objects.

The anatomical structure shown in fig. 1-1 also includes a lacrimal system including an upper lacrimal canaliculus 10 and a lower lacrimal canaliculus 12 (collectively, lacrimal canaliculus) and a nasolacrimal duct or lacrimal sac 14. The superior and inferior canaliculi terminate at an upper punctum 11 and a lower punctum 13, also known as the lacrimal punctum. The lacrimal orifice is located slightly higher than the center of the eyelid margin at the connection 15 of the ciliary portion and the lacrimal portion near the inner canthus 17. The lacrimal orifice is a circular or slightly oval opening surrounded by a tissue engagement ring. Each lacrimal canaliculus opening 11, 13 is connected to the vertical portion 10a, 12a of each lacrimal canaliculus before the entrance of the lacrimal sac 14 is connected to another lacrimal canaliculus when the vertical portion 10a, 12a of each lacrimal canaliculus turns to the horizontal direction. The canaliculus is tubular and lined with a stratified squamous epithelium surrounded by elastic tissue that allows the canaliculus to expand.

Fig. 1A is a top cross-sectional view illustrating a sustained release implant 100 for treating an optical defect of the eye, according to an embodiment of the present invention. The implant 100 includes a drug core 110. The drug core 110 is an implantable structure that holds a therapeutic agent. The drug core 110 includes a matrix 170 containing therapeutic agent inclusions 160. The inclusion bodies 160 generally include a concentrated form of the therapeutic agent, e.g., a crystalline form of the therapeutic agent, which can dissolve into the matrix 170 of the drug core 110 over time. The matrix 170 may include a silicone matrix or the like, and the mixture of therapeutic agents in the matrix 170 may be heterogeneous. In many embodiments, the heterogeneous mixture comprises a silicone matrix portion saturated with the therapeutic agent and an inclusion body portion comprising inclusion bodies of the therapeutic agent, such that the heterogeneous mixture comprises a heterogeneous mixture of phases. In some embodiments, inclusion bodies 160 comprise oil droplets of a therapeutic agent, such as latanoprost oil. In some embodiments, the inclusion bodies 160 can include particles of a therapeutic agent, such as bimatoprost solid particles in crystalline form. In many embodiments, the matrix 170 encapsulates the inclusion bodies 160, and the inclusion bodies 160 may comprise microparticles having a size of about 1 μm to about 100 μm. The encapsulated inclusion bodies dissolve into the surrounding solid matrix, e.g., silicone, encapsulating the microparticles, such that matrix 170 is substantially saturated with the therapeutic agent as it is released from the core.

The drug core 110 is surrounded by the sheath body 120. The sheath 120 is substantially impermeable to the therapeutic agent, and thus the therapeutic agent is typically released from exposed surfaces on the ends of the drug core 110 that are not covered by the sheath 120. The retention structure 130 is coupled to the drug core 110 and the sheath body 120. The retention structure 130 is shaped to retain the implant in a hollow tissue structure, such as the punctum of the lacrimal canaliculus described above.

The closing unit 140 is disposed on the holding structure 130 and surrounds the holding structure 130. The occlusive element 140 is impermeable to tear flow and occludes the hollow tissue structure, and may also protect the tissue of the tissue structure from the retention structure 130 by providing a more benign tissue-engaging surface. The sheath 120 includes a sheath portion 150 coupled to the retention structure 130 to retain the sheath 120 and the drug core 110. The sheath body 150 can include a stop that limits the movement of the sheath body 120 and the drug core 110. In many embodiments, the sheath body 150 can be formed to have a bulbous tip 150B. Bulbous end 150B may include a convex exterior that provides atraumatic access when introduced into the lacrimal canaliculus. In many embodiments, the sheath portion 150B may be integral with the occlusion unit 140.

Fig. 1B is a side cross-sectional view illustrating the sustained-release implant of fig. 1A. The drug core 110 is cylindrical and appears to have a circular cross-section. The sheath body includes an annular portion disposed on the core 110. The retaining structure 130 includes a plurality of longitudinal struts 131. The longitudinal struts 131 are connected together near the ends of the retaining structure. Although longitudinal struts are shown, circumferential struts may also be used. The occlusive element 140 is supported by and disposed over the longitudinal struts 131 of the retaining structure 130 and may comprise a radially expandable membrane or the like.

Fig. 1C is a perspective view illustrating a sustained release implant 102 having a coil retention structure 132, according to an embodiment of the present invention. The retaining structure 132 includes a coil and retains the drug core 112. For delivery of the therapeutic agent for application to the nose and body, a lumen, such as channel 112C, may extend through the drug core 112 to allow tear flow therethrough. In addition to using the channel 112C, or by using the channel 112C in combination, the dimensions of the retention structure 132 and the core 112 can be varied to allow tear flow around the core and sheath while the retention unit maintains the lacrimal canaliculus tissue away from the core. The drug core 112 may be partially covered. The sheath includes a first component 112A covering a first end of the drug core 112 and a second component 112B covering a second end of the drug core. As described above, the occlusive element may be disposed over the retaining structure, and/or the retaining structure may be dip coated.

Fig. 1D is a perspective view illustrating a sustained release implant 104 having a retention structure 134 including struts, according to an embodiment of the present invention. The retaining structure 134 includes longitudinal struts and retains the drug core 114. The majority of the drug core 114 is covered by the sheath 124. As described above, the drug core releases the therapeutic agent through the exposed tip, and the sheath 124 annularly covers a majority of the drug core. As described above, the occlusive element may be disposed over the retaining structure, or the retaining structure may be dip coated. A protrusion that can be engaged with an implement, such as a hook, loop, suture, or loop 124R, etc., can extend from the sheath body 124 such that the drug core and sheath body can be removed together to facilitate replacement of the sheath body and core while the retention structure remains implanted in the lacrimal canaliculus. In some embodiments, a protrusion that can be engaged with an instrument comprising a hook, loop, suture, or loop can extend from the retention structure 134 to remove the sustained release implant by removing the retention structure along with the protrusion, drug core, and sheath.

Fig. 1E is a perspective view illustrating a sustained release implant 106 having a cage-like retention structure 136 according to an embodiment of the present invention. The retaining structure 136 includes a plurality of metal connecting wires and retains the drug core 116. The drug core 116 is covered by the sheath body 126 over a substantial portion of the drug core 116. As described above, the drug core releases the therapeutic agent through the exposed tip, and the sheath 126 annularly covers a majority of the drug core. As described above, the occlusive element may be disposed over the retaining structure, or the retaining structure may be dip coated.

FIG. 1F is a perspective view illustrating a sustained release implant including a core and a sheath according to an embodiment of the present invention. The drug core 118 is covered by the sheath body 128 over a substantial portion of the drug core 118. The core releases the therapeutic agent through the exposed tip as described above, with the sheath 128 annularly covering a majority of the core. The rate of release of the therapeutic agent is controlled by the surface area of the exposed drug core and the materials included in the drug core 118. In many embodiments, the therapeutic agent dissolution rate is strongly and substantially correlated with the exposed surface area of the drug core, and weakly dependent on the concentration of the drug in the inclusion bodies disposed in the drug core. For an annular exposed surface, the dissolution rate is strongly dependent on the diameter of the exposed surface, e.g. the diameter of the exposed core surface near the end of a cylindrical core. Such implants may be implanted into ocular tissue, such as beneath the conjunctival tissue layer 9 or above the scleral tissue layer 8 of the eye, as shown in fig. 1F, or only partially within the scleral tissue layer so as not to penetrate the scleral tissue. It should be noted that the drug core 118 may be used with any of the retention structures and occlusive members described herein.

In one embodiment, a drug core without sheath 128 is implanted between sclera 8 and conjunctiva 9. Without a sheath in this embodiment, the physical properties of the drug core can be adjusted to compensate for the increased exposed surface of the drug core, for example by reducing the concentration of the therapeutic agent dissolved in the drug matrix as described herein.

Fig. 1G is a schematic illustration of a sustained release implant 180 including a flow-restricting retention structure 186, a core 182, and a sheath 184, according to an embodiment of the present invention. The sheath 184 may at least partially cover the drug core 182. The drug core 182 may include inclusions of the therapeutic agent therein that provide sustained release of the therapeutic agent. The drug core 182 may include an exposed convex surface region 182A. The exposed convex surface region 182A can provide an increased surface area for release of the therapeutic agent. An occlusive element 188 may be disposed over the retention structure 186 to block tear flow through the lacrimal canaliculus. In many embodiments, the retaining structure 186 may be located within the occlusion structure 188 to provide an occlusion unit that is integral with the retaining structure. The flow-restricting retention structure 186 and the occlusive element 188 may be sized to block tear flow through the lacrimal canaliculus.

The core and sheath described herein can be implanted into a variety of tissues by a variety of methods. Many of the cores and sheaths described herein, particularly the structures described with reference to fig. 2A-2J, may be implanted separately as punctal plugs. In addition, many of the cores and sheaths described herein may include a drug core, a sheath, and/or the like to facilitate implantation thereof using the retention structures and occlusion elements described herein.

Fig. 2A is a cross-sectional view illustrating a sustained release implant 200 having a core with an increased exposed surface area according to an embodiment of the present invention. The drug core 210 is covered by the sheath body 220. The sheath 220 includes an opening 220A. The opening 220 has a diameter that approximates the maximum cross-sectional diameter of the drug core 210. The drug core 210 includes an exposed surface 210E (also referred to as an active surface). The exposed surface 210E includes three surfaces: an annular surface 210A, a cylindrical surface 210B, and an end surface 210C. The annular surface 210A has an outer diameter that approximates the maximum cross-sectional diameter of the core 210 and an inner diameter that approximates the outer diameter of the cylindrical surface 210B. The end surface 210C has a diameter that matches the diameter of the cylindrical surface 210B. The surface area of the exposed surface 210E is the sum of the areas of the annular surface 210A, the cylindrical surface 210B, and the end surface 210C. The surface area may be increased by the size of the cylindrical surface region 210B extending longitudinally along the axis of the core 210.

Fig. 2B is a cross-sectional view illustrating a sustained release implant 202 having a core 212 with an increased exposed surface area 212A, in accordance with an embodiment of the present invention. The sheath 222 extends over the core 212. The therapeutic agent may be released from the core as described above. The exposed surface area 212A is near conical, and may be ellipsoidal or spherical, extending outward from the sheath to increase the exposed surface area of the drug core 212.

Fig. 2C and 2D are perspective and cross-sectional views, respectively, illustrating a sustained release implant 204 having a drug core 214 with a reduced exposed surface area 214A, in accordance with an embodiment of the present invention. The drug core 214 is enclosed within a sheath 224. The sheath 224 includes an annular tip portion 224A defining an opening from which the drug core 214 extends. The drug core 214 includes an exposed surface 214A that releases the therapeutic agent. The exposed surface 214A has a diameter 214D that is less than a maximum dimension, e.g., a maximum diameter, across the drug core 214.

Fig. 2E is a cross-sectional view illustrating a sustained release implant 206 having a drug core 216 in accordance with one embodiment of the present invention, the drug core 216 including an enlarged exposed surface area 216A having castellations extending from the exposed surface area 216A. The castellations comprise a plurality of spaced apart fingers 216F to provide an increased surface area of the exposed surface 216A. In addition to the increased surface area provided by the castellations, the drug core 216 may also include grooves 216I. The groove 216I may have an inverted cone shape. The core 216 is covered by a sheath 226. The sheath 226 is open at one end to provide an exposed surface 216A on the drug core 216. The sheath 226 also includes fingers and has a castellated pattern that matches the core 216.

Fig. 2F is a perspective view illustrating a sustained release implant 250 including a core having corrugations, according to an embodiment of the present invention. The implant 250 includes a core 260 and a sheath 270. The core 260 has an exposed surface 260A on the end of the core that allows the drug to migrate to the surrounding tear or tear film fluid. Core 260 also includes pleats 260F. Pleats 260F increase the surface area of the core that is exposed to the surrounding tear or tear film fluid. By this increase in exposed surface area, pleats 260F increase movement of the therapeutic agent from core 260 into the tear or tear film fluid and the targeted treatment area. Forming pleats 260F forms channels 260C in core 260. Channel 260C connects to the end of the core as an opening in exposed surface 260A and provides for movement of the therapeutic agent. Thus, the entire exposed surface area of the core 260 is included. Exposed surface 260A directly exposed to tear or tear film fluid, and the surface of fold 260F exposed to tear or tear film fluid through the connection of channel 260C with exposed surface 260A and tear or tear film fluid.

Fig. 2G is a perspective view illustrating a sustained release implant having a core with channels having a porous interior surface according to an embodiment of the present invention. The implant 252 includes a core 262 and a sheath 272. The core 262 has an exposed surface 260A on the end of the core that allows the drug to migrate to the surrounding tear or tear film fluid. The core 262 also includes a channel 262C. The channels 262C increase the surface area of the channels by forming a porous interior surface 262P within the channels toward the core. The channel 262C extends to the end of the core near the exposed surface 262A of the core. The surface area of the core exposed to the surrounding tear or tear film fluid may include the interior of the core 262 exposed to the channel 262C. This increase in exposed surface area can increase the movement of the therapeutic agent from the core 262 into the tear or tear film fluid and the targeted treatment area. As such, the entire exposed surface area of the core 262 may include the exposed surface 260A that is directly exposed to the tear or tear film fluid, as well as the porous interior surface 262P that is exposed to the tear or tear film fluid through the connection of the channels 262C with the exposed surface 262A and the tear or tear film fluid.

Fig. 2H is a perspective view illustrating a sustained release implant 254 having a core 264 including channels for increasing drug migration in accordance with an embodiment of the present invention. The implant 254 includes a core 264 and a sheath 274. The exposed surface 264A is located at the end of the core 264, but the exposed surface may be located elsewhere. The exposed surface 264A allows the drug to migrate to the surrounding tear or tear film fluid. The core 264 also includes a channel 264C. The channel 264C extends to the exposed surface 264A. The channel 264C is large enough to allow the entry of tears or tear film fluid into the channel, thereby increasing the surface area of the core 264 that is in contact with the tears or tear film fluid. The surface area of the core exposed to the surrounding tear fluid or tear film liquid includes an interior surface 264P of the core 262 defining the channel 264C. With this increase in exposed surface area, the channel 264C increases the movement of the therapeutic agent from the core 264 into the tear or tear film fluid and the target treatment area. As such, the entire exposed surface area of the core 264 includes the exposed surface 264A that is directly exposed to the tear or tear film fluid, as well as the interior surface 264P that is exposed to the tear or tear film fluid through the connection of the channel 262C with the exposed surface 264A and the tear or tear film fluid.

Fig. 2I is a perspective view illustrating a sustained release implant 256 having a drug core 266 with a convex exposed surface 266A according to one embodiment of the present invention. The drug core 266 is partially covered by a sheath 276, and the sheath 276 extends at least partially over the drug core 266 to define a convex exposed surface 266A. The sheath 276 includes a shaft portion 276S. The convex exposed surface 266A provides an increased surface area over the sheath. The convex exposed surface 266A has a cross-sectional area greater than the cross-sectional area of the shaft portion 276S of the sheath 276. In addition to this larger cross-sectional area, the convex exposed surface 266A has a larger surface area due to the convex shape extending outwardly from the core. The sheath 276 includes a plurality of fingers 276F that support the drug core 266 in the sheath and provide support to the drug core to hold the drug core 266 in place on the sheath 276. Fingers 276F are spaced apart from one another to allow transfer of the drug from the core into the tear or tear film fluid between the fingers. The projection 276P extends outwardly on the sheath 276. The protrusion 276P can be pressed inward to release the drug core 266 from the sheath. The drug core 266 may be replaced with another drug core after an appropriate time, such as after the drug core 266 has released the majority of the therapeutic agent.

Fig. 2J is a side view illustrating a sustained release implant 258 having a core 268, the core 268 including an exposed surface area having a plurality of soft brush-like members 268F, according to one embodiment of the present invention. Drug core 268 is partially covered by sheath 278, and sheath 278 extends at least partially over drug core 268 to define exposed surface 268A. The sheath 278 includes a shaft portion 278S. The soft brush-like member 268F extends outwardly from the cartridge 268 and provides an increased exposed surface area to the cartridge 268. The soft brush or like member 268F is also soft, resilient and pliable so that the members do not irritate adjacent tissue. Although the cartridge 268 may be manufactured from a variety of materials as described above, silicone is a suitable material for manufacturing the cartridge 268 including the soft brush-like component 268F. The exposed surface 268A of the drug core 268 also includes a recess 268I such that at least a portion of the exposed surface 268A is concave.

Figure 2K is a side view illustrating a sustained release implant 259 having a drug core 269 including a convex exposed surface 269A according to one embodiment of the invention. The drug core 269 is partially covered by the sheath 279, and the sheath 279 extends at least partially over the drug core 269 to define a convex exposed surface 269A. The sheath 279 includes a shaft portion 279S. The convex exposed surface 269 provides increased storm over the sheathExposing the surface area. The convex exposed surface 269A has a cross-sectional area that is greater than the cross-sectional area of the shaft portion 279S of the sheath 279. In addition to this larger cross-sectional area, the convex exposed surface 269A has a larger surface area due to the convex shape extending outward from the core. Retaining structure 289 may be attached to sheath 279. The retaining structure 289 may comprise any of the retaining structures described above, including for example Nitinol^TMCoils of superelastic shape memory alloy. The retaining structure 289 may be dip coated to make the retaining structure 289 biocompatible.

Fig. 2L is a side view illustrating a sustained release implant 230 having a drug core 232 with a recessed indented surface 232A for increasing the exposed surface area of the core, according to one embodiment of the present invention. The sheath 234 extends at least partially over the core 232. A recessed indented surface 232A is formed at the exposed end of the drug core 232 to provide an increased exposed surface area of the drug core.

Fig. 2M is a top view illustrating a sustained release implant 240 having a drug core 242 according to an embodiment of the present invention, the drug core 242 including a concave surface 242A having channels 242C formed therein for increasing the exposed surface area of the core. The sheath 244 extends at least partially over the core 242. A recessed indented surface 242A is formed at the exposed end of the drug core 232 to provide an increased exposed surface area of the drug core. Channels 242C are formed in the cartridge 242 to provide an increased exposed surface area of the cartridge. Channel 242C may extend onto recessed indented surface 242A such that channel 242C provides an increased surface area of the core exposed to the tear or tear film fluid.

Fig. 3A illustrates an implant 310 including a sheath 320 having an extension 322, according to one embodiment of the invention. The extension 322 attaches the sheath 320 to the retention unit to hold the core near the punctum. The sheath 320 extends over the core 330 to define an exposed surface 332 of the core 330. The extension 322 can be elastic and engage the retention unit and/or the occlusion unit to affix the sheath core to the retention unit to retain the core near the punctum.

Fig. 3B shows an implant 350 including a retention unit 380 having an extension 382, according to an embodiment of the present invention. The extension 382 retains the sheath 360 and the core 370. The sheath 360 extends over the core 370 to define an exposed surface 372 of the core 370. The exposed surface 372 is disposed near the proximal end of the core 370. The extension 382 extends downward to retain the core 370 and the sheath 360.

Fig. 4A and 4B are cross-sectional views illustrating an implant 400 having a retaining structure 430 with a larger cross-sectional profile shape than a smaller cross-sectional profile shape in the length direction, according to an embodiment of the present invention. Implant 400 includes a distal end 402 and a proximal end 404. Implant 400 includes a drug core 410 and a sheath body 420. The sheath body 420 at least partially covers the drug core 410 and defines an exposed surface 412 of the drug core 410. The occlusive element 440 may be attached to and supported by the holding structure 430. The occlusive element 440 may move with the retention structure 430, for example, as the retention element 430 expands from the small cross-sectional profile shape to the large cross-sectional profile shape. In many embodiments, the retention structure and the occlusive element are sized to correspond to, e.g., match or are slightly larger than, the diameter of the lacrimal canaliculus so that occlusive fluid flows through the lacrimal canaliculus and/or is anchored in the lacrimal canaliculus.

As shown in fig. 4A, the retention structure 430 and the occlusive element 440 are in a low profile shape. Such a low profile shape may occur when the blocking unit and the holding unit are arranged at the tip of the insertion tool and are arranged to be covered. The retention element 430 and the occlusion element 440 extend completely along the length of the sheath body 420 and the drug core 410. The holding unit 430 is attached to the sheath 420 near the distal end 402. In many embodiments, the retention unit 430 and the occlusion unit 440 have a diameter sized to fit or slide into the lacrimal canaliculus when in the low profile shape, while in the second high profile shape, the retention unit and the occlusion unit may be sized to anchor within the lacrimal canaliculus.

As shown in fig. 4B, the retention structure 430 and the occlusive element 440 are in a large profile shape. Such a large profile shape may occur when the occlusive and retention units are deployed in the lacrimal canaliculus. In this large profile shape, the length of the occlusive element 440 and the retention structure 430 is shorter than the short distance 450 in the small profile shape. The proximal ends of the retention structure 430 and the occlusive element 440 may be slid over the sheath 420 while the sheath and retention structure exhibit a high profile shape, such that the proximal ends of the drug core 410 and the sheath 420 protrude from the retention structure and the occlusive element. In some embodiments, the sheath is a short distance 450 from the core 410 such that when the retention structure and the occlusive element are in a large profile shape, more of the core is exposed than when the retention structure and the occlusive element are in a small profile shape. In such embodiments, the retention structure and the occlusive element contract to expose the drug core.

Fig. 5A-6 illustrate embodiments of tools that may be used to insert the various implants described herein.

Fig. 5A shows an insertion tool 500 according to an embodiment of the invention, with a plunger 530 that can be depressed to insert the implant into the punctum. Insertion tool 500 includes dilator 510 that can be inserted into the punctum prior to insertion of the implant to pre-dilate the punctum. Implant 520 may be pre-loaded onto tool 500 prior to dilation of the punctum. An internal wire 540 may be coupled to the implant 520 to retain the implant. With the punctum pre-dilated with dilator 510, implant 520 can be inserted into the punctum with tool 500. When the implant 520 is positioned in the punctum, the plunger 530 can be depressed to engage the wire 540 and release the implant 520 from the tool 500.

Fig. 5B shows an insertion tool 550 for inserting an implant 570 into a punctum with a slidable plunger according to an embodiment of the present invention. Insertion tool 550 includes a dilator 560 with a tapered cross-section for dilating the punctum. The insertion tool 550 includes a plunger 580 that can be slid distally to advance the implant 570 into the lumen. The shaft 590 is coupled to the plunger 580 to advance the implant 570 distally as the plunger 580 is advanced distally. When the punctum is dilated with dilator 560, plunger 580 can be advanced distally to deploy implant 570 into the canalicular lumen near the punctum. In many embodiments, a button may be depressed to advance the implant distally into the cavity, such as a button connected to the shaft 590 with an intermediary mechanism.

Fig. 6 shows an insertion tool 600 for inserting an implant into a punctum with a sheath 610 for positioning the implant in the canalicular lumen by constriction, according to an embodiment of the invention. At least a portion of the sheath 610 is shaped to dilate the punctum. The sheath 610 is formed to hold a low profile shape of the implant 620. The insertion tool 600 includes a ring structure 615, which may comprise a portion of the body 605 of the insertion tool 600. The sheath 610 and the ring structure 615 are shaped to dilate the punctum and often include a nearly sloped surface to dilate the punctum. The implant 620, sheath 610, and ring structure 615 may be at least partially inserted into the punctum to deploy the implant in the canalicular lumen. The ring structure 615 is disposed over the sheath 610 such that the sheath 610 can be retracted and slid under the ring structure 615. When the sheath 610 is retracted proximally to expose the implant 620, a stopper 625 may be coupled to the body 605 to maintain the implant 620 at a desired depth within the lacrimal canaliculus lumen.

Once the implant 620 is deployed in the lacrimal canaliculus lumen at the desired depth to the punctum, the sheath 610 is retracted to expose the implant 620 at the desired location in the lacrimal canaliculus lumen. Sheath 610 may be retracted using plunger 630. The shaft 630 mechanically connects the sheath 610 to the plunger 630. Such that proximal retraction of the plunger 630 retracts the sheath 610 in a proximal direction to expose the implant at a desired location in the canalicular lumen. Implant 620 may be any of the implants described herein. Typically, implant 620 includes a resilient member that expands to a high profile shape when sheath 610 is retracted. In many embodiments, insertion tool 600 may include a dilator to dilate the punctum prior to insertion of the implant, and as described above, a dilator may be disposed on the insertion tool at the end opposite the end loaded with the implant.

Fig. 5A to 5C are schematic explanatory views of an alternative drug core 510 and sheath 520 according to an embodiment of the present invention. Implant 700 includes a drug core 510, a sheath body 520, and a retention structure 530. The implant 500 may include an occlusive element supported by and movable with a retaining structure 530. Generally, the retention structure 530 exhibits a first profile shape, a low profile shape, prior to implantation, and a second profile shape, a high profile shape, after implantation. The retention structure 530 is shown in a large profile shape and is implanted into the canalicular lumen. The sheath 520 includes extensions 525A and 525B to attach the sheath and the drug core to the retention structure 530 such that the sheath and the drug core are retained by the retention structure 530. The drug core 510 and sheath 520 may be removed together by pulling the drug core 510 proximally as indicated by arrow 540. As shown in fig. 5B, the retention structure 530 may remain implanted in the lacrimal canaliculus tissue after the drug core 510 and the sheath body 520 are removed. As shown in fig. 5C, the replacement drug core 560 and the replacement sheath 570 may be inserted together. Preferably, this replacement is performed after the drug core 510 has released an effective amount of the therapeutic agent, the supply of the therapeutic agent in the drug core is reduced, and the rate of release of the therapeutic agent approaches the minimum effective level. The replacement sheath 570 includes an extension 575A and an extension 575B. The replacement drug core 560 and replacement sheath 570 may be advanced distally as indicated by arrow 590 to insert the replacement drug core 560 and replacement sheath 570 into the retention structure 530. When the replacement drug core 560 and replacement sheath 570 are inserted into the resilient member 530, the retention structure 530 remains substantially in the same position.

Fig. 6A to 6C show the arrangement of a sustained-release implant according to an embodiment of the present invention. As shown in fig. 6A, a deployment tool 610 is inserted into the lacrimal canaliculus 600 through the punctum 600A. A sustained release implant 620 is loaded onto the tip of the deployment tool 610 and a sheath 612 covers the sustained release implant 620. When the sheath 612 is disposed over the retaining structure 630, the retaining structure 630 exhibits a low profile shape. As shown in fig. 6B, the outer sheath 612 of the deployment tool 610 is withdrawn to expose the retention structure 630 of the sustained release implant 620. The exposed portion of the holding unit 630 exhibits a large outline shape. As shown in fig. 6C, the deployment tool 610 has been removed and a sustained release implant 620 is implanted in the lacrimal canaliculus 600. The drug core 640 is attached to the retention structure 630 and is retained in the lacrimal canaliculus. The outer body sheath 650 covers at least a portion of the drug core 640, and the drug core 640 releases the therapeutic agent into the tear fluid or tear film fluid 660 near the punctum 600A of the lacrimal canaliculus 600.

Sheath body

The sheath includes suitable shapes and materials to control the movement of the therapeutic agent from the drug core. The sheath contains the core and may fit closely to the core. The sheath is made of a material that is substantially impermeable to the therapeutic agent such that the rate of transfer of the therapeutic agent can be controlled primarily by the exposed surface area of the drug core not covered by the sheath. In many embodiments, the movement of the therapeutic agent through the sheath can be about one tenth or less, typically one hundredth or less, of the movement of the therapeutic agent through the exposed surface of the drug core. In other words, the movement of the therapeutic agent through the sheath is at least about an order of magnitude less than the movement of the therapeutic agent through the exposed surface of the drug core. Suitable sheath materials include polyimide, polyethylene terephthalate (hereinafter "PET"). The sheath has a thickness defined from a sheath surface adjacent the core to an opposite sheath surface distal from the core of about 0.00025 "to about 0.0015". The overall diameter of the sheath across the core is between about 0.2mm and 1.2 mm. The core may be formed by dip coating the core in a sheath material. Alternatively, or in combination therewith, the sheath may comprise a tube and a core inserted into the sheath, e.g. injected and/or extruded as a slidable liquid or solid into the sheath tube. The sheath may also be dip coated around the core, such as around a preformed core.

The sheath may be endowed with additional features to facilitate clinical application of the implant. For example, the sheath may receive a replaceable drug core while the retention structure and sheath body are still implanted in the patient. The sheath is typically rigidly attached to the retaining structure as described above, and the drug core is replaceable while the retaining structure retains the sheath. In particular embodiments, the sheath may be given an external protrusion for applying a load to the sheath when the core is squeezed or ejected from the sheath. Another drug core may then be placed in the sheath. In many embodiments, the sheath and/or retaining structure may have distinctive features, such as distinctive colors for indicating placement, so that the patient may readily notice the placement of the sheath and/or retaining structure in the lacrimal canaliculus or other bodily tissue structures. The retention unit and/or sheath may include at least one marker for indicating a depth of deployment in the lacrimal canaliculus, such that the retention unit and/or sheath may be placed into the lacrimal canaliculus at a desired depth based on the at least one marker.

Holding structure

The retention structure comprises a suitable material that is sized and shaped so that the implant can be easily positioned in a desired tissue location, such as the lacrimal canaliculus. The retaining structure may be mechanically configured and typically expanded to a desired cross-sectional shape, for example, having a cross-sectional shape including, for example, Nitinol^TMAnd superelastic shape memory alloys. Nitinol may also be used^TMOther materials than elastic metals or polymers, plastically deformable metals or polymers, shape memory polymers, etc., to provide the desired expansion. In some embodiments, polymers and coated fibers available from Biogeneral, inc. Many metals such as stainless steel and non-shape memory alloys can be used and provide the required expansion. This expansion capability allows the implant to fit into hollow tissue structures of various sizes, such as 0.3mm to 1.2mm lacrimal canaliculus (i.e., one size may fit all needs). Although a single retention structure can be made to fit canaliculi 0.3mm to 1.2mm wide, alternative retention structures can be used instead as needed to fit this range, such as a first retention structure for a 0.3 to 0.9mm canaliculi and a second retention structure for a 0.9 to 1.2mm canaliculi. The retention structure has a length suitable for the anatomical structure to which it is attached, for example, the retention structure is placed near the punctum of the lacrimal canaliculus and has a length of about 3 mm. The length may be adapted to provide sufficient retention for different anatomical structures, for example a length of 1mm to 15mm may be suitable.

While the sheath and core are attached to one end of the retention structure as described above, in many embodiments, the other end of the retention structure is unattached to the core and the sheath so that the retention structure can slide over the sheath and the core as the retention structure expands. Such sliding capability at one end is preferred because the retaining structure may shorten in length as it expands in width to exhibit the desired cross-sectional width. It is noted, however, that many embodiments may use sheaths that do not slide relative to the core.

In many embodiments, the retaining structure may be retrieved from the tissue. The projections, such as hooks, loops or loops, may be expanded from the retaining structure to facilitate removal of the retaining structure.

Blocking unit

The occlusive element comprises a suitable material that changes size and shape such that the implant can at least partially inhibit, or even block, fluid flow through the hollow tissue structure, such as tear fluid flow through the lacrimal canaliculus. The occluding material shown here is a thin-walled membrane of a biocompatible material, such as silicone, that can expand and contract with the retaining structure. The occlusive element is formed as a separate thin tube of material that slides over the end of the retaining structure and anchors to one end of the retaining structure as described above. Alternatively, the occlusive element may be formed by dip coating the retention structure in a biocompatible polymer, such as a silicone polymer. The thickness of the occlusive element can range broadly from about 0.0.1mm to about 0.15mm, and is typically in the range of about 0.05mm to 0.1 mm.

Therapeutic agents

"therapeutic agent" may include drugs which may be any one of the following or any equivalent, derivative or analogue thereof, including: anti-glaucoma agents (e.g., adrenergic agonists, adrenergic antagonists (β -blockers), carbonic anhydrase inhibitors (CAIs, systemic and topical), parasympathomimetics, prostaglandins, and ocular hypotensive lipids and combinations thereof), antibacterial agents (e.g., antibiotics, antivirals, antiparasitics, antifungals, etc.), corticosteroids or other anti-inflammatory agents (e.g., NSAIDs), decongestants (e.g., vasoconstrictors), prophylactic agents to ameliorate allergic reactions (e.g., antihistamines, cytokine inhibitors, leukotriene inhibitors, IgE inhibitors, immunomodulators), mast cell stabilizers, cycloplegics, or the like. Examples of conditions that may be treated with a therapeutic agent(s) include, but are not limited to, glaucoma, pre-and post-operative treatments, dry eye and allergies. In some embodiments, the therapeutic agent may be a lubricant or surfactant, such as a lubricant for the treatment of dry eye.

Typical therapeutic agents include, but are not limited to: a thrombin inhibitor; an antithrombotic agent; a thrombolytic agent; a fibrinolytic agent; an inhibitor of vasospasm; a vasodilator; an antihypertensive agent; antibacterial agents, such as antibiotics (e.g., tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline, chloramphenicol, rifampin, ciprofloxacin, tobramycin, gentamicin, erythromycin, penicillin, sulfonamides, sulfadiazine, sulfacetamide, sulfamethylthiadiazole, sulfaisoxazole, furacilin, sodium propionate), antifungal agents (e.g., amphotericin B and miconazole) and antiviral agents (e.g., idoxuridine, acyclovir, propoxyguanil, interferon); inhibitors of surface glycoprotein receptors; anti-platelet agents; an anti-mitotic agent; a microtubule inhibitor; a secretion inhibitor; an activity inhibitor; a reconstitution inhibitor; an antisense nucleotide; an antimetabolite; antiproliferative agents (including angiogenesis inhibitors); anti-cancer chemotherapeutic agents; anti-inflammatory agents (e.g., hydrocortisone acetate, dexamethasone 21-phosphate, fluocinolone, medrysone, methylprednisolone, prednisolone 21-phosphate, prednisolone acetate, fluorometholone, betamethasone, triamcinolone acetonide); non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., salicylic acid, indomethacin, ibuprofen, diclofenac, flurbiprofen, piroxicam indomethacin, ibuprofen, naproxen, piroxicam and nabumetone). For example, such anti-inflammatory steroids contemplated for use in the methods of the present invention include triamcinolone acetonide (common name), corticosteroids include, for example, triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, flumethasone (flumetholone) and derivatives thereof; antiallergic drugs (e.g. sodium cromoglycate, antazoline, methapirine, chlorpheniramine, cetirizine, mepyramine, pheniramine); antiproliferative agents (e.g., 1, 3-cis-retinoic acid, 5-fluorouracil, paclitaxel, rapamycin, mitomycin C, and cisplatin); decongestants (e.g., phenylephrine, naphazoline, tetrahydrozoline); miotics and anticholinesterases (e.g., pilocarpine, salicylate, carbachol, chloroacetylcholine, physostigmine, dichlorline, profluorine, liocorm, dimeglumine); antineoplastic agents (e.g., carmustine, cisplatin, fluorouracil 3; immunological drugs (e.g., vaccines and immunostimulants), hormones (e.g., estrogen, -estradiol, progestational agents, progesterone, insulin, calcitonin, parathyroid hormone, peptide, and vasopressin hypothalamic releasing factor), immunosuppressants, growth hormone antagonists, growth factors (e.g., epidermal growth factor, fibroblast growth factor, platelet derived growth factor, transforming growth factor beta, growth hormone, fibronectin), angiogenesis inhibitors (e.g., angiostatin, anecortave acetate, thrombin sensitive protein, anti-VEGF antibodies), dopamine agonists, radiotherapeutic agents, peptides, proteins, enzymes, extracellular matrices, components, ACE inhibitors, free radical scavengers, chelators, antioxidants, anti-polymerases, photodynamic therapeutics, gene therapeutics, and other therapeutics such as prostaglandins, anti-prostaglandins, prostaglandin precursors, including anti-glaucoma drugs including beta-blockers such as timolol, betaxolol, levobunolol, atenolol, and prostaglandin analogs such as bimatoprost, travoprost, latanoprost, and the like; carbonic anhydrase inhibitors such as acetazolamide, dorzolamide, brinzolamide, methazolamide, dichlorfenamide, danus; neuroprotective agents such as lubeluzole, nimodipine and related compounds; and parasympathomimetics such as pilocarpine, carbachol, physostigmine, and the like.

The amount of drug associated with the drug delivery device may depend on the particular agent, the desired therapeutic effect, and the time the device is to be treated. Because the devices of the present invention come in a variety of shapes, sizes and delivery mechanisms, the amount of drug associated with the device will depend on the particular disease or disorder being treated, as well as the dosage and duration of the treatment desired. Generally, the amount of drug, at least upon release from the device, is an amount effective to achieve the desired physiological or pharmacological local or systemic effect.

Embodiments of the drug delivery device of the present invention may be adapted to provide drug delivery at a daily rate substantially lower than the eye drop regime of therapeutically effective treatment, thereby providing a wide range of treatments with a wide margin of safety. For example, in many embodiments, the eye is treated at therapeutic levels of up to 5-10% of the daily eye drop dose for an extended period of time. Such that the implant can dissolve the therapeutic agent at a rate substantially higher than the sustained release level and substantially lower than the daily eye drop dosage for a period of about 1-3 days of rapid administration or washout. For example, an average sustained release level of 100ng per day, and an initial release rate of 1000-1500 ng per day, while initially releasing less than 2500ng of the drug in an eye drop to which the drug is administered to the eye. The use of sustained release levels as used herein is substantially lower than the amount of drug in one and/or more eye drops administered per day, thus allowing the device to release a therapeutically effective amount of drug to achieve the desired therapeutic effect with a wide margin of safety while avoiding insufficient or excessive amounts of drug in the intended site or area.

An extended period may refer to a relatively short period, such as minutes or hours (e.g., for use of anesthetics), days or weeks (e.g., pre-or post-operative use of antibiotics, steroids or NSAIDs, etc.) or longer (e.g., in the case of glaucoma treatment), such as months or years (based on a recycling basis for use of the device).

For example, a drug such as timolol maleate, a β and β 2 (non-selective) adrenergic receptor blocker, may be suitable for use in the device, released for an extended period of time such as 3 months although the device may provide longer or shorter duration treatment, 3 months is a relatively typical elapsed time in the topical eye drop treatment of glaucoma patients with glaucoma medication by physicians.In the 3 month example, 0.25% of timolol is converted to deliver 2.5-5 mg/1000. mu.L of timolol, especially 2.5 mg/1000. mu.L of timolol. Timolol eye drops for topical administration are typically 40-60 μ L, especially 50 μ L. Thus, there may be 0.08-0.15 mg, especially 0.125mg of timolol in the eye drops. After 5 minutes, there may be about 8% (optionally 6-10%) eye drops remaining in the eye, so about 10 μ g of drug is effective at this time. Timolol can have a bioavailability of 30-50%, meaning 1.5-7.5 μ g, e.g., 4 μ g of drug is effective for the eye. Timolol is typically administered twice daily, so that 8 μ g (or 3-15 μ g) per day is achieved for the eye. Thus, the drug delivery device may comprise 270-1350 μ g, e.g. 720 μ g, of drug for extended release over 90 days or 3 months. The drug may be contained within the device and dissolved based on the polymer or drug/hydrogel concentration. For olopatadine hydrochlorideAnd other drugs, may also be included on the device and dissolved in the same manner as timolol.

Commercially available timolol maleate solutions exist in 0.25% and 0.5% formulations, and the starting dose may be twice daily with 1 drop of the 0.25% solution. Timolol at a concentration of 0.25% corresponds to 2.5 mg/1000. mu.l. The sustained release amount of timolol released from the drug core per day may be about 3-15 mug per day. Although the amount of sustained release released from the device per day may vary, a sustained release administration of about 8 μ g per day corresponds to about 3.2% of 0.250mg of timolol given 2 drops of a 0.25% solution.

For example, in the case of latanoprost (prida), prostaglandin F2 α analog, a glaucoma drug, has a concentrate of about timolol 1/10. Thus, the amount of drug on the implantable device depends on bioavailability, which is significantly reduced by-about 20-135 μ g, especially 50-100 μ g, for latanoprost and other prostaglandin analogs. It can also be converted into a device that is smaller than the device used for the administration of the beta-blocker or that can hold more drug for a longer release period.

The alisda eye drops contained about 2.5 μ g of latanoprost, expressed as a 50 μ L eye drop volume. Thus, assuming that about 2.5 μ g of 8% is present 5 minutes after instillation, only about 200ng of drug remains in the eye. Based on the latanoprost clinical trial, this amount is effective in lowering IOP for at least 24 hours. Several dose-response studies were performed in pfeiri/famasia in support of the NDA of ulida. The dosage of the latanoprost is 12.5 mu g/mL-115 mu g/mL. Once daily dosing, a general dose of 50 μ g/mL per administration of latanoprost proved to be preferred. However, even the lowest dose of 12.5 μ g/mL QD or 15 μ g/mL BID consistently provided IOP reduction of about 60-75% of the 50 μ g/mL QD dose. Based on the above assumptions, a concentration of 12.5 μ g/mL in 50 μ L eye drops provided 0.625 μ g of latanoprost, resulting in only about 50ng (8%) of drug remaining in the eye after 5 minutes.

In many embodiments, the concentration of latanoprost is about 1/100 or 1% of timolol, and in particular embodiments, the concentration of latanoprost is likely about 1/50 or 2% of timolol. For example, commercially available latanoprost solution formulations exist at 0.005% concentration, typically 1 drop per day. In many embodiments, the therapeutically effective concentration of drug released from the device per day may be about 1/100 for timolol, about 30-150 ng per day, e.g., about 80ng, exhibiting tear clearance and bioavailability similar to timolol. For example, for latanoprost and other prostaglandin analogs, the amount of drug on the implantable device can be very low, about 1% to 2% timolol, e.g., 2.7 to 13.5 μ g, or about 3 to 20 μ g. Although the amount of sustained release of latanoprost released per day may vary, a sustained release of about 80ng per day corresponds to about 3.2% of 2.5 μ g of latanoprost given 1 drop of 0.005% solution.

For example, in the case of bimatoprost (lumeigen), a glaucoma drug that synthesizes prostamide prostaglandin analogs may have a concentration of timolol 1/20 or less. Thus, for bimatoprost and analogs and derivatives thereof, the amount of drug loaded on the extended release device for extended release over 3-6 months can be very low-about 5-30 μ g, especially 10-20 μ g, depending on bioavailability. In many embodiments, the implant can hold more drug for a longer sustained release period, for example using 20-40 μ g of bimatoprost and its derivatives for a sustained release period of 6-12 months. This reduction in drug concentration can also translate into a smaller device than would be required for the administration of a beta-blocker.

The commercially available bimatoprost solution is at a concentration of 0.03% by weight and is typically administered 1 time per day. Although the amount of sustained release of bimatoprost released per day may vary, a sustained release of 300ng per day corresponds to about 2% of 15 μ g of bimatoprost given 1 drop of 0.03% solution. Studies related to the present invention show that even lower sustained release doses of bimatoprost can provide at least some reduction in intraocular pressure, for example 20-200 ng bimatoprost and 0.2-2% of the daily sustained release dose of the daily eye drop dose.

For example, for travoprost (threatenet), a prostaglandin F2 α analog, this glaucoma medication may have a concentration of 2% or less of timolol. For example, a commercially available solution is administered at a concentration of 0.004%, typically 1 time per day. In many embodiments, a therapeutically effective concentration of drug released from the device per day may be about 65ng, exhibiting tear clearance and bioavailability similar to timolol. Thus, the amount of drug on the implantable device, which is dependent on bioavailability, can be significantly reduced. It can also be converted into a device that is smaller than the device used for the administration of the beta-blocker or that can hold more drug for a longer release period. For example, for travoprost, latanoprost, and other prostaglandin F2 alpha analogs, the amount of drug on the implantable device is very low, about 1/100 of timolol, e.g., 2.7-13.5 μ g, particularly about 3-20 μ g. Although the amount of sustained release of latanoprost released per day may vary, a sustained release of 65ng per day corresponds to about 3.2% of 2.0 μ g of travoprost given 1 drop of 0.004% solution.

In some embodiments, the therapeutic agent may include a corticosteroid, such as fluocinolone acetonide for treatment of the targeted ocular tissue. In particular embodiments, fluocinolone acetonide may be released from the lacrimal canaliculus and delivered into the retina as a therapeutic agent for Diabetic Macular Edema (DME).

It is also within the scope of the present invention to modify or adapt the device for administration at a high release rate, a low release rate, a rapid release (bolus release), a burst release, or a combination thereof. The rapid release of the drug may be released by forming an erodible polymeric cap that is rapidly dissolved into the tear or tear film. Upon contact of the polymer cap with the tear or tear film, the dissolution properties of the polymer cause the cap to erode and all of the drug is released immediately. Burst release of the drug can be achieved using polymers that are lost in the tear or tear film based on polymer solubility. In this example, the drug and polymer may be layered along the length of the device such that the drug is released immediately upon dissolution of the outer polymer layer. High or low release rates of the drug can be achieved by changing the solubility of the erodable polymer layer so that the drug layer is released rapidly or slowly. Other methods of drug release may be achieved by porous membranes based on the size of the drug molecule, soluble gels (e.g., soluble gels in typical eye drops), particulate encapsulation of the drug or nanoparticle encapsulation.

Medicine core

The drug core includes a therapeutic agent and a material that provides sustained release of the therapeutic agent. The therapeutic agent migrates from the drug core into the tissue of interest, such as the ciliary muscle of the eye. The therapeutic agent may optionally be only sparingly soluble in the matrix, such that a small amount of the therapeutic agent is dissolved in the matrix and available for release from the surface of the drug core 110. The rate of movement from the core to the tear or tear film may be related to the concentration of the therapeutic agent dissolved in the matrix as the therapeutic agent diffuses from the exposed surface of the core into the tear or tear film. Additionally or in combination therewith, the rate of movement of the therapeutic agent from the core to the tear or tear film may be related to the nature of the matrix in which the therapeutic agent is dissolved. In particular embodiments, the rate of migration from the drug core to the tear or tear film may be based on the silicone formulation. In some embodiments, the concentration of the therapeutic agent dissolved in the drug core can be controlled to provide a desired release rate of the therapeutic agent. The therapeutic agent contained in the core may include a liquid, a solid gel, a solid crystal, a solid amorphous, a solid particulate, and/or a dissolved form of the therapeutic agent. In a preferred embodiment, the drug core comprises a silicone matrix containing the therapeutic agent. The therapeutic agent may comprise liquid or solid inclusions, such as liquid latanoprost droplets or solid bimatoprost particles, respectively, dispersed in a silicone matrix.

The drug core may include one or more biocompatible materials having the ability to provide sustained release of the therapeutic agent. Although the core is illustrated in an embodiment comprising a substantially non-biodegradable silicone matrix with inclusions of drug dissolved therein, the core may include structures that provide sustained release of the therapeutic agent, such as a biodegradable matrix, a porous core, a liquid core, and a solid core. The matrix comprising the therapeutic agent may be formed from any one of a biodegradable polymer or a non-biodegradable polymer. The non-biodegradable core may include silicone, acrylate, polyethylene, polyurethane, hydrogel, polyester (e.g., available from e.i. du Pont de Nemours and Company of wilmington, tera)Polypropylene, Polytetrafluoroethylene (PTFE), expanded PTFE (eptfe), Polyetheretherketone (PEEK), nylon, extruded collagen, polymeric foam, silicone rubber, polyethylene terephthalate, ultra-high molecular weight polyethylene, polycarbonate urethane, polyurethane, polyimide, stainless steel, nickel-titanium alloys (e.g., Nitinol), titanium, stainless steel, cobalt-chromium alloys (e.g., available from Elgin Specialty Metals of elm, illinois)Available from Carpenter Metals, Wyoission, PaThe biodegradable core can include one or more biodegradable polymers, such as proteins, hydrogels, polyglycolic acid (PGA), polylactic acid (PLA), poly (L-lactic acid) (PLLA), poly (L-glycolic acid) (PLGA), polyglycolide, poly-L-lactide, poly-D-lactide, poly (amino acids), polydiolsThe core may include at least one hydrogel polymer, in some embodiments, the core may include at least one hydrogel polymer, and the core may include at least one of a polycaprolactone, a polygluconate, a polylactic acid-polyethylene oxide copolymer, a modified cellulose, a collagen, a polyorthoester, a polyhydroxybutyrate, a polyanhydride, a polyphosphate, a poly (α -hydroxy acid), and combinations thereof.

The therapeutic agent is released at an effective level

The release rate of the therapeutic agent can be related to the concentration of the therapeutic agent dissolved in the drug core. In many embodiments, the drug core includes a non-therapeutic agent selected to provide a desired solubility of the therapeutic agent in the drug core. The non-therapeutic agent of the core may include the polymers and additives described above. The polymer of the core may be selected to provide the desired solubility of the therapeutic agent in the matrix. For example, the core may include a hydrogel that may enhance the solubility of the hydrophilic therapeutic agent. In some embodiments, functional groups may be added to the polymer to provide a desired solubility of the therapeutic agent in the matrix. For example, the functional groups may be attached to a silicone polymer.

In some embodiments, additives may be used to control the release kinetics of the therapeutic agent. For example, additives may be used to control the concentration of the therapeutic agent by increasing or decreasing the solubility of the therapeutic agent in the drug core to control the release kinetics of the therapeutic agent. Solubility can be controlled by providing suitable molecules and/or substances that can increase and/or decrease the solubility of the dissolved therapeutic agent to the matrix. The solubility of the therapeutic agent to be solubilized may be related to the hydrophobic and/or hydrophilic properties of the matrix and the therapeutic agent. For example, surfactants, tinafine, salts and water can be added to the matrix and it is possible to increase the solubility of the hydrophilic therapeutic agent in the matrix. In addition, oils and hydrophobic molecules may be added to the matrix and it is possible to increase the solubility of the hydrophobic therapeutic agent in the matrix.

In addition to controlling the rate of movement of the therapeutic agent based on its concentration dissolved in the matrix, the surface area of the drug core may also be controlled to obtain a desired rate of movement of the drug from the drug core to the site of interest, instead of or as an additional means. For example, a larger exposed surface area of the core increases the rate of movement of the therapeutic agent from the drug core to the target site, while a smaller exposed surface area of the drug core decreases the rate of movement of the therapeutic agent from the drug core to the target site. The exposed surface area of the drug core can be increased by any of a number of methods, such as by castellation of the exposed surface, a porous surface with exposed channels connected to the tear or tear film, grooves of the exposed surface, protrusions of the exposed surface. The exposed surface may be made porous by adding dissolved salt, which once dissolved leaves a porous cavity. Hydrogels may also be used, which may swell in size to provide a larger exposed surface area. Such hydrogels may also be made porous to further increase the rate of migration of the therapeutic agent.

Further, implants having the ability to deliver two or more drugs in combination may be used, such as the structure disclosed in US patent 4281654 (Shell). for example, in the case of glaucoma treatment, it may be necessary to use multiple prostaglandins or one prostaglandin and a cholinergic or adrenergic antagonist (β -blocker) such asOr a prostaglandin and carbonic anhydrase inhibitor, to treat the patient.

In addition, drug impregnated screens such as the drug impregnated screen disclosed in U.S. patent application No. 2002/0055701 or the biostable polymer layer described in U.S. patent application No. 2005/0129731 may be used. It is possible to use certain polymeric processes to incorporate drugs into the device of the present invention, such as so-called "self-releasing drugs" or polymeric drugs (Polymerix corporation of Piscataway, new jersey) designed to degrade only into therapeutically useful compounds and physiologically inert linker molecules, as further specified in U.S. patent publication No. 2005/0048121 (East), which is incorporated herein by reference in its entirety. Such release polymers may be configured in the devices of the present invention to provide a release rate that is equal to the polymer erosion and degradation rate and constant during treatment. Such release polymers may be used as device coatings or in the form of microspheres for injectable drug depots (e.g. reservoirs of the invention). Further polymer delivery techniques may also be suitable for use with the device of the present invention, such as those described in U.S. patent publication No. 2004/0170685 (Carpenter) and available from Medivas (san Diego, Calif.).

In particular embodiments, the drug core matrix comprises a solid material, such as a silicone encapsulating drug inclusions. The drug comprises molecules that are extremely insoluble in water and slightly soluble in the drug core-encapsulating matrix. The inclusion bodies by the drug core encapsulation may be microparticles having a size of about 1 μm to about 100 μm wide. The drug inclusions may comprise crystals, such as bimatoprost crystals, and/or oil droplets, such as latanoprost oil. The drug inclusions can be dissolved in a solid core matrix that is substantially saturated with the drug, such as latanoprost oil. The drug dissolved into the drug core matrix is transported from the exposed surface of the drug core into the tear film, typically by diffusion. Since the drug core matrix is substantially saturated with the drug, in many embodiments, the rate-limiting step in drug release is drug transport from the surface of the drug core matrix exposed to the tear film. Since the drug core matrix is substantially saturated with the drug, the drug concentration gradient within the matrix is minimal and does not significantly promote the rate of drug release. Since the surface area of the drug core exposed to the tear film is nearly constant, the rate of drug transport from the drug core to the tear film is substantially constant. Relevant studies conducted in connection with the present invention have shown that the solubility of the therapeutic agent in water and the molecular weight of the drug can have an effect on the transport of the drug from the solid matrix into the tear. In many embodiments, the therapeutic agent is practically insoluble in water, has a water solubility of about 0.03% to 0.002% by weight, and a molecular weight of about 400g/mol to about 1200 g/mol.

In many embodiments, the therapeutic agent has an extremely low solubility in water, for example, from about 0.03% by weight to about 0.002% by weight, and a molecular weight of from about 400 grams per mole (g/mol) to about 1200g/mol, while being readily soluble in organic solvents. Cyclosporin a (csa) is a solid with an aqueous solubility at 25 ℃ of 27.67 μ g/mL or 0.0027% by weight, and a molecular weight (M.W.) of 1202.6 g/mol. Latanoprost (aptida) is a prostaglandin F2 alpha analogue, is a liquid oil at room temperature, has a water solubility in water of 50 μ g/mL or about 0.005% by weight at 25 ℃, and a m.w. of 432.6 g/mol. Bimatoprost (lumeigen) is a synthetic prostamide analog, solid at room temperature, water solubility at 25 ℃ of 300 μ g/mL or 0.03% by weight, and m.w. of 415.6 g/mol.

Relevant studies conducted in connection with the present invention have shown that naturally occurring surfactants in the tear film, such as surfactant D and phospholipids, may have an effect on the transport of drugs dissolved in a solid matrix from the core to the tear film. The drug core may be adapted to provide sustained release of the drug into the tear film at therapeutic levels due to the surfactant in the tear film. For example, empirical data may be obtained for surfactant levels from the number of patients, e.g., 10 patients, whose tears are collected and analyzed. The dissolution profile of a sparingly water-soluble drug such as cyclosporin in collected tears can be determined and compared to the dissolution profile in buffer and surfactant to establish an in vitro model of tear surfactant. An in vitro solution with a surfactant based on this empirical data can be used to adjust the drug core to correspond to the surfactant of the tear film.

The core may also be modified according to the size of the molecule to be delivered to utilize carrier excipients such as nanoparticles or microparticles, for example for complexation and nanoweavingA textured Surface latent reactive nanofiber composition (Innovative Surface Technologies, Inc. of St. Paul, Minn.) is referred to asIncluding micron-sized particles, membranes, woven fibers or micro-implant devices (pSividia, Limited, UK) and protein nanocage systems (Chimeracore) targeted for administration to selected cells.

In many embodiments, the drug insert comprises a thin-walled polyimide sheath with a drug core containing latanoprost dispersed in Nusil6385 (MAF 970), a pharmaceutical grade solid silicone as the dosing matrix. The distal end of the drug insert was sealed with a cured film of solid Loctite4305 pharmaceutical grade adhesive. The drug insert may be disposed within the aperture of the lacrimal plug without the Loctite4305 adhesive contacting either the tissue or the tear film. The drug insert may have an inner diameter of 0.32mm and a length of 0.95 mm. Three latanoprost concentrations in the finished pharmaceutical product can be tested clinically: the drug core may comprise 3.5, 7 or 14 μ g latanoprost at a concentration of 5, 10 and 20% by weight, respectively. Assuming a total dissolution rate of about 100 ng/day, a drug core containing 14 μ g latanoprost is suitable for releasing the drug for at least about 100 days, e.g., 120 days. The total weight of the drug core containing latanoprost may be-70 μ g. The weight of the drug insert including the polyimide cannula may be about 100 μ g.

In many embodiments, the core may be dissolved as follows: an initial high level of therapeutic agent is followed by a substantially constant dissolution of the therapeutic agent. In many cases, the therapeutic dose released from the core per day may be below therapeutic levels, but still provide an effect to the patient. The high level of therapeutic agent that is dissolved in combination with a sub-therapeutic amount of therapeutic agent that alleviates the patient's pain can result in residual amounts of therapeutic agent and/or residual efficacy of the therapeutic agent. In embodiments, the therapeutic level is about 80 ng/day, and the device can release about 100ng per day during the initial release period. An additional 20ng per day may have a beneficial effect when the therapeutic agent is released at a sub-therapeutic level, e.g. 60 ng/day. Since the amount of drug released can be precisely controlled, it is possible that the initial high dose will not cause complications and/or side effects to the patient.

Example 1.1 Latanoprost drug core dissolution data

The drug cores described above were prepared with different cross-sectional dimensions of 0.006 inch, 0.012 inch and 0.025 inch with drug concentrations of 5%, 10% and 20% in the silicone matrix. These cores can be prepared using a syringe and cartridge device, mixing latanoprost with silicone, injecting the mixture into a polyimide tube that is cut to the desired length and sealed. The core has a length of about 0.80 to 0.95mm and corresponds to a total latanoprost content contained in the core of about 3.5, 7 and 14 μ g, respectively, for concentrations of 5%, 10% and 20% respectively, at a diameter of 0.012 inches (0.32 mm).

Syringe and cartridge devices. 1. Three different diameters were taken: 0.006 inch, 0.0125 inch, and 0.025 inch polyimide tubes. 2. Polyimide tubes of different diameters were cut to-15 cm length. 3. The polyimide tube was inserted into the syringe adapter. 4. The polyimide tube was bonded with an adhesive into a thick pin joint (Loctite, low viscosity UV cure). 5. The device end is trimmed. 6. The cartridge device was washed with distilled water and then methanol and dried in an oven at 60 ℃.

Latanoprost is mixed with silicone. Preparing latanoprost. Latanoprost is provided as a 1% methyl acetate solution. The appropriate amount of solvent was placed in a vessel and the solution was evaporated with nitrogen until only latanoprost remained. The vessel with latanoprost oil was placed in vacuum for 30 minutes. Latanoprost is mixed with silicone. Three different concentrations of latanoprost in silicone Nusil6385 (5%, 10% and 20%) were prepared and injected into tubes of different diameters (0.006 inch, 0.012 inch and 0.025 inch) to form a 3 x 3 matrix. The percentage of latanoprost in silicone is determined by the total weight of the drug matrix. Calculating the formula: weight of latanoprost/(weight of latanoprost + weight of silicone) × 100= drug percentage.

And (4) injecting a tube. 1. The cartridge and polyimide tubing set were inserted into a 1ml syringe. 2.1 drop of catalyst (MED-6385 curative) was added to the syringe. 3. Excess catalyst was removed from the polyimide tube with clean air. 4. The syringe was filled with a silicone drug matrix. 5. The drug matrix is injected into the tube until the tube is filled or the syringe plunger becomes very difficult to push. 6. The distal end of the polyimide tube was closed and pressure was maintained until the silicone began to cure. 7. Cured at room temperature for 12 hours. 8. The mixture was placed in vacuum for 30 minutes. 9. The tubes were placed in a sizing fixture (made to hold different sized tubes inside) and the drug inserts were cut to length (0.80-0.95 mm).

And (4) testing. Dissolution studies (in vitro). 1. 10 plungers of the same size and the same concentration were placed in each centrifuge tube, and 1.5ml of a buffer solution having a pH of 7.4 was added thereto. 2. After an appropriate time the solvent was replaced with fresh buffer at pH 7.4. 3. HPLC of the eluate was performed at 210nm using a PDA detector 2996, Sunfire C18, 3mm X10 mm chromatography column (Waters corporation, Milford, Mass.). Gradient elution was performed using a mixture of acetonitrile and water. Internal calibration was performed before or after each analysis using an internal standard at precisely weighed latanoprost concentrations. 4. The amount of drug released per day per device was calculated for different sized tubes with different concentrations of latanoprost. 5. The dissolution rates versus area and concentration were plotted on day 1 and day 14.

Figures 7A and 7B show dissolution data for latanoprost at day 1 and day 14 for three cores of 0.006, 0.012, and 0.025 inch diameter and three concentrations of about 5%, 11%, and 18% latanoprost, respectively. The dissolution rate of latanoprost in nanograms (ng)/day is plotted against the percent concentration. These data indicate that the dissolution rate is slightly concentration dependent and strongly dependent on the exposed surface area over the same time period. On day 1, the 0.006 inch, 0.012 inch, and 0.025 inch diameter cores released about 200ng, 400ng, and 1200ng of latanoprost, respectively, indicating that the amount of latanoprost released increased with increasing size of the exposed surface area of the drug core. For each tube diameter, the amount of latanoprost released was compared to the concentration of drug in the drug core using a least squares regression line. The slopes of the regression lines were 11.8, 7.4, and 23.4 for the 0.006, 0.012, and 0.025 inch drug cores, respectively. As described above, these values indicate that doubling the concentration of latanoprost drug in the core does not cause doubling of the dissolution rate of latanoprost from the core, consistent with droplets of latanoprost suspended in the drug core matrix and the substantial saturation of the drug core matrix with latanoprost dissolved therein as described above.

On day 14, the 0.006 inch, 0.012 inch (0.32 mm), and 0.025 inch diameter cores released about 25ng, 100ng, and 300ng of latanoprost, respectively, indicating that as the exposed surface area size of the drug core increased over an extended period of time, the amount of latanoprost released increased and was slightly dependent on the concentration of the therapeutic agent in the core. For each tube diameter, the amount of latanoprost released was compared to the concentration of drug in the drug core using a least squares regression line. The slopes of the regression lines were 3.0, 4.3, and 2.2 for the 0.006, 0.012, and 0.025 inch drug cores, respectively. As noted above, for the 0.012 and 0.025 inch drug cores, these values indicate that doubling the concentration of latanoprost drug in the core does not cause a doubling of the dissolution rate of latanoprost from the core, consistent with droplets of latanoprost suspended in the drug core matrix and substantial saturation of the drug core matrix with latanoprost dissolved therein. However, for a 0.006 inch diameter core, there is an approximately first order relationship between the initial amount in the core and the amount of drug released at day 14, which may be due to depletion of the latanoprost drug droplets in the core.

Fig. 7D and 7E show the dependence of dissolution rate on the exposed surface area of the drug core for three core diameters and three concentrations of latanoprost on day 1 and day 14 as shown in fig. 7A and 7B, respectively, according to an embodiment of the present invention. Plotting Latanoprost in nanograms (ng)/dayFor the dissolution rate in mm²A graph showing the exposed surface area of the core as determined by the diameter of the core. These data indicate that the dissolution rate is slightly dependent on the drug concentration in the core and strongly dependent on the exposed surface area on day 1 and 14. The exposed surface areas of the 0.006 inch, 0.012 inch and 0.025 inch diameter cores were about 0.02, 0.07 and 0.32mm, respectively². On day 1, the stated 0.02, 0.07 and 0.32mm²The cores of (a) released about 200ng, 400ng and 1200ng of latanoprost, respectively, indicating that the amount of latanoprost released increased with the increase in the size of the exposed surface area of the drug core. For each drug core concentration of therapeutic agent, the amount of latanoprost released is compared to the exposed surface area of the drug core using a least squares regression line. For drug cores of 5.1%, 11.2% and 17.9%, the slopes of the regression lines were 2837.8, 3286.1 and 3411.6, respectively, with an R of 0.9925, 0.9701 and 1, respectively²And (4) the coefficient. On day 14, the stated 0.02, 0.07 and 0.32mm²The cores released about 25ng, 100ng and 300ng of latanoprost, respectively, indicating that the amount of latanoprost released increases with the increase in the size of the exposed surface area of the drug core. For 5.1%, 11.2% and 17.9% drug cores, the slopes of the regression lines were 812.19, 1060.1 and 764.35, respectively, with an R of 0.9904, 0.9924 and 0.9663, respectively²And (4) the coefficient. As described above, these values indicate that the rate of latanoprost dissolution from the core increases linearly with the surface area of the core, consistent with a sheath that can control the exposed surface area. The weak dependence of latanoprost dissolution on the concentration in the drug core is consistent with droplets of latanoprost suspended in the drug core matrix and substantial saturation of the drug core matrix with latanoprost dissolved therein.

Figure 7C shows dissolution data for latanoprost according to an embodiment of the invention from 0.32mm diameter, 0.95mm length drug cores having concentrations of 5, 10, and 20%, and drug weights of 3.5, 7, and 14 μ g, respectively. The core was prepared as described above. The dissolution rate was plotted in ng/day from 0 to 40 days. The 14 μ g core exhibited a rate of about 100 ng/day from about 10-40 days. The 7 μ g core showed comparable rates from about 10 to 20 days. As described above, these data are consistent with droplets of latanoprost suspended in the drug core matrix and substantial saturation of the drug core matrix with latanoprost dissolved therein.

Table 2 shows the required parameters for each drug concentration. As shown in figure 1C, in vitro results in a buffered saline dissolution system showed that the punctal plugs initially dissolved about 500ng latanoprost/day, rapidly decreasing to 100 ng/day within 7-14 days, depending on the initial drug concentration.

TABLE 2 drug elution Properties

Total latanoprost amount	14μg	7μg	3.5μg
				In vitro dissolution rate	See FIG. 1C	See FIG. 1C	See FIG. 1C
Duration of time	About 100 days	About 45 days	About 25 days

In many embodiments, the duration of the drug core may be determined based on the calculated time at which-10% of the original amount of drug is retained in the drug insert, e.g., the dissolution rate level exceeds or remains substantially constant at about 100 ng/day.

Example 2 cyclosporin core dissolution data

The drug core in example 1 above was prepared with cyclosporin at a concentration of 21.2%. Fig. 8A shows a dissolution profile of cyclosporin according to an embodiment of the invention from the drug core into the buffer without surfactant and with surfactant. The buffer was prepared as described above. The surfactant-containing solution comprised 95% buffer and 5% surfactant, and UP-1005 Ultra Pure Fluid was obtained from Dow Corning, Midland, Mich. Related studies conducted on embodiments of the present invention have shown that, in at least some instances, surfactants can be used in vitro to simulate in situ dissolution from the eye, as the eye can include a natural surfactant, such as surfactant protein D, in the tear film. The amount of cyclosporin dissolved in the surfactant is about 50 to 100 ng/day from 30 to 60 days. Empirical data for a population of patients, for example, tears from 10 patients, can be determined and used to improve in vitro models with appropriate amounts of surfactant. The drug core matrix can be modified based on human tear surfactants, which can be determined using modified in vitro models. The drug core may be modified to correspond to the human tear film surfactant by a number of methods, such as by increased exposed surface area and/or additives that increase the amount of cyclosporin drug dissolved in the core, as described above, to increase dissolution from the core to therapeutic levels, if appropriate.

Example 3 Total bimatoprost dissolution data

A total sample of 1% bimatoprost having a known diameter of 0.076cm (0.76 mm) was prepared. The height of each sample is determined by the weight and known diameter of the sample.

TABLE 2 Total sample size

The calculated height is 0.33cm to 0.42 cm. For 0.019cm and 0.33cm samples respectively³And 0.015cm³The volume of (a), each end exposed surface area of each total sample was 0.045cm². The exposed surface area of the exposed sample without the sheath, calculated from height and diameter, was about 0.1cm². Three formulations were evaluated: 1) silicone 4011, 0.1% bimatoprost, 0% surfactant; 2) silicone 4011, 1% bimatoprost, about 11% surfactant; and 3) silicone 4011, 1% bimatoprost, about 33% surfactant. Assuming a total device surface area of 0.1cm²Surface area of the clinical device was 0.00078cm²(0.3 mm diameter), the dissolution data determined for the total samples with formulations 1, 2 and 3 were normalized to ng per device per day (ng/device/day). Figure 9A shows a normalized elution profile in ng/device/day over 100 days for a total sample of silicone with 1% bimatoprost assuming a 0.3mm exposed surface diameter of the device tip, according to an embodiment of the present invention. The normalized dissolution profile was about 10 ng/day. The data show about zero order release kinetics for each formulation from about 10 days to about 90 days. As described above, these data are consistent with bimatoprost particles suspended in a drug core matrix and substantial saturation of the drug core matrix with bimatoprost dissolved therein. As described above, a similar formulation having a drug core sheath and a shaped exposed surface of the core exposed to the tear can be used to increase the exposed surface area and release the drug in therapeutic amounts over an extended period of time.

In some embodiments, the core may include a core having an exposed surface area of 0.0045cm²A 0.76mm diameter core with a comparable exposed surface diameter of 0.76 mm. As described above, the core may be covered by a sheath to define an exposed surface of the core. The normalized dissolution profile of such a device based on the above total sample data is approximately 6 times (0.0045 cm) the dissolution profile of a device having a 0.3mm diameter exposed surface area²/0.00078cm²). Thus, a zero order release dissolution profile with a dissolution rate of about 60 ng/day can be obtained over a period of about 90 days. If it isThe exposed surface area is increased to 0.0078cm²E.g., having a plurality of exposed surface shapes as described above, the zero order release dissolution rate is about 100 ng/day over a period of about 90 days. The concentration can also be increased from 1%. The same dissolution profile can also be obtained with latanoprost.

Example 4 Latanoprost dissolution data

The cores with latanoprost, silicone 4011, 6385 and/or NaCl were prepared as described above. The following four formulations were prepared: 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. Fig. 10A shows the elution profile of latanoprost from the core for four latanoprost formulations according to an embodiment of the present invention. The results show a decrease from an initial rate of about 300 ng/device/day to about 100 ng/device/day over 3 weeks (21 days). The results are for an unsterilized core. The same results have been obtained with sterile cores of latanoprost. As described above, these data are consistent with droplets of latanoprost suspended in the drug core matrix and substantial saturation of the drug core matrix with latanoprost dissolved therein.

Exemplary embodiments have been described in detail by way of example for purposes of clarity of understanding, and those skilled in the art will recognize that numerous modifications, adaptations, and variations may be made. For example, multiple release mechanisms may be employed, and device embodiments may be adapted to include other features or materials, and further, multiple features or materials may be employed in a single device. Accordingly, the scope of the invention is to be limited only by the following claims.

Claims

1. An implant adapted to be inserted into a punctum of a patient to provide sustained release of a therapeutic agent to an eye of the patient, the implant comprising:

a plug body comprising a distal end, a proximal end, and an axis therebetween, the distal end of the plug body being inserted distally through the punctum into a lacrimal canaliculus lumen, wherein the plug body is disposed for sustained dissolution of the therapeutic agent into tear fluid, wherein the plug body comprises an exterior surface formed to engage lumen wall tissue to inhibit expulsion of the plug body when disposed in the lumen, and wherein the plug body comprises a drug core comprising the therapeutic agent contained in a matrix, and the drug core is exposed to direct contact with tears or tear film fluid.

2. The implant of claim 1, wherein the therapeutic agent is selected from the group consisting of prostaglandin analogs, timolol maleate, NSAIDs, and cyclosporines.

3. The implant of claim 2, wherein the therapeutic agent is latanoprost, travoprost, or bimatoprost.

4. The implant of claim 3, wherein the therapeutic agent is latanoprost, and the plug body is arranged such that the daily dissolution of the latanoprost drops from 300ng to 100ng within 3 weeks after insertion of the plug body into the punctum.

5. The implant of claim 3, wherein the therapeutic agent is bimatoprost and the plug is arranged to dissolve between 5ng and 500ng of bimatoprost per day.

6. The implant of claim 1, wherein the drug core further comprises an additive that increases or decreases the solubility of the therapeutic agent to control the release of the therapeutic agent.

7. The implant of claim 1, wherein the plug is arranged to dissolve therapeutic levels of the therapeutic agent for up to 3 weeks.