WO2016189504A1 - Non-lyophilized compositions of aripiprazole and methods of preparation thereof - Google Patents

Non-lyophilized compositions of aripiprazole and methods of preparation thereof Download PDF

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Publication number
WO2016189504A1
WO2016189504A1 PCT/IB2016/053120 IB2016053120W WO2016189504A1 WO 2016189504 A1 WO2016189504 A1 WO 2016189504A1 IB 2016053120 W IB2016053120 W IB 2016053120W WO 2016189504 A1 WO2016189504 A1 WO 2016189504A1
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Prior art keywords
aripiprazole
agents
formulation
spray dried
sustained release
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PCT/IB2016/053120
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French (fr)
Inventor
Kocherlakota Chandrashekhar
Banda Nagaraju
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Leiutis Pharmaceuticals Pvt Ltd
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Publication of WO2016189504A1 publication Critical patent/WO2016189504A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone

Definitions

  • Aripiprazole is an atypical antipsychotic useful for the treatment of schizophrenia and acute manic and mixed episodes associated with bipolar disorder.
  • Aripiprazole chemically known as 7-[4-[4-(2,3-dichlorophenyl)-l-piperazinyl]butoxy]-3,4- dihydrocarbostyril, has the empirical formula of C23H27CI2N3O2 and molecular weight of 448.38.
  • the chemical structure of Aripiprazole is shown below:
  • Aripiprazole is disclosed in U.S. patent Nos. 4,734,416 assigned to Kazuo et al., and 5,006,528 assigned to Yasuo et al., wherein it is described as an atypical antipsychotic agent useful in the treatment of schizophrenia and other CNS disorders.
  • U.S. Pat. Nos.7,807,680, 8,030,313 and 8,722,679 assigned to Janusz W. et al. also disclose Aripiprazole formulations.
  • the patents describe freeze-dried controlled release formulations of Aripiprazole.
  • U.S. Pat. Nos. 7,115,587 and 7,550,445 assigned to Manoj et al. disclose an injectable formulation that delivers an Aripiprazole solution complexed with a substituted ⁇ -cyclodextrin to the muscular site.
  • Aripiprazole is available as an extended-release injectable suspension under the brand name Abilify Maintena ® in United States.
  • the product is supplied as pre-filled dual chamber syringes and vials filled with sterile lyophilized powder which forms an injectable suspension when reconstituted with water, and the re-suspension (injectable preparation) is intramuscularly injected into a patient.
  • the lyophilization process requires specialized equipment and is time consuming and often incurs significant expense. Hence, there is a strong need to develop alternate formulations of Aripiprazole.
  • lyophilization products are characterized by fast reconstitution and easy dispersibility of the product.
  • the inventors of the present invention have developed an alternate formulation in the form of a spray dried product having comparable dispersibility with that of lyophilized product.
  • the process of spray drying overcomes the limitations known to be associated with lyophilized process.
  • the present invention describes long acting Aripiprazole parenteral formulations comprising spray dried Aripiprazole along with a diluent.
  • the invention formulation can be supplied as a kit comprising of Aripiprazole spray dried product and diluent for reconstitution.
  • One aspect of the invention provides long acting Aripiprazole parenteral formulations comprising spray dried Aripiprazole and a diluent for reconstitution.
  • Another aspect of the invention provides a method for preparing spray-dried formulations of Aripiprazole.
  • Yet another aspect of present invention provides diluent compositions for Aripiprazole formulations and methods of preparation thereof.
  • the process of "spray drying” refers to a process wherein the solution or suspension is atomized to form a fine mist and dried by direct contact with carrier gases maintained at appropriate temperature.
  • the final product can be in the form of powder, granulate or agglomerate.
  • Aripiprazole refers to the pharmaceutically acceptable salts, solvates, hydrates, free base and anhydrous forms thereof.
  • Spray drying involves the atomization of liquid feed slurry into a spray of droplets and rapidly removing solvent from the mixture resulting in dried product.
  • the spray can be produced by either rotary (wheel), nozzle, or ultrasonic atomizers.
  • the process of evaporation of the solvent or moisture is carried out under controlled conditions such as temperature, air flow rate, nozzle diameter and feed rate of the suspension.
  • the process conditions and the characteristics of the feed slurry like solid content of the suspension may be altered to achieve the desired effect.
  • the long acting Aripiprazole parenteral formulations of the invention comprise:
  • the long acting Aripiprazole parenteral formulations of the invention comprise:
  • solvents selected from the group comprising of water, ethanol, propylene glycol, glycerine and the like.
  • c) optionally other pharmaceutically acceptable adjuvants such as viscosity modifying agent or suspending agents, surfactants, release rate modifiers/ sustained release agents, dispersing agents, solubilizing agents, tonicity modifiers, pH adjusting agents and the like.
  • the excipients may be selected from the group comprising bulking agents, solvents, buffering agents, wetting agents, viscosity modifying agents, suspending agents, release rate modifiers/sustained release agents, isotonicity agents, antioxidants, preservatives, stabilizers, pH adjusting agents, plasticizers and the like.
  • the diluent may comprise one or more agents selected from viscosity modifying agent or suspending agents, surfactants, release rate modifiers/sustained release agents, dispersing agents, solubilizing agents, tonicity modifiers, solvents, buffering agents, pH adjusting agents, electrolytes, or any other suitable adjuvant thereof.
  • the long acting Aripiprazole parenteral formulations of the invention comprise:
  • compositions include the following, but not limited to mannitol, glucose, sucrose, maltose, xylitol, starches, sorbitol, lactose, maltitol, trehalose, dextrose, dextran, raffinose, sodium chloride and the like.
  • Suitable solvents include the following, but are not limited to tertiary butyl alcohol (TBA), N-methylpyrrolidone (NMP), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ⁇ , ⁇ -dimethylacetamide (DMA), tetrahydrofuran (THF), tetrahydropyran, dioxane, trioxane and other cyclic mono-, di- and tri-ethers, lower alkanols (such as ethanol, propanol, isopropanol, sec-butanol, t-butyl alcohol, and n-butyl alcohol), ethyl acetate, propylene glycol (PG), glycerine, water, acetone, acetonitrile, ethoxy ethanol, methanol or other organic solvents and mixtures of suitable solvents thereof or their equivalents.
  • Preferred solvents are tertiary butyl alcohol, ethanol, gly
  • Viscosity modifying or suspending agents include the following, but not limited to acacia, agar, alginic acid, bentonite, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropylethyl cellulose, hydroxypropylmethyl cellulose, carrageenan, hydroxyethylmethyl cellulose, hydroxypropyl starch, methylcellulose, starch and the like or mixtures thereof.
  • suspending agents include various polymers such as, low molecular weight oligomers, gelatin, casein, dextran, glycerol, gum acacia, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, dodecyl trimethyl ammonium bromide, carboxymethyl cellulose tri calcium, noncrystalline cellulose, triethanolamine, polyvinyl alcohol, poloxamers and the like.
  • polymers such as, low molecular weight oligomers, gelatin, casein, dextran, glycerol, gum acacia, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, dodecyl trimethyl ammonium bromide, carboxymethyl cellulose tri calcium, noncrystalline cellulose, triethanolamine, polyvinyl alcohol, poloxamers and the like.
  • Dispersing agent refers to those compounds capable of dispersing the compounds in the liquid media.
  • suitable dispersing agents include polyoxyethylated castor oils, polyoxyethylene sorbitan esters and the like.
  • surfactants are used, including but not limited to nonionic and ionic surfactants, such as cetyl pyridinium chloride, acetyl alcohol, cocamide diethanolamine, monoethanolamine, poloxamer, polyglycerol, polysorbate, fatty alcohols, ethylene glycol monostearate, glycerol monostearate, sorbitan fatty acid esters (spans), tween ethers of fatty alcohols with polyethylene glycol (PEG), fatty acid esters of PEG and the like or mixtures thereof.
  • nonionic and ionic surfactants such as cetyl pyridinium chloride, acetyl alcohol, cocamide diethanolamine, monoethanolamine, poloxamer, polyglycerol, polysorbate, fatty alcohols, ethylene glycol monostearate, glycerol monostearate, sorbitan fatty acid esters (spans), tween ethers of fatty alcohols with polyethylene glycol (P
  • Release rate modifiers/sustained releasing agents include the following, but not limited to natural polymers such as high molecular weight polysaccharides such as agarose, alginate, chitosan and dextran, or proteins such as collagen, albumin, gelatin, elastin, and silk fibroin; synthetic polymers such as cellulose derivatives, acrylic polymers, polaxamers, polaxamines, polyethylene glycols, polyvinylpyrrolidone, polyesters, polyanhydrides, polyamides, phosphorus based polymers and polyurethanes; biocompatible and biodegradable polymers such as poly (D, L- lactide), poly (D,L- lactide, co-glycolide acid) and block co polymers.
  • natural polymers such as high molecular weight polysaccharides such as agarose, alginate, chitosan and dextran, or proteins such as collagen, albumin, gelatin, elastin, and silk fibroin
  • Most preferred agents are polyethylene glycol and polyvinylpyrrolidone. Percentage of the sustained releasing agent in the formulation is less than 20% w/w based on the weight of the formulation, preferably less than 10% w/w based on the weight of the formulation.
  • Buffers are typically included in pharmaceutical formulations to maintain the pH of the formulation at a physiologically acceptable pH.
  • the desirable pH for a formulation may also be affected by the active agent.
  • suitable buffers include phosphate, aconitic, citric, glutaric, malic, succinic and carbonic acid, alkali or alkaline earth salt of one of these acids, tris buffer, histidine buffers, meglumine or any suitable buffer thereof.
  • pH adjusting agents include, but are not limited to sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, ammonium carbonate, hydrochloric acid, citric acid, lactic acid, phosphoric acid, sodium phosphate, sulfuric acid and the like.
  • compositions of the present invention may contain one or more anti-oxidants and preservatives such as butylated hydroxyanisole, butylated hydroxyl toluene, citric acid, tocopherol, monothioglycerol, ascorbic acid, propyl gallate, aminoacids and mixtures thereof.
  • the pharmaceutical compositions of the present invention optionally contain stabilizers, chelating agents and the like.
  • Another aspect of the invention provides process for the preparation of spray dried Aripiprazole formulation. The process comprises of the following steps.
  • a micro suspension of Aripiprazole was prepared using a bead mill (Model: LBM 48, Make: Jay instruments).
  • Aripiprazole, mannitol and tertiary butyl alcohol were added to a manufacturing vessel maintained at 25 °C and mixed at 300-500 rpm for about 30 minutes to form a sterile primary suspension.
  • the bead mill was prepared by partially filling the grinding chamber with zirconium oxide beads. The primary suspension was then passed through the mill operating at the following conditions:
  • micro suspension was then aseptically spray dried in a spray dryer (Model: SPD 401, Make: Jay instruments) according to the following parameters:
  • the spray dried product was then aseptically filled in sterilized vials, stoppered and sealed.
  • a diluent for reconstitution of Aripiprazole spray dried product prior to administration was prepared as follows
  • Polysorbate 80 was added to a manufacturing vessel containing water for injection and mixed to get a uniform mixture.
  • Sodium phosphate monobasic monohydrate was dissolved in another manufacturing vessel containing water for injection and stirred to get a clear solution followed by the addition of polyethylene glycol 3350. Both the solutions were mixed and pH was adjusted with 0.1N sodium hydroxide solution. The solution was filtered, filled in vials and stoppered.
  • Table 1 Comparative dissolution data of Aripiprazole invention formulation with reference product.
  • Sterile Aripiprazole, mannitol, tertiary butyl alcohol and water were added to a manufacturing vessel maintained at 25°C and mixed at 300-500 rpm for about 30 minutes to form a sterile primary suspension.
  • a diluent for reconstitution of Aripiprazole spray dried product prior to administration was prepared as follows
  • Carboxymethyl cellulose sodium was added to a manufacturing vessel containing water for injection and mixed to get a uniform mixture.
  • Polyethylene glycol 3350 was added followed by the addition of sodium phosphate monobasic monohydrate.
  • Polysorbate was added to the above mixture and stirred to get a clear solution.
  • the pH was adjusted with 0.1N sodium hydroxide solution to around 7.0. The solution was filtered, filled in vials and stoppered.
  • Reconstitution time for products of Example 1 and 2 was less than 30 seconds which is comparable to that of reference product (Abilify Maintena ® , Batch No. aBS0414).
  • the reconstituted suspension was evaluated for particle size distribution (PSD) using Mastersizer Hydro 2000s particle size distribution analyzer. The data is summarized in table 2.
  • Table 2 Particle size distribution data of Aripiprazole suspension.
  • a micro suspension of Aripiprazole was prepared using a bead mill.
  • Aripiprazole, mannitol and tertiary butyl alcohol were added to a manufacturing vessel maintained at 25°C and mixed at 300-500 rpm for about 30 minutes to form a sterile primary suspension.
  • micro suspension was then aseptically spray dried in a spray dryer according to the parameters mentioned in example 1.
  • the spray dried product was then aseptically filled in sterilized vials, stoppered and sealed.
  • a diluent for reconstitution of Aripiprazole spray dried product prior to administration was prepared as follows Ingredients mg/niL
  • Carboxymethyl cellulose sodium was added to a manufacturing vessel containing water for injection and mixed to get a uniform mixture.
  • Polyethylene glycol 3350 was added followed by the addition of sodium phosphate monobasic monohydrate.
  • Polysorbate was added to the above mixture and stirred to get a clear solution.
  • the pH was adjusted with 0.1N sodium hydroxide solution to around 7.0. The solution was filtered, filled in vials and stoppered.
  • a micro suspension of Aripiprazole was prepared using a bead mill. The following ingredients were added to a manufacturing vessel maintained at 25 °C and mixed at 300- 500 rpm for about 30 minutes to form a sterile primary suspension.
  • micro suspension was then aseptically spray dried in a spray dryer with specified bead milling parameters as mentioned in example 1.
  • the spray dried product was then aseptically filled in sterilized vials, stoppered and sealed.
  • Carboxymethyl cellulose sodium (7L2P) was added to a manufacturing vessel containing water for injection and mixed to get a uniform mixture.
  • Polysorbate 20 was dissolved in above solution and stirred to get a clear solution followed by the addition of sodium phosphate monobasic monohydrate and pH was adjusted with 0.1N sodium hydroxide solution. The solution was filtered, filled in vials and stoppered.

Abstract

The present invention relates to non-lyophilized long acting parenteral formulation of Aripiprazole. Further the present invention provides spray dried compositions of Aripiprazole intended for parenteral administration.

Description

NON-LYOPHILIZED COMPOSITIONS OF ARIPIPRAZOLE AND METHODS
OF PREPARATION THEREOF
Background of the invention
Aripiprazole is an atypical antipsychotic useful for the treatment of schizophrenia and acute manic and mixed episodes associated with bipolar disorder. Aripiprazole, chemically known as 7-[4-[4-(2,3-dichlorophenyl)-l-piperazinyl]butoxy]-3,4- dihydrocarbostyril, has the empirical formula of C23H27CI2N3O2 and molecular weight of 448.38. The chemical structure of Aripiprazole is shown below:
Figure imgf000002_0001
Aripiprazole is disclosed in U.S. patent Nos. 4,734,416 assigned to Kazuo et al., and 5,006,528 assigned to Yasuo et al., wherein it is described as an atypical antipsychotic agent useful in the treatment of schizophrenia and other CNS disorders.
U.S. Pat. Nos.7,807,680, 8,030,313 and 8,722,679 assigned to Janusz W. et al., also disclose Aripiprazole formulations. The patents describe freeze-dried controlled release formulations of Aripiprazole. U.S. Pat. Nos. 7,115,587 and 7,550,445 assigned to Manoj et al., disclose an injectable formulation that delivers an Aripiprazole solution complexed with a substituted β-cyclodextrin to the muscular site.
Aripiprazole is available as an extended-release injectable suspension under the brand name Abilify Maintena® in United States. The product is supplied as pre-filled dual chamber syringes and vials filled with sterile lyophilized powder which forms an injectable suspension when reconstituted with water, and the re-suspension (injectable preparation) is intramuscularly injected into a patient. The lyophilization process requires specialized equipment and is time consuming and often incurs significant expense. Hence, there is a strong need to develop alternate formulations of Aripiprazole.
Conventional lyophilization products are characterized by fast reconstitution and easy dispersibility of the product. The inventors of the present invention have developed an alternate formulation in the form of a spray dried product having comparable dispersibility with that of lyophilized product. The process of spray drying overcomes the limitations known to be associated with lyophilized process.
The present invention describes long acting Aripiprazole parenteral formulations comprising spray dried Aripiprazole along with a diluent. The invention formulation can be supplied as a kit comprising of Aripiprazole spray dried product and diluent for reconstitution.
Summary of the Invention
One aspect of the invention provides long acting Aripiprazole parenteral formulations comprising spray dried Aripiprazole and a diluent for reconstitution.
Another aspect of the invention provides a method for preparing spray-dried formulations of Aripiprazole.
Yet another aspect of present invention provides diluent compositions for Aripiprazole formulations and methods of preparation thereof.
Detailed description of the invention
As defined herein, the process of "spray drying" refers to a process wherein the solution or suspension is atomized to form a fine mist and dried by direct contact with carrier gases maintained at appropriate temperature. The final product can be in the form of powder, granulate or agglomerate. As used herein the term "Aripiprazole" refers to the pharmaceutically acceptable salts, solvates, hydrates, free base and anhydrous forms thereof.
Spray drying involves the atomization of liquid feed slurry into a spray of droplets and rapidly removing solvent from the mixture resulting in dried product. The spray can be produced by either rotary (wheel), nozzle, or ultrasonic atomizers. The process of evaporation of the solvent or moisture is carried out under controlled conditions such as temperature, air flow rate, nozzle diameter and feed rate of the suspension. The process conditions and the characteristics of the feed slurry like solid content of the suspension may be altered to achieve the desired effect.
The long acting Aripiprazole parenteral formulations of the invention comprise:
(i) spray dried Aripiprazole alone or in combination with one or more excipients and
(ii) a diluent for reconstitution.
In one of the preferred embodiment, the long acting Aripiprazole parenteral formulations of the invention comprise:
(i) Spray dried product of Aripiprazole comprising
(a) Aripiprazole
(b) Bulking agents selected from the group comprising of mannitol, glucose, sucrose, maltose, xylitol, starches, sorbitol, dextrose, sodium chloride and the like.
(c) One or more solvents selected from the group comprising of tertiary butyl alcohol, ethanol, water and the like.
(d) Optionally other pharmaceutically acceptable adjuvants such as viscosity modifying agents, release rate modifiers/sustained release agents, tonicity modifiers and buffering agents.
(ii) Diluent comprising
(a) Buffering agents
(b) One or more solvents selected from the group comprising of water, ethanol, propylene glycol, glycerine and the like. (c) Optionally other pharmaceutically acceptable adjuvants such as viscosity modifying agent or suspending agents, surfactants, release rate modifiers/ sustained release agents, dispersing agents, solubilizing agents, tonicity modifiers, pH adjusting agents and the like.
The excipients may be selected from the group comprising bulking agents, solvents, buffering agents, wetting agents, viscosity modifying agents, suspending agents, release rate modifiers/sustained release agents, isotonicity agents, antioxidants, preservatives, stabilizers, pH adjusting agents, plasticizers and the like.
The diluent may comprise one or more agents selected from viscosity modifying agent or suspending agents, surfactants, release rate modifiers/sustained release agents, dispersing agents, solubilizing agents, tonicity modifiers, solvents, buffering agents, pH adjusting agents, electrolytes, or any other suitable adjuvant thereof.
In a preferred embodiment, the long acting Aripiprazole parenteral formulations of the invention comprise:
(i) Spray dried product of Aripiprazole comprising
(a) Aripiprazole
(b) Bulking agents such as mannitol, sucrose, sodium chloride.
(c) One or more solvents such as tertiary butyl alcohol and water
(d) Optionally other pharmaceutically acceptable adjuvants such as viscosity modifying agents, release rate modifiers/sustained release agents, tonicity modifiers and buffering agents.
(ii) Diluent comprising
(a) Buffering agents
(b) Water
(c) Optionally other pharmaceutically acceptable adjuvants such as viscosity modifying agents or suspending agents, surfactants, release rate modifiers/sustained release agents, dispersing agents, solubilizing agents, tonicity modifiers, pH adjusting agents and the like. Bulking agents include the following, but not limited to mannitol, glucose, sucrose, maltose, xylitol, starches, sorbitol, lactose, maltitol, trehalose, dextrose, dextran, raffinose, sodium chloride and the like.
Suitable solvents include the following, but are not limited to tertiary butyl alcohol (TBA), N-methylpyrrolidone (NMP), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), Ν,Ν-dimethylacetamide (DMA), tetrahydrofuran (THF), tetrahydropyran, dioxane, trioxane and other cyclic mono-, di- and tri-ethers, lower alkanols (such as ethanol, propanol, isopropanol, sec-butanol, t-butyl alcohol, and n-butyl alcohol), ethyl acetate, propylene glycol (PG), glycerine, water, acetone, acetonitrile, ethoxy ethanol, methanol or other organic solvents and mixtures of suitable solvents thereof or their equivalents. Preferred solvents are tertiary butyl alcohol, ethanol, glycerol and water.
Viscosity modifying or suspending agents include the following, but not limited to acacia, agar, alginic acid, bentonite, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropylethyl cellulose, hydroxypropylmethyl cellulose, carrageenan, hydroxyethylmethyl cellulose, hydroxypropyl starch, methylcellulose, starch and the like or mixtures thereof. Other suitable suspending agents include various polymers such as, low molecular weight oligomers, gelatin, casein, dextran, glycerol, gum acacia, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, dodecyl trimethyl ammonium bromide, carboxymethyl cellulose tri calcium, noncrystalline cellulose, triethanolamine, polyvinyl alcohol, poloxamers and the like.
Dispersing agent refers to those compounds capable of dispersing the compounds in the liquid media. Examples of suitable dispersing agents include polyoxyethylated castor oils, polyoxyethylene sorbitan esters and the like.
In some embodiments of the present invention surfactants are used, including but not limited to nonionic and ionic surfactants, such as cetyl pyridinium chloride, acetyl alcohol, cocamide diethanolamine, monoethanolamine, poloxamer, polyglycerol, polysorbate, fatty alcohols, ethylene glycol monostearate, glycerol monostearate, sorbitan fatty acid esters (spans), tween ethers of fatty alcohols with polyethylene glycol (PEG), fatty acid esters of PEG and the like or mixtures thereof.
Release rate modifiers/sustained releasing agents include the following, but not limited to natural polymers such as high molecular weight polysaccharides such as agarose, alginate, chitosan and dextran, or proteins such as collagen, albumin, gelatin, elastin, and silk fibroin; synthetic polymers such as cellulose derivatives, acrylic polymers, polaxamers, polaxamines, polyethylene glycols, polyvinylpyrrolidone, polyesters, polyanhydrides, polyamides, phosphorus based polymers and polyurethanes; biocompatible and biodegradable polymers such as poly (D, L- lactide), poly (D,L- lactide, co-glycolide acid) and block co polymers. Most preferred agents are polyethylene glycol and polyvinylpyrrolidone. Percentage of the sustained releasing agent in the formulation is less than 20% w/w based on the weight of the formulation, preferably less than 10% w/w based on the weight of the formulation.
Buffers are typically included in pharmaceutical formulations to maintain the pH of the formulation at a physiologically acceptable pH. The desirable pH for a formulation may also be affected by the active agent. Examples of suitable buffers include phosphate, aconitic, citric, glutaric, malic, succinic and carbonic acid, alkali or alkaline earth salt of one of these acids, tris buffer, histidine buffers, meglumine or any suitable buffer thereof. pH adjusting agents include, but are not limited to sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, ammonium carbonate, hydrochloric acid, citric acid, lactic acid, phosphoric acid, sodium phosphate, sulfuric acid and the like.
The pharmaceutical compositions of the present invention may contain one or more anti-oxidants and preservatives such as butylated hydroxyanisole, butylated hydroxyl toluene, citric acid, tocopherol, monothioglycerol, ascorbic acid, propyl gallate, aminoacids and mixtures thereof. The pharmaceutical compositions of the present invention optionally contain stabilizers, chelating agents and the like. Another aspect of the invention provides process for the preparation of spray dried Aripiprazole formulation. The process comprises of the following steps.
(i) Mixing sterile Aripiprazole, sterile vehicle and optionally other excipients such as bulking agents/ viscosity modifying agents/sustained release agents/ tonicity modifiers/dispersing agents to form a suspension;
(ii) Reducing the mean particle size of Aripiprazole in the suspension by subjecting to aseptic wet milling.
(iii) Spray drying the milled suspension.
(iv) Filling the spray dried product in sterile containers.
The following examples illustrate methods of carrying out the invention. Example 1
(a) Preparation of Aripiprazole spray dried product
A micro suspension of Aripiprazole was prepared using a bead mill (Model: LBM 48, Make: Jay instruments). Aripiprazole, mannitol and tertiary butyl alcohol were added to a manufacturing vessel maintained at 25 °C and mixed at 300-500 rpm for about 30 minutes to form a sterile primary suspension.
Ingredients mg/vial
Aripiprazole 400
Mannitol 100
Tertiary butyl alcohol Q.S*
*Q.S: Quantity Sufficient
The bead mill was prepared by partially filling the grinding chamber with zirconium oxide beads. The primary suspension was then passed through the mill operating at the following conditions:
RPM 2100
Time 25 to 45 minutes Bead 1 mm (75%)
Mesh 0.3 mm
Product Temp 25°C
Peristaltic Pump 45 RPM
Stirrer 500
The micro suspension was then aseptically spray dried in a spray dryer (Model: SPD 401, Make: Jay instruments) according to the following parameters:
Aspiration 1400 mmWC
Feed RPM 12 RPM*
Nozzle 0.7mm
Inlet Temperature 50 - 80°C
outlet Temperature 30 - 50°C
Atomization Pressure 80 PSI#
RPM: Rotations per minute
#PSI: Pounds per square inch
The spray dried product was then aseptically filled in sterilized vials, stoppered and sealed.
(b) Diluent for Aripiprazole spray dried product
A diluent for reconstitution of Aripiprazole spray dried product prior to administration was prepared as follows
Ingredients mg/niL
Sodium phosphate monobasic monohydrate 0.74
Polysorbate 80 20
Polyethylene glycol 3350 30
Sodium hydroxide Q.S* to adjust the pH
Water for Injection Q.S* to 1 mL
*Quantity sufficient Polysorbate 80 was added to a manufacturing vessel containing water for injection and mixed to get a uniform mixture. Sodium phosphate monobasic monohydrate was dissolved in another manufacturing vessel containing water for injection and stirred to get a clear solution followed by the addition of polyethylene glycol 3350. Both the solutions were mixed and pH was adjusted with 0.1N sodium hydroxide solution. The solution was filtered, filled in vials and stoppered.
In-vitro dissolution testing was performed using dissolution apparatus type 2 in 900ml of 0.25% SLS (sodium lauryl sulphate) medium at 50RPM at 37°C. Comparative dissolution profile is summarized in table 1.
Table 1: Comparative dissolution data of Aripiprazole invention formulation with reference product.
Figure imgf000010_0001
Reference product is Abilify Maintena*
Example 2
(a) Preparation of Aripiprazole spray dried product
Sterile Aripiprazole, mannitol, tertiary butyl alcohol and water were added to a manufacturing vessel maintained at 25°C and mixed at 300-500 rpm for about 30 minutes to form a sterile primary suspension.
Ingredients mg/vial
Aripiprazole 400
Mannitol 100
Tertiary butyl alcohol Q.S*
Water for Injection Q.S*
Q.S: Quantity sufficient The primary suspension was then passed through the bead mill with specified bead milling parameters as mentioned in example 1. The milled micro suspension was then aseptically spray dried in a spray dryer with specified spray drying parameters as mentioned in example 1. The spray dried product was aseptically filled in sterilized vials, stoppered and sealed.
(b) Diluent for Aripiprazole spray dried product
A diluent for reconstitution of Aripiprazole spray dried product prior to administration was prepared as follows
Ingredients mg/niL
Carboxymethyl cellulose sodium 8.32
Sodium phosphate monobasic monohydrate 0.74
Polysorbate 80 20
Polyethylene glycol 3350 30
Sodium hydroxide Q.S* to adjust the pH
Water for Injection Q.S* to 1 mL
*Quantity sufficient
Carboxymethyl cellulose sodium was added to a manufacturing vessel containing water for injection and mixed to get a uniform mixture. Polyethylene glycol 3350 was added followed by the addition of sodium phosphate monobasic monohydrate. Polysorbate was added to the above mixture and stirred to get a clear solution. The pH was adjusted with 0.1N sodium hydroxide solution to around 7.0. The solution was filtered, filled in vials and stoppered.
Reconstitution time for products of Example 1 and 2 was less than 30 seconds which is comparable to that of reference product (Abilify Maintena®, Batch No. aBS0414).
The reconstituted suspension was evaluated for particle size distribution (PSD) using Mastersizer Hydro 2000s particle size distribution analyzer. The data is summarized in table 2. Table 2: Particle size distribution data of Aripiprazole suspension.
Figure imgf000012_0001
Example 3
(a) Preparation of Aripiprazole spray dried product
A micro suspension of Aripiprazole was prepared using a bead mill. Aripiprazole, mannitol and tertiary butyl alcohol were added to a manufacturing vessel maintained at 25°C and mixed at 300-500 rpm for about 30 minutes to form a sterile primary suspension.
Ingredients mg/vial
Aripiprazole 400
Mannitol 100
Tertiary butyl alcohol Q.S*
*Q.S: Quantity Sufficient
The micro suspension was then aseptically spray dried in a spray dryer according to the parameters mentioned in example 1.
The spray dried product was then aseptically filled in sterilized vials, stoppered and sealed.
(b) Diluent for Aripiprazole spray dried product
A diluent for reconstitution of Aripiprazole spray dried product prior to administration was prepared as follows Ingredients mg/niL
Carboxymethyl cellulose sodium 8.32
Sodium phosphate monobasic monohydrate 0.74
Polysorbate 80 20
Polyethylene glycol 3350 30
Sodium hydroxide Q.S* to adjust the pH
Water for Injection Q.S* to 1 mL
Quantity sufficient
Carboxymethyl cellulose sodium was added to a manufacturing vessel containing water for injection and mixed to get a uniform mixture. Polyethylene glycol 3350 was added followed by the addition of sodium phosphate monobasic monohydrate. Polysorbate was added to the above mixture and stirred to get a clear solution. The pH was adjusted with 0.1N sodium hydroxide solution to around 7.0. The solution was filtered, filled in vials and stoppered.
Example 4
(a) Spray dried product of Aripiprazole
A micro suspension of Aripiprazole was prepared using a bead mill. The following ingredients were added to a manufacturing vessel maintained at 25 °C and mixed at 300- 500 rpm for about 30 minutes to form a sterile primary suspension.
Ingredients mg/vial
Aripiprazole 400
Mannitol 100
Polyvinyl pyrrolidone (Kollidone 17 PF) 0.4
Tertiary butyl alcohol Q.S*
*Q.S: Quantity Sufficient The micro suspension was then aseptically spray dried in a spray dryer with specified bead milling parameters as mentioned in example 1. The spray dried product was then aseptically filled in sterilized vials, stoppered and sealed.
(b) Diluent for reconstitution of Aripiprazole spray dried product
Ingredients m» /ml.
Carboxymethyl cellulose sodium (7L2P) 8.32
Sodium phosphate monobasic monohydrate 0.74
Polysorbate 20 10
Sodium hydroxide Q.S* to adjust the pH
Water for Injection Q.S* to 1 mL
Quantity sufficient
Carboxymethyl cellulose sodium (7L2P) was added to a manufacturing vessel containing water for injection and mixed to get a uniform mixture. Polysorbate 20 was dissolved in above solution and stirred to get a clear solution followed by the addition of sodium phosphate monobasic monohydrate and pH was adjusted with 0.1N sodium hydroxide solution. The solution was filtered, filled in vials and stoppered.

Claims

We Claim
Claim 1: A long acting Aripiprazole parenteral formulation comprising:
(i) spray dried Aripiprazole alone or in combination with one or more excipients and
(ii) a diluent for reconstitution.
Claim 2: The long acting Aripiprazole parenteral formulation of claim 1 comprising:
(i) spray dried product of Aripiprazole comprising
(a) Aripiprazole
(b) Bulking agents selected from the group comprising of mannitol, glucose, sucrose, maltose, xylitol, starches, sorbitol, dextrose, sodium chloride and the like.
(c) One or more solvents
(d) Optionally other pharmaceutically acceptable adjuvants such as viscosity modifying agents, release rate modifiers/ sustained release agents, tonicity modifiers and buffering agents.
(ii) Diluent comprising
(a) Buffering agents
(b) One or more solvents
(c) Optionally other pharmaceutically acceptable adjuvants such as viscosity modifying agents or suspending agents, surfactants, release rate modifiers/sustained release agents, dispersing agents, solubilizing agents, tonicity modifiers, pH adjusting agents and the like.
Claim 3: The formulation of claim 2, wherein the bulking agent is mannitol and the solvent is tertiary butyl alcohol and/or water.
Claim 4: The formulation of claim 2, wherein the formulation comprises a sustained release agent selected from polyethylene glycol and polyvinylpyrrolidone. Claim 5: The formulation of claim 4, wherein the percentage of the sustained release agent is less than 20% w/w based on the weight of the formulation.
PCT/IB2016/053120 2015-05-28 2016-05-27 Non-lyophilized compositions of aripiprazole and methods of preparation thereof WO2016189504A1 (en)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
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US8030313B2 (en) * 2003-10-23 2011-10-04 Otsuka Pharmaceutical Co., Ltd. Controlled release sterile injectable aripiprazole formulation and method
EP1381367B1 (en) * 2001-04-25 2011-12-21 Bristol-Myers Squibb Company Aripiprazole oral solution
US8865722B2 (en) * 2006-01-05 2014-10-21 Teva Pharmaceutical Industries Ltd. Wet formulations of aripiprazole
WO2015106963A1 (en) * 2014-01-16 2015-07-23 Pharmathen S.A. Pharmaceutical composition comprising aripiprazole or salt thereof

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EP1381367B1 (en) * 2001-04-25 2011-12-21 Bristol-Myers Squibb Company Aripiprazole oral solution
US8030313B2 (en) * 2003-10-23 2011-10-04 Otsuka Pharmaceutical Co., Ltd. Controlled release sterile injectable aripiprazole formulation and method
US8865722B2 (en) * 2006-01-05 2014-10-21 Teva Pharmaceutical Industries Ltd. Wet formulations of aripiprazole
WO2008020820A2 (en) * 2006-08-15 2008-02-21 Nobel Ilac Sanayii Ve Ticaret A.S. Pharmaceutical compositions comprising aripiprazole
WO2015106963A1 (en) * 2014-01-16 2015-07-23 Pharmathen S.A. Pharmaceutical composition comprising aripiprazole or salt thereof

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WO2021199076A1 (en) * 2020-03-30 2021-10-07 Cipla Limited Injectable aripiprazole formulation

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