Method for preparing microparticles comprising glatiramer acetate

Abstract

The present invention provides an improved process for preparing microparticles comprising glatiramer acetate having low levels of residual organic solvent, in particular dichloromethane. The microparticles are incorporated into long-acting parenteral pharmaceutical compositions in a depot form, suitable for subcutaneous or intramuscular implantation or injection and useful for the treatment of multiple sclerosis.

Description

[0001] This application is a divisional application of the international application PCT / IL2017 / 050954 filed on August 28, 2017, which entered the Chinese national phase on February 28, 2019, with application number 201780053557.3 and the invention title "Method for preparing microparticles containing glatiramer acetate". Technical Field

[0002] This invention relates to an improved method for preparing microparticles containing glatiramer acetate, the microparticles having low levels of residual organic solvents, particularly dichloromethane (DCM). The microparticles are incorporated into a long-acting parenteral pharmaceutical composition in depot form, the long-acting parenteral pharmaceutical composition being suitable for subcutaneous or intramuscular implantation or injection, and the long-acting parenteral pharmaceutical composition being used to treat multiple sclerosis. Background Technology

[0003] By product name The glatiramer acetate (GA) sold is indicated for the treatment of patients with relapsing-remitting forms of multiple sclerosis. Glatiramer acetate is a random polymer containing four amino acids found in myelin basic protein. Glatiramer acetate comprises acetates of polypeptides containing L-glutamic acid, L-alanine, L-tyrosine, and L-lysine. The average molar fractions of these amino acids are 0.141, 0.427, 0.095, and 0.338, respectively, and the average molecular weight of copolymer-1 is between 5,000 and 9,000 Daltons. Chemically, glatiramer acetate is referred to as the acetate of a polymer of L-glutamic acid with L-alanine, L-lysine, and L-tyrosine. Its structural formula is (Glu, Ala, Lys, Tyr). x CH3COOH, approximately in proportion to Glu 14 Ala 43 Tyr 10 Lyz 34x (CH3COOH) 20 .

[0004] It is manufactured as a solution for subcutaneous injection. Each 1 mL... The solution contains 20 mg or 40 mg of glatiramer acetate and 40 mg of mannitol. A strength of 20 mg / mL is suitable for daily injection, while a strength of 40 mg / mL is suitable for injection three times a week. Common side effects include injection site lumps (injection site reaction), pain, fever, and chills.

[0005] U.S. Patent Nos. 8,377,885 and 8,796,226 describe pharmaceutically acceptable parenteral compositions of glatiramer (including glatiramer acetate) in reservoir form suitable for subcutaneous or intramuscular implantation or injection. These are compatible with daily injectable... Compared to other formulations, this long-acting composition provides the same or better therapeutic efficacy with reduced incidence and / or severity of side effects such as injection site irritation due to the reduced frequency of administration. The composition is prepared via a "double emulsification" method. An aqueous solution of glatiramer acetate is dispersed in a solution of a biodegradable polymer (PLGA) in a water-immiscible volatile organic solvent. The resulting "water-in-oil (w / o) emulsion" is dispersed in a continuous external aqueous phase containing a surfactant to form "water-in-oil-in-water (w / o / w) double emulsion" droplets. The organic solvent is slowly evaporated by stirring the double emulsion in a fume hood. The resulting microparticles are collected by filtration or centrifugation, washed with water, and lyophilized. The solvents used in the above method are halogenated hydrocarbons, particularly chloroform or dichloromethane, which act as solvents for the polymer. However, the presence of residual but detectable halogenated hydrocarbon solvents in the final product is undesirable due to the general toxicity and potential carcinogenic activity of halogenated hydrocarbon solvents. To address this issue, regulatory agencies have imposed limits on the amount of residual organic solvents present in pharmaceutical compositions intended for human and veterinary use.

[0006] There is a need in the art for improved and reliable methods for preparing microparticles containing glatiramer acetate, wherein the microparticles have low levels of residual organic solvents, particularly halogenated organic solvents. Summary of the Invention

[0007] This invention provides an improved method for preparing microparticles containing glatiramer acetate, the microparticles having low levels of residual organic solvents, particularly halogenated hydrocarbons such as dichloromethane. Unexpectedly, it has been found that by modifying the organic solvent evaporation step in the double emulsification method previously described in US8,377,885 and US8,796,226, the organic solvent level can be reduced to a regulatoryly acceptable level (e.g., less than about 600 ppm for dichloromethane). A major challenge in modifying the method is maintaining the microparticle morphology, binding percentage, and release profile of the active ingredient glatiramer acetate while the method is modified. It has now been found that products produced by applying vacuum and / or airflow to a double water-in-oil-in-water double emulsion have reduced levels of organic solvents while still retaining intact glatiramer acetate microparticles. In particular, by carefully adjusting the mixing, air bubbling, and / or vacuum intensity, microparticles with desired morphology and therapeutic properties (e.g., drug release profiles) can be obtained while minimizing the organic solvent level to a regulatoryly acceptable level. For example, the regulatory limit for chlorinated organic solvents such as dichloromethane (DCM, also known interchangeably as methylene chloride) is 600 ppm according to ICH guidelines.

[0008] Therefore, the present invention provides a method for preparing microparticles containing glatiramer acetate, the method comprising the following steps: (a) preparing an internal aqueous phase containing glatiramer acetate and water; (b) preparing an organic phase containing a biodegradable polymer or a bionon-degradable polymer and a volatile organic solvent immiscible with water; (c) preparing an external aqueous phase containing water and a surfactant; (d) mixing the internal aqueous phase obtained in step (a) with the organic phase obtained in step (b) to form a water-in-oil (w / o) emulsion; (e) mixing the water-in-oil (w / o) emulsion obtained in step (d) with the external aqueous phase obtained in step (c) to obtain a water-in-oil (w / o / w) double emulsion; (f) removing the organic solvent by mixing the water-in-oil (w / o / w) double emulsion obtained in step (e) and applying an airflow and / or vacuum; and (g) drying to obtain microparticles of glatiramer acetate containing less than about 1,000 ppm of residual organic solvent. In one embodiment, step (f) is carried out under conditions sufficient to reduce the level of the organic solvent to at least about 1,000 ppm, preferably less than about 600 ppm.

[0009] As anticipated herein, the products produced by the methods of the present invention have reduced levels of residual organic solvents, thereby complying with regulatory restrictions. In one embodiment, the particles contain less than about 600 ppm of residual organic solvents, which is a regulatory restriction on chlorinated solvents such as DCM according to ICH guidelines. In another embodiment, the particles contain less than about 500 ppm of residual organic solvents. In yet another embodiment, the particles contain less than about 250 ppm of residual organic solvents. In still another embodiment, the particles contain less than about 100 ppm of residual organic solvents.

[0010] In other embodiments, the particles contain less than about 0.1% residual organic solvent. In another embodiment, the particles contain less than about 0.05% residual organic solvent. In yet another embodiment, the particles contain less than about 0.01% residual organic solvent.

[0011] The organic solvent used in the method of this invention is immiscible with water and is volatile. In some preferred embodiments of the invention, the organic solvent is a halogenated organic solvent, such as a halogenated hydrocarbon. In some preferred embodiments of the invention, the chlorinated hydrocarbon is dichloromethane or chloroform, each of which represents a separate embodiment of the invention.

[0012] In one particular embodiment, the method of the present invention utilizes dichloromethane as an organic solvent. According to this embodiment, the resulting particles contain less than about 600 ppm, preferably less than about 500 ppm, less than about 250 ppm, or less than about 100 ppm of residual dichloromethane.

[0013] The solvent removal step (f) comprises mixing the water-in-oil-in-water (w / o / w) dual emulsion and applying an airflow and / or vacuum to the water-in-oil-in-water (w / o / w) dual emulsion. As described herein, the mixing, application of the airflow, and / or vacuum are carried out under suitable conditions that do not affect the integrity of the final product (e.g., its morphology, GA binding percentage, or release profile) while still producing a product with low levels of organic solvents.

[0014] In some embodiments, a homogenizer may be used to mix the w / o / w dual emulsion, preferably at a speed of at least about 2,500 rpm, and preferably at least about 2,750 RPM. In some embodiments, step (f) includes a combination of mixing the w / o / w dual emulsion and applying a vacuum. Preferably, the vacuum is applied for at least about 3 hours, or at least about 5 hours. In other embodiments, step (f) includes a combination of mixing the w / o / w dual emulsion and applying a compressed air stream to the w / o / w dual emulsion at a pressure of about 0.1 bar to 1 bar, preferably about 0.5 bar, or any value therebetween. In yet another embodiment, as described above, step (f) includes mixing the w / o / w dual emulsion while simultaneously applying a compressed air stream and a vacuum.

[0015] After solvent evaporation, glatiramer acetate microparticles are separated by drying (step (g)). In some embodiments, this step includes drying the obtained microparticles into bulk or unit dose preparations. Drying can be carried out by any method known in the art, such as lyophilization or freeze-drying, or any other suitable drying method. In other embodiments, the method further includes filtering or centrifuging the product of step (f), optionally washing with water prior to drying, thereby obtaining glatiramer acetate microparticles. The polymer used in the organic phase can be biodegradable or bionon-biodegradable. In some embodiments, the biodegradable or bionon-biodegradable polymer is selected from the group consisting of poly(D,L,l,l) lactic acid (PLA), polyglycolic acid (PGA), poly(lactide-co-glycolic acid) (PLGA), polycaprolactone, polyhydroxybutyrate, polyorthoester, polyalkaneanhydride, gelatin, collagen, oxidized cellulose, and polyphosphazene, wherein each possibility represents a separate embodiment of the invention. In some preferred embodiments of the invention, the polymer is a biodegradable polymer selected from the group consisting of PLA, PGA, and PLGA. A preferred biodegradable polymer of the present invention is PLGA.

[0016] In another embodiment, the external aqueous phase comprises a surfactant selected from polyvinyl alcohol (PVA), partially hydrolyzed polyvinyl alcohol (PVA), polysorbate, polyethylene oxide-polypropylene oxide block copolymer, and cellulose ester. Each possibility represents a separate embodiment of the invention. In a preferred embodiment of the invention, the surfactant is PVA or partially hydrolyzed PVA.

[0017] In another embodiment, the composition further comprises a tension modifier. A preferred tension modifier is sodium chloride, which is added to one or more aqueous phases to generate osmotic equilibrium. Other suitable tension modifiers are described in detail below.

[0018] According to some implementation schemes, glatiramer acetate contains acetates of L-alanine, L-glutamic acid, L-lysine and L-tyrosine in the following molar ratios: about 0.14 glutamic acid, about 0.43 alanine, about 0.10 tyrosine and about 0.33 lysine.

[0019] According to other embodiments, glatiramer acetate or other pharmaceutically acceptable salts of glatiramer contain about 15 to about 100 amino acids.

[0020] In some embodiments, the microparticles contain about 20 mg to about 750 mg of glatiramer acetate. In other embodiments, the microparticles contain about 40 mg of glatiramer acetate. In other embodiments, the microparticles contain about 80 mg of glatiramer acetate.

[0021] As anticipated herein, glatiramer acetate microparticles are prepared in the form of a reservoir formulation suitable for subcutaneous or intramuscular implantation at a medically acceptable location in a subject with appropriate need. Therefore, in some embodiments, the present invention relates to a long-acting parenteral pharmaceutical composition comprising a therapeutically effective amount of glatiramer acetate, said composition being in the form of a sustained-release reservoir, said composition being suitable for subcutaneous or intramuscular implantation at a medically acceptable location in a subject with appropriate need, said composition comprising glatiramer acetate microparticles prepared according to the method of the present invention.

[0022] According to some embodiments, the long-acting reservoir is suitable for a dosing regimen from about once a week to about once every 6 months. According to a specific embodiment, the composition is suitable for dosing from about once every 2 weeks to about once a month.

[0023] According to other embodiments, the long-acting reservoir releases a therapeutically effective amount of glatiramer acetate over a period of approximately one week to approximately six months. According to other embodiments, the long-acting reservoir releases a therapeutically effective amount of glatiramer acetate over a period of approximately two weeks to approximately one month. Specific examples of long-acting compositions include biodegradable or non-biodegradable microspheres, implants of any suitable geometry, implantable rods, implantable capsules, implantable rings, or extended-release gels and erosive matrices. Each possibility represents a separate embodiment of the invention.

[0024] The present invention also provides a method for treating multiple sclerosis, the method comprising parenteral administration or implantation of a reservoir composition comprising a therapeutically effective amount of glatiramer acetate, the composition being prepared according to the method of the present invention.

[0025] Advantageously, the pharmaceutical composition provides equivalent or better therapeutic efficacy than commercially available daily injectable formulations, with a reduced incidence and / or severity of side effects at local or systemic levels.

[0026] This invention includes a composition comprising glatiramer acetate in reservoir form prepared according to the method of the invention. This reservoir formulation is suitable for implantation in individuals with the appropriate need for use in the treatment of multiple sclerosis, particularly relapsing-remitting multiple sclerosis (RRMS).

[0027] The present invention also includes the use of an implantable reservoir of glatiramer acetate prepared according to the method of the present invention, the reservoir being adapted to provide prolonged release or prolonged action of glatiramer in a subject.

[0028] Further embodiments and the full scope of the invention will become apparent from the detailed description given below. However, it should be understood that while the detailed description and specific embodiments illustrate preferred embodiments of the invention, they are given by way of example only, as various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art based on this detailed description. Detailed Implementation

[0029] This invention provides an improved method for preparing microparticles containing glatiramer acetate, the microparticles having low levels of residual organic solvents, particularly dichloromethane. The microparticles are in the form of a reservoir formulation that can be administered via parenteral (e.g., intramuscular or subcutaneous) and daily. Injection provides equivalent or better therapeutic efficacy compared to the reservoir formulation, and thus leads to improved patient compliance. In addition to providing similar therapeutic efficacy and reduced side effects, the long-acting reservoir composition contains low levels of residual organic solvents (e.g., dichloromethane), thereby complying with regulatory requirements regarding permissible residual amounts of these solvents.

[0030] The particulate compositions of the present invention comprise a water-in-oil-in-water (w / o / w) dual emulsion. The dual emulsion comprises an inner aqueous phase containing glatiramer acetate, an oil phase or an organic phase immiscible with water containing a biodegradable or non-biodegradable polymer and an organic solvent immiscible with water, and an outer aqueous phase containing a surfactant and optionally a surface tension modifier. The terms "oil phase" and "water-immiscible organic phase" are used interchangeably herein.

[0031] Preparation of microparticles The compositions of the present invention can be prepared into injectable microparticles by a method known as the “double emulsification” method, which represents an improvement on the methods described in US 8,377,885 and US 8,796,226. According to the principles of the invention, a solution of glatiramer acetate is dispersed in a solution of a biodegradable polymer or a bionon-degradable polymer in a volatile organic solvent immiscible with water. The resulting “water-in-oil (w / o) emulsion” is then dispersed in a continuous external aqueous phase containing a surfactant to form “water-in-oil (w / o / w) double emulsion” droplets. The water-in-oil (w / o / w) double emulsion is then removed (i.e. evaporated) by mixing the water-in-oil (w / o / w) double emulsion under conditions sufficient to reduce the amount of organic solvent to a level acceptable for pharmaceutical application (e.g., in accordance with ICH guidelines) and applying an airflow and / or vacuum. The methods described in US 8,377,885 and US 8,796,226 do not contemplate applying an airflow or vacuum during the solvent evaporation step. In some embodiments, the level of residual organic solvent is reduced to at least the maximum residual solvent allowed by the regulatory authority. Typically, the level of residual organic solvent is reduced to at least about 1,000 ppm. When using halogenated organic solvents (e.g., dichloromethane), this level is preferably reduced to at least about 600 ppm, which is the maximum level allowed by the regulator. After evaporation of the organic solvent, the microparticles are solidified and collected by filtration or centrifugation. The collected microparticles (MPs) are washed with purified water to remove most of the surfactants and unbound peptides and centrifuged again. The washed MPs are collected and lyophilized without additives or the addition of cryoprotectants (e.g., mannitol) to facilitate their subsequent remodeling. Surprisingly, using the method of the present invention, the glatiramer acetate microparticles obtained retain the desired properties of the microparticles, such as morphology, binding percentage (“potency”), and release profile, while still achieving a reduced level of organic solvent.

[0032] According to the present invention, glatiramer acetate microparticles are prepared by a method comprising the following steps: (a) preparing an inner aqueous phase comprising glatiramer acetate and water; (b) preparing an organic phase comprising a biodegradable polymer or a bionon-degradable polymer and a volatile organic solvent immiscible with water; (c) preparing an outer aqueous phase comprising water and a surfactant; (d) mixing the inner aqueous phase obtained in step (a) with the organic phase obtained in step (b) to form a water-in-oil (w / o) emulsion; (e) mixing the water-in-oil (w / o) emulsion obtained in step (d) with the outer aqueous phase obtained in step (c) to obtain a water-in-oil (w / o / w) double emulsion; (f) removing the organic solvent by mixing the water-in-oil (w / o / w) double emulsion obtained in step (e) and applying an air stream and / or vacuum; and (g) drying to obtain glatiramer acetate microparticles containing less than about 1,000 ppm, preferably less than 600 ppm, of residual organic solvent. In one embodiment, step (f) is carried out under conditions sufficient to reduce the level of the organic solvent to at least about 1,000 ppm, preferably less than about 600 ppm.

[0033] Internal water phase The internal aqueous phase comprises glatiramer acetate and water, preferably sterile water for injection (WFI). Suitable concentrations of glatiramer acetate in the internal aqueous phase range from about 10 mg / mL to about 150 mg / mL, or any amount in between. For example, the concentration of glatiramer acetate in the internal aqueous phase can be between 80 mg / mL and 120 mg / mL, between 90 mg / mL and 110 mg / mL, and so on.

[0034] To prepare the internal aqueous phase, a solution containing sterile WFI and glatiramer acetate was prepared and optionally filtered.

[0035] Organic phase (phase that is immiscible with water) The organic phase comprises a biodegradable or non-biodegradable polymer and an organic solvent. The organic solvent is immiscible with water and volatile. In some preferred embodiments of the invention, the organic solvent is a halogenated hydrocarbon. In some embodiments, the halogenated solvent is a chlorinated solvent, such as dichloromethane or chloroform. Dichloromethane may also be interchangeably referred to as dichloromethane or DCM. Each possibility represents a separate embodiment of the invention.

[0036] In one particular embodiment, the method of the present invention utilizes dichloromethane as an organic solvent. The regulatory-permitted amount of this solvent in the pharmaceutical composition is about 600 ppm. Therefore, the particles obtained by the method of the present invention preferably contain less than about 600 ppm of dichloromethane. In a preferred embodiment, the resulting particles contain less than about 500 ppm, for example less than about 250 ppm or less than about 100 ppm of residual dichloromethane. Each possibility represents a separate embodiment of the present invention.

[0037] The polymer can be a biodegradable polymer or a non-biodegradable polymer, with biodegradable polymers being preferred. As used herein, the term "biodegradable" refers to a component that, at least in part, undergoes erosion or degradation over time at its surface due to contact with substances present in the surrounding tissue fluid or through cellular action. Specifically, biodegradable components are polymers, such as, but not limited to, lactic acid-based polymers, such as polylactide, for example, poly(D,L-lactide) i.e., PLA; and glycolic acid-based polymers, such as polyglycolic acid (PGA), for example, from Durect. Poly(D,L-lactide-co-glycolic acid) is also known as PLGA (from Boehringer). RG-504 RG-502 RG-504H, RG-502H, RG-504S RG-502S, from Durect Polycaprolactones, such as poly(e-caprolactone), i.e., PCL (from Durect), are used in this context. Poly(acrylic anhydride); Poly(sebacic acid) SA; Poly(ricinoleic acid) RA; Poly(fumaric acid), FA; Poly(fatty acid dimer), FAD; Poly(terephthalic acid), TA; Poly(isophthalic acid), IPA; Poly(p-carboxyphenoxymethane), CPM; Poly(p-carboxyphenoxypropane), CPP; Poly(p-carboxyphenoxyhexane), CPH; Polyamines, Polyurethanes, Polyesteramides, Polyorthoesters {CHDM: cis / trans-cyclohexyldiethanol, HD: 1,6-hexanediol, DETOU: (3,9-diethylidene-2,4,8,10-tetraoxolobutane)}; Polydioxanones; Polyhydroxybutyrate; Polyalkylene oxalate; Polyamide; Polyesteramide; Polyurethane; Polyacetal; Polyketal; Poly Carbonates; polyorthocarbonates; polysiloxanes; polyphosphazenes; succinates; hyaluronic acid; poly(malic acid); poly(amino acid); polyhydroxyvalerate; polyalkylene succinate; polyvinylpyrrolidone; polystyrene; synthetic cellulose esters; polyacrylic acid; polybutyric acid; triblock copolymers (PLGA-PEG-PLGA), triblock copolymers (PEG-PLGA-PEG), poly(N-isopropylacrylamide) (PNIPAAm), poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymers (PEO-PPO-PEO), polyvaleric acid; polyethylene glycol; polyhydroxyalkyl cellulose; chitin; chitosan; polyorthoesters and copolymers, terpolymers; lipids such as cholesterol, lecithin; poly(glutamic acid-co-ethylglutamic acid), etc., or mixtures thereof. Each possibility represents a separate embodiment of the invention.

[0038] In some embodiments, the microparticles comprise a biodegradable polymer selected from, but not limited to, PLGA, PLA, PGA, polycaprolactone, polyhydroxybutyrate, polyorthoester, polyalkane anhydrides, gelatin, collagen, oxidized cellulose, polyphosphazene, etc. In other embodiments, the microparticles comprise a biodegradable polymer selected from, but not limited to, PLGA, PLA, and PGA. Each possibility represents a separate embodiment of the invention.

[0039] The preferred biodegradable polymers of the present invention are lactic acid-based polymers, more preferably polylactide or poly(D,L-lactide-co-glycolic acid), i.e., PLGA. Preferably, the biodegradable polymer is present in an amount between about 10% and about 98% w / w of the composition. The lactic acid-based polymer has a monomer ratio of lactic acid to glycolic acid in the range of about 100:0 to about 0:100, preferably about 100:0 to about 10:90, and has an average molecular weight from about 1,000 Daltons to about 2,000 Daltons. However, it should be understood that the amount of biodegradable polymer is determined by parameters such as duration of use.

[0040] PLGA polymers are available from several suppliers: Alkermes (Medisorb polymers), AbsorbablePolymers International (formerly known as Birmingham Polymers (a division of Durect)), Purac, and Boehringer Ingelheim.

[0041] To prepare the internal aqueous phase, the organic solvent and polymer are mixed and optionally filtered.

[0042] external water phase The external aqueous phase comprises water and a surfactant. The water is preferably sterile WFI. The external aqueous phase may also contain a surface tension modifier to maintain osmotic balance. A preferred surface tension modifier is sodium chloride, which is added to the external aqueous phase. Other suitable surface tension modifiers include, but are not limited to, mannitol and glucose. Each possibility represents a separate embodiment of the invention.

[0043] The surfactant in the external aqueous phase is preferably polyvinyl alcohol (PVA). However, other surfactants may be used, such as polysorbate, polyethylene oxide-polypropylene oxide block copolymers or cellulose esters, or any co-surfactants described below.

[0044] To prepare the external aqueous phase (step (c)), a surfactant and optionally a tension modifier are mixed in water, preferably in a sterile water-based fluidized bed (WFI), and optionally filtered. Alternatively, the surfactant solution in water may be dispersed or dissolved in a solution of water containing the tension modifier. In one embodiment of the invention, the external aqueous phase is prepared by preparing a partially hydrolyzed PVA solution in a sterile WFI and then filtering it through a membrane. Separately, a NaCl solution is prepared in a sterile WFI and then filtered through a membrane. The NaCl solution is added to the PVA solution to form the external aqueous phase.

[0045] Preparation of water-in-oil (w / o) emulsions After preparing each aqueous and organic phase, a w / o emulsion is formed. For this purpose, the inner aqueous phase and organic phase are optionally mixed using a homogenizer or other high-shear mixing method under conditions sufficient to form a w / o emulsion. In one embodiment, the inner aqueous phase is added to the organic phase, and the mixture is treated using a homogenizer equipped with a rotor-stator dispersion device at a time interval ranging from 1 minute to 30 minutes at 2,500-10,000 rpm. In a specific embodiment, the w / o emulsion is prepared by homogenizing at 7,200 RPM for 10 minutes (high-shear mixing).

[0046] Preparation of water-in-oil-in-water (w / o / w) double emulsions Next, the w / o emulsion is mixed with the external aqueous phase to form a water-in-oil-in-water (w / o / w) dual emulsion. Mixing can be performed using a homogenizer or other high-shear mixing methods and can be done in one or more batches. For example, the w / o emulsion can be added to a portion of the external aqueous phase, followed by mixing, and then the remaining external aqueous phase can be added. The w / o emulsion is mixed as described above. In one embodiment, the w / o / w emulsion is prepared by adding the w / o emulsion to half of the external aqueous phase during continuous emulsion mixing. The w / o / w dual emulsion is treated using a homogenizer equipped with a rotor-stator dispersion device at 2,500-10,000 rpm for a period ranging from 1 minute to 30 minutes. In one specific embodiment, the w / o / w dual emulsion is prepared by homogenizing a mixture containing half of the external aqueous phase and the organic phase at 2,900 RPM for 3 minutes, followed by adding the remaining external aqueous phase (quenching).

[0047] Solvent removal / evaporation Next, the organic solvent is removed. The solvent removal step involves mixing the water-in-oil-in-water (w / o / w) double emulsion and applying a combination of airflow and / or vacuum to the water-in-oil-in-water (w / o / w) double emulsion. As described herein, mixing, applying airflow, and / or vacuum are performed under suitable conditions that do not affect the integrity of the final product and will produce a product with low levels of organic solvent.

[0048] In some embodiments, a homogenizer or other high-shear mixing method may be used to mix the w / o / w dual emulsion, preferably at a speed of at least about 2,500 RPM, and more preferably at least about 2,750 RPM. Higher or lower mixing speeds may be used if desired.

[0049] In some embodiments, the solvent removal step includes combining the mixing of the w / o / w dual emulsion with the application of a vacuum. The vacuum can be applied for a desired amount of time to achieve the desired result, i.e., solvent removal. For example, the vacuum can be applied for at least 1 hour, at least 2 hours, preferably at least about 3 hours, at least about 5 hours, etc. The vacuum can also be applied for longer amounts of time, such as 12-24 hours or overnight.

[0050] In other embodiments, the solvent removal step includes a combination of mixing the w / o / w dual emulsion and applying a compressed air stream to the w / o / w dual emulsion. The air stream can be applied at a pressure of about 0.1 bar to about 1 bar, preferably about 0.5 bar. Depending on the desired results, the air stream can be applied at a higher or lower pressure. The air pressure can be applied for a desired period of time, such as 1-24 hours, 5-24 hours, 10-20 hours, 10-12 hours, etc.

[0051] In other embodiments, the solvent removal step includes mixing the w / o / w dual emulsion and applying a combination of compressed air flow and vacuum.

[0052] In some specific embodiments, the w / o / w dual emulsion is mixed using a homogenizer at different speeds for 15-17 hours. Compressed air is bubbled through the emulsion at 0.5 Pa for 10-12 hours. A vacuum is applied to a portion of the process, for example, for about 3 or about 5 hours.

[0053] The particle size of the "water-in-oil-in-water (w / o / w) dual emulsion" can be determined by a variety of parameters, including but not limited to the amount of force applied in this step, the mixing speed, and the type and concentration of the surfactant. A suitable particle size is approximately 1. To approximately 100 .

[0054] Separation and washing After solvent evaporation, glatiramer acetate microparticles are separated from the reaction mixture. In some embodiments, this step includes filtering or centrifuging the suspension obtained from the solvent evaporation step. Centrifugation can be performed at any speed and for any time to achieve separation of the microparticles from the emulsion. For example, in a non-limiting example, centrifugation can be performed at speeds from 2,500 RPM to 10,000 RPM for a time period ranging from, for example, 5 to 30 minutes. The resulting pellet can optionally be washed with water once or multiple times. In one specific embodiment, the suspension is centrifuged at 5,300 RPM for 10 minutes. The supernatant is discarded, and the pellet (precipitated microparticles) is resuspended in WFI and mixed using a magnetic stirrer. The resuspended microparticles are centrifuged again at 2,900 RPM for 10 minutes to obtain glatiramer acetate microparticles.

[0055] dry The washed microparticles are then dried by, for example, lyophilization / freeze-drying or other drying methods known in the art to obtain glatiramer acetate microparticles for batch (in bulk) or unit dose products. Drying is carried out at a temperature sufficient to remove the solvent and obtain dried microparticles for a certain period of time. For example, lyophilization can be performed at -20°C. Or at lower temperatures for periods ranging from 12 to 48 hours.

[0056] As envisioned herein, the method of the present invention produces a product with reduced levels of residual organic solvents, thereby complying with regulatory restrictions. In one embodiment, the particles contain less than about 600 ppm of residual organic solvents. In another embodiment, the particles contain less than about 500 ppm of residual organic solvents. In yet another embodiment, the particles contain less than about 250 ppm of residual organic solvents. In yet another embodiment, the particles contain less than about 100 ppm of residual organic solvents. In a preferred embodiment, the organic solvent is a halogenated organic solvent, such as a chlorinated organic solvent like dichloromethane or chloroform. In this case, the particles should have no more than 600 ppm of residual solvent, 600 ppm being the maximum regulatory allowable level.

[0057] Active ingredients As used herein, the term "glatiramer acetate" refers to the compound previously known as copolymer 1, which is traded under the name... For sale, and composed of acetates of synthetic polypeptides containing average molar fractions of 0.141, 0.427, 0.095, and 0.338 of four naturally occurring amino acids: L-glutamic acid, L-alanine, L-tyrosine, and L-lysine. The average molecular weight of glatiramer acetate is 5,000-9,000 Daltons (FDA). (Trademark) and the number of amino acids ranges from about 15 to about 100. The term also refers to chemical derivatives and analogs of the compound.

[0058] Grantiramer acetate can be prepared and characterized in detail in any one of U.S. Patent Nos. 8,377,885, 8,796,226, 7,199,098, 6,620,847, 6,362,161, 6,342,476, 6,054,430, 6,048,898, and 5,981,589, the contents of each of which are incorporated herein by reference in their entirety.

[0059] Storage composition The microparticles prepared by the method of the present invention are preferably in the form of a long-acting parenteral pharmaceutical composition containing a therapeutically effective amount of glatiramer acetate, particularly in the form of a reservoir formulation suitable for subcutaneous or intramuscular implantation at a medically acceptable location in a subject with the appropriate need.

[0060] As used in this article, the term "extracorporeal" refers to routes selected from subcutaneous (SC), intravenous (IV), intramuscular (IM), intradermal (ID), intraperitoneal (IP), etc.

[0061] As used herein, the term "therapeutic effective dose" is intended to define the amount of glatiramer acetate copolymer that will achieve the purpose of alleviating the symptoms of multiple sclerosis. For each dosage form, a suitable dose includes, but is not limited to, 20-750 mg. However, it should be understood that the amount of glatiramer acetate copolymer administered will be determined by a physician based on a number of parameters, including the chosen route of administration, the patient's age, weight, and the severity of the patient's symptoms. For example, the therapeutic effective dose range for glatiramer acetate can be about 20-100 mg. In some embodiments, the therapeutic effective dose of glatiramer acetate in a reservoir formulation is 40 mg. In some embodiments, the therapeutic effective dose of glatiramer acetate in a reservoir formulation is 80 mg.

[0062] As used herein, the term "long-acting" refers to a composition that provides prolonged, sustained, or delayed release of glatiramer acetate into the whole body circulation of a subject or to a local site of action in the subject. The term can also refer to a composition that provides a prolonged, sustained, or delayed duration of action (pharmacokinetic) of glatiramer salt in a subject. Specifically, long-acting pharmaceutical compositions are provided with dosing regimens ranging from once weekly to once every 6 months. According to a preferred embodiment of the invention, dosing regimens range from once weekly, twice monthly (approximately every two weeks) to once monthly. Depending on the desired duration of action, each reservoir or implantable device will typically contain between about 20 mg and 750 mg of the active ingredient, such as 40 mg or 80 mg, designed to release over a period ranging from about 1 week to about 6 months, for example, from about 2 weeks to about 1 month.

[0063] This invention also provides a method for treating multiple sclerosis by parenteral administration of a long-acting pharmaceutical composition comprising a therapeutically effective amount of glatiramer acetate to a subject with appropriate need, wherein the pharmaceutical composition is prepared according to the method of the invention and comprises an organic solvent at reduced levels as described herein. As used herein, the term "treatment" refers to the suppression or reduction of symptoms after a multiple sclerosis attack. Common symptoms following a multiple sclerosis attack include, but are not limited to, decreased or lost vision, unsteady and uneven gait, slurred speech, and urinary frequency and incontinence. Additionally, multiple sclerosis can cause mood changes and depression, muscle spasms, and severe paralysis. The "subject" to whom the medication is administered is a mammal, preferably but not limited to humans. As used herein, the term "multiple sclerosis" refers to an autoimmune disease of the central nervous system accompanied by one or more of the symptoms described above.

[0064] The present invention also provides a method for alleviating at least one symptom of RRMS in a patient suffering from relapsing-remitting multiple sclerosis (RRMS), the method comprising administering to the patient a long-acting pharmaceutical composition comprising a therapeutically effective amount of glatiramer acetate, wherein the pharmaceutical composition is prepared according to the method of the present invention and comprises an organic solvent at reduced levels as described herein.

[0065] In another aspect, the present invention also provides a method for increasing the tolerability of GA treatment in human patients suffering from relapsing-remitting multiple sclerosis (RRMS), the method comprising administering to the patient a long-acting pharmaceutical composition comprising a therapeutically effective amount of glatiramer acetate, wherein the pharmaceutical composition is prepared according to the method of the present invention and comprises a reduced level of an organic solvent as described herein.

[0066] In another aspect, the present invention also provides a method for reducing the relapse frequency in human patients suffering from relapsing-remitting multiple sclerosis (RRMS), the method comprising administering to the patient a long-acting pharmaceutical composition comprising a therapeutically effective amount of glatiramer acetate, wherein the pharmaceutical composition is prepared according to the method of the present invention and comprises an organic solvent at a reduced level as described herein.

[0067] In another aspect, the present invention also provides a method for preventing or slowing the progression of RRMS in human patients suffering from relapsing-remitting multiple sclerosis (RRMS), the method comprising administering to the patient a long-acting pharmaceutical composition comprising a therapeutically effective amount of glatiramer acetate, wherein the pharmaceutical composition is prepared according to the method of the present invention and comprises a reduced level of an organic solvent as described herein.

[0068] The reservoir composition may also contain one or more pharmaceutically acceptable excipients selected from (but not limited to) the following: co-surfactants, solvents / co-solvents, solvents immiscible with water, water, solvents miscible with water, oily components, hydrophilic solvents, emulsifiers, preservatives, antioxidants, defoamers, stabilizers, buffers, pH adjusters, penetrants, channel-forming agents, osmotic modifiers, or any other excipients known in the art. Suitable co-surfactants include, but are not limited to, polyethylene glycol, polyoxyethylene-polyoxypropylene block copolymers known as "poloxamer," polyglycerol fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate, dehydrated sorbitol fatty acid esters such as dehydrated sorbitol monostearate, polyoxyethylene dehydrated sorbitol fatty acid esters such as polyoxyethylene dehydrated sorbitol monooleate (Tween), polyethylene glycol fatty acid esters such as polyoxyethylene monostearate, polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether, polyoxyethylene castor oil and hardened castor oil such as polyoxyethylene hardened castor oil, etc., or mixtures thereof. Suitable solvents / co-solvents include, but are not limited to, alcohols, glyceryl triacetate, dimethyl isosorbide, tetraethylene triethylene glycol (glycofurol), propylene carbonate, water, dimethylacetamide, etc., or mixtures thereof. Suitable defoamers include, but are not limited to, silicone emulsions or sorbitan sesquioleate. Suitable stabilizers for preventing or reducing the deterioration of components in the composition include, but are not limited to, antioxidants such as glycine. - Tocopherol or ascorbate, BHA, BHT, etc., or mixtures thereof. Suitable tension modifiers include, but are not limited to, mannitol, sodium chloride, and glucose. Suitable buffers include, but are not limited to, acetate, phosphate, and citrate with suitable cations.

[0069] Reservoir systems include any form known to those skilled in the art. Suitable forms include, but are not limited to, biodegradable or non-biodegradable microspheres, implantable rods, implantable capsules, and implantable rings. Extended-release gel reservoirs and erosive matrices are also contemplated. Suitable implantable systems are described, for example, in US 2008 / 0063687, the contents of which are incorporated herein by reference in their entirety. Implantable rods can be prepared using suitable microextruders as known in the art.

[0070] In some embodiments, the long-acting pharmaceutical compositions described herein provide equivalent or better therapeutic efficacy than commercially available daily injectable formulations, with a reduced incidence and severity of side effects at local and / or systemic levels. In some embodiments, the compositions provide prolonged release or prolonged effect of glatiramer acetate in subjects compared to substantially similar doses of immediately released formulations.

[0071] The following examples are provided to more fully illustrate certain embodiments of the invention. However, they should in no way be construed as limiting the broad scope of the invention. Many variations and modifications of the principles disclosed herein will be readily conceived by those skilled in the art without departing from the scope of the invention.

[0072] Example Example 1: Preparation of PLGA-based glatiramer acetate reservoir microparticles containing low levels of dichloromethane Table 1: Raw Materials and Their Functions Prepared according to the method of US 7,199,098.

[0073] Preparation method (1) Preparation of external aqueous phase: A partially hydrolyzed polyvinyl alcohol (PVA) solution with a concentration of 2% w / w in sterile WFI was prepared in a reactor and passed through 0.22 Membrane filtration. A solution of NaCl in sterile WFI was prepared and filtered through 0.22... The membrane is filtered into a reactor containing PVA.

[0074] (3) Organic phase preparation: An organic phase containing dichloromethane and poly(lactide-co-glycolic acid) was prepared in a reactor and subjected to 0.22... Membrane filtration.

[0075] (4) Preparation of the internal aqueous phase: A solution containing sterile WFI and glatiramer acetate was prepared and subjected to 0.22 Membrane filtration.

[0076] (5) Preparation of water-in-oil (w / o) emulsion: The aqueous phase was added to the organic phase and homogenized at 7,200 RPM for 10 minutes using an IKA Ultra-Turrax T50 homogenizer equipped with a rotor-stator dispersion device (high shear mixing).

[0077] (6) Preparation of water-in-oil-in-water (w / o / w) emulsion: During continuous mixing of the water-in-oil (w / o) emulsion, the w / o emulsion prepared in step 5 is added to half of the external aqueous phase. From the end of the w / o transfer to the external aqueous phase, the w / o / w dual emulsion is treated at 2,900 RPM for 3 minutes using an IKA Ultra-Turrax UTS80 homogenizer with a rotor-stator head. Subsequently, another 30 liters of external aqueous phase are added to the emulsion (quenched).

[0078] (7) Solvent Removal / Evaporation: The w / o / w dual emulsion formed in step (6) is mixed at different speeds for 15-17 hours using an IKA UTS80 homogenizer. Compressed air is bubbled through the emulsion at 0.5 Pa for 10-12 hours. A vacuum is applied to a portion of the process.

[0079] (8) Separation and washing: Centrifuge the suspension at 5,300 RPM for 10 minutes. Discard the supernatant and resuspend the precipitate (precipitated particles) in 550 g WFI and mix with a magnetic stirrer for 3 minutes. Centrifuge the resuspended particles at 2900 RPM for 10 minutes.

[0080] (9) Freeze-drying: The washed microparticles are resuspended in approximately 750 g of sterile WFI and kept at -20°C. Until lyophilized. Lyophilize using a sterile Lyoguard tray as follows: at -40°C. Freeze for 24 hours; at 0.2 hPa, -5 Initial drying time was 48 hours; at 0.2 hPa, 10 Then, dry for 48 hours.

[0081] The dried GA storage composition is provided in Table 2: Table 2: GA storage capacity of 40mg composition / vial

[0082] Evaporation during the freeze-drying process Removed during production and not incorporated into the final product. #Each vial contains 10% excess to compensate for losses during the removal of the reconstituted product. The procedures, equipment, and materials involved in preparing a 55g GA reservoir using a 100L reactor system are summarized in Table 3: Table 3: Results and discussion DCM Residual Content: Table 4 details the evaporation rate, duration of vacuum application, and DCM residual content for the eight batches prepared. Results showed that the residual DCM content in the final formulation from the GA reservoir was reduced by increasing the evaporation rate and vacuum time. At a rate of 2,750 RPM and a vacuum of 5 hours, as implemented in the placebo batch (6), the residual DCM met the limits. Two additional batches (7, (placebo)) and (8, (glatiramer acetate)) were prepared under the same evaporation conditions to ensure reproducibility.

[0083] Table 4: Sterility and bacterial endotoxins: The first four batches of placebo were not aseptically prepared, and therefore the sterility and bacterial endotoxin data were not correlated. Subsequent batches were proven to be sterile and fell within the bacterial endotoxin limits, as can be observed in Table 5 below.

[0084] Table 5: In vitro release curve In vitro systems, as described in US 8,377,885 and US 8,796,226, are summarized as follows: Materials and methods equipment 20ml small bottle Multi-point magnetic stirrer Incubator Pipettors Shimadzu 1601 UV-Vis Spectrophotometer Reagents and plastic / glassware Test items: dried lyophilized microparticles containing glatiramer acetate prepared by the method of the present invention (lot 9) or by the method according to US8,377,885 and US8,796,226 (lot 10).

[0085] Temperature: 37 5% 2,4,6-trinitrobenzenesulfonic acid (TNBS, picryl sulfonic acid, 170.5 mM) in MeOH.

[0086] Method Description: Add 20 ml of PBS (0.01 M phosphate, 0.05% NaN3) pH 7.4 to each vial. Place the vials at 37°C. Stir with a small magnet. Add 600... The sample was centrifuged at 10,000g for 5 minutes. 500... Transfer the supernatant to a 1.5 ml microtube, then add 500 ml of [unclear text - possibly a specific ingredient or solution]. 0.1M borate buffer (2-fold dilution) and 50 TNBS. The resulting composition was mixed and held on a worktable for 30 minutes. Analysis was performed using the TNBS method (described below).

[0087] The remaining precipitated particles were treated with 500... The solution was resuspended in fresh PBS (containing NaN3) and returned to the vial. Correct calculation of the released amount of glatiramer acetate at each time point was performed in a further release process.

[0088] Using a 37 equipped with a multi-point magnetic stirrer The release of glatiramer acetate was carried out in a tightly sealed 20 ml glass vial using an incubator. Phosphate-buffered saline (PBS) with a pH of 7.4 was used as the release medium.

[0089] The release of glatiramer acetate was tested over a period of 1–30 days. The amount of GA released was determined by GPC.

[0090] Instrumentation: A suitable HPLC system equipped with a UV detector. Column: Superose 12HR 10 / 30 column Detection: UV at 208nm Flow rate: 0.5 ml / min Injection volume: 10 Column temperature: Ambient temperature Mobile phase: 0.2M phosphate buffer, pH 1.5 Representative release curves of two representative samples from the GA reservoir prepared by the method of the present invention are provided in Table 6.

[0091] Table 6: Release curves of 100 LGA reservoirs for two representative batches, batch (9) prepared by the method of the present invention, and batch (10) prepared by the method described in US8,377,885 and US8,796,226.

[0092] in conclusion As demonstrated herein, it can be concluded that it is possible to optimize DCM evaporation and obtain results falling to the required specifications by increasing the evaporation rate and subsequently applying a vacuum. Results show that the optimal evaporation conditions are a homogenization rate of approximately 2,750 RPM and a vacuum of approximately 5 hours. Surprisingly, the method of this invention enables the minimization of DCM levels while still maintaining the desired product properties (although the method is modified, the GA binding percentage, particle morphology, and release profile of the glatiramer acetate active ingredient remain unchanged).

[0093] In addition, these batches were tested for bacterial endotoxins and sterility, and they also met the acceptance criteria.

[0094] Example 2: Comparative Experiment The GA reservoir was prepared according to the method described in Example 3 of WO 2011 / 080733 (corresponding to US 8,377,885 and US 8,796,226). For solvent (DCM) removal, an open beaker containing the dual emulsion was placed on a magnetic plate stirrer and stirred in a fume hood at room temperature for 3–4 hours until all solvent evaporated and the particles solidified. No airflow and / or vacuum was applied.

[0095] The DCM level in the lyophilized samples was tested using headspace GC. The average amount of DCM detected in the samples was 19,453 ppm.

[0096] Although the invention has been specifically described, those skilled in the art will understand that many variations and modifications can be made. Therefore, the invention is not to be construed as limited to the specifically described embodiments, but its scope and concept will be more readily understood by referring to the appended claims.

Claims

1. A method for preparing microparticles containing glatiramer acetate, the method comprising the following steps: a. Preparation of an internal aqueous phase comprising glatiramer acetate and water; b. To prepare an organic phase comprising a biodegradable polymer or a non-biodegradable polymer and a volatile organic solvent immiscible with water; c. Prepare an external aqueous phase containing water and surfactants; d. The aqueous phase obtained in step (a) is mixed with the organic phase obtained in step (b) to form a water-in-oil (w / o) emulsion; e. Mix the water-in-oil (w / o) emulsion obtained in step (d) with the external aqueous phase obtained in step (c) to obtain a water-in-oil (w / o / w) dual emulsion; f. By mixing the water-in-oil-in-water (w / o / w) dual emulsion obtained in step (e), and applying an airflow and / or vacuum to remove the organic solvent; and g. Drying to obtain glatiramer acetate microparticles containing less than about 1,000 ppm of residual organic solvent.

2. The method of claim 1, wherein the particles contain less than about 600 ppm, preferably less than about 500 ppm, less than about 250 ppm or less than about 100 ppm of residual organic solvent.

3. The method according to claim 1, wherein the volatile organic solvent that is immiscible with water is a halogenated organic solvent.

4. The method according to claim 3, wherein the halogenated organic solvent is a chlorinated hydrocarbon selected from the group consisting of dichloromethane (DCM) and chloroform.

5. The method according to claim 4, wherein the chlorinated organic solvent is dichloromethane (DCM).

6. The method of claim 5, wherein the particles contain less than about 600 ppm, preferably less than about 250 ppm, and more preferably less than about 100 ppm of residual dichloromethane (DCM).

7. The method according to any one of the preceding claims, wherein step (f) comprises mixing the w / o / w dual emulsion in a homogenizer at a speed of at least about 2,500 rpm, preferably at least about 2,750 rpm.

8. The method according to any one of the preceding claims, wherein step (f) comprises applying a vacuum to the w / o / w dual emulsion for at least about 5 hours.

9. The method according to any one of the preceding claims, wherein step (f) comprises applying a compressed air stream to the w / o / w dual emulsion at a pressure of about 0.1 bar to 1 bar, preferably about 0.5 bar.

10. The method according to any one of the preceding claims, wherein step (f) comprises mixing the w / o / w dual emulsion in a homogenizer at a rate of at least about 2,750 RPM, applying a compressed air stream at a pressure of about 0.5 bar, and applying a vacuum for at least about 5 hours.

11. The method according to any one of the preceding claims, further comprising the product of the filtering or centrifugation step (f) and optionally washing with water prior to the drying step (g).

12. The method according to any one of the preceding claims, wherein the drying step (g) comprises freeze-drying or lyophilization.

13. The method according to any one of the preceding claims, wherein the biodegradable polymer or the bionon-degradable polymer is selected from the group consisting of poly(D,L,l,l) lactic acid (PLA), polyglycolic acid (PGA), poly(lactide-co-glycolic acid) (PLGA), polycaprolactone, polyhydroxybutyrate, polyorthoester, polyalkylene anhydride, gelatin, collagen, oxidized cellulose and polyphosphazene.

14. The method of claim 13, wherein the polymer is a biodegradable polymer selected from the group consisting of PLA, PGA and PLGA, preferably wherein the polymer is PLGA.

15. The method according to any one of the preceding claims, wherein the surfactant in the external aqueous phase obtained in step (c) is selected from the group consisting of polyvinyl alcohol (PVA), partially hydrolyzed polyvinyl alcohol (PVA), polysorbate, polyethylene oxide-polypropylene oxide block copolymer and cellulose ester, preferably wherein the surfactant is partially hydrolyzed PVA.

16. The method according to any one of the preceding claims, wherein the inner aqueous phase and / or outer aqueous phase further comprises a tension modifier.

17. The method of claim 16, wherein the tension modifier is NaCl.

18. The method according to any one of the preceding claims, wherein the glatiramer acetate comprises L-alanine, L-glutamic acid, L-lysine and L-tyrosine in the following molar ratio: about 0.14 glutamic acid, about 0.43 alanine, about 0.10 tyrosine and about 0.33 lysine.

19. The method according to any one of the preceding claims, wherein the glatiramer acetate comprises about 15 to about 100 amino acids.

20. The method according to any one of the preceding claims, wherein the glatiramer acetate microparticles are in the form of a long-acting parenteral pharmaceutical composition in the form of a sustained-release reservoir, the sustained-release reservoir being suitable for subcutaneous or intramuscular implantation at a medically acceptable location in a subject with appropriate need.

21. The method according to any one of the preceding claims, wherein the microparticles comprise about 20 mg to about 750 mg of glatiramer acetate.

22. The method of claim 21, wherein the microparticles comprise 40 mg of glatiramer acetate.

23. The method of claim 21, wherein the microparticles comprise 80 mg of glatiramer acetate.

24. A long-acting parenteral pharmaceutical composition comprising a therapeutically effective amount of glatiramer acetate, the pharmaceutical composition being in the form of a sustained-release reservoir suitable for subcutaneous or intramuscular implantation at a medically acceptable location in a subject with appropriate need, the composition comprising microparticles of glatiramer acetate prepared according to any of the preceding claims.

25. The pharmaceutical composition of claim 24, wherein the reservoir composition releases a therapeutically effective amount of glatiramer acetate over a period of about 1 week to about 6 months.

26. The pharmaceutical composition of claim 24, wherein the reservoir composition releases a therapeutically effective amount of glatiramer acetate over a period of about 2 weeks to about 1 month.

27. The pharmaceutical composition of claim 24, wherein the reservoir composition is in the form of a group selected from biodegradable microspheres, non-biodegradable microspheres, implants of any suitable geometry, implantable rods, implantable capsules, implantable rings, or extended-release gels or erosive matrices.

28. Use of the pharmaceutical composition according to any one of claims 24-27 in the preparation of a medicament for treating multiple sclerosis.

29. The use according to claim 28, wherein the multiple sclerosis is relapsing-remitting multiple sclerosis (RRMS).

30. A system for preparing pharmaceutical microparticles from a water-in-oil-in-water (w / o / w) dual emulsion, the system comprising: Multiple reactors equipped with filter membranes; A homogenizer equipped with a rotor-stator dispersion device; Compressed air source; and vacuum pump, The plurality of reactors includes at least a first reactor, a second reactor, and a third reactor, for preparing an inner aqueous phase containing a pharmaceutical active ingredient and water, an organic phase containing a biodegradable polymer or a bionon-degradable polymer and a volatile organic solvent immiscible with water, respectively; and an outer aqueous phase containing water and a surfactant. The homogenizer is used to receive and homogenize the inner aqueous phase, organic phase and outer aqueous phase from the first reactor, the second reactor and the third reactor, respectively, to produce a water-in-oil-in-water (w / o / w) double emulsion; The compressed air source is connected to the homogenizer to supply compressed air to the homogenizer; and The vacuum pump is connected to the homogenizer to apply a vacuum to the homogenizer. The compressed air and the vacuum are applied to remove the organic solvent from the water-in-oil-in-water (w / o / w) double emulsion, thereby obtaining drug microparticles.

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