Microsphere formulations including ketamine and methods of making and using the same

Abstract

The present invention provides injectable microsphere formulations comprising extended release of ketamine, and also provides methods of making and using the microsphere formulations.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 067,068, filed on August 18, 2020, and U.S. Provisional Patent Application No. 63 / 149,911, filed on February 17, 2021, each of which is incorporated herein by reference in its entirety. Background Art

[0003] Ketamine (chemical formula C 13 H 16 ClNO, IUPAC name 2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one), is characterized by the following general structure:

[0004]

[0005] Ketamine is an N-methyl-D-aspartate ("NMDA") receptor antagonist. Ketamine is primarily used for anesthesia in humans and animals, as well as for chronic pain and sedation. Ketamine is typically sold commercially in liquid form for use as a fast-acting injection.

[0006] Ketamine is a racemic mixture of two enantiomers, (S)-(+)-ketamine and (R)-(-)-ketamine. The (S)-(+) enantiomer (also known as esketamine) is significantly more potent as an NMDA receptor antagonist and anesthetic than the (R)-(-) enantiomer (also known as axlamine).

[0007] Ketamine and its enantiomers are also being studied for the treatment of depression. The U.S. Food and Drug Administration ("FDA") has approved esketamine for use in combination with oral antidepressants for the treatment of treatment-resistant depression ("TRD") and major depressive disorder ("MDD") in adults. In particular, the FDA-approved Nasal spray. For the treatment of TRD, the manufacturer recommends dosing twice weekly for the first four weeks, once weekly for the next four weeks, and then weekly or biweekly thereafter.

[0008] Ketamine is also used by recreational drug users and abusers. Ketamine is a Schedule III drug under the Controlled Substances Act of the United States Drug Enforcement Administration. Partly because of its significant potential for diversion, The nasal spray is only approved for administration under the direct supervision of a healthcare provider. This requires patients to visit a doctor's office or hospital multiple times a week for the first four weeks, followed by weekly visits, which is inconvenient for patients. Patients are also required to remain in the doctor's office or hospital for at least two hours after administration, which increases the inconvenience for patients. There has been a long-standing, unmet need for a ketamine formulation that can reduce the number of visits required to a provider's office for treatment, thereby reducing costs and inconvenience for both patients and providers, while maintaining the ability to keep the medication in the hands of healthcare providers to prevent diversion. Summary of the Invention

[0009] A microsphere formulation comprising ketamine is provided. The microsphere formulation comprises 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 a poly(lactide) ("PLA") polymer. Each polymer microsphere may comprise a drug loading of about 10 wt / wt% to about 30 wt / wt%, and the polymer microsphere may have a drug size greater than 60 μm (D 50 ), including about 80μm (D 50 ) to about 110 μm (D 50 ). In some aspects, the polymer microspheres are characterized by a plurality of internal emulsifiers, each emulsion comprising water and a surfactant. In some aspects, the polymer microspheres can be subjected to dehydration, in which case the polymer microspheres are characterized by a plurality of internal macropores.

[0010] In some aspects, the polymer microspheres are double emulsified. A method for preparing double emulsion polymer microspheres is provided, comprising: (i) contacting ketamine with a biodegradable PLA polymer in the presence of a solvent to form an organic component and providing the organic component to a first homogenizer; (ii) providing an internal aqueous component comprising water and a first surfactant to the first homogenizer; (iii) homogenizing the organic component with the internal aqueous component to form a primary emulsifier; (iv) providing the primary emulsifier 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 emulsifier and the continuous phase; and (iv) removing the solvent to form polymer microspheres, wherein each of the formed polymer microspheres incorporates at least a portion of the internal aqueous component in the form of a plurality of emulsifiers. In some aspects, the polymer microspheres can be subjected to dehydration, in which case the polymer microspheres are characterized by a plurality of internal macropores.

[0011] In another aspect, a method for treating depression, including TRD and / or MDD, is provided. The method may include administering to a patient in need thereof 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 a PLA polymer. Each polymer microsphere may comprise a drug load of about 10 wt / wt% to about 30 wt / wt%, and the polymer microsphere may have a drug size greater than 60 μm (D 50 ), including about 80μm (D 50 ) to about 110 μm (D 50 ) in an average particle size of . In some aspects, the microsphere formulation is administered to a patient by intramuscular or subcutaneous injection at a dosing schedule of about every 30 days.

[0012] In another aspect, a method of treating pain is provided. The method may comprise administering to a patient in need thereof a microsphere formulation prepared according to the methods described herein by intramuscular or subcutaneous injection.

[0013] In another aspect, disclosed is the use of 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 a PLA polymer, wherein each polymer microsphere may comprise a drug load of about 10 wt / wt% to about 30 wt / wt%, and the polymer microsphere may have a diameter greater than 60 μm (D 50 ), including about 80μm (D 50 ) to about 110 μm (D 50 )’s average particle size.

[0014] In another aspect, a microsphere formulation comprises 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 a PLA polymer, wherein each polymer microsphere may comprise a drug load of about 10 wt / wt% to about 30 wt / wt%, and the polymer microsphere may have a drug size greater than 60 μm (D 50 ), including about 80μm (D 50 ) to about 110 μm (D 50 ) and is used as a drug for treating depression. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 is a flow chart illustrating an exemplary method for preparing a single emulsion microsphere formulation.

[0016] Figure 2 is a graph showing an exemplary effect of drug loading on the amount of ketamine released in vitro over time from microsphere formulations prepared using a single emulsification technique.

[0017] Figure 3 is a graph showing exemplary effects of the comonomer ratio of a biodegradable polymer on the amount of ketamine released in vitro over time from microsphere formulations prepared using a single emulsification technique.

[0018] Figure 4 is a graph showing the effect of average polymer microsphere size on the amount of ketamine released in vitro over time from microsphere formulations prepared using a single emulsification technique.

[0019] Figure 5 is a graph showing exemplary effects of inherent viscosity of a biodegradable polymer and / or solvent selection on the in vitro release of ketamine over time from three exemplary double-emulsion microsphere formulations and one exemplary single-emulsion formulation.

[0020] Figure 6 is a flow chart illustrating an exemplary method for preparing a double-emulsion microsphere formulation.

[0021] Figure 7 is a graph showing the amount of ketamine released in vitro over time from an exemplary double-emulsion microsphere formulation.

[0022] Figure 8 is a graph showing example results of a pharmacokinetic study in rats using the microsphere formulations described herein.

[0023] Figure 9 is a graph showing the time-dependent in vitro release of ketamine from several microsphere formulations prepared using double emulsion technology.

[0024] Figure 10 is a graph showing the in vitro release of ketamine over time versus the linear 30-day release of microsphere formulations prepared using double emulsion technology.

[0025] Figure 11A and 11B It is shown that the double emulsification technique ( Figure 11A ) and single emulsion technology ( Figure 11B ) Two photographs comparing polymer microspheres prepared by , each before dehydration. DETAILED DESCRIPTION

[0026] A microsphere formulation comprising ketamine is provided. The microsphere formulation comprises 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 a PLA polymer. Each polymer microsphere may comprise a drug load of about 10 wt / wt% to about 30 wt / wt%, and the polymer microsphere may have a diameter greater than 60 μm (D 50 ), including about 80μm (D 50 ) to about 110 μm (D 50 ). In some aspects, the polymer microspheres are characterized by a plurality of internal emulsifiers, each emulsion comprising water and a surfactant. In some aspects, the polymer microspheres can be subjected to dehydration, in which case the polymer microspheres are characterized by a plurality of internal macropores.

[0027] In some aspects, the polymer microspheres are double emulsified. A method for preparing double emulsion polymer microspheres is provided, comprising: (i) contacting ketamine with a biodegradable PLA polymer in the presence of a solvent to form an organic component and providing the organic component to a first homogenizer; (ii) providing an internal aqueous component comprising water and a first surfactant to the first homogenizer; (iii) homogenizing the organic component with the internal aqueous component to form a primary emulsifier; (iv) providing the primary emulsifier 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 emulsifier and the continuous phase; and (iv) removing the solvent to form polymer microspheres, wherein each of the formed polymer microspheres incorporates at least a portion of the internal aqueous component in the form of a plurality of emulsifiers. In some aspects, the polymer microspheres can be subjected to dehydration, in which case the polymer microspheres are characterized by a plurality of internal macropores.

[0028] API-Ketamine

[0029] In some aspects, ketamine includes a racemic mixture. In some aspects, ketamine can include esketamine to the exclusion of arketamine. Alternatively, ketamine can include arketamine to the exclusion of esketamine.

[0030] In some aspects, ketamine can include a pharmaceutically acceptable salt form or free base form of any of ketamine, esketamine excluding axylamine, and axylamine excluding axylamine. Suitable salts can include hydrochlorides, sulfates, acetates, phosphates, diphosphates, chlorides, maleates, citrates, methanesulfonates, nitrates, tartrates, gluconates, and the like. In other aspects, complex salts can be used to reduce solubility, such as ketamine palmitate, ketamine benzoate, ketamine p-toluenesulfonic acid, ketamine camphorsulfonic acid, and the like.

[0031] Unless otherwise indicated, as used herein, the term "ketamine" is intended to include the racemic mixture as well as its two individual enantiomers. In some aspects, ketamine can be used in its racemic form. Alternatively, ketamine can be used in its enantiomeric form, such as in its "S" or "R" form. One aspect can also include purified forms of the enantiomers. For example, but not limited to, the ratio of the "S" enantiomer to the "R" enantiomer can be from 51:49 to 100:0, and each range included therein. Alternative aspects can include a more purified form of the "R" enantiomer relative to the "S" enantiomer. For example, but not limited to, the ratio of the "R" enantiomer to the "S" enantiomer can be from 51:49 to 100:0, and each range included therein. Each enantiomer can also exist in its (+) or (-) form, such as in S(+) or S(-). Another aspect is the use of a purified form of esketamine, wherein the ratio of S(+) to S(-) can be from 51:49 to 100:0, and each range included therein. Another aspect is the use of a purified form of esketamine, wherein the ratio of S(-) to S(+) can be from 51:49 to 100:0, and each range included therein.

[0032] In one aspect, the API consists of or consists essentially of (S)-ketamine base (esketamine base).In one aspect, the microsphere formulation does not include hydromorphone.

[0033] Biodegradable polymers

[0034] PLA can be a suitable biodegradable polymer. In one aspect, PLA can have an inherent viscosity ("IV") of about 0.30 to about 1.8 dL / g, including about 0.60 to about 0.70 dL / g, and including about 0.66 dL / g or about 0.67 dL / g. In another aspect, PLA can have an IV of about 0.67 dL / g. In one aspect, the biodegradable polymer is Ashland DL 07E PLA polymer with an IV of about 0.67 dL / g.

[0035] As used herein, "poly(lactide) polymer" is distinguished from and does not include poly(lactic acid-co-glycolic acid) polymers. When referring to poly(lactic acid-co-glycolic acid), it will be explicitly listed. In certain explicitly stated aspects, suitable biodegradable polymers may include poly(lactic acid-co-glycolic acid) ("PLGA") copolymers, polyesteramides, polyanhydrides, polyacetals, polycaprolactones, and polycarbonates. In some aspects, biodegradable polymers may include PLGA copolymers having a comonomer ratio of lactide to glycolide content of about 50:50 to about 85:15. In one aspect, the biodegradable polymer may have an average molecular weight of about 30 kDa to about 300 kDa.

[0036] In some aspects, copolymers are specifically excluded. In one aspect, PLGA polymers are specifically excluded. In some aspects, PLGA polymers having a comonomer ratio of lactide to glycolide content of about 50:50 are specifically excluded.

[0037] In some aspects, the biodegradable polymer is ester terminated. In some aspects, acid terminated biodegradable polymers are specifically excluded.

[0038] Dispersed phase / organic component-solvent

[0039] Ketamine and the polymer can 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 can include methylene chloride (also known as dichloromethane or DCM), ethanol, ethyl acetate, acetic acid, acetone, acetonitrile, acetylacetone, acrolein, acrylonitrile, allyl alcohol, 1,3-butanediol, 1,4-butanediol, 1-butanol, 2-butanol, tert-butanol, 2-butoxyethanol, n-butylamine, diethylene glycol butyl ether acetate, butyraldehyde, butyric acid, 2-chloroethanol, diacetone alcohol, diacetyl, diethylamine, diethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol monobutyl ether, diethylene glycol monobutyl ether acetate, diethylene glycol monoethyl ether, diethylene glycol monoethyl ether acetate, diethylene glycol monomethyl ether, N,N-diethylnicotinamide, dimethyl sulfoxide In some respects, solvent comprises DCM, ethanol, ethyl acetate or two or all of them. In some respects, solvent comprises DCM, ethanol, ethyl acetate or two or all of them. In some respects, solvent comprises DCM and ethanol, or a combination thereof. In some aspects, the solvent consists of or consists essentially of about a 5:1 (by volume) ratio of DCM:ethanol.

[0040] Double emulsion polymer microspheres-internal aqueous component

[0041] In one aspect, the organic component and the internal aqueous component are homogenized to form a primary emulsifier. In one aspect, the internal aqueous component comprises water. In one aspect, the internal aqueous component comprises water and a surfactant. In one aspect, the surfactant comprises polyvinyl alcohol ("PVA"). In some aspects, the internal aqueous component comprises the PVA in an amount of about 0.35wt% to about 1.0wt% in water. In some aspects, the internal aqueous component comprises the PVA in an amount of about 0.35wt% in water. In some aspects, the internal aqueous component comprises the PVA in an amount of about 1.0wt% in water.

[0042] Figure 11A and 11B It is shown that the double emulsification technique ( Figure 11A ) and single emulsion technology ( Figure 11B) two photographs comparing polymer microspheres prepared using a double-emulsion method, each prior to dehydration. Double-emulsion polymer microspheres are characterized in that each polymer microsphere is combined with a plurality of emulsifiers including water and a surfactant. In some aspects, the polymer microspheres can be subjected to dehydration, in which case the polymer microspheres are characterized by a plurality of internal macropores.

[0043] In one aspect, dehydration can be achieved by freeze drying, including by lyophilization or freeze drying, a low-temperature dehydration method that involves freezing the polymer microspheres, reducing the pressure, and removing the ice by sublimation. This is in contrast to dehydration methods that use heat to evaporate water.

[0044] continuous phase

[0045] The dispersed phase or primary emulsifier can be homogenized with a continuous phase comprising water and an optional surfactant, such as PVA, to form a secondary emulsifier. The surfactant component can be present in the continuous phase in an amount of about 0.35 wt % to about 1.0 wt % in water. In one aspect, the surfactant component comprises PVA in an amount of about 0.35 wt % in water. In another aspect, the surfactant component comprises PVA in an amount of about 1.0 wt % in water. The secondary emulsifier can be subjected to a solvent removal and washing process to form double emulsion polymer microspheres.

[0046] In some aspects, the dispersed phase / primary emulsifier flow rate to the homogenizer can be 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 can be about 2 L / min. Therefore, in one aspect, the continuous phase: dispersed phase / primary emulsifier ratio can be from about 66:1 to about 200:1, including about 100:1 and about 80:1.

[0047] The continuous phase can be provided at room temperature or above or below room temperature. In some aspects, the continuous phase can 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 0°C, and any range or value between any of those values.

[0048] Homogenizer

[0049] In some aspects, homogenization of the organic component and the inner aqueous component can be performed in a high-speed homogenizer, such as a T25 Ultra-turrax high-speed homogenizer, for example, at 21,500 rpm for 30 seconds to form a primary emulsion. In other aspects, homogenization of the organic component and the inner aqueous component can be performed in an ultrasonicator, such as a Q700 Sonicator (manufactured by Qsonica), or in a magic DR (manufactured by IKA).

[0050] In some aspects, homogenization of the dispersed phase / primary emulsifier and the continuous phase can be performed in an emulsifier or a homogenizer. For simplicity, and because the method is equally applicable to either, the phrase "homogenizer" contemplates systems or apparatus that can homogenize the dispersed phase / primary emulsifier and the continuous phase, emulsify the dispersed phase / primary emulsifier and the continuous phase, or both, which are known in the art. For example, in one aspect, the homogenizer is an in-line Silverson homogenizer (commercially available from Silverson Machines, Waterside UK) or a homogenizer used in BPS-i100 integrated pump system, for example, as described in US20210001290, which is incorporated herein by reference in its entirety. In one aspect, the homogenizer is a membrane emulsifier. In one aspect, the homogenizer operates at an impeller speed of about 1,000 to about 4,000 revolutions per minute ("RPM"), including about 1,600 RPM.

[0051] Average particle size

[0052] The polymer microspheres can be of any size that can be safely and effectively injected intramuscularly or subcutaneously. In one aspect, the polymer microspheres can have a diameter greater than 60 μm (D 50 ) to about 110 μm (D 50 ), including about 80μm (D 50 ) to about 110 μm (D 50 ) average particle size. In one aspect, particle sizes of 60 μm or less are excluded. In one aspect, particle sizes less than 80 μm (D 50 ) particle size.

[0053] Drug payload

[0054] The drug loading per polymer microsphere expressed as a percentage of the drug to polymer ratio can range from about 10 wt / wt% to about 50 wt / wt%, about 10 wt / wt% to about 30 wt / wt%, or about 10 wt / wt% to about 20 wt / wt%.

[0055] Extended release

[0056] The microsphere formulations are characterized in that they have a duration of ketamine release in vitro (under physiologically relevant conditions) and in vivo of about 30 days. In some aspects, the microsphere formulations are characterized in that ketamine is released from the polymer microspheres at an average rate of about 2.5% to about 3.5% per day over a 30-day period.

[0057] Therapeutic benefits

[0058] Possible conditions that can be treated using microsphere formulations include depression, TRD, MDD, conditions involving excitotoxicity, including neurodegenerative diseases and benzodiazepine withdrawal, pain, and other diseases or conditions that can be treated by inhibiting the action of NMDA receptors.

[0059] In one aspect, depression, TRD, or MDD is treated with a microsphere formulation, wherein the microsphere formulation is administered once every about 30 days.

[0060] In another aspect, a method for treating depression, including TRD and / or MDD, is provided. The method may include administering to a patient in need thereof 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 a PLA polymer, wherein each polymer microsphere may comprise a drug load of about 10 wt / wt% to about 30 wt / wt%, and the polymer microsphere may have a diameter greater than 60 μm (D 50 ), including about 80μm (D 50 ) to about 110 μm (D 50 ) in an average particle size of . In some aspects, the microsphere formulation is administered to a patient by intramuscular or subcutaneous injection at a dosing schedule of about every 30 days.

[0061] In another aspect, a method of treating pain is provided. The method may comprise administering to a patient in need thereof a microsphere formulation prepared according to the methods described herein by intramuscular or subcutaneous injection.

[0062] In another aspect, disclosed is the use of 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 a PLA polymer, wherein each polymer microsphere may comprise a drug load of about 10 wt / wt% to about 30 wt / wt%, and the polymer microsphere may have a diameter greater than 60 μm (D 50 ), including about 80μm (D 50 ) to about 110 μm (D 50 )’s average particle size.

[0063] In another aspect, a microsphere formulation comprises 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 a PLA polymer, wherein each polymer microsphere may comprise a drug load of about 10 wt / wt% to about 30 wt / wt%, and the polymer microsphere may have a drug size greater than 60 μm (D 50 ), including about 80μm (D 50 ) to about 110 μm (D 50 ) and is used as a drug for treating depression.

[0064] The microsphere formulation is an injectable formulation for extended release by intramuscular or subcutaneous injection rather than intrathecal administration. In some aspects, the intramuscular or subcutaneous injection formulation may further include sodium carboxymethylcellulose, Tween 80 and mannitol.

[0065] Example

[0066] Example 1 - General Method for Preparing Polymer Microspheres Including Ketamine by a Single Emulsifier Method

[0067] Microsphere formation stage. Figure 1 , a dispersed phase ("DP") 10 is formed as follows: a polymer matrix (e.g., PLA or PLGA polymer) is dissolved in an organic solvent (e.g., DMC or ethyl acetate), and ketamine is then added and mixed until completely dissolved. The DP10 is filtered using a 0.2 μm sterile PTFE or PVDF membrane filter (e.g., EMFLON, available from Pall or Sartorious AG) and pumped into a homogenizer 30, such as an online Silverson homogenizer (available from Silverson Machines, Waterside UK) or a Levitronix i100 (as described in US20210001290), at a specified flow rate. A continuous phase ("CP") 20 comprising water and optional PVA is also pumped into the homogenizer 30 at a defined flow rate. The speed of the homogenizer 30 is typically fixed to obtain the desired polymer microsphere size distribution. A representative continuous "upstream" microsphere formation stage is described in U.S. Patent No. 5,945,126, which is incorporated herein by reference in its entirety.

[0068] Microsphere processing stage. The formed microspheres leave the homogenizer 30 and enter the solvent removal vessel ("SRV") 40. Water can be added to the SRV 40 during the microsphere formation process to minimize the solvent content in the aqueous medium. After the DP 10 is used up, the flow of CP and water is stopped and a washing step is started. Solvent removal is achieved using water washing and a hollow fiber filter (commercially available as HFF from GE Healthcare) 50. A representative "downstream" microsphere processing stage is described in U.S. Patent No. 6,270,802, which is incorporated herein by reference in its entirety.

[0069] The washed microspheres were collected and freeze-dried overnight in a lyophilizer (Virtis) to remove any moisture. The resulting microspheres were a free-flowing off-white bulk powder.

[0070] Example 2 - Preparation of PLGA-based single emulsifier microsphere formulation

[0071] Batch 1: DP was formed by dissolving 1.25 g of ester-terminated PLGA Evonik LG 855S polymer (IV = 3.0 dL / g) in 25.5 g of DCM, followed by the addition of esketamine (3.75 g) with mixing until completely dissolved. The DP was filtered and pumped at 30 mL / min into a Silverson L4RT inline homogenizer operating at 2,000 rpm. CP, consisting of water and 0.35% PVA, was simultaneously pumped into the homogenizer at 2 L / min to form a single emulsion.

[0072] The formed microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV at 2 L / min. The solvent was removed using water washing and a hollow fiber filter. The bulk suspension was collected by filtration and lyophilized to obtain a free-flowing powder with a yield of approximately 45%.

[0073] Batch 1 was tested in an in vitro assay simulating physiological conditions and resulted in the release of esketamine over a period of approximately 45 days, exceeding the desired 30-day release profile.

[0074] Example 3 - Preparation of PLA-based single emulsifier microsphere formulation

[0075] Batch 2: DP was formed by dissolving 1.25 g of ester-terminated PLA Evonik LG 209S polymer (IV = 2.9 dL / g) in 25.5 g of DCM, followed by the addition of esketamine (3.75 g) with mixing until completely dissolved. The DP was filtered and pumped at 30 mL / min into a Silverson L4RT inline homogenizer operating at 2,000 rpm. CP, consisting of water and 0.35% PVA, was simultaneously pumped into the homogenizer at 2 L / min to form a single emulsion.

[0076] The formed microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV at 2 L / min. The solvent was removed using water washing and a hollow fiber filter. The bulk suspension was collected by filtration and lyophilized to obtain a free-flowing powder with a yield of approximately 36%.

[0077] Batch 2 was tested in an in vitro assay simulating physiological conditions and resulted in the release of esketamine over a period of approximately 60 days, exceeding the desired 30-day release profile.

[0078] Example 4 - Effect of drug loading on ketamine release from PLGA-based single emulsion microsphere formulations

[0079] Batch 3: DP was formed by dissolving 4.5 g of ester-terminated PLGA Evonik LG 855S polymer (having an ester-terminated PLGA ratio of 85:15 and an inherent viscosity of 3.0 dL / g) in 65.0 g of DCM, and then adding esketamine (0.5 g) with mixing until completely dissolved. The DP was filtered and pumped at 30 mL / min into a Silverson L4RT inline homogenizer operating at 1,000 rpm. CP, consisting of water and 0.35% PVA, was simultaneously pumped into the homogenizer at 2 L / min to form a single emulsion.

[0080] The formed microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV at 2 L / min. The solvent was removed using water washing and a hollow fiber filter. The bulk suspension was collected by filtration and lyophilized to obtain a free-flowing powder with a yield of approximately 9%. The drug loading was 8.0 wt / wt% (80% drug encapsulation efficiency based on a target drug loading of 10 wt / wt%).

[0081] Batch 3 was tested in an in vitro assay simulating physiological conditions and resulted in the release of esketamine over a period of >60 days, exceeding the desired 30-day release profile. Figure 2 .

[0082] Batch 4: To test the effect of drug loading on ketamine release from a PLGA-based single-emulsion microsphere formulation, another batch (Batch 4) was prepared with a target drug loading of 75 wt / wt%. Thus, a DP was formed by dissolving 2.5 g of the same 85:15 PLGA used in Batch 3 in 51.0 g of DCM, followed by the addition of esketamine (7.5 g) with mixing until completely dissolved. The DP was filtered and pumped at 30 mL / min into a Silverson L4RT inline homogenizer operating at 1,500 rpm. A CP consisting of water and 0.35% PVA was simultaneously pumped into the homogenizer at 2 L / min to form a single emulsion.

[0083] The formed microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV at 2 L / min. The solvent was removed using water washing and a hollow fiber filter. The bulk suspension was collected by filtration and lyophilized to obtain a free-flowing powder with a yield of approximately 34%. The drug loading was 48.2 wt / wt% (64% drug encapsulation efficiency based on a target drug loading of 75 wt / wt%).

[0084] Batch 4 was tested in an in vitro assay simulating physiological conditions. The cumulative percentage release of ketamine over time is shown in Figure 2 Batch 4 experienced an unacceptably significant "burst," releasing >60% in the first five days and continuing to release ketamine beyond the desired 30-day release profile. Figure 2 .

[0085] Example 5 - Effect of comonomer ratio on ketamine release from single emulsion microsphere formulations based on PLGA and PLA ring

[0086] Batch 5: To test the effect of the comonomer ratio, another batch (Batch 5) with 75% drug loading was prepared, this time using PLA polymer. Thus, DP was formed by dissolving 1.25 g of ester-terminated Evonik LG 209S polymer (PLA with IV = 2.9 dL / g) in 26.0 g of DCM, followed by the addition of esketamine (3.75 g) with mixing until complete dissolution. The DP was filtered and pumped at 30 mL / min into a Silverson L4RT inline homogenizer operating at 2,000 rpm. CP, consisting of water and 0.35% PVA, was simultaneously pumped into the homogenizer at 2 L / min to form a single emulsion.

[0087] The formed microspheres left the homogenizer and entered the SRV. Deionized water was added to the SRV at 2 L / min. The solvent was removed using water washing and a hollow fiber filter. The bulk suspension was collected by filtration and lyophilized to give a free-flowing powder with a yield of approximately 46%. The drug loading was 76.0 wt / wt% (101% drug encapsulation efficiency based on a target drug loading of 75 wt / wt%). The polymer microspheres in batch 5 had a diameter of 52 μm (D 10 )、108μm(D 50 )、184μm(D 90 )’s average particle size.

[0088] Batch 5 was tested in an in vitro assay simulating physiological conditions. The cumulative percentage release of ketamine over time is shown in Figure 3 Batch 5 experienced a much smaller substantial burst than Batch 4, releasing >30% in the first five days. However, Batch 5 continued to release ketamine beyond the desired 30-day release profile.

[0089] Example 6 - Effect of polymer microsphere size on ketamine release from PLGA-based single emulsion microsphere formulations

[0090] Batches 6 and 6A: The DP for each batch was formed by dissolving 12.75 g of the same 85:15 PLGA polymer used in batches 3 and 4 in 255.0 g of DCM, followed by the addition of esketamine (37.5 g) with mixing until completely dissolved. The DP was filtered and pumped into a Silverson L4RT inline homogenizer at 30 mL / min. For batch 6, the homogenizer was operated at 4,000 rpm. For batch 6A, the homogenizer was operated at 3,000 rpm. For each batch, a CP consisting of water and 0.35% PVA was simultaneously pumped into the homogenizer at 2 L / min to form a single emulsion.

[0091] For each batch, formed or developing microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV at 2 L / min. The solvent was removed using water washing and a hollow fiber filter. The bulk suspension was collected by filtration and lyophilized to yield a free-flowing powder.

[0092] The yield of batch 6 was about 23%. The drug loading was 17.0 wt / wt% (23% drug encapsulation efficiency based on a target drug loading of 75 wt / wt%). The particle size was 8 μm (D 10 ), 27μm(D 50 ), 57μm(D 90 ).

[0093] The yield of batch 6A was about 29%. The drug loading was 32.0 wt / wt% (43% drug encapsulation efficiency based on a target drug loading of 75 wt / wt%). The particle size was 24 μm (D 10 ), 60μm(D 50 ), 113μm(D 90 ).

[0094] Batches 6 and 6A were tested in an in vitro assay simulating physiological conditions. The cumulative percentage release of ketamine over time as a function of particle size is shown in Figure 4 Batches 6 and 6A were ultimately deemed defective due to insufficient yield and encapsulation efficiency.

[0095] Example 7 - Effect of Ethyl Acetate as a Solvent on Ketamine Release from PLA-Based Single Emulsion Microsphere Formulations

[0096] Batch 7: DP was formed by dissolving 7.0 g of ester-terminated PLA Ashland Viatel 07E polymer (IV = 0.66 dL / g) in 31.5 g of ethyl acetate, and then adding esketamine (3.0 g) with mixing until completely dissolved. The DP was filtered and pumped at 30 mL / min into a Levitronix i100 (as described in US20210001290) operating at 1,600 rpm. CP, including water and 0.35% PVA, was simultaneously pumped into the homogenizer at 2 L / min to form a single emulsion.

[0097] The formed microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV at 2 L / min. The solvent was removed using water washing and a tangential flow filter. The bulk suspension was collected by filtration and lyophilized to yield a free-flowing powder.

[0098] The yield of batch 7 was approximately 70%. The drug loading was 25.6 wt / wt% (85% drug encapsulation efficiency based on a target drug loading of 30 wt / wt%).

[0099] Batch 7 was tested in an in vitro assay simulating physiological conditions. The cumulative percentage release of ketamine over time is shown in Figure 5 Batch 7 was ultimately deemed defective because it had unacceptably large ruptures (which were even more evident in vivo, as shown in Figure 2). Figure 8 shown).

[0100] Example 8 - General method for preparing microsphere formulations including ketamine by double emulsion method

[0101] Microsphere formation stage. Figure 6 , using the same numbers to represent the same components to provide Figure 1 In parallel with the single emulsifier method described in , an organic component 12 is formed by dissolving a biodegradable polymer (e.g., PLA polymer) in an organic solvent (e.g., DCM, ethanol, or a combination thereof) and subsequently adding ketamine and mixing until completely dissolved. The organic component 12 is mixed with an inner aqueous component ("IA component") 14 comprising water and optionally PVA in a high-speed homogenizer probe (e.g., a T25 Ultra-turrax, sonicator, or magic ) 16 is homogenized to form a primary emulsifier ("PE") instead of DP 10. PE is pumped into a homogenizer 30 at a specified flow rate, such as an online Silverson homogenizer or Levitronix i100 (as described in US20210001290). CP 20, which includes water and optionally PVA, is also pumped into the homogenizer 30 at a defined flow rate.

[0102] Microsphere Processing Stage. The formed microspheres exit homogenizer 30 and enter SRV 40. Water 22 is added to SRV 40 during microsphere formation to minimize solvent content. The resulting suspension is mixed in SRV 40 during microsphere formation. After PE is depleted, CP and water addition are stopped, and a wash step is initiated.

[0103] Solvent removal is achieved by washing the microspheres with ambient water 24 (i.e., 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 preparation.

[0104] The washed microspheres were collected on a filter membrane and freeze-dried overnight in a lyophilizer (Virtis) to remove moisture. The resulting microspheres were a free-flowing off-white bulk powder.

[0105] The double emulsion method consistently produced surprisingly high yields compared to the single emulsion method.

[0106] Example 9 - Preparation and Evaluation of Low Inherent Viscosity (0.66 dL / g) PLA-Based Double Emulsion Microsphere Formulations

[0107] Batch 8: An organic component was formed by dissolving 7.0 g of ester-terminated PLA Ashland Viatel 07E polymer (IV = 0.66 dL / g) in 39 g of DCM and 4.6 g of ethanol (5:1 volume ratio), followed by the addition of esketamine (3.0 g) with mixing until completely dissolved. The organic component was homogenized with the IA component consisting of 1 mL of deionized water in a T25 Ultra-turrax high-speed homogenizer operated at 21,500 rpm for 30 seconds to form a PE.

[0108] PE was pumped together with CP comprising water and 0.35% PVA into a Levitronix i100 (as described in US20210001290) operated at 1,600 rpm at a rate of 30 mL / min, which was pumped at a rate of 2 L / min with a CP:PE ratio of 66:1.

[0109] The formed microspheres leave the homogenizer and enter the SRV. Deionized water is added to the SRV at 2 L / min. Solvent removal is achieved by washing the microspheres with ambient water (ie 25°C) and hot water (35-39°C) and filtering them through a hollow fiber filter.

[0110] The bulk suspension was collected by filtration and lyophilized to give a free-flowing powder with a yield of approximately 59%. The drug loading was 16.5 wt / wt% (55% drug encapsulation efficiency based on a target drug loading of 30 wt / wt%). The average particle size was 47 μm (D10 )、82μm(D 50 )、132μm(D 90 ).

[0111] Batch 8 was tested in an in vitro assay simulating physiological conditions. The cumulative percentage release of ketamine over time is shown in Figure 5 (as a function of inherent viscosity of the biodegradable polymer compared to other single and double emulsion batches) and Figure 7 middle.

[0112] Example 10 - Low inherent viscosity (0.66 dL / g) PLA-based double emulsion including PVA in the IA component Preparation and evaluation of microsphere preparations

[0113] Batch 9: An organic component was formed by dissolving 70.0 g of ester-terminated PLA Ashland Viatel 07E polymer (IV = 0.66 dL / g) in 388 g of DCM and 46 g of ethanol (5:1 volume ratio), followed by the addition of esketamine (30.0 g) with mixing until complete dissolution. The organic component was homogenized with the IA component consisting of 11 mL of 0.35% PVA solution in a T25 Ultra-turrax high-speed homogenizer operated at 21,500 rpm for 45 seconds to form a PE.

[0114] PE was pumped together with CP comprising water and 0.35% PVA into a Levitronix i100 (as described in US20210001290) operated at 1,600 rpm at a rate of 30 mL / min, which was pumped at a rate of 2 L / min with a CP:PE ratio of 66:1.

[0115] The formed microspheres leave the homogenizer and enter the SRV. Deionized water is added to the SRV at 2 L / min. Solvent removal is achieved by washing the microspheres with ambient water (ie 25°C) and hot water (35-39°C) and filtering them through a hollow fiber filter.

[0116] The bulk suspension was collected by filtration and lyophilized to give a free-flowing powder with a yield of approximately 72%. The drug loading was 14.6 wt / wt% (49% drug encapsulation efficiency based on a target drug loading of 30 wt / wt%). The average particle size was 38 μm (D 10 )、75μm(D 50 )、123μm(D 90 ).

[0117] Batch 9 was tested in an in vitro assay simulating physiological conditions. The cumulative percentage release of ketamine over time is shown in Figure 5 Medium (compared to other single and double emulsion batches as a function of the inherent viscosity of the biodegradable polymer).

[0118] Example 11 - Preparation of a PLA-based double emulsion microsphere formulation with a higher inherent viscosity (1.80 dL / g) Preparation and evaluation

[0119] Batch 10: An organic component was formed by dissolving 7.0 g of ester-terminated PLA Evonik LG 207S polymer (IV = 1.80 dL / g) in 63 g of DCM and 4.6 g of ethanol (8:1 volume ratio), followed by the addition of esketamine (3.0 g) with mixing until complete dissolution. The organic component was homogenized with the IA component consisting of 1 mL of 0.35% PVA solution in a T25 Ultra-turrax high-speed homogenizer operated at 21,500 rpm for 30 seconds to form a PE.

[0120] PE was pumped together with CP including water and 0.35% PVA into a Levitronix i100 (as described in US20210001290) operated at 1,600 rpm at a rate of 30 mL / min, which was pumped at a rate of 2 L / min with a CP:DP ratio of 66:1.

[0121] The formed microspheres leave the homogenizer and enter the SRV. Deionized water is added to the SRV at 2 L / min. Solvent removal is achieved by washing the microspheres with ambient water (ie 25°C) and hot water (35-39°C) and filtering them through a hollow fiber filter.

[0122] The bulk suspension was collected by filtration and lyophilized to obtain a free-flowing powder with a yield of approximately 56%. The drug loading was 17.4 wt / wt% (58% drug encapsulation efficiency based on a target drug loading of 30 wt / wt%). The average particle size was 27 μm (D 10 )、67μm(D 50 )、136μm(D 90 ).

[0123] Batch 10 was tested in an in vitro assay simulating physiological conditions. The cumulative percentage release of ketamine over time is shown in Figure 5 Medium (compared to other single and double emulsion batches as a function of the inherent viscosity of the biodegradable polymer).

[0124] Example 12 - Pharmacokinetic Study in Batches 7, 9 and 10 of Rats

[0125] The pharmacokinetics of ketamine following subcutaneous administration of a sustained-release ketamine formulation were studied in male Sprague-Dawley rats. Rats received a 50 mg / kg dose of the designated batches, at a ketamine concentration of 33.33 mg / mL, in a volume of 1.5 mL / kg. The microsphere suspension concentrations (mg / mL) were as follows: (a) Batch 7: 130.21 mg / mL; (b) Batch 9: 228.31 mg / mL; and (c) Batch 10: 191.57 mg / mL. Blood was collected at 0.5, 1, 2, 4, 24, 48, 168, 264, 360, 480, 600, 720, 840, 960, 1080, and 1200 hours. Figure 8 is a graph showing the measured mean blood concentration (ng / mL) of ketamine for batches 7 (Example 7), 9 (Example 10), and 10 (Example 11) over time.

[0126] Example 13 - Low inherent viscosity (0.67 dL / g) PLA-based double emulsion with a CP:PE ratio of 100:1 Microsphere preparations

[0127] Batches 11A and 11B: An organic component was formed by dissolving 14.0 g of ester-terminated PLA Ashland DL Viatel 07E polymer (IV = 0.67 dL / g) in 77.58 g of DCM and 9.2 g of ethanol (5:1 volume ratio), followed by the addition of esketamine (6.0 g) with mixing until completely dissolved. The organic component was homogenized with the IA component consisting of 2.18 g of a 0.35% PVA solution in a T25 Ultra-turrax high-speed homogenizer operated at 21,500 rpm for 30 seconds to form a PE having an organic:IA component ratio of approximately 49:1 (based on mass).

[0128] The primary emulsifier was pumped into a Levitronix i100 (as described in US20210001290) operating at 1,600 rpm at a rate of 20 mL / min, along with CP comprising water and 0.35% PVA, which was pumped at a rate of 2 L / min at a CP:PE ratio of 100:1.

[0129] The formed or forming microspheres left the homogenizer and a portion of the suspension (Batch 11A) entered the first SRV where the microspheres were immediately subjected to 2 L / min of deionized water. 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 of the suspension was collected by filtration and freeze-dried to give 6.6 g of a free-flowing powder. The drug loading was 23.0 wt / wt% (77% drug encapsulation efficiency based on a target drug loading of 30 wt / wt%). The average particle size was 53 μm (D 10 )、94μm(D 50)、152μm(D 90 ).

[0130] The second portion of the suspension (Batch 11B) was passed into a second SRV where it was held for 4 hours. At the end of the 4-hour hold, the microspheres were washed, filtered, and lyophilized as described for Batch 11A to yield 6.7 g of a free-flowing powder. The drug loading was 9.2 wt / wt% (31% drug encapsulation efficiency based on a target drug loading of 30 wt / wt%). The average particle size was 50 μm (D 10 )、90μm(D 50 )、143μm(D 90 The combined yield of batches 11A and 11B was 66.3%.

[0131] Batches 11A and 11B were tested in an in vitro assay simulating physiological conditions. The cumulative percentage release of ketamine over time is graphically shown in Figure 9 middle.

[0132] Example 14 - Low inherent viscosity (0.67 dL / g) PLA-based double emulsion microgel with a CP:PE ratio of 80:1 Ball preparation.

[0133] Batches 12A and 12B: An organic component was formed by dissolving 10.5 g of ester-terminated PLA Ashland DL 07E polymer (IV = 0.67 dL / g) in 58.19 g of DCM and 6.9 g of ethanol (5:1 volume ratio), followed by the addition of esketamine (4.5 g) with mixing until completely dissolved. The organic component was homogenized with the IA component consisting of 1.64 g of a 0.35% PVA solution in a T25 Ultra-turrax high-speed homogenizer operated at 21,500 rpm for 30 seconds to form a PE having an organic:IA component ratio of approximately 49:1 (based on mass).

[0134] PE was pumped into a Levitronix i100 (as described in US20210001290) operated at 1,600 rpm at a rate of 25 mL / min, together with CP comprising water and 0.35% PVA, which was pumped at a rate of 2 L / min at a CP:PE ratio of 80:1.

[0135] The formed or forming microspheres left the homogenizer and a portion of the suspension (batch 12A) entered the first SRV where the microspheres were immediately subjected to 2 L / min of deionized water. 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.

[0136] The bulk suspension was collected by filtration and freeze-dried to yield 0.89 g of free-flowing powder. The drug loading was 24.8 wt / wt% (83% drug encapsulation efficiency based on a target drug loading of 30 wt / wt%). The average particle size was 57 μm (D 10 )、111μm(D 50 )、189μm(D 90 ).

[0137] The second portion of the suspension (Batch 12B) was passed into the second SRV where it was held for 4 hours. At the end of the 4-hour hold, the microspheres were washed, filtered, and lyophilized as described for Batch 12A to yield 7.2 g of a free-flowing powder. The drug loading was 17.4 wt / wt% (58% drug encapsulation efficiency based on a target drug loading of 30 wt / wt%). The average particle size was 54 μm (D 10 )、99μm(D 50 )、161μm(D 90 The combined yield of batches 12A and 12B was 54%.

[0138] Batches 12A and 12B were tested in an in vitro assay simulating physiological conditions. The cumulative percentage release of ketamine over time is graphically shown in Figure 9 middle.

[0139] Example 15 - Low inherent viscosity (0.67 dL / g) PLA-based double emulsion microgel with a CP:PE ratio of 80:1 Ball preparations

[0140] Batches 13A and 13B: An organic component was formed by dissolving 10.5 g of ester-terminated PLA Ashland DL 07E polymer (IV = 0.67 dL / g) in 58.19 g of DCM and 6.9 g of ethanol (5:1 volume ratio), followed by the addition of esketamine (4.5 g) with mixing until completely dissolved. The organic component was homogenized with the IA component consisting of 1.64 g of a 0.35% PVA solution in a T25 Ultra-turrax high-speed homogenizer operated at 21,500 rpm for 30 seconds to form a PE having an organic:IA component ratio of approximately 49:1 (based on mass).

[0141] PE was pumped together with CP comprising water and 0.35% PVA into a Levitronix i100 (as described in US20210001290) operated at 1,600 rpm at a rate of 25 mL / min, which was pumped at a rate of 2 L / min with a CP:DP ratio of 80:1.

[0142] The formed or forming microspheres left the homogenizer and a portion of the suspension (batch 13A) entered the first SRV where the microspheres were immediately subjected to 2 L / min of deionized water. 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.

[0143] The bulk suspension was collected by filtration and freeze-dried to yield 2.99 g of free-flowing powder. The drug loading was 29.4 wt / wt% (98% drug encapsulation efficiency based on a target drug loading of 30 wt / wt%). The average particle size was 46 μm (D 10 )、104μm(D 50 )、190μm(D 90 ).

[0144] The second portion of the suspension (Batch 13B) was passed into the second SRV where it was held for 4 hours. At the end of the 4-hour hold, the microspheres were washed, filtered, and lyophilized as described for Batch 13A to yield 7.09 g of a free-flowing powder. The drug loading was 26.4 wt / wt% (88% drug encapsulation efficiency based on a target drug loading of 30 wt / wt%). The average particle size was 52 μm (D 10 )、99μm(D 50 )、162μm(D 90 The combined yield of batches 13A and 13B was 67%.

[0145] Batches 13A and 13B were tested in an in vitro assay simulating physiological conditions. The cumulative percentage release of ketamine over time is graphically shown in Figure 9 middle.

[0146] Example 16 - Low inherent viscosity (0.67 dL / g) of CP (1.0% PVA) with a CP:PE ratio of 80:1 Double emulsion microsphere preparation of PLA

[0147] Batches 14A and 14B: An organic component was formed by dissolving 12.45 g of ester-terminated PLA Ashland DL 07E polymer (IV = 0.67 dL / g) in 70.74 g of DCM and 8.39 g of ethanol (5:1 volume ratio), followed by the addition of esketamine (2.55 g) with mixing until completely dissolved. The organic component was homogenized with the IA component consisting of 1.64 g of a 0.35% PVA solution in a T25 Ultra-turrax high-speed homogenizer operated at 21,500 rpm for 30 seconds to form a PE having an organic:IA component ratio of approximately 57:1 (based on mass).

[0148] PE was pumped together with CP comprising water and 1.0% PVA into a Levitronix i100 (as described in US20210001290) operated at 1,600 rpm at a rate of 25 mL / min, which was pumped at a rate of 2 L / min with a CP:PE ratio of 80:1.

[0149] The formed or forming microspheres left the homogenizer and a portion of the suspension (batch 14A) entered the first SRV where the microspheres were immediately subjected to 2 L / min of deionized water. 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.

[0150] The bulk suspension was collected by filtration and freeze-dried to yield 2.99 g of free-flowing powder. The drug loading was 14.5 wt / wt% (85% drug encapsulation efficiency based on a target drug loading of 17 wt / wt%). The average particle size was 32 μm (D 10 )、87μm(D 50 )、149μm(D 90 ).

[0151] The second portion of the suspension (Batch 14B) was passed into a second SRV where it was held for 4 hours. At the end of the 4-hour hold, the microspheres were washed, filtered, and lyophilized as described for Batch 14A to yield 6.95 g of a free-flowing powder. The drug loading was 13.7 wt / wt% (81% drug encapsulation efficiency based on a target drug loading of 17 wt / wt%). The average particle size was 37 μm (D 10 )、88μm(D 50 )、148μm(D 90 The combined yield of batches 14A and 14B was 75%.

[0152] Batches 14A and 14B were tested in an in vitro assay simulating physiological conditions. The cumulative percentage release of ketamine over time compared to the expected 30-day release profile is shown graphically in Figure 10 middle.

[0153] The aspects disclosed herein are not intended to be exhaustive or restrictive. Those skilled in the art will recognize that other aspects or modifications may be made to aspects of the present invention without departing from the spirit or scope of the present invention. Various aspects of the present disclosure, as generally described herein and shown in the accompanying drawings, may be arranged, replaced, combined, separated, and designed into various different configurations, all of which are contemplated herein.

[0154] Unless otherwise indicated, "a," "an," "the," "one or more," and "at least one" are used interchangeably. The singular forms "a," "an," and "the" include their plural forms. Numerical ranges expressed by endpoints include all values ​​included in that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.). The terms "comprising" and "including" are intended to be equivalent and open-ended. The phrase "essentially consisting of" means that the composition or method may include additional ingredients and / or steps, but only when the additional ingredients and / or steps do not substantially change the basic and novel features of the claimed composition or method. The phrase "selected from the group consisting of" is meant to include mixtures of the listed groups.

[0155] When referring to the term "each," it does not mean "each and every one, without exception." For example, if reference is made to a microsphere formulation comprising polymeric microspheres, and "each polymeric microsphere" is said to have a particular ketamine content, if there are 10 polymeric microspheres, and two or more of the polymeric microspheres have a particular ketamine content, then a subset of the two or more polymeric microspheres is intended to meet that limitation.

[0156] The term "about" in conjunction with a number is intended to include ±10% of that number. This is true whether "about" modifies an individual number or modifies a number at one or both ends of a numerical range. In other words, "about 10" means 9 to 11. Similarly, "about 10 to about 20" encompasses 9 to 22 and 11 to 18. In the absence of the term "about," the exact number is intended. In other words, "10" means 10.

Claims

1. A microsphere preparation comprising: Polymer microspheres, each polymer microsphere comprising: (i) esketamine; and (ii) a biodegradable poly(lactide) polymer having an inherent viscosity of about 0.6 dL / g to about 0.7 dL / g, wherein each polymer microsphere has an esketamine drug loading of about 12 wt / wt% to about 17 wt / wt%; The polymer microspheres are 50 having a particle size of about 80 μm to about 110 μm; wherein the term about in conjunction with a number is intended to include ±10% of the number; and The polymer microspheres are characterized by: Each of the polymer microspheres comprises a plurality of internal macropores; and The method for producing the polymer microspheres comprises: (i) contacting the esketamine with the biodegradable poly(lactide) polymer in the presence of a solvent to form an organic component and providing the organic component to a first homogenizer; (ii) providing an internal aqueous component comprising water and a first surfactant to the first homogenizer; (iii) homogenizing the organic component with the inner aqueous component to form a primary emulsion; (iv) providing the primary emulsifier to the 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 emulsifier and the continuous phase; and (vii) removing the solvent to form the polymer microspheres.

2. The microsphere formulation of claim 1, wherein the polymer microspheres are characterized in that the esketamine exhibits an average in vivo release rate from the polymer microspheres of about 2.5% to about 3.5% per day over a 30-day period in humans.

3. The microsphere formulation of claim 1 , wherein the method further comprises dehydrating the polymer microspheres, wherein the dehydrated polymer microspheres are characterized in that each of the polymer microspheres comprises a plurality of internal macropores. The microsphere preparation according to claim 1 , wherein the solvent comprises a mixture of dichloromethane and ethanol.

5. The microsphere formulation of claim 1, wherein the solvent comprises a mixture of dichloromethane and ethanol in a volume ratio of about 5:

1.

6. Use of the microsphere preparation according to any one of claims 1 to 5 in the preparation of a medicament for treating depression.

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