WO2023133554A2 - Formulations de microsphères contenant de la kétamine et procédés de fabrication et d'utilisation associés - Google Patents

Formulations de microsphères contenant de la kétamine et procédés de fabrication et d'utilisation associés Download PDF

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Publication number
WO2023133554A2
WO2023133554A2 PCT/US2023/060315 US2023060315W WO2023133554A2 WO 2023133554 A2 WO2023133554 A2 WO 2023133554A2 US 2023060315 W US2023060315 W US 2023060315W WO 2023133554 A2 WO2023133554 A2 WO 2023133554A2
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polymer
microsphere
ketamine
microspheres
formulation
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PCT/US2023/060315
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English (en)
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WO2023133554A3 (fr
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Rachel GALASKA
Tracy RICHEY
Michaela GILTNER
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Oakwood Laboratories, Llc
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Publication of WO2023133554A2 publication Critical patent/WO2023133554A2/fr
Publication of WO2023133554A3 publication Critical patent/WO2023133554A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline

Definitions

  • Ketamine (chemical formula CnHieClNO, IUPAC name 2-(2-chlorophenyl)-2-
  • Ketamine can be an effective analgesic. What is needed is an extended release (e.g., 1-3 days) formulation comprising ketamine for treating pain, including, for example, post-operative pain.
  • microsphere formulations comprising ketamine are provided.
  • the microsphere formulations comprise polymer microspheres, each polymer microsphere comprising: (i) an active pharmaceutical ingredient (“API”) comprising, consisting essentially of, or consisting of ketamine; and (ii) a biodegradable polymer comprising, consisting essentially of, or consisting of an acid end-capped poly(lactide) (a “PLA”) polymer or an acid end-capped poly(D,L-lactide-co- glycolide) (a “PLGA”) polymer, wherein the biodegradable polymer has an inherent viscosity (an “IV”) of about 0.1 to about 0.3 dL/g.
  • API active pharmaceutical ingredient
  • a biodegradable polymer comprising, consisting essentially of, or consisting of an acid end-capped poly(lactide) (a “PLA”) polymer or an acid end-capped poly(D,L-lactide-co- glycolide) (a “PLGA”) polymer, wherein
  • Each polymer microsphere may comprise a drug load of between about 20 wt/wt% to about 50 wt/wt%, and the polymer microspheres may have an average particle size of between about 30 pm to about 90 pm (Dso).
  • the polymer microspheres are characterized by a plurality of internal emulsions, each emulsion comprising water and a surfactant.
  • the polymer microspheres may be subjected to dehydration, in which case the polymer microspheres are characterized by a plurality of internal macrovoids.
  • the polymer microspheres are double emulsified.
  • a method for making double emulsified polymer microspheres comprising: (i) contacting ketamine with a biodegradable PLA or PLGA polymer in the presence of a solvent to form an organic component and providing the organic component to a first homogenizer; (ii) providing an inner aqueous component comprising water and, optionally, a first surfactant, and, optionally, NaCl, to the first homogenizer; (iii) homogenizing the organic component with the inner aqueous component to form a primary emulsion; (iv) providing the primary emulsion to a second homogenizer at a first flow rate; (v) providing a continuous phase comprising water and a second surfactant to the second homogenizer at a second flow rate; (vi) homogenizing the primary emulsion and the continuous phase; and (vii) removing the solvent to form the polymer microspheres, where
  • a method for treating pain may comprise administering to a patient in need thereof a microsphere formulation, the microsphere formulation comprising: polymer microspheres, each polymer microsphere comprising: (i) an API comprising, consisting essentially of, or consisting of ketamine; and (ii) a biodegradable polymer comprising, consisting essentially of, or consisting of an acid end-capped PLA polymer or an acid end-capped PLGA polymer, wherein the biodegradable polymer has an IV of about 0.1 to about 0.3 dL/g.
  • Each polymer microsphere may comprise a drug load of between about 20 wt/wt% to about 50 wt/wt%, and the polymer microspheres may have an average particle size of between about 30 pm to about 90 pm (Dso).
  • the microsphere formulation is administered to the patient by intramuscular or subcutaneous injection with a dosing schedule of about every 1-3 days.
  • a method for treating pain may comprise administering by intramuscular or subcutaneous injection to a patient in need thereof a microsphere formulation made according to the methods described herein.
  • a microsphere formulation comprising polymer microspheres, each polymer microsphere comprising: (i) an API comprising, consisting essentially of, or consisting of ketamine; and (ii) a biodegradable polymer comprising, consisting essentially of, or consisting of an acid end-capped PLA polymer or an acid end-capped PLGA polymer, wherein the biodegradable polymer has an IV of about 0.1 to about 0.3 dL/g, wherein each polymer microsphere may comprise a drug load of between about 20 wt/wt% to about 50 wt/wt%, and wherein the polymer microspheres may have an average particle size of between about 30 pm to about 90 pm (Dso), in the manufacture of a medicament for the treatment of pain.
  • each polymer microsphere comprising: (i) an API comprising, consisting essentially of, or consisting of ketamine; and (ii) a biodegradable polymer comprising, consisting essentially of, or consisting of an acid end-
  • a microsphere formulation comprising polymer microspheres, each polymer microsphere comprising: (i) an API comprising, consisting essentially of, or consisting of ketamine; and (ii) a biodegradable polymer comprising, consisting essentially of, or consisting of an acid end-capped PLA polymer or an acid end-capped PLGA polymer, wherein the biodegradable polymer has an IV of about 0.1 to about 0.3 dL/g, wherein each polymer microsphere may comprise a drug load of between about 20 wt/wt% to about 50 wt/wt%, and wherein the polymer microspheres may have an average particle size of between about 30 pm to about 90 pm (Dso), is provided for use as a medicament for the treatment of pain.
  • an API comprising, consisting essentially of, or consisting of ketamine
  • a biodegradable polymer comprising, consisting essentially of, or consisting of an acid end-capped PLA polymer or an acid end-capped PLGA poly
  • kits comprising: (i) an API comprising, consisting essentially of, or consisting of ketamine; and (ii) a biodegradable polymer comprising, consisting essentially of, or consisting of an acid end-capped PLA polymer or an acid end-capped PLGA polymer, wherein the biodegradable polymer has an IV of about 0.1 to about 0.3 dL/g, wherein each polymer microsphere may comprise a drug load of between about 20 wt/wt% to about 50 wt/wt%, and wherein the polymer microspheres may have an average particle size of between about 30 pm to about 90 pm (Dso).
  • the kit further comprises a diluent for administration.
  • Figure l is a flow chart illustrating an example method for making a double-emulsified microsphere formulation.
  • Figures 2A and 2B are two photographs showing a comparison between polymer microspheres prepared using a double emulsion technique (Figure 2A) and a single emulsion technique (Figure 2B), each prior to dehydration.
  • Figure 3 is a graph showing an amount of ketamine released in vitro over time from several example double emulsified microsphere formulations (Batch Nos. 1-5).
  • Figure 4 is a graph showing an amount of ketamine released in vitro over time from several example double emulsified microsphere formulations that included NaCl in the inner aqueous component during preparation (Batch Nos. 6-8) compared to one double emulsified microsphere formulation that included NaCl in the inner aqueous component during preparation (Batch No. 1).
  • Microsphere formulations comprising ketamine are provided.
  • the microsphere formulations comprise polymer microspheres, each polymer microsphere comprising: (i) an API comprising, consisting essentially of, or consisting of ketamine; and (ii) a biodegradable polymer comprising, consisting essentially of, or consisting of an acid end-capped PLA polymer or an acid end-capped PLGA polymer, wherein the biodegradable polymer has an IV of about 0.1 to about 0.3 dL/g.
  • Each polymer microsphere may comprise a drug load of between about 20 wt/wt% to about 50 wt/wt%, and the polymer microspheres may have an average particle size of between about 30 pm to about 90 pm (Dso).
  • the polymer microspheres are characterized by a plurality of internal emulsions, each emulsion comprising water and a surfactant.
  • the polymer microspheres may be subjected to dehydration, in which case the polymer microspheres are characterized by a plurality of internal macrovoids.
  • the polymer microspheres are double emulsified.
  • a method for making double emulsified polymer microspheres comprising: (i) contacting ketamine with a biodegradable PLA or PLGA polymer in the presence of a solvent to form an organic component and providing the organic component to a first homogenizer or a sonicator; (ii) providing an inner aqueous component comprising water and, optionally, a first surfactant, and, optionally, NaCl, to the first homogenizer or sonicator; (iii) homogenizing the organic component with the inner aqueous component to form a primary emulsion; (iv) providing the primary emulsion to a second homogenizer at a first flow rate; (v) providing a continuous phase comprising water and a second surfactant to the second homogenizer at a second flow rate; (vi) homogenizing the primary emulsion and the continuous phase; and (vii) removing
  • the ketamine comprises a racemic mixture.
  • the ketamine may comprise the (S)-(+)-enantiomer (“esketamine”) to the exclusion of the (R)-(-)- enantiomer (“arketamine”).
  • the ketamine may comprise arketamine to the exclusion of esketamine.
  • the ketamine may comprise a pharmaceutically acceptable salt form or a free base form of any of ketamine, esketamine to the exclusion of arketamine, or arketamine to the exclusion of esketamine.
  • Suitable salts may include hydrochloride, sulfate, acetate, phosphate, diphosphate, chloride, maleate, citrate, mesylate, nitrate, tartrate, gluconate, and the like.
  • a complex salt may be used to decrease solubility, such as ketamine palmitate, ketamine benzoic acid, ketamine tosylic acid, ketamine camphor-sulfonic acid, and the like.
  • the term “ketamine” is intended to include the racemic mixture as well as both of its individual enantiomers.
  • the ketamine may be used in its racemic form.
  • the ketamine may be used in its enantiomeric forms, such as in its “S” or “R” forms.
  • An aspect may also include purified forms of the enantiomeric forms.
  • the “S” enantiomer to “R” enantiomer ratio may be from 51 :49 up to 100:0 and every range included therein.
  • the “R” enantiomer to “S” enantiomer ratio may be from 51 :49 up to 100:0 and every range included therein.
  • Each enantiomer may also exist in its (+) or (-) forms, such as in S(+) or S(-) forms.
  • An alternative aspect is the use of a purified form of esketamine in which the ratio of S(+) to S(-) may be from 51 :49 up to 100:0 and every range included therein.
  • An alternate aspect is the use of a purified form of esketamine in which the ratio of S(-) to S(+) may be from 51 :49 up to 100:0 and every range included there.
  • the API consists or consists essentially of (S)-ketamine base (esketamine base).
  • the microsphere formulation is exclusive of hydromorphone.
  • a PLA may be a suitable biodegradable polymer.
  • the PLA may have an IV between about 0.1 to about 0.3 dL/g, including from about 0.13 to about 0.26 dL/g.
  • the biodegradable polymer is an Ashland DL 02 A PLA polymer having an IV of about 0.13 dL/g.
  • the biodegradable polymer is an Ashland DL 02 A PLA polymer having an IV of about 0.18 dL/g.
  • the biodegradable polymer is an Ashland DL 02 A PLA polymer having an IV of about 0.26 dL/g.
  • the biodegradable polymer is a mixture (e.g., a 1 : 1 mixture) of Ashland DL 02 A PLA polymers having an average IV of about 0.21 dL/g.
  • a “poly(lactide) polymer” is to be distinguished from and does not include a poly(lactic-co-glycolic acid) polymer.
  • suitable biodegradable polymers may include poly(lactic-co-glycolic acid) (“PLGA”) copolymers.
  • the biodegradable polymer may comprise a PLGA copolymer having a co-monomer ratio for lactide to glycolide content of about 50:50 to about 85: 15, including 75:25.
  • the PLGA may have an IV between about 0.1 to about 0.3 dL/g, including about 0.18 dL/g.
  • copolymers are specifically excluded.
  • PLGA polymers are specifically excluded.
  • PLGA polymers having a co-monomer ratio for lactide to glycolide content of about 50:50 are specifically excluded.
  • the biodegradable polymers are acid end-capped. In some aspects, ester end-capped biodegradable polymers are specifically excluded.
  • the ketamine and the polymer may be dissolved in a solvent mixture to form a dispersed phase (when using a single emulsion technique) or an organic component (when using a double emulsion technique).
  • Suitable solvents may include methylene chloride (also known as di chloromethane or DCM), ethanol, ethyl acetate, acetic acid, acetone, acetonitrile, acetyl acetone, acrolein, acrylonitrile, allyl alcohol, 1,3 -butanediol, 1,4-butanediol, 1-butanol, 2-butanol, tertbutanol, 2-butoxyethanol, n-butyl amine, butyl dioxitol acetate, butyraldehyde, butyric acid, 2- chloroethanol, diacetone alcohol, diacetyl, diethylamine, diethylene glycol diethyl ether, diethylene glycol dimethyl
  • the solvent comprises DCM, ethanol, ethyl acetate, or a combination of two or all of them. In some aspects, the solvent consists or consists essentially of a combination of DCM and ethanol. In some aspects, the solvent consists or consists essentially of an about 5: 1 (by volume) ratio of DCM: ethanol.
  • the organic component is homogenized with an inner aqueous component to form a primary emulsion.
  • the inner aqueous component comprises water.
  • the inner aqueous component comprises water and a surfactant.
  • the surfactant comprises polyvinyl alcohol (“PVA”).
  • the inner aqueous component comprises PVA in an amount of about 0.35% to about 1.0% by weight in water.
  • the inner aqueous component comprises PVA in an amount of about 0.35% by weight in water.
  • the inner aqueous component comprises PVA in an amount of about 1.0% by weight in water.
  • the inner aqueous component comprises NaCl.
  • the inner aqueous component comprises up to 10 wt% NaCl, including about 0.5 wt%, about 1.0 wt%, about 1.5 wt%, about 2.0 wt%, about 2.5 wt%, about 3.0 wt%, about 3.5 wt%, about 4.0 wt%, about 4.5 wt%, about 5.0 wt%, about 5.5 wt%, about 6.0 wt%, about 6.5 wt%, about 7.0 wt%, about 7.5 wt%, about 8.0 wt%, about 8.5 wt%, about 9.0 wt%, and about 9.5 wt% NaCl.
  • the inner aqueous component comprises between about 2.5 w% to about 5 wt% NaCl.
  • Figures 2A and 2B are two photographs showing a comparison between polymer microspheres prepared using a double emulsion technique (Figure 2A) and a conventional single emulsion technique ( Figure 2B) (an example of each of which is described in U.S. Nonprovisional Patent Application No. 17/404,128, which is incorporated herein by reference in its entirety), each prior to dehydration.
  • the double emulsified polymer microspheres are characterized in that each of the polymer microspheres incorporates a plurality of emulsions comprising water and the surfactant.
  • the polymer microspheres may be subjected to dehydration, in which case the polymer microspheres are characterized by a plurality of internal macrovoids.
  • dehydration may be achieved by freeze drying, including by lyophilization or cryodesiccation, i.e., a low temperature dehydration process that involves freezing the polymer microspheres, lowering pressure, and removing the ice by sublimation. This is in contrast to dehydration methods that evaporate water using heat.
  • the dispersed phase or the primary emulsion may be homogenized with a continuous phase comprising water and, optionally, a surfactant, such as PVA, to form a secondary emulsion.
  • the surfactant component may be present in the continuous phase in an amount of about 0.35% to about 1.0% by weight in water.
  • the surfactant component comprises PVA in an amount of about 0.35% by weight in water.
  • the surfactant component comprises PVA in an amount of about 1.0% by weight in water.
  • the secondary emulsion may be subjected to solvent removal and washing processes to form the double emulsified polymer microspheres.
  • the dispersed phase/primary emulsion flow rate to the homogenizer may from about 10 mL/min to about 30 mL/min, including about 20 mL/min and about 25 mL/min. In some aspects, the continuous phase flow rate to the homogenizer may be about 2L/min. Thus, in one aspect, the continuous phase: dispersed phase/primary emulsion ratio may be from about 66: 1 to about 200:1, including about 100: 1 and about 80: 1. [0030] The continuous phase may be provided at room temperature or above or below room temperature.
  • the continuous phase may be provided at about 40 °C, about 37 °C, about 35 °C, about 30 °C, about 25 °C, about 20 °C, about 15 °C, about 10 °C, about 5 °C, about
  • the homogenization of the organic component and the inner aqueous component may be conducted in a high-speed homogenizer, e.g., in a T25 Ultra-turrax high-speed homogenizer operating, e.g., at 21,500 rpm for 30 seconds (e.g., run in 15 second intervals for two intervals) to form the primary emulsion.
  • the homogenization of the organic component and the inner aqueous component may be conducted in a sonicator, e.g., a Q700 Sonicator (manufactured by Qsonica), or in a magic LAB® DISP AX-RE ACTOR® DR (manufactured by IK A).
  • the homogenization of the primary emulsion and the continuous phase may be conducted in an emulsifier or a homogenizer.
  • the phrase “homogenizer” contemplates a system or apparatus that can homogenize the primary emulsion and the continuous phase, emulsify the primary emulsion and the continuous phase, or both, which systems and apparatuses are known in the art.
  • the homogenizer is an in-line Silverson Homogenizer (commercially available from Silverson Machines, Waterside UK) or a Levitronix® BPS-ilOO integrated pump system used, e.g., as described in U.S. Patent No.
  • the homogenizer is a membrane emulsifier. In one aspect, the homogenizer runs at an impeller speed of about 1,000 to about 4,000 revolutions per minute (“RPM”), including about 1,000 RPM, about 1,200 RPM, about 1,600 RPM, or about 2,500 RPM. Average Particle Size
  • the polymer microspheres may be any size that is safely and efficaciously injectable by intramuscular or subcutaneous injection.
  • the polymer microspheres may have an average particle size of less than 100 pm, or between about 30 pm and about 90 pm, including about 30 pm, about 35 pm, about 40 pm, about 45 pm, about 50 pm, about 55 pm, about 60 pm, about 65 pm, about 70 pm, about 75 pm, about 80 pm, about 85 pm, about 90 pm, and about 95 pm, and any range between such values.
  • the drug load of each polymer microsphere in a drug to polymer ratio may range from between about 20 wt/wt% to about 50 wt/wt%, including about 20 wt/wt%, about 25 wt/wt%, about 30 wt/wt%, about 35 wt/wt%, about 40 wt/wt%, about 45% wt/wt%, and about 50% wt/wt%, and any range between such values.
  • microsphere formulations are characterized in that they have an in vitro (under physiologically relevant conditions) and an in vivo duration of ketamine release of about 1-3 days.
  • pain including for example, post-operative pain
  • the microsphere formulations may be treated using the microsphere formulations, wherein the microsphere formulations are administered every about 1-3 days.
  • a method for treating pain may comprise administering to a patient in need thereof a microsphere formulation, the microsphere formulation comprising: polymer microspheres, each polymer microsphere comprising: (i) an API comprising, consisting essentially of, or consisting of ketamine; and (ii) a biodegradable polymer comprising, consisting essentially of, or consisting of an acid end-capped PLA polymer or an acid end-capped PLGA polymer, wherein the biodegradable polymer has an IV of about 0.1 to about 0.3 dL/g.
  • Each polymer microsphere may comprise a drug load of between about 20 wt/wt% to about 50 wt/wt%, and the polymer microspheres may have an average particle size of between about 30 pm to about 90 pm (Dso).
  • the microsphere formulation is administered to the patient by intramuscular or subcutaneous injection with a dosing schedule of about every one to three days.
  • a method for treating pain may comprise administering by intramuscular or subcutaneous injection to a patient in need thereof a microsphere formulation made according to the methods described herein.
  • a microsphere formulation comprising polymer microspheres, each polymer microsphere comprising: (i) an API comprising, consisting essentially of, or consisting of ketamine; and (ii) a biodegradable polymer comprising, consisting essentially of, or consisting of an acid end-capped PLA polymer or an acid end-capped PLGA polymer, wherein the biodegradable polymer has an IV of about 0.1 to about 0.3 dL/g, wherein each polymer microsphere may comprise a drug load of between about 20 wt/wt% to about 50 wt/wt%, and wherein the polymer microspheres may have an average particle size of between about 30 pm to about 90 pm (Dso), in the manufacture of a medicament for the treatment of pain.
  • each polymer microsphere comprising: (i) an API comprising, consisting essentially of, or consisting of ketamine; and (ii) a biodegradable polymer comprising, consisting essentially of, or consisting of an acid end-
  • a microsphere formulation comprising polymer microspheres, each polymer microsphere comprising: (i) an API comprising, consisting essentially of, or consisting of ketamine; and (ii) a biodegradable polymer comprising, consisting essentially of, or consisting of an acid end-capped PLA polymer or an acid end-capped PLGA polymer, wherein the biodegradable polymer has an IV of about 0.1 to about 0.3 dL/g, wherein each polymer microsphere may comprise a drug load of between about 20 wt/wt% to about 50 wt/wt%, and wherein the polymer microspheres may have an average particle size of between about 30 pm to about 90 pm (Dso), is provided for use as a medicament for the treatment of pain.
  • an API comprising, consisting essentially of, or consisting of ketamine
  • a biodegradable polymer comprising, consisting essentially of, or consisting of an acid end-capped PLA polymer or an acid end-capped PLGA poly
  • kits comprising: (i) an API comprising, consisting essentially of, or consisting of ketamine; and (ii) a biodegradable polymer comprising, consisting essentially of, or consisting of an acid end-capped PLA polymer or an acid end-capped PLGA polymer, wherein the biodegradable polymer has an IV of about 0.1 to about 0.3 dL/g, wherein each polymer microsphere may comprise a drug load of between about 20 wt/wt% to about 50 wt/wt%, and wherein the polymer microspheres may have an average particle size of between about 30 pm to about 90 pm (Dso).
  • the kit further comprises a diluent for administration.
  • the microsphere formulations are injectable formulations for administration via intramuscular or subcutaneous injection and not intrathecally.
  • the intramuscularly or subcutaneously injectable formulation may further include sodium carboxymethylcellulose, tween 80, and mannitol.
  • Example 1 General preparation of microsphere formulations comprising ketamine via a double emulsion method
  • an organic component 12 is formed by dissolving a biodegradable polymer (such as a PLA or a PLGA polymer) in an organic solvent (such as DCM, ethanol, or a combination thereof), followed by the addition of ketamine with mixing until completely dissolved.
  • the organic component 12 is homogenized with an inner aqueous component (“IA component”) 14 comprising water and, optionally, PVA, and, optionally, NaCl, in a high-speed homogenizer probe (such as a T25 Ultra-turrax, sonicator, or magic Lab® DI SP AX-RE AC TOR®) 16 to form a primary emulsion (“PE”) in place of DP 10.
  • IA component inner aqueous component
  • the PE is pumped into a homogenizer 30, such as an in-line Silverson Homogenizer or a Levitronix ilOO (as described in U.S. Patent No. 11, 167,256), at a defined flow rate.
  • a homogenizer 30 such as an in-line Silverson Homogenizer or a Levitronix ilOO (as described in U.S. Patent No. 11, 167,256), at a defined flow rate.
  • the CP 20 comprising water and, optionally, PVA, is also pumped into the homogenizer 30 at a defined flow rate.
  • Microsphere Processing Phase The formed or forming microspheres exit the homogenizer 30 and enter an SRV 40. Water 22 is added to the SRV 40 during microsphere formation to minimize the solvent level. The resulting suspension is mixed in the SRV 40 during the microsphere formation period. After the PE is exhausted, the CP and water flow additions are stopped, and the washing steps are initiated.
  • Solvent removal is achieved by washing the microspheres with room temperature water 24 (e.g., 25 °C) and hot water (35-39 °C) and filtering them through a hollow fiber filter 50 (commercially available as HFF from GE Healthcare). Excess solvent is removed and discarded, and the filtered microspheres are returned to the SRV until the desired level of solvent is removed from the microsphere formulation.
  • room temperature water 24 e.g. 25 °C
  • hot water 35-39 °C
  • the washed microspheres are collected on a filter membrane and freeze-dried overnight in a lyophilizer (Virtis) to remove moisture.
  • the resulting microspheres are a free-flowing off- white bulk powder.
  • Example 2 Preparation and evaluation of an ultra-low inherent viscosity (0.18 dL/g) PLGA-based double emulsion microsphere formulation
  • the PE was pumped into a Levitronix i 100 (as described in U.S. PatentNo. 11,167,256) operating at 2,500 RPM at a rate of 25 mL/minute, along with a CP comprising water and 1.0% PVA, which was pumped at a rate of 2 L/min, for a CP:PE ratio of 80: 1.
  • the formed or forming microspheres exited the homogenizer and entered an SRV.
  • Deionized water was added to the SRV at 2L/min. Solvent removal was achieved by washing the microspheres with ambient water (i.e., 25 °C) and hot water (35-39 °C) and filtering them through a hollow fiber filter.
  • the bulk suspension was collected via filtration and lyophilized to obtain a free- flowing powder with a yield of about 50%.
  • the drug load was 22.8 wt/wt % (46% drug encapsulation efficiency based on a target drug load of 50 wt/wt%).
  • the average particle size was 10 pm (Dio), 32 pm (Dso), 68 pm (D90).
  • Example 3 Preparation and evaluation of an ultra-low inherent viscosity (0.18 dL/g) PLA-based double emulsion microsphere formulation
  • the organic component was homogenized with an IA component consisting of 1 mL of CP comprising water and 0.35% PVA in a T25 Ultra-turrax high-speed homogenizer operating at 21,500 rpm for 30 seconds to form the PE.
  • the PE was pumped into a Levitronix i 100 (as described in U.S. PatentNo. 11,167,256) operating at 1,600 RPM at a rate of 25 mL/minute, along with a CP comprising water and 1.0% PVA, which was pumped at a rate of 2 L/min, for a CP:PE ratio of 80: 1.
  • the formed or forming microspheres exited the homogenizer and entered an SRV.
  • Deionized water was added to the SRV at 2L/min. Solvent removal was achieved by washing the microspheres with ambient water (i.e., 25 °C) and hot water (35-39 °C) and filtering them through a hollow fiber filter.
  • the bulk suspension was collected via filtration and lyophilized to obtain a free- flowing powder with a yield of about 67.1%.
  • the drug load was 27.1 wt/wt % (67.8% drug encapsulation efficiency based on a target drug load of 40 wt/wt%).
  • the average particle size was 24 pm (Dio), 52 pm (Dso), 96 pm (D90).
  • Example 4 Preparation and evaluation of an ultra-low inherent viscosity (0.18 dL/g) PLA-based double emulsion microsphere formulation
  • the organic component was homogenized with an IA component consisting of 1 mL of CP comprising water and 0.35% PVA in a T25 Ultra-turrax high-speed homogenizer operating at 21,500 rpm for 30 seconds to form the PE.
  • the PE was pumped into a Levitronix i 100 (as described in U.S. PatentNo. 11,167,256) operating at 1,200 RPM at a rate of 25 mL/minute, along with a CP comprising water and 1.0%
  • the formed or forming microspheres exited the homogenizer and entered an SRV.
  • Deionized water was added to the SRV at 2L/min. Solvent removal was achieved by washing the microspheres with ambient water (i.e., 25 °C) and hot water (35-39 °C) and filtering them through a hollow fiber filter.
  • the bulk suspension was collected via filtration and lyophilized to obtain a free- flowing powder with a yield of about 65.5%.
  • the drug load was 31.1 wt/wt % (77.8% drug encapsulation efficiency based on a target drug load of 40 wt/wt%).
  • the average particle size was 28 pm (Dio), 63 pm (Dso), 111 pm (D90).
  • Example 5 Preparation and evaluation of an ultra-low inherent viscosity (0.26 dL/g) PLA-based double emulsion microsphere formulation
  • the organic component was homogenized with an IA component consisting of 1 mL of CP comprising water and 0.35% PVA in a T25 Ultra-turrax high-speed homogenizer operating at 21,500 rpm for 30 seconds to form the PE.
  • the PE was pumped into a Levitronix i 100 (as described in U.S. PatentNo. 11,167,256) operating at 1,600 RPM at a rate of 25 mL/minute, along with a CP comprising water and 1.0%
  • the formed or forming microspheres exited the homogenizer and entered an SRV.
  • Deionized water was added to the SRV at 2L/min. Solvent removal was achieved by washing the microspheres with ambient water (i.e., 25 °C) and hot water (35-39 °C) and filtering them through a hollow fiber filter.
  • the bulk suspension was collected via filtration and lyophilized to obtain a free- flowing powder with a yield of about 67.0%.
  • the drug load was 31.2 wt/wt % (78.0% drug encapsulation efficiency based on a target drug load of 40 wt/wt%).
  • the average particle size was 27 pm (D10), 63 pm (D50), 111 pm (D90).
  • Example 6 Preparation and evaluation of a 1 : 1 combination of ultra-low inherent viscosity (average 0.21 dL/g) PLAs in a double emulsion microsphere formulation
  • the organic component was homogenized with an IA component consisting of 1 mL of CP comprising water and 0.35% PVA in a T25 Ultra-turrax highspeed homogenizer operating at 21,500 rpm for 30 seconds to form the PE.
  • the PE was pumped into a Levitronix i 100 (as described in U.S. PatentNo. 11,167,256) operating at 1,600 RPM at a rate of 25 mL/minute, along with a CP comprising water and 1.0%
  • the formed or forming microspheres exited the homogenizer and entered an SRV.
  • Deionized water was added to the SRV at 2L/min. Solvent removal was achieved by washing the microspheres with ambient water (i.e., 25 °C) and hot water (35-39 °C) and filtering them through a hollow fiber filter.
  • the bulk suspension was collected via filtration and lyophilized to obtain a free- flowing powder with a yield of about 66.7%.
  • the drug load was 30.7 wt/wt % (76.8% drug encapsulation efficiency based on a target drug load of 40 wt/wt%).
  • the average particle size was 20 pm (D10), 53 pm (D50), 93 pm (D90).
  • Example 7 Preparation and evaluation of an ultra-low inherent viscosity (average 0.13 dL/g) PLA in a double emulsion microsphere formulation, including NaCl in the inner aqueous component
  • the organic component was homogenized with an IA component consisting of 1 mL of CP comprising water and 5% NaCl in 0.35% PVA in a T25 Ultra-turrax high-speed homogenizer operating at 21,500 rpm for 30 seconds to form the PE.
  • the PE was pumped into a Levitronix i 100 (as described in U.S. PatentNo. 11,167,256) operating at 1,000 RPM at a rate of 25 mL/minute, along with a CP comprising water and 1.0%
  • the formed or forming microspheres exited the homogenizer and entered an SRV.
  • Deionized water was added to the SRV at 2L/min. Solvent removal was achieved by washing the microspheres with room temperature water (e.g., 25 °C) and hot water (35-39 °C) and filtering them through a hollow fiber filter.
  • the bulk suspension was collected via filtration and lyophilized to obtain a free- flowing powder with a yield of about 62%.
  • the drug load was 26.6 wt/wt % (66.5% drug encapsulation efficiency based on a target drug load of 40 wt/wt%).
  • the average particle size was 17 pm (D10), 46 pm (D50), 85 pm (D90).
  • the microsphere molecular weight was 10.4 kDa.
  • Example 8 Preparation and evaluation of an ultra-low inherent viscosity (average 0.13 dL/g) PLA in a double emulsion microsphere formulation, including NaCl in the inner aqueous component [0077]
  • the organic component was homogenized with an IA component consisting of 1 mL of CP comprising water and 2.5% NaCl in 0.35% PVA in a T25 Ultra-turrax high-speed homogenizer operating at 21,500 rpm for 30 seconds to form the PE.
  • the PE was pumped into a Levitronix i 100 (as described in U.S. PatentNo. 11,167,256) operating at 1,000 RPM at a rate of 25 mL/minute, along with a CP comprising water and 1.0%
  • the formed or forming microspheres exited the homogenizer and entered an SRV.
  • Deionized water was added to the SRV at 2L/min. Solvent removal was achieved by washing the microspheres with ambient water (i.e., 25 °C) and hot water (35-39 °C) and filtering them through a hollow fiber filter.
  • the bulk suspension was collected via filtration and lyophilized to obtain a free- flowing powder with a yield of about 66%.
  • the drug load was 25.6 wt/wt % (64.0% drug encapsulation efficiency based on a target drug load of 40 wt/wt%).
  • the average particle size was 35 pm (D10), 78 pm (D50), 132 pm (D90).
  • the microsphere molecular weight was 10.3 kDa.
  • Example 9 Preparation and evaluation of an ultra-low inherent viscosity (average 0.13 dL/g) PLA in a double emulsion microsphere formulation, including NaCl in the inner aqueous component
  • the organic component was homogenized with an IA component consisting of 1 mL of CP comprising water and 2.5% NaCl in 0.35% PVA in a T25 Ultra-turrax high-speed homogenizer operating at 21,500 rpm for 30 seconds to form the PE.
  • the PE was pumped into a Levitronix i 100 (as described in U.S. PatentNo. 11,167,256) operating at 1,000 RPM at a rate of 25 mL/minute, along with a CP comprising water and 1.0%
  • the formed or forming microspheres exited the homogenizer and entered an SRV.
  • Deionized water was added to the SRV at 2L/min. Solvent removal was achieved by washing the microspheres with ambient water (i.e., 25 °C) and hot water (35-39 °C) and filtering them through a hollow fiber filter.
  • the bulk suspension was collected via filtration and lyophilized to obtain a free- flowing powder with a yield of about 53.6%.
  • the drug load was 28.5 wt/wt % (71.3% drug encapsulation efficiency based on a target drug load of 40 wt/wt%).
  • the average particle size was 11 pm (D10), 88 pm (D50), 172 pm (D90).
  • the microsphere molecular weight was 10.4 kDa.
  • each it is not meant to mean “each and every, without exception.”
  • microsphere formulation comprising polymer microspheres, and “each polymer microsphere” is said to have a particular ketamine content, if there are 10 polymer microspheres, and two or more of the polymer microspheres have the particular ketamine content, then that subset of two or more polymer microspheres is intended to meet the limitation.

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Abstract

L'invention concerne des formulations de microsphères injectables à libération prolongée contenant de la kétamine. L'invention concerne également des procédés de fabrication et d'utilisation des formulations de microsphères.
PCT/US2023/060315 2022-01-07 2023-01-09 Formulations de microsphères contenant de la kétamine et procédés de fabrication et d'utilisation associés WO2023133554A2 (fr)

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