US20200093834A1 - Compositions for delivering a bio-active agent or bio-active agents - Google Patents

Compositions for delivering a bio-active agent or bio-active agents Download PDF

Info

Publication number
US20200093834A1
US20200093834A1 US16/531,665 US201916531665A US2020093834A1 US 20200093834 A1 US20200093834 A1 US 20200093834A1 US 201916531665 A US201916531665 A US 201916531665A US 2020093834 A1 US2020093834 A1 US 2020093834A1
Authority
US
United States
Prior art keywords
active agent
composition
weight
present
kaolin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US16/531,665
Inventor
Eyal Sheetrit
Izhar Halahmi
Ishay Attar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eximore Ltd
Original Assignee
Eximore Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eximore Ltd filed Critical Eximore Ltd
Priority to US16/531,665 priority Critical patent/US20200093834A1/en
Publication of US20200093834A1 publication Critical patent/US20200093834A1/en
Assigned to EXIMORE LTD. reassignment EXIMORE LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ATTAR, ISHAY, HALAHMI, IZHAR, SHEETRIT, EYAL
Priority to US17/078,534 priority patent/US20210137942A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A61K9/0051—Ocular inserts, ocular implants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Abstract

In some embodiments, the present invention is a composition, including: a bulking agent, where the bulking agent is a kaolin, an absorbent material, where the absorbent material is a fumed silica, a binder, where the binder is an epoxy, and a first active agent, where the first active agent is Latanoprost.

Description

    RELATED APPLICATIONS
  • This application is a Divisional of U.S. patent application Ser. No. 15/529,474 filed on May 24, 2017, whish is a 371 National Entry of International Application No. PCT/IB2015/002345, which claims the priority of U.S. provisional application U.S. Patent Appln. No. 62/084,387; filed Nov. 25, 2014, which are incorporated herein by reference in their entirety for all purposes.
    • TECHNICAL FIELD
  • In some embodiments, the instant invention is related to compositions and methods for delivering a bio-active agent or bio-active agents.
    • BACKGROUND
  • Glaucoma is the most frequent cause for irreversible and preventable blindness worldwide. About two percent of the population over 40 years of age suffers from glaucoma. The major risk factor and only treatable factor in glaucoma is increased intraocular pressure. While glaucoma is incurable, treatment can slow or arrest the progressive vision loss.
    • SUMMARY OF INVENTION
  • In some embodiments, the composition of the present invention is a drug-delivery device comprising: a) a composite comprising the following elements: (i) particles of inert materials, where the inert materials are adsorbed with drug on surface of particles (e.g., drug bound to particles) or inside porosity (e.g., drug housed within pores); (ii) a bulking agent; (iii) an adhesive binder; or any combination thereof, and b) an optional coating on the whole or partial outer surface of the body/core; where the coating is complete/continuous or perforated, e.g., but not limited to, where the coating can be butvar and/or parylene.
  • In some embodiments, the present invention is a composition, including: a bulking agent including a kaolin and/or a pectin, an absorbent material including a fumed silica, a binder including an epoxy, and a first active agent including Latanoprost. In some embodiments, the first active agent measures between 5-50% by weight (w/w). In some embodiments, the first active agent measures between 5-45% by weight (w/w). In some embodiments, the first active agent measures between 5-40% by weight (w/w). In some embodiments, the first active agent measures between 5-35% by weight (w/w). In some embodiments, the first active agent measures between 5-30% by weight (w/w). In some embodiments, the first active agent measures between 5-25% by weight (w/w). In some embodiments, the first active agent measures between 5-20% by weight (w/w). In some embodiments, the first active agent measures between 5-15% by weight (w/w). In some embodiments, the first active agent measures between 5-10% by weight (w/w). In some embodiments, the first active agent measures between 10-50% by weight (w/w). In some embodiments, the first active agent measures between 15-50% by weight (w/w). In some embodiments, the first active agent measures between 20-50% by weight (w/w). In some embodiments, the first active agent measures between 25-50% by weight (w/w). In some embodiments, the first active agent measures between 30-50% by weight (w/w). In some embodiments, the first active agent measures between 35-50% by weight (w/w). In some embodiments, the first active agent measures between 40-50% by weight (w/w). In some embodiments, the first active agent measures between 45-50% by weight (w/w). In some embodiments, the first active agent measures between 10-45% by weight (w/w). In some embodiments, the first active agent measures between 15-40% by weight (w/w). In some embodiments, the first active agent measures between 20-35% by weight (w/w). In some embodiments, the first active agent measures between 20-30% by weight (w/w). In some embodiments, the compound further includes a second active agent. In some embodiments, the second active agent is Timolol. In some embodiments, the second active agent measures between 5-40% by weight (w/w). In some embodiments, the second active agent measures between 5-35% by weight (w/w). In some embodiments, the second active agent measures between 5-30% by weight (w/w). In some embodiments, the second active agent measures between 5-25% by weight (w/w). In some embodiments, the second active agent measures between 5-20% by weight (w/w). In some embodiments, the second active agent measures between 5-15% by weight (w/w). In some embodiments, the second active agent measures between 5-10% by weight (w/w). In some embodiments, the second active agent measures between 10-40% by weight (w/w). In some embodiments, the second active agent measures between 15-40% by weight (w/w). In some embodiments, the second active agent measures between 20-40% by weight (w/w). In some embodiments, the second active agent measures between 25-40% by weight (w/w). In some embodiments, the second active agent measures between 30-40% by weight (w/w). In some embodiments, the second active agent measures between 35-40% by weight (w/w). In some embodiments, the second active agent measures between 10-35% by weight (w/w). In some embodiments, the second active agent measures between 15-30% by weight (w/w). In some embodiments, the second active agent measures between 20-25% by weight (w/w). In some embodiments, the composition further includes polyurethane. In some embodiments, the composition further includes a parylene coating. In some embodiments, the parylene coating measures between 2-5 micrometers (e.g., but not limited to, 2.1 micrometers, 2.2 micrometers, etc.) in thickness. In some embodiments, the composition includes a butvar coating. In some embodiments, the butvar coating measures between 2-5 micrometers (e.g., but not limited to, 2.1 micrometers, 2.2 micrometers, etc.) in thickness. In some embodiments, the composition is in the form of a punctal plug.
  • In some embodiments, the present invention is a method, including: administering a composition to an eye of a mammal in need thereof, where the composition releases between 0.5-10 micrograms of a first active agent per day, and where the composition includes: a bulking agent including a kaolin, an absorbent material including a fumed silica, a binder including an epoxy, and the first active agent includes Latanoprost. In some embodiments, the first active agent measures between 5-50% by weight (w/w). In some embodiments, the first active agent measures between 5-45% by weight (w/w). In some embodiments, the first active agent measures between 5-40% by weight (w/w). In some embodiments, the first active agent measures between 5-35% by weight (w/w). In some embodiments, the first active agent measures between 5-30% by weight (w/w). In some embodiments, the first active agent measures between 5-25% by weight (w/w). In some embodiments, the first active agent measures between 5-20% by weight (w/w). In some embodiments, the first active agent measures between 5-15% by weight (w/w). In some embodiments, the first active agent measures between 5-10% by weight (w/w). In some embodiments, the first active agent measures between 10-50% by weight (w/w). In some embodiments, the first active agent measures between 15-50% by weight (w/w). In some embodiments, the first active agent measures between 20-50% by weight (w/w). In some embodiments, the first active agent measures between 25-50% by weight (w/w). In some embodiments, the first active agent measures between 30-50% by weight (w/w). In some embodiments, the first active agent measures between 35-50% by weight (w/w). In some embodiments, the first active agent measures between 40-50% by weight (w/w). In some embodiments, the first active agent measures between 45-50% by weight (w/w). In some embodiments, the first active agent measures between 10-35% by weight (w/w). In some embodiments, the first active agent measures between 10-45% by weight (w/w). In some embodiments, the first active agent measures between 15-40% by weight (w/w). In some embodiments, the first active agent measures between 20-35% by weight (w/w). In some embodiments, the first active agent measures between 25-30% by weight (w/w). In some embodiments, the method includes a second active agent. In some embodiments, the second active agent is Timolol. In some embodiments, the second active agent includes between 5-40% by weight (w/w). In some embodiments, the second active agent measures between 5-35% by weight (w/w). In some embodiments, the second active agent measures between 5-30% by weight (w/w). In some embodiments, the second active agent measures between 5-25% by weight (w/w). In some embodiments, the second active agent measures between 5-20% by weight (w/w). In some embodiments, the second active agent measures between 5-15% by weight (w/w). In some embodiments, the second active agent measures between 5-10% by weight (w/w). In some embodiments, the second active agent measures between 10-40% by weight (w/w). In some embodiments, the second active agent measures between 15-40% by weight (w/w). In some embodiments, the second active agent measures between 20-40% by weight (w/w). In some embodiments, the second active agent measures between 25-40% by weight (w/w). In some embodiments, the second active agent measures between 30-40% by weight (w/w). In some embodiments, the second active agent measures between 35-40% by weight (w/w). In some embodiments, the second active agent measures between 10-35% by weight (w/w). In some embodiments, the second active agent measures between 15-30% by weight (w/w). In some embodiments, the second active agent measures between 20-25% by weight (w/w). In some embodiments, the method includes a parylene coating. In some embodiments, the parylene coating measures between 2-5 micrometers (e.g., but not limited to, 2.1 micrometers, 2.2 micrometers, etc.) in thickness. In some embodiments, the composition includes a butvar coating. In some embodiments, the butvar coating measures between 2-5 micrometers (e.g., but not limited to, 2.1 micrometers, 2.2 micrometers, etc.) in thickness. In some embodiments, the composition is in the form of a punctal plug.
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • The present invention will be further explained with reference to the attached drawings, wherein like structures are referred to by like numerals throughout the several views. The drawings shown are not necessarily to scale, with emphasis instead generally being placed upon illustrating the principles of the present invention. Further, some features may be exaggerated to show details of particular components.
  • FIGS. 1A-C illustrate embodiments of the composition of the present invention, showing various plugs.
  • FIGS. 2A and B illustrate embodiments of the process for generating the composition of the present invention.
  • FIG. 3 illustrates an embodiment of the composition of the present invention, showing a release profile.
  • FIGS. 4 and 5 illustrate embodiments of placement of the compositions of the present invention.
  • FIGS. 6 and 7 illustrate embodiments of applicators for placing the compositions of the present invention in an eye.
  • FIG. 8 is a schematic depiction of liquid at the surface of a non-porous particle (left) and of liquid absorbed in the pores of fumed silica (right).
  • FIG. 9 illustrates a calibration curve of an embodiment of the composition of the present invention.
  • FIG. 10 illustrates a chromatogram of a standard solution.
  • FIG. 11 illustrates a chromatogram of an embodiment of the composition of the present invention.
  • FIG. 12 illustrates a chromatogram of an embodiment of the composition of the present invention.
  • FIGS. 13 and 14A-14B illustrate a typical chromatogram of a standard solution.
  • FIG. 15 illustrates a signal to noise ratio of an embodiment of the composition of the present invention.
  • FIG. 16 illustrates a signal to noise ratio of an embodiment of the composition of the present invention.
  • FIGS. 17, 18, 19A-B illustrate chromatograms of embodiments of the compositions of the present invention.
  • FIG. 20 illustrates an embodiment of the method of the present invention.
  • FIGS. 21 and 22 illustrate graphs of release profiles of embodiments of the composition of the present invention.
  • FIGS. 23-27 illustrate graphs of release profiles of embodiments of the composition of the present invention.
  • FIGS. 28A and 28B are photographs of embodiments of the composition of the present invention.
  • FIG. 29 is a photograph of a composite sample of an embodiment of the composition of the present invention.
  • FIG. 30 illustrates desiccators used while generating embodiments of the compositions of the present invention.
    •
  • In addition, any measurements, specifications and the like shown in the figures are intended to be illustrative, and not restrictive. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a representative basis for teaching one skilled in the art to variously employ the present invention.
    • DESCRIPTION OF EXEMPLARY EMBODIMENTS
  • The figures constitute a part of this specification and include illustrative embodiments of the present invention and illustrate various objects and features thereof. Further, the figures are not necessarily to scale, some features may be exaggerated to show details of particular components. In addition, any measurements, specifications and the like shown in the figures are intended to be illustrative, and not restrictive. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a representative basis for teaching one skilled in the art to variously employ the present invention.
  • Among those benefits and improvements that have been disclosed, other objects and advantages of this invention will become apparent from the following description taken in conjunction with the accompanying figures. Detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely illustrative of the invention that may be embodied in various forms. In addition, each of the examples given in connection with the various embodiments of the invention which are intended to be illustrative, and not restrictive.
  • Throughout the specification and claims, the following terms take the meanings explicitly associated herein, unless the context clearly dictates otherwise. The phrases “in one embodiment” and “in some embodiments” as used herein do not necessarily refer to the same embodiment(s), though it may. Furthermore, the phrases “in another embodiment” and “in some other embodiments” as used herein do not necessarily refer to a different embodiment, although it may. Thus, as described below, various embodiments of the invention may be readily combined, without departing from the scope or spirit of the invention.
  • In addition, as used herein, the term “or” is an inclusive “or” operator, and is equivalent to the term “and/or,” unless the context clearly dictates otherwise. The term “based on” is not exclusive and allows for being based on additional factors not described, unless the context clearly dictates otherwise. In addition, throughout the specification, the meaning of “a,” “an,” and “the” include plural references. The meaning of “in” includes “in” and “on.”
  • The present invention relates generally to the field of medicine combining drug in a device, for administering a bio-active agent over a prolonged period of time. More particularly, it concerns implantable ocular devices for the sustained delivery of a therapeutic compound to the eye. FIGS. 4-6 illustrate the lacrimal duct system of the human eye and embodiments of the compositions of the present invention placed within the lacrimal duct system of the human eye. In an embodiment, the composition of the present invention is placed in an eye by performing the following steps: (1) hold the applicator (where the ridges are on the tube); (2) insert the applicator (big tube) into the punctum; (3) push the bottom of the small tube completely up inside the big tube (this slides the plug out of the applicator and into the punctum); and (4) gently take out both applicator tubes together.
  • In an embodiment, FIG. 7 illustrates a composition of the present invention. In an embodiment, the composition of the present invention is placed in an eye by performing the following steps: (1) hold the applicator (where the ridges are on the static tube); (2) insert the plug's inserter (metal part) into the punctum; and (3) push the moving plunger completely up with the plug (both the plug and the plunger are moving on the static metal inserter (this slides the plug out of the applicator into the punctum (the plunger remains outside the punctum); gently take out both plunger and holder together.
  • In some embodiments, the present invention is a composite device that configured to contain and release an amount of drug per volume. In some embodiments, the device is configured to allow multiple drug loading (e.g., but not limited to, 2 drugs, 3 drugs, 4 drugs, 5 drugs, etc.). In some embodiments, the drug molecules are physically bound to the matrix. In some embodiments, a non-metallic coating provides zero-order or near zero-order drug-release kinetics. In some embodiments, a release profile provides zero-order or near zero-order drug-release kinetics at two different rates; initially higher rate at the first several weeks, and thereafter a lower rate.
  • In some embodiments, the composition of the present invention is a drug-delivery device composite shaped into the desired body/shape; whereas the composite comprising of the following: (1) particles of inert materials, having a porous structure, with an increase surface area and low bulk density. Fumed silica, silica gel, activated carbon, activated alumina or zeolite products offer a porous structure with an interconnected capillary network similar to an open cell sponge. FIG. 8 is a schematic depiction of liquid at the surface of a non-porous particle (left) and of liquid absorbed in the pores of fumed silica (right).
  • The small diameter of the pores leads to high capillary forces that draw the liquid into the particle. This physical absorption mechanism is independent of the chemical characteristics of the liquid; therefore both polar as well as non-polar liquids can be absorbed. For instance, in Fumed Silica the surface area is 10-600 m2/gr, in silica gel it is around 800 m2/gr. Hence, the finished absorbate can contain between 50-75% of the liquid actives with drug on surface of particles or inside porosity, e.g., but not limited to, fumed silica loaded (i.e., bound) with prostaglandin; (2) a bulking agent e.g., but not limited to, kaolin and/or pectin; (3) an adhesive binder, e.g., but not limited to, ceramic adhesive, e.g., but not limited to, epoxy adhesive; (4) a hydrophobic flexible polymer e.g., but not limited to, PU, or any combination thereof. In some embodiments, the physical mechanism of adsorbing liquid actives is passive.
  • In some embodiments, the composition of the present invention is a drug-delivery device comprising: a) a composite comprising the following elements: (i) particles of inert materials, where the inert materials are adsorbed with drug on surface of particles (e.g., drug bound to particles) or inside porosity (e.g., drug housed within pores); (ii) a bulking agent; (iii) an adhesive binder; (iv) a hydrophobic flexible polymer; or any combination thereof, and b) an optional coating on the whole or partial outer surface of the body/core; where the coating is complete/continuous or perforated, e.g., but not limited to, where the coating can be butvar and/or parylene.
  • In some embodiments, the composition of the present invention includes an ophthalmic drug, where the ophthalmic drug is a prostaglandin analog, beta blocker, Alpha agonist, carbonic anhydrase inhibitor, adenosine agonist, Rho Kinase inhibitor or any combination thereof. In some embodiments, the prostaglandin is cloprostenol, fluprostenol, latanoprost, travoprost, unoprostone, Latanoprostene bunod or any combination thereof. In some embodiments, more than one drug (e.g., 2, 3, 4, 5, etc.) is loaded into the matrix to be release independently and in parallel whereas each drug is released according to (a) its natural solubility in the external medium and (b) to the barriers whether by the hydrophobic polymer, the external impermeable barrier or both. In some embodiments, the concentration of the prostaglandin in the matrix is between about 1% to about 20% by weight. In some embodiments, the concentration of the prostaglandin in the matrix is between about 10% to about 17% by weight.
  • In some embodiments of the composition of the present invention, the concentration of the prostaglandin in the matrix is between about 10% to about 15% by weight. In some embodiments, the concentration of the prostaglandin in the matrix is between about 10% to about 13% by weight. In some embodiments, the concentration of the prostaglandin in the matrix is between about 5% to about 20% by weight. In some embodiments, the concentration of the prostaglandin in the matrix is between about 10% to about 20% by weight. In some embodiments, the concentration of the prostaglandin in the matrix is between about 13% to about 20% by weight. In some embodiments, the concentration of the prostaglandin in the matrix is between about 15% to about 20% by weight.
  • In some embodiments, the composition of the present invention is a drug-delivery device comprising: a) a composite comprising the following elements: (i) particles of inert materials, where the inert materials are adsorbed with drug on surface of particles (e.g., drug bound to particles) or inside porosity (e.g., drug housed within pores); (ii) a bulking agent; (iii) an adhesive binder; and b) a optional coating on the whole or partial outer surface of the body/core; where the coating is complete/continuous or perforated, e.g., but not limited to, where the coating can be butvar and/or parylene.
  • In some embodiments, the composition of the present invention includes an ophthalmic drug, where the ophthalmic drug is a prostaglandin analog, beta blocker, Alpha agonist, carbonic anhydrase inhibitor, adenosine agonist, Rho Kinase inhibitor or any combination thereof. In some embodiments, the prostaglandin is cloprostenol, fluprostenol, latanoprost, travoprost, unoprostone, Latanoprostene bunod or any combination thereof. In some embodiments, more than one drug (e.g., 2, 3, 4, 5, etc.) is loaded into the matrix to be release independently and in parallel whereas each drug is released according to (a) its natural solubility in the external medium and (b) to the barriers whether by the composite, the external semi-permeable barrier or both. In some embodiments, the concentration of the prostaglandin in the matrix is between about 1% to about 50% by weight. In some embodiments, the concentration of the prostaglandin in the matrix is between about 30% to about 40% by weight.
  • In some embodiments of the composition of the present invention, the concentration of the prostaglandin in the matrix is between about 30% to about 40% by weight. In some embodiments, the concentration of the prostaglandin in the matrix is between about 32% to about 38% by weight. In some embodiments, the concentration of the prostaglandin in the matrix is between about 5% to about 40% by weight. In some embodiments, the concentration of the prostaglandin in the matrix is between about 10% to about 40% by weight. In some embodiments, the concentration of the prostaglandin in the matrix is between about 23% to about 40% by weight. In some embodiments, the concentration of the prostaglandin in the matrix is between about 15% to about 40% by weight.
  • In some embodiments of the composition of the present invention, the parylene coating is between about 0.3 μm to about 20 μm thick. In some embodiments, the parylene coating is between about 0.3 μm to about 10 μm thick. In some embodiments, the parylene coating is between about 0.3 μm to about 5 μm thick. In some embodiments, the parylene coating is between about 0.3 μm to about 3 μm thick. In some embodiments, the parylene coating is between about 0.3 μm to about 1 μm thick. In some embodiments, the parylene coating is between about 1 μm to about 20 μm thick. In some embodiments, the parylene coating is between about 3 μm to about 20 μm thick. In some embodiments, the parylene coating is between about 5 μm to about 20 μm thick. In some embodiments, the parylene coating is between about 10 μm to about 20 μm thick.
  • In some embodiments of the composition of the present invention, the butvar coating is between about 1 μm to about 20 μm thick. In some embodiments, the butvar coating is between about 5 μm to about 20 μm thick. In some embodiments, the butvar coating is between about 10 μm to about 20 μm thick. In some embodiments, the butvar coating is between about 15 μm to about 20 μm thick. In some embodiments, the butvar coating is between about 1 μm to about 15 μm thick. In some embodiments, the butvar coating is between about 1 μm to about 10 μm thick. In some embodiments, the butvar coating is between about 1 μm to about 5 μm thick. In some embodiments, the butvar coating is between about 5 μm to about 15 μm thick.
  • In some embodiments of the composition of the present invention, the core/body further comprises a canalicular extension attached to the distal tip portion of the core/body, where the canalicular extension is configured for insertion through the punctual aperture and the punctum and positioning in the lacrimal canaliculus. In some embodiments, the canalicular extension has a length L1 and the body has a length L2, wherein the ratio of the length L1 to the length L2 is between about 2:1 to about 10:1. In some embodiments, the ratio of the length L1 to the length L2 is between about 2:1 to about 8:1. In some embodiments, the ratio of the length L1 to the length L2 is between about 2:1 to about 6:1. In some embodiments, the ratio of the length L1 to the length L2 is between about 2:1 to about 4:1. In some embodiments, the ratio of the length L1 to the length L2 is between about 4:1 to about 10:1. In some embodiments, the ratio of the length L1 to the length L2 is between about 6:1 to about 10:1. In some embodiments, the ratio of the length L1 to the length L2 is between about 8:1 to about 10:1.
  • In some embodiments of the composition of the present invention, the canalicular extension is configured for positioning in a lacrimal canaliculus and/or a nasolacrimal duct. In some embodiments, a core/body has an outer surface and is configured to be inserted through a punctal aperture and positioned in a punctum or lacrimal canaliculus, wherein the body is a monolithic capsule structure or cylinder shape. In some embodiments, the composition includes a parylene coating or butvar coating covering the outer surface of the body, the parylene coating or butvar coating being substantially impermeable (its surface is impermeable above thicknesses of 1.4 nanometers.) to drug (e.g., a prostaglandin); and at least one pore in the parylene coating or butvar coating pore, wherein the amount and/or size of the pore is configured to release the prostaglandin (e.g., but not limited to, Latanoprost) at a therapeutically effective dose for a period of 1 to 360 days (e.g., 1, 2, 3, 4, 5, etc. days). In some embodiments, the period measures between 1 to 180 days. In some embodiments, the period measures between 1 to 120 days. In some embodiments, the period measures between 1 to 60 days. In some embodiments, the period measures between 1 to 30 days. In some embodiments, the period measures between 30 to 180 days. In some embodiments, the period measures between 60 to 180 days. In some embodiments, the period measures between 90 to 180 days. In some embodiments, the period measures between 120 to 180 days. In some embodiments, the period measures between 30 to 120 days. In some embodiments, the period measures between 60 to 90 days.
  • In some embodiments of the composition of the present invention, the beta-adrenergic receptor antagonists can be timolol, levobunolol (Betagan), betaxolol, or any combination thereof.
  • In some embodiments, timolol is a non-selective beta-adrenergic receptor antagonist indicated for treating glaucoma, heart attacks, hypertension, and migraine headaches. The chemical structure for timolol is:
  • Figure US20200093834A1-20200326-C00001
  • In some embodiments, latanoprost is a medication administered into the eyes of a mammal to control the progression of glaucoma or ocular hypertension by reducing intraocular pressure. It is a prostaglandin analog. The chemical structure for latanoprost is:
  • Figure US20200093834A1-20200326-C00002
  • In some embodiments of the composition of the present invention, the Carbonic anhydrase inhibitors can be dorzolamide (Trusopt), ation thereofbrinzolamide (Azopt), acetazolamide (Diamox), or any combination thereof. Examples of agents used for glaucoma inclu β-blockers (e.g., timolol, betaxolol, levobetaxolol, carteolol, levobunolol, propranolol), carbonic anhydrase inhibitors (e.g., brinzolamide and dorzolamide), α1 antagonists (e.g., nipradolol), α2 agonists (e.g. iopidine and brimonidine), miotics (e.g., pilocarpine and epinephrine), prostaglandin analogs (e.g., latanoprost, travoprost, unoprostone, and compounds set forth in U.S. Pat. Nos. 5,889,052; 5,296,504; 5,422,368; and 5,151,444), “hypotensive lipids” (e.g., bimatoprost and compounds set forth in U.S. Pat. No. 5,352,708), and neuroprotectants (e.g., compounds from U.S. Pat. No. 4,690,931, particularly eliprodil and R-eliprodil, as set forth in a pending application U.S. Ser. No. 60/203,350, and compounds from WO 94/13275, including memantine, where all patents and patent application publications are incorporated herein by reference in their entireties for all purposes. In some embodiments, the composition of the present invention can include Adenosine agonist, Rho Kinase inhibitors and molecules with combined activity such as Latanoparostene Bunod, where a “combined activity” refers to two molecules which are capable of serving two mechanisms of action for reducing intraocular pressure.
  • In some embodiments of the composition of the present invention, the concentration of the prostaglandin in the composite is 50% to 60% by weight, where the concentration of the prostaglandin in the final plug is between 10% to 20%.
  • The present invention provides a pharmaceutical composition and glaucoma treatment methods. The present invention is a composition in the form of an implant, where the implant is configured to provide for extended release times 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 prostaglandin. In some embodiments, the prostaglandin is latanoprost.
  • In some embodiments of the composition of the present invention, an implant is configured to release the drug over a period of time, for example, for at least one week or for example for between about two months and about six months, after intraocular administration of a latanoprost containing implant. In some embodiments, the composition further includes timolol. In some embodiments, the period of time is between one month and one year. In some embodiments, the period of time is between one month and nine months. In some embodiments, the period of time is between one month and six months. In some embodiments, the period of time is between one month and three months. In some embodiments, the period of time is between three months and one year. In some embodiments, the period of time is between six months and one year. In some embodiments, the period of time is between nine months and one year. In some embodiments, the period of time is between three months and nine months. In some embodiments, the period of time is between three months and six months. In some embodiments, the period of time is between six months and nine months.
  • In an embodiment of the composition of the present invention, a composition is a pharmaceutical composition plug configured to provide an intraocular use, e.g., to treat ocular condition. In some embodiments, the pharmaceutical composition is a plug comprising a solid composite powder, where the solid composite powder is dispersed in at least one soft polymer. In some embodiments, the solid composite powder includes an organic particulate including a bio-active agent, inert carrier, binder, or any combination thereof. In some embodiments of the composition of the present invention, an organic particulate is configured to absorb a drug, i.e., is configured carry the drug (i.e., a drug carrier; e.g., but not limited to, fumed silica). The organic particulate can have a surface area between 5 to 1000 m{circumflex over ( )}2/gram (fumed silica surface area is 10-600 m2/gr; silica gel around 800 m2/gr; calcium carbonate surface area is 5-24 m2/gr).
  • In some embodiments of the composition of the present invention, the bio-active agent can be dissolved, dispersed, emulsified, bound, adsorbed, impregnated, mixed, or otherwise placed into a solid organic matrix. In some embodiments, the bio-active agent may be directly mixed in with the organic matrix. In some embodiments, the bio-active agent may be adsorbed to another material, e.g., a particulate and/or fibrous matter, which can be mixed with the organic matrix.
  • In some embodiments of the composition of the present invention, the bio-active agent is first dissolved, dispersed, or emulsified into an organic compound (or, e.g., its precursors) melt, solution, emulsion or dispersion. In some embodiments, the solid organic matrix can be comprised of polymers, oligomers, monomers, wax, oils, plasticizers, and any combinations thereof.
  • In some embodiments of the composition of the present invention, the organic particulate comprising the drug (e.g., a prostaglandin, e.g., latanoprost) can be mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as, but not limited to, sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants such as glycerol; (d) disintegrating agents such as agar-agar, calcium carbonate, 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.
  • In some embodiments of the composition of the present invention, the organic particulate and the inert carrier are bound together with a binder to generate the composite matrix. In some embodiments, exemplary polymers include, but are not limited to, poly(dimethylsiloxane), polyurethanes, epoxies, methyl methacrylate polymers, acrylic copolymers, polyesters, polyamides, polyethylene, polypropylene, ethylene copolymers and terpolymers, propylene copolymers and terpolymers, fluoropolymers, vinyls, styrenics, polycarbonates, amino resins, and phenolic resins. Other exemplary polymers include crosslinked acrylic or methacrylic networks, including networks formed by ultraviolet (UV) curing. In some embodiments, the core (where the drug is absorbed or exist) comprises a thermosetting polymer. In some embodiments, exemplary waxes include, but are not limited to, paraffins, amides, esters, fatty acid derivatives, fatty alcohol derivatives, silicones, and phospholipids.
  • In some embodiments of the composition of the present invention, the composite matrix containing a bio-active agent (e.g., but not limited to, a prostaglandin, e.g., but not limited to, latanoprost) can be in a solid form such as powder, flakes, fibers, or any combination thereof. In some embodiments, the composite can be milled and/or micronized to the size of a fine powder <100 μm or to size <30 μm, using milling apparatus like mortar and pestle, electronic grinder, etc. In some embodiments, the fine composite powder can be dispersed and/or mixed with a flexible polymer. In some embodiments, the flexible polymer can be a medical polymer such as, e.g., including a polymer having hydrophilic and/or hydrophobic characteristics. In some embodiments, exemplary polymers include, but are not limited to: a silicone, a polyacrylate, a polyurethane, or a combination of two or more of the polymers.
  • In some embodiments of the composition of the present invention, polyurethanes can be shaped as desired, or its permeability can be tailored as desired, to achieve a pre-determined release rate of the bio-active agent from the device to the patient. In some embodiments, the polymer comprises one or more polymers, made of the homopolymers or heteropolymers.
  • In some embodiments of the composition of the present invention, a mixture includes (1) a polymer and (2) a powder, which is formed into a solid, self-supporting shape. In some embodiments, the self-supporting shape can be the desired shape of the composition (i.e., the solid core), further processed by, e.g., trimming or cutting, into the desired shape. In some embodiments, a shape can be, but is not limited to, a cylinder, plug, coin, disk, plate, cube, sphere, fiber, box, diamond, ring, “S”, “L”, “T”, web, net, mesh, “U”, or “V”.
  • In some embodiments of the composition of the present invention, an outer shell coating may be added to the exterior of a solid core. In some embodiments, the coating comprises a second non-biodegradable polymer that is substantially impermeable to a therapeutic compound (e.g., but not limited to, a prostaglandin, e.g., latanoprost). In some embodiments, the coating is at least less permeable (e.g., 1% less permeable, 5% less permeable, 10% less permeable, 20% less permeable, 30% less permeable, 40% less permeable, 50% less permeable, 60% less permeable, 70% less permeable, etc.) to the therapeutic compound compared with the permeability of the therapeutic compound to the first non-biodegradable polymer. In some embodiments, the outer shell coating can be butvar and/or parylene.
  • FIG. 1A-C illustrates an embodiment of the present invention, showing a schematic drawing of the device, with composite powder dispersed in polymer.
  • FIGS. 2A and 2B illustrates an embodiment of the present invention, showing a schematic drawing of the process.
  • FIG. 3 illustrates an embodiment of the present invention, showing a graph of in vitro percentage cumulative release of latanoprost from a plug sample over a test period measuring 7 days.
  • FIGS. 4-7 illustrate embodiments of the placement of the composition of the present invention in a human eye.
  • FIG. 8 is a schematic depiction of liquid at the surface of a non-porous particle (left) and of liquid absorbed in the pores of fumed silica (right).
  • The present invention describes a drug delivery device including: 1) particles of inert materials, absorbed with drug on surface of particles or inside porosity; 2) inert polymer matrix, where drug-inert particles are dispersed, where the polymer has no chemical interaction with drug and is providing mechanical package, and where the concentration of drug on particles, and the loading of particles in polymer matrix, is configured to control drug reservoir capacity; 3) an hydrophobic flexible polymer, which connects the polymer matrix into a shape and creates a barrier for drug release; 4) where the hydrophobic polymer is insufficient for controlling the release, a perforated outer barrier is applied to the solid core. In some embodiments, the permeability, and/or size and number of apertures in barrier are configured to control a release rate of the drug (e.g., but not limited to, a prostaglandin, but not limited to, e.g. latanoprost).
  • In some embodiments, the composition of the present invention includes: (i) a first pharmaceutical agent, a bulking agent, at least one inert material configured to have an increased surface area and a bulk density of between 1-3 gr/cm3 (e.g., but not limited to, 1 gr/cm3, 1.1 gr/cm3, 1.2 gr/cm3, etc.). In some embodiments, the first pharmaceutical agent is a prostaglandin or a prostaglandin analog. In some embodiments, the prostaglandin is selected from a group including: cloprostenol, fluprostenol, latanoprost, travoprost, unoprostone, and any combination thereof. In some embodiments, the composition further includes a second pharmaceutical agent, where the second pharmaceutical agent is an alpha agonist selected from the group including: iopidine and/or brimonidine. In some embodiments, the second pharmaceutical agent is a beta-blocker, where the beta-blocker is selected from the group including: timolol, betaxolol, levobetaxolol, carteolol, levobunolol, propranolol, and any combination thereof. In some embodiments, the composition further includes a third pharmaceutical agent, where the third pharmaceutical agent is an alpha agonist selected from the group including: iopidine and/or brimonidine.
  • In some embodiments, the composition of the present invention includes: cloprostenol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: cloprostenol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: cloprostenol, brimonidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: cloprostenol, timolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: cloprostenol, timolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: cloprostenol, timolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: cloprostenol, betaxolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: cloprostenol, betaxolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: cloprostenol, betaxolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: cloprostenol, levobetaxolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: cloprostenol, levobetaxolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: cloprostenol, levobetaxolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: cloprostenol, carteolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: cloprostenol, carteolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: cloprostenol, carteolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: cloprostenol, levobunolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: cloprostenol, levobunolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: cloprostenol, levobunolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: cloprostenol, propranolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: cloprostenol, propranolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: cloprostenol, propranolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: fluprostenol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: fluprostenol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: fluprostenol, brimonidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: fluprostenol, timolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: fluprostenol, timolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: fluprostenol, timolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: fluprostenol, betaxolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: fluprostenol, betaxolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: fluprostenol, betaxolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: fluprostenol, levobetaxolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: fluprostenol, levobetaxolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: fluprostenol, levobetaxolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: fluprostenol, carteolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: fluprostenol, carteolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: fluprostenol, carteolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: fluprostenol, levobunolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: fluprostenol, levobunolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: fluprostenol, levobunolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: fluprostenol, propranolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: fluprostenol, propranolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: fluprostenol, propranolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: latanoprost, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: latanoprost, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: latanoprost, brimonidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: latanoprost, timolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: latanoprost, timolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: latanoprost, timolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: latanoprost, betaxolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: latanoprost, betaxolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: latanoprost, betaxolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: latanoprost, levobetaxolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: latanoprost, levobetaxolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: latanoprost, levobetaxolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: latanoprost, carteolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: latanoprost, carteolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: latanoprost, carteolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: latanoprost, levobunolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: latanoprost, levobunolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: latanoprost, levobunolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: latanoprost, propranolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: latanoprost, propranolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: latanoprost, propranolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: travoprost, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: travoprost, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: travoprost, brimonidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: travoprost, timolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: travoprost, timolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: travoprost, timolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: travoprost, betaxolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: travoprost, betaxolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: travoprost, betaxolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: travoprost, levobetaxolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: travoprost, levobetaxolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: travoprost, levobetaxolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: travoprost, carteolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: travoprost, carteolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: travoprost, carteolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: travoprost, levobunolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: travoprost, levobunolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: travoprost, levobunolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: travoprost, propranolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: travoprost, propranolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: travoprost, propranolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: unoprostone, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: unoprostone, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: unoprostone, brimonidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: unoprostone, timolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: unoprostone, timolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: unoprostone, timolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: unoprostone, betaxolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: unoprostone, betaxolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: unoprostone, betaxolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: unoprostone, levobetaxolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: unoprostone, levobetaxolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: unoprostone, levobetaxolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: unoprostone, carteolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: unoprostone, carteolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: unoprostone, carteolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: unoprostone, levobunolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: unoprostone, levobunolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: unoprostone, levobunolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, the composition of the present invention includes: unoprostone, propranolol, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: unoprostone, propranolol, iopidine, kaolin, and fumed silica. In some embodiments, the composition of the present invention includes: unoprostone, propranolol, brimonidine, kaolin, and fumed silica.
  • In some embodiments, where the composition of the present invention includes at least one active agent (e.g., but not limited to, Latanoprost, unoprostone, propranolol, timolol, etc.), the same amounts of bulking agents and inert materials (e.g., but not limited to, fumed silica, epoxy, and kaolin) will be used to generate the composition as shown in the examples below.
    • Example: Preparation of Plug/Solid Core
  • In an example of an embodiment of the composition of the present invention, plug samples containing Latanoprost were prepared. Samples were incubated at 37 degrees Celsius for varying times to determine time effect on Latanoprost release profile from the sample into a polar solution (PBS).
  • Particulate Preparation
  • Initially, a bio-active agent was adsorbed or loaded on fumed silica (FS). The bio-active agent was Latanoprost (LP). 0.16 g of FS was mixed with 0.25 g LP dissolved in 2 g solvents 1 THF: 1 Ethanol (w/w). Additional examples of polar solvents are: Methanol, Isopropanol, Acetone, and/or Ethyl acetate. The LP/FS mixture was dried at ambient temperature for 24 hours.
  • Composite Matrix Preparation
  • 0.13 g of kaolin powder and 0.4 g of FS particulate and 0.13 g medical grade epoxy (EPO-TEK 301, manufactured by Epo-Tek from USA) were mixed together. The mixture was mixed until a paste was formed, where the paste had a viscosity of about 250,000 CP. The paste was cured at ambient temperature for 24 hours. The resulting composition had the characteristics of a solid composite.
  • Composite Milling and Molding
  • The solid composite was milled using pestle and mortar. The composite fine powder was mixed with polyurethane in a ratio of 40%:60%. The mixture molded in a polyacetal (DELRIN) mold for 12 hours at ambient room temperature and removed from the mold. This formed the plug shape.
  • Solution Preparation—Releasing Medium Buffer
  • The solution included the following: 0.01M PBS, 0.005% BAK, and 0.1% TRITON X-100.
  • Plug Coating Process
  • The outer layer coating of the plug can be: (1) Butvar 5% (W/V) in Tetrahydrofuran (THF) as solvent or (2) Parylene coating—Polyurethane plugs were coated with 2-5 μm of parylene using a vapor deposition process. To coat the plug, the plugs were placed in a vacuum deposition chamber (Simtal Coating Ltd.) and a vacuum was drawn in the chamber to approximately 0.1 torr. A parylene dimer (di-para-xylylene) was vaporized at approximately 150° C. Then pyrolysis of the monomer (para-xylylene) was affected at approximately 680° C. and 0.5 torr (e.g., but not limited to, the Aryl-chlorine bond in dichloro[2.2]paracyclophane breaks at 680° C. (standard pyrolysis temperature). The monomer then entered the deposition chamber at approximately room temperature (approximately 25° C.) and was adsorbed and polymerized onto the polyurethane plug.
  • Final Plug Sample Properties
  • Composites weight 14.1 grams with 18% Latanoprost. See Table 1 for details:
  • TABLE 1
    PBS +
    Hours BAK
    at 37 Com- (0.005%) +
    in PBS + posite TRITON Accumu-
    BAK + Weight (0.1%) lative
    Plug Sample Name Triton mg g PPM PPM
    1 LP18S-1014-6HR 6 14.1 0.527 63.8  63.8
    2 LP18S-1014-12HR 12 14.1 0.504 51.1 114.9
    3 LP18S-1014-24HR 24 14.1 0.553 26.8 141.7
    4 LP18S-1014-48HR 48 14.1 0.560 41.6 183.3
    5 LP18S-1014-96HR 96 14.1 0.503 42.5 225.8
    6 LP18S-1014-7D 168 14.1 0.548 33.9 259.7
  • The shell can be parylene or butvar. The organic matrix can be kaolin and/or epoxy. The drug absorbing material is fumed silica. No encapsulation of drug.
  • In an embodiment, active agent is latanoprost, organic matrix is kaolin, the absorbance material is fumed silica. The solvents for the drug are ethanol and HFE. Drying is performed for 24 hours at RT. The Binder (i.e., for mixing with the drug powder) is epoxy. Molding to plug is RT molding. Additional components may include 0.1% Triton and 0.005% BAK.
    • Example: Method of Using HPLC-UV to Quantify Latanoprost API from a Solution in the Presence of Benzalkonium Chloride (BAK) and Triton X-100
  • 51 samples of Latanoprost in PBS buffer with BAK and Triton X-100 were analyzed according to the following conditions:
  • Column: Synergy, MAX-RP 250 mm 4.6 mm, 4 micrometer
  • Flow rate: 1 mL/min
  • Detector: UV at 210 nm
  • Inj. Volume: 5 microliters
  • Sample Temperature: 10±5° C.
  • Column Temperature: 25±5° C.
  • Mobile phase A: 0.05M phosphate buffer pH=3: Acetonitrile (“ACN”) (40:60, v/v)
  • Mobile phase B: ACN
  • Gradient program:
  • Time (min) Mobile Phase (A) Mobile Phase (B)
    0 100 0
    1.0 100 0
    15.0 50 50
    15.1 100 0
    20.0 100 0
  • Run Time: 20 min
  • Results:
  • Days at 37° C. PBS + Amount Amount
    NEXTAR in PBS + Composite BAK(0.005%) + of of
    Sample RUN # BAK + Weight TRITON Latanoprost Latanoprost
    ID 6 + 9 + 10 Triton 5 mg (0.1%) 0.5 g (μg/mL) (μg)
    6-47 168 4.00 0.5920 70.7 41.9
    6-48 168 5.10 0.5040 96.8 48.8
    6-49 168 4.80 0.5160 114.3 59.0
    10-1 LP14-0315-1W-CO1 1 5.71 0.5331 26.0 14.9
    10-2 LP14-0315-3W-CO1 3 5.71 0.5339 52.3 27.9
    10-3 LP14-0315-5W-CO1 5 5.71 0.5318 50.3 26.7
    10-4 LP14-0315-7W-CO1 7 5.71 0.5336 43.9 23.4
    10-5 LP14-0315-9W-CO1 9 5.71 0.5343 35.4 18.9
    10-6 LP14-0315-14W-CO1 14 5.71 0.5345 46.1 24.6
    10-7 LP14-0315-21W-CO1 21 5.71 0.5331 50.3 32.2
    10-8 LP14-0315-28W-CO1 28 5.71 0.5315 50.2 25.7
    10-12 LP14-0315-1W-CO2 1 5.81 0.5320 45.6 24.3
    10-13 LP14-0315-3W-CO2 3 5.81 0.5319 47.4 25.2
    10-14 LP14-0315-5W-CO2 5 5.81 0.5293 44.8 23.7
    10-15 LP14-0315-7W-CO2 7 5.81 0.5187 43.0 22.3
    10-16 LP14-0315-9W-CO2 9 5.81 0.5191 42.2 21.9
    10-17 LP14-0315-14W-CO2 14 5.81 0.5254 51.7 27.2
    10-18 LP14-0315-21W-CO2 21 5.81 0.5140 52.3 32.0
    10-19 LP14-0315-28W-CO2 28 5.81 0.5099 52.7 32.0
    10-23 LP14-0315-1W-P1 1 4.80 0.5080 17.9 9.1
    10-24 LP14-0315-3W-P1 3 4.80 0.5156 37.5 19.4
    10-25 LP14-0315-5W-P1 5 4.80 0.5138 35.7 18.4
    10-26 LP14-0315-7W-P1 7 4.80 0.5132 42.9 22.0
    10-27 LP14-0315-9W-P1 9 4.80 0.5146 36.9 19.0
    10-28 LP14-0315-14W-P1 14 4.80 0.5087 53.7 26.9
    10-29 LP14-0315-21W-P1 21 4.80 0.5203 55.8 34.2
    10-30 LP14-0315-28W-P1 28 4.80 0.5122 50.3 30.9
    10-34 LP14-0315-1W-P2 1 5.15 0.5232 22.7 11.9
    10-35 LP14-0315-3W-P2 3 5.15 0.5211 33.1 17.2
    10-36 LP14-0315-5W-P2 5 5.15 0.5195 29.9 15.5
    10-37 LP14-0315-7W-P2 7 5.15 0.5261 34.4 18.1
    10-38 LP14-0315-9W-P2 9 5.15 0.5206 47.0 24.4
    10-39 LP14-0315-14W-P2 14 5.15 0.5151 58.6 30.2
    10-40 LP14-0315-21W-P2 21 5.15 0.5204 74.5 38.8
    10-41 LP14-0315-28W-P2 28 5.15 0.5192 51.4 26.7
     9-1 LP14-0315-1W-PY1 1 4.46 0.5303 3.8 2.0
     9-2 LP14-0315-3W-PY1 3 4.46 0.5320 5.7 3.5
     9-3 LP14-0315-5W-PY1 5 4.46 0.5309 5.1 3.2
     9-4 LP14-0315-7W-PY1 7 4.46 0.5306 6.2 3.3
     9-5 LP14-0315-9W-PY1 9 4.46 0.5317 6.3 3.4
     9-6 LP14-0315-14W-PY1 14 4.46 0.5381 12.2 5.6
     9-7 LP14-0315-21W-PY1 21 4.46 0.5342 12.1 5.4
     9-8 LP14-0315-28W-PY1 28 4.46 0.5366 12.2 5.5
     9-12 LP14-0315-1W-PY2 1 4.23 0.5367 4.7 2.5
     9-13 LP14-0315-3W-PY2 3 4.23 0.5352 8.5 4.5
     9-14 LP14-0315-5W-PY2 5 4.23 0.5303 7.1 3.8
     9-15 LP14-0315-7W-PY2 7 4.23 0.5320 6.6 3.5
     9-16 LP14-0315-9W-PY2 9 4.23 0.5325 4.7 2.5
     9-17 LP14-0315-14W-PY2 14 4.23 0.5337 7.8 4.2
     9-18 LP14-0315-21W-PY2 21 4.23 0.5322 9.6 5.1
     9-19 LP14-0315-28W-PY2 28 4.23 0.5305 9.5 5.0
  • The composite weight was not taken into account in the above table.
  • Calculations: the samples were injected as is and quantified against Latanoprost RM from Neore Pharma Group Col. Ltd., using 6 points calibration curve from concentrations of 0.5-50 micrograms/mL.
    • Example: Chromatographic Method Using HPLC-UV to Quantify Latanoprost API from a Solution in the Presence of BAK and Triton X-100
  • Thirty two samples of Latanoprost in PBS buffer with BAK and Triton X-100 were analyzed using the following conditions:
  • Column: Synergy, MAX-RP 250 4.6 mm, 4 micrometer
  • Flow rate: 1 mL/min
  • Detector: uV at 210 nm
  • Inj. Volume: 5 microliters
  • Sample Temperature: 10±5° C.
  • Column Temperature: 25±5° C.
  • Mobile phase A: 0.05M phosphate buffer pH=3 (40:60, v/v)
  • Mobile phase B: ACN
  • Gradient program:
  • Time (min) Mobile Phase (A) Mobile Phase (B)
    0 100 0
    1.0 100 0
    15.0 50 50
    15.1 100 0
    20.0 100 0
  • Run Time: 20 min
  • Results:
  • Days at 37° C. Amount of
    COMPOSITE FS60 + PU in PBS + BAK + Composite PBS + BAK(0.005%) + Latanoprost
    NEXTAR RUN 7 Triton Weight 3 mg TRITON(0.1%) 0.5 g (pg/ml)
    1 Con2(PBS + BAK + TRITON + LP) 28 days at 4° C. 3.70 0.516 388.5
    2 Con3(PBS + BAK + TRITON + LP) 28 days at 37° C. 3.5 0.634 1521.0
    3 LP14-1114-1D-E 1 2.0 0.548 48.6
    4 LP14-1114-3D-E 3 2.0 0.566 28.8
    5 LP14-1114-5D-E 5 2.0 0.583 25.5
    6 LP14-1114-7D-E 7 2.0 0.571 23.7
    7 LP14-1114-9D-E 9 2.0 0.553 24.3
    8 LP14-1114-140 -E 14 2.0 0.546 37.2
    9 LP14-1114-1D-F 1 3.6 0.526 0.57
    10 LP14-1114-3D-F 3 3.6 0.542 1.02
    11 LP14-1114-5D-F 5 3.6 0.599 0.81
    12 LP14-1114-7D-F 7 3.6 0.549 1.31
    13 LP14-1114-9D-F 9 3.6 0.494 1.41
    14 LP14-1114-140 -F 14 3.6 0.507 3.26
    15 LP14-1114-1D-G 1 2.8 0.544 6.0
    16 LP14-1114-3D-G 3 2.8 0.515 3.7
    17 LP14-1114-5D-G 5 2.8 0.575 3.7
    18 LP14-1114-7D-G 7 2.8 0.523 6.2
    19 LP14-1114-9D-G 9 2.8 0.618 3.7
    20 LP14-1114-140-G 14 2.8 0.564 8.0
    21 LP14-1114-1D-H 1 3.3 0.587 24.0
    22 LP14-1114-3D-H 3 3.3 0.611 26.4
    23 LP14-1114-5D-H 5 3.3 0.546 30.8
    24 LP14-1114-7D-H 7 3.3 0.531 32.7
    25 LP14-1114-9D-H 9 3.3 0.504 32.9
    26 LP14-1114-140 -H 14 3.3 0.536 40.6
    27 LP14-1114-1D-I 1 2.6 0.510 10.6
    28 LP14-1114-3D-I 3 2.6 0.580 15.7
    29 LP14-1114-5D-I 5 2.6 0.541 14.7
    30 LP14-1114-7D-I 7 2.6 0.553 21.0
    31 LP14-1114-9D-I 9 2.6 0.539 16.1
    32 LP14-1114-14DI 14 2.6 0.549 27.3
  • Calculations: the samples were injected and quantified against Latanoprost RM using 6 points weighted calibration curve from 0.5-50 micrograms/mL concentrations.
    • Example: Chromatographic Method by HPLC-UV which Will be Suitable to Quantify Latanoprost API from Solution in Presence of BAK and Triton X-100
  • Thirty four samples of latanoprost in PBS buffer with BAK and Triton X-100 were tested using the following method:
  • Column: Synergy, MAX-RP 250 4.6 mm, 4 micrometer
  • Flow rate: 1 mL/min
  • Detector: uV at 210 nm
  • Inj. Volume: 100 microliters
  • Sample Temperature: 10±5° C.
  • Column Temperature: 25±5° C.
  • Mobile phase A: 0.05M phosphate buffer pH=3 (40:60, v/v)
  • Mobile phase B: ACN
  • Gradient program:
  • Time (min) Mobile Phase (A) Mobile Phase (B)
    0 100 0
    1.0 100 0
    15.0 50 50
    15.1 100 0
    20.0 100 0
  • Run Time: 20 min
  • Results (using 5 microliters injection volume):
  • Days at 37° C. PBS + Amount Amount
    in PBS + Composite BAK(0.005%) + of of
    Sample COMPOSITE F860 + PU BAK + Weight TRITON Latanoprost Latanoprost
    No. NEXTAR RUN 6 Triton (mg) (0.1%) g (μg/mL) (μg)
    1 Con2 (PBS + BAK + TRITON + LP) 28 days at 4° C. 5.60 0.5073 216 109.6
    2 Con3 (PBS + BAK + TRITON + LP)  28 days at 37° C. 4.4 0.5090 229 116.6
    3 LP14-1114-3D-A 3 4.0 0.5033 31.8 16.0
    4 LP14-1114-5D-A 5 4.0 0.5270 25.5 13.4
    5 LP14-1114-7D-A 7 4.0 0.5188 27.1 14.1
    6 LP14-1114-9D-A 9 4.0 0.5207 38.8 20.1
    7 LP14-1114-14D-A 14 4.0 0.5189 54.3 28.2
    8 LP14-1114-21D-A 21 4.0 0.5027 41.4 20.8
    9 LP14-1114-25D-A 25 4.0 0.5076 34.0 17.3
    10 LP14-1114-28D-A 28 4.0 0.5243 36 18.9
    11 LP14B-1114-3D-B 3 5.1 0.5010 45.0 22.5
    12 LP14B-1114-5D-B 5 5.1 0.5143 34.0 17.5
    13 LP14B-1114-7D-B 7 5.1 0.5215 34.8 18.1
    14 LP14B-1114-9D-B 9 5.1 0.4927 57.2 28.2
    15 LP14B-1114-14D-B 14 5.1 0.4963 83.3 41.3
    16 LP14B-1114-21D-B 21 5.1 0.5095 61.6 31.4
    17 LP14B-1114-25D-B 25 5.1 0.5277 49.1 25.9
    18 LP14B-1114-28D-B 28 5.1 0.5085 55.5 28.1
    19 LP14-1114-3D-C 3 4.8 0.5128 41.0 21.0
    20 LP14-1114-5D-C 5 4.8 0.5085 37.9 19.2
    21 LP14-1114-7D-C 7 4.8 0.5202 42.9 22.3
    22 LP14-1114-9D-C 9 4.8 0.5224 70.4 36.8
    23 LP14-1114-14D-C 14 4.8 0.5036 95.4 48.0
    24 LP14-1114-21D-C 21 4.8 0.5287 64.8 34.1
    25 LP14-1114-25D-C 25 4.8 0.5054 63.5 32.1
    26 LP14-1114-28D-C 28 4.8 0.5097 58.5 29.8
    27 LP14B-1114-3D-D 3 5.0 0.5282 36.4 19.2
    28 LP14B-1114-5D-D 5 5.0 0.5133 31.5 16.2
    29 LP14B-1114-7D-D 7 5.0 0.5388 34.3 18.4
    30 LP14B-1114-9D-D 9 5.0 0.5285 38.1 20.1
    31 LP14B-1114-14D-D 14 5.0 0.5097 64.7 33.0
    32 LP14B-1114-21D-D 21 5.0 0.5134 49.1 25.2
    33 LP14B-1114-25D-D 25 5.0 0.5009 39.8 19.9
    34 LP14B-1114-28D-D 28 5.0 0.5071 38.6 19.6
    Notes:
    The composite weight does not taken into account.
  • Calculations: the samples were injected and quantified against latanoprost RM using 6 points calibration curve from 0.04-50 micrograms/mL concentrations.
    • Example: HPLC Method for Determining Timolol Maleate (TM) in Solution Containing Latanoprost, PBS, Benzalkonium Chloride (BAK) and Triton x-100, Using a C-18 Column and a UV Detection at 285 nm for TM and 210 nm for Latanoprost
  • Forty eight samples were analyzed using a Waters Alliance HPLC equipped with UV Detector, a micro analytical balance, Mettler Toledo, MX (QC-601), and a magnetic stirrer.
  • Linearity of TM was demonstrated in the range from 1-265 micrograms/mL with a square correlation coefficient of 1.0. The limit of quantitation was evaluated on standard solution at concentration of 1 microgram/mL and a signal to noise ratio of 88 was found.
  • Linearity of Latanoprost was demonstrated in the range from 0.48-240 micrograms/mL with a square correlation coefficient of 0.9999. The limit of quantitation was evaluated on standard solution at concentration of 0.48 micrograms/mL and a signal to noise ratio of 14.8 was found.
  • Analytical method development and conditions: HPLC method was developed for the determination and quantitation of Timolol Maleate and Latanoprost in aqueous solution containing PBS, BAK and Triton X-100. The chromatographic conditions were as follows:
  • Parameter Analytical condition
    HPLC Column Synergi, 4μ, MAX-RP 80A, 250 × 4.6 mm, 5 μm
    Cat. No. OOG-4337-EO. Nextar No. 86A-1.
    Mobile Phase A: 0.1% TFA in water:Acetonitrile 70:30, (v/v)
    B: 0.1% TFA in Acetonitrile
    Gradient Program see table below
    Flow Rate 1.0 mL/min
    Injection Volume
    20 μL
    Auto sampler
    10° c. ± 5°
    temperature
    Column oven
    40° c. ± 5°
    temperature
    Detection UV at 210 nm for Latanoprost
    UV at 285 nm for TM
  • Gradient Program:
  • Time (min) Mobile Phase (A) Mobile Phase (B)
    0 100 0
    3.0 100 0
    16.0 0 100
    16.1 100 0
    22.0 100 0
  • The sample diluent was 85% water and 15% methanol.
  • Results: the following parameters were evaluated during the method development: specificity, linearity and range, detection limit and quantitation limit.
  • Specificity: the sample diluent (85% water:15% methanol) was injected for the specificity test. No interference was detected at the retention time of TM and Latanoprost.
  • Linearity Tests:
  • TM: The linearity of Tm was evaluated from a concentration of 0.53-265 micrograms/mL. Seven standard solutions were prepared separately in order to test the linearity of the HPLC method: 0.53 micrograms/mL, 2.65 micrograms/mL, 13.3 micrograms/mL, 26.5 micrograms/mL, 53.0 micrograms/mL, 132.6 micrograms/mL, and 265.3 micrograms/mL. The correlation between the instrument response and concentration was demonstrated with a squared correlation coefficient of 1.0. FIG. 12 shows the chromatogram results of the TM standard solution at 53 micrograms/mL, where an injection volume of 20 microliters was used for a run time of 22 minutes.
  • Latanoprost: The linearity of Latanoprost was evaluated from a concentration of 0.48 micrograms/mL to 241 micrograms/mL. Seven standard solutions were prepared separately to test the linearity of the HPLC method: 0.48 micrograms/mL, 2.41 micrograms/mL, 12.0 micrograms/mL, 24.1 micrograms/mL, 48.1 micrograms/mL, 120.3 micrograms/mL, and 240.6 micrograms/mL. A correlation between the instrument response and concentration was demonstrated with a squared correlation coefficient (R2) of 1.0. FIGS. 13 and 14A-B illustrate a typical chromatogram of a standard solution at a concentration of 48 micrograms/mL and calibration curve results, respectively.
  • Limit of Quantitation and Limit of Detection:
  • Limit of quantitation for TM: the limit of detection (LOD) and the limit of quantitation (LOQ) values were determined by testing standard solution at a concentration of 0.53 micrograms/mL. As used herein, LOD refers to the lowest amount of analyte that can be detected above baseline noise, but not necessarily quantified as an exact value. As used herein, LOQ refers to the lowest amount of analyte which can be reproducibly quantitated above the baseline noise. The signal-to-noise ratio (S/N) for LOD should be about 3 and for LOQ about 10. A signal to noise ratio of 89 was found at standard solution containing 0.53 micrograms/mL. FIG. 15 shows a signal to noise ratio of 88.589 for TM at 285 nm.
  • Limit of quantitation for Latanoprost: The LOD and the LOQ values were determined. The signal-to noise ratio (S/N) for LOD is about 3 and for LOQ is about 10. A signal to noise ratio of 14.8 was found at standard solution containing 0.48 micrograms/mL, and is shown in FIG. 16.
  • System suitability parameters: The system suitability test is performed to demonstrate that the system is fit for the purpose of the analysis, and the following parameters were tested: percent RSD of 5 replicates of the standard solution, tailing factor (T), resolution (R), and number of theoretical plates (N). The table below shows the results of a sample:
  • Tailing Factor Theoretical Plates Resolution*
    API Name (T) (P) (R)
    TM 1.3 8469 2.0
    Latanoprost 1.3 112292 1.2
    *Resolution of API to nearest peak
  • System precision: the system precision was demonstrated on control standard at a nominal concentration of 50 micrograms/mL. The percent relative standard deviation (RSD) was calculated from the beginning of the sequence log until the end of the sequence log. RSD of less than 2% was found for both API's in all standard injections. The results are shown in the table below:
  • Std TM Latanoprost
    Replicate Peak area (AU) Peak area(AU)
    Injection 1 989723 1157736
    Injection 2 984361 1152543
    Injection 3 990732 1143846
    Injection 4 982226 1139423
    Injection 5 981758 1135124
    Injection 6 975390 1129086
    Injection 7 976605 1128033
    Injection 8 982001 1131109
    Injection 9 977782 1130783
    Mean 982286 1138631
    (%) RSD 0.5 0.9
  • Sample preparation: the sample solutions were shaken using a vortex shaker and transferred into an HPLC vial. The sample solutions were injected into HPLC as is without further dilution. Results are shown in the table below:
  • Composite Sample Amount of Amount of Amount of Amount of
    Sample NEXTAR RUN 12 Days Weight Volume Latanoprost Latanoprost Timolol Timolol
    ID (TIMOLOL) at 37° C. (mg) (ml) (μg/mL) (μg) (μg/mL) (μg)
    1 2-1 LP&TML-0615-1d-CO1 1 5.91 0.524 17.2 9.0 1049.1 549.7
    12-2 LP&TML-0615-3d-CO1 3 5.91 0.526 53.8 28.3 446.4 234.8
    12-3 LP&TML-0615-5d-CO1 5 6.91 0.501 74.3 37.2 162.2 81.3
    12-4 LP&TML-0615-7d-CO1 7 6.91 0.614 76.1 40.1 56.3 28.9
    12-5 LP&TML-0615-9d-CO1 9 5.91 0.519 55.5 28.8 11.0 5.7
    12-6 LP&TML-0615-14d-CO1 14 5.91 0.519 104.3 54.1 5.6 2.9
    12-7 LP&TML-0615-21d-CO1 21 5.91 0.518 85.2 44.1 0.9 0.5
    12-8 LP&TML-0615-28d-CO1 28 5.91 0.520 89.2 46.4 1.8 1.0
    12-1 2 LP&TML-0615-1d-CO2 1 6.00 0.517 17.6 9.1 944.2 488.1
    12-13 LP&TML-0615-3d-CO2 3 6.00 0.517 52.8 27.3 448.2 231.7
    12-14 LP&TML-0615-5d-CO2 5 6.00 0.527 59.0 31.1 162.2 85.5
    12-15 LP&TML-0615-7d-CO2 7 6.00 0.515 82.2 42.4 77.1 39.8
    12-16 LP&TML-0615-9d-CO2 9 6.00 0.620 59.2 30.8 20.5 10.7
    12-17 LP&TML-0615-14d-CO2 14 6.00 0.616 88.4 45.6 9.7 5.0
    12-18 LP&TML-0615-21d-CO2 21 6.00 0.518 102.6 53.1 1.1 0.8
    12-19 LP&TML-0615-28d-CO2 28 6.00 0.518 98.0 50.8 0.3 0.2
    12-23 LP&TML-0615-1d-P1 1 3.90 0.525 17.6 9.2 106.7 56.0
    12-24 LP&TML-0615-3d-P1 3 3.90 0.518 30.1 15.6 100.4 52.0
    12-25 LP&TML-0615-5d-P1 5 3.90 0.520 32.5 16.9 84.8 33.7
    12-26 LP&TML-0615-7d-P1 7 3.90 0.521 38.3 20.0 81.8 32.2
    12-27 LP&TML-0615-9d-P1 9 3.90 0.617 28.2 13.5 31.6 16.3
    12-28 LP&TML-0615-14d-P1 14 3.90 0.614 39.5 20.3 63.5 32.6
    12-29 LP&TML-0615-21d-P1 21 3.90 0.516 51.2 26.4 40.9 21.1
    12-30 LP&TML-0615-28d-P1 28 3.90 0.521 39.5 20.6 13.6 7.1
    12-34 LP&TML-0615-1d-P2 1 3.50 0.524 9.1 4.8 74.4 39.0
    12-35 LP&TML-0615-3d-P2 3 3.50 0.520 26.0 13.5 69.1 36.0
    12-36 LP&TML-0615-5d-32 5 3.50 0.517 28.6 14.8 48.6 25.1
    12-37 LP&TML-0615-7d-P2 7 3.50 0.522 29.2 15.2 43.6 22.8
    12-38 LP&TML-0615-9d-P2 9 3.50 0.519 20.6 10.7 22.6 117
    12-39 LP&TML-0615-14d-P2 14 3.50 0.522 35.5 18.5 51.9 27.1
    124 0 LP&TML-0615-21d-P2 21 3.50 0.616 31.0 16.0 35.0 18.1
    124 1 LP&TML-0615-28d-P2 28 3.50 0.521 31.2 16.3 21.5 11.2
    12-48 LP&TML-0615-1d-TPU 1 7.36 0.523 14.9 7.8 1079.0 564.3
    12-49 LP&TML-0615-3d-TPU 3 7.36 0.523 54.9 28.7 463.8 242.6
    12 0 LP&TML-0615-5d-TPU 5 7.36 0.526 64.6 34.0 140.5 73.9
    12 1 LP&TML-0615-7d-TPU 7 7.36 0.512 71.8 36.6 52.0 26.8
    12 2 LP&TML-0615-9d-TPU 9 7.36 0.519 68.9 35.8 10.2 5.3
    12 3 LP&TML-0615-14d-TPU 14 7.36 0.530 90.3 47.9 4.4 2.3
    12-54 LP&TML-0615-21d-TPU 21 7.36 0.528 88.9 47.0 0.9 0.5
    12 5 LP&TML-0615-28d-TPU 28 7.36 0.530 92.5 49.0 0.2 0.1
    12 0 LP&TML-061 5-1d-TPUSP- 1 7.35 0.532 7.8 4.1 902.7 480.2
    12 1 LP&TML-061 5-7d-TPUSP- 7 7.35 0.511 80.1 40.9 893.5 354.4
    12 2 LP&TML-061 5-1d-TPUSP- 1 5.35 0.608 21.9 111 834.5 423.9
    12 3 LP&TML-061 5-7d-TPUSP- 7 5.35 0.607 97.0 49.2 896.4 454.5
    12 4 LP&TML-0615-1d- Powder 1 4.11 0.604 88.5 34.5 7.3 3.7
    12 5 LP&TML-0615-7d-Powder 7 4.11 0.530 129.7 68.7 2.2 1.2
  • The composite weight was not taken into the calculations of the above table.
  • The squared correlation of the linear calibration curve was 1.0 for both API's. The samples were quantified against Latanoprost from Neore Pharmaceutical Group and TM from Signam-Aldrich, Cat. No. T6394.
  • FIGS. 17, 18 and 19A-B illustrate chromatograms: FIG. 19A is a diluent chromatogram at 285 nm for Timolol Maleate; FIG. 19B is a diluent chromatogram at 210 nm for Latanoprost; FIG. 19C is a typical sample chromatogram at 285 nm for Timolol Maleate; FIG. 19D is a typical sample chromatogram at 210 for Latanoprost.
  • Examples of Release Profiles
  • Two latanoprost plugs were loaded with either 280 micrograms of latanoprost or 1000 micrograms, where the plugs had the dimensions: diameter was 0.9 mm and length was 3 mm. For the plug loaded with 280 micrograms of latanoprost, about 150-200 micrograms was released within 170 days at rates from 5 micrograms/day to 0.5 micrograms/day. For the plug loaded with 1000 micrograms of latanoprost, about 300-350 micrograms of latanoprost was released within 110 days at rates from 10 micrograms/day to 2 micrograms/day. For the 1000 microgram loaded plugs, the plugs can be coated to release 70-80 micrograms within 110 days at rates of 2-0.5 micrograms/day. FIGS. 1B and 1C illustrate the latanoprost plug and the timolol plug, respectively. The plug can contain between 0-35% Latanoprost w/w (e.g., 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.). The plug can contain between 0-35% Timolol w/w (e.g., 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.).
  • A plug loaded with 400 micrograms Timolol and 250 micrograms Latanoprost, where the plug has dimensions of a diameter measuring 0.9 mm and a length measuring 3 mm, the release profile was about 300 micrograms of timolol and about 160 micrograms of Latanoprost within 30 days at rates of 50-5 micrograms/day for TM and 10 to 5 micrograms/day for latanoprost.
    • Example: Particulate Preparation
  • A solvent mixture was prepared, including THF:Ethanol in a 1:1 (w/w) ratio. First, Latanoprost is mixed with these solvents and then Latanoprost is added to fumed silica (Sigma Aldrich 0.2-0.3 micrometers as the average particle size, CAS 112945-52-5). For example: FS60 (60% drug, e.g., Latanoprost): 0.3 g FS+(0.2 g Latanoprost+5 g solvent), where FS is fumed silica. The mixture is then dried at room temperature for about 2 days. The percent moisture (relative humidity, “RH”) can be between 30-70%.
    • Example: Composite Matrix
  • To prepare an epoxy solution, 1 g Part A (Bisphenol A) is added to 0.25 g Part B (Reactive diluent; Epo-tek 301). Kaolin, FS60, and epoxy are mixed, and later molded into a shape (e.g., a punctual plug shape). Then, the mixture is cured at room temperature for 2 days. In an example, the composite (36% drug, e.g., Latanoprost): 0.2 g Kolin+0.2 g epoxy+0.6 g FS60 is mixed, molded into a shape, and cured.
    • Example: Dispersed Composite Matrix in Polyurethane
  • To prepare an epoxy solution, 1 g Part A is added to 0.25 g Part B. Kaolin (Sigma, CAS 1332-58-7), FS60, and Epoxy are mixed and this mixture is cured at room temperature for 2 days. The composite is ground and vacuum dried for 24 hours. The polyurethane solution is prepared using 4 g Part A and 1 g Part B (polyurethane steralloy 2781, Hapco Inc.). The Polyurethane is mixed with composite powder, and then molded into a shape (e.g., a punctual plug). For example, a plug having 14% drug (e.g., Latanoprost) would be generated by adding a composite powder to polyurethane to yield 0.5 g (composite powder) and 0.75 g polyurethane.
    • Example: Two Active Agents Dispersed in Polyurethane
  • Part 1: Particulate Preparation
  • The particulate was prepared by mixing solvents, e.g., tetrahydrofuran (THF):ethanol in a 1:1 (w/w) ratio. Then, Latanoprost was mixed with the solvents and added to fumed silica. Timolol (TML) was then mixed with the solvents and added to fumed silica. For example, FS60TML (60% Timolol drug):0.3 g FS+(0.2 g TML+5 g solvent), then FS60LTP (60% Latanoprost drug):0.3 g FS+(0.2 g Latanoprost drug+5 g solvent), and then the mixture is dried for two days at room temperature (relative humidity is between 30-70%).
  • Part 2: Composite Matrix
  • The epoxy solution was prepared using 1 g Part A and 0.25 g Part B. Kaolin, FS60LTP, FS60TML, and epoxy were mixed and then cured at room temperature for 2 days at a relative humidity of between 30-70%. The composite was then ground, creating <10 micrometer sized particles (e.g., but not limited to, between 0.001, 0.01, 0.1, 1, 2, 3 micrometers, etc.), and vacuum dried. The polyurethane solution was then prepared using 4 g Part A and 1 g Part B, and the polyurethane preparation was then mixed with the composite powder and subsequently molded into a shape, e.g., a punctual plug.
  • In another example of generating a composite matrix, the epoxy solution was prepared using 1 g Part A and 0.25 g Part B. Kaolin, FS60LTP, FA60TML, and epoxy were then mixed and this mixture was cured at room temperature for two days. The composite was ground into powder, creating <10 micrometer sized particles (e.g., but not limited to, between 0.001, 0.01, 0.1, 1, 2, 3 micrometers, etc.) and subsequently vacuum dried. For example, a composite matrix formulation was generated using 0.6 g FS60TML, 0.4 g FS60LTP, 0.33 g Kaolin and 0.4 g Epoxy, yielding a final dose in composition having 20% Timolol and 13.5% Latanoprost.
  • Part 3: Dispersed Composite Powder in Polyurethane
  • The polyurethane solution was prepared using 4 g Part A and 1 g Prt B. This preparation was then mixed with composite powder and molded. For example, the plug with 8.1% Timolol and 5.4% Latanoprost was generated using 0.35 g (Timolol and Latanoprost) composite powder and polyurethane, and then molded into a shape, e.g., a punctual plug. For example, a plug having 8.1% Timolol and 5.4% Latanoprost would be generated using 0.35 g (20.3% Timolol and 13.5% Latanoprost composite powder) and 0.53 g polyurethane.
    • Example: In Vitro Studies
  • The general protocol for the analytics study design was as follows: (1) preparing the following solution: phosphate buffered saline (10×PBS)+benzalkonium chloride (BAK) (0.005%)+Triton-X (0.1%), and adding 0.5 mL of this solution into 1.5 mL vials. The plugs were weighed (about 5 mg/plug), and then each plug was placed into vials (i.e., one plug per vial) containing solution. The vials containing the plugs were then agitated in a heater at 37° C. at 30 rpm. The samples were taken according to time intervals by removing the plug sample from the vial and putting vials in a refrigerator at 4 degrees C. A figure describing these steps is shown as FIG. 20. FIG. 21 is a graph showing 6 months release of Latanoprost. FIG. 22 is a graph showing release of Latanoprost per day.
  • FIG. 23 illustrates the cumulative Latanoprost release of a parylene coated punctual plug (e.g., but not limited to, where the microhole is between 0.5-5.0 microns (e.g., but not limited to, 0.5 microns, 0.6 microns, 0.7 microns, etc.)), where the parylene coating measures between 0.2-5.0 microns in thickness (e.g., but not limited to, 0.2 microns, 0.3 microns, 0.4 microns, 0.5 microns, 0.6 microns, etc.)
  • FIG. 24 illustrates a three month release profile, comparing EXP-LP02=Only composite (without polyurethane), EXP-LP01=Composite powder in polyurethane, and EXP-LP01C=Coated Composite powder in polyurethane.
  • Each EXP graph made of duplicate), LP-02, and LP01C experiments. FIG. 25 illustrates a three month release profile, showing the amount of Latanoprost released per day.
  • FIG. 26 illustrates the cumulative drug released, e.g., Timolol (TML) and Latanoprost (LP), from the punctual plugs.
  • FIG. 27 illustrates the amount of LP (5%) and TML (8%) released from a 5 mg punctual plug per day.
    • Example: Comparison of Latanoprost Composite, Latanoprost-Polyurethane and Parylene Coated Plugs
  • Three types of punctual plug were prepared for an HPLC analytics test: (1) polyurethane/fused silica with composite powder containing drug (PU:FS60) at a ratio of 60:40, with the final drug content of 14%; (2) polyurethane/fused silica (PU:FS60) with composite powder containing drug and having a parylene coating with a final drug content of 14%; and (3) Only composite (FS60+Kaolin+Epoxy) having a final drug content of 14.62%.
  • Reagents:
      • Kaolin USP Sigma C.N k1512-500G, Lot. No
      • Figure US20200093834A1-20200326-P00001
        , ANHYDROUS, 95%, Sigma C.N 295090-1L, Lot. No
      • Silica, Fumed Avg. Part, Size, 0.2-0.3 Sigma C.N S5505-500G, Lot. No
      • EPOXY EPO-TEK Part A Batch PB116550 date # Exp March 2015
      • EPOXY EPO-TEK Part B Batch PB116544 date of Exp March 2015
      • THF,
        Figure US20200093834A1-20200326-P00002
        CAS Number 109-99-9
      • Ethyl alcohol (Ethanol) 96% CAS 64-17-5
      • Figure US20200093834A1-20200326-P00003
        CAS 1302-9-82-4 Lot PG01-20140101 Mfg date May 1, 2014 Manufacturer codes—R-
        Figure US20200093834A1-20200326-P00004
        584-03
      • Polyurethane HAPCO
        Figure US20200093834A1-20200326-P00005
        FDG—Elastomeric, No. 2781 (4A: B)
      • Triton™ X-100, SIGMA-ALDRICH 5 ml—CAS Number 9002-93-1
  • Equipment:
      • Kern ABJ 80-4NM Analytical balance 0.1 mg
      • Freezer EL2280 Electra.
      • Mini dry bath—Miniib-100, Miulab instruments,
        Figure US20200093834A1-20200326-P00006
        ltd
      • Mortar and pestle
      • Orbital Shaker—SSM1, Stuart—England
      • Desiccators (Pre-dried in oven for 2 hours, 200° C.) 334278 SIGMA-ALDRICH, Molecular sieves, 3 Å, pellets, 3.2 mm.
  • Additional materials used:
      • Molding bock—pressing and molding the composite with PU into blinder shape
      • Aluminum
      • Plastic cups
  • Sample Preparation Methodology:
  • Only Composite Samples (Type 3):
  • 1. Particulate Preparation (FS60) for Only Composite Sample
      • 6 ml solvents mixture of THF:Ethanol 1:1 (w/w)
      • First Latanoprost mixing with solvents and then adding FS
      • FS60: 0.29 g FS+(0.44 g LP+5 g solvent)→Drying 2 days RT
  • 2. Matrix Preparation (See Table 4.1 Below for Amounts)
      • EPOXY solution preparation→1 g Part A and 0.25 g Part B
      • Kaolin+FS60+Epoxy 4 Dried at Room Temp for 2 days
      • LP14.5% Composite plug to 5 mg sample (cylinder shape)
  • TABLE 4.1
    Final
    Matrix FS60(gr) KAOLIN(gr) EPOXY(gr) LP
    LP14.5% Composite 0.054 0.0824 0.0863 14.62%
  • PU+Composite Powder (Type 1 and Type 2)
  • 1. Particulate Preparation (FS60) for PU+Composite Powder
      • 10 ml solvents mixture of THF:Ethanol 1:1 (w/w)
      • First Latanoprost mixing with solvents and then adding FS
      • FS60: 0.6648 g FS+(1 g LP+10 g solvent)→Drying 2 days RT
  • 2. Matrix Preparation (See Table 4.2 Below for Amounts)
      • EPOXY solution preparation→1 g Part A and 0.25 g Part B
      • Kaolin+FS60+Epoxy→Dried at Room Temp for 2 days
      • Grinding dried LP-FS60 using mortar.
      • Drying grinded LP-FS60 using desiccators for 3 days.
  • TABLE 4.2
    Composite
    Final
    Matrix FS60(gr) KAOLIN(gr) EPOXY(gr) LP
    LP35.5%-Composite 1.203 0.421 0.409 35.53%
    (for PU)
  • 3. PU Sample Preparation:
      • Polyurethane HAPCO 2781 solution preparation→4 g Part A and 1 g Part B.
  • Samples:
  • LP35.5%-Composite-15- Final
    Plug Sample (PU 03-2015 (gr) PU (gr) LP %
    LP14% 0.509 0.78 14.0%
  • Solution Preparation for the Incubation of the Plugs (PBS+BAK+Triton)
      • Weighting BAK and TRITON (see table for amounts)
      • Adding PBS
  • TRITON % TRITON (gr) BAK % BAK (gr) PBS ml
    0.1006 0.0403 0.0056 0.0023 40.00
  • Samples:
      • Preparing controls according to the table
      • Adding 0.5 ml gr solution to 1.5 vials
      • Putting samples into vials
      • Putting vials into heater at 37 degrees C.
      • Putting heater onto agitator on 30 RPM
      • Remove samples according to “sink condition method”
  • Sample
  • Composite PBS + BAK(0.005%) +
    SAMPLES Days at 37 Weight TRITON(0.1%)
    NEXTAR RUN 9 in PBS + BAK + Triton 5 mg 0.5 g PLUG DESIGN
    10-1  LP14-0315-1W-CO1 1 5.71 0.5331 ONLY COMPOSITE
    10-2  LP14-0315-3W-CO1 3 5.71 0.5339 ONLY COMPOSITE
    10-3  LP14-0315-5W-CO1 5 5.71 0.5318 ONLY COMPOSITE
    10-4  LP14-0315-7W-CO1 7 5.71 0.5336 ONLY COMPOSITE
    10-5  LP14-0315-9W-CO1 9 5.71 0.5343 ONLY COMPOSITE
    10-6  LP14-0315-14W-CO1 14 5.71 0.5345 ONLY COMPOSITE
    10-7  LP14-0315-21W-CO1 21 5.71 0.5331 ONLY COMPOSITE
    10-8  LP14-0315-28W-CO1 28 5.71 0.5315 ONLY COMPOSITE
    10-9  LP14-0315-48W-CO1 48 5.71 0.5290 ONLY COMPOSITE
    10-10 LP14-0315-79W-CO1 79 5.71 0.5341 ONLY COMPOSITE
    10-11 LP14-0315-109W-CO1 109 5.71 0.5300 ONLY COMPOSITE
    10-12 LP14-0315-1W-CO2 1 5.81 0.5320 ONLY COMPOSITE
    10-13 LP14-0315-3W-CO2 3 5.81 0.5319 ONLY COMPOSITE
    10-14 LP14-0315-5W-CO2 5 5.81 0.5293 ONLY COMPOSITE
    10-15 LP14-0315-7W-CO2 7 5.81 0.5187 ONLY COMPOSITE
    10-16 LP14-0315-9W-CO2 9 5.81 0.5191 ONLY COMPOSITE
    10-17 LP14-0315-14W-CO2 14 5.81 0.5264 ONLY COMPOSITE
    10-18 LP14-0315-21W-CO2 21 5.81 0.5140 ONLY COMPOSITE
    10-19 LP14-0315-28W-CO2 28 5.81 0.5099 ONLY COMPOSITE
    10-20 LP14-0315-48W-CO2 48 5.81 0.5177 ONLY COMPOSITE
    10-21 LP14-0315-79W-CO2 79 5.81 0.5078 ONLY COMPOSITE
    10-22 LP14-0315-109W-CO2 109 5.81 0.5124 ONLY COMPOSITE
    10-23 LP14-0315-1W-P1 1 4.80 0.5080 POWDER with PU
    10-24 LP14-0315-3W-P1 3 4.80 0.5158 POWDER with PU
    10-25 LP14-0315-5W-P1 5 4.80 0.5138 POWDER with PU
    10-26 LP14-0315-7W-P1 7 4.80 0.5132 POWDER with PU
    10-27 LP14-0315-9W-P1 9 4.80 0.5146 POWDER with PU
    10-28 LP14-0315-14W-P1 14 4.80 0.5007 POWDER with PU
    10-29 LP14-0315-21W-P1 21 4.80 0.5203 POWDER with PU
    10-30 LP14-0315-28W-P1 28 4.80 0.5122 POWDER with PU
    10-31 LP14-0315-48W-P1 48 4.80 0.5217 POWDER with PU
    10-32 LP14-0315-79W-P1 79 4.80 0.5150 POWDER with PU
    10-33 LP14-0315-109W-P1 109 4.80 0.5230 POWDER with PU
    10-34 LP14-0315-1W-P2 1 5.15 0.5232 POWDER with PU
    10-35 LP14-0315-3W-P2 3 5.15 0.5211 POWDER with PU
    10-36 LP14-0315-5W-P2 5 5.15 0.5195 POWDER with PU
    10-37 LP14-0315-7W-P2 7 5.15 0.5261 POWDER with PU
    10-38 LP14-0315-9W-P2 9 5.15 0.5206 POWDER with PU
    10-39 LP14-0315-14W-P2 14 5.15 0.5151 POWDER with PU
    10-40 LP14-0315-21W-P2 21 5.15 0.5204 POWDER with PU
    10-41 LP14-0315-28W-P2 28 5.15 0.5192 POWDER with PU
    10-42 LP14-0315-48W-P2 48 5.15 0.5158 POWDER with PU
    10-43 LP14-0315-79W-P2 79 5.15 0.5197 POWDER with PU
    10-44 LP14-0315-109W-P2 109 5.15 0.5191 POWDER with PU
    9-1 LP14-0315-1W-PY1 1 4.46 0.5303 COATED POWDER with PU
    9-2 LP14-0315-3W-PY1 3 4.46 0.5320 COATED POWDER with PU
    9-3 LP14-0315-5W-PY1 5 4.46 0.5309 COATED POWDER with PU
    9-4 LP14-0315-7W-PY1 7 4.46 0.5306 COATED POWDER with PU
    9-5 LP14-0315-9W-PY1 9 4.46 0.5317 COATED POWDER with PU
    9-6 LP14-0315-14W-PY1 14 4.46 0.5381 COATED POWDER with PU
    9-7 LP14-0315-21W-PY1 21 4.46 0.5342 COATED POWDER with PU
    9-8 LP14-0315-28W-PY1 28 4.46 0.5366 COATED POWDER with PU
    9-9 LP14-0315-48W-PY1 48 4.46 0.5357 COATED POWDER with PU
     9-10 LP14-0315-79W-PY1 79 4.46 0.5366 COATED POWDER with PU
     9-11 LP14-0315-109W-PY1 109 4.46 0.5316 COATED POWDER with PU
     9-12 LP14-0315-1W-PY2 1 4.23 0.5367 COATED POWDER with PU
     9-13 LP14-0315-3W-PY2 3 4.23 0.5352 COATED POWDER with PU
     9-14 LP14-0315-5W-PY2 5 4.23 0.5303 COATED POWDER with PU
     9-15 LP14-0315-7W-PY2 7 4.23 0.5320 COATED POWDER with PU
     9-16 LP14-0315-9W-PY2 9 4.23 0.5325 COATED POWDER with PU
     9-17 LP14-0315-14W-PY2 14 4.23 0.5337 COATED POWDER with PU
     9-18 LP14-0315-21W-PY2 21 4.23 0.5322 COATED POWDER with PU
     9-19 LP14-0315-28W-PY2 28 4.23 0.5305 COATED POWDER with PU
     9-20 LP14-0315-48W-PY2 48 4.23 0.5297 COATED POWDER with PU
     9-21 LP14-0315-79W-PY2 79 4.23 0.5339 COATED POWDER with PU
     9-22 LP14-0315-109W-PY2 109 4.23 0.5388 COATED POWDER with PU
    • Example: Sample Testing of Polyurethane Coated Plugs
  • Plugs tested: Polyurethane:FS60 (60% Fused Silica:40% Latanoprost); final drug content is 14.4%. Samples were incubated at 37 degrees Celsius for varying time periods to determine the time effect of Latanoprost release profile from the sample into the PBS solution.
  • Reagents and Equipment:
  • Reagents
      • Kaolin USP Sigma C.N k1512-500G,
      • Hexan, ANHYDROUS, 95%, Sigma C.N 296090-1L,
      • Silica, Fumed Avg. Part. Size. 0.2-0.3 Sigma C.N S5505-500G,
      • EPOXY EPO-TEK Part A Batch PB046370
      • EPOXY EPO-TEK Part B Batch PB046149
      • Toluene Sigma CAS 108-88-3
      • THF, tetrahydrofuran CAS Number 109-99-9
      • Ethyl alcohol (Ethanol) 96% CAS 64-17-5
      • Latanoprost CAS 1302-9-82-4 Lot PG01-20140101 Manufacturer codes—R-0673.14, 584-03
      • Triton™ X-100, SIGMA-ALDRICH 5 ml—CAS Number 9002-93-1
      • Polyurethane PMC780 DRY shore80 2A:1B (not medical PU)
  • Equipment
      • Kern ABJ 80-4NM Analytical balance 0.1 mg
      • Freezer EL2280 Electra.
      • Mini dry bath—Miniib-100, Miulab instruments, Lumitron ltd
      • Mortar and pestle
      • Orbital Shaker—SSM1, Stuart—England
      • Desiccators (Pre-dried in oven for 2 hours, 200° C.) 334278 SIGMA-ALDRICH, Molecular sieves, 3 Å, pellets, 3.2 mm.
  • Other Materials
      • Molding block—pressing and molding the composite with PU into cylinder shape
      • Aluminium foil
      • Plastic cups
  • Sample Preparation Methodology:
  • Particulate Preparation (FS60) LP-FS60
      • 6 ml solvents mixture of THF:Ethanol 1:1 (w/w)
      • First Latanoprost mixing with solvents and then adding FS
      • FS60: 0.2 g FS+(0.3 g LP+5 g solvent)→Drying 2 days RT
      • FS with 5% TRITON (1 gr FS+0.053 g TRITON+10 g Ethanol)
  • Matrix Preparation (See Tables 4.2 for Amounts)
      • EPOXY solution preparation→1 g Part A and 0.25 g Part B
      • Kaolin+FS60+Epoxy→Dried at Room Temp for 2 days
      • Grinding dried LP-FS60 using mortar and pestle.
      • Drying grinded LP-FS60 using desiccators for 3 days.
  • Composite
    Final
    Matrix FS60(gr) KAOLIN(gr) EPOXY(gr) LP
    LP36%-Composite 0.34 0.11 0.11 36.0%
      • Sample Preparation (See Table Below for Amounts)
      • Polyurethane PMC780 solution preparation→2 g Part A and 1 g Part B
  • Samples
    Parylene Butvar Exposure
    Sample Company Type Shore Coating Coating degree
    E Smooth-on PMC 780 80 NO NO CONTROL
    F Smooth-on PMC 780 80 YES NO Micro hole
    G Smooth-on PMC 780 80 YES NO One side
    H Smooth-on PMC 780 80 NO YES NO
    I Smooth-on PMC 780 80 YES NO Two sides
  • Final Samples
    LP36%-Composite-09- Final
    Plug Sample 2014 (gr) PU (gr) LP %
    LP14% 0.055 0.085 14%
  • Solution Preparation
      • 0.01M PBS+0.005% BAK+0.1% TRITON X-100
  • Table 4.5 Samples
  • 2. Samples Preparation: FS60 (Particulate Preparation)
      • Weighing 3 g HFE+3 g Ethanol=6 ml solvents mixture
      • Weighing 0.3 g LP
      • Mixing gently LP with 2 g solvents mixture using magnetic stirrer
      • Weighing 0.2 g FS
      • Adding LP with solvents to 0.2 g FS
      • Mixing gently materials using spatula to avoid air
      • Keeping in RT for 2 days
  • FIG. 28A shows the sample at the beginning of a 2 day incubation at RT. FIG. 28B shows the sample after 2 days at RT.
  • Composite Preparation:
      • Weighing FS60 and KAOLIN (see table for amounts)
      • Mixing gently materials using spatula
      • Adding EPOXY (Final solution A+B) (see table for amounts)
      • Mixing materials using spatula
      • Cutting 2 PE sheets
      • Putting small composite granules (Cuscus shape)
      • Staying in Refrigeration (4 Celsius) for two days
  • The composite samples are shown in FIG. 29.
  • Final formulation
    FS
    % con-
    % 5% FS drug in cen-
    Ethanol (X100) (X100) (X100) com- Epoxy Kaolin trate
    gr Final gr gr posite gr gr gr
    0.300 0.120 0.001 0.015 35.675 0.130 0.111 0.375
    Final
    2.3
  • Composite Milling
      • Putting granules into mortar and use pestle to mill the granules to fine powder.
      • Adding dried desiccators into plastic cup and adding powder to a small cup.
  • FIG. 30 shows the dried desiccators placed in a plastic cup and adding powder to the 10 mL cup.
  • PU+Composite:
      • Weighting 0.055 Composite
      • Weighting part A and part B of PU
      • Mixing for 5 minutes PU
      • Weighting 0.085 PU
      • Mixing PU and Composite into smooth paste (e.g., no particles were observed in this mixture)
      • Putting the paste onto the molding block.
      • Curing for 48 hr in an ambient temperature
  • LP36%-Composite-09- Final
    Plug Sample 2014 (gr) PU (gr) LP %
    LP14% 0.056 0.086 14.0%
      • Solution preparation (PBS+BAK+Triton)
      • Weighting BAK and TRITON (see table for amounts)
      • Adding PBS
  • TRITON % TRITON (gr) BAK % BAK (gr) PBS ml
    0.095 0.0285 0.0060 0.0018 30.026
  • Samples
      • Preparing controls according to the table
      • Adding 0.5 ml gr solution to 1.5 vials
      • Weighting 5 mg samples (0.005 gr)
      • Putting samples into vials
      • Putting vials into heater at 37 degrees C.
      • Putting heater onto agitator on 30 RPM
      • Remove samples according to “sink condition method” for example: Samples No. 3, 11, 19, 27 Removing composites from vial after 3 days and putting vials in the refrigerator than put the composite in new vials 1, 3, 5, 7, 9, etc. (See, e.g., FIG. 20)
  • Composite PBS + BAK(0.005%) +
    COMPOSITE FS60 + PU Days at 37 Weight TRITON(0.1%)
    NEXTAR RUN 7 in PBS + BAK + Triton 3 mg 0.5 g
    1 Con2 (PBS + BAK + TRITON + LP) 28 days at 4 Celcius 3.70 0.516
    2 Con3 (PBS + BAK + TRITON + LP) 28 days at 37 3.5 0.634
    3 LP14-1114-1D-E 1 2.0 0.548
    4 LP14-1114-3D-E 3 2.0 0.566
    5 LP14-1114-5D-E 5 2.0 0.583
    6 LP14-1114-7D-E 7 2.0 0.571
    7 LP14-1114-9D-E 9 2.0 0.553
    8 LP14-1114-14D-E 14 2.0 0.546
    9 LP14-1114-1D-F 1 3.6 0.526
    10 LP14-1114-3D-F 3 3.6 0.542
    11 LP14-1114-5D-F 5 3.6 0.599
    12 LP14-1114-7D-F 7 3.6 0.549
    13 LP14-1114-9D-F 9 3.6 0.494
    14 LP14-1114-14D-F 14 3.6 0.507
    15 LP14-1114-1D-G 1 2.8 0.544
    16 LP14-1114-3D-G 3 2.8 0.515
    17 LP14-1114-5D-G 5 2.8 0.575
    18 LP14-1114-7D-G 7 2.8 0.523
    19 LP14-1114-9D-G 9 2.8 0.618
    20 LP14-1114-14D-G 14 2.8 0.564
    21 LP14-1114-1D-H 1 3.3 0.587
    22 LP14-1114-3D-H 3 3.3 0.611
    23 LP14-1114-5D-H 5 3.3 0.546
    24 LP14-1114-7D-H 7 3.3 0.531
    25 LP14-1114-9D-H 9 3.3 0.504
    26 LP14-1114-14D-H 14 3.3 0.536
    27 LP14-1114-1D-I 1 2.6 0.510
    28 LP14-1114-3D-I 3 2.6 0.580
    29 LP14-1114-5D-I 5 2.6 0.541
    30 LP14-1114-7D-I 7 2.6 0.553
    31 LP14-1114-9D-I 9 2.6 0.539
    32 LP14-1114-14D-I 14 2.6 0.549
    • Example: Timolol and Latanoprost
  • This example focuses on a sample containing:
  • PU (Hapco2781):FS60-(60% Latanoprost:40% Timolol), final Timolol content % is 8.1% and the final Latanoprost content % is 5.4%.
  • Reagents and equipment:
  • Reagents
      • Kaolin USP Sigma C.N k1512-500G,
      • Hexan, ANHYDROUS, 95%, Sigma C.N 296090-1L
      • Silica, Fumed Avg. Part. Size. 0.2-0.3 Sigma C.N S5505-500G,
      • EPOXY EPO-TEK Part A Batch PB116550
      • EPOXY EPO-TEK Part B Batch PB116544
      • THF, tetrahydrofuran CAS Number 109-99-9
      • Ethyl alcohol (Ethanol) 96% CAS 64-17-5
      • Latanoprost CAS 1302-9-82-4 Lot PG01-20140101
      • Manufacturer codes—R-0673.14, 584-03 (NEORE PHARMA)
      • Timolol CAS 26921-17-5 Lot 140303 Mfg date March 2014 (NEORE PHARMA)
      • Polyurethane HAPCO—Steralloy™ FDG—Elastomeric, No. 2781 (4A: B)
      • Triton™ X-100, SIGMA-ALDRICH 5 ml—CAS Number 9002-93-1
  • Equipment
      • Kern ABJ 80-4NM Analytical balance 0.1 mg
      • Freezer EL2280 Electra.
      • Mini dry bath—Miniib-100, Miulab instruments, Lumitron ltd
      • Mortar and pestle
      • Orbital Shaker—SSM1, Stuart—England
      • Desiccators (Pre-dried in oven for 2 hours, 200° C.) 334278 SIGMA-ALDRICH, Molecular sieves, 3 Å, pellets, 3.2 mm.
  • Other Materials
      • Molding block—pressing and molding the composite with PU into cylinder shape
      • Aluminum foil
      • Plastic cups
  • Sample Preparation Methodology:
  • Particulate Preparation (FS60LTP) LP-FS60
      • 6 ml solvents mixture of THF:Ethanol 1:1 (w/w)
      • Latanoprost mixing with solvents and then adding FS
      • FS60: 0.2 g FS+(0.33 g LP+5 g solvent)→Drying 2 days RT
  • Particulate Preparation (FS60TML) TML-FS60
      • 6 ml solvents mixture of THF:Ethanol 1:1 (w/w)
      • Timolol mixing with solvents and then adding FS
      • FS60: 0.2 g FS+(0.33 g TML+5 g solvent)→Drying 1 day RT
  • Composite Matrix Preparation (See Table Below for Amounts)
      • EPOXY solution preparation→1 g Part A and 0.25 g Part B
      • Kaolin+FS60+Epoxy→Dried at Room Temp for 2 days (see table below)
      • Grinding dried FS60 (for PU) using mortar.
      • Drying grinded FS60 (for PU) using desiccators for 3 days.
  • Composite
    % drug in % drug in FS FT
    composite composite Epoxy Kaolin FS LTP TIM
    LTP TIM gr gr TOTAL gr gr
    13.53834586 20.3075188 0.44 0.333333333 1 0.4 0.6
    % % %
  • Sample Preparation (See Tables 4.3 for Amounts)
      • Polyurethane HAPCO 2781 solution preparation→4 g Part A and 1 g Part B were mixed together and 0.53 grams of the mixture was used for the formulation
  • Samples
    Final Final
    Plug Sample Composite powder (gr) PU (gr) TML % LP %
    LP&TML-0615 0.35 0.53 8.1% 5.4%
  • Solution Preparation
      • 0.01M PBS+0.005% BAK+0.1% TRITON X-100
  • TABLE 4.5
    Samples
    PBS +
    Days at 37 Composite BAK(0.005%) +
    SAMPLES in PBS + Weight TRITON(0.1%)
    NEXTAR RUN 12 BAK + Triton 5 mg 0.5 g
    LP&TML-0615-1d-P1 1 3.90 0.525
    LP&TML-0615-3d-P1 3 3.90 0.518
    LP&TML-0615-5d-P1 5 3.90 0.520
    LP&TML-0615-7d-P1 7 3.90 0.521
    LP&TML-0615-9d-P1 9 3.90 0.517
    LP&TML-0615-14d-P1 14 3.90 0.514
    LP&TML-0615-21d-P1 21 3.90 0.516
    LP&TML-0615-28d-P1 28 3.90 0.521
    LP&TML-0615-48d-P1 58 3.90 0.516
    LP&TML-0615-79d-P1 96 3.90 0.517
    LP&TML-0615-109d-P1 126 3.90 0.565
    LP&TML-0615-1d-P2 1 3.50 0.524
    LP&TML-0615-3d-P2 3 3.50 0.520
    LP&TML-0615-5d-P2 5 3.50 0.517
    LP&TML-0615-7d-P2 7 3.50 0.522
    LP&TML-0615-9d-P2 9 3.50 0.519
    LP&TML-0615-14d-P2 14 3.50 0.522
    LP&TML-0615-21d-P2 21 3.50 0.516
    LP&TML-0615-28d-P2 28 3.50 0.521
  • Sample Preparation
  • LP-FS60 (Particulate Preparation)
      • Weighing 3 g HFE+3 g Ethanol=6 ml solvents mixture
      • Weighing 0.2 g LP
      • Mixing gently LP with 5 g solvents mixture using magnetic stirrer
      • Weighing 0.3 g FS
      • Adding LP with solvents to 0.3 g FS
      • Mixing gently materials using spatula to avoid air
      • Keeping in RT for 1 day
  • TML-FS60 (Particulate Preparation)
      • Weighing 3 g HFE+3 g Ethanol=6 ml solvents mixture
      • Weighing 0.2 g TML
      • Mixing gently TML with 5 g solvents mixture using magnetic stirrer
      • Weighing 0.3 g FS
      • Adding LP with solvents to 0.3 g FS
      • Mixing gently materials using spatula to avoid air
      • Keeping in RT for 1 day
  • Composite
      • Weighing FS60 and KAOLIN (as shown in table above)
      • Mixing gently materials using spatula
      • Adding EPOXY (Final solution A+B) (as shown in table above)
      • Mixing materials using spatula
      • Cutting 2 PE sheets
      • Putting small composite granules (Cuscus shape)
      • Staying in RT for two days
  • Composite Milling and PU
      • Putting granules into mortar and use pestle to mill the granules to fine powder (e.g., but not limited to, <100 microns; e.g., but not limited to, 0.01 micron, 0.1 micron, 1 micron, etc.).
      • Weighting 0.350 Composite powder
      • Weighting part A and part B of PU
      • Mixing for 5 minutes PU
      • Weighting 0.53 PU
      • Mixing PU and Composite into smooth paste
      • Putting the paste onto the molding block.
      • Curing for 48 hr (to 30/06)
  • Solution Preparation (PBS+BAK+Triton)
      • Weighting BAK and TRITON (see table for amounts)
      • Adding PBS
  • TRITON % TRITON (gr) BAK % BAK (gr) PBS ml
    0.1116 0.0447 0.0058 0.0023 40.00
  • Samples
      • Preparing controls
      • Adding 0.5 ml gr solution to 1.5 vials
      • Putting samples into vials
      • Putting vials into heater at 37 degrees C.
      • Putting heater onto agitator on 30 RPM
      • Remove samples according to “sink condition method”
  • In some embodiments, the present invention is a composition, including: a bulking agent including a kaolin, an absorbent material including a fumed silica, a binder including an epoxy, and a first active agent including Latanoprost. In some embodiments, the first active agent measures between 5-40% by weight (w/w). In some embodiments, the first active agent measures between 5-35% by weight (w/w). In some embodiments, the first active agent measures between 5-30% by weight (w/w). In some embodiments, the first active agent measures between 5-25% by weight (w/w). In some embodiments, the first active agent measures between 5-20% by weight (w/w). In some embodiments, the first active agent measures between 5-15% by weight (w/w). In some embodiments, the first active agent measures between 5-10% by weight (w/w). In some embodiments, the first active agent measures between 10-40% by weight (w/w). In some embodiments, the first active agent measures between 15-40% by weight (w/w). In some embodiments, the first active agent measures between 20-40% by weight (w/w). In some embodiments, the first active agent measures between 25-40% by weight (w/w). In some embodiments, the first active agent measures between 30-40% by weight (w/w). In some embodiments, the first active agent measures between 35-40% by weight (w/w). In some embodiments, the first active agent measures between 10-35% by weight (w/w). In some embodiments, the first active agent measures between 15-30% by weight (w/w). In some embodiments, the first active agent measures between 20-25% by weight (w/w). In some embodiments, the compound further includes a second active agent. In some embodiments, the second active agent is Timolol. In some embodiments, the second active agent measures between 5-40% by weight (w/w). In some embodiments, the second active agent measures between 5-35% by weight (w/w). In some embodiments, the second active agent measures between 5-30% by weight (w/w). In some embodiments, the second active agent measures between 5-25% by weight (w/w). In some embodiments, the second active agent measures between 5-20% by weight (w/w). In some embodiments, the second active agent measures between 5-15% by weight (w/w). In some embodiments, the second active agent measures between 5-10% by weight (w/w). In some embodiments, the second active agent measures between 10-40% by weight (w/w). In some embodiments, the second active agent measures between 15-40% by weight (w/w). In some embodiments, the second active agent measures between 20-40% by weight (w/w). In some embodiments, the second active agent measures between 25-40% by weight (w/w). In some embodiments, the second active agent measures between 30-40% by weight (w/w). In some embodiments, the second active agent measures between 35-40% by weight (w/w). In some embodiments, the second active agent measures between 10-35% by weight (w/w). In some embodiments, the second active agent measures between 15-30% by weight (w/w). In some embodiments, the second active agent measures between 20-25% by weight (w/w). In some embodiments, the composition further includes polyurethane. In some embodiments, the composition further includes a parylene coating. In some embodiments, the parylene coating measures between 2-5 micrometers (e.g., but not limited to, 2.1 micrometers, 2.2 micrometers, etc.) in thickness. In some embodiments, the composition includes a butvar coating. In some embodiments, the butvar coating measures between 2-5 micrometers (e.g., but not limited to, 2.1 micrometers, 2.2 micrometers, etc.) in thickness. In some embodiments, the composition is in the form of a punctal plug.
  • In some embodiments, the present invention is a method, including: administering a composition to an eye of a mammal in need thereof, where the composition releases between 0.5-10 micrograms of a first active agent per day, and where the composition includes: a bulking agent including a kaolin, an absorbent material including a fumed silica, a binder including an epoxy, and the first active agent includes Latanoprost. In some embodiments, the first active agent measures between 5-40% by weight (w/w). In some embodiments, the first active agent measures between 5-35% by weight (w/w). In some embodiments, the first active agent measures between 5-30% by weight (w/w). In some embodiments, the first active agent measures between 5-25% by weight (w/w). In some embodiments, the first active agent measures between 5-20% by weight (w/w). In some embodiments, the first active agent measures between 5-15% by weight (w/w). In some embodiments, the first active agent measures between 5-10% by weight (w/w). In some embodiments, the first active agent measures between 10-40% by weight (w/w). In some embodiments, the first active agent measures between 15-40% by weight (w/w). In some embodiments, the first active agent measures between 20-40% by weight (w/w). In some embodiments, the first active agent measures between 25-40% by weight (w/w). In some embodiments, the first active agent measures between 30-40% by weight (w/w). In some embodiments, the first active agent measures between 35-40% by weight (w/w). In some embodiments, the first active agent measures between 10-35% by weight (w/w). In some embodiments, the first active agent measures between 15-30% by weight (w/w). In some embodiments, the first active agent measures between 20-25% by weight (w/w). In some embodiments, the method includes a second active agent. In some embodiments, the second active agent is Timolol. In some embodiments, the second active agent includes between 5-40% by weight (w/w). In some embodiments, the second active agent measures between 5-35% by weight (w/w). In some embodiments, the second active agent measures between 5-30% by weight (w/w). In some embodiments, the second active agent measures between 5-25% by weight (w/w). In some embodiments, the second active agent measures between 5-20% by weight (w/w). In some embodiments, the second active agent measures between 5-15% by weight (w/w). In some embodiments, the second active agent measures between 5-10% by weight (w/w). In some embodiments, the second active agent measures between 10-40% by weight (w/w). In some embodiments, the second active agent measures between 15-40% by weight (w/w). In some embodiments, the second active agent measures between 20-40% by weight (w/w). In some embodiments, the second active agent measures between 25-40% by weight (w/w). In some embodiments, the second active agent measures between 30-40% by weight (w/w). In some embodiments, the second active agent measures between 35-40% by weight (w/w). In some embodiments, the second active agent measures between 10-35% by weight (w/w). In some embodiments, the second active agent measures between 15-30% by weight (w/w). In some embodiments, the second active agent measures between 20-25% by weight (w/w). In some embodiments, the method includes a parylene coating. In some embodiments, the parylene coating measures between 2-5 micrometers (e.g., but not limited to, 2.1 micrometers, 2.2 micrometers, etc.) in thickness. In some embodiments, the composition includes a butvar coating. In some embodiments, the butvar coating measures between 2-5 micrometers (e.g., but not limited to, 2.1 micrometers, 2.2 micrometers, etc.) in thickness. In some embodiments, the composition is in the form of a punctal plug.
  • In some embodiments, the composition of the present invention is a drug-delivery device comprising: a) a composite comprising the following elements: (i) particles of inert materials, where the inert materials are adsorbed with drug on surface of particles (e.g., drug bound to particles) or inside porosity (e.g., drug housed within pores); (ii) a bulking agent; (iii) an adhesive binder; or any combination thereof, and b) an optional coating on the whole or partial outer surface of the body/core; where the coating is complete/continuous or perforated, e.g., but not limited to, where the coating can be butvar and/or parylene.
  • In some embodiments, the present invention is a composition, including: a bulking agent including a kaolin and/or a pectin, an absorbent material including a fumed silica, a binder including an epoxy, and a first active agent including Latanoprost. In some embodiments, the first active agent measures between 5-50% by weight (w/w). In some embodiments, the first active agent measures between 5-45% by weight (w/w). In some embodiments, the first active agent measures between 5-40% by weight (w/w). In some embodiments, the first active agent measures between 5-35% by weight (w/w). In some embodiments, the first active agent measures between 5-30% by weight (w/w). In some embodiments, the first active agent measures between 5-25% by weight (w/w). In some embodiments, the first active agent measures between 5-20% by weight (w/w). In some embodiments, the first active agent measures between 5-15% by weight (w/w). In some embodiments, the first active agent measures between 5-10% by weight (w/w). In some embodiments, the first active agent measures between 10-50% by weight (w/w). In some embodiments, the first active agent measures between 15-50% by weight (w/w). In some embodiments, the first active agent measures between 20-50% by weight (w/w). In some embodiments, the first active agent measures between 25-50% by weight (w/w). In some embodiments, the first active agent measures between 30-50% by weight (w/w). In some embodiments, the first active agent measures between 35-50% by weight (w/w). In some embodiments, the first active agent measures between 40-50% by weight (w/w). In some embodiments, the first active agent measures between 45-50% by weight (w/w). In some embodiments, the first active agent measures between 10-45% by weight (w/w). In some embodiments, the first active agent measures between 15-40% by weight (w/w). In some embodiments, the first active agent measures between 20-35% by weight (w/w). In some embodiments, the first active agent measures between 20-30% by weight (w/w). In some embodiments, the compound further includes a second active agent. In some embodiments, the second active agent is Timolol. In some embodiments, the second active agent measures between 5-40% by weight (w/w). In some embodiments, the second active agent measures between 5-35% by weight (w/w). In some embodiments, the second active agent measures between 5-30% by weight (w/w). In some embodiments, the second active agent measures between 5-25% by weight (w/w). In some embodiments, the second active agent measures between 5-20% by weight (w/w). In some embodiments, the second active agent measures between 5-15% by weight (w/w). In some embodiments, the second active agent measures between 5-10% by weight (w/w). In some embodiments, the second active agent measures between 10-40% by weight (w/w). In some embodiments, the second active agent measures between 15-40% by weight (w/w). In some embodiments, the second active agent measures between 20-40% by weight (w/w). In some embodiments, the second active agent measures between 25-40% by weight (w/w). In some embodiments, the second active agent measures between 30-40% by weight (w/w). In some embodiments, the second active agent measures between 35-40% by weight (w/w). In some embodiments, the second active agent measures between 10-35% by weight (w/w). In some embodiments, the second active agent measures between 15-30% by weight (w/w). In some embodiments, the second active agent measures between 20-25% by weight (w/w). In some embodiments, the composition further includes polyurethane. In some embodiments, the composition further includes a parylene coating. In some embodiments, the parylene coating measures between 2-5 micrometers (e.g., but not limited to, 2.1 micrometers, 2.2 micrometers, etc.) in thickness. In some embodiments, the composition includes a butvar coating. In some embodiments, the butvar coating measures between 2-5 micrometers (e.g., but not limited to, 2.1 micrometers, 2.2 micrometers, etc.) in thickness. In some embodiments, the composition is in the form of a punctal plug.
  • In some embodiments, the present invention is a method, including: administering a composition to an eye of a mammal in need thereof, where the composition releases between 0.5-10 micrograms of a first active agent per day, and where the composition includes: a bulking agent including a kaolin, an absorbent material including a fumed silica, a binder including an epoxy, and the first active agent includes Latanoprost. In some embodiments, the first active agent measures between 5-50% by weight (w/w). In some embodiments, the first active agent measures between 5-45% by weight (w/w). In some embodiments, the first active agent measures between 5-40% by weight (w/w). In some embodiments, the first active agent measures between 5-35% by weight (w/w). In some embodiments, the first active agent measures between 5-30% by weight (w/w). In some embodiments, the first active agent measures between 5-25% by weight (w/w). In some embodiments, the first active agent measures between 5-20% by weight (w/w). In some embodiments, the first active agent measures between 5-15% by weight (w/w). In some embodiments, the first active agent measures between 5-10% by weight (w/w). In some embodiments, the first active agent measures between 10-50% by weight (w/w). In some embodiments, the first active agent measures between 15-50% by weight (w/w). In some embodiments, the first active agent measures between 20-50% by weight (w/w). In some embodiments, the first active agent measures between 25-50% by weight (w/w). In some embodiments, the first active agent measures between 30-50% by weight (w/w). In some embodiments, the first active agent measures between 35-50% by weight (w/w). In some embodiments, the first active agent measures between 40-50% by weight (w/w). In some embodiments, the first active agent measures between 45-50% by weight (w/w). In some embodiments, the first active agent measures between 10-35% by weight (w/w). In some embodiments, the first active agent measures between 10-45% by weight (w/w). In some embodiments, the first active agent measures between 15-40% by weight (w/w). In some embodiments, the first active agent measures between 20-35% by weight (w/w). In some embodiments, the first active agent measures between 25-30% by weight (w/w). In some embodiments, the method includes a second active agent. In some embodiments, the second active agent is Timolol. In some embodiments, the second active agent includes between 5-40% by weight (w/w). In some embodiments, the second active agent measures between 5-35% by weight (w/w). In some embodiments, the second active agent measures between 5-30% by weight (w/w). In some embodiments, the second active agent measures between 5-25% by weight (w/w). In some embodiments, the second active agent measures between 5-20% by weight (w/w). In some embodiments, the second active agent measures between 5-15% by weight (w/w). In some embodiments, the second active agent measures between 5-10% by weight (w/w). In some embodiments, the second active agent measures between 10-40% by weight (w/w). In some embodiments, the second active agent measures between 15-40% by weight (w/w). In some embodiments, the second active agent measures between 20-40% by weight (w/w). In some embodiments, the second active agent measures between 25-40% by weight (w/w). In some embodiments, the second active agent measures between 30-40% by weight (w/w). In some embodiments, the second active agent measures between 35-40% by weight (w/w). In some embodiments, the second active agent measures between 10-35% by weight (w/w). In some embodiments, the second active agent measures between 15-30% by weight (w/w). In some embodiments, the second active agent measures between 20-25% by weight (w/w). In some embodiments, the method includes a parylene coating. In some embodiments, the parylene coating measures between 2-5 micrometers (e.g., but not limited to, 2.1 micrometers, 2.2 micrometers, etc.) in thickness. In some embodiments, the composition includes a butvar coating. In some embodiments, the butvar coating measures between 2-5 micrometers (e.g., but not limited to, 2.1 micrometers, 2.2 micrometers, etc.) in thickness. In some embodiments, the composition is in the form of a punctal plug.
  • While a number of embodiments of the present invention have been described, it is understood that these embodiments are illustrative only, and not restrictive, and that many modifications may become apparent to those of ordinary skill in the art. Further still, the various steps may be carried out in any desired order (and any desired steps may be added and/or any desired steps may be eliminated).

Claims (11)

1. A composition, comprising:
a bulking agent comprising a kaolin,
an absorbent material comprising a fumed silica,
a binder comprising an epoxy, and
a first active agent comprising Latanoprost
wherein the bulking agent, the absorbent material, the binder, and
the first active agent are present in a composite; and
wherein the composition is in the form of a punctal plug.
2. The composition of claim 1, wherein the first active agent is present in an amount of 5-40% by weight (w/w) of the composition.
3. The composition of claim 1, further comprising a second active agent, wherein the second active agent comprises Timolol.
4. The composition of claim 3, wherein the Timolol is present in an amount of 5-40% by weight (w/w) of the composition.
5. The composition of claim 1, wherein the composition further comprises polyurethane.
6. The composition of claim 1, wherein the composition further comprises a parylene coating.
7. The composition of claim 6, wherein a thickness of the parylene coating ranges from 2-5 micrometers.
8. The composition of claim 1, wherein the composition further comprises a butvar coating.
9. The composition of claim 8, wherein a thickness of the butvar coating ranges from 2-5 micrometers.
10.-20. (canceled)
21. The composition of claim 1, wherein the composition is configured to release from 0.5-10 micrograms of the first active agent per day to an eye of a mammal in need thereof.
US16/531,665 2014-11-25 2019-08-05 Compositions for delivering a bio-active agent or bio-active agents Abandoned US20200093834A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US16/531,665 US20200093834A1 (en) 2014-11-25 2019-08-05 Compositions for delivering a bio-active agent or bio-active agents
US17/078,534 US20210137942A1 (en) 2014-11-25 2020-10-23 Devices and methods for delivering a bio-active agent or bio-active agents

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201462084387P 2014-11-25 2014-11-25
PCT/IB2015/002345 WO2016083891A1 (en) 2014-11-25 2015-11-25 Compositions and methods for delivering a bio-active agent or bio-active agents
US201715529474A 2017-05-24 2017-05-24
US16/531,665 US20200093834A1 (en) 2014-11-25 2019-08-05 Compositions for delivering a bio-active agent or bio-active agents

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
PCT/IB2015/002345 Division WO2016083891A1 (en) 2014-11-25 2015-11-25 Compositions and methods for delivering a bio-active agent or bio-active agents
US15/529,474 Division US10471070B2 (en) 2014-11-25 2015-11-25 Methods for delivering a bio-active agent or bio-active agents to an eye of a mammal

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US17/078,534 Division US20210137942A1 (en) 2014-11-25 2020-10-23 Devices and methods for delivering a bio-active agent or bio-active agents

Publications (1)

Publication Number Publication Date
US20200093834A1 true US20200093834A1 (en) 2020-03-26

Family

ID=56073684

Family Applications (3)

Application Number Title Priority Date Filing Date
US15/529,474 Active US10471070B2 (en) 2014-11-25 2015-11-25 Methods for delivering a bio-active agent or bio-active agents to an eye of a mammal
US16/531,665 Abandoned US20200093834A1 (en) 2014-11-25 2019-08-05 Compositions for delivering a bio-active agent or bio-active agents
US17/078,534 Pending US20210137942A1 (en) 2014-11-25 2020-10-23 Devices and methods for delivering a bio-active agent or bio-active agents

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US15/529,474 Active US10471070B2 (en) 2014-11-25 2015-11-25 Methods for delivering a bio-active agent or bio-active agents to an eye of a mammal

Family Applications After (1)

Application Number Title Priority Date Filing Date
US17/078,534 Pending US20210137942A1 (en) 2014-11-25 2020-10-23 Devices and methods for delivering a bio-active agent or bio-active agents

Country Status (7)

Country Link
US (3) US10471070B2 (en)
EP (1) EP3223793B1 (en)
JP (1) JP6686023B2 (en)
KR (1) KR102511830B1 (en)
CN (1) CN107645951B (en)
CA (1) CA2968926C (en)
WO (1) WO2016083891A1 (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200147055A1 (en) * 2017-05-30 2020-05-14 Eximore Ltd. Compositions and methods for treating dry eye syndrome delivering antibiotic macrolide
CN111110636B (en) * 2018-11-01 2022-09-27 复旦大学附属眼耳鼻喉科医院 High-efficiency loading and sustained-release anti-glaucoma drug by using nano mesoporous silica
US11207267B2 (en) 2019-10-02 2021-12-28 Segal Innovations LLC Bio-adhesive dissolving compounds and device
EP4069220A4 (en) * 2019-12-04 2024-04-24 Restore Vision Llc Ophthalmic formulations for the treatment of presbyopia
US20230414495A1 (en) * 2020-11-09 2023-12-28 Eximore Ltd. Punctal plugs containing micelle-encapsulated ophthalmic pharmaceuticals and methods for making thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080181930A1 (en) * 2007-01-31 2008-07-31 Alcon Research, Ltd. Punctal Plugs and Methods of Delivering Therapeutic Agents
US20090306595A1 (en) * 2008-05-08 2009-12-10 Jason Shih Implantable drug-delivery devices, and apparatus and methods for filling the devices
US20130142858A1 (en) * 2010-05-17 2013-06-06 Aerie Pharmaceuticals, Inc. Drug delivery devices for delivery of ocular therapeutic agents

Family Cites Families (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2534580A1 (en) 1982-10-13 1984-04-20 Synthelabo PHENYL-1 PIPERIDINO-2 PROPANOL DERIVATIVES, THEIR PREPARATION, AND MEDICINES THAT CONTAIN THEM
US5151444B1 (en) 1987-09-18 1999-07-06 R Tech Ueno Ltd Ocular hypotensive agents
EP1224935A3 (en) 1988-09-06 2003-03-26 Pharmacia Aktiebolag Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension
US5296504A (en) 1988-09-06 1994-03-22 Kabi Pharmacia Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension
US5352708A (en) 1992-09-21 1994-10-04 Allergan, Inc. Non-acidic cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents
US5922773A (en) 1992-12-04 1999-07-13 The Children's Medical Center Corp. Glaucoma treatment
US5510383A (en) 1993-08-03 1996-04-23 Alcon Laboratories, Inc. Use of cloprostenol, fluprostenol and their salts and esters to treat glaucoma and ocular hypertension
TWI290470B (en) * 1999-12-01 2007-12-01 Sankyo Co The composition for treating glaucoma
US20020172693A1 (en) * 2000-03-31 2002-11-21 Delong Michell Anthony Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
CN103393483B (en) * 2006-03-31 2016-08-24 玛提治疗有限公司 Medicine release method, structure and composition for nose tear system
CN101505695A (en) * 2006-06-21 2009-08-12 庄臣及庄臣视力保护公司 Punctal plugs for the delivery of active agents
MX2010002616A (en) * 2007-09-07 2010-08-04 Qlt Plug Delivery Inc Drug cores for sustained release of therapeutic agents.
US9095404B2 (en) 2008-05-12 2015-08-04 University Of Utah Research Foundation Intraocular drug delivery device and associated methods
EP2303184A4 (en) 2008-06-24 2013-06-19 Quadra Logic Tech Inc Combination treatment of glaucoma
US20100158980A1 (en) 2008-12-18 2010-06-24 Casey Kopczynski Drug delivery devices for delivery of therapeutic agents
WO2012088306A2 (en) 2010-12-22 2012-06-28 Psivida Us, Inc. Two-piece injectable drug delivery device with heat-cured seal
US8715713B2 (en) * 2011-04-29 2014-05-06 Allergan, Inc. Solvent cast film sustained release latanoprost implant
DK3290024T3 (en) * 2011-08-29 2019-06-03 Mati Therapeutics Inc CONTINUING SUBMISSION OF ACTIVE RESOURCES FOR TREATMENT OF GLAUCUM AND OCULAR HYPERTENSION
BR112014027296B1 (en) 2012-05-03 2022-09-13 Kala Pharmaceuticals, Inc PHARMACEUTICAL NANOPARTICLES SHOWING IMPROVED MUCOSAL TRANSPORT
US20160022695A1 (en) * 2013-03-27 2016-01-28 Forsight Vision5, Inc. Bimatoprost Ocular Silicone Inserts and Methods of Use Thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080181930A1 (en) * 2007-01-31 2008-07-31 Alcon Research, Ltd. Punctal Plugs and Methods of Delivering Therapeutic Agents
US20090306595A1 (en) * 2008-05-08 2009-12-10 Jason Shih Implantable drug-delivery devices, and apparatus and methods for filling the devices
US20130142858A1 (en) * 2010-05-17 2013-06-06 Aerie Pharmaceuticals, Inc. Drug delivery devices for delivery of ocular therapeutic agents

Also Published As

Publication number Publication date
KR102511830B1 (en) 2023-03-17
US10471070B2 (en) 2019-11-12
EP3223793A1 (en) 2017-10-04
JP6686023B2 (en) 2020-04-22
JP2017535592A (en) 2017-11-30
EP3223793A4 (en) 2018-08-01
CA2968926C (en) 2023-01-17
CN107645951A (en) 2018-01-30
KR20170103776A (en) 2017-09-13
CN107645951B (en) 2021-05-04
US20210137942A1 (en) 2021-05-13
EP3223793B1 (en) 2023-06-28
CA2968926A1 (en) 2016-06-02
WO2016083891A1 (en) 2016-06-02
US20170266200A1 (en) 2017-09-21

Similar Documents

Publication Publication Date Title
US20210137942A1 (en) Devices and methods for delivering a bio-active agent or bio-active agents
US10130589B2 (en) Polyvinylpyrrolidone for the stabilization of a solid dispersion of the non-crystalline form of rotigotine
ES2248622T3 (en) MEDICINAL PRODUCT CONTAINING 3- (3-DIMETHYLAMINE-1-ETIL-2-METHYLPROPIL) PHENOL AND PROVIDING A DELAYED RELEASE OF THE ACTIVE PRINCIPLE.
CN1239152C (en) Therapeutic formulation for administering tolterodine with controlled release
EP1928424B1 (en) Controlled release pharmaceutical composition of venlafaxine hydrochloride, and process for preparation thereof
KR20000029530A (en) Tramadol multiple unit formulations
CA2861947A1 (en) A drug delivery system
WO2002078604A2 (en) Transdermal delivery of bioactive material
JP2023113647A (en) Compositions and methods for delivering antibiotic macrolide, for treating dry eye syndrome
KR20080106358A (en) Controlled release formulation of tolterodine
US20220125791A1 (en) Novel devices
WO2006117803A2 (en) Transmucosal drug delivery systems
JP2017019880A (en) Sustained release formulations of lorazepam
RU2745045C1 (en) New carrier particles for dry powder compositions for inhalation
US10010511B2 (en) Transdermal drug delivery system
RU2097026C1 (en) Medicinal agent for prevention and arresting bronchial asthma attack and medicinal formula

Legal Events

Date Code Title Description
STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

AS Assignment

Owner name: EXIMORE LTD., ISRAEL

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SHEETRIT, EYAL;HALAHMI, IZHAR;ATTAR, ISHAY;REEL/FRAME:052838/0814

Effective date: 20170521

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION