Compositions and methods for delivering antibiotic macrolides to treat dry eye syndrome - Patents.com

Abstract

To provide compositions and methods for delivering a bio-active agent, for treating dry eye syndrome.SOLUTION: The present invention provides a method of treating dry eye syndrome, comprising: administering a composition to an eye of a mammal in need thereof; wherein the composition is a sustained release composition; wherein the composition is configured to release an effective amount of an active agent per day for a treatment period of at least seven days; and wherein the active agent is Tacrolimus.SELECTED DRAWING: None

Description

[Technical field]

[0001] Related Applications This application claims priority to a U.S. provisional application (U.S. Patent Application No. 62 / 512,682; entitled "Compositions and Methods for Delivering Non-Antibiotic Macrolides") filed May 30, 2017, which is incorporated by reference in its entirety for all purposes.

[0002] Technical Field In embodiments, the present invention relates to compositions and methods for delivering bioactive agents. [Background technology]

[0003] background Keratoconjunctivitis sicca (KCS), also known as dry eye syndrome, is a chronic eye disease resulting from a deficiency of one or more elements in the precorneal tear film. Approximately 2 percent of the population over the age of 50 suffers from KCS. Common symptoms of KCS include reduced tear production or inadequate secretion of tears, and excessive tear evaporation. Long-term treatment of KCS can help alleviate these symptoms. Summary of the Invention

[0004] In an embodiment, the composition of the present invention is a drug delivery device in which tacrolimus (FK-506) may be added to the composition. Ocular inflammation due to hyperosmolarity of the tear film can be treated using topical immunosuppressants such as cyclosporine or tacrolimus (FK-506). In one particular embodiment, topical immunosuppressants such as cyclosporine or tacrolimus (FK-506) can be used to suppress ocular inflammation due to hyperosmolarity of the tear film. In another embodiment, a composite matrix episcleral implant or punctal plug delivers a drug such as tacrolimus to the cornea in a sustained manner. In one example, the ocular implant of the present invention provides long-term treatment of KCS with a punctal plug made of composite matrix-tacrolimus. In yet another embodiment, a composite matrix episcleral implant or composite matrix plug containing tacrolimus allows for sustained release of tacrolimus below toxic levels, allowing for higher drug concentrations than topical therapy without systemic side effects.

[0005] In another embodiment, the implant contains about 900 micrograms of TAC. In one specific example, TAC release is 2 μg / day in vitro for the first month, followed by a steady state release of 1.5 μg / day for the next 2-3 months, averaging about 1.7 μg / day for the first 3 months. In yet another embodiment, the estimated duration of release in vitro is 6 months. [Brief description of the drawings]

[0006] The present invention will be further described with reference to the accompanying drawings, in which like structure is referenced by like numerals throughout the several views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention. In addition, some features may be exaggerated to show details of particular components. [Figure 1] FIG. 1 illustrates an embodiment of the composition of the present invention showing chemical structures. [Diagram 2] 2A-2E illustrate various embodiments of the composition of the present invention using various views of a plug. [Diagram 3] FIG. 3 illustrates an embodiment of a method for making a composition of the present invention. [Figure 4] FIG. 4 illustrates an embodiment of a composition of the present invention showing a release profile. [Diagram 5] FIG. 5 shows a graph of the release profile of an embodiment of a composition of the present invention. [Figure 6] Figures 6A and 6B are photographs of an embodiment of a composition arrangement of the present invention, and Figure 6C shows a graph illustrating an embodiment of the composition of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] Description of exemplary embodiments The drawings constitute a part of this specification and include exemplary embodiments of the present invention and illustrate various objects and features thereof. Moreover, the drawings are not necessarily to scale and some features may be exaggerated to show details of particular components. Moreover, all dimensions, specifications, etc. shown in the figures are for illustrative purposes and not limiting. Therefore, specific structural and functional details disclosed herein should not be construed as limiting, but merely as a typical basis for teaching those skilled in the art to variously apply the present invention.

[0008] Among these disclosed benefits and improvements, other objects and advantages of the present invention will become apparent from the following description taken in conjunction with the accompanying drawings. Detailed embodiments of the present invention are disclosed herein; however, it is understood that the disclosed embodiments are merely exemplary of the invention, which may be embodied in various forms. Moreover, each of the examples described in connection with various embodiments of the present invention are intended to be illustrative and not limiting.

[0009] Throughout the specification and claims, the following terms have the meanings expressly associated therewith, unless otherwise clear from the context. The terms "in one embodiment" and "in an embodiment" as used herein do not necessarily refer to the same embodiment, but may. Additionally, the terms "in another embodiment" and "in another embodiment" as used herein may, but do not necessarily, refer to different embodiments. Thus, as described below, various embodiments of the invention can be readily combined without departing from the scope or spirit of the invention.

[0010] Additionally, the term "or" as used herein is an inclusive "or" operator and is equivalent to the term "and / or" unless the context clearly indicates otherwise. The term "based on" is not exclusive and allows for based on additional unrecited elements unless the context clearly indicates otherwise. Additionally, throughout this specification, the meanings of "a," "an," and "the" include plural references. The meaning of "in" includes "in" and "on."

[0011] The present invention relates generally to the field of pharmaceutical device-drug combinations for the administration of bioactive agents over extended periods of time. More specifically, it relates to implantable ophthalmic devices for sustained delivery of therapeutic compounds to the eye. In the context of the present invention, sustained release is a type of dosage form designed to release drug at a predetermined rate to maintain a substantially constant drug concentration for a specified period of time with minimal systemic side effects.

[0012] In embodiments, the present invention is a composite device configured to contain and release a certain amount of drug per unit volume. In embodiments, the device is configured to allow loading of multiple drugs, including but not limited to two drugs, three drugs, four drugs, five drugs. In embodiments, the drug molecules are physically bound to the matrix. In embodiments, the non-metallic coating provides zero-order or near-zero-order drug release kinetics at two different rates, a higher rate for the first few weeks and a lower rate thereafter.

[0013] In an embodiment, the composition of the present invention is a drug delivery device composite formed into a desired body / shape, the composite comprising at least: particles of an inert material with a porous structure having a high surface area and low bulk density. Suitable inert materials include, but are not limited to, fumed silica, silica gel, activated carbon, activated alumina, zeolite products, or combinations thereof, which provide a porous structure with an interconnected capillary network similar to an open cell sponge.

[0014] In embodiments, the small diameter of the pores results in high capillary forces that draw the liquid into the particles. This physical absorption mechanism does not appear to be dependent on the chemical properties of the liquid, and therefore may absorb both polar and non-polar liquids. For example, fumed silica has a surface area of ​​10-600 m2. 2 / g, and for silica gel it is about 800m 2 / g. In one example, the finished adsorbent includes: (1) a liquid active agent with 50-75% drug on the particle surface or inside the pores (e.g., including but not limited to, fumed silica loaded (i.e., bonded) with a macrolide); (2) a bulking agent (e.g., including but not limited to, kaolin); (3) an adhesive binder (e.g., including but not limited to, a ceramic adhesive, e.g., an epoxy adhesive); (4) a hydrophobic plastic polymer (e.g., including but not limited to, a polyurethane), or any combination thereof. In an embodiment, the physical mechanism for adsorbing the liquid active agent is passive.

[0015] In embodiments, the finished imbibe comprises: (1) a liquid active agent (e.g., including but not limited to, fumed silica loaded (i.e., bonded) with 50-75% drug on the particle surface or within the pores); (2) an adhesive binder (e.g., including but not limited to, a ceramic adhesive, e.g., an epoxy adhesive); (3) a hydrophobic plastic polymer (e.g., including but not limited to, a polyurethane), or any combination thereof.

[0016] In some embodiments, the composition of the present invention comprises: a) a composite comprising: (i) particles of an inert material having a drug adsorbed on the surface of the particle (e.g., a drug that is bound to the particle) or within the pores (e.g., a drug that is contained within the pores); (ii) a bulking agent; (iii) an adhesive binder; (iv) a hydrophobic plastic polymer, or any combination thereof; and b) optionally, a coating of the entire or a portion of the outer surface of the body / core (this coating can be a full / continuous or perforated coating, for example, but not limited to, the coating can be butvar and / or parylene); A drug delivery device comprising:

[0017] In some embodiments, the composition of the present invention comprises: a) a composite comprising: (i) particles of an inert material having a drug adsorbed on the surface of the particle (e.g., a drug that is bound to the particle) or within the pores (e.g., a drug that is contained within the pores); (ii) an adhesive binder; (iii) a hydrophobic plastic polymer, or any combination thereof; and b) optionally, a coating of the entire or a portion of the outer surface of the body / core (this coating can be a full / continuous or perforated coating, for example, but not limited to, the coating can be butvar and / or parylene); A drug delivery device comprising:

[0018] In an embodiment, the composition of the present invention contains an immunosuppressant, which may be cyclosporine, azathioprine, tacrolimus, or derivatives thereof, or any combination thereof. In an embodiment, the composition of the present invention contains an immunosuppressant, which may be tacrolimus, cyclosporine, pimecrolimus, or antibiotic macrolides, such as sirolimus, everolimus, deforolimus, temsirolimus, zotarolimus, avetimus, gusperimus, and mycophenolic acid, used as immunosuppressants or immunomodulators, or any combination thereof. In an embodiment, two or more (e.g., 2, 3, 4, 5) drugs are contained in the matrix and released independently and in parallel, each drug being released according to (a) its inherent solubility in the external medium, and (b) the barrier of a hydrophobic polymer, an external impermeable barrier, or both. In an embodiment, the concentration of the macrolide in the matrix is ​​about 1 to about 60% by weight. In an embodiment, the concentration of the macrolide in the matrix is ​​from about 30% to about 40% by weight.In an embodiment, the concentration of the macrolide in the matrix is ​​from about 10 to about 17% by weight.

[0019] In an embodiment of the composition of the present invention, the concentration of the macrolide in the matrix is ​​about 10 to about 15% by weight. In an embodiment, the concentration of the macrolide in the matrix is ​​about 10 to about 13% by weight. In an embodiment, the concentration of the macrolide in the matrix is ​​about 5 to about 20% by weight. In an embodiment, the concentration of the macrolide in the matrix is ​​about 10 to about 20% by weight. In an embodiment, the concentration of the macrolide in the matrix is ​​about 13 to about 20% by weight. In an embodiment, the concentration of the macrolide in the matrix is ​​about 15 to about 20% by weight.

[0020] In an embodiment, the composition of the present invention comprises: a) a composite comprising: (i) particles of an inert material having a drug adsorbed on the surface of the particle (e.g., a drug that is bound to the particle) or within the pores (e.g., a drug that is contained within the pores); (ii) a bulking agent; (iii) an adhesive binder; and b) optionally, a coating of the entire or a portion of the exterior surface of the body / core (this coating can be a full / continuous or perforated coating, for example, but not limited to, the coating can be parylene); A drug delivery device comprising:

[0021] In an embodiment, the composition of the present invention comprises: a) a composite comprising: (i) particles of an inert material having a drug adsorbed on the surface of the particle (e.g., a drug that is bound to the particle) or within the pores (e.g., a drug that is contained within the pores); (ii) an adhesive binder; and b) optionally, a coating of the entire or a portion of the exterior surface of the body / core (this coating can be a complete / continuous or perforated coating, for example, but not limited to, the coating can be parylene); A drug delivery device comprising:

[0022] In embodiments of the compositions of the present invention, the concentration of the macrolide in the matrix is ​​about 30 to about 40% by weight. In embodiments, the concentration of the macrolide in the matrix is ​​about 32 to about 38% by weight. In embodiments, the concentration of the macrolide in the matrix is ​​about 5 to about 40% by weight. In embodiments, the concentration of the macrolide in the matrix is ​​about 10 to about 40% by weight. In some embodiments, the concentration of the macrolide in the matrix is ​​about 23 to about 40% by weight. In embodiments, the concentration of the macrolide in the matrix is ​​about 15 to about 40% by weight.

[0023] In an embodiment of the composition of the present invention, the parylene coating has a thickness of about 0.3 μm to about 20 μm. In an embodiment, the parylene coating has a thickness of about 0.3 μm to about 10 μm. In an embodiment, the parylene coating has a thickness of about 0.3 μm to about 5 μm. In an embodiment, the parylene coating has a thickness of about 0.3 μm to about 3 μm. In an embodiment, the parylene coating has a thickness of about 0.3 μm to about 1 μm. In an embodiment, the parylene coating has a thickness of about 1 μm to about 20 μm. In an embodiment, the parylene coating has a thickness of about 3 μm to about 20 μm. In an embodiment, the parylene coating has a thickness of about 5 μm to about 20 μm. In an embodiment, the parylene coating has a thickness of about 10 μm to about 20 μm.

[0024] In an embodiment of the composition of the present invention, the butabar coating has a thickness of about 1 μm to about 20 μm. In an embodiment, the butabar coating has a thickness of about 5 μm to about 20 μm. In an embodiment, the butabar coating has a thickness of about 10 μm to about 20 μm. In an embodiment, the butabar coating has a thickness of about 15 μm to about 20 μm. In an embodiment, the butabar coating has a thickness of about 1 μm to about 15 μm. In an embodiment, the butabar coating has a thickness of about 1 μm to about 10 μm. In an embodiment, the butabar coating has a thickness of about 1 μm to about 5 μm. In an embodiment, the butabar coating has a thickness of about 5 μm to about 15 μm.

[0025] In an embodiment of the composition of the present invention, the core / body further comprises a capillary extension attached to a distal tip portion of the core / body, the capillary extension being configured to be inserted through the punctal opening and the punctum and positioned within the lacrimal canaliculus. In some embodiments, the capillary extension has a length L1 and the body has a length L2, the ratio of length L1 to length L2 being about 2:1 to about 10:1. In some embodiments, the ratio of length L1 to length L2 is about 2:1 to about 8:1. In some embodiments, the ratio of length L1 to length L2 is about 2:1 to about 6:1. In some embodiments, the ratio of length L1 to length L2 is about 2:1 to about 4:1. In some embodiments, the ratio of length L1 to length L2 is about 4:1 to about 10:1. In some embodiments, the ratio of length L1 to length L2 is about 6:1 to about 10:1. In embodiments, the ratio of length L1 to length L2 is from about 8:1 to about 10:1.

[0026] In an embodiment of the composition of the invention, the capillary extension is configured to be placed in the lacrimal canaliculus and / or nasolacrimal duct. In an embodiment, the core / body has an outer surface and is configured to be inserted through the punctal opening and placed in the lacrimal punctum or canaliculus, the body being a monolithic capsule structure or in the shape of a cylinder. In an embodiment, the composition includes a parylene or butabal coating covering the outer surface of the body, the parylene or butabal coating being substantially impermeable to the drug (e.g., macrolide) (the surface is impermeable when the thickness is greater than 1.4 nanometers); and at least one of the pores of the parylene or butabal coating, the amount and / or size of the pores being configured to release a therapeutically effective dose of the macrolide (e.g., including but not limited to, tacrolimus) for 1-360 days (e.g., 1, 2, 3, 4, 5 days). In an embodiment, the period is 1-180 days. In an embodiment, the period is 1-120 days. In an embodiment, the period is 1-90 days. In an embodiment, the period is 1 to 60 days. In an embodiment, the period is 1 to 30 days. In an embodiment, the period is 1 to 21 days. In an embodiment, the period is 1 to 14 days. In an embodiment, the period is 1 to 10 days. In an embodiment, the period is 1 to 7 days. In an embodiment, the period is 7 to 180 days. In an embodiment, the period is 10 to 180 days. In an embodiment, the period is 14 to 180 days. In an embodiment, the period is 21 to 180 days. In an embodiment, the period is 30 to 180 days. In an embodiment, the period is 60 to 180 days. In an embodiment, the period is 90 to 180 days. In an embodiment, the period is 120 to 180 days. In an embodiment, the period is 7 to 180 days. In an embodiment, the period is 10 to 180 days. In an embodiment, the period is 14 to 180 days. In an embodiment, the period is between 21 and 180 days. In an embodiment, the period is between 30 and 120 days. In an embodiment, the period is between 60 and 120 days. In an embodiment, the period is between 90 and 120 days. In an embodiment, the period is between 60 and 90 days.

[0027] As an embodiment, tacrolimus (FK-506), an antibiotic macrolide derived from the bacterium Streptomyces tsukubaensis, is a potent immunomodulator that can reduce the production of inflammatory mediators by T lymphocytes through inhibition of calcineurin, a protein essential for interleukin (IL)-2 and IL-4 transcription.

[0028] Tacrolimus (IUPAC name: (3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,19R,26aS)-5,19-dihydroxy-3-{(1E)-1-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]propan-1-en-2-yl}-14,16-dimethoxy-4,10,12 ,18-Tetramethyl-8-(propan-2-en-1-yl)-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-3H-15,19-epoxypyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone;C 44 H 69 NO 12 (also known as FK-506, FR-900506, fujimycin) is a macrolide isolated from Streptomyces having the chemical structure shown in FIG. 1.

[0029] Tacrolimus binds to the FKBP-12 protein and forms a complex with calcium-dependent proteins, thereby inhibiting calcineurin phosphatase activity and resulting in reduced cytokine production. The drug exhibits potent immunosuppressant activity in vivo, preventing the activation of T lymphocytes in response to antigenic or mitogenic stimulation.

[0030] Tacrolimus is also effective in treating immune-mediated diseases such as corneal graft rejection, ocular inflammation, ocular pemphigoid, allergic rhinitis, and uveitis.

[0031] In an embodiment of the composition of the present invention, the concentration of the macrolide in the composite is 1-50% by weight, and the concentration of the macrolide in the final punctal plug is 20%-40%.

[0032] The present invention provides pharmaceutical compositions and methods for treating KCS. The present invention provides compositions in the form of an implant, the implant configured to provide an extended release time of one or more therapeutic agents. In some embodiments, the implant is in the shape of a core. In some embodiments, the implant is in the shape of a plug. In some embodiments, the therapeutic agent is a macrolide. In some embodiments, the macrolide is tacrolimus.

[0033] In some embodiments of the compositions of the invention, the implant is configured to release the drug over a period of time, for example, at least 1 week, or for example, from about 2 months to about 6 months, following intraocular administration of the tacrolimus-containing implant. In some embodiments, the period is 1 week to 1 year. In some embodiments, the period is 1 week to 9 months. In some embodiments, the period is 1 week to 6 months. In some embodiments, the period is 1 week to 3 months. In some embodiments, the period is 1 week to 1 month. In some embodiments, the period is 1 month to 1 year. In some embodiments, the period is 1 month to 9 months. In some embodiments, the period is 1 month to 6 months. In some embodiments, the period is 1 month to 3 months. In some embodiments, the period is 3 months to 1 year. In some embodiments, the period is 6 months to 1 year. In some embodiments, the period is 9 months to 1 year. In some embodiments, the period is 3 months to 9 months. In some embodiments, the period is 3 months to 6 months. In one embodiment, the period is 6 to 9 months.

[0034] In an embodiment of the composition of the invention, the composition is a pharmaceutical composition plug configured for intraocular use, for example to treat an ocular condition. In an embodiment, the pharmaceutical composition is a plug comprising a solid composite powder, the solid composite powder being dispersed in at least one soft polymer. In an embodiment, the solid composite powder comprises organic microparticles comprising a bioactive agent, an inert carrier, a binder, or any combination thereof. In an embodiment of the composition of the invention, the organic microparticles are configured to absorb a drug, i.e., to carry a drug (i.e., a drug carrier; for example, but not limited to, fumed silica). The organic microparticles have a surface area of ​​5-1000 m 2 / g (The surface area of ​​fumed silica is 10 to 600 m 2 / g, silica gel is about 800m 2 / g, and the surface area of ​​calcium carbonate is 5 to 24 m 2 / g).

[0035] In embodiments of the compositions of the invention, the bioactive agent can be dissolved, dispersed, emulsified, bound, adsorbed, impregnated, mixed, or otherwise incorporated into the solid organic matrix. In embodiments, the bioactive agent can be directly mixed with the organic matrix. In embodiments, the bioactive agent can be adsorbed onto another material, such as particulate matter and / or fibrous matter, which can be mixed with the organic matrix.

[0036] In embodiments of the compositions of the present invention, the bioactive agent is first dissolved, dispersed, or emulsified in an organic compound (or, e.g., a precursor thereof) melt, solution, emulsion, or dispersion. In embodiments, the solid organic matrix may be comprised of polymers, oligomers, monomers, waxes, oils, plasticizers, and any combination thereof.

[0037] In an embodiment of the composition of the present invention, the organic particles containing a drug (e.g., a macrolide, e.g., tacrolimus) are mixed with at least one inert pharma- ceutically acceptable excipient or carrier (e.g., sodium citrate or dicalcium phosphate) and / or (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia; (c) humectants, such as glycerol; (d) agar, calcium carbonate, jasmine, or the like; (e) glycerol, glycerol, or the like; (f) glycerol, ... (e) disintegrating agents such as potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (e) solution retarding agents such as paraffin; (f) absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol monostearate; (h) absorbents such as kaolin and bentonite clay and pectin; (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or any combination thereof.

[0038] In an embodiment of the composition of the present invention, the organic particulates and the inert carrier are bound together with a binder to produce a composite matrix. In an embodiment, examples of polymers include, but are not limited to, poly(dimethylsiloxane), polyurethane, epoxy, methyl methacrylate polymer, acrylic copolymer, polyester, polyamide, polyethylene, polypropylene, ethylene copolymer and terpolymer, propylene copolymer and terpolymer, fluoropolymer, vinyl, styrene, polycarbonate, amino resin, and phenolic resin, or combinations thereof. Examples of other polymers include crosslinked acrylic or methacrylic networks, including networks formed by ultraviolet (UV) curing. In an embodiment, the core (in which the drug is absorbed or present) comprises a thermosetting polymer. In an embodiment, examples of waxes include, but are not limited to, paraffin, amide, ester, fatty acid derivative, fatty alcohol derivative, silicone, and phospholipid.

[0039] In some embodiments of the composition of the present invention, the composite matrix containing the bioactive agent (e.g., but not limited to, tacrolimus) can be in the form of a solid, such as a powder, flake, fiber, or any combination thereof. In embodiments, the composite can be ground and / or pulverized into a fine powder of size <100 μm or <30 μm using a grinding device such as a mortar and pestle, an electronic grinder, etc. In embodiments, the fine composite powder can be dispersed and / or mixed with a plastic polymer. In embodiments, the plastic polymer can be a medical polymer, including, for example, a polymer with hydrophilic and / or hydrophobic properties. In embodiments, examples of polymers include, but are not limited to, silicone, polyacrylate, polyurethane, or a combination of two or more polymers.

[0040] In embodiments of the compositions of the invention, the polyurethane can be shaped or its permeability tailored to achieve a desired release rate of the bioactive agent from the device to the patient. In embodiments, the polymer comprises one or more polymers made of homopolymers or heteropolymers.

[0041] In an embodiment of the composition of the invention, the mixture includes (1) a polymer and (2) a powder that is formed into a solid, self-supporting shape. In an embodiment, the self-supporting shape can be the desired shape of the composition (i.e., the solid core) and can be further processed, for example, by trimming or cutting, into the desired shape. In an embodiment, the shape can include, but is not limited to, a cylinder, a plug, a coin, a disk, a plate, a cube, a sphere, a fiber, a box, a diamond, a ring, an "S", an "L", an "T", a spider web, a net, a mesh, a "U", or a "V".

[0042] In embodiments, the composition of the punctal plugs may be suitably similar to one or more of the following compositions: Evolute® (Mati Therapeutics, Austin, TX), Bimatoprost SR (Allergan, Dublin, Ireland), ENV515 (Envisia Therapeutics, Inc., Durham, NC), OTX-TP (Ocular Therapeutics, Bedford, MA), and iDose™ (Glaukos, San Clemente, CA).

[0043] In an embodiment of the composition of the present invention, an outer shell coating may be added to the outside of the solid core. In an embodiment, the coating comprises a second non-biodegradable polymer that is substantially impermeable to a therapeutic compound (e.g., but not limited to, a macrolide, such as tacrolimus). In an embodiment, the coating is at least less permeable (e.g., less than 1% permeable, less than 5% permeable, less than 10% permeable, less than 20% permeable, less than 30% permeable, less than 40% permeable, less than 50% permeable, less than 60% permeable, less than 70% permeable, etc.) than the permeability of the therapeutic compound to the first non-biodegradable polymer. In an embodiment, the outer shell coating may be butabar and / or parylene.

[0044] The present invention describes a drug delivery device that includes: 1) particles of inert material with drug absorbed on the surface or inside the pores of the particles; 2) an inert polymer matrix in which the drug-inert material particles are dispersed, where the polymer does not chemically interact with the drug and provides a mechanical package, and the drug concentration on the particles and the particle loading in the polymer matrix are set to control the drug storage capacity; 3) a hydrophobic plastic polymer that connects to the polymer matrix in a shape to create a barrier for drug release; 4) a porous outer barrier is applied to the solid core when the hydrophobic polymer is insufficient to control the release. In embodiments, the permeability of the barrier and / or the size and number of pores are configured to control the release rate of the drug (e.g., but not limited to, tacrolimus).

[0045] FIG. 2A illustrates an embodiment of the present invention showing a perspective view of a punctal plug or implant.

[0046] FIG. 2B illustrates an embodiment of the present invention, where cross section AA shows a perspective view of a punctal plug or implant looking from below up at an implant having one or more cavities for tear drainage.

[0047] FIG. 2C illustrates an embodiment of the invention and shows a perspective view of a punctal plug or implant, with line AA being the side of the implant.

[0048] 2D and 2E illustrate an embodiment of the present invention and show a perspective view of a punctal plug or implant, where section BB is a cross-sectional view taken along line BB.

[0049] FIG. 3 illustrates an embodiment of the present invention and shows a schematic diagram of the manufacturing process of the punctal plug. In one embodiment, the first step of the process consists of the production of a microparticle (PS) consisting of tacrolimus, fumed silica, and a solvent. The second step of the process is the creation of a composite matrix, which consists of combining the particulate matter with kaolin and then mixing it with an epoxy adhesive. The composite matrix forms a paste-like mixture and is used to fill the punctal plug mold cavity. After 24 hours of composite curing, the final shaped plug is extracted from the mold.

[0050] In an embodiment of the composition of the invention, the composition comprises a drug delivery composition including: (1) a bulking agent comprising kaolin; (2) an absorbent material comprising fumed silica; (3) a binder comprising an epoxy; and (4) a first active agent comprising 5-40% by weight tacrolimus.

[0051] In an embodiment of the composition of the invention, the composition comprises a drug delivery composition including: (1) a bulking agent comprising kaolin; (2) an absorbent material comprising fumed silica; (3) a binder comprising an epoxy; and (4) a first active agent comprising 5-40% by weight tacrolimus, and is in the form of a punctal plug.

[0052] In an embodiment, the invention is a method comprising: (1) administering to an eye of a mammal in need thereof a composition that releases 0.5 to 10 micrograms of a first active agent per day, the composition containing (2) a bulking agent comprising kaolin, (3) an absorbing material comprising fumed silica, (4) a binder comprising an epoxy, and (5) 5 to 40% by weight of the first active agent comprising tacrolimus.

[0053] In an embodiment of the composition of the invention, the composition comprises a drug delivery composition containing: (1) an absorbent material comprising fumed silica; (2) a binder comprising an epoxy; and (3) a first active agent comprising 5-40% by weight tacrolimus.

[0054] In an embodiment of the composition of the invention, the composition comprises a drug delivery composition including: (1) an absorbent material comprising fumed silica; (2) a binder comprising an epoxy; and (3) a first active agent comprising 5-40% by weight tacrolimus, and is in the form of a punctal plug.

[0055] In an embodiment, the invention is a method comprising administering (1) a composition releasing 0.5-10 micrograms of a first active agent per day to an eye of a mammal in need thereof, the composition containing (2) an absorbent material comprising fumed silica, (3) a binder comprising an epoxy, and (4) a first active agent comprising 5-40% by weight tacrolimus.

[0056] Some embodiments of the methods and compositions of the present invention may further employ the methods and compositions described in PCT / IB2015 / 002345, published as WO 2016 / 083891, which is incorporated herein by reference in its entirety. EXAMPLES

[0057] Example: Preparation of plug / solid core In one embodiment of the composition of the present invention, plug samples containing tacrolimus were prepared and incubated at 37° C. for various times to determine the effect of time on the release profile of tacrolimus from the sample into a polar solution (PBS).

[0058] Preparation of microparticles First, the bioactive agent was adsorbed or loaded onto fumed silica (FS). The bioactive agent was tacrolimus (TAC). 0.331 g of FS was mixed with 0.222 g of TAC dissolved in 10 g of solvent (THF:ethanol (1:1 (w / w)). Other examples of polar solvents include methanol, isopropanol, acetone, and / or ethyl acetate. The TAC / FS mixture was allowed to dry at room temperature for 24 hours.

[0059] Preparation and molding of composite matrices Type A: Composite matrix As an example of the preparation of a composite matrix, 0.046 g of kaolin powder was mixed with 0.123 g of FS microparticles and 0.076 g of medical grade epoxy (EPO-TEK 301, Epo-Tek, USA). Mixing was continued until a paste was formed. The paste was cured in a mold at room temperature for 24 hours. The resulting composition had the properties of a solid composite plug. Figure 3 is a schematic diagram showing the preparation and fabrication of a composite matrix punctal plug.

[0060] Type B: Epoxy matrix As an example of making an epoxy matrix without using a filler (i.e., kaolin powder), 0.123 g of FS particles was mixed with 0.123 g of medical grade epoxy (EPO-TEK 301, Epo-Tek, USA). Mixing was continued until a paste was formed. The paste was cured in a mold at room temperature for 24 hours. The resulting composition had the properties of a solid composite plug.

[0061] Solution Preparation - Release Media Buffer The solution contained: 0.01M PBS, 0.005% BAK, and 0.1% TRITON X-100.

[0062] Plug Coating Process The outer coating of the plug can be: (1) 5% (W / V) butvar in tetrahydrofuran (THF) as a solvent or (2) parylene coating - polyurethane plugs were coated with 2-5 μm of parylene using a deposition process. To coat the plugs, they were placed in a vacuum deposition chamber (Simtal Coating Ltd.) and the chamber was evacuated to about 0.1 torr. Parylene dimer (di-para-xylylene) was vaporized at about 150°C. The monomer (para-xylylene) was then pyrolyzed at about 680°C and 0.5 torr (e.g., but not limited to, the aryl-chlorine bond of dichloro[2.2]paracyclophane is cleaved at 680°C (standard pyrolysis temperature)). The monomer was then placed in the deposition chamber at about room temperature (about 25°C) and allowed to adsorb and polymerize onto the polyurethane plug.

[0063] Characteristics of the final plug samples The composite contains 30% tacrolimus and weighs 3 mg. See Table 1 for details. [Table 1] Working Example

[0064] Development of an HPLC-MS-MS method for tacrolimus (TCM) Tacrolimus (TCM) calibration curve: [Table 2]

[0065] Standard solution chromatogram (PBS) [Table 3]

[0066] Representative chromatogram of sample solution [Table 4]

[0067] result: Table 2 shows the list of samples used in the sustained release profile and cumulative sustained release profile shown in Figures 4 and 5, respectively. Samples 19-1 to 19-8 are Type A, COM TAC 1. Samples 19-9 to 19-16 are Type A, COM TAC 2. Samples 19-17 to 19-24 are Type B, EPO TAC 1. Samples 19-25 to 19-32 are Type B, EPO TAC 2. See Table 2 for details. [Table 5]

[0068] FIG. 4 shows the 3-month sustained release profile of the composite matrix tacrolimus plug and the epoxy matrix tacrolimus plug.

[0069] FIG. 5 shows the 3-month cumulative sustained release profiles of the composite matrix tacrolimus plug and the epoxy matrix tacrolimus plug.

[0070] In vivo experiments A study to evaluate the efficacy and feasibility of EXP-DE punctal plugs in a canine model Model: Pekingese dog with severe clinical KCS, Schirmer test for tears = 0mm / min, no tear production. The reference range for normal tear production in dogs is 15-20mm / min. Procedure: A punctal plug containing tacrolimus was implanted subconjunctivally under anesthesia in each eye.

[0071] 6A and 6B show subconjunctival implantation of punctal plugs in a canine model.

[0072] The punctal plugs were cylindrical in shape, with lengths and diameters as shown in Table 3. [Table 6]

[0073] Follow-up at 2, 4, 8, and 16 weeks after surgery (for red eye, ocular discharge, and performance of the Schirmer tear test (STT)).

[0074] result: ·Porting: OD, OS STT=0 Two weeks after surgery: OD, OS STT = 10 mm / min 4 weeks after surgery: OD, OS STT>20 mm / min New transplant: OD 8 weeks after surgery: OD=12 mm / min OS=7 mm / min 13 weeks after surgery: OD=15 mm / min OS=10 mm / min

[0075] FIG. 6C shows the results of an STT demonstrating the effect of a subconjunctival punctal plug implant containing tacrolimus on tear production in a canine model.

Claims

1. A sustained release punctal plug composition for the treatment of dry eye syndrome in a mammal in need thereof, comprising: The composition is administered to the eye of a mammal in need thereof; The composition is configured to release an effective amount of the active agent per day for a treatment period of at least 7 days; The composition comprises: An absorbent material comprising fumed silica; a bonding agent comprising an epoxy adhesive; and Active Agent Comprising Tacrolimus comprising The composition further comprises a coating. composition.

2. The composition of claim 1, wherein the effective amount of active agent released is 0.5 to 10 micrograms per day.

3. The composition of claim 1, wherein the composition comprises 1 to 60% by weight (w / w) of an active agent.

4. The composition of claim 1, wherein the coating is a non-metallic coating.

5. The composition of claim 1, wherein the coating is a coating on an outer surface of the composition.

6. The composition described in claim 5, wherein the coating is a full or partial coating on the outer surface of the composition.

7. The composition of claim 1, wherein the coating is a continuous or porous coating.

8. The composition of claim 1, wherein the coating comprises parylene and / or butabar.

9. The composition of claim 1, wherein the coating comprises parylene.

10. The composition of claim 1, wherein the coating comprises butabar.

11. The composition of claim 9, wherein the parylene coating has a thickness of about 0.3 μm to about 20 μm.

12. The composition of claim 10, wherein the thickness of the butabar coating is from about 1 μm to about 20 μm.

13. Use of a composition for the manufacture of a medicament for administration to the eye of a mammal, comprising: The composition is in the form of a punctal plug; The composition comprises: An absorbent material comprising fumed silica; a bonding agent comprising an epoxy adhesive; and Active Agent Comprising Tacrolimus and a composite comprising The composition further comprises a coating. use.

14. The use of claim 13, wherein the composition releases 0.5 to 10 micrograms of active agent per day.

15. The use of claim 13, wherein the coating is a non-metallic coating.

16. The use of claim 13, wherein the coating is a coating on the outer surface of the composition.

17. The use of claim 16, wherein the coating is a full or partial coating on the outer surface of the composition.

18. The use of claim 13, wherein the coating is a continuous or perforated coating.

19. The use of claim 13, wherein the coating comprises parylene and / or butabal.

20. The use of claim 19, wherein the thickness of the parylene coating is from about 0.3 μm to about 20 μm.

21. The use of claim 19, wherein the thickness of the butabar coating is from about 1 μm to about 20 μm.

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