Classifications

• • 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
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
• • 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
  • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
  • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
• • 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
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• • 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
  • 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
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
  • A61K31/5578—Eicosanoids, e.g. leukotrienes or prostaglandins having a pentalene ring system, e.g. carbacyclin, iloprost
• • 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
• • 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
  • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
  • A61K9/0092—Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
• • 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
  • A61K9/20—Pills, tablets, discs, rods
• • 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
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• the present invention relates to sustained release implants for intraocular use, which implants are configured for primarily intracameral administration but also intrascleral, intracorneal, anterior vitreal administration to a patient suffering from an intraocular condition, said implant comprising a core of a drug, for treating said condition, surrounded by a polymer, which limits the rate of passage of the drug from the implant into the eye of said patient.
• matrix drug delivery systems such as microspheres and implants, where the active
• the present invention provides a sustained release implant for intraocular use and, in particular, to treat elevated intraocular pressure, which implant is configured for intracameral or anterior vitreal administration to a patient with an ocular condition, e.g. elevated intraocular pressure (IOP), said implant comprising a core of an ocular drug. e.g. an antihypertensive agent, surrounded by a polymer, which limits the rate of passage of the drug or antihypertensive agent from the implant into the eye of said patient and said implant provides a linear rate of release of therapeutically effective amounts of said anti-hypertensive agent into the eye for a period of time of between approximately 14 days and 365 days.
• IOP elevated intraocular pressure
• a reservoir implant suitable for releasing a hypotensive lipid comprising a core made with a mixture of a hypotensive lipid and a biodegradable polymer, e.g. a polycaprolactone, or a nonbiodegradible polymer, e.g. a silicone elastomer, and/or an excipient, e.g. a surfactant such as a tri block copolymers of ethylene oxide and propylene oxide or an ethylene oxide adduct of a fatty acid or alcohol, extruded into thin filaments and coated with the rate limiting polymer, e.g. cellulose acetate, wherein said reservoir implant provides a linear release rate of hypotensive lipid over a period of 12 days or more.
• a biodegradable polymer e.g. a polycaprolactone
• a nonbiodegradible polymer e.g. a silicone elastomer
• an excipient e.g. a
• a reservoir implant suitable for releasing a hypotensive lipid, said implant comprising a core of said hypotensive lipid centrally located in a silicone tube having the ends closed by an impermeable ethylene vinyl acetate polymer, wherein the drug elutes from the sides of the silicone tube to provide a linear release over a period of 21 days or more.
• Figure 1 shows a matrix drug delivery system, as formed, and during the initial
• Figure 2 shows the reservoir drug delivery system, as formed, and during the initial dissolving stage after placement in the eye.
• Figure 3 shows the implant, described in Example 1, releasing the API, isopropyl 5- ⁇ 3-
• Figure 4 shows a reservoir implant, as described in Example 1, releases a hypotensive lipid after being placed intracamerally in a dog to reduce the intraocular pressure approximately
• Figure 5 shows, a reservoir implant, as described in Example 1, releases a hypotensive lipid after being placed intravitreally in a dog to reduce the intraocular pressure to
• Figure 7 shows, a reservoir implant, as described in example 2, releases a hypotensive lipid after being placed intracamerally in a dog to reduce the intraocular pressure to
• hypotensive lipid after being placed sub-Tenon's in a dog to reduce the intraocular pressure to approximately a maximum of 18 to 20% below baseline over the initial 2 weeks.
• Figure 10 shows sub-Tenon's reservoir implants (arrow) releasing an EP2 agonist as described in Example 2.
• Figure 12 describes certain implants of the invention comprising varying amounts of bimatoprost in the core surrounded by a polycaprolactone hollow tube of varying wall thicknesses.
• Figure 13 shows the release rates of certain of the implants of Figure 12.
• Figure 14 shows the release rates of certain of the implants of Figure 12.
• Figure 15 shows the release rates of certain of the implants of Figure 12.
• the drug delivery system comprises an implant (10) configured for implantation in the anterior vitreal, space which implant comprises a core (11), which, in the embodiment shown in this figure, is fabricated as a bundle of individual fibers (15), said fibers comprising a drug for treating an ocular condition.
• Said drug may be combined with one or more excipients to form a mixture and the mixture extruded into fibers, which fibers are bundled to form a contiguous body to provide the core of the implant.
• the core is surrounded by a polymer (15) which is permeable to the drug and controls the passage of the drug from the core into the eye in which the implant is placed.
• the rate limiting polymer completely surrounds the drug-containing core.
• the advantage of a reservoir drug delivery system over matrix drug delivery systems is that the reservoir delivers a smaller initial drug burst followed by a steady-state release rate that persists until the majority of the drug reservoir is depleted.
• the release rate is directly proportional to both the surface area of the implant, the diffusivity (i.e. the diffusion coefficient of the drug through the rate-limiting polymers), and indirectly proportional to the thickness of the surrounding polymers.
• the drug release from the reservoir implant can be tuned to the desired release rate by altering the surface area of drug diffusion, changing the polymer, and/or varying the thickness of the polymer coating.
• Another advantage of a reservoir implant is the ability to harbor large drug loads so that the implant can release for a minimum of 3 months and up to 5 years.
• the drug reservoirs and the rate-controlling polymer membranes can be fabricated using separate processes then assembled together to form implants. Mild fabrication process can be selected for making the drug reservoirs so that the activity and/or chemical integrity of the drugs or pharmaceutical agents in the reservoirs are protected from harsh conditions (high temperature and high shearing force) that may be needed for melt extrusion. Therefore, drug degradation is minimized. This is particularly useful for delivery of heat-labile drug compounds.
• the rate-controlling membranes can also shield the drugs in the reservoirs from enzymatic degradation.
• the drug reservoirs can contain drug, only, or a mixture of drug and excipients.
• excipients can be incorporated in the formulations of the said drug reservoirs. These include, but are not limited to, surfactants, e.g. tri block copolymers of ethylene oxide and propylene oxide and ethylene oxide adducts of fatty acids or alcohols; anti-oxidants; pH modulating agents; bulking agents; osmotic agents; tonicity agents; disintegrating agents; binders, gliding agents; etc.
• surfactants e.g. tri block copolymers of ethylene oxide and propylene oxide and ethylene oxide adducts of fatty acids or alcohols
• anti-oxidants e.g. tri block copolymers of ethylene oxide and propylene oxide and ethylene oxide adducts of fatty acids or alcohols
• pH modulating agents e.g. tri block copolymers of ethylene oxide and propylene oxide and ethylene oxide adducts of fatty acids or alcohols
• bulking agents e.g. tri block copolymers of
• the said excipients can be selected from the following: Pluronic F68, Pluronic F127 (Polyoxamer 407), polysorbate 80, polysorbate 20, sodium dodecyl sulfate, hydroxypropyl-beta-cyclodextrin, poly(ethylene oxide), poly(ethylene glycol), polyvinylpyrrolidone, hydroxypropyl methylcellulose, carboxymethylcellulose, sodium phosphate, sodium chloride.
• the drug reservoirs can be fabricated using a various methods including compression, packing, and/or extrusion. The preferred surfactants are further described below:
• Poloxamer 407 is a triblock copolymer consisting of a central hydrophobic block of polypropylene glycol flanked by two hydrophilic blocks of polyethylene glycol. The approximate lengths of the two PEG blocks is 101 repeat units while the approximate length of the propylene glycol block is 56 repeat units. This particular compound is also known by the BASF trade name Pluronic F127.
• Poloxamer 188 also known as Pluronic F68, is also a triblock copolymer with a similar chemical structure to Poloxamer 407 containing a center block of polypropylene glycol (PPG) flanked by a poly(ethylene glycol) (PEG) block on each side.
• PPG polypropylene glycol
• PEG poly(ethylene glycol)
• the rate-controlling membranes surrounding the drug reservoirs can be made of non- degradable polymers including, but not limited to, silicone elastomers, poly(ethylene-co- vinylacetate), polyurethane, or biodegradable polymers such as aliphatic polyesters.
• the membranes can be fabricated by solution casting, spray coating, or melt extrusion.
• the implants can be fabricated in the following ways:
• the rate-controlling membranes are made of
• degradable aliphatic polyesters such as, but not limited to, poly(8-caprolactone), poly(D,L- lactide), poly(L-lactide), copolymers of lactones such as poly(D,L-lactide-co-glycolide), and mixtures of two or more of these polymers.
• the polymers can be melt-extruded or molded into capsules with one of the ends open. Drug reservoirs in their solid or liquid forms are then filled into the open-ended capsules and the open ends are subsequently sealed. The drug load can be released over time and the polymer structure bioerodes within ⁇ 6 to 12 months of drug release.
• the reservoir delivery systems can be also placed in the sub-Tenon's, subconjunctival, episcleral, intrascleral, suprachoroidal, intrachoroidal, and sub-retinal spaces.
• PCL Poly(s-caprolactone)
• s-caprolactone is a biodegradable aliphatic polyester. It is usually prepared by ring-opening polymerization of ⁇ -caprolactone using a catalyst such as stannous octoate.
• the chemical structure of PCL is as follows:
• -Hypotensive lipids e.g. bimatoprost and compounds set forth in U.S. Pat. No.
• the prostaglandin analogues increase uveoscleral outflow of aqueous humor and bimatoprost also increases trabecular outflow.
• -Miotic agents parasympathomimetics
• pilocarpine work by contraction of the ciliary muscle, tightening the trabecular meshwork and allowing increased outflow of the aqueous humor.
• -Carbonic anhydrase inhibitors like dorzolamide (Trusopt), brinzolamide (Azopt), acetazolamide (Diamox) lower secretion of aqueous humor by inhibiting carbonic anhydrase in the ciliary body.
• Combinations of ocular anti-hypertensives such as a beta blocker and a prostaglandin analogue, can also be used in the delivery systems. These include Ganfort
• an agent that confers neuroprotection can also be placed in the delivery system and includes memantine and serotonergics [e.g., 5- HT.sub.2 agonists, such as S-(+)-l-(2-aminopropyl)-indazole-6-ol)].
• memantine and serotonergics e.g., 5- HT.sub.2 agonists, such as S-(+)-l-(2-aminopropyl)-indazole-6-ol
• Non-antihypertensive agents can also be used, such as anti-VEGF compounds to treat anterior or posterior segment neovascularization, or corticosteroids to treat uveitis, macular edema, and neovascular diseases.
• the intraocular pressure was reduced approximately 30 to 45% below baseline for a minimum of 5 weeks (See Figure 4).
• a similar reservoir implant was placed intravitreally in a dog.
• the intraocular pressure was reduced to approximately a maximum of 15 to 20% below baseline over the initial 3 weeks (See Figure 5).
• phenyl ⁇ -5-oxypyrrolidin-2-yl]propyl ⁇ thiophene-2-carboxylate was formulated into a reservoir implant using a silicone tube, 1 mm in diameter.
• the drug reservoir was the API centrally located in tube and the ends were closed using ethylene vinyl acetate polymer. Implants with two effective lengths, 2 mm and 3 mm, were made.
• the drug loading was 563 ⁇ g in the 2 mm implants and 997 ⁇ g in the 3 mm implants. In vitro release rates of these implants were 6.3 ⁇ g/day and 9.3 ug/day for the 2 mm and 3 mm implants, respectively (See Figure 6).
• the drug elutes from the sides of the silicone tube with a linear release observed over a 21 day time period.
• Implantation of an implant was performed in the anterior chamber of a dog.
• An intracameral injection of an implant releasing at 6.3 ug/day was performed in a dog.
• the intracameral implant was well tolerated and biocompatible (See Figure 8).
• Three implants were placed in the sub-Tenon's space in a dog and the intraocular pressure was reduced to approximately a maximum of 18 to 20% below baseline over the initial 2 weeks (See Figure 9).
• the sub-Tenon's implants were well tolerated with no clinical signs of inflammation (See Figure 10).
• PCL Poly(8-caprolactone) (PCL) tubes with an inner diameter (ID) of 790 ⁇ and outer diameters (OD) of 1090 ⁇ and 1350 ⁇ were cut into 6 mm in length.
• ID inner diameter
• OD outer diameters
• In vitro release profiles are shown in Figure 11.
• the drug release rate was 46 ⁇ g/day for the implants with the outer diameter of 1090 ⁇ and 66 ⁇ g/day for the ones with the outer diameter of 1350 ⁇ .
• a sustained release implant comprising a core of an antihypertensive agent surrounded by a polymer, and configured for intracameral or anterior vitreal administration to a patient, is used to treat a patient with elevated intraocular pressure (IOP).
• IOP intraocular pressure
• the polymer utilized in said implant limits the rate of passage of the antihypertensive agent from the implant into the eye of the patient and provides a linear rate of release of therapeutically effective amounts of the antihypertensive into the eye for from 12 days to 365 days.
• the implant comprises a
• nonbiodegradable polymer selected from the group consisting of silicone elastomers, poly(ethylene-co-vinylacetate)and polyurethane. or the implant comprises a biodegradable polymer, i.e., an aliphatic polyester.
• epinephrine and dipivefrin miotic agents, i.e. pilocarpine; carbonic anhydrase inhibitors, i.e. dorzolamide, brinzolamide and acetazolamide; Rho-kinase inhibitors, i.e. Latrunculin B compound, PF-04217329, PF-03187207, AR-102, AL-6221, and AL-3789, calcium channel blockers, vasopressin-receptor antagonists, i.e. vaptans, anecortave acetate and analogues and ethacrynic acid and cannabinoids.
• miotic agents i.e. pilocarpine
• carbonic anhydrase inhibitors i.e. dorzolamide, brinzolamide and acetazolamide
• Rho-kinase inhibitors i.e. Latrunculin B compound, PF-04217329, PF-03187207, AR-
• the antihypertensive agent is a combination of ocular anti-hypertensives, and the combination is selected from the group consisting of bimatoprost/timolol, travoprost/timolol, latanoprost/timolol, brimonidine/timolol, and dorzolamide/timolol.
• the intraocular pressure is reduced approximately 30 to 45% below
• the intraocular pressure is reduced to approximately a maximum of 15 to 20% below baseline over the initial 3 weeks.
• the total drug loading is 200 ⁇ g.
• the drug release rate is 0.2 ⁇ g/day.
• a reservoir implant releasing a hypotensive lipid is used to treat an ocular condition.
• Said implant comprises a core of the hypotensive lipid centrally located in a silicone tube having the ends closed by an impermeable ethylene vinyl acetate polymer, wherein the drug elutes from the sides of the silicone tube to provide a linear release over a 21 day time period.
• the silicone tube has a diameter of 1 mm.
• the hypotensive lipid is an EP2 agonist.
• the intraocular pressure is reduced approximately 18 to 20% below baseline for a minimum of 2 weeks when placed in the sub-Tenon's space.
• a reservoir implant releasing a hypotensive lipid is used to treat an ocular condition.
• Said implant comprises a core of the hypotensive lipid centrally located in a polycaprolactone tube having the ends heat sealed wherein the drug elutes from the sides of the silicone tube to provide a linear release observed over a 14 day time period.
• the tube has an inner diameter of 790 ⁇ .
• the tube may has an outer diameter of 1090 ⁇ and releases drug at a rate of 46 ⁇ g/day or the tube has an outer diameter of 1350 ⁇ and releases drug at a rate of 66 ⁇ g/day.
• the implant comprises from about 10 to about 50 weight percent of the anti-hypertensive agent and from about 50 to about 90 weight percent of the polymer.
• PCL Poly(8-caprolactone) (PCL) tubes with inner diameters (ID) of 800 ⁇ and 1000 and an outer diameters (OD) of 980, 1150, 1170 and 1180 ⁇ were cut into 8 mm lengths.
• ID inner diameters
• OD outer diameters
• One of the open ends of the tubes was heat sealed and varying amounts, i.e. from about 0.08 to 0.4 mg., of bimatoprost were filled into each of the tubes using a syringe. (See Figure 12.) The open end was then heat sealed to form a capsule-like implant. In-vitro release profiles are shown in Figures 13 through 15.
• dissolution rate in the tubing is rate-determining step, as diffusion through the wall is fast and the release rate can be increased by increasing the filling.

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• 2011
  • 2011-04-05 RU RU2012146630/15A patent/RU2012146630A/ru not_active Application Discontinuation
  • 2011-04-05 AU AU2011237788A patent/AU2011237788A1/en not_active Abandoned
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  • 2011-04-05 CN CN201180023027.7A patent/CN102905688B/zh not_active Expired - Fee Related
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