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WO2025096944A1 - Systèmes pour l'administration intraoculaire prolongée d'inhibiteurs de la double leucine zipper kinase et de la leucine zipper kinase - Google Patents

Systèmes pour l'administration intraoculaire prolongée d'inhibiteurs de la double leucine zipper kinase et de la leucine zipper kinase Download PDF

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Publication number
WO2025096944A1
WO2025096944A1 PCT/US2024/054121 US2024054121W WO2025096944A1 WO 2025096944 A1 WO2025096944 A1 WO 2025096944A1 US 2024054121 W US2024054121 W US 2024054121W WO 2025096944 A1 WO2025096944 A1 WO 2025096944A1
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Prior art keywords
cyclodextrin
formulation
dlk
lzk
inhibitor
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Thomas Malone
K. Angela Macfarlane
Anne Brody Rubin
Larry A. Wheeler
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Perceive Pharma Inc
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Perceive Pharma Inc
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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/10—Dispersions; Emulsions

Definitions

  • the present invention generally relates to systems for the sustained intraocular delivery of a Dual Leucine Zipper Kinase (DLK) and Leucine Zipper Kinase (LZK) inhibitor.
  • the system can include a therapeutic device and a formulation of a DLK and/or LZK inhibitor capable of delivering drug for a sustained period of time.
  • the system can extend the half-life of the DLK and/or LZK inhibitor by delivering the formulation by diffusion from a therapeutic device.
  • Glaucoma is a neurodegenerative disease that affects millions of patients and results in damage to retinal ganglion cells (RGCs) whose axons comprise the optic nerve.
  • Glaucoma is a neurodegenerative disease of the retinal ganglion cells (RGCs) that occurs when the RGCs’ axons are under stress, often from elevated intraocular pressure (TOP).
  • TOP intraocular pressure
  • Currently, all approved pharmacotherapies treat glaucoma by lowering TOP as their mechanism of action. It is estimated that 53 million people in the world have primary open angle glaucoma (POAG) with a prevalence of 3.0% in the population aged 40 to 80 years. (Gedde 2021).
  • POAG primary open angle glaucoma
  • DLK and/or LZK inhibitors may be useful in treating ophthalmological neurodegeneration disorders
  • systems and formulations of such inhibitors that can be administered to the eye of a patient.
  • the preparation of a formulation of a therapeutic agent with low solubility can present major challenges. These challenges are exacerbated when delivering such a composition to the eye of a patient, which has a unique anatomy and physiology. Therefore, there is a need for formulations and delivery systems, which can provide relative non-invasive prolonged delivery of a DLK and/or LZK inhibitor to target tissues of the eye.
  • the present invention generally relates to systems for the sustained intraocular delivery of a DLK and/or LZK inhibitor.
  • the system can include a therapeutic device and a formulation of a DLK and/or LZK inhibitor capable of delivering drug for a sustained period of time.
  • the system can extend the duration of effect of the DLK and/or LZK inhibitor by delivering the formulation by diffusion from a therapeutic device.
  • the system can comprise a therapeutic device for intravitreal delivery of a DLK and/or LZK inhibitor and formulations comprising the DLK and/or LZK inhibitor.
  • the device implanted in the eye comprises a reservoir chamber to store the DLK and/or LZK inhibitor and a porous structure coupled to the reservoir chamber to release the DLK and/or LZK inhibitor into the vitreous humor or the aqueous humor of the eye.
  • the components of a particular device such as a refillable sustained release therapeutic device, and the formulation when adjusted or tuned to achieve a stability and concentration of the DLK and/or LZK inhibitor can achieve a desired delivery release rate of the DLK and/or LZK inhibitor.
  • the formulation of the DLK and/or LZK inhibitor can achieve high solubility and concentration of the active ingredient from the device.
  • the formulation of the DLK and/or LZK inhibitor can be a suspension which upon dissolution can achieve high concentration of active ingredient released from the device.
  • the formulation can achieve and maintain a desired concentration of the DLK and/or LZK inhibitor in the vitreous for an extended period of time after delivery.
  • the release rate of the DLK and/or LZK inhibitor can be modified from the reservoir of a therapeutic device to achieve the desired sustained release profile and desired vitreous concentration levels.
  • the modification can be achieved by the design of a Port Delivery System implant, which includes a porous structure for controlling DLK and/or LZK inhibitor release.
  • the porous structure can have porosity and tortuosity, further having geometrical dimensions.
  • the modification of the release rate of the DLK and/or LZK inhibitor can be achieved by varying the reservoir volume and/or the porosity of the release control element of the implant.
  • the composition of the DLK and/or LZK inhibitor can also be modified to increase stability and concentration of the active ingredient in the formulation and to control the rate of delivery from the reservoir.
  • modifying the DLK and/or LZK inhibitor release rate depends on the formulation type (e.g., suspension versus solution) and formulation components, such as the type and concentration of the complexing agent and/or the concentration of the DLK and/or LZK inhibitor in the reservoir.
  • modifying the DLK and/or LZK inhibitor release rate of depends on modification of the porosity of the release control element of the implant.
  • modifying the DLK and/or LZK inhibitor release rate can be achieved by increasing or decreasing the particle size distribution of the DLK and/or LZK inhibitor suspension formulation.
  • a system comprising a therapeutic device and a formulation comprising a DLK and/or LZK inhibitor, wherein the formulation is contained in the device.
  • the device has a reservoir chamber coupled to a porous structure for controlled release of the DLK and/or LZK inhibitor in the vitreous of the eye after the system is placed or inserted into the eye.
  • the formulation is placed in the reservoir either before or after insertion of the implant into the eye, and the controlled release of the DLK and/or LZK inhibitor and formulation agents from the reservoir diffuse through the porous structure increasing the duration of effect of the DLK and/or LZK inhibitor in the vitreous based on the desired, predetermined rate.
  • the DLK and/or LZK inhibitor is selected from the group consisting of PB 1-069, PB 1-287, PBL671, and PBL743.
  • the concentration of the DLK and/or LZK inhibitor in the reservoir is about 1 to about 100 mg/ml, from about 1 to about 50 mg/ml, from about 1 to about 40 mg/ml, from about 1 to about 30 mg/ml, from about 2 to about 50 mg/ml, from about 3 to about 50 mg/ml, from about 4 to about 50 mg/ml, from about 5 to about 50 mg/ml, from about 8 to about 35 mg/ml, or from about 8 to about 26 mg/ml.
  • the concentration of the DLK and/or LZK inhibitor in the reservoir is about 9 mg/mL. In certain embodiments, the concentration of the DLK and/or LZK inhibitor in the reservoir is about 18 mg/mL. In certain embodiments, the concentration of the DLK and/or LZK inhibitor in the reservoir is about 20 mg/mL. In certain embodiments, the concentration of the DLK and/or LZK inhibitor in the reservoir is about 26 mg/mL. In certain embodiments, the concentration of the DLK and/or LZK inhibitor in the reservoir is about 35 mg/mL.
  • the formulation comprises one or more complexing agents.
  • the complexing agent is selected from the group consisting of 2- hydroxypropyl-P-cyclodextrin, methyl-P-cyclodextrin, randomly methylated-P-cyclodextrin, ethylated-P-cyclodextrin, triacetyl- P -cyclodextrin, peracetylated-P-cyclodextrin, carboxymethyl- P-cyclodextrin, hydroxyethyl-P-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-P- cyclodextrin, glucosyl-P-cyclodextrin, maltosyl-P-cyclodextrin, sulfobutyl ether-P-cyclodextrin, branched-P-cyclodextrin, hydroxypropyl-y-cyclodextr
  • the complexing agent is selected from the group consisting of sulfobutyl ether-P-cyclodextrin, 2-hydroxypropyl-P-cyclodextrin, and randomly methylated-P- cyclodextrin.
  • the ratio of active ingredient to complexing agent is in the range of about 1:1 to about 1:5, 1:1 to about 1:10, 1:1 to about 1:15, 1:1 to about 1:20, 1:1 to about 1:120, 1:5 to about 1:120, about 1:10 to about 1:120, about 1:50 to about 1:120, about 1:60 to about 1 : 120, about 1 :70 to about 1 : 120, or about 1 :80 to about 1 : 120 of DLK and/or LZK inhibitor: complexing agent.
  • the formulation agents comprise one or more solubilizing agents, stabilizing agents, pH adjusting agents, and/or buffering agents.
  • the pH adjusting agent is selected from the group consisting of sodium hydroxide, hydrochloric acid, citric acid, malic acid, tartaric acid, acetic acid, phosphoric acid, maleic acid, glycine, sodium lactate, lactic acid, sodium citrate, ascorbic acid, sodium acetate, acetic acid, sodium bicarbonate, sodium carbonate, carbonic acid, sodium succinate, succinic acid, sodium benzoate, benzoic acid, sodium phosphates, tris(hydroxymethyl)aminomethane, histidine, histidine hydrochloride, and combinations thereof.
  • the pH of the formulation is between about 5.5 and about 8.0.
  • the formulation comprises a suspension of a DLK and/or LZK inhibitor.
  • the formulation comprises a DLK and/or LZK inhibitor and sodium hyaluronate.
  • the DLK and/or LZK inhibitor is selected from the group consisting of PBL069, PBL287, PBI-671, and PBL743.
  • the pharmaceutical formulation can comprise the DLK and LZK inhibitor in an amount between about 0.1% to about 25.0% w/v or an amount between about 0.7% to about 2.0% w/v.
  • the formulation composition comprises 0.7% w/v or 2.0% w/v of the DLK and LZK inhibitor.
  • the DLK and LZK inhibitor has a particle size less than about 150 pm. In certain embodiments, the DLK and LZK inhibitor has a particle size less than about 50 pm.
  • the DLK and/or LZK inhibitor is delivered for up to about twelve months after the system is inserted into the eye of a subject. In certain embodiments, the DLK and/or LZK inhibitor is delivered for up to about nine months after the system is inserted into the eye of a subject. In certain embodiments, the DLK and/or LZK inhibitor is delivered for up to about six months after the system is inserted into the eye of a subject. In certain embodiments, the DLK and/or LZK inhibitor is delivered for up to about five months after the system is inserted into the eye of a subject. In certain embodiments, the DLK and/or LZK inhibitor is delivered for up to about four months after the system is inserted into the eye of a subject.
  • the DLK and/or LZK inhibitor is delivered for up to about three months after the system is inserted into the eye of a subject. DLK and/or LZK. In certain embodiments, the DLK and/or LZK inhibitor is delivered for up to about two months after the system is inserted into the eye of a subject. In certain embodiments, the DLK and/or LZK inhibitor is delivered for up to about one month after the system is inserted into the eye of a subject.
  • the DLK and/or LZK inhibitor is released at a release rate of about 0.1-50 pg/day from the porous structure after the device is inserted into the eye. In certain embodiments, the DLK and/or LZK inhibitor is released at a release rate of about 0.1 pg/day to about 25 pg/day. In certain embodiments, the DLK and/or LZK inhibitor is released at a release rate of about 0.5 pg/day to about 10 pg/day. In certain embodiments, the DLK and/or LZK inhibitor is released at a release rate of about 0.5 pg/day to about 5 pg/day. In certain embodiments, the DLK and/or LZK inhibitor is released at a release rate of about 0.5 pg/day to about 3 pg/day.
  • the therapeutic device comprises a drug load of the DLK and/or LZK inhibitor of about 50 pg to about 3000 pg. In certain embodiments, the therapeutic device comprises a drug load of the DLK and/or LZK inhibitor of about 50 pg to about 1500 pg.
  • the therapeutic device comprises a drug load of the DLK and/or LZK inhibitor of about 50 g to about 1200 g. In certain embodiments, the therapeutic device comprises a drug load of the DLK and/or LZK inhibitor of about 50 pg to about 1000 pg. In certain embodiments, the therapeutic device comprises a drug load of the DLK and/or LZK inhibitor of about 100 pg to about 1200 pg. In certain embodiments, the therapeutic device comprises a drug load of the DLK and/or LZK inhibitor of about 150 pg to about 900 pg. In certain embodiments, the therapeutic device comprises a drug load of the DLK and/or LZK inhibitor of about 50 pg to about 650 pg.
  • the therapeutic device comprises a drug load of the DLK and/or LZK inhibitor of about 150 pg to about 650 pg. In certain embodiments, the therapeutic device comprises a drug load of the DLK and/or LZK inhibitor of about 150 pg to about 600 pg.
  • a method of treating a subject comprises implanting a therapeutic device into the eye of a patient suffering from an ophthalmological neurodegenerative disorder.
  • the therapeutic device comprises a reservoir chamber and a porous structure, the reservoir chamber having a volume sized to receive an injection of an amount of a formulation of a DLK and/or LZK inhibitor, and the porous structure is configured to release an effective dose of the DLK and/or LZK inhibitor into the vitreous humor of the eye.
  • the formulation is injected into the reservoir chamber before the device is inserted into the eye.
  • the formulation can be any one of the formulations described herein.
  • the ophthalmological neurodegenerative disorder is selected from the group consisting of glaucoma, inherited retinal degenerations, Leber’s hereditary optic neuropathy, non-exudative AMD/geographic atrophy, retinal vascular diseases that produce ischemia (diabetes, vein occlusion), retinal detachments and edema-producing diseases (including exudative AMD).
  • the solution comprising the DLK and/or LZK inhibitor is cleared from the vitreous of a patient at a rate of between about 5 ml/day to about 25 ml/day.
  • the solution comprising the DLK and/or LZK inhibitor is cleared from the vitreous of a patient at a rate of between about 13 ml/day to about 20 ml/day. In certain embodiments, the solution comprising the DLK and/or LZK inhibitor is cleared from the vitreous of a patient at a rate of between about 14.5 ml/day to about 17.5 ml/day.
  • FIG. 1 is a therapeutic device implanted within the sclera of the eye such that a therapeutic drug can be administered to the vitreous of a patient.
  • FIG. 2 is a therapeutic device configured for placement into the eye of a patient.
  • FIG. 3 is a phase-solubility plot providing the solubility of PBI-287 (mg/ml) in different concentrations (%) of cyclodextrins, including sulfobutylether P-cyclodextrin (SBECD), 2-hydroxypropyl p-cyclodextrin (HPBCD), 2-hyxroxypropyl y-cyclodextrin (HPGCD), randomly methylated P-cyclodextrin (RAMEB), and 20% (w/v) for 'y-cyclodextrin (GCD).
  • SBECD sulfobutylether P-cyclodextrin
  • HPBCD 2-hydroxypropyl p-cyclodextrin
  • HPGCD 2-hyxroxypropyl y-cyclodextrin
  • RAMEB randomly methylated P-cyclodextrin
  • GCD w/v
  • FIG. 4 is a phase-solubility plot providing the solubility of PBL671 (mg/ml) in different concentrations (%) of cyclodextrins, including sulfobutylether P-cyclodextrin
  • SBECD 2-hydroxypropyl P-cyclodextrin
  • HPBCD 2-hydroxypropyl P-cyclodextrin
  • HPGCD 2-hyxroxypropyl y-cyclodextrin
  • RAMEB randomly methylated P-cyclodextrin
  • GCD y-cyclodextrin
  • FIG. 5 shows the phase solubility profile of PBI-671 in CAPTISOL®, a commercially available sulfobutylether P-cyclodextrin, wherein the x-axis denotes the concentration of CAPTISOL® and the y-axis denotes the concentration of PBI-671.
  • FIG. 6 is a flow diagram showing an exemplary method of manufacture for a pharmaceutical formulation.
  • FIG. 7 is an accelerated dissolution plot providing the dissolution profile over time (minutes) of PBI-671 in sodium hyaluronate at different particle sizes.
  • an active ingredient includes a single ingredient and two or more different ingredients.
  • agent is used herein to include any other compound that may be contained in or combined with one or more of the disclosed inhibitors that is not a therapeutically or biologically active compound. As such, an agent should be pharmaceutically or biologically acceptable or relevant (for example, an agent should generally be non-toxic to the subject).
  • agent includes a single such compound and is also intended to include a plurality of agents.
  • agent and carrier are used interchangeably throughout the description of the present disclosure and said terms are defined herein as, “ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition.”
  • composition and “formulation” are used interchangeably and refer to the conventional understanding, as known in the art, of a composition or formulation.
  • composition or “formulation” as used herein comprises a therapeutic agent or agents and formulation or composition excipients.
  • DLK and/or LZK inhibitor delivery device and “Port Delivery System” are used interchangeably herein.
  • the “DLK and/or LZK inhibitor delivery device” or “Port Delivery System” contemplates any variation of the disclosed device designed to achieve the objectives disclosed herein.
  • “DLK and/or LZK inhibitor delivery device” or “Port Delivery System” may have a design to include an opening, a diffusion barrier, a diffusion mechanism so as to release therapeutic amounts of DLK and/or LZK inhibitor for extended periods of time, e.g., 30 days, 60 days, 90 days, 6 months, 9 months, 12 months or more.
  • DLK and/or LZK inhibitor delivery device or Port Delivery System examples have been disclosed in WO2013/003620, U.S. Patent No. 8,277,830, U.S. Patent No. 9,968,603, and U.S. Patent No. 11,642,310, each of which is incorporated by reference herein in its entirety.
  • the term “effective” refers to an amount of a compound, agent, substance, formulation or composition that is of sufficient quantity to result in a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.
  • the amount may be as a single dose or according to a multiple dose regimen, alone or in combination with other compounds, agents or substances.
  • a pharmaceutically acceptable component is one that has been approved by a regulatory agency of the Federal or a state government or listed in the U.S.
  • a “formulation” according to the invention may be present in the form of a composition, wherein the different active ingredients and diluents and/or carriers are mixed with each other, or may take the form of a combined preparation, where the active ingredients are present in partially or totally distinct form.
  • An example for such a combination or combined preparation is a kit-of-parts.
  • PBI-069 refers to 2-Amino-N-[(2S)-butan- 2-yl]-7-(l - ⁇ 2-methyl-l-[6-(trifluoromethyl)pyridin-3-yl]propyl ⁇ -lH-pyrazol-4- yl)[l,2,4]triazolo[l,5-a]pyridine-5-carboxamide.
  • PBI-287 refers to 2-Amino-N-[(2S)-butan-
  • PBI-671 refers to 1,1 -Dimethylethyl 4-[(S)- [4-[2-amino-8-[[[( 15)-l-methylpropyl]amino]carbonyl][ 1 ,2,4]triazolo[ l,5-a]pyridin-6-yl]- 1H- pyrazol-l-yl][6-(trifluoromethyl)-3-pyridinyl]methyl]-l-piperidinecarboxylate.
  • PB 1-743 refers to 6-(l- ⁇ (l-Acetylpiperidin- 4-yl)[6-(trifhioromethyl)pyridin-3-yl]methyl ⁇ -lH-pyrazol-4-yl)-2-amino-N-[(2S)-butan-2- yl] [ 1 ,2,4]triazolo[ 1 ,5-a]pyridine-8-carboxamide.
  • the terms “patient” or “subject” most are used interchangeably, refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans.
  • the terms “patient” or “subject” may include any mammal that may benefit from the compounds described herein.
  • the subject is a human.
  • the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.
  • a “therapeutic amount” or “therapeutically effective amount” is an amount of a therapeutic agent sufficient to achieve the intended purpose.
  • the effective amount of a given therapeutic agent will vary with factors such as the nature of the agent, the route of administration, the size of the subject to receive the therapeutic agent, and the purpose of the administration.
  • treat means accomplishing one or more of the following: (a) reducing the severity and/or duration of the disorder; (b) limiting or preventing development of symptoms characteristic of the disorder(s) being treated; (c) inhibiting worsening of symptoms characteristic of the disorder(s) being treated; (d) limiting or preventing recurrence of the disorder(s) in patients that have previously had the disorder(s); and (e) limiting or preventing recurrence of symptoms in patients that were previously symptomatic for the disorder(s).
  • w/v represents the relative concentration of the components in the composition as “weight to volume.”
  • w/w represents the relative concentration of the components in the composition as “weight to weight” (i.e., percentage refers to percentage of total weight), rather than based on volume or other quantities.
  • the present invention generally relates to systems for the sustained intraocular delivery of a DLK and/or LZK inhibitor.
  • the system can include a therapeutic device comprising a formulation of a DLK and/or LZK inhibitor capable of delivering drug for a sustained period of time.
  • the system can extend the duration of effect of the DLK and/or LZK inhibitor by delivering the formulation by diffusion from a therapeutic device.
  • the system can comprise a therapeutic device, such as one of the therapeutic devices described herein, and a formulation, such as one of the formulations described herein.
  • the formulation can comprise a DLK and/or LZK inhibitor and a complexing agent contained in a reservoir chamber of the therapeutic device coupled to a release control element for controlled release of the DLK and/or LZK inhibitor at the vitreous of the eye.
  • the formulation can also comprise a DLK and/or LZK inhibitor as a suspension contained in a reservoir chamber of the therapeutic device coupled to a release control element for controlled release of the DLK and/or LZK inhibitor at the vitreous of the eye.
  • DLK and/or LZK Inhibitors are also comprised in a suspension contained in a reservoir chamber of the therapeutic device coupled to a release control element for controlled release of the DLK and/or LZK inhibitor at the vitreous of the eye.
  • the DLK and/or LZK inhibitor can be one of the compounds disclosed in U.S. Patent Publication No. 2023/0086702, which is incorporated by reference herein.
  • the active ingredient can include one of the compounds disclosed in WO 2022/081522A1, which is incorporated by reference herein.
  • the DLK and/or LZK inhibitor is one of the pyrazole containing compounds disclosed herein.
  • the pyrazole amide compounds disclosed herein display potent DLK and/or LZK activity.
  • the pyrazole containing compounds all displayed neuroprotective in vivo activity in the Optic Nerve Crush Target Engagement Assay (“ONC”) when administered via intravitreal administration.
  • ONC Optic Nerve Crush Target Engagement Assay
  • the DLK and/or LZK inhibitor is a compound having the structure of Formula (I): in which
  • X is nitrogen and Y is carbon, or
  • X is carbon and Y is nitrogen, R 1 and R 2 are each independently hydrogen or (Ci-C3)-alkyl,
  • R 3 is (Ci-Ce)-alkyl, (C3-C7)-cycloalkyl or (C3-C?)-cycloalkyl-(Ci-C3)-alkyl wherein the (Ci-Ce)- alkyl, (C3-C7)-cycloalkyl, or (C3-C7)-cycloalkyl-(Ci-C3)-alkyl may be substituted by hydroxyl, (Ci-C4)-alkoxy, oxo, cyano, chlorine, bromine, or up to three times by fluorine, where (C1-C4)- alkoxy may be substituted up to three times by fluorine, or
  • R 1 is hydrogen and R 2 and R 3 are joined to one another and, taken together with the carbon atom to which they are attached, form a 4- to 7-membered ring containing up to two heteroatoms selected from the group consisting of O or N, wherein the ring may be substituted by hydroxyl, (Ci-C4)-alkoxy, (Ci-C4)-alkyl, oxo, cyano, chlorine, bromine, or fluorine, where (Ci-C4)-alkoxy and (Ci-C4)-alkyl may be substituted up to three times by fluorine,
  • R 4 is hydrogen, (Ci-Ce)-alkyl, (C3-C7)-cycloalkyl or 4- to 7-membered heterocyclyl wherein the (Ci-Cfi)-alkyl, (C3-C7)-cycloalkyl or 4- to 7-membered heterocyclyl may be substituted by (Ci- C4)-alkyl, (Ci-C4)-alkoxy, oxo, cyano, chlorine, bromine or up to three times by fluorine, where (Ci-C4)-alkoxy and (Ci-C4)-alkyl may be substituted up to three times by fluorine, and the nitrogen of a 4- to 7-membered heterocyclyl may be substituted by C(O)OR 6 or C(O)R 6 , R 5 is (C3-C7)-cycloalkyl, phenyl or heteroaryl wherein the (C3-C7)-cycloalkyl, phenyl or heteroaryl may be substitute
  • R 4 and R 5 are joined to one another and, taken together with the carbon atom to which they are attached, form a 4- to 7-membered ring containing up to two heteroatoms selected from the group consisting of O or N, wherein the ring may be substituted by benzyl, 4- to 7-membered heterocyclyl, (Ci-C4)-alkyl, (Ci-C4)-alkoxy, oxo, cyano, chlorine, bromine or up to three times by fluorine, or may be annelated with phenyl or heteroaryl where (Ci-C4)-alkyl is optionally substituted by 4- to 7-membered heterocyclyl or up to three times by fluorine, and the nitrogen of each of the 4- to 7-membered heterocyclyls may independently be substituted by C(O)OR 6 or C(O)R 6 ,
  • R 6 is (Ci-C 4 )-alkyl, or a salt, solvate or solvate of the salt thereof.
  • the DLK and/or LZK inhibitor is a compound having the structure of Formula (II): wherein
  • X is nitrogen and Y is carbon, or
  • X is carbon and Y is nitrogen
  • R E is hydrogen, -C(O)-NR A R B , C(O)OR 6 , -S(O) 2 NH(Ci-C 6 )-alkyl, (Ci-C 6 )-alkyl, halo, (C 6 -
  • Cio -aryl, or heteroaryl, wherein the (Ci-C6)-alkyl, (C6-Cio)-aryl, and heteroaryl can be substituted by one or more independently selected (Ci-C4)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)- cycloalkyl-(Ci-C3)-alkyl, 4- to 7-membered heterocyclyl, (Ci-C4)-alkoxy, (C3-C7)-cycloalkoxy, - SO2R 4 , -NR 4 R 5 , cyano, hydroxyl, or halo, wherein the (Ci-C4)-alkyl, (C3-C7)-cycloalkyl, (Ci- C4)-alkoxy, (C3-C7)-cycloalkyl-(Ci-C3)-alkyl, and (C3-C7)-cycloalkoxy can be substituted by one or more independently selected hydroxyl,
  • R A is hydrogen or -CR 1 R 2 R 3 ,
  • R B is hydrogen or (Ci-C6)-alkyl
  • R 1 and R 2 are each independently hydrogen or (Ci-C3)-alkyl, wherein the (Ci-C3)-alkyl can be substituted by one or more independently selected halo,
  • R 3 is hydrogen, (Ci-Ce)-alkyl, (C3-C7)-cycloalkyl, or (C3-C7)-cycloalkyl-(Ci-C3)-alkyl, wherein the (Ci-Ce)-alkyl, (C3-C7)-cycloalkyl, or (C3-C7)-cycloalkyl-(Ci-C3)-alkyl can be substituted by one or more independently selected hydroxyl, (Ci-C4)-alkoxy, oxo, cyano, or halo, and wherein the (Ci-C4)-alkoxy can be substituted by one or more independently selected halo, or
  • R 1 is hydrogen and R 2 and R 3 are joined to one another and, taken together with the carbon atom to which they are attached, form a 3- to 7-membered ring containing up to two heteroatoms selected from the group consisting of O or N, wherein the ring can be substituted by one or more independently selected hydroxyl, (Ci-C4)-alkoxy, (Ci-C4)-alkyl, oxo, cyano, or halo, and wherein the (Ci-C4)-alkoxy and (Ci-C4)-alkyl can be substituted by one or more independently selected hydroxyl or halo,
  • R c is hydrogen, (C6-Cio)-aryl, or CR 4 R 5 R 7 , wherein the (C6-Cio)-aryl is optionally substituted by one or more independently selected (Ci-C4)-alkyl, (Ci-C4)-alkoxy, or halo, and wherein the (Ci-C4)-alkyl and (Ci-C4)-alkoxy can be substituted by one or more independently selected hydroxyl or halo,
  • R 4 is hydrogen, (Ci-Cej-alkyl, (C3-C7)-cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the (Ci-Ce)-alkyl, (C3-C7)-cycloalkyl, or 4- to 7-membered heterocyclyl can be substituted by one or more independently selected (Ci-C4)-alkyl, (Ci-C4)-alkoxy, hydroxyl, oxo, cyano, or halo, wherein the (Ci-C4)-alkoxy and (Ci-C4)-alkyl can be substituted by one or more independently selected halo, and any nitrogen of the 4- to 7-membered heterocyclyl can be substituted by C(O)OR 6 or C(O)R 6 ,
  • R 5 is (Ci-C6)-alkyl, (C3-C?)-cycloalkyl, cyanomethyl, (C6-Cio)-aryl, (C6-Cio)-aryl-(Ci-C4)- alkyl, heteroaryl, or 4- to 7-membered heterocyclyl wherein:
  • (i) the (Ci-C6)-alkyl, (C -C7)-cycloalkyl, (Ce-Cio)-aryl, (C6-Cio)-aryl-(Ci-C4)-alkyl, heteroaryl, or 4- to 7-membered heterocyclyl can be substituted by one or more independently selected (Ci-C4)-alkyl, (Ci-C4)-alkoxy, C(O)OR 6 , (C3-C7)-cycloalkoxy, cyano, 4- to 7-membered heterocyclyl, or halo, and wherein the (Ci-C4)-alkyl and (Ci- C4)-alkoxy can be substituted by one or more independently selected 4- to 7-membered heterocyclyl optionally substituted with oxo or (Ci-C4)-alkyl, (Ci-C4)-alkoxy, -NR’R”, or halo, and
  • the (ii) the (C3-C7)-cycloalkyl, (C6-Cio)-aryl, (C6-Cio)-aryl-(Ci-C4)-alkyl, heteroaryl, or 4- to 7-membered heterocyclyl can be fused with a 4- to 7-membered heterocyclyl or (C3-C7)- cycloalkyl, or
  • R 4 and R 5 are joined to one another and, taken together with the carbon atom to which they are attached, form a 3- to 8-membered monocyclic or bridged bicyclic ring containing up to two heteroatoms selected from the group consisting of O or N, wherein:
  • the ring can be substituted by one or more independently selected (C6-Cio)-aryl-(Ci- C4)-alkyl, (Ce-Cio)-aryl, 4- to 7-membered heterocyclyl, (Ci-C4)-alkyl, (Ci-C4)-alkoxy, oxo, cyano, or halo, wherein the (Ci-C4)-alkyl and (C6-Cio)-aryl can be substituted by one or more independently selected 4- to 7-membered heterocyclyl, (Ci-C4)-alkoxy, or halo, and the nitrogen of each of the 4- to 7-membered heterocyclyl can independently be substituted by C(O)OR 6 or C(O)R 6 , and
  • the ring can be fused with (C6-Cio)-aryl, heteroaryl, or 4- to 7-membered heterocyclyl, each of which is optionally substituted with one or more independently selected (Ci-Cri-alkoxy or halo, or
  • R 6 is hydrogen or (Ci-C4)-alkyl
  • R 7 is hydrogen, (Ci-C6)-alkyl, (C3-C7)-cycloalkyl, (C6-Cio)-aryl, or 4- to 7-membered heterocyclyl, wherein the (Ci-C6)-alkyl, (Ca-Cvj-cycloalkyl, (C6-Cio)-aryl, or 4- to 7-membered heterocyclyl can be substituted by one or more independently selected (Ci-C4)-alkyl, (C1-C4)- alkoxy, oxo, cyano, or halo, wherein the (Ci-C4)-alkoxy and (Ci-C4)-alkyl can be substituted by one or more independently selected halo, and the nitrogen of the 4- to 7-membered heterocyclyl can be substituted by C(O)OR 6 or C(O)R 6 ,
  • R D is hydrogen or (Ci-Ce)-alkyl, or
  • R c and R D are joined to one another and, taken together with the carbon atom to which they are attached, form a 4- to 10-membered monocyclic or bicyclic ring containing up to three heteroatoms selected from the group consisting of O or N, and wherein the 4- to 10-membered monocyclic or bicyclic ring is optionally substituted with one or more independently selected (Ci-Cej-alkyl or (Ci-C4)-alkoxy,
  • Z is -NHR F or H
  • R F is hydrogen or (Ci-Cej-alkyl, wherein the (Ci-Cej-alkyl is optionally substituted with one or more independently selected -NR’R”, each occurrence of R’ and R” is selected from hydrogen and (Ci-C4)-alkyl, or R’ and R”, joined to one another and, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclyl,
  • R G is hydrogen or halo
  • R H is hydrogen, halo, or (Ci-C4)-alkyl, and salts, solvates, and solvates of salts thereof.
  • the DLK and/or LZK inhibitor is a compound having the following molecular structure:
  • the compound has the chemical name 2-Amino-N-[(2S)-butan-2-yl]-7- ⁇ l-[2- methyl-l-phenylpropyl]-lH-pyrazol-4-yl][l,2,4]triazolo[l,5-a]pyridine-5-carboxamide.
  • the compound exhibited a DLK IC50 (nM) of 1.1 and an LZK IC50 (nM) of 18. This compound is disclosed as Example 1-26 in U.S. Patent Publication No. 2023/0086702, which is incorporated by reference herein.
  • the DLK and/or LZK inhibitor is a compound having the following molecular structure:
  • the compound has the chemical name 2-Amino-N-[(2S)-butan-2-yl]-6- ⁇ l-[l-(4- fluorophenyl)-2-methylpropyl]- lH-pyrazol-4-yl ⁇ [ 1 ,2,4]triazolo[ 1 ,5-a]pyridine-8-carboxamide.
  • the compound exhibited a DLK IC50 (nM) of 1.3 and an LZK IC50 (nM) of 32.
  • This compound is disclosed as Example 1-45 in U.S. Patent Publication No. 2023/0086702, which is incorporated by reference herein.
  • the DLK and/or LZK inhibitor is a compound having the following molecular structure:
  • the compound has the chemical name 2-Amino-N-[(2S)-butan-2-yl]-6- ⁇ l-[l-(5-chloropyridin-3- yl)-2-methylpropyl]-lH-pyrazol-4-yl ⁇ [l,2,4]triazolo[l,5-a]pyridine-8-carboxamide.
  • the compound exhibited a DLK IC50 (nM) of 0.4 and an LZK IC50 (nM) of 5.2.
  • This compound is disclosed as Example 1-63 in U.S. Patent Publication No. 2023/0086702, which is incorporated by reference herein.
  • the DLK and/or LZK inhibitor is a compound having the following molecular structure:
  • the compound has the chemical name 2-Amino-N-[(2S)-butan-2-yl]-6-(l- ⁇ (lS)- l-[6-(trifluoromethyl)pyridin-3-yl]propyl]-lH-pyrazoT4-yl)[l,2,4]triazolo[l,5-a]pyridine-8- carboxamide.
  • the compound exhibited a DLK IC50 (nM) of 1.4 and an LZK IC50 (nM) of 4.5.
  • This compound is disclosed as Example 1-71 in U.S. Patent Publication No. 2023/0086702, which is incorporated by reference herein.
  • the DLK and/or LZK inhibitors is PBL671.
  • PB 1-671 is a compound of the molecular structure: PBT-671 has the chemical name 1 ,1 -Dimethylethyl 4-[(S)-[4-[2-amino-8-[[[(lS)- l- methylpropyl] amino] carbonyl] [ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-6-yl] - IH-pyrazol- 1 -yl] [6- (trifluoromethyl)-3-pyridinyl]methyl]-l-piperidinecarboxylate.
  • the compound exhibited a DLK IC50 (nM) of 6.65 and an LZK IC50 (nM) of 8.5.
  • Example 1-81 2023/0086702 as Example 1-81, which is incorporated by reference herein.
  • the formulation described herein can include PBI-671 as a free base or a pharmaceutically acceptable salt.
  • the solid form of PBI-671 is as an amorphous free base.
  • the DLK and/or LZK inhibitor is PBL287.
  • PBL287 is a compound having the following molecular structure:
  • the compound has the chemical name 2-Amino-N-[(2S)-butan-2-yl]-6-(l- ⁇ piperidin-4-yl[6-(trifluoromethyl)pyridin-3-yl]methyl ⁇ -lH-pyrazol-4-yl)[l,2,4]triazolo[l,5- a]pyridine-8-carboxamide.
  • the compound exhibited a DLK IC50 (nM) of 0.3 and an LZK IC50 (nM) of 0.7.
  • This compound is disclosed as Example 1-83 in U.S. Patent Publication No. 2023/0086702, which is incorporated by reference herein.
  • the DLK and/or LZK inhibitor is PBI-743.
  • PBI-743 is a compound having the following molecular structure:
  • the compound has the chemical name 6-(l- ⁇ (l-Acetylpiperidin-4-yl)[6- (trifluoromethyl)pyridin-3-yl]methyl ⁇ -lH-pyrazol-4-yl)-2-amino-N-[(2S)-butan-2- yl][l,2,4]triazolo[l,5-a]pyridine-8-carboxamide.
  • the compound exhibited a DLK IC50 (nM) of
  • the DLK and/or LZK inhibitor is a compound having the following molecular structure:
  • the compound has the chemical name 2-Amino-N-[(2S)-butan-2-yl]-7-(l- ⁇ l-[6-
  • the DLK and/or LZK inhibitor is PB 1-069.
  • PBL069 is a compound having the following molecular structure:
  • the compound has the chemical name 2-Amino-N-[(2S)-butan-2-yl]-7-(l- ⁇ 2- methyl- 1 - [6-(trifluoromethyl)pyridin-3-yl]propyl ⁇ - lH-pyrazol-4-yl) [ 1 ,2,4]triazolo[ 1,5- a]pyridine-5-carboxamide.
  • the compound exhibited a DLK IC50 (nM) of 1.0 and an LZK IC50 (nM) of 1.6. This compound is disclosed as Example 1-106 in U.S. Patent Publication No.
  • the DLK and/or LZK inhibitor is a compound having the following molecular structure: [00070] The compound has the chemical name 2-Amino-N-[(2S)-butan-2-yl]-7-(l -
  • the DLK and/or LZK inhibitor is a compound having the following molecular structure:
  • the compound has the chemical name 2-Amino-N-[(2S)-butan-2-yl]-7- ⁇ l-[l-(2- methoxypyridin-4-yl)-2-methylpropyl]-lH-pyrazol-4-yl][l,2,4]triazolo[l,5-a]pyridine-5- carboxamide.
  • the compound exhibited a DLK IC50 (nM) of 0.5 and an LZK IC50 (nM) of 3.3.
  • This compound is disclosed as Example 1-128 in U.S. Patent Publication No. 2023/0086702, which is incorporated by reference herein.
  • the DLK and/or LZK inhibitor is one of the thiophene containing compounds disclosed herein.
  • Certain of the thiophene containing compounds displayed some level of neuroprotective in vivo activity in the Optic Nerve Crush Target Engagement Assay (“ONC”) when administered via intraperitoneal administration.
  • ONC Optic Nerve Crush Target Engagement Assay
  • the DLK and/or LZK inhibitor is a compound having the following molecular structure:
  • the compound has the chemical name 2-Amino-6-[5-[[[(lS)-l-(4- fluorophenyl)ethyl]amino]carbonyl]-3-thienyl]-N-(l-methylethyl)[l,2,4]triazolo[l,5-a]pyridine- 8-carboxamide.
  • the compound exhibited a DLK IC50 (nM) of 8.65, an LZK IC50 (nM) of 109, and an RGC Cell Based Assay EC50 (nM) of 266.
  • the DLK and/or LZK inhibitor is a compound having the following molecular structure:
  • the compound has the chemical name 2-Amino-6-[5-[[[(lS)-l-(4- fhiorophenyl)ethyl]amino]carbonyl]-3-thienyl]-N-[(lS)-l-methylpropyl][l,2,4]triazolo[l,5- a]pyridine-8-carboxamide.
  • the compound exhibited a DLK IC50 (nM) of 4.75, an LZK IC50
  • the DLK and/or LZK inhibitor is a compound having the following molecular structure:
  • the compound has the chemical name 2-Amino-6-[5-[[[(lS)-l-(4- fhiorophenyl)propyl]amino]carbonyl]-3-thienyl]-N-[(lS)-l-methylpropyl][l,2,4]triazolo[l,5- a]pyridine-8-carboxamide.
  • the compound exhibited a DLK IC50 (nM) of 3.20, an LZK IC50 (nM) of 29, and an RGC Cell Based Assay EC50 (nM) of 17.
  • the DLK and/or LZK inhibitor is a compound having the following molecular structure: [00081]
  • the compound has the chemical name 2-Amino-7-[5-[[[(lS)-l-(4- fluorophenyl)propyl]amino]carbonyl]-3-thienyl]-N-[(lS)-l-methylpropyl][l,2,4]triazolo[l,5- a]pyridine-5-carboxamide.
  • the compound exhibited a DLK IC50 (nM) of 7.5 and an LZK IC50 (nM) of 79.
  • the DLK and/or LZK inhibitor is a compound having the following molecular structure:
  • the compound has the chemical name 2-Amino-7-[5-[[[(lS)-l-(4- fluorophenyl)ethyl] amino] carbonyl] -3-thienyl] -N - [( 1 S)- 1 -methylpropyl] [ 1 ,2,4] triazolo [1,5- a]pyridine-5-carboxamide.
  • the compound exhibited a DLK IC50 (nM) of 6.3 and an LZK IC50 (nM) of 52.
  • the therapeutic device is a DLK and/or LZK inhibitor delivery device or Port Delivery System.
  • the therapeutic device is one disclosed in
  • the therapeutic device is the device shown in FIGs. 1-6 of U.S. Patent No.
  • the therapeutic device is used with an exchange apparatus such as one of the exchange apparatuses of U.S. Patent No. 10,653,554, which is incorporated by reference herein.
  • FIG. 1 illustrates an exemplary therapeutic device 100 implanted at least partially within the sclera 102 of the eye 101 as in FIG. 1.
  • the therapeutic device can comprise a retention structure 120 to couple the device to the sclera 102.
  • the therapeutic device can extend through the sclera into the vitreous humor 103, such that the therapeutic device can release the therapeutic agent into the vitreous humor.
  • FIG. 2 shows an exemplary therapeutic device 100 for placement in an eye.
  • the therapeutic device 100 can comprise a retention structure 120 to couple the therapeutic device 100 to the sclera.
  • the retention structure 120 can be a protrusion located on a proximal end of the device.
  • the therapeutic device 100 can comprise a container 130 coupled to the retention structure 120.
  • An active ingredient 110 can be contained within a reservoir 140.
  • the reservoir can comprise a chamber 132 defined by a container 130 of the device.
  • the container 130 can comprise a porous structure 150 comprising a porous material 152.
  • the porous material can be a porous glass frit 154, and a barrier 160 can inhibit release of the active ingredient 110.
  • the bander can include a non-permeable membrane 162.
  • the non-permeable membrane 162 can comprise a substantially non-permeable material 164.
  • the non-permeable membrane 162 can comprise an opening 166 sized to release therapeutic amounts of the active ingredient 110 for the extended time.
  • the porous structure 150 can have a thickness and pore sizes configured in conjunction with the opening 166 so as to release therapeutic amounts of the active ingredient for the extended time.
  • the container 130 can comprise a reservoir 140 having a chamber with a volume sized to contain a therapeutic quantity of the active ingredient 110 for release over the extended time.
  • the therapeutic device can comprise a needle stop 170. Proteins in the vitreous humor can enter the device and compete for adsorption sites on the porous structure and thereby can contribute to the release of active ingredient. The active ingredient 110 contained in the reservoir 140 can equilibrate with proteins in the vitreous humor, such that the system is driven towards equilibrium and the active ingredient 110 is released in therapeutic amounts.
  • the therapeutic device is a DLK and/or LZK inhibitor delivery device or Port Delivery System formed from biocompatible materials and positioned and sized such that vision is not impaired when implanted into the eye.
  • the device comprises a reservoir capacity from about 0.005 cubic centimeter (cc) to about 0.2 cc, for example from about 0.01 cc to about 0.1 cc, and a device volume of no more than about 2 cc.
  • a vitrectomy may be performed for device volumes larger than 0.1 cc.
  • the length of the therapeutic device does not interfere with the patient’ s vision and is dependent on the shape of the device, as well as the location of the implanted device with respect to the eye. The length of the device also depends on the angle in which the device is inserted.
  • a length of the device comprises from about 4 to 6 mm. Since the diameter of the human eye is about 24 mm, a device extending no more than about 6 mm from the sclera into the vitreous has a minimal effect on patient vision.
  • the therapeutic device also comprises at least one of an opening, a diffusion barrier, a diffusion mechanism so as to release therapeutic amounts of DLK and/or LZK inhibitor for the extended time.
  • the therapeutic device can be positioned so as to extend from the pars plana region of the eye into the vitreous humor to release the DLK and/or LZK inhibitor.
  • the DLK and/or LZK inhibitor can be released into the vitreous humor, such that the DLK and/or LZK inhibitor arrives at the retina and choroid and provides a therapeutic effect on the macula.
  • the vitreous humor of the eye comprises a liquid disposed between the lens and the retina.
  • the vitreous humor may comprise convection currents to deliver the DLK and/or LZK inhibitor to the retina and macula.
  • the therapeutic device is implanted at least partially within the sclera of the eye.
  • the therapeutic device can comprise a retention structure, for example, a flange, to couple the device to the sclera.
  • the therapeutic device may extend through the sclera into vitreous humor, such that the therapeutic device can release the DLK and/or LZK inhibitor into the vitreous humor.
  • the therapeutic device is implanted under the conjunctiva and extends through the sclera to release a DLK and/or LZK inhibitor into the vitreous humor of the eye so as to treat the retina of the eye.
  • the therapeutic device can comprise a retention structure such as a smooth flange configured for placement along the sclera and under the conjunctiva, such that the conjunctiva can cover the therapeutic device and protect the therapeutic device.
  • the DLK and/or LZK inhibitor may be placed in the device prior to initial implantation, or injected after placement of the device in the eye.
  • the conjunctiva When the DLK and/or LZK inhibitor device is initially inserted into the eye, the conjunctiva may be lifted away, incised, and the device is placed through the sclera and into the posterior chamber of the eye.
  • the flange secures the device against the sclera to prevent movement and/or relocation of the device and a conjunctival flap is placed over the device to allow for the healing of the tissues located over the device.
  • the eye may comprise an insertion of the tendon of the superior rectus muscle to couple the sclera of the eye to the superior rectus muscle.
  • the device may be positioned in several locations of the pars plana region.
  • the device is positioned away from tendon and one or more of posterior to the tendon, posterior to the tendon, under the tendon, or with nasal or temporal placement of the therapeutic device. While the implant can be positioned in the eye in many ways, placement in the pars plana region can release DLK and/or LZK inhibitor into the vitreous to treat the retina.
  • the therapeutic device can be implanted in the eye to treat the eye for as long as is helpful and beneficial to the patient.
  • the device can be implanted for at least about 5 years, such as permanently for the life of the patient.
  • the device can also be removed when no longer helpful or beneficial for treatment of the patient.
  • an exchange apparatus for refilling the reservoir chamber is incorporated into the Port Delivery System.
  • the exchange apparatus can be one of the apparatuses disclosed in U.S. Patent No. 10,653,554, which is incorporated herein by reference.
  • the exchange apparatus needle can be inserted into the implantable device to refill the implantable device while removing any existing fluid from the device.
  • the exchange apparatus can displace therapeutic fluid from the reservoir chamber when refilling the reservoir chamber with the therapeutic formulation.
  • the fluid in the reservoir chamber can be displaced when therapeutic fluid is injected, for example, and a receiver container can be provided to receive the implantable fluid from the therapeutic device.
  • the device may comprise a retention structure to couple the device to the sclera.
  • the device includes a flange disposed on a proximal end of the device.
  • the retention structure may be coupled to a suture that secures the device to the sclera, but eliminates the need for a larger flange or other structure.
  • the device can comprise a container affixed to the retention structure.
  • the DLK and/or LZK inhibitor can be contained within a reservoir, for example, a chamber defined by a container of the device.
  • the container can comprise a porous structure comprising a release control element and a barrier to inhibit release of the DLK and/or LZK inhibitor.
  • the barrier can comprise a substantially non- permeable material.
  • the barrier can comprise an opening sized to release therapeutic amounts of the DLK and/or LZK inhibitor for the extended time.
  • the porous structure can be configured to have a thickness and pore sizes in conjunction with the opening so as to release therapeutic amounts of the DLK and/or LZK inhibitor for an extended time.
  • the container may comprise a reservoir having a chamber with a volume sized to contain a therapeutic quantity of the DLK and/or LZK inhibitor for release over an extended time.
  • the device may comprise a needle stop. Proteins in the vitreous humor may enter the device and compete for adsorption sites on the porous structure and thereby may contribute to the release of DLK and/or LZK inhibitor.
  • the DLK and/or LZK inhibitor contained in the reservoir can equilibrate with fluids and proteins in the vitreous humor through the porous release control element, such that the system is driven towards equilibrium and the DLK and/or LZK inhibitor is released in therapeutic amounts.
  • the bander, the porous material, the reservoir, and the retention structure may comprise many configurations to deliver the DLK and/or LZK inhibitor.
  • the barrier may comprise an annular tube joined by a disc having at least one opening fonned thereon to release the DLK and/or LZK inhibitor.
  • the reservoir can be shape-changing for ease of insertion, e.g., the shape can change once it is filled with DLK and/or LZK inhibitor.
  • the porous structure can be configured in many ways to release the DLK and/or
  • the porous structure comprises a plurality of openings on a first side facing the reservoir and a plurality of openings on a second side facing the vitreous humor, with a plurality of interconnecting channels disposed there between so as to couple the openings of the first side with the openings of the second side.
  • the porous structure comprises a material having at least one hole disposed therein, nano-channels, nano-channels etched in a rigid material, laser etched nano-channels, a capillary channel, a plurality of capillary channels, one or more tortuous channels, tortuous microchannels, sintered nano-particles, an open cell foam or a hydrogel such as an open cell hydrogel.
  • the device comprises a retention structure to couple to the sclera and the barrier comprises a tube.
  • the DLK and/or LZK inhibitor is contained within tube comprising a non-permeable material.
  • a porous material is disposed at the distal end of the tube to provide a sustained release of the DLK and/or LZK inhibitor at therapeutic concentrations for the extended period.
  • the non-permeable material may extend distally around the porous material so as to define an opening to couple the porous material to the vitreous humor when the device is inserted into the eye.
  • the tube and retention structure are configured to receive a tube, and the tube can be injected with the DLK and/or LZK inhibitor.
  • the tube can be replaced with a new tube.
  • the tube can be made of glass, silicone, silicon, polyimide, polydimethylsiloxane, polycarbonate, polystyrene, polypropylene, polyurethane, polyisobutylene, polyvinyl acetate, polymethylmethacrylate, polyhydroxylethylmethacrylate, and the like.
  • the therapeutic device comprises a plurality of chambers and channels connecting the chambers so as to linearize the release of the DLK and/or LZK inhibitor.
  • a first chamber may comprise a reservoir having a first volume to contain the therapeutic quantity of the DLK and/or LZK inhibitor.
  • a second chamber can be disposed distally to the first chamber, with a first opening connecting the first chamber and the second chamber. The DLK and/or LZK inhibitor can diffuse through the first opening into the second chamber.
  • the second chamber comprises a second volume, such that the DLK and/or LZK inhibitor is temporarily stored in the second chamber so as to linearize the delivery of the DLK and/or LZK inhibitor.
  • a second opening can extend from the second chamber toward the vitreous humor. The first opening, the second opening and the second volume can be sized so as to linearize the delivery of the DLK and/or LZK inhibitor for the sustained release at therapeutic levels for the extended time.
  • the therapeutic device comprises a needle stop located at the bottom of the therapeutic device.
  • the needle stop can be included in the therapeutic device to keep the injection needle from penetrating through and possibly damaging the exit port of the therapeutic device.
  • the needle stop is made of a material of sufficient rigidity to prevent the advancement of the injection needle past a certain level in the therapeutic device.
  • the therapeutic device contains an access port, which can be disposed on a proximal end of the device.
  • the access port comprises an opening formed in the retention structure with a penetrable barrier comprising a septum disposed thereon.
  • the access port is configured for placement under the conjunctiva of the patient and above the sclera.
  • the therapeutic device can be configured such that an injector is used to inject and remove material from the device.
  • the injector may comprise a needle having a first lumen and a second lumen configured to insert into a container of the device. The injector may simultaneously inject a DLK and/or LZK inhibitor into and withdraw liquid from the device.
  • the injector may comprise a first one way valve and a second one way valve coupled to the first lumen and the second lumen, respectively.
  • the therapeutic device comprises a container having a penetrable barrier disposed on a first end, a porous structure disposed on a second end to release the DLK and/or LZK inhibitor for an extended period, and a retention structure comprising an extension protruding outward from the container to couple to the sclera and the conjunctiva.
  • the retention structure may comprise an indentation that is sized to receive the sclera.
  • the container may comprise a tubular barrier that defines at least a portion of the reservoir.
  • the retention structure comprises an indentation configured to receive the sclera when the extension extends between the sclera and the conjunctive.
  • the penetrable barrier comprises a septum disposed on a proximal end of the container, in which the septum comprises a barrier that can be penetrated with a sharp object such as a needle for injection of the DLK and/or LZK inhibitor.
  • the formulations of the present invention include one or more of the previously described DLK and/or LZK inhibitors.
  • the DLK and/or LZK inhibitor is selected from the group consisting of PBL069, PBL287, PBI-671, and PBL743.
  • the formulations are capable of providing efficient and sustained intravitreal delivery of the DLK and/or LZK inhibitor into the vitreous humor of the eye.
  • the concentration of the DLK and/or LZK inhibitor in the reservoir is about 0.01 mg/ml to about 100 mg/ml.
  • the concentration of the DLK and/or LZK inhibitor in the reservoir is about 0.1 to about 100 mg/ml, from about 1 to about 50 mg/ml, from about 1 to about 40 mg/ml, from about 1 to about 30 mg/ml, from about 2 to about 50 mg/ml, from about 3 to about 50 mg/ml, from about 4 to about 50 mg/ml, from about 5 to about 50 mg/ml, from about 8 to about 35 mg/ml, or from about 8 to about 26 mg/ml.
  • the concentration of the DLK and/or LZK inhibitor in the reservoir chamber is between about 0.1 mg/ml to about 30 mg/ml.
  • the concentration of the DLK and/or LZK inhibitor is about 1 mg/ml to about 15 mg/ml. In one embodiment, the concentration of the DLK and/or LZK inhibitor is about 3 mg/ml to about 10 mg/ml.
  • the concentration is about 0.1 mg/ml, 0.2 mg/ml, 0.3 mg/ml, 0.4 mg/ml, 0.5 mg/ml, 0.6 mg/ml, 0.7 mg/ml, 0.8 mg/ml, 0.9 mg/ml, 1 mg/ml, 2 mg/ml, 3 mg/ml, 4 mg/ml, 5 mg/ml, 6 mg/ml, 7 mg/ml, 8 mg/ml, 9 mg/ml, 10 mg/ml, 11 mg/ml, 12 mg/ml, 13 mg/ml, 14 mg/ml, 15 mg/ml, 16 mg/ml, 17 mg/ml, 18 mg/ml, 19 mg/ml, 20 mg/ml, 21 mg/ml, 22 mg/ml, 23 mg/ml, 24 mg/ml, 25 mg/ml, 26 mg/ml, 27 mg/ml, 28 mg/ml, 29 mg/ml, 30 mg/ml, 31 mg/ml, 31
  • the formulation comprises a DLK and/or LZK inhibitor in an amount of about 50 pg to about 3000 pg. In certain embodiments, the formulation comprises a DLK and/or LZK inhibitor in an amount of about 50 pg to about 1500 pg. In certain embodiments, the formulation comprises a DLK and/or LZK inhibitor in an amount of about 50 pg to about 1200 pg. In certain embodiments, the formulation comprises a DLK and/or LZK inhibitor in an amount of about 50 pg to about 1000 pg. In certain embodiments, the formulation comprises a DLK and/or LZK inhibitor in an amount of about 100 pg to about 1200 pg.
  • the formulation comprises a DLK and/or LZK inhibitor in an amount of about 150 pg to about 900 pg. In certain embodiments, the formulation comprises a DLK and/or LZK inhibitor in an amount of about 150 pg to about 650 pg. In certain embodiments, the formulation comprises a DLK and/or LZK inhibitor in an amount of about 150 pg to about 600 Pg-
  • the formulation can comprise the DLK and LZK inhibitor in a range from about 0.1% to about 25.0%, about 0.1% to about 20.0%, about 0.5% to about 25.0%, about 0.5% to about 20.0%, about 1.0% to about 25.0%, about 1.0% to about 20.0%, about 2.0% to about 25.0%, about 2.0% to about 20.0%, about 3.0% to about 25.0%, about 3.0% to about 20.0%, about 4.0% to about 25.0%, about 4.0% to about 20.0%, about 5.0% to about 25.0%, about 5.0% to about 20.0%, about 6.0% to about 25.0%, about 6.0% to about 20.0%, about 0.7% to about 25.0%, about 0.1% to about 10.0%, about 0.5% to about 10.0%, about 0.5% to about 10.0%, about 0.1% to about 5.0%, about 0.5% to about 5.0%, about 0.5% to about 5.0%, about 0.5% to about 5.0%, about 0.5% to about 5.0%, about 0.1% to about 5.0%, about 0.5% to about 5.0%, about 0.5% to
  • the formulation comprises any of the following w/v percent of the DLK and/or LZK inhibitor: 0.1%, 0.2%, 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 10.5%, 11.0%, 11.5%, 12.0%, 12.5%, 13.0%, 13.5%, 14.0%, 14.5%, 15.0%, 15.5%, 16.0%, 16.5%, 17.0%, 17.5%, 18.0%, 18.5%, 19.0%, 19.5%, 20.0%, 20.5%, 21%, 21 .5%, 22.0%, 22.5%, 23.0%, 23.5%, 24.0%, 24.5%, or 25.0%.
  • the formulation comprises a DLK and/or LZK inhibitor and one or more complexing agents.
  • the DLK and/or LZK inhibitor is selected from the group consisting of PBI-069, PB 1-287, PBI-671, and PB 1-743.
  • the complexing agent is selected from the group consisting of 2-hydroxypropyl-P- cyclodextrin, methyl-P-cyclodextrin, randomly methylated-P-cyclodextrin, ethylated-P- cyclodextrin, triacetyl-P-cyclodextrin, peracetylated-P-cyclodextrin, carboxymethyl-P- cyclodextrin, hydroxyethyl-P-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-P- cyclodextrin, glucosyl-p-cyclodextrin, maltosyl-p-cyclodextrin, sulfobutylether p-cyclodextrin, branched-P-cyclodextrin, hydroxypropyl-y-cyclodcxtrin.
  • the complexing agent is selected from the group consisting of sulfobutylether P-cyclodextrin, 2 -hydroxypropyl- P-cyclodextrin, and randomly methylated-P- cyclodextrin.
  • the complexing agent is sulfobutyl ether-P-cyclodextrin (“SBEPCD”) or CAPTISOL®.
  • SBEPCD sulfobutyl ether-P-cyclodextrin
  • CAPTISOL® sulfobutyl ether-P-cyclodextrin
  • Interaction of DLK and/or LZK inhibitors with CAPTISOL® provides a beneficial and protected environment for the DLK and/or LZK inhibitor in the lipophilic cavity of CAPTISOL®, while the hydrophobic surface of CAPTISOL® provides effective water solubility, thereby boosting both solubility and stability of the DLK and/or LZK inhibitor.
  • Lurthermore interaction of the DLK and/or LZK inhibitors with CAPTISOL® reduces decomposition of the DLK and/or LZK inhibitor by protecting labile regions from the potential reactants in the aqueous environment.
  • the ratio of DLK and/or LZK inhibitor to complexing agent is in the range of about 1 : 1 to about 1 :5, 1 : 1 to about 1 :10, 1 :1 to about 1 :15, 1 :1 to about 1:20, 1:5 to about 1:150, about 1:10 to about 1:150, about 1:15 to about 1:150, about 1:20 to about 1:150, about 1:25 to about 1:150, about 1:30 to about 1:150, about 1:35 to about 1:150, about 1:40 to about 1:150, about 1:40 to about 1:150, about 1:50 to about 1:150, about 1:5 to about 1 : 120, about 1 :60 to about 1 : 150, about 1 :70 to about 1 : 150, about 1 :80 to about 1 : 150, about 1:50 to about 1:140, about 1:60 to about 1:140, about 1:70 to about 1:140, about 1:80 to about 1:140, about 1:50 to about 1:130, about 1:
  • the formulation comprises one or more amphiphilic agents such as polysorbates, block copolymers of ethylene oxide and propylene oxide, di-block polymers or tri-block copolymers of polyethylene oxide and polypropylene oxide, ethoxylated emulsifiers, polyethylene glycol esters, sucrose laurate, Tocopherol-PEG-succinate, phospholipids and their derivatives, other non-ionic self-emulsifying agents, or combinations thereof.
  • amphiphilic agents such as polysorbates, block copolymers of ethylene oxide and propylene oxide, di-block polymers or tri-block copolymers of polyethylene oxide and polypropylene oxide, ethoxylated emulsifiers, polyethylene glycol esters, sucrose laurate, Tocopherol-PEG-succinate, phospholipids and their derivatives, other non-ionic self-emulsifying agents, or combinations thereof.
  • the formulation comprises one or more solubilizing/stabilizing agents, for example, trehalose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium hyaluronate, sodium alginate, chitosan and its derivatives, polyethylene glycol, glycerin, propylene glycol, Triacetin, N,N- Dimethylacetamide, poly(vinyl pyrrolidone), pyrrolidone, dimethyl sulfoxide, ethanol, N-(-beta- Hydroxyethyl)-lactamide, l-Methyl-2-pyrrolidinone, triglycerides, monothioglycerol, sorbitol, lecithin, methylparaben, propylparaben, or combinations thereof.
  • solubilizing/stabilizing agents for example, trehalose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose
  • the formulation comprises one or more pH adjusting agents.
  • the formulation comprises one or more agents for increasing buffering capacity of the formulation.
  • the pH adjustment agent is selected from the group consisting of sodium hydroxide, hydrochloric acid, citric acid, malic acid, tartaric acid, acetic acid, phosphoric acid, maleic acid, glycine, sodium lactate, lactic acid, sodium citrate, ascorbic acid, sodium acetate, acetic acid, sodium bicarbonate, sodium carbonate, carbonic acid, sodium succinate, succinic acid, sodium benzoate, benzoic acid, sodium phosphates, tris(hydroxymethyl)aminomethane, histidine, histidine hydrochloride, and combinations thereof.
  • the pH of the formulation in the reservoir is in the range from a pH of 2.0 to 8.0.
  • the pH is between about 5.5 and about 8.0, between about 5.5 and about 7.8, between about 5.5 and about 7.6, between about 5.8 and about 8.0, between about 5.8 and about 7.8, between about 5.8 and about 7.6, between about 6.0 and about 8.0, between about 6.0 and about 7.8, between about 6.0 and about 7.6, between about 6.2 and about 8.0, between about 6.2 and about 7.8, between about 6.2 and about 7.6, between about
  • the pH of the formulation in the reservoir is in the range from about pH
  • the formulation includes a tonicity adjusting agent.
  • the tonicity adjusting agent can be selected from the group consisting of sodium chloride, sodium phosphate, or combinations thereof.
  • the osmolality of the formulation is between about 250 to about 400 mOsm/kg, between about 270 to 330 mOsm/kg, between about 270 to 300 mOsm/kg, or between about 270 to 280 mOsm/kg. In certain embodiments, the formulation is between about 800 to about 1200 mOsm/kg, between about 900 to about 1100 mOsm/kg, or between about 950 to about 1000 mOsm/kg. [000119] In certain embodiments, the DLK and/or LZK inhibitor can have a certain particle size distribution. Particle size of the drug can be assessed using laser diffraction methods.
  • Laser diffraction is recognized by standards and guidance agencies, including for example USP ⁇ 429>, which is incorporated by reference herein.
  • the sample is passed through a laser beam, which results in laser light scattered at a range of angles.
  • Detectors placed at fixed angles measure the intensity of light scattered at that position.
  • a mathematical model is then applied to generate a particle size distribution.
  • the median value is defined as the value where half of the population resides above this point, and half resides below this point.
  • the median is called the D50.
  • the D50 is the size that splits the distribution width half above and half below this diameter.
  • the distribution width may also be characterized by citing one, two, three, or four values on the x-axis, typically some combination of the D10, D50, D90, and D99.
  • the D50, the median has been defined above as the diameter where half of the population lies below this value. Similarly, 90 percent of the distribution lies below the D90, and 10 percent of the population lies below the D10. Likewise, 99 percent of the distribution lies below the D99.
  • the DLK and/or LZK inhibitor has a particle size distribution such that the drug remains in suspension. In certain embodiments, the DLK and/or LZK inhibitor has a particle size distribution such that the drug remains in suspension, and gradually solubilizes into the vitreous humor of the eye following administration. In certain embodiments, the DLK and/or LZK inhibitor is pre-milled (wet or dry milled), jet milled or sieved or spray-dried to create particle size uniformity. In certain embodiments, the DLK and/or
  • the LZK inhibitor has a particle size equal to or less than 30 pm, 31 pm, 32 pm, 33 pm, 33 pm, 34 m, 35 pm, 36 pm, 37 pm, 38 pm, 39 pm, 40 pm, 45 pm, or 50 pm.
  • the DLK and/or LZK inhibitor has a particle size in the range of about 0.001 pm to about 50 pm, about 0.001 pm to about 40 pm, about 0.01 pm to about 50 pm, or about 0.01 pm to about 40 pm.
  • the DLK and/or LZK inhibitor has a particle size distribution characterized by a D90 less than or equal to 60 pm, 55 pm, 50 pm, 45 pm, or 40 pm.
  • the DLK and/or LZK inhibitor ha a particle sizes distributed as characterized by a D99 less than or equal to 60 pm, 55 pm, 50 pm, 45 pm, or 40 pm.
  • the formulation comprises a DLK and/or LZK inhibitor and a viscosity enhancing agent.
  • the viscosity enhancing agent can be selected from the group consisting of alamic acid, alginic acid carboxymethylcellulose, carrageenan, cellulose, dextrin, gelatin, gellan gum, guar gum, hydroxypropylmethylcellulose, maltodextrin, methylcellulose, polyvinyl alcohol, povidone, polyethylene glycol, sodium hyaluronate, sodium alginate, silicon dioxide, colloidal silicon dioxide, chitosan and its derivatives, alginate, xantham gum, xyloglucan, and or a carbomer.
  • the viscosity enhancing agent is sodium hyaluronate, and a phosphate buffered saline.
  • the formulation can comprise a viscosity enhancing agent.
  • the viscosity enhancing agent is sodium hyaluronate.
  • the sodium hyaluronate can be present in a range from about 0.01% to about 5.0%, about 0.01% to about 4.0%, 0.01% to about 3.0%, 0.01% to about 2.0%, 0.01% to about 1.50%, 0.1% to about 5.0%, about 0.1 % to about 4.0%, 0.1 % to about 3.0%, 0.1 % to about 2.0%, 0.1 % to about 1.50%, 0.25% to about 5.0%, about 0.25% to about 4.0%, 0.25% to about 3.0%, 0.25% to about 2.0%, 0.25% to about 1.5%, 0.5% to about 5.0%, about 0.5% to about 4.0%, 0.5% to about 3.0%, 0.5% to about 2.0%, 0.5% to about 1.50%, 1.0% to about 5.0%, about 1.0% to about 4.0%, 0.5% to about 3.0%, 0.5% to about 2.0%, 0.5% to about 1.50%, 1.0% to about 5.0%, about 1.0% to about 4.0%, about 1.0% to about 3.0%, 0.5% to about 2.0%, 0.5% to about 1.50%, 1.
  • the formulation comprises any of the following w/v percent of the viscosity enhancing agent such as sodium hyaluronate: 0.01%, 0.25%, 0.5%, 0.75%, 1.0%, 1.25%, 1.5%, 1.75%, 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25%, 4.5%, 4.75%, or 5.0%.
  • the viscosity enhancing agent such as sodium hyaluronate: 0.01%, 0.25%, 0.5%, 0.75%, 1.0%, 1.25%, 1.5%, 1.75%, 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25%, 4.5%, 4.75%, or 5.0%.
  • the formulation can further comprise a phosphate buffered saline.
  • the phosphate buffered saline can be added in a quantity sufficient to make 100% (q.s. ad 100%).
  • the phosphate buffered saline can be present in a range from about 70% to about 99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% to about 99.5%, about 90% to about 99.5%, about 70% to about 99%, about 75% to about 99%, about 80% to about 99%, about 85% to about 99%, about 90% to about 99%, about 70% to about 98%, about 75% to about 98%, about 80% to about 98%, about 85% to about 98%, about 90% to about 98%, about 70% to about 95%, about 75% to about 95%, about 80% to about 95%, about 85% to about 95%, or about 90% to about 95%.
  • the formulation comprises any of the following w/v percent of the phosphate buffered saline: 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5%.
  • the composition of phosphate buffered saline is set forth in
  • Table 1 Composition of Phosphate Buffered Saline.
  • the formulations have high stability during the use time of the Port Delivery System implant.
  • formulations are stable in the Port Delivery System reservoir chamber at 37° C at physiological conditions for at least 12 months, at least 9 months, at least 6 months, or at least 3 months.
  • the formulations are stable in the PDS in the presence of vitreous components diffusing from the vitreous.
  • the Port Delivery System is designed such that it provides sustained release of the DLK and/or LZK inhibitor.
  • the delivery of the DLK and/or LZK inhibitor can be controlled based on several considerations.
  • DLK and/or LZK inhibitor elution from the Port Delivery System is based on molecular diffusion through the release control element (RCE), which consists of irregular shaped channels.
  • RCE release control element
  • the irregular shaped channels were described in WO 2012/065006, which is incorporated by reference herein in its entireties.
  • the rate of delivery of the DLK and/or LZK inhibitor from the Port Delivery System is modified so as to achieve the desired sustained release profile.
  • the modification is achieved by the design of the Port Delivery System implant, which includes a porous structure for controlling DLK and/or LZK inhibitor release.
  • the porous structure has a desired porosity and tortuosity, desired geometrical dimensions, and desired materials (such as titanium, polymeric, and/or coating) to achieve a certain sustained release profile.
  • the rate of delivery of the DLK and/or LZK inhibitor can also be achieved by varying the reservoir volume.
  • the volume of the reservoir is capable of holding about 5 pL to about 50 pL or about 10 pL to about 25 pL of the DLK and/or LZK inhibitor formulation. In certain embodiments, the reservoir is capable of holding 23 pL of DLK and/or LZK inhibitor formulation.
  • the porous structure comprises a needle stop that limits penetration of the needle.
  • the porous structure comprises a plurality of channels configured for the extended release of the DLK and/or LZK inhibitor.
  • the porous structure comprises a rigid sintered material having characteristics suitable for the sustained release of the material.
  • the porous structure comprises porosity, a thickness, a channel parameter and a surface area configured to release therapeutic amounts for the extended period.
  • the porous material comprises a porosity corresponding to the fraction of void space of the channels extending within the material.
  • the porosity comprises a value within a range from about 3% to about IWc.
  • the porosity comprises a value with a range from about 5% to about 10% or from about 10% to about 25%, or for example from about 15% to about 20%. Porosity is determined from the weight and macroscopic volume or is measured via nitrogen gas adsorption.
  • the porous structure comprises a plurality of porous structures, and the area used in the equation for calculation comprises the combined area of the plurality of porous structures.
  • the release rate of the DLK and/or LZK inhibitor is higher at the time zero and monotonically decreases over time. In some embodiments, the release rate of the DLK and/or LZK inhibitor is constant over time.
  • the formulations disclosed herein release the DLK and/or LZK inhibitor for a period of months.
  • the formulation is capable of remaining stable during the extended delivery period.
  • the DLK and/or LZK inhibitor is delivered for up to 12 months.
  • the DLK and/or LZK inhibitor is delivered for up to 9 months.
  • the DLK and/or LZK inhibitor is delivered for up to 6 months.
  • the DLK and/or LZK inhibitor is delivered for up to 5 months.
  • the DLK and/or LZK inhibitor is delivered for up to 4 months.
  • the DLK and/or LZK inhibitor is delivered for up to 3 months.
  • the DLK and/or LZK inhibitor is delivered for up to 2 months. In certain embodiments, the DLK and/or LZK inhibitor is delivered for up to 1 month. In certain embodiments, the reservoir chamber of the Port Delivery System is refilled without the need for a new implant. In certain embodiments, each time the reservoir chamber is refilled, the DLK and/or LZK inhibitor can be delivered for one the periods of time discussed herein. [000136] In certain embodiments, the DLK and/or LZK inhibitor is released at a release rate of about 0.1 pg/day to about 50 pg/day from the porous structure.
  • the DLK and/or LZK inhibitor is released at a release rate of about 0.1 pg/day to about 25 pg/day. In certain embodiments, the DLK and/or LZK inhibitor is released at a release rate of about 0.5 pg/day to about 10 pg/day. In certain embodiments, the DLK and/or LZK inhibitor is released at a release rate of about 0.5 pg/day to about 5 pg/day. In certain embodiments, the DLK and/or LZK inhibitor is released at a release rate of about 0.5 pg/day to about 3 pg/day.
  • the intravitreal clearance rate and half-life of the DLK and/or LZK inhibitor in the vitreous humor of the eye is determined based on the DLK and/or LZK inhibitor and the species (e.g., whether the eye is a human, rabbit or monkey eye).
  • the therapeutic device can be tuned to receive the volume of formulation based on the half-life of the DLK and/or LZK inhibitor in the human vitreous humor, or an animal vitreous humor, or combinations thereof.
  • the clearance rate of the solution comprising the DLK and/or LZK inhibitor from the human vitreous is between about 5 ml/day to about 25 ml/day, between about 14 ml/day to about 18 ml/day, or between about 14.5 ml/day to about 17.5 ml/day.
  • the intravitreal clearance rate of the solution comprising the DLK and/or LZK inhibitor is 1 ml/day, 2 ml/day, 3 ml/day, 4 ml/day, 5 ml/day, 6 ml/day, 7 ml/day, 8 ml/day, 9 ml/day, 10 ml/day, 11 ml/day, 12 ml/day, 13 ml/day, 14 ml/day, 15 ml/day, 16 ml/day, 17 ml/day, 18 ml/day, 19 ml/day, 20 ml/day, 21 ml/day, 22 ml/day, 23 ml/day, 24 ml/day, 25 ml/day, 26 ml/day, 27 ml/day, 28 ml/day, 29 ml/day, 30 ml/day, or more.
  • the half-life of the concentration in solution of the DLK and/or LZK inhibitor of the current formulations in the human vitreous is between about 1 hour to about 3 hours. In certain embodiments, the half-life of the concentration in solution of the DLK and/or LZK inhibitor of the current formulations in the human vitreous is about 0.1 hours, 0.2 hours, 0.3 hours, 0.4 hours, 0.5 hours, 0.6 hours, 0.7 hours, 0.8 hours, 0.9 hours, 1.0 hour, 1.1 hours, 1.2 hours, 1.3 hours, 1.4 hours, 1.5 hours, 1.6 hours, 1.7 hours, 1.8 hours, 1.9 hours, 2.0 hours, 2.1 hours, 2.2 hours, 2.3 hours, 2.4 hours, 2.5 hours, 2.6 hours, 2.7 hours, 2.8 hours, 2.9 hours, 3.0 hours, 3.1 hours, 3.2 hours, 3.3 hours, 3.4 hours, 3.5 hours, 3.6 hours, 3.7 hours, 3.8 hours, 3.9 hours, 4.0 hours, 4.1 hours, 4.2 hours, 4.3
  • a method of treating a subject comprises implanting a therapeutic device into the eye of a patient suffering from a neurodegenerative disorder.
  • the therapeutic device comprises a reservoir chamber and a porous structure, the reservoir chamber having a volume sized to receive an injection of an amount of a formulation of a DLK and/or LZK inhibitor.
  • the formulation is injected into the reservoir chamber before the device is inserted into the eye.
  • the porous structure is configured to release an effective dose of the DLK and/or LZK inhibitor into the vitreous humor of the eye.
  • the neurodegenerative disorder is an ophthalmological neurodegenerative disorder.
  • the neurodegenerative disorder is an ophthalmological neurodegenerative disorder.
  • the ophthalmological neurodegenerative disorder is selected from the group consisting of: age-related macular degeneration (AMD) including dry (non-exudative) and wet (exudative, neovascular) AMD, choroidal neovascularization (CNV), choroidal neovascular membranes (CNVM), cystoid macular oedema (CME), epiretinal membranes (ERM) and macular perforations, myopia- associated choroidal neovascularization, angioid and vascular streaks, retinal detachment, diabetic retinopathy, diabetic macular oedema (DME), atrophic and hypertrophic lesions in the retinal pigment epithelium, retinal vein occlusion, choroidal retinal vein
  • Stargardt disease retinopathy of prematurity
  • glaucoma including open-angle and narrow/closed-angle glaucoma, primary and secondary glaucoma, normal tension and high-IOP glaucoma
  • other optic neuropathies including toxic optic neuropathy (e.g. methanol, ethambutol), nonarteritic ischemic optic neuropathy, arteritic ischemic optic neuropathy/giant cell arteritis, traumatic optic neuropathy (including traumatic brain injury), idiopathic intracranial hypertension/pseudotumor cerebri, inflammatory optic neuropathies (e.g. optic neuritis), compressive optic neuropathies (e.g.
  • infiltrative optic neuropathies e.g. sarcoidosis, lymphoma
  • autoimmune optic neuropathies lipid storage diseases (e.g. Tay-Sachs)
  • nutritional optic neuropathies Leber's hereditary optic neuropathy, dominant optic atrophy, Friedrich's ataxia, radiation-induced optic neuropathy, iatrogenic optic neuropathies, space flight-associated neuro-ocular syndrome (SANS), inflammation disorders of the eye, for example uveitis, scleritis, cataract, refraction anomalies, for example myopia, hyperopia, astigmatism or keratoconus, neurotrophic keratopathy, corneal denervation and promoting corneal reinnervation and diabetic keratopathy.
  • the ophthalmological neurodegenerative disorder is selected from the group consisting of: glaucoma, inherited retinal degenerations, non-exudative AMD/geographic atrophy, retinal vascular diseases that produce ischemia (diabetes, vein occlusion), retinal detachments and edema-producing diseases (including exudative AMD).
  • the neurodegenerative disease is a non-ophthalmological disorder.
  • the neurodegenerative disease can be selected from the group consisting of: Amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, Parkinson’ s-plus disease, Huntington’s disease, peripheral neuropathies, ischemia, stroke, intracranial haemorrhage, cerebral haemorrhage, nerve damage caused by exposure to toxic compounds selected from the group consisting of heavy metals, industrial solvents, drugs and chemotherapeutic agents, injury to the nervous system caused by physical, mechanical or chemical trauma trigeminal neuralgia, glossopharyngeal neuralgia, Bell’s Palsy, myasthenia gravis, muscular dystrophy, progressive muscular atrophy, primary lateral sclerosis (PLS), spinal muscular atrophy, inherited muscular atrophy, invertebrate disk syndromes, cervical spondylosis, plexus disorders, thoracic outlet destruction syndromes, porphyria, pseudobul
  • ALS Amyo
  • a vial of the DLK and/or LZK inhibitor can be combined with a syringe of the diluent to manufacture the formulation.
  • the formulation is comprised of two components: a terminally sterilized vial containing the DLK and/or LZK inhibitor drug powder and an aseptically filled syringe filled with a diluent solution (e.g., sodium hyaluronate and phosphate buffered saline solution).
  • a diluent solution e.g., sodium hyaluronate and phosphate buffered saline solution.
  • the active ingredient (API) is in a suspension after these two components are mixed.
  • dispersion of the API within the gel suspension may also be accomplished using a high-speed mixer (such as a Flacktek SpeedMixer) prior to administration depending on the time between manufacturing and administration.
  • a high-speed mixer such as a Flacktek SpeedMixer
  • FIG. 6 provides a flow diagram illustrating the method of manufacture in certain embodiments.
  • the DLK and/or LZK inhibitor is packaged in a glass vial, stoppered, sealed, and terminally irradiated prior to preparation of the formulation.
  • the DLK and/or LZK inhibitor is filled into vial, for example a 7-25 mg of the DLK and LZK inhibitor is weighed into a 2R vial.
  • the vial is terminally irradiated by electron beam irradiation to form a drug powder vial.
  • the sodium hyaluronate and phosphate buffer solution can be combined to form a diluent solution and aseptically packaged in a syringe or other suitable container.
  • the diluent solution can be aseptically filled in an amount of 0.5 - 1.5 ml in a syringe or other suitable container.
  • the diluent Prior to administration, the diluent is injected into the glass vial containing the active ingredient and mixed to create a gel suspension.
  • This embodiment can provide for flexibility in terms of the dose of the drug, as well as improved stability of the product components over time.
  • the drug product is processed in a batch process and stored in a combined manner in a vial.
  • the DLK and/or LZK inhibitor and diluent solution e.g., sodium hyaluronate and phosphate buffered solution
  • diluent solution e.g., sodium hyaluronate and phosphate buffered solution
  • a re-mixing step may be utilized to ensure uniform particle size distribution with the dosing vial.
  • a dosing syringe can then be inserted, and dose drawn up and administered into the delivery device reservoir.
  • the drug product and diluent are processed in a batch process.
  • the formulation can be stored in a combined manner in a pre-filled syringe.
  • the glass vial is a 2R glass vial with 13mm a chlorobutyl serum stopper with a flip-off seal.
  • the syringe is a 2.25 mL HypakTM glass syringe with a polypropylene cap.
  • a stock solution of each cyclodextrin was prepared with MilliQ water, at 25% (w/v) for sulfobutylether P-cyclodextrin (SBECD), 2-hydroxypropyl P-cyclodextrin (HPBCD), 2-hyxroxypropyl y-cyclodextrin (HPGCD), randomly methylated P-cyclodextrin (RAMEB), and 20% (w/v) for y-cyclodextrin (GCD).
  • SBECD sulfobutylether P-cyclodextrin
  • HPBCD 2-hydroxypropyl P-cyclodextrin
  • HPGCD 2-hyxroxypropyl y-cyclodextrin
  • RAMEB randomly methylated P-cyclodextrin
  • GCD y-cyclodextrin
  • each cyclodextrin was prepared with MilliQ water, at 25% (w/v) for sulfobutylether - cyclodextrin (SBECD), 2-hydroxypropyl P -cyclodextrin (HPBCD), 2-hyxroxypropyl y- cyclodextrin (HPGCD), randomly methylated P -cyclodextrin (RAMEB), and 20% (w/v) for y- cyclodextrin (GCD).
  • SBECD sulfobutylether - cyclodextrin
  • HPBCD 2-hydroxypropyl P -cyclodextrin
  • HPGCD 2-hyxroxypropyl y- cyclodextrin
  • RAMEB randomly methylated P -cyclodextrin
  • GCD y- cyclodextrin
  • phase solubility profile of PB 1-671 with different cyclodextrins is further illustrated in FIG. 4.
  • the best solubilizing agents were HPBCD and RAMEB. At high concentrations (25%) even 25 mg/ml can be achieved with RAMEB and over 15 mg/ml with
  • HPBCD HPBCD.
  • the P-cyclodextrins appear to be preferred over the y-cyclodextrins.
  • compositions of PBI-671 were prepared: (1) 3 mg/ml PB 1-671 in 300 mg/ml Captisol; and (2) 10 mg/ml PBI-671 in 600 mg/ml Captisol.
  • the first composition i.e., 3 mg/ml PBI-671 in 300 mg/ml Captisol
  • DLK and/or LZK ICsos were determined via biochemical assay. Enzymatic activity was measured by monitoring phosphorylation of the physiological substrate MKK7 (MAP2K7, Dual specificity mitogen-activated protein kinase 7). Phosphorylation was detected by a TR-FRET system, Phosphorylation of MKK7 results in an increased TR-FRET signal and inhibition of enzymatic activity decreases the TR-FRET signal.
  • MKK7 phosphorylation of the physiological substrate MKK7
  • TR-FRET Dual specificity mitogen-activated protein kinase 7
  • DLK and/or LZK IC50 values of PBI-671 were determined to be 6.65 nM and 8.5 nM (4.27 and 5.45 ng/mL), respectively.
  • DLK and/or LZK IC50 values of PBL287 were determined to be 0.3 nM and 0.7 nM, respectively.
  • DLK and/or LZK IC50 values of PBL743 were determined to be 0.5 nM and 1.2 nM, respectively.
  • DLK and/or LZK IC50 values of PBL 069 were determined to be 1.0 nM and 1.6 nM, respectively. The determined DLK and/or LZK IC50 values demonstrate high potency for the target kinases.
  • Mouse and human primary retinal ganglion cells were utilized to evaluate the effect of PBI-671 on cell viability using Cell Titer Gio. Cells were incubated with 0.00015 - 50 micromolar PBI-671 (solubilized in DMSO) for 72 hours and viability was then assessed. The EC50 values for mouse and human RGC viability were 30.2 nM and 14.6 nM (19.4 ng/mL and
  • Table 5 describes estimations of drug release rates and estimated drug load to achieve desired vitreal concentrations of PBI-671 based on calculated clearance data. It has been determined that the EC50 of PBI-671 for protection of mouse and human RGC cells is 30.2 and 14.6 nM (19.4 and 9.3 ng/mL), respectively (Example 5). The clearance data calculated from the equations described above predicted that the solution comprising PBI-671 would be cleared from the human vitreous at a rate of 17.4 mL/day (high clearance) or 11.3 mL/day (low clearance).
  • the therapeutic device In order to achieve a human vitreous concentration of PBI-671 ten-fold higher than the human RGC EC50 with a high clearance rate, the therapeutic device would need to release PBI-671 at a rate of 1.62 pg/day. To maintain this drug release rate for at least 30 days (one month), the device would require a drug load of 48.6 pg.
  • This data can be extrapolated to predict the required drug load to maintain a drug release rate for a longer period of time, for example, it can be predicted that to release PBI-671 at a rate of 1.62 pg/day for a period of nine months a drug load of 437.4 pg.
  • the therapeutic device In order to achieve a human vitreous concentration of PBI-671 ten-fold higher than the human RGC EC50 with a low clearance rate, the therapeutic device would need to release PBI- 671 at a rate of 1 .05 pg/day. To maintain this drug release rate for at least 30 days (one month), the device would require a drug load of 31.5 pg.
  • This data can be extrapolated to predict the required drug load to maintain a drug release rate for a longer period of time, for example, it can be predicted that to release PBI-671 at a rate of 1.05 pg/day for a period of nine months a drug load of 283.5 pg.
  • a formulation of PBI-671 gel as disclosed in Table 6 was prepared.
  • the composition of phosphate buffered saline was as described in Table 1.
  • Sodium hyaluronate, 1.5 - 1.6 MDa was used, and Dulbecco’s Phosphate Buffered Saline (w/o Mg and Ca) was used.
  • the composition was a clear colorless gel, essentially free from visible particulate matter.

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Abstract

L'invention concerne des systèmes pour l'administration intraoculaire prolongée d'un inhibiteur de la double leucine zipper kinase (DLK) et de la leucine zipper kinase (LZK). Le système peut comprendre un dispositif thérapeutique et une formulation d'un inhibiteur de DLK et/ou de LZK susceptible d'administrer un médicament pendant un laps de temps prolongé. Les formulations comprennent un inhibiteur de DLK et/ou de LZK, tel que PBI-069, PBI-287, PBI-671 et PBI-743. Le système peut prolonger la durée d'effet de l'inhibiteur de DLK et/ou de LZK par administration de la formulation par diffusion à partir d'un dispositif thérapeutique.
PCT/US2024/054121 2023-11-03 2024-11-01 Systèmes pour l'administration intraoculaire prolongée d'inhibiteurs de la double leucine zipper kinase et de la leucine zipper kinase Pending WO2025096944A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013003620A2 (fr) * 2011-06-28 2013-01-03 Forsight Vision4, Inc. Procédés et appareil de diagnostic
US20230086702A1 (en) * 2019-04-18 2023-03-23 The Johns Hopkins University Substituted 2-amino-pyrazolyl-[1,2,4]triazolo[1,5a]pyridine derivatives and use thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013003620A2 (fr) * 2011-06-28 2013-01-03 Forsight Vision4, Inc. Procédés et appareil de diagnostic
US20230086702A1 (en) * 2019-04-18 2023-03-23 The Johns Hopkins University Substituted 2-amino-pyrazolyl-[1,2,4]triazolo[1,5a]pyridine derivatives and use thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MALANGA ET AL.: "Back to the Future'': A New Look at Hydroxypropyl Beta-Cyclodextrins", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 105, 2016, pages 2921 - 2931, XP055526940, DOI: 10.1016/j.xphs.2016.04.034 *

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