US20200337990A1 - Hydrogel implants for lowering intraocular pressure - Google Patents

Hydrogel implants for lowering intraocular pressure Download PDF

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Publication number
US20200337990A1
US20200337990A1 US16/857,464 US202016857464A US2020337990A1 US 20200337990 A1 US20200337990 A1 US 20200337990A1 US 202016857464 A US202016857464 A US 202016857464A US 2020337990 A1 US2020337990 A1 US 2020337990A1
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Prior art keywords
peg
implant
travoprost
polymer network
hydrogel implant
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Michael Goldstein
Arthur Driscoll
Charles D. Blizzard
Ankita Desai
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Ocular Therapeutix Inc
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Ocular Therapeutix Inc
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Priority to US16/857,464 priority Critical patent/US20200337990A1/en
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Assigned to MIDCAP FINANCIAL TRUST, AS AGENT reassignment MIDCAP FINANCIAL TRUST, AS AGENT AMENDED AND RESTATED SECURITY INTEREST Assignors: OCULAR THERAPEUTIX, INC.
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Assigned to OCULAR THERAPEUTIX, INC. reassignment OCULAR THERAPEUTIX, INC. RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: MIDCAP FINANCIAL TRUST, AS AGENT
Priority to US18/384,564 priority patent/US20240165018A1/en
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    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • 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
    • 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

Definitions

  • Glaucoma is a group of eye disorders that lead to progressive damage to the optic nerve. Glaucoma is the second-leading cause of blindness in the United States and most often occurs in people over age 40. Although there are many theories on the cause of glaucoma, most associate the condition as a result of prolonged increase in the fluid pressure inside the eye. Indeed, lowering intraocular pressure (IOP) is a critical factor for slowing progression for both glaucoma and ocular hypertension. See e.g., Noecker R J, Ther Clin Risk Manag. 2006; 2(2):193-206.
  • IOP intraocular pressure
  • Prostaglandin analogues such travoprost are commonly used as the first line of therapy to effectively lower IOP.
  • limitations with the application of topical drops are serious issues affecting IOP control management.
  • sustained release ocular hydrogel implants comprising travoprost.
  • a single dose of the disclosed implants delivers sustained travoprost free acid levels through 4 months with drug depleted by 5 months. See e.g., FIG. 5 .
  • no statistically significant difference in central corneal thickness (CCT) was observed over 4 and 7 months. See e.g., FIGS. 3 and 4 .
  • FIG. 1 shows fluorescein visualization of a disclosed implant at 3 days in vivo in beagles residing in the inferior iridocorneal angle using cobalt-blue light illumination through a yellow filter.
  • FIG. 2 shows ultrasound images in beagles of a disclosed implant residing in the iridocorneal angle at 1 month and 3 months after injection.
  • FIG. 3 shows the central corneal thickness pre- and post-administration of a disclosed implant in beagles demonstrating no significant change over 7 months compared to baseline.
  • FIG. 4 shows the central corneal thickness pre- and post-administration of a disclosed implant in beagle eyes demonstrating no significant change over 4 months.
  • FIG. 5 shows the pharmacokinetics of travoprost released from a disclosed implant in vivo (rabbits) and in vitro over 5 months.
  • FIG. 6 shows in vitro release testing of an inventive implant over 147 days.
  • FIG. 7 shows the pharmacokinetics for travoprost free acid in the aqueous humor of beagle dogs following low and high dose administration of an inventive implant.
  • FIG. 8 shows a comparison of travoprost free acid in the aqueous humor of beagle dogs compared to the theoretical maximal concentration from in vitro release testing.
  • FIG. 9 shows the effect of selected concentrations of travoprost in beagles with primary open angle glaucoma on IOP.
  • FIG. 10 shows the effect of selected concentrations of travoprost on pupil diameter in beagles with primary open angle glaucoma.
  • FIG. 11 shows pre- and post-dose inventive implant administration IOP change relative to baseline for each test group over the study duration.
  • FIG. 12 shows the study design for primary open angle glaucoma or ocular hypertension trials using inventive implant.
  • FIG. 13A shows the mean IOP Change from Baseline, Cohort 1 from the study design for primary open angle glaucoma or ocular hypertension with measurements taken at 8AM.
  • FIG. 13B compares the mean IOP Change from Baseline of different loading concentrations of travoprost from the study design for primary open angle glaucoma or ocular hypertension.
  • FIG. 14 shows implant resorption over a clinical study in human eyes (top, left to right) Days 1, 14, 28, and (bottom) Month 4, 5, 6.
  • FIG. 15 illustrates the endothelial cell count over time for subjects administered inventive implant.
  • sustained release biodegradable hydrogel implants comprising travoprost and a polymer network.
  • biodegradable refers to a material, such as the disclosed hydrogel implants, which degrades in vivo. Degradation of the material occurs over time and may occur concurrently with, or subsequent to, release of travoprost. In one aspect, “biodegradable” means that complete dissolution of the implant occurs, i.e., there is no residual hydrogel implant matter in the eye. In an alternative aspect, degradation may occur independently of travoprost release such that e.g., residual travoprost remains following degradation.
  • polymer network refers to a group of polymers comprising multiple branch structures (also referred to as “arms”) cross-linked to other polymer chains.
  • the polymer chains may be of the same or different chemical structures, e.g., as in complementary or non-complementary repeating units.
  • Nomenclature for synthetic precursors used to generate the disclosed polymer networks are referenced using the number of arms followed by the MW of the PEG and then the reactive group (e.g., electrophile or nucleophile).
  • 4a20K PEG SAZ refers to a 20,000 Da PEG with 4 arms with a succinimidylazelate end group
  • 4a20K PEG SAP refers to a 20,000 Da PEG with 4 arms with a succinimidyladipate end group
  • 4a20K PEG SG refers to a 20,000 Da PEG with 4 arms with a succinimidylglutarate end group
  • 4a20K PEG SS refers to a 20,000 Da PEG with 4 arms with a succinimidylsuccinate end group, etc.
  • 4a20K PEG NH2 means a 20,000 Da PEG with 4 arms with an amine end group
  • 8a20K PEG NH2 means a 20,000 Da PEG with 8 arms with an amine end group,
  • si-crystalline refers to a polymer or polymer network which possesses some crystalline character, i.e., exhibits crystalline properties in thermal analysis, X-ray scattering or electron scattering experiments.
  • “semi-crystalline” polymers or networks of polymers have a highly ordered molecular structure with sharp melt points.
  • “semi-crystalline” polymers or networks of polymers do not gradually soften with a temperature increase and instead remain solid until a given quantity of heat is absorbed and then rapidly change into a rubber or liquid.
  • homogenously dispersed means the component, such as the travoprost, is uniformly dispersed throughout the hydrogel or polymer network.
  • treat refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disclosed condition (e.g., ocular hypertension or glaucoma), or one or more symptoms thereof, as described herein.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a particular organism, or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to delay their recurrence.
  • subject and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).
  • companion animals e.g., dogs, cats, and the like
  • farm animals e.g., cows, pigs, horses, sheep, goats and the like
  • laboratory animals e.g., rats, mice, guinea pigs and the like.
  • the subject is a human in need of treatment.
  • a sustained release biodegradable intracameral hydrogel implant comprising travoprost and a polymer network.
  • the polymer network of the disclosed hydrogel implant (e.g., as in the first embodiment) comprises a plurality of polyethylene glycol (PEG) units.
  • PEG polyethylene glycol
  • the plurality of polyethylene glycol (PEG) units included in the disclosed implants are cross-linked to form a polymer network comprising a plurality of multi-arm PEG units having at least 2 arms, wherein the remaining features of the implants are described herein e.g., as in the first or second embodiment.
  • the polymer network of the disclosed implants comprise a plurality of multi-arm PEG units having from 2 to 10 arms, wherein the remaining features of the implants are described herein e.g., as in the first or second embodiment.
  • the polymer network of the disclosed implants comprise a plurality of multi-arm PEG units having from 4 to 8 arms, wherein the remaining features of the implants are described herein e.g., as in the first or second embodiment.
  • the polymer network of the disclosed implants comprise a plurality of 4-arm PEG units, wherein the remaining features of the implants are described herein e.g., as in the first or second embodiment.
  • the polymer network of the disclosed implants comprise a plurality of 8-arm PEG units, wherein the remaining features of the implants are described herein e.g., as in the first or second embodiment.
  • the polymer network of the disclosed implants comprises a plurality of PEG units having a number average molecular weight (Mn) ranging from about 5 KDa to about 50 KDa, wherein the remaining features of the implants are described herein e.g., as in the first through third embodiments.
  • the polymer network of the disclosed implants comprise a plurality of PEG units having a number average molecular weight (Mn) ranging from about 5 KDa to about 40 KDa, wherein the remaining features of the implants are described herein e.g., as in the first through third embodiments.
  • the polymer network of the disclosed implants comprise a plurality of PEG units having a number average molecular weight (Mn) ranging from about 5 KDa to about 30 KDa, wherein the remaining features of the implants are described herein e.g., as in the first through third embodiments.
  • the polymer network of the disclosed implants comprise a plurality of PEG units having a number average molecular weight (Mn) ranging from about 10 KDa to about 50 KDa, wherein the remaining features of the implants are described herein e.g., as in the first through third embodiments.
  • the polymer network of the disclosed implants comprise a plurality of PEG units having a number average molecular weight (Mn) ranging from about 10 KDa to about 40 KDa, wherein the remaining features of the implants are described herein e.g., as in the first through third embodiments.
  • the polymer network of the disclosed implants comprise a plurality of PEG units having a number average molecular weight (Mn) ranging from about 10 KDa to about 30 KDa, wherein the remaining features of the implants are described herein e.g., as in the first through third embodiments.
  • the polymer network of the disclosed implants comprise a plurality of PEG units having a number average molecular weight (Mn) ranging from about 10 KDa to about 20 KDa, wherein the remaining features of the implants are described herein e.g., as in the first through third embodiments.
  • the polymer network of the disclosed implants comprise a plurality of PEG units having a number average molecular weight (Mn) ranging from about 30 KDa to about 50 KDa, wherein the remaining features of the implants are described herein e.g., as in the first through third embodiments.
  • the polymer network of the disclosed implants comprise a plurality of PEG units having a number average molecular weight (Mn) ranging from about 35 KDa to about 45 KDa, wherein the remaining features of the implants are described herein e.g., as in the first through third embodiments.
  • the polymer network of the disclosed implants comprise a plurality of PEG units having a number average molecular weight (Mn) ranging from about 15 KDa to about 30 KDa, wherein the remaining features of the implants are described herein e.g., as in the first through third embodiments.
  • the polymer network of the disclosed implants comprise a plurality of PEG units having a number average molecular weight (Mn) ranging from about 15 KDa to about 25 KDa, wherein the remaining features of the implants are described herein e.g., as in the first through third embodiments.
  • the polymer network of the disclosed implants comprise a plurality of PEG units having a number average molecular weight (Mn) of at least about 5 KDa, wherein the remaining features of the implants are described herein e.g., as in the first through third embodiments.
  • the polymer network of the disclosed implants comprise a plurality of PEG units having a number average molecular weight (Mn) of at least about 10 KDa, wherein the remaining features of the implants are described herein e.g., as in the first through third embodiments.
  • the polymer network of the disclosed implants comprise a plurality of PEG units having a number average molecular weight (Mn) of at least 15 about KDa, wherein the remaining features of the implants are described herein e.g., as in the first through third embodiments.
  • the polymer network of the disclosed implants comprise a plurality of PEG units having a number average molecular weight (Mn) of at least 20 about KDa, wherein the remaining features of the implants are described herein e.g., as in the first through third embodiments.
  • the polymer network of the disclosed implants comprise a plurality of PEG units having a number average molecular weight (Mn) of at least 30 about KDa, wherein the remaining features of the implants are described herein e.g., as in the first through third embodiments.
  • the polymer network of the disclosed implants comprise a plurality of PEG units having a number average molecular weight (Mn) of at least 40 about KDa, wherein the remaining features of the implants are described herein e.g., as in the first through third embodiments.
  • the polymer network of the disclosed implants comprise a plurality of PEG units having a number average molecular weight (Mn) of about 10 KDa, wherein the remaining features of the implants are described herein e.g., as in the first through third embodiments.
  • the polymer network of the disclosed implants comprise a plurality of PEG units having a number average molecular weight (Mn) of about 15 KDa, wherein the remaining features of the implants are described herein e.g., as in the first through third embodiments.
  • the polymer network of the disclosed implants comprise a plurality of PEG units having a number average molecular weight (Mn) of about 20 KDa, wherein the remaining features of the implants are described herein e.g., as in the first through third embodiments.
  • the polymer network of the disclosed implants comprise a plurality of PEG units having a number average molecular weight (Mn) of about 40 KDa, wherein the remaining features of the implants are described herein e.g., as in the first through third embodiments.
  • the polymer network of the disclosed implants comprise a plurality of PEG units crosslinked by a hydrolyzable linker, wherein the remaining features of the disclosed implants are described herein e.g., as in the first through fourth embodiments.
  • the polymer network of the disclosed implants comprise a plurality of PEG units crosslinked by a hydrolyzable linker having the formula:
  • the polymer network of the disclosed implants comprise a plurality of PEG units crosslinked by a hydrolyzable linker having the formula:
  • the polymer network of the disclosed implants comprise a plurality of PEG units having the formula:
  • the polymer network of the disclosed implants comprise a plurality of PEG units having the formula set forth above, but with an 8-arm PEG scaffold, wherein the remaining features of the implants are described herein e.g., as in the first through fourth embodiments.
  • the polymer network of the disclosed hydrogel implant is formed by reacting a plurality of polyethylene glycol (PEG) units comprising groups which are susceptible to nucleophilic attack with one or more nucleophilic groups to form the polymer network, wherein the remaining features of the hydrogel are described herein e.g., as in the first through fifth embodiments.
  • PEG polyethylene glycol
  • suitable groups which are susceptible to nucleophilic attack include, but art not limited to activated esters (e.g., thioesters, succinimidyl esters, benzotriazolyl esters, esters of acrylic acids, and the like).
  • suitable nucleophilic groups include, but art not limited to, amines and thiols.
  • the polymer network of the disclosed hydrogel implant is formed by reacting a plurality of polyethylene glycol (PEG) units, each having a molecule weight as described above in the fourth embodiment and which comprise groups which are susceptible to nucleophilic attack, with one or more nucleophilic groups to form the polymer network, wherein the remaining features of the hydrogel are described herein e.g., as in the first through sixth embodiments.
  • PEG polyethylene glycol
  • the polymer network of the disclosed hydrogel implant is formed by reacting a plurality of polyethylene glycol (PEG) units, each having a molecule weight as described above in the fourth embodiment and which comprise a succinimidyl ester group, with one or more nucleophilic groups to form the polymer network, wherein the remaining features of the hydrogel are described herein e.g., as in the first through sixth embodiments.
  • PEG polyethylene glycol
  • the polymer network of the disclosed hydrogel implant is formed by reacting a plurality of polyethylene glycol (PEG) units selected from 4a20K PEG SAZ, 4a20K PEG SAP, 4a20K PEG SG, 4a20K PEG SS, 8a20K PEG SAZ, 8a20K PEG SAP, 8a20K PEG SG, 8a20K PEG SS, wherein the remaining features of the hydrogel are described herein e.g., as in the first through sixth embodiments.
  • PEG polyethylene glycol
  • the polymer network of the disclosed hydrogel implant is formed by reacting a plurality of polyethylene glycol (PEG) units comprising groups which are susceptible to nucleophilic attack with one or more amine groups to form the polymer network, wherein the remaining features of the hydrogel are described herein e.g., as in the first through seventh embodiments.
  • the polymer network of the disclosed hydrogel implant is formed by reacting a plurality of polyethylene glycol (PEG) units comprising groups which are susceptible to nucleophilic attack with one or more PEG or Lysine based-amine groups to form the polymer network, wherein the remaining features of the hydrogel are described herein e.g., as in the first through seventh embodiments.
  • the polymer network of the disclosed hydrogel implant is formed by reacting a plurality of polyethylene glycol (PEG) units comprising groups which are susceptible to nucleophilic attack with one or more PEG or Lysine based-amine groups selected from 4a20K PEG NH2, 8a20K PEG NH2, and trilysine, or salts thereof, wherein the remaining features of the hydrogel are described herein e.g., as in the first through seventh embodiments.
  • PEG polyethylene glycol
  • the polymer network of the disclosed implants are amorphous (e.g., under aqueous conditions such as in vivo), wherein the remaining features of the implants are described herein e.g., as in the first through eighth embodiments.
  • the polymer network of the disclosed implants are semi-crystalline (e.g., in the absence of water), wherein the remaining features of the compositions are described herein e.g., as in the first through eighth embodiments.
  • the travoprost of the disclosed implants is homogenously dispersed within the polymer network, wherein the remaining features of the implants are described herein e.g., as in the first through ninth embodiments.
  • the travoprost is delivered to the eye in a sustained manner for a period ranging from about 1 month to about 1 year, wherein the remaining features of the implants are described herein e.g., as in the first through tenth embodiments.
  • the travoprost is delivered to the eye in a sustained manner for a period ranging from about 1 month to about 11 months, wherein the remaining features of the implants are described herein e.g., as in the first through tenth embodiments.
  • the travoprost is delivered to the eye in a sustained manner for a period ranging from about 1 month to about 10 months, wherein the remaining features of the implants are described herein e.g., as in the first through tenth embodiments.
  • the travoprost is delivered to the eye in a sustained manner for a period ranging from about 1 month to about 9 months, wherein the remaining features of the implants are described herein e.g., as in the first through tenth embodiments.
  • the travoprost is delivered to the eye in a sustained manner for a period ranging from about 1 month to about 8 months, wherein the remaining features of the implants are described herein e.g., as in the first through tenth embodiments.
  • the travoprost is delivered to the eye in a sustained manner for a period ranging from about 2 month to about 8 months, wherein the remaining features of the implants are described herein e.g., as in the first through tenth embodiments.
  • the travoprost is delivered to the eye in a sustained manner for a period ranging from about 3 month to about 7 months, wherein the remaining features of the implants are described herein e.g., as in the first through tenth embodiments.
  • the travoprost is delivered to the eye in a sustained manner for a period ranging from about 4 month to about 6 months, wherein the remaining features of the implants are described herein e.g., as in the first through tenth embodiments.
  • the travoprost is delivered to the eye in a sustained manner for a period of about 1 month, wherein the remaining features of the implants are described herein e.g., as in the first through tenth embodiments.
  • the travoprost is delivered to the eye in a sustained manner for a period of about 2 months, wherein the remaining features of the implants are described herein e.g., as in the first through tenth embodiments.
  • the travoprost is delivered to the eye in a sustained manner for a period of about 3 months, wherein the remaining features of the implants are described herein e.g., as in the first through tenth embodiments.
  • the travoprost is delivered to the eye in a sustained manner for a period of about 4 months, wherein the remaining features of the implants are described herein e.g., as in the first through tenth embodiments.
  • the travoprost is delivered to the eye in a sustained manner for a period of about 5 months, wherein the remaining features of the implants are described herein e.g., as in the first through tenth embodiments.
  • the travoprost is delivered to the eye in a sustained manner for a period of about 6 months, wherein the remaining features of the implants are described herein e.g., as in the first through tenth embodiments.
  • sustained release of the travoprost occurs in the aqueous humor, wherein the remaining features of the implants are described herein e.g., as in the first through eleventh embodiments.
  • travoprost in the disclosed implants is microencapsulated, wherein the remaining features of the implants are described herein e.g., as in the first through eleventh embodiments.
  • travoprost in the disclosed implants is microencapsulated with poly(lactic-co-glycolic acid) (PLGA) or poly(lactic acid) (PLA), or a combination thereof, wherein the remaining features of the implants are described herein e.g., as in the first through eleventh embodiments.
  • PLGA poly(lactic-co-glycolic acid)
  • PLA poly(lactic acid)
  • travoprost in the disclosed implants is microencapsulated with PLA, wherein the remaining features of the implants are described herein e.g., as in the first through eleventh embodiments.
  • the polymer network of the disclosed hydrogel implants is conjugated to fluorescein, wherein the remaining features of the implants are described herein e.g., as in the first through twelfth embodiments.
  • the disclosed implants are designed for implantation near the corneal endothelial cells, wherein the remaining features of the implants are described herein e.g., as in the first through thirteenth embodiments.
  • the disclosed implants are designed for implantation in the inferior iridocorneal angle, wherein the remaining features of the implants are described herein e.g., as in the first through fourteenth embodiments.
  • the disclosed implants comprise 5 ⁇ g, 15 ⁇ g or 26 ⁇ g of travoprost, wherein the remaining features of the implants are described herein e.g., as in the first through fifteenth embodiments.
  • the disclosed implants comprise 5 ⁇ g, 15 ⁇ g or 26 ⁇ g of travoprost; and comprises a polymer networks formed by reacting a plurality of polyethylene glycol (PEG) units comprising groups which are susceptible to nucleophilic attack with one or more PEG or Lysine based-amine groups selected from 4a20K PEG NH2, 8a20K PEG NH2, and trilysine, wherein the remaining features of the hydrogel are described herein e.g., as in the first through seventh embodiments.
  • PEG polyethylene glycol
  • the disclosed implants are fully degraded following complete release of travoprost, wherein the remaining features of the implants are described herein e.g., as in the first through fifteenth embodiments.
  • the hydrogel implant is fully degraded after about 12 months, after about 11 months, after about 10 months, after about 9 months, after about 8 months, after about 6 months, after about 5 months, after about 4 months, after about 3 months, after about 2 months, after about 1 month (i.e., after about 30 days) following complete release of travoprost, wherein the remaining features of the implants are described herein e.g., as in the first through fifteenth embodiments.
  • the hydrogel implant is fully degraded following at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) release of travoprost, wherein the remaining features of the implants are described herein e.g., as in the first through fifteenth embodiments.
  • the disclosed implants are useful in lowering ocular pressure.
  • methods of lowering ocular pressure in a subject in need thereof comprising administering a hydrogel implant described herein.
  • a disclosed implant for lowering ocular pressure in a subject comprising administering a hydrogel implant described herein.
  • a disclosed implant for lowering ocular pressure in a subject comprising administering a hydrogel implant described herein.
  • a disclosed implant for lowering ocular pressure in a subject comprising administering a hydrogel implant described herein.
  • a disclosed implant for lowering ocular pressure in a subject comprising administering a hydrogel implant described herein.
  • a disclosed implant for lowering ocular pressure in a subject comprising administering a hydrogel implant described herein.
  • a disclosed implant for lowering ocular pressure in a subject comprising administering a hydrogel implant described herein.
  • a disclosed implant for lowering ocular pressure in a subject comprising administering a hydrogel implant described herein.
  • Also provided are methods of treating ocular hypertension in a subject in need thereof comprising administering a hydrogel implant described herein. Also disclosed in the use of a disclosed implant for treating ocular hypertension in a subject. Further provided is the use of a disclosed implant in the manufacture of a medicament for treating ocular hypertension.
  • Intracameral Depot comprises travoprost as the active pharmaceutical ingredient (API), polylactide (PLA) microparticles which provide sustained delivery of the API and 8-arm polyethylene glycol (PEG) based hydrogel conjugated with fluorescein which serves as the inactive delivery platform.
  • API active pharmaceutical ingredient
  • PLA polylactide
  • PEG polyethylene glycol
  • Microparticle Encapsulation Step Manufacturing Action 1 Prepare Polyvinyl Alcohol (PVA) stock solution in water. 2 Prepare dispersed phase (DP) by dissolving travoprost and PLA in dichloromethane (DCM). 3 Prepare continuous phase (CP) by diluting the PVA stock solution with water in a reactor and mix using an overhead mixer. Prepare CP with DCM in a separate reactor if required (for 4A, 7A, 9A, 5.5E PLA). 4 Inject the travoprost/PLA solution (DP) at the inlet of the homogenizer through a cannula positioned perpendicular to the flow of the continuous phase. After homogenization, the nascent microparticles flow into the quench reactor.
  • PVA Polyvinyl Alcohol
  • DP dispersed phase
  • CP continuous phase
  • CP continuous phase
  • CP continuous phase
  • 4 Inject the travoprost/PLA solution (DP) at the inlet of the homogenizer through a cannula
  • TLA Trilysine Acetate
  • FL NHS Fluorescein
  • Step Manufacturing Action 1 Prepare syringe assemblies, package in foil pouches and sterilize. 2 Attach a needle to the pre-sterilized syringe assembly and poke a hole through the luer hub of the needle. 3 Cut an appropriate size wire and feed it into the tip of the needle. Ensure the wire is flush with the tip of the needle. Withdraw the plunger and ensure the wire sits on top of the plunger in upright position. Clip the syringe lock onto the plunger. 4 Insert a single implant into the needle. Insert a second piece of wire into the tip of the wire. Place the protective cap on the needle. 5 Place the syringe kit assembly in the foil pouch with the needle cap oriented away from the opening of the foil pouch.
  • Example 1 Pharmacokinetic Release of Travoprost Using an Inventive Hydrogel Implant
  • In vivo drug release was assessed by collecting aqueous humor samples from 6 eyes at Days 34 and 63, and 12 eyes at Days 91, 126 and 153. Drug concentrations in the aqueous humor were measured by LC/MS/MS.
  • In vitro drug release was assessed in physiologically representative conditions (PBS with a surfactant (polyoxyl hydrogenated castor oil 40), pH 7.4, 37° C.) at Days 28, 63, 92, 119, and 126, and analyzed by UPLC/UV. Pharmacokinetic findings are shown below and in Table 1 and FIG. 5 .
  • Aqueous humor sample in rabbits demonstrated elevated travoprost free acid level post-injection through 3-4 months and an absence at 5 months.
  • the inventive implant released approximately 25% of the travoprost sustained dose in vitro each month for 4 months.
  • the decrease in travoprost free acid concentration observed at 4 months aligns with the decrease in in vitro release rate observed at 4 months.
  • inventive implant drug concentrations of 10.9, 20.0, and 8.7 ng/mL at 1, 2, and 3 months are comparable to or exceed the maximum travoprost free acid concentration of 10.2 ⁇ 3.0 ng/mL from a single drop administration of Travoprost Z (travoprost solution/drops Alcon laboratories) in rabbits at 1 hour, as reported in the literature (Travatan Z NDA 21-994).
  • Longer release durations e.g., >6 months
  • Inventive hydrogel implant containing 18 ⁇ g travoprost per implant and designed to degrade over time providing sustained release of travoprost over 4-6 months, was injected via a 27 gauge needle into the lower portion of the anterior chamber on Day 0 (Table 2), where the implant resides in the iridocorneal angle.
  • the purpose of the study was to inject the inventive hydrogel implant containing either 5 ⁇ g, 15 ⁇ g or 26 ⁇ g of the active ingredient travoprost into the anterior chamber of beagle dogs and collect aqueous humor and plasma samples over time to assess the travoprost and travoprost free acid pharmacokinetic profile using the same batch of hydrogel test articles containing 18 ⁇ g of travoprost per implant that was assessed in the 120-day Intracameral Ocular Toxicity Study in Beagle Dogs.
  • a secondary assessment for pharmacodynamic evaluation measured the intraocular pressure and pupil diameter over the study duration.
  • a safety evaluation included daily clinical observations and daily ocular irritation assessments over the study duration.
  • travoprost prodrug ester
  • travoprost free acid active
  • AH aqueous humor
  • Travoprost and travoprost free acid concentrations were measured in beagle AH that were collected pre-dose and post-dose (1 and 4 hours, and at 2, 4, 6, 8, 10, 12, 14 and 16 weeks) to determine pharmacokinetics of drug levels in AH.
  • the LOQ for this method is 0.05 ng/mL and values less than the LOQ are reported as zero.
  • Test results are presented in Table 3.
  • the T max for travoprost occurs 1 hour post dose with a reported mean C max of 68.7 ng/mL.
  • the T max for travoprost free acid occurs 4 hours post dose with a reported mean C max of 16.7 ng/mL.
  • the TFA levels in beagles were an average of 1.4 ng/mL (range 0.3 to 4.2 ng/mL) for the 18 ⁇ g dosage strength from Days 1 to 112.
  • the T max aligns with the in vitro burst release from inventive implant, which occurs within 1 day of dissolution testing in release media.
  • Steady state drug release (zero-order kinetics) from inventive implant is observed from Day 1 through 4 months during dissolution testing in release media, as seen in FIG. 6 .
  • the in vitro release of the test articles studied was performed in biorelevant conditions that utilized a dissolution media of 1 ⁇ PBS, 0.5% polyoxyl 40 hydrogenated castor oil, 0.01% sodium fluoride, pH 7.2-7.4 performed at 37° C.
  • the polyoxyl 40 hydrogenated castor oil is added as a nonionic surfactant to aid travoprost solubility to ensure sink conditions and it is used for this purpose to aid solubility in commercial Travatan® eye drop formulations. Because of the duration of the release test, sodium fluoride is added as a bacteriostatic agent to the release media.
  • the basis of travoprost release from inventive implant is the degradation of the PLA microparticles to lower molecular weights by ester hydrolysis in the presence of water and the subsequent release of the entrapped travoprost from within the microparticles.
  • inventive implant comprising travoprost in male beagle dogs over a 7-month period at two dosage strengths.
  • Drug levels of travoprost (prodrug ester) and travoprost free acid (active) in aqueous humor (AH) released from inventive implant were determined in beagles over the study duration to generate pharmacokinetic profiles.
  • Sample analysis was performed using a validated LC-MS/MS assay method. The LOQ for this method is 0.050 ng/mL and values less than the LOQ are reported as zero.
  • Travoprost and travoprost free acid (TFA) concentrations were measured as ⁇ LOQ for all pre-dose AH samples.
  • the travoprost ester form in the AH was ⁇ LOQ for all study timepoints and only TFA levels above the LOQ were observed. It has been demonstrated that travoprost released from a sustained released intracameral depot converts to the active travoprost free acid form in the aqueous humor within the anterior chamber of normotensive beagle eyes.
  • the mean TFA results for both dosage strengths are presented in FIG. 7 .
  • Results demonstrate an average TFA concentration with standard deviations in the beagle AH of 1.1 ⁇ 0.2 ng/mL for the low dosage strength and 3.0 ⁇ 0.8 ng/mL for the high dosage strength through 120 days. Following 120 days the values drop to 0.1 ng/mL for both dosage strengths and then are below the LOQ for the remainder of the study.
  • a comparison between the travoprost concentrations released in vitro was made to the concentrations measured in vivo in the beagle AH over the study duration.
  • the amount of travoprost released from the test articles in vitro was converted to daily concentrations by determining the daily amount of travoprost mass released between sampling points in vitro divided by the aqueous humor daily flow rate in beagles (8.5 mL/day).
  • the in vitro value approximates the theoretical maximal concentration of cumulative travoprost and/or TFA in the beagle AH. This is plotted on the right side y-axis in FIG. 8 and compared to the PK profiles previously presented in FIG.
  • Results demonstrate an approximate 10-fold difference in concentration for both dosage strengths between the in vivo TFA levels and the in vitro cumulative travoprost levels over the study duration. This is an early demonstration of an in vitro/in vivo relationship, showing an approximate bioavailability of 10% in an animal model that is maintained over the study duration at two different dosage strengths. The remaining 90% of released travoprost most likely passes directly into outflow pathways due to close proximity in the inferior angle.
  • a dose relationship is established since the 3 ⁇ difference in TFA concentrations in the AH correlates with the 3 ⁇ difference in dose between the low (14 ⁇ g) and high (41 ⁇ g) strengths assessed in this study.
  • a Travatan® eye drop is a 25 uL drop size at 40 ug/mL or 1 ug per drop and it is administered once per day.
  • a single and twice a day dose of 0.3 ⁇ g travoprost has been demonstrated to reduce IOP by 19-26% and 19%-30% in lasered hypertensive cynomolgus monkeys, respectively.
  • a single dose of 0.1 ⁇ g travoprost did not significantly lower IOP, however continued twice a day dosing at 0.1 ⁇ g resulted in significant lowering of IOP after doses 4 and 5 (Travatan NDA 021257 Pharmacology Review). This IOP reduction observed in the monkey with more frequent low dose delivery of travoprost augments the basis for efficacy via sustained drug delivery from the inventive (travoprost) implant.
  • a pharmacodynamic study performed in twelve glaucomatous beagles evaluated the changes in intraocular pressure (IOP) and pupil diameter (PD) after instillations of 0.033, 0.0033, 0.001, 0.00033, and 0.0001% travoprost in multiple single-dose studies.
  • This suggests travoprost is effective in the dog to lower IOP and reduce pupil size at concentrations starting between 0.0001 and 0.00033% (1/12 the commercially available concentration).
  • only the ⁇ 0.001% travoprost dosage strength maintained IOP reduction for 24 hours and no dosage strength maintained pupil constriction for 24 hours.
  • the purpose of the study was to inject inventive implant into the anterior chamber of beagle dogs and collect aqueous humor and plasma samples over time to assess the travoprost and travoprost free acid pharmacokinetic profile using the same batch of inventive implant test articles containing 18 ⁇ g of travoprost per implant that was assessed in the 120-day Intracameral Ocular Toxicity Study in Beagle Dogs.
  • a secondary assessment for pharmacodynamic evaluation measured the intraocular pressure and pupil diameter over the study duration is discussed in this section.
  • a safety evaluation included daily clinical observations and daily ocular irritation assessments over the study duration.
  • IOP measurements taken pre- and post-administration of inventive implant are presented in Table 4. All animals received the same inventive implant test article and were divided into four groups for pharmacokinetic sampling purposes. Results demonstrate a mean baseline of IOP of 19 mmHg followed by an IOP reduction to 11 mmHg ( ⁇ 42%) at 1 month, 13 mmHg ( ⁇ 32%) at 2-months, 12 mmHg ( ⁇ 37%) at 3-months and 15 mmHg ( ⁇ 21%) at 4 months demonstrating the intended primary pharmacodynamic response of IOP reduction post administration over the study duration.
  • Travoprost is a miotic agent in beagles demonstrating strong pupil constriction after administration of inventive implant.
  • Pupil diameter measurements taken pre- and post-administration of inventive implant over the study duration are presented in Table 5.
  • Results demonstrate sustained pupil constriction following inventive implant administration demonstrating a secondary pharmacodynamic response in beagles over the 4-month study duration.
  • the Group 2 hydrogel formulation composition was the same as tested in Cohorts A (15 ⁇ g travoprost dose) and B (26 ⁇ g travoprost dose) in the Phase 1 clinical study.
  • Intraocular pressure was measured using a TonoVet® tonometer and pupil diameter was measured using an embossed pictorial scale on a penlight with both measurements done pre- and monthly post-dose administration.
  • IOP results for each study group are reported in Table 6 and graphically represented as mean IOP change relative to baseline in FIG. 11 .
  • Pupil diameter results for each study group are reported in Table 7.
  • the median visual persistence of the Group 1 implant was 2 months and the Group 2 implant was 4 months.
  • the Group 2 duration is consistent with a median persistence finding of 4 months in a previous beagle study.
  • IOP results demonstrate that the 2-month persisting hydrogel implant (Group 1) created a similar decrease in IOP compared to the 4-month persisting hydrogel implant (Group 2) through 4 months, and statistically the mean difference from baseline IOP results were within one-standard deviation between the two formulations, see Table 6 and FIG. 11 .
  • the IOP decrease at 3 months between the present hydrogel (Group 2) or absent hydrogel (Group 1) made no difference on the IOP reduction from baseline, whereby the Group 1 hydrogel had been absent for 1 month in most eyes indicating that travoprost release from the microparticles was still regulating IOP reduction in the anterior chamber of the beagle eye.
  • Both travoprost containing hydrogel formulations demonstrated a greater decrease in IOP compared to the control article (Group 3).
  • Example 5 Safety, Tolerability and Efficacy of Inventive (Travoprost) Implant in Subjects with Primary Open-Angle Glaucoma or Ocular Hypertension
  • a 4-month low dose (15 ⁇ g) or high dose (26 ⁇ g) of travoprost encapsulated in microparticles (4A/7A/9A/5.5E) was formulated in a 12% inventive hydrogel comprising a polymer matrix formed from 8a15K PEG-SAZ and trilysine with the 12% being the PEG weight dived by the fluid weight times 100 and was injected via 27G needle into the anterior chamber of 10 subjects over 7 months; one eye per patient treated. See FIG. 12 .
  • Patient population was controlled ocular hypertension or primary open-angle glaucoma; open, normal anterior chamber angles on gonioscopy.
  • Mean IOP values were decreased in patients receiving both OTX-TIC and topical travoprost as early as two days following administration ( FIGS. 13A and 13B ). In patients receiving OTX-TIC, mean IOP was decreased approximately 5-11 mmHg from Day 3 through Month 9. Mean IOP values remained decreased from baseline values through the study period (Month 7) and beyond (Month 9) in two of two patients.
  • implant Upon injection, implant hydrated quickly and resided in the iridocorneal angle. The implant was visualized in all subjects at all visits through 7 months ( FIG. 14 ). The implant was not observed to move at slit lamp; in one subject, there was slight rotation noted at the Day 14 visit as compared to the Day 7 visit. Implant biodegraded in 2 of 2 subjects by Month 7.

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US11622935B2 (en) 2020-02-06 2023-04-11 Ocular Therapeutix, Inc. Methods of treating ocular diseases using polyalkylene glycol intracameral implants with polyactide travoprost particles

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US10226417B2 (en) * 2011-09-16 2019-03-12 Peter Jarrett Drug delivery systems and applications
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US20210228408A1 (en) * 2015-07-23 2021-07-29 Allergan, Inc. Glaucoma Treatment Via Intracameral Ocular Implants
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