A tablet comprising micronized brexpiprazole

Abstract

The present invention relates to a film coated tablet comprises micronized brexpiprazole or a salt thereof as an active ingredient and at least one pharmaceutically acceptable excipient. Further, the present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient process.

Description

[0001] A TABLET COMPRISING MICRONIZED BREXPIPRAZOLE

[0002] Field of the Invention

[0003] The present invention relates to a film coated tablet comprises micronized brexpiprazole or a salt thereof as an active ingredient and at least one pharmaceutically acceptable excipient. Further, the present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient process.

[0004] Background of the Invention

[0005] Brexpiprazole acts as a partial agonist of the serotonin 5-HT1A receptor and the dopamine D2 and D3 receptors. Brexpiprazole has been described for use in the treatment of schizophrenia, depression and other central nervous system disorders, and for use in the prophylaxis and / or treatment of behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental disease.

[0006] Brexpiprazole is a compound represented by the following Formula I, and its chemical name is 7-[4-[4-(1 -benzothiophen-4-yl)piperazin-1 -yl]butoxy]-1 H-quinolin-2-one.

[0007] Brexpiprazole is an antidepressant and antipsychotic drug marketed under the brand Rexulti® for the oral treatment of schizophrenia and as an adjunctive treatment to antidepressants in major depressive disorder. REXULTI tablets are intended for oral administration and available in 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg and 4 mg strengths. The product was approved in the U.S. in 2015 for the aforementioned indications and is currently in phase III trials for the treatment of agitation associated with Alzheimer's disease and the treatment of PTSD (post-traumatic stress disorder).

[0008] Brexpiprazole has poor solubility in water. The major limitation of the drug is its low solubility and permeability leading to poor bioavailability. So, in a formulation comprising brexpiprazole, solubility is important. WO 2013 / 054872 patent application discloses pharmaceutical formulations comprising brexpiprazole and methods for their manufacture. In particular, the document describes producing uncoated or coated tablets of brexpiprazole using the following components: brexpiprazole, lactose, corn starch, microcrystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylcellulose and magnesium stearate. The compositions described therein are prepared by wet granulation techniques.

[0009] CN105412036 patent application discloses an orally disintegrating tablet containing Brexpiprazole where the improvement in dissolution is provided by the reduction of the active substance particle size below 10 pm in a course of co- grinding process utilizing lactose.

[0010] In prior art, low solubility of brexpiprazole has been approached in several ways. However, these studies in the prior art have been it strongly affects the dissolution profile of pharmaceutical compositions comprising brexpiprazole, and therefore causes problems with the development of a pharmaceutical formulation with a specified dissolution profile, it is not the case that only the careful selection of excipients, binders, disintegrants and other ingredients customarily used in pharmaceutical compositions or reducing particle size of active agent is important for the development of a composition with favorable solubility characteristics.

[0011] There is thus still a need for a film coated tablet comprising brexpiprazole or a salt thereof that provides a film coated tablet having the desired stability, dissolution profile, hardness and compressibility, in another words the disadvantages seen in the active substance will able to overcome. The formulation has been developed by using standard techniques which is simple and cost-effective method.

[0012] Detailed Description of the Invention

[0013] The main object of the present invention is to eliminate problems caused by active substance, brexpiprazole, and bringing additional advantages to the relevant prior art.

[0014] Another object of the present invention is to provide a film coated tablet comprising brexpiprazole with high stability, having desired level of dissolution rate which overcomes the above described problems in prior art and have additive advantages over them.

[0015] Another object of the present invention is to provide a film coated tablet comprising brexpiprazole having improved content uniformity and compressibility.

[0016] As used here in, ‘particle size’ means the cumulative volume size distrubition as tested by any conventionally accepted method such as the laser diffraction method (i.e. Malvern Mastersizer 2000 analysis). The term d (0.9) means the size at which %90 by volume of the particles are finer.

[0017] We have found that brexpiprazole or a salt thereof having the following particle sizes is very important for formulation. Especially, it positively affects the dissolution properties and powder homogenization. The obtained film coated tablets have the desired dissolution profile. The powder is more homogeneous. The content uniformity of the film coated tablets obtained from the more homogeneous powder is more ideal. Therefore, it provides better bioavailability. In addition to this having amount of disintegrant is between 0.1% and 25.0% by weight helps to provide the desired dissolution profile in the formulation.

[0018] According to one embodiment of the present invention, a film coated tablet comprises brexpiprazole or a salt thereof as an active ingredient and at least one pharmaceutically acceptable excipient wherein brexpiprazole or a salt thereof having particle size d90 less than about 50 microns and the amount of disintegrant in the tablet is 0.1% to 25.0% by weight.

[0019] In one embodiment of the invention, brexpiprazole or a salt thereof has a d (0.9) particle size less than 45 pm, preferably less than 40 pm.

[0020] According to one embodiment of the present invention, the amount of brexpiprazole or a salt thereof is between 0.1% and 10.0% by weight of the total composition.

[0021] In general terms, excipients provided in a formulation may positively or negatively influence the physicochemical and pharmacokinetic properties, e.g. the solubility, absorption, bioavailability of an active agent. For this reason, the excipients which accompany an active agent have to be selected in a careful and conscious manner while a formulation is developed. The formulations should have no physicochemical incompatibility between the active agent and the excipients.

[0022] Suitable disintegrants are selected from the group comprising sodium starch glycolate, crospovidone, cross-linked carboxymethyl cellulose (croscarmellose sodium), low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, sodium alginate, corn starch, alginic acid, magnesium aluminium silica, poloxamer, sodium glycine carbonate or mixtures thereof.

[0023] According to this embodiment of the present invention, the disintegrant is sodium starch glycolate. Especially, using sodium starch glycolate helps to provide the desired dissolution profile. Sodium starch glycolate absorbs water rapidly, resulting in swelling which leads to rapid disintegration of tablets.

[0024] According to this embodiment of the present invention, the amount of disintegrant in the tablet is 0.1% to 20.0% by weight, preferably 0.1% to 10.0% by weight of the total composition.

[0025] According to this embodiment of the present invention, the pharmaceutically acceptable excipients are selected from the group comprising fillers, binders, lubricants, surfactants or mixtures thereof.

[0026] Suitable fillers are selected from group comprising lactose monohydrate, microcrystalline cellulose, mannitol, pregelatinized starch, ammonium alginate, calcium carbonate, anhydrous lactose, calcium phosphate, calcium phosphate dehydrate, neutral pellets, calcium sulfate, cellulose, cellulose acetate, dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose, glyceryl palmitostearate, isomalt, kaolin, lactitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides, polydextrose, polymethacrylates, sodium alginate, sodium chloride, sorbitol, starch, sucrose, sugar sphericals, sulfobutylether betacyclodextrin, talc, tragacanth, trehalose, polysorbate 80, xylitol or mixtures thereof.

[0027] According to this embodiment of the present invention, the filler is lactose monohydrate, microcrystalline cellulose, mannitol or pregelatinized starch or mixtures thereof.

[0028] According to this embodiment of the present invention, the amount of filler in the tablet is 60.0% to 90.0% by weight of the total composition.

[0029] Suitable binders are selected from the group comprising polyvinylpyrrolidone, carboxymethylcellulose sodium, sugars, agar, alginates, carbomers, cellulose acetate phthalate, chitosan, starch, corn starch, starch mucilage, acacia mucilage, dextrates, dextrin, dextrose, ethylcellulose, glyceryl behenate, hydrogenated vegetable oil type I, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, hypromellose, magnesium aluminum silicate, maltodextrin, methylcellulose, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, aluminia hydroxide, stearic acid, sucrose, , polyoxyethilene-alkyl ethers, pullulan or mixtures thereof.

[0030] According to this embodiment of the present invention, the binder is polyvinylpyrrolidone or carboxymethylcellulose sodium or mixtures thereof.

[0031] According to this embodiment of the present invention, the amount of binder in the tablet is 0.1% to 20.0% by weight of the total composition. According to this embodiment of the present invention, the amount of binder in the tablet is 0.1% to 10.0% by weight of the total composition.

[0032] Suitable lubricants are selected from the group comprising sodium stearyl fumarate, magnesium stearate, calcium stearate, zinc stearate, talc, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, fumaric acid, glyceryl palmito sulphate, sodium lauryl sulphate or mixtures thereof.

[0033] According to this embodiment of the present invention, the lubricant is sodium stearyl fumarate. It improves the powder processing properties of film coated tablet formulation. Also, it enhances powder flow by reducing the inter-particle friction.

[0034] According to this embodiment of the present invention, the amount of lubricant in the tablet is 0.1% to 5.0% by weight of the total composition.

[0035] A surfactant is a substance that is generally a compound which lowers the surface tension between two liquids or between a liquid and a solid. Suitable surfactants are selected from the group comprising sodium lauryl sulphate, benzalconium chloride, docusate sodium, glyceryl esters, glyceryl monoleate, poloxamer, polyethylene alkyl ethers, polyglyceryl esters, polysorbates, polyoxyetylene esters, polyoxyetylene stearates, sodium stearate, hexadecyl pyridinium chloride or mixtures thereof.

[0036] According to this embodiment of the present invention, the surfactant is sodium lauryl sulphate.

[0037] According to this embodiment of the present invention, the amount of surfactant in the tablet is 0.1% to 10.0% by weight of the total composition.

[0038] In another embodiment of this present invention, a film coat on the tablet protects from moisture and further contributes to the ease with which it can be swallowed. Also, it is used in order to minimize for stability problems.

[0039] The film coated tablet of the present invention may prepared by direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion / spheronization, slugging, spray drying or solvent evaporation.

[0040] According to this embodiment of the present invention, the film coated tablet is prepared wet granulation which is simple and cost-effective method. Also, this process helps to provide stability and dissolution profile of the film coated tablet. Solvent is used in the process. Suitable solvents are selected from the group comprising water, ethanol, dichloromethane, 0.1 N HCI, methanol, isopropyl alcohol, benzyl alcohol, propylene glycol, polyethylene glycol, glycerine, cyclomethicone, glycerine triacetate, diethylene glycol monoethyl ether, glycerol formal, propylene carbonate or mixtures thereof.

[0041] According to this embodiment of the present invention, the solvent during wet granulation is water or ethanol or mixtures thereof.

[0042] According to this embodiment of the present invention, the solvent during wet granulation is ethanokwater (50:50) mixture.

[0043] According to this embodiment of the present invention, the film coated tablet is prepared by dry granulation- compaction which is simple and cost-effective method.

[0044] According to this embodiment of the present invention, the film coated tablet comprises;

[0045] ■ Brexpiprazole or a salt thereof having particle size d90 less than about 50 microns,

[0046] ■ 0.1-25.0% by weight of sodium starch glycolate

[0047] ■ 0.1 -5.0% by weight of lubricants of the total composition.

[0048] According to this embodiment of the present invention, the film coated tablet comprises;

[0049] ■ Brexpiprazole or a salt thereof having particle size d90 less than about 50 microns,

[0050] ■ Sodium starch glycolate

[0051] ■ Sodium stearyl fumarate

[0052] Example 1 : The film coated tablet is prepared by wet granulation with water A process for example 1 ; a) Mixing brexpiprazole and 14 of lactose monohydrate by weight, b) Adding half of the remaining lactose monohydrate and mixing, c) Adding the remaining part of lactose monohydrate and mixing, d) Adding Microcrystalline cellulose and mixing, e) Adding sodium starch glycolate and polyvinylpyrrolidone and then mixing, f) Granulating the mixture with water, g) Sieving and then drying, h) Sieving the dried granules and adding sodium stearyl fumarate and then mixing, i) Compressing the total mixture into tablets j) Coating the tablets with film coating.

[0053] Example 2: The film coated tablet is prepared by wet granulation with water

[0054] A process for example 2; a) Mixing brexpiprazole and 14 of pregelatinized starch by weight, b) Adding half of the remaining pregelatinized starch and mixing, c) Adding the remaining part of pregelatinized starch and mixing, d) Adding mannitol and mixing, e) Adding sodium starch glycolate and polyvinylpyrrolidone and then mixing, f) Granulating the mixture with water, g) Sieving and then drying, h) Sieving the dried granules and adding sodium stearyl fumarate and then mixing, i) Compressing the total mixture into tablets j) Coating the tablets with film coating. Example 3: The film coated tablet is prepared by wet granulation with water or ethanol-water mixture

[0055] A process for example 3; a) Mixing Lactose Monohydrate, Microcrystalline Cellulose, Sodium starch glycolate b) Dissolving carboxymethylcellulose sodium and sodium lauryl sulphate in water and then adding ethanol c) Adding brexpiprazole to step (b) and homogenizing the mixture, d) Granulating the mixture at step (a) with the mixture step (c), e) Sieving and then drying, f) Sieving the dried granules and adding sodium stearyl fumarate and then mixing, g) Compressing the total mixture into tablets h) Coating the tablets with film coating.

[0056] Example 4: The film coated tablet is prepared by dry granulation- compaction

[0057] A process for example 4; a) Mixing brexpiprazole, lactose monohydrate, mannitol, polyvinylpyrrolidone, sodium starch glycolate, b) Compacting the mixture at step (a), sieving and then mixing, c) Adding sodium stearyl fumarate and then mixing, d) Compressing the total mixture into tablets e) Coating the tablets with film coating.

Claims

CLAIMS A film coated tablet comprising brexpiprazole or a salt thereof as an active ingredient and at least one pharmaceutically acceptable excipient wherein brexpiprazole or a salt thereof having particle size d90 less than about 50 microns and the amount of disintegrant in the tablet is 0.1% to 25.0% by weight. The film coated tablet according to claim 1 , wherein disintegrants are selected from the group comprising sodium starch glycolate, crospovidone, cross-linked carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, sodium alginate, corn starch, alginic acid, magnesium aluminium silica, poloxamer, sodium glycine carbonate or mixtures thereof. The film coated tablet according to any preceding claim, wherein disintegrant is sodium starch glycolate. The film coated tablet according to any preceding claim, wherein amount of disintegrant in the tablet is 0.1% to 20.0% by weight, preferably 0.1% to 10.0% by weight of the total composition. The film coated tablet according to claim 1 , wherein the pharmaceutically acceptable excipients are selected from the group comprising fillers, binders, lubricants, surfactants or mixtures thereof. The film coated tablet according to claim 5, wherein fillers are selected from group comprising lactose monohydrate, microcrystalline cellulose, mannitol, pregelatinized starch, ammonium alginate, calcium carbonate, anhydrous lactose, calcium phosphate, calcium phosphate dehydrate, neutral pellets, calcium sulfate, cellulose, cellulose acetate, dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose, glyceryl palmitostearate, isomalt, kaolin, lactitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides, polydextrose, polymethacrylates, sodium alginate, sodium chloride, sorbitol, starch, sucrose, sugar sphericals, sulfobutylether beta-cyclodextrin, talc, tragacanth, trehalose, polysorbate 80, xylitol or mixtures thereof. The film coated tablet according to any preceding claim, wherein the filler is lactose monohydrate, microcrystalline cellulose, mannitol or pregelatinized starch or mixtures thereof.

8. The film coated tablet according to claim 5, wherein binders are selected from the group comprising polyvinylpyrrolidone, carboxymethylcellulose sodium, sugars, agar, alginates, carbomers, cellulose acetate phthalate, chitosan, starch, corn starch, starch mucilage, acacia mucilage, dextrates, dextrin, dextrose, ethylcellulose, glyceryl behenate, hydrogenated vegetable oil type I, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, hypromellose, magnesium aluminum silicate, maltodextrin, methylcellulose, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, aluminia hydroxide, stearic acid, sucrose, , polyoxyethilene-alkyl ethers, pullulan or mixtures thereof.

9. The film coated tablet according to any preceding claim, wherein the binder is polyvinylpyrrolidone or carboxymethylcellulose sodium or mixtures thereof.

10. The film coated tablet according to claim 5, wherein lubricants are selected from the group comprising sodium stearyl fumarate, magnesium stearate, calcium stearate, zinc stearate, talc, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, fumaric acid, glyceryl palmito sulphate, sodium lauryl sulphate or mixtures thereof.11 . The film coated tablet according to claim any preceding claim, wherein the lubricant is sodium stearyl fumarate.

12. The film coated tablet according to claim 5, wherein surfactants are selected from the group comprising sodium lauryl sulphate, benzalconium chloride, docusate sodium, glyceryl esters, glyceryl monoleate, poloxamer, polyethylene alkyl ethers, polyglyceryl esters, polysorbates, polyoxyetylene esters, polyoxyetylene stearates, sodium stearate, hexadecyl pyridinium chloride or mixtures thereof.

13. The film coated tablet according to any preceding claim, wherein the surfactant is sodium lauryl sulphate.

14. The film coated tablet according to claim 1 , wherein the tablet comprising;- Brexpiprazole or a salt thereof having particle size d90 less than about 50 microns,- 0.1-25.0% by weight of sodium starch glycolate- 0.1 -5.0% by weight of lubricants of the total composition.

15. The film coated tablet according to claim 5, wherein the tablet comprising;- Brexpiprazole or a salt thereof having particle size d90 less than about 50 microns,- Sodium starch glycolate- Sodium stearyl fumarate

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