Microsphere formulations containing ketamine and methods of making and using same

Abstract

Sustained-release injectable microsphere formulations containing ketamine are provided. Methods of making and using the microsphere formulations are also provided.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 067,068, filed August 18, 2020, and U.S. Provisional Patent Application No. 63 / 149,911, filed February 16, 2021, each of which is incorporated by reference in its entirety. [Background technology]

[0002] General structure: [ka] Ketamine (chemical formula C) is characterized by 13 H 16 ClNO, IUPAC name 2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one, is an N-methyl-D-aspartate ("NMDA") receptor antagonist. Ketamine has been used primarily for human and animal anesthesia, as well as chronic pain and sedation. Ketamine is typically available commercially in liquid form for use as a fast-acting injectable.

[0003] 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 alketamine.

[0004] 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. Specifically, the FDA has approved Spravato® nasal spray. For the treatment of TRD, the manufacturer recommends administering the drug twice weekly for the first four weeks, weekly for the next four weeks, and then weekly or biweekly.

[0005] Ketamine is also used by recreational drug users and abusers. Ketamine is a Schedule III drug under the U.S. Drug Enforcement Agency's controlled substance classification under the Controlled Substances Act. In part due to the high potential for diversion, Spravato® nasal spray is approved only 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, and then weekly thereafter, making it an inconvenient procedure for patients. Patients also need to stay in the doctor's office or hospital for at least two hours after administration, adding to the inconvenience. Until now, there has been a long-felt, unmet need for a ketamine formulation that reduces the number of visits patients need to make to a provider's office for treatment, reducing costs and inconvenience for patients and providers, while maintaining the ability to keep the drug in the hands of healthcare providers to prevent diversion. Summary of the Invention

[0006] Microsphere formulations containing ketamine are provided. The microsphere formulations include polymeric microspheres, each of which contains (i) an active pharmaceutical ingredient ("API") that comprises, consists essentially of, or consists of ketamine, and (ii) a biodegradable polymer that comprises, consists essentially of, or consists of a poly(lactide) ("PLA") polymer. Each polymeric microsphere can have a drug load of about 10 wt / wt% to about 30 wt / wt%, and the polymeric microspheres have a diameter of about 80 μm (D 50 ) ~ approx. 110 μm (D 50 ), including 60 μm (D 50 ) or greater. In some aspects, the polymeric microspheres are characterized by multiple internal emulsions, each emulsion comprising water and a surfactant. In some aspects, the polymeric microspheres can be subjected to dehydration, in which case the polymeric microspheres are characterized by multiple internal macrovoids.

[0007] In some embodiments, the polymer microspheres are double-emulsified. A method for making double-emulsion polymer microspheres is provided, the method comprising: (i) contacting ketamine with a biodegradable PLA polymer in the presence of a solvent to form an organic component, and feeding the organic component to a first homogenizer; (ii) feeding an inner 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) feeding the primary emulsion to a second homogenizer at a first flow rate; (v) feeding 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 (iv) removing the solvent to form polymer microspheres, each of which incorporates at least a portion of the inner aqueous component in the form of multiple emulsions. In some embodiments, the polymeric microspheres may be subjected to dehydration, where the polymeric microspheres are characterized by a plurality of internal macrovoids.

[0008] In another aspect, a method for treating depression, including TRD and / or MDD, is provided. The method comprises administering a microsphere formulation to a patient in need thereof, the microsphere formulation comprising polymeric microspheres, each polymeric microsphere comprising: (i) an API that comprises, consists essentially of, or consists of ketamine; and (ii) a biodegradable polymer that comprises, consists essentially of, or consists of a PLA polymer. Each polymeric microsphere can comprise a drug load of about 10 wt / wt% to about 30 wt / wt%, and the polymeric microspheres can have a diameter of about 80 μm (D 50 ) ~ approx. 110 μm (D 50 ), including 60 μm (D 50 In some embodiments, the microsphere formulation is administered to a patient by intramuscular or subcutaneous injection on a dosing schedule of about every 30 days.

[0009] In another aspect, a method of treating pain is provided, which may include administering a microsphere formulation made by the methods described herein to a patient in need thereof via intramuscular or subcutaneous injection.

[0010] In another aspect, disclosed is the use of a microsphere formulation comprising polymer microspheres, each polymer microsphere comprising (i) an API that comprises, consists essentially of, or consists of ketamine; and (ii) a biodegradable polymer that comprises, consists essentially of, or consists of a PLA polymer, each polymer microsphere can have a drug load of about 10 wt / wt% to about 30 wt / wt%, the polymer microspheres having a diameter of about 80 μm (D 50 ) ~ approx. 110 μm (D 50 ), including 60 μm (D 50 ) average particle size.

[0011] In another aspect, a microsphere formulation comprising polymeric microspheres, each polymeric microsphere comprising (i) an API that comprises, consists essentially of, or consists of ketamine; and (ii) a biodegradable polymer that comprises, consists essentially of, or consists of a PLA polymer, wherein each polymeric microsphere can comprise a drug load of about 10 wt / wt% to about 30 wt / wt%, and wherein the polymeric microspheres have a diameter of about 80 μm (D 50 ) ~ approx. 110 μm (D 50 ), including 60 μm (D 50 ) for use as a medicament for treating depression. [Brief explanation of the drawings]

[0012] [Figure 1] 1 is a flow chart illustrating an exemplary method for making a single-emulsion microsphere formulation.

[0013] [Figure 2] 1 is a graph showing an exemplary effect of drug load on the amount of ketamine released over time in vitro from microsphere formulations prepared using a single emulsion technique.

[0014] [Figure 3] 1 is a graph showing an exemplary effect of the comonomer ratio of a biodegradable polymer on the amount of ketamine released over time in vitro from microsphere formulations prepared using a single emulsion technique.

[0015] [Figure 4] 1 is a graph showing the effect of average polymer microsphere size on the amount of ketamine released over time in vitro from microsphere formulations prepared using a single emulsion technique.

[0016] [Figure 5] 1 is a graph showing exemplary effects of intrinsic viscosity of a biodegradable polymer and / or choice of solvent on in vitro ketamine release from three exemplary double emulsion microsphere formulations and one exemplary single emulsion formulation.

[0017] [Figure 6] 1 is a flow chart illustrating an exemplary method for making a double emulsion microsphere formulation.

[0018] [Figure 7] 1 is a graph showing the amount of ketamine released over time in vitro from an exemplary double emulsion microsphere formulation.

[0019] [Figure 8] 1 is a graph showing exemplary results of a pharmacokinetic study in rats using a microsphere formulation described herein.

[0020] [Figure 9]1 is a graph showing the amount of ketamine release over time in vitro from several microsphere formulations prepared using the double emulsion technique.

[0021] [Figure 10] 1 is a graph showing the amount of ketamine released over time in vitro from microsphere formulations prepared using double emulsification technology versus the amount of ketamine released over 30 days of linear release.

[0022] [Figure 11A] 1 is a photograph of polymer microspheres prepared using the double emulsion technique before dehydration. [Figure 11B] 1 is a photograph of polymer microspheres prepared using the single emulsion technique before dehydration. DETAILED DESCRIPTION OF THE INVENTION

[0023] Microsphere formulations containing ketamine are provided. The microsphere formulations include polymeric microspheres, each of which contains (i) an API that comprises, consists essentially of, or consists of ketamine; and (ii) a biodegradable polymer that comprises, consists essentially of, or consists of a PLA polymer. Each polymeric microsphere can have a drug load of about 10 wt / wt% to about 30 wt / wt%, and the polymeric microspheres have a diameter of about 80 μm (D 50 ) ~ approx. 110 μm (D 50 ), including 60 μm (D 50 ) or greater. In some aspects, the polymeric microspheres are characterized by multiple internal emulsions, each emulsion comprising water and a surfactant. In some aspects, the polymeric microspheres can be subjected to dehydration, in which case the polymeric microspheres are characterized by multiple internal macrovoids.

[0024] In some embodiments, the polymer microspheres are double-emulsified. A method for making double-emulsion polymer microspheres is provided, the method comprising: (i) contacting ketamine with a biodegradable PLA polymer in the presence of a solvent to form an organic component, and feeding the organic component to a first homogenizer; (ii) feeding an inner 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) feeding the primary emulsion to a second homogenizer at a first flow rate; (v) feeding 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 (iv) removing the solvent to form polymer microspheres, each of which incorporates at least a portion of the inner aqueous component in the form of multiple emulsions. In some embodiments, the polymeric microspheres may be subjected to dehydration, where the polymeric microspheres are characterized by a plurality of internal macrovoids.

[0025] API-Ketamine In some embodiments, ketamine comprises a racemic mixture. In some embodiments, ketamine can comprise esketamine, excluding alkene. Alternatively, ketamine can comprise alkene, excluding esketamine.

[0026] In some embodiments, ketamine can include any of ketamine, esketamine excluding alkene, and alkene excluding esketamine in a pharmaceutically acceptable salt or free base form. Suitable salts can include hydrochloride, sulfate, acetate, phosphate, diphosphate, chloride, maleate, citrate, mesylate, nitrate, tartrate, gluconate, etc. In other embodiments, complex salts such as ketamine palmitate, ketamine benzoate, ketamine tosylate, and ketamine camphorsulfonate can be used to reduce solubility.

[0027] Unless otherwise specified, the term "ketamine," as used herein, is intended to include both the racemic mixture as well as its individual enantiomers. In some embodiments, ketamine may be used in its racemic form. Alternatively, ketamine may be used in an enantiomeric form, such as its "S" or "R" form. Some embodiments may also include purified forms of the enantiomeric forms. For example, but not limited to, the ratio of the "S" enantiomer to the "R" enantiomer may be from 51:49 to 100:0, and all ranges included therein. Alternative embodiments may include a more purified form of the "R" enantiomer than the "S" enantiomer. For example, but not limited to, the ratio of the "R" enantiomer to the "S" enantiomer may be from 51:49 to 100:0, and all ranges included therein. Each enantiomer may also be present in its (+) or (-) form, e.g., S(+) or S(-) form. An alternative embodiment 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 all ranges included therein.An alternative embodiment 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 all ranges included therein.

[0028] In one embodiment, the API consists of or consists essentially of (S)-ketamine base (esketamine base). In one embodiment, the microsphere formulation does not include hydromorphone.

[0029] biodegradable polymers PLA can be a suitable biodegradable polymer. In one embodiment, the PLA can have an intrinsic viscosity ("IV") of about 0.30 to about 1.8 dL / g (including about 0.60 to about 0.70 dL / g, including about 0.66 dL / g or about 0.67 dL / g). In another embodiment, the PLA can have an IV of about 0.67 dL / g. In one embodiment, the biodegradable polymer is Ashland DL 07E PLA polymer, which has an IV of about 0.67 dL / g.

[0030] As the phrase is used herein, "poly(lactide) polymer" should be distinguished from and does not include poly(lactic-co-glycolic acid) polymers. When poly(lactic-co-glycolic acid) is intended, it is explicitly recited. In certain explicitly recited embodiments, suitable biodegradable polymers may include poly(lactic-co-glycolic acid) ("PLGA") copolymers, polyesteramides, polyanhydrides, polyacetals, polycaprolactones, and polycarbonates. In some embodiments, the biodegradable polymer may include a PLGA copolymer having a lactide to glycolide comonomer content ratio of about 50:50 to about 85:15. In one embodiment, the biodegradable polymer may have an average molecular weight of about 30 kDa to about 300 kDa.

[0031] In some embodiments, copolymers are specifically excluded. In one embodiment, PLGA polymers are specifically excluded. In some embodiments, PLGA polymers having a comonomer content ratio of about 50:50 lactide to glycolide are specifically excluded.

[0032] In some embodiments, the biodegradable polymers are ester end-capped. In some embodiments, acid end-capped biodegradable polymers are specifically excluded.

[0033] Dispersed Phase / Organic Component-Solvent Ketamine and polymer can be dissolved in a solvent mixture to form a dispersed phase (when using the single emulsion technique) or an organic component (when using the double emulsion technique). Suitable solvents 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, butyldioxitol 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-diethyl Examples of suitable solvents include nicotinamide, dimethyl sulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, 2-ethoxyethyl acetate, ethyl acetate, ethyl formate, ethylene glycol methyl ether acetate, formic acid, furfural, glycofurol, hexylene glycol, isobutanol, isopropyl alcohol, 2,6-lutidine, methyl acetate, methyl ethyl ketone, methyl isopropyl ketone, methyl propionate, N-methylpyrrolidone, morpholine, tert-pentanol, 2-picoline, 3-picoline, 4-picoline, piperidine, 1-propanol, propionaldehyde, propylene oxide, pyridine, pyrimidine, pyrrolidine, tetrahydrofuran, tetramethylurea, triacetin, triethylene glycol, trimethyl phosphate, and combinations thereof. In some embodiments, the solvent comprises DCM, ethanol, ethyl acetate, or a combination of two or all of these. In some embodiments, the solvent consists of or consists essentially of a combination of DCM and ethanol.In some embodiments, the solvent consists of or consists essentially of about a 5:1 (by volume) ratio of DCM:ethanol.

[0034] Double emulsion polymer microspheres - inner aqueous component In one embodiment, the organic component is homogenized with the internal aqueous component to form a primary emulsion. In one embodiment, the internal aqueous component comprises water. In one embodiment, the internal aqueous component comprises water and a surfactant. In one embodiment, the surfactant comprises polyvinyl alcohol ("PVA"). In some embodiments, the internal aqueous component comprises PVA in an amount of about 0.35% to about 1.0% by weight in water. In some embodiments, the internal aqueous component comprises PVA in an amount of about 0.35% by weight in water. In some embodiments, the internal aqueous component comprises PVA in an amount of about 1.0% by weight in water.

[0035] 11A and 11B are two photographs showing a comparison between polymer microspheres prepared using the double emulsion technique (FIG. 11A) and the single emulsion technique (FIG. 11B), respectively, before dehydration. Double emulsion polymer microspheres are characterized in that each polymer microsphere incorporates multiple emulsions comprising water and surfactant. In some embodiments, the polymer microspheres may be subjected to dehydration, in which case the polymer microspheres are characterized by multiple internal macrovoids.

[0036] In one aspect, dehydration can be achieved by freeze-drying, including lyophilization or cryodesication, a low-temperature dehydration process that involves freezing the polymer microspheres, reducing pressure, and removing the ice by sublimation, as opposed to dehydration methods that use heat to evaporate the water.

[0037] Continuous Phase The dispersed phase or primary emulsion can be homogenized with a continuous phase comprising water and, optionally, a surfactant such as PVA to form a secondary emulsion. The surfactant component can be present in the continuous phase in an amount of about 0.35% to about 1.0% by weight in water. In one embodiment, the surfactant component comprises PVA in an amount of about 0.35% by weight in water. In one embodiment, the surfactant component comprises PVA in an amount of about 1.0% by weight in water. The secondary emulsion can be subjected to a solvent removal and washing process to form double emulsion polymer microspheres.

[0038] In some embodiments, the flow rate of the dispersed phase / primary emulsion 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 embodiments, the flow rate of the continuous phase to the homogenizer can be about 2 L / min. Thus, in one embodiment, the continuous phase:dispersed phase / primary emulsion ratio can be from about 66:1 to about 200:1, including about 100:1 and about 80:1.

[0039] The continuous phase can be provided at, above, or below room temperature, hi some embodiments, 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 these values.

[0040] Homogenizer In some embodiments, homogenization of the organic component and the inner aqueous component may be performed in a high-speed homogenizer, such as a T25 Ultra-turrax high-speed homogenizer operating at 21,500 rpm for 30 seconds to form a primary emulsion. In other embodiments, homogenization of the organic component and the inner aqueous component may be performed in an ultrasonic processor, such as a Q700 Sonicator (Qsonica) or a Magic LAB® DISPAX-REACTOR® DR (IKA).

[0041] In some embodiments, homogenization of the dispersed phase / primary emulsion and the continuous phase may be performed in an emulsifier or homogenizer. For simplicity, and because the method is equally applicable to either, the term "homogenizer" contemplates a system or device capable of homogenizing the dispersed phase / primary emulsion and the continuous phase, emulsifying the dispersed phase / primary emulsion and the continuous phase, or both, which systems and devices are known in the art. For example, in one embodiment, the homogenizer is used an in-line Silverson Homogenizer (commercially available from Silverson Machines, Waterside, UK) or a Levitronix® BPS-i100 integrated pump system, as described, for example, in US20210001290, the entire contents of which are incorporated herein by reference. In one embodiment, the homogenizer is a membrane emulsifier. In one embodiment, the homogenizer operates at an impeller speed of about 1,000 to about 4,000 revolutions per minute ("RPM"), including about 1,600 RPM.

[0042] Average particle size The polymeric microspheres can be of any size that is safe and effective to inject by intramuscular or subcutaneous injection. In one embodiment, the polymeric microspheres are about 80 μm (D 50 ) ~ approx. 110 μm (D 50 ), including 60 μm (D 50 ) ultra~approx. 110 μm (D 50 In one embodiment, particle sizes of 60 μm or less are excluded. In one embodiment, particle sizes of less than 80 μm (D 50 ) particle size is excluded.

[0043] Drug load The drug load ratio of each polymer microsphere, expressed as a percentage, of drug to polymer can range from about 10 wt / wt% to about 50 wt / wt%, from about 10 wt / wt% to about 30 wt / wt%, or from about 10 wt / wt% to about 20 wt / wt%.

[0044] Sustained release The microsphere formulations are characterized by a duration of ketamine release of about 30 days in vitro (under physiologically relevant conditions) and in vivo. In some embodiments, 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.

[0045] Therapeutic benefits Potential conditions that may be treated using the microsphere formulations include depression, TRD, MDD, neurodegenerative diseases and conditions associated with excitotoxicity, including benzodiazepine withdrawal, pain, and other diseases or conditions that may be treated by inhibiting the action of NMDA receptors.

[0046] In one embodiment, depression, TRD, or MDD can be treated using a microsphere formulation, where the microsphere formulation is administered about every 30 days.

[0047] In another aspect, a method for treating depression, including TRD and / or MDD, is provided. The method comprises administering a microsphere formulation to a patient in need thereof, the microsphere formulation comprising polymeric microspheres, each polymeric microsphere comprising: (i) an API that comprises, consists essentially of, or consists of ketamine; and (ii) a biodegradable polymer that comprises, consists essentially of, or consists of a PLA polymer, each polymeric microsphere can comprise about 10 wt / wt% to about 30 wt / wt% drug load, and the polymeric microspheres have a diameter of about 80 μm (D 50 ) ~ approx. 110 μm (D 50 ), including 60 μm (D 50 In some embodiments, the microsphere formulation is administered to a patient by intramuscular or subcutaneous injection on a dosing schedule of about every 30 days.

[0048] In another aspect, a method of treating pain is provided, which may include administering a microsphere formulation made by the methods described herein to a patient in need thereof via intramuscular or subcutaneous injection.

[0049] In another aspect, disclosed is the use of a microsphere formulation comprising polymer microspheres, each polymer microsphere comprising (i) an API that comprises, consists essentially of, or consists of ketamine; and (ii) a biodegradable polymer that comprises, consists essentially of, or consists of a PLA polymer, each polymer microsphere can have a drug load of about 10 wt / wt% to about 30 wt / wt%, the polymer microspheres having a diameter of about 80 μm (D 50 ) ~ approx. 110 μm (D 50 ), including 60 μm (D 50 ) average particle size.

[0050] In another aspect, a microsphere formulation comprising polymeric microspheres, each polymeric microsphere comprising (i) an API that comprises, consists essentially of, or consists of ketamine; and (ii) a biodegradable polymer that comprises, consists essentially of, or consists of a PLA polymer, wherein each polymeric microsphere can comprise a drug load of about 10 wt / wt% to about 30 wt / wt%, and wherein the polymeric microspheres have a diameter of about 80 μm (D 50 ) ~ approx. 110 μm (D 50 ), including 60 μm (D 50 ) for use as a medicament for treating depression.

[0051] The microsphere formulation is a sustained release injectable formulation for administration by intramuscular or subcutaneous injection, but not intrathecally. In some embodiments, the intramuscular or subcutaneous injection formulation may further comprise sodium carboxymethylcellulose, Tween 80, and mannitol. [Example]

[0052] Example 1 - General preparation of polymer microspheres containing ketamine by single emulsion method Microsphere Formation Stage. Referring to Figure 1, a dispersed phase ("DP") 10 is formed by dissolving a polymer matrix (e.g., a PLA or PLGA polymer) in an organic solvent (e.g., DMC or ethyl acetate), followed by the addition of ketamine while mixing until completely dissolved. DP 10 is filtered using a 0.2 μm sterile PTFE or PVDF membrane filter (e.g., EMFLON, commercially available from Pall or Sartorious AG) and pumped at a specified flow rate into a homogenizer 30, such as an in-line Silverson homogenizer (commercially available from Silverson Machines, Waterside, UK) or a Levitronix i100 (described in US20210001290). A continuous phase ("CP") 20, comprising water and optionally PVA, is also pumped at a specified flow rate into the homogenizer 30. The speed of the homogenizer 30 is generally fixed to achieve the desired polymer microsphere size distribution. A representative sequential "upstream" microsphere formation step is described in US Pat. No. 5,945,126, which is incorporated herein by reference in its entirety.

[0053] Microsphere Processing Stages. Formed or forming microspheres exit the homogenizer 30 and enter a solvent removal vessel ("SRV") 40. During microsphere formation, water may be added to the SRV 40 to minimize the solvent level in the aqueous medium. After the DP 10 is discharged, the CP and water flow rates are stopped and a wash step is initiated. Solvent removal is achieved using a water wash and hollow fiber filter (commercially available as HFF from GE Healthcare) 50. Exemplary "downstream" microsphere processing stages are described in U.S. Patent No. 6,270,802, which is incorporated herein by reference in its entirety.

[0054] The washed microspheres are collected and freeze-dried overnight in a lyophilizer (Virtis) to remove moisture. The resulting microspheres are a free-flowing, off-white bulk powder.

[0055] Example 2 - Preparation of PLGA-based single emulsion microsphere formulations Batch No. 1: DP was formed by dissolving 1.25 g of ester-end-capped 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 in-line homogenizer operating at 2,000 rpm. CP containing water and 0.35% PVA was simultaneously pumped into the homogenizer at 2 L / min to form a single emulsion.

[0056] The formed or forming microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV at 2 L / min. Solvent removal was achieved using water washes and a hollow fiber filter. The bulk suspension was recovered by filtration and lyophilized to yield a free-flowing powder in approximately 45% yield.

[0057] Batch No. 1 was tested in an in vitro assay mimicking physiological conditions and resulted in esketamine release over a period of approximately 45 days, exceeding the desired 30 day release profile.

[0058] Example 3 - Preparation of PLA-based single emulsion microsphere formulations Batch No. 2: DP was formed by dissolving 1.25 g of ester-endcapped 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) while mixing until completely dissolved. The DP was filtered and pumped at 30 mL / min into a Silverson L4RT in-line homogenizer operating at 2,000 rpm. Water and CP containing 0.35% PVA were simultaneously pumped into the homogenizer at 2 L / min to form a single emulsion.

[0059] The formed or forming microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV at 2 L / min. Solvent removal was achieved using water washes and a hollow fiber filter. The bulk suspension was recovered by filtration and lyophilized to yield a free-flowing powder in approximately 36% yield.

[0060] Batch No. 2 was tested in an in vitro assay mimicking physiological conditions and resulted in esketamine release over a period of approximately 60 days, exceeding the desired 30-day release profile.

[0061] Example 4 - Effect of drug load on ketamine release in PLGA-based single emulsion microsphere formulations Batch No. 3: DP was formed by dissolving 4.5 g of ester-end-capped PLGA Evonik LG 855S polymer (85:15 PLGA with ester end-caps and an intrinsic viscosity of 3.0 dL / g) in 65.0 g of DCM, followed by the addition of esketamine (0.5 g) with mixing until completely dissolved. The DP was filtered and pumped at 30 mL / min into a Silverson L4RT in-line homogenizer operating at 1,000 rpm. Water and CP containing 0.35% PVA were simultaneously pumped into the homogenizer at 2 L / min to form a single emulsion.

[0062] The formed or forming microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV at 2 L / min. Solvent removal was achieved using water washes and a hollow fiber filter. The bulk suspension was recovered by filtration and lyophilized to yield a free-flowing powder in approximately 9% yield. The drug load was 8.0 wt / wt% (80% drug encapsulation efficiency based on a target drug load of 10 wt / wt%).

[0063] Batch No. 3 was tested in an in vitro assay mimicking physiological conditions and provided esketamine release over a period of more than 60 days, exceeding the desired 30-day release profile. See Figure 2.

[0064] Batch No. 4: To test the effect of drug load on ketamine release in PLGA-based single-emulsion microsphere formulations, another batch (Batch No. 4) was prepared with a target drug load of 75 wt / wt%. Therefore, DP was formed by dissolving 2.5 g of the same 85:15 PLGA used in Batch No. 3 in 51.0 g of DCM, followed by the addition of esketamine (7.5 g) while mixing until completely dissolved. The DP was filtered and pumped at 30 mL / min into a Silverson L4RT in-line homogenizer operating at 1,500 rpm. A CP containing water and 0.35% PVA was simultaneously pumped into the homogenizer at 2 L / min to form a single emulsion.

[0065] The formed or forming microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV at 2 L / min. Solvent removal was achieved using water washes and a hollow fiber filter. The bulk suspension was recovered by filtration and lyophilized to yield a free-flowing powder in approximately 34% yield. The drug load was 48.2 wt / wt% (64% drug encapsulation efficiency based on a target drug load of 75 wt / wt%).

[0066] Batch No. 4 was tested in an in vitro assay that mimics physiological conditions. The cumulative percent release of ketamine over time is shown in Figure 2. Batch No. 4 experienced an unacceptable "burst" with over 60% release in the first 5 days and continued to release ketamine beyond the desired 30-day release profile. See Figure 2.

[0067] Example 5 - Effect of comonomer ratio on ketamine release in PLGA- and PLA-based single emulsion microsphere formulations Batch No. 5: To test the effect of comonomer ratio, another batch (Batch No. 5) with a 75% drug load was prepared, this time using PLA polymer. Here, 1.25 g of ester-end-capped Evonik LG 209S polymer (PLA with an IV of 2.9 dL / g) was dissolved in 26.0 g of DCM, followed by the addition of esketamine (3.75 g) while mixing until completely dissolved to form a DP. The DP was filtered and pumped at 30 mL / min into a Silverson L4RT in-line homogenizer operating at 2,000 rpm. A CP containing water and 0.35% PVA was simultaneously pumped into the homogenizer at 2 L / min to form a single emulsion.

[0068] The formed or forming microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV at 2 L / min. Solvent removal was achieved using water washes and a hollow fiber filter. The bulk suspension was recovered by filtration and lyophilized to give a free-flowing powder in approximately 46% yield. The drug load was 76.0 wt / wt% (101% drug encapsulation efficiency based on a target drug load of 75 wt / wt%). The polymer microspheres of batch number 5 were 52 μm (D 10 ), 108 μm (D 50 ), 184 μm (D 90 ) average particle size.

[0069] Batch No. 5 was tested in an in vitro assay that mimics physiological conditions. The cumulative percent release of ketamine over time is shown in Figure 3. Batch No. 5 experienced a much less severe burst than Batch No. 4, with over 30% release in the first 5 days. However, Batch No. 5 continued to release ketamine beyond the desired 30-day release profile.

[0070] Example 6 - Effect of polymer microsphere size on ketamine release in PLGA-based single emulsion microsphere formulations Batch Nos. 6 and 6A: Each batch of DP was formed by dissolving 12.75 g of the same 85:15 PLGA polymer used in Batches Nos. 3 and 4 in 255.0 g of DCM, followed by the addition of esketamine (37.5 g) while mixing until completely dissolved. The DP was filtered and pumped into a Silverson L4RT in-line homogenizer at 30 mL / min. For Batch No. 6, the homogenizer was operated at 4,000 rpm. For Batch No. 6A, the homogenizer was operated at 3,000 rpm. For each batch, water and CP containing 0.35% PVA were simultaneously pumped into the homogenizer at 2 L / min to form a single emulsion.

[0071] For each batch, the formed or forming microspheres exited the homogenizer and entered an SRV. Deionized water was added to the SRV at 2 L / min. Solvent removal was achieved using water washes and a hollow fiber filter. The bulk suspension was recovered by filtration and lyophilized to yield a free-flowing powder.

[0072] Batch No. 6 resulted in a yield of approximately 23%. The drug load was 17.0 wt / wt% (23% drug encapsulation efficiency based on a target drug load of 75 wt / wt%). The particle size was 8 μm (D 10 ), 27μm(D 50 ), 57 μm (D 90 ) was.

[0073] Batch No. 6A resulted in a yield of approximately 29%. The drug load was 32.0 wt / wt% (43% drug encapsulation efficiency based on a target drug load of 75 wt / wt%). The particle size was 24 μm (D 10 ), 60 μm (D 50 ), 113 μm (D 90 ) was.

[0074] Batches Nos. 6 and 6A were tested in an in vitro assay mimicking physiological conditions. The cumulative percent release of ketamine over time as a function of particle size is shown in Figure 4. Batches Nos. 6 and 6A were ultimately deemed defective due to poor yield and encapsulation efficiency.

[0075] Example 7 - Effect of ethyl acetate as a solvent on ketamine release in PLA-based single emulsion microsphere formulations Batch No. 7: DP was formed by dissolving 7.0 g of ester-end-capped PLA Ashland Viatel 07 E polymer (IV = 0.66 dL / g) in 31.5 g of ethyl acetate, followed by the addition of esketamine (3.0 g) with mixing until completely dissolved. The DP was filtered and pumped at 30 mL / min into a Levitronix i100 (described in US20210001290) operating at 1,600 rpm. A CP containing water and 0.35% PVA was simultaneously pumped into the homogenizer at 2 L / min to form a single emulsion.

[0076] The formed or forming microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV at 2 L / min. Solvent removal was achieved using water washes and a tangential flow filter. The bulk suspension was recovered by filtration and lyophilized to yield a free-flowing powder.

[0077] Batch No. 7 gave a yield of approximately 70% with a drug load of 25.6 wt / wt% (85% drug encapsulation efficiency based on a target drug load of 30 wt / wt%).

[0078] Batch No. 7 was tested in an in vitro assay mimicking physiological conditions. The cumulative percent release of ketamine over time is shown in Figure 5. Batch No. 7 was ultimately deemed defective due to an unacceptably large burst, which is even more evident in vivo, as shown in Figure 8.

[0079] Example 8 - General preparation of polymer microsphere formulations containing ketamine by double emulsification method Microsphere Formation Stage. Referring to Figure 6, using like numerals for like elements to juxtapose to the single emulsion method shown in Figure 1, 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) followed by the addition of ketamine while mixing until completely dissolved. The organic component 12 is homogenized with an inner aqueous component ("IA component") 14, which contains water and optionally PVA, in a high-speed homogenizer probe (e.g., a T25 Ultra-turrax, sonicator, or Magic Lab® DISPAX-REACTOR®) 16 to form a primary emulsion ("PE") in place of the DP 10. The PE is pumped at a specified flow rate into a homogenizer 30, such as an in-line Silverson homogenizer or Levitronix i100 (described in US20210001290). CP20, which contains water and optionally PVA, is also pumped into homogenizer 30 at a specified flow rate.

[0080] Microsphere Processing Stage. Formed or forming microspheres exit the homogenizer 30 and enter the SRV 40. During microsphere formation, water 22 is added to the SRV 40 to minimize the solvent level. The resulting suspension is mixed in the SRV 40 for the duration of microsphere formation. After the PE is discharged, the addition of the CP and water flows is stopped and a wash step is initiated.

[0081] Solvent removal is achieved by washing the microspheres with ambient water (i.e., 25 °C) and warm water (35-39 °C) and filtering them through a hollow fiber filter (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 has been removed from the microsphere formulation.

[0082] 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.

[0083] The double emulsion method consistently resulted in surprisingly high yields compared to the single emulsion method.

[0084] Example 9 - Preparation and evaluation of low intrinsic viscosity (0.66 dL / g) PLA-based double emulsion microsphere formulations Batch No. 8: The organic component was formed by dissolving 7.0 g of ester-endcapped PLA Ashland Viatel 07 E 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) while mixing until completely dissolved. The organic component was homogenized with 1 mL of deionized water in a T25 Ultra-turrax high-speed homogenizer operating at 21,500 rpm for 30 seconds to form the PE.

[0085] The PE was pumped at a rate of 30 mL / min into a Levitronix i100 (described in US20210001290) operating at 1,600 rpm, with the CP containing water and 0.35% PVA pumped at a rate of 2 L / min, resulting in a CP:PE ratio of 66:1.

[0086] The formed or forming microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV at 2 L / min. Solvent removal was achieved by washing the microspheres with ambient water (i.e., 25 °C) and warm water (35-39 °C) and filtering through a hollow fiber filter.

[0087] The bulk suspension was collected by filtration and lyophilized to give a free-flowing powder with a yield of approximately 59%. The drug load was 16.5 wt / wt% (55% drug encapsulation efficiency based on a target drug load of 30 wt / wt%). The mean particle size was 47 μm (D 10 ), 82 μm (D 50 ), 132 μm (D 90 ) was.

[0088] Batch No. 8 was tested in an in vitro assay mimicking physiological conditions, and the cumulative percent release of ketamine over time is shown in Figure 5 (as a function of intrinsic viscosity of the biodegradable polymer, compared to other single and double emulsion batches) and Figure 7.

[0089] Example 10 - Preparation and evaluation of low intrinsic viscosity (0.66 dL / g) PLA-based double emulsion microsphere formulations containing PVA in the IA component Batch No. 9: The organic component was formed by dissolving 70.0 g of ester-endcapped PLA Ashland Viatel 07 E 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) while mixing until completely dissolved. The organic component was homogenized with the IA component, consisting of 11 mL of 0.35% PVA solution, for 45 seconds in a T25 Ultra-turrax high-speed homogenizer operating at 21,500 rpm to form the PE.

[0090] The PE was pumped at a rate of 30 mL / min into a Levitronix i100 (described in US20210001290) operating at 1,600 rpm, with the CP containing water and 0.35% PVA pumped at a rate of 2 L / min, resulting in a CP:PE ratio of 66:1.

[0091] The formed or forming microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV at 2 L / min. Solvent removal was achieved by washing the microspheres with ambient water (i.e., 25 °C) and warm water (35-39 °C) and filtering through a hollow fiber filter.

[0092] The bulk suspension was collected by filtration and lyophilized to give a free-flowing powder with a yield of approximately 72%. The drug load was 14.6 wt / wt% (49% drug encapsulation efficiency based on a target drug load of 30 wt / wt%). The mean particle size was 38 μm (D 10 ), 75μm(D 50 ), 123 μm (D 90 ) was.

[0093] Batch No. 9 was tested in an in vitro assay that mimics physiological conditions, and the cumulative percent release of ketamine over time (as a function of the intrinsic viscosity of the biodegradable polymer, compared to other single and double emulsion batches) is shown graphically in Figure 5.

[0094] Example 11 - Preparation and evaluation of high intrinsic viscosity (1.80 dL / g) PLA-based double emulsion microsphere formulations Batch No. 10: The organic component was formed by dissolving 7.0 g of ester-endcapped 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) while mixing until completely dissolved. The organic component was homogenized with the IA component, consisting of 1 mL of 0.35% PVA solution, for 30 seconds in a T25 Ultra-turrax high-speed homogenizer operating at 21,500 rpm to form the PE.

[0095] The PE was pumped at a rate of 30 mL / min into a Levitronix i100 (described in US20210001290) operating at 1,600 rpm, with CP containing water and 0.35% PVA pumped at a rate of 2 L / min, resulting in a CP:DP ratio of 66:1.

[0096] The formed or forming microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV at 2 L / min. Solvent removal was achieved by washing the microspheres with ambient water (i.e., 25 °C) and warm water (35-39 °C) and filtering through a hollow fiber filter.

[0097] The bulk suspension was collected by filtration and lyophilized to give a free-flowing powder with a yield of approximately 56%. The drug load was 17.4 wt / wt% (58% drug encapsulation efficiency based on a target drug load of 30 wt / wt%). The mean particle size was 27 μm (D 10 ), 67 μm (D 50 ), 136 μm (D 90 ) was.

[0098] Batch No. 10 was tested in an in vitro assay that mimics physiological conditions, and the cumulative percent release of ketamine over time (as a function of the intrinsic viscosity of the biodegradable polymer, compared to other single and double emulsion batches) is shown graphically in Figure 5.

[0099] Example 12 - Pharmacokinetic study in rats of batches no. 7, 9 and 10 The pharmacokinetic profile of ketamine was studied after subcutaneous injection of a sustained-release ketamine formulation into male Sprague-Dawly rats. Rats received a 50 mg / kg dose of the indicated batch number, with a ketamine concentration of 33.33 mg / mL and a volume of 1.5 mL / kg. The microsphere suspension concentrations (mg / mL) were as follows: (a) Batch No. 7: 130.21 mg; (b) Batch No. 9: 228.31 mg; and (c) Batch No. 10: 191.57 mg / mL. Blood samples were collected at 0.5, 1, 2, 4, 24, 48, 168, 264, 360, 480, 600, 720, 840, 960, 1080, and 1200 hours. FIG. 8 is a graph showing the mean blood concentrations (ng / mL) of ketamine measured as a function of time for batch numbers 7 (Example 7), 9 (Example 10), and 10 (Example 11).

[0100] Example 13 - Low intrinsic viscosity (0.67 dL / g) PLA-based double emulsion microsphere formulation with CP:PE ratio of 100:1 Batch Nos. 11A and 11B: An organic component was formed by dissolving 14.0 g of ester-endcapped PLA Ashland DL Viatel 07 E 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) while mixing until completely dissolved. The organic component was homogenized with an IA component consisting of 2.18 g of 0.35 PVA solution in a T25 Ultra-turrax high-speed homogenizer operating at 21,500 rpm for 30 seconds to form a PE with an organic:IA component ratio of approximately 49:1 (by weight).

[0101] The primary emulsion was pumped at a rate of 20 mL / min into a Levitronix i100 (described in US20210001290) operating at 1,600 rpm, with CP containing water and 0.35% PVA pumped at a rate of 2 L / min, resulting in a CP:PE ratio of 100:1.

[0102] The formed or forming microspheres exited the homogenizer, and a portion of the suspension (Batch No. 11A) entered the first SRV, where the microspheres were immediately subjected to deionized water at 2 L / min. Solvent removal was achieved by washing the microspheres with ambient water (i.e., 25°C) and warm water (35-39°C) and filtering through a hollow fiber filter. The bulk suspension was recovered by filtration and lyophilized to yield 6.6 g of a free-flowing powder. The drug load was 23.0 wt / wt% (77% drug encapsulation efficiency based on a target drug load of 30 wt / wt%). The mean particle size was 53 μm (D 10 ), 94μm(D 50 ), 152 μm (D 90 ) was.

[0103] The second portion of the suspension (Batch No. 11B) entered 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 No. 11A to yield 6.7 g of a free-flowing powder. The drug load was 9.2 wt / wt% (31% drug encapsulation efficiency based on a target drug load of 30 wt / wt%). The mean particle size was 50 μm (D 10 ), 90μm(D 50 ), 143 μm (D 90 The overall yield of batches 11A and 11B was 66.3%.

[0104] Batches 11A and 11B were tested in an in vitro assay that mimics physiological conditions, and the cumulative percent release of ketamine over time is shown graphically in FIG.

[0105] Example 14 - Low intrinsic viscosity (0.67 dL / g) PLA-based double emulsion microsphere formulation with CP:PE ratio of 80:1 Batch Nos. 12A and 12B: An organic component was formed by dissolving 10.5 g of ester-endcapped PLA Ashland DL 07 E 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) while mixing until completely dissolved. The organic component was homogenized with an IA component consisting of 1.64 g of a 0.35% PVA solution in a T25 Ultra-turrax high-speed homogenizer operating at 21,500 rpm for 30 seconds to form a PE with an organic:IA component ratio of approximately 49:1 (by weight).

[0106] The PE was pumped at a rate of 25 mL / min into a Levitronix i100 (described in US20210001290) operating at 1,600 rpm, with the CP containing water and 0.35% PVA pumped at a rate of 2 L / min, resulting in a CP:PE ratio of 80:1.

[0107] The formed or forming microspheres exited the homogenizer, and a portion of the suspension (Batch No. 12A) entered the first SRV, where the microspheres were immediately subjected to deionized water at 2 L / min. Solvent removal was achieved by washing the microspheres with ambient water (i.e., 25°C) and warm water (35-39°C) and filtering through a hollow fiber filter.

[0108] The bulk suspension was collected by filtration and lyophilized to yield 0.89 g of a free-flowing powder. The drug load was 24.8 wt / wt% (83% drug encapsulation efficiency based on a target drug load of 30 wt / wt%). The mean particle size was 57 μm (D 10 ), 111 μm (D 50 ), 189 μm (D 90 ) was.

[0109] The second portion of the suspension (Batch No. 12B) entered 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 No. 12A to yield 7.2 g of a free-flowing powder. The drug load was 17.4 wt / wt% (58% drug encapsulation efficiency based on a target drug load of 30 wt / wt%). The mean particle size was 54 μm (D 10 ), 99μm(D 50 ), 161 μm (D 90 The overall yield of batches 12A and 12B was 54%.

[0110] Batches Nos. 12A and 12B were tested in an in vitro assay that mimics physiological conditions, and the cumulative percent release of ketamine over time is shown graphically in FIG.

[0111] Example 15 - Low intrinsic viscosity (0.67 dL / g) PLA-based double emulsion microsphere formulation with CP:PE ratio of 80:1 Batch Nos. 13A and 13B: An organic component was formed by dissolving 10.5 g of ester-endcapped PLA Ashland DL 07 E 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) while mixing until completely dissolved. The organic component was homogenized with an IA component consisting of 1.64 g of a 0.35% PVA solution in a T25 Ultra-turrax high-speed homogenizer operating at 21,500 rpm for 30 seconds to form a PE with an organic:IA component ratio of approximately 49:1 (by weight).

[0112] The PE was pumped at a rate of 25 mL / min into a Levitronix i100 (described in US20210001290) operating at 1,600 rpm, with CP containing water and 0.35% PVA pumped at a rate of 2 L / min, resulting in a CP:DP ratio of 80:1.

[0113] The formed or forming microspheres exited the homogenizer, and a portion of the suspension (Batch No. 13A) entered the first SRV, where the microspheres were immediately subjected to deionized water at 2 L / min. Solvent removal was achieved by washing the microspheres with ambient water (i.e., 25°C) and warm water (35-39°C) and filtering through a hollow fiber filter.

[0114] The bulk suspension was collected by filtration and lyophilized to yield 2.99 g of a free-flowing powder. The drug load was 29.4 wt / wt% (98% drug encapsulation efficiency based on a target drug load of 30 wt / wt%). The mean particle size was 46 μm (D 10 ), 104 μm (D 50 ), 190 μm (D 90 ) was.

[0115] The second portion of the suspension (Batch No. 13B) entered 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 No. 13A to yield 7.09 g of a free-flowing powder. The drug load was 26.4 wt / wt% (88% drug encapsulation efficiency based on a target drug load of 30 wt / wt%). The mean particle size was 52 μm (D 10 ), 99μm(D 50 ), 162 μm (D 90 The overall yield of batches 13A and 13B was 67%.

[0116] Batches Nos. 13A and 13B were tested in an in vitro assay that mimics physiological conditions, and the cumulative percent release of ketamine over time is shown graphically in FIG.

[0117] Example 16 - Double emulsion microsphere formulation based on CP (1.0% PVA) and low intrinsic viscosity (0.67 dL / g) PLA with a CP:PE ratio of 80:1 Batch Nos. 14A and 14B: An organic component was formed by dissolving 12.45 g of ester-endcapped PLA Ashland DL 07 E 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) while mixing until completely dissolved. The organic component was homogenized with an IA component consisting of 1.64 g of a 0.35% PVA solution in a T25 Ultra-turrax high-speed homogenizer operating at 21,500 rpm for 30 seconds to form a PE with an organic:IA component ratio of approximately 57:1 (by weight).

[0118] The PE was pumped at a rate of 25 mL / min into a Levitronix i100 (described in US20210001290) operating at 1,600 rpm, with the CP containing water and 1.0% PVA pumped at a rate of 2 L / min, resulting in a CP:PE ratio of 80:1.

[0119] The formed or forming microspheres exited the homogenizer, and a portion of the suspension (Batch No. 14A) entered the first SRV, where the microspheres were immediately subjected to deionized water at 2 L / min. Solvent removal was achieved by washing the microspheres with ambient water (i.e., 25°C) and warm water (35-39°C) and filtering through a hollow fiber filter.

[0120] The bulk suspension was collected by filtration and lyophilized to yield 2.99 g of a free-flowing powder. The drug load was 14.5 wt / wt% (85% drug encapsulation efficiency based on a target drug load of 17 wt / wt%). The mean particle size was 32 μm (D 10 ), 87μm(D 50 ), 149 μm (D 90 ) was.

[0121] The second portion of the suspension (Batch No. 14B) entered 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 No. 14A to yield 6.95 g of a free-flowing powder. The drug load was 13.7 wt / wt% (81% drug encapsulation efficiency based on a target drug load of 17 wt / wt%). The mean particle size was 37 μm (D 10 ), 88μm(D 50 ), 148 μm (D 90 The overall yield of batches 14A and 14B was 75%.

[0122] Batches 14A and 14B were tested in an in vitro assay that mimics physiological conditions, and the cumulative percent release of ketamine over time is shown graphically in Figure 10, compared to an ideal 30-day release profile.

[0123] The embodiments disclosed herein are not intended to be exhaustive or limiting. Those skilled in the art will recognize that other embodiments or modifications to the embodiments may be made without departing from the spirit or scope of the present invention. The embodiments of the present disclosure, as generally described herein and illustrated in the figures, can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are contemplated herein. The present disclosure also includes the following preferred embodiments. (1) A microsphere formulation comprising: The preparation polymer microspheres, each polymer microsphere comprising: (i) esketamine; and (ii) a biodegradable poly(lactide) polymer having an intrinsic viscosity of about 0.6 dL / g to about 0.7 dL / g; Including, each polymeric microsphere having a ketamine drug loading of about 12 wt / wt% to about 17 wt / wt%; The polymer microspheres are approximately 80 μm (D 50 ) ~ approx. 110 μm (D 50 ) having a particle size of; and The polymeric microspheres are characterized in that each of the polymeric microspheres contains a plurality of internal macrovoids. The microsphere formulation. (2) The microsphere formulation of (1), wherein the polymer microspheres exhibit an average in vivo release rate of esketamine from the polymer microspheres of about 2.5% to about 3.5% per day over a 30-day period in humans. (3) A microsphere formulation comprising: The preparation polymer microspheres, each polymer microsphere comprising: (i) ketamine; and (ii) Biodegradable poly(lactide) polymers Including, each polymer microsphere having a drug loading of about 10 wt / wt% to about 30 wt / wt% of ketamine; The polymer microspheres are 60 μm (D 50 ) particle size greater than The microsphere formulation. (4) The polymer microspheres are approximately 80 μm (D 50 ) ~ approx. 110 μm (D 50 The microsphere preparation according to (3), having a particle size of (5) The microsphere formulation of (3), wherein the ketamine comprises esketamine in free base form. (6) 4. The microsphere formulation of (3), wherein each polymer microsphere has a drug loading of about 12 wt / wt% to about 17 wt / wt% of ketamine. (7) The microsphere formulation according to (3), wherein the biodegradable poly(lactide) polymer has an intrinsic viscosity of about 0.6 dL / g to about 0.7 dL / g. (8) The microsphere formulation of (3), wherein ketamine 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. (9) The microsphere formulation according to (3), wherein each of the polymer microspheres contains multiple internal emulsions comprising water and a surfactant. (10) The microsphere formulation according to (3), wherein each of the polymer microspheres contains a plurality of internal macrovoids. (11) 1. A method of making polymeric microspheres, the method comprising: (i) contacting ketamine with a biodegradable poly(lactide) polymer in the presence of a solvent to form an organic component, and feeding the organic component into a first homogenizer; (ii) providing an internal aqueous component comprising water and a first surfactant to a first homogenizer; (iii) homogenizing the organic component with the inner aqueous component to form a primary emulsion; (iv) feeding the primary emulsion at a first flow rate into a second homogenizer; (v) feeding a continuous phase comprising water and a second surfactant at a second flow rate to a second homogenizer; (vi) homogenizing the primary emulsion and the continuous phase; and (iv) Removing the solvent to form polymer microspheres. Including, The above method, wherein each of the formed polymeric microspheres entraps at least a portion of the internal aqueous component in the form of multiple emulsions. (12) 12. The method of claim 11, further comprising dehydrating the polymer microspheres, wherein the dehydrated polymer microspheres each comprise a plurality of internal macrovoids. (13) 12. The method of claim 11, wherein the biodegradable poly(lactide) polymer has an intrinsic viscosity of about 0.6 dL / g to about 0.7 dL / g. (14) 12. The method of claim 11, wherein the first surfactant comprises polyvinyl alcohol in water in an amount of about 0.35% by weight. (15) The method of (11), wherein the biodegradable poly(lactide) polymer comprises about 10% to about 15% of the organic component. (16) The method according to (11), wherein the solvent comprises a mixture of methylene chloride and ethanol. (17) The method according to (11), wherein the solvent comprises a mixture of methylene chloride and ethanol in a volume ratio of 5:1. (18) The method according to (11), wherein the ketamine contains about 3.3% to about 5.5% organic components. (19) The method according to (11), wherein the second surfactant comprises polyvinyl alcohol in an amount of about 0.35% by weight to about 1.0% by weight in water. (20) The method of (11), wherein the second surfactant comprises polyvinyl alcohol in an amount of about 1.0% by weight in water. (21) The method according to (11), wherein the ratio of the continuous phase flow rate to the primary emulsion flow rate is from about 66:1 to about 200:1. (22) 1. A method for treating depression, the method comprising intramuscularly or subcutaneously injecting a therapeutically effective amount of a microsphere formulation into a patient in need thereof, the microsphere formulation comprising: polymer microspheres, each polymer microsphere comprising: (i) esketamine; and (ii) Biodegradable poly(lactide) polymers Includes; each polymer microsphere having a drug loading of about 10 wt / wt% to about 30 wt / wt% of ketamine; The polymer microspheres are 60 μm (D 50 ) particle size greater than The above method. (23) The polymer microspheres are approximately 80 μm (D 50 ) ~ approx. 110 μm (D 50 The method according to (22), wherein the particle size is (24) 22. The method of claim 21, wherein each polymer microsphere has a drug loading of about 12 wt / wt% to about 17 wt / wt% of ketamine. (25) 22. The method of claim 21, wherein the biodegradable poly(lactide) polymer has an intrinsic viscosity of about 0.6 dL / g to about 0.7 dL / g. (26) 22. The method of claim 21, wherein the ketamine 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.

[0124] Unless otherwise stated, "a," "an," "the," "one or more of," and "at least one" are used interchangeably. The singular forms "a," "an," and "the" include their plural forms. The recitation of numerical ranges by endpoints includes all numbers subsumed within 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 "consisting essentially of" means that the composition or method may include additional ingredients and / or steps, but only if the additional ingredients and / or steps do not materially alter the basic and novel characteristics of the claimed composition or method. The phrase "selected from the group consisting of" means including mixtures of the recited group.

[0125] Reference to the term "each" does not mean "each and every, without exception." For example, when referring to a microsphere formulation containing polymer microspheres, and saying that "each polymer microsphere" has a particular ketamine content, if there are 10 polymer microspheres and two or more of the polymer microspheres have the particular ketamine content, then it is intended that a subset of the two or more polymer microspheres satisfy the constraint.

[0126] The term "about" in connection with a number is intended to include ±10% of that number. This is true whether "about" is modifying an individual number or either or both numbers at the ends of a numerical range. In other words, "about 10" means 9 to 11. Similarly, "about 10 to about 20" contemplates 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 formulation comprising: The preparation polymer microspheres, each polymer microsphere comprising: Ketamine or esketamine; and Biodegradable polymers made from poly(lactide) polymers Including, each polymeric microsphere having a drug loading of 10 wt / wt% to 30 wt / wt% of ketamine or esketamine; The polymer microspheres are 60 μm (D ５０ ) and The polymeric microspheres are characterized in that each of the polymeric microspheres contains a plurality of internal macrovoids. The microsphere formulation.

2. The polymer microspheres are 60 μm (D ５０ ) Ultra~110μm (D ５０ 2. The microsphere formulation of claim 1, having a particle size of 0.15 .mu.m.

3. 10. The microsphere formulation of claim 1, wherein each polymeric microsphere has a drug loading of 12 wt / wt% to 17 wt / wt% of ketamine or esketamine.

4. The microsphere formulation of claim 1, wherein the biodegradable polymer consisting of a poly(lactide) polymer has an intrinsic viscosity of 0.6 dL / g to 0.7 dL / g.

5. 10. The microsphere formulation of claim 1, wherein the ketamine or esketamine exhibits an in vivo release of 75% to 100% over a period of 30 days ± 10% after injection into a subject, but wherein at most 10% of the ketamine or esketamine is released within 24 hours after injection into a subject.

6. 10. A method of making the microsphere formulation of claim 1, the method comprising: (i) contacting ketamine or esketamine with a biodegradable polymer comprising a 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 inner aqueous component comprising water and a first surfactant to a first homogenizer; (iii) homogenizing the organic component with the inner aqueous component to form a primary emulsion; (iv) feeding the primary emulsion at a first flow rate into a second homogenizer; (v) feeding a continuous phase comprising water and a second surfactant at a second flow rate to a second homogenizer; (vi) homogenizing the primary emulsion and the continuous phase; and (iv) Removing the solvent to form polymer microspheres. Including, The above method, wherein each of the formed polymeric microspheres entraps at least a portion of the internal aqueous component in the form of multiple emulsions.

7. 7. The method of claim 6, further comprising dehydrating the polymeric microspheres to form a plurality of internal macrovoids.

8. The method of claim 6, wherein the biodegradable polymer comprising a poly(lactide) polymer has an intrinsic viscosity of 0.6 dL / g to 0.7 dL / g.

9. 7. The method of claim 6, wherein the solvent comprises a mixture of methylene chloride and ethanol.

10. 7. The method of claim 6, wherein the solvent comprises a mixture of methylene chloride and ethanol in a 5:1 volume ratio.

11. 1. A composition for use in a method for treating depression, comprising a therapeutically effective amount of the microsphere formulation of claim 1, the method comprising intramuscularly or subcutaneously injecting the composition into a patient in need of treatment. The above composition.

12. The polymer microspheres are 60 μm (D ５０ ) Ultra~110μm (D ５０ 12. The composition of claim 11, wherein the particle size is 0.05 to 0.15 μm.

13. 12. The composition of claim 11, wherein each polymeric microsphere has a drug loading of 12 wt / wt% to 17 wt / wt% of ketamine or esketamine.

14. The composition of claim 11, wherein the biodegradable polymer comprising a poly(lactide) polymer has an intrinsic viscosity of 0.6 dL / g to 0.7 dL / g.

15. 12. The composition of claim 11, wherein the ketamine or esketamine exhibits an in vivo release of 75% to 100% over a period of 30 days ± 10% after injection into a subject, but wherein at most 10% of the ketamine or esketamine is released within 24 hours after injection into a subject.

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