A tablet formulation of lurasidone hydrochloride

Abstract

The present invention relates to a film coated tablet formulation comprising lurasidone hydrochloride wherein lurasidone hydrochloride has a d (0.9) particle size between 15 and 0.5 µm and the weight ratio of lurasidone hydrochloride to binders is between 1.0 and 2.0. The present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient method of preparing the formulation.

Description

[0001] A TABLET FORMULATION OF LURASIDONE HYDROCHLORIDE

[0002] Field of Invention

[0003] The present invention relates to a film coated tablet formulation comprising lurasidone hydrochloride wherein lurasidone hydrochloride has a d (0.9) particle size between 15 and 0.5 pm and the weight ratio of lurasidone hydrochloride to binders is between 1.0 and 2.0. The present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient method of preparing the formulation.

[0004] Background of Invention

[0005] Atypical antipsychotics are newer antipsychotic agents that have a pharmacological profile different from older or typical antipsychotic drugs. They are also called second generation antipsychotics. The drugs in this class of antipsychotics act on many receptor types including dopamine and serotonin, but they are more selective for dopamine receptors. They cause less extrapyramidal side effects compared to the older typical antipsychotic drugs. They are more effective in treatment-resistant patients and have a greater efficacy to treat negative symptoms, compared to the typical antipsychotics.

[0006] Lurasidone is an atypical antipsychotic which belongs to the chemical class of benzisothiazol derivatives. Its chemical name is (3aR,4S,7R,7aS)-2-{(lR,2R)-2-[4-(l,2-benzisothiazol-3-yl)piperazin-l- ylmethyl]cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-l, 3-dione and its chemical structure is shown in the Formula 1.

[0007] Formula 1. Lurasidone Lurasidone hydrochloride is a salt of lurasidone which is developed by Dainippon Sumitomo under the trade name Latuda® which is indicated for the treatment of patients with schizophrenia and with major depressive episodes associated with bipolar I disorder (bipolar depression).

[0008] According to the BCS classification, lurasidone hydrochloride belongs to Class II and is a low-soluble and hypertonic drug.

[0009] CN105395493B patent discloses a lurasidone hydrochloride tablet and its preparation method. The solid dispersion technology is used to disperse lurasidone hydrochloride in a matrix material in an amorphous manner to increase the dissolution rate of lurasidone hydrochloride. It ensures bioavailability in the body, but the drugs in the tablets are dispersed in an amorphous form, and there is a problem of poor stability caused by crystallization. At the same time, it is difficult to achieve larger batch production with a hot melt extruder, which requires high energy consumption and equipment requirements, higher.

[0010] Yet another patent application no. US2015157628A1 asserts pharmaceutical compositions comprising lurasidone and starch derivatives in lower ratios in comparison with the state of art and aims to decrease the weight of a tablet. However, the recommended amounts of lurasidone and starch derivatives are rather high, between 20-50% and more than 50% by weight of the composition, respectively. Moreover, in the preparation process of this composition, only water is used to form binder / granulation solution which gives rise to undesired long dry time.

[0011] Patent CN 102048734 B discloses the prescription and preparation process of commercially available lurasidone hydrochloride tablets. The raw material drug is micronized to control the average particle size below 4 pm. One-step granulation is carried out. However, this patent does not provide a solution for problems affecting stability such as homogeneity and fluidity caused by the micronizing of the active substance.

[0012] In the prior art, several patents have been done for the dissolution profile problem. However, some studies for the dissolution profile may cause stability problems. For this reason, the excipients used in the formulation of the tablet comprising lurasidone hydrochloride and their weight ratios have gained importance.

[0013] There still remains a need in the art to provide an improved a film coated tablet comprising lurasidone hydrochloride having excellent pharmacochemical properties, long-term stability. In the present invention, the film coated tablet is created to overcome the above problems and provides additional advantages to the relevant field of art. Other advantages and embodiments of the present invention will be clarified in the following description.

[0014] Detailed Description of the Invention

[0015] The main object of the present invention is to provide a film coated tablet formulation comprising a therapeutically effective amount of lurasidone hydrochloride with the desired dissolution profile and stability.

[0016] Another object of the present invention is to provide a film coated tablet formulation comprising lurasidone hydrochloride with improved compressibility, flowability, homogeneity.

[0017] A further object of the present invention is to improve a process for preparing the said lurasidone hydrochloride tablet, comprising spray granulation method which makes round and compact granules having a high bulk density.

[0018] As used here in, 'particle size' means the cumulative volume size distribution as tested by any conventionally accepted method such as the laser diffraction method (i.e. Malvern analysis). The term d (0.9) means the size at which %90 by volume of the particles are finer, the term d (0.5) means the size at which %50 by volume of the particles are finer, the term d (0.1) means the size at which %10 by volume of the particles are finer.

[0019] Lurasidone is very slightly soluble in water, practically insoluble or insoluble in 0.1 N HCI, slightly soluble in ethanol, sparingly soluble in methanol, practically insoluble or insoluble in toluene and very slightly soluble in acetone. This causes problems of dissolution profile and bioavailability. The problems negatively affect the stability. We have found that lurasidone hydrochloride having suitable particle sizes is very important for formulation. The desired dissolution profile is achieved by using micronized particle size, but this may cause some flowability and powder homogeneity problems. We have seen that these problems are not seen when lurasidone is in a certain weight ratio to the binder. Thus, we were able to obtain a product with the desired dissolution profile as well as high homogeneity and good flowability. This provides both stability and convenience in the process steps.

[0020] According to one embodiment, a film coated tablet formulation comprising lurasidone hydrochloride wherein lurasidone hydrochloride has a d (0.9) particle size between 15 and 0.5 pm and the weight ratio of lurasidone hydrochloride to binders is between 1.0 and 2.0. According to the preferred embodiment, lurasidone hydrochloride has a d (0.9) particle size between 13 and 2 pm or between 10 and 3 pm or between 8 and 4 pm.

[0021] According to the preferred embodiment, lurasidone hydrochloride has a d (0.5) particle size between 9 and 0.1 pm, preferably between 5 and 1 pm.

[0022] According to the preferred embodiment, lurasidone hydrochloride has a d (0.1) particle size between 6 and 0.1 pm, preferably between 4 and 0.8 pm.

[0023] According to the preferred embodiment, the weight ratio of lurasidone hydrochloride to binders is between 1.1 and 1.7.

[0024] According to the preferred embodiment, the amount of lurasidone hydrochloride is between 8.0% and 25.0 % by weight of the total composition. Preferably the amount of lurasidone hydrochloride is between 13.0% and 20.0% by weight of the total composition.

[0025] According to this embodiment, lurasidone hydrochloride is present in an amount of between 1 to 300 mg, preferably 10 to 240 mg and more preferably it is 60 to 120 mg.

[0026] Suitable binder is selected from the group comprising copovidone, copolyvidone, polyvinylpyrrolidone (PVP), povidone K30, hydroxypropyl methyl cellulose (HPMC), pullulan, polymethacrylate, glyceryl behenate, hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), methyl cellulose (MC), hydroxyethyl cellulose, sodium carboxymethyl cellulose (Na CMC), carboxymethyl cellulose calcium, ethyl cellulose, polymetacrylates, polyethylene oxide, polyvinyl alcohol, starch, pregelatinized starch, cellulose acetate phthalate, hydroxypropyl starch, hydroxyethyl methyl cellulose, polyethylene glycol (PEG), polyoxyethylene-alkyl ethers, polydextrose or mixtures thereof.

[0027] According to the preferred embodiment, binder used in this present invention is pregelatinized starch or polyvinylpyrrolidone or mixtures thereof. Preferably, pregelatinized starch and polyvinylpyrrolidone are used together.

[0028] According to the preferred embodiment, the amount of pregelatinized starch is between 3.0% and 15.0%, preferably 6-11% by weight of the total composition.

[0029] According to the preferred embodiment, the amount of polyvinylpyrrolidone is between 2.0% and 10.0% by weight of the total composition. 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.

[0030] According to one embodiment, the tablet formulation further comprises at least one pharmaceutically acceptable excipient selected from diluents, disintegrants, lubricants or mixtures thereof.

[0031] Suitable diluent is selected from the group comprising lactose monohydrate, lactose, dibasic calcium phosphate, microcrystalline cellulose, mannitol, spray-dried mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.

[0032] According to the preferred embodiment, diluent used in this present invention is mannitol or microcrystalline cellulose or mixtures thereof. Preferably, mannitol and microcrystalline cellulose are used together. The diluents help to provide the desired dissolution profile.

[0033] According to the preferred embodiment, the amount of mannitol is between 25.0 and 40.0% by weight of the total composition. Preferably, it is between 28.0 and 35.0% by weight of the total composition.

[0034] According to the preferred embodiment, the amount of microcrystalline cellulose is between 20.0% and 35.0%, preferably 22.0% and 30.0% by weight of the total composition.

[0035] Suitable disintegrant is selected from the group comprising croscarmellose sodium, sodium carbonate, hydroxypropyl cellulose (HPC), cross-linked polyvinylpyrrolidone (crosspovidone), copovidon, sodium starch glycolate, starch, alginic acid and alginates, ion-exchange resins, magnesium aluminum silica, sodium dodecyl sulphate, sodium carboxy methyl cellulose, carboxy methyl cellulose calcium, guar gum, polyacrylic potassium, sodium alginate, sodium lauryl sulphate or mixtures thereof.

[0036] According to the preferred embodiment, the disintegrant used in this present invention is croscarmellose sodium. According to this preferred embodiment, the amount of croscarmellose sodium is between 5.0% and 12.0% by weight of the total composition.

[0037] Suitable lubricant is selected from the group comprising sodium lauryl sulphate, sodium stearyl fumarate, magnesium stearate, zinc stearate, calcium stearate, talc, polyethylene glycol, glyceryl monostearate, glyceryl palmitostearate, magnesium lauryl sulphate, fumaric acid, zinc stearate, stearic acid, hydrogenated natural oils, or mixtures thereof.

[0038] According to the preferred embodiment, lubricant used in this present invention is magnesium stearate.

[0039] The amount of magnesium stearate is between 0.1% and 2.0% by weight of the total composition.

[0040] According to these embodiments, the solid oral pharmaceutical composition comprises at least one coating layer to protect the composition against the moisture and maintain the stability. Suitable coating ingredients are selected from the group comprising hydroxypropylmethyl cellulose (hypromellose), hydroxypropyl cellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), talc, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat IR), ethylcellulose dispersions (Surelease), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA) and all kinds of OpadryTM, pigments, dyes, titanium dioxide, iron oxide or polymethylmetacrylate copolymers (Eudragit) and mixtures thereof.

[0041] According to one preferred embodiment, the tablet formulation comprises lurasidone hydrochloride as active agent, pregelatinized starch and polyvinylpyrrolidone as binders, microcrystalline cellulose and mannitol as diluents, croscarmellose sodium as disintegrant, magnesium stearate as lubricant and a coating layer.

[0042] According to this preferred embodiment, the tablet comprises;

[0043] - lurasidone hydrochloride having a d (0.9) particle size between 15 and 0.5 pm

[0044] - pregelatinized starch

[0045] - polyvinylpyrrolidone.

[0046] According to this preferred embodiment, the tablet comprises;

[0047] - the amount of lurasidone hydrochloride is between 8-25%

[0048] - the amount of pregelatinized starch is between 3-15%,

[0049] - the amount of polyvinylpyrrolidone is between 2-10%,

[0050] - the amount of microcrystalline cellulose is between 20-35%, - the amount of croscarmellose sodium is between 5-12%,

[0051] - the amount of mannitol is between 25-40%,

[0052] - the amount of magnesium stearate is between 0.1-2%,

[0053] - the amount of the coating layer is between 1-5%, by weight of the total composition. According to all these embodiments, the below given formulations can be used in the tablet formulation subjected to the invention.

[0054] According to this embodiment of the invention, the film coated tablet of the present invention can be prepared by using spray granulation. The desired dissolution profile and a desired homogeneity of the film coated tablet is obtained and it has a simple preparation process, in favor of industrial production.

[0055] According to this embodiment of the present invention, a solvent is used at spray granulation.

[0056] Suitable solvents are selected from the group comprising pure water, dichloromethane, 0.1N HCI, methanol, ethanol, propylene glycol, polyethylene glycol, glycerine triacetate or mixtures thereof. Preferably, the solvent is water-ethanol mixture. Example 1: Opadry white coated tablet The tablet formulation mentioned above are prepared by following these steps:

[0057] — Swelling polyvinylpyrrolidone in a 70% alcohol solution comprising ethanol and water, thus preparing a granulation solution,

[0058] — Mixing microcrystalline cellulose, pregelatinized starch, croscarmellose sodium and lurasidone hydrochloride in a fluid bed dryer for 10 minutes to prepare a powder mixture,

[0059] — Granulating the powder mixture with the granulation solution using spray granulation method,

[0060] — Drying the granules, preferably until they have 3% moisture ratio,

[0061] — Sieving the granules preferably with a 0,7mm sieving mesh and grinding them,

[0062] — Mixing the grinded granules with mannitol for 15 minutes in a container mixer,

[0063] — Adding magnesium stearate to the mannitolized granules and mixing for 3 more minutes,

[0064] — Weighing the final mixture and compress into tablets,

[0065] — Coating these tablets with a film coating.

[0066] Spray granulation method which is performed to granulate the powder mixture results in granules with a round, compact structure, excellent flow properties, a high bulk density and a narrower range of particle sizes. These properties make easier to process further. As a result of these advantages, the tablet composition has an enhanced stability during its shelf-life.

Claims

CLAIMS1) A film coated tablet formulation comprising lurasidone hydrochloride wherein lurasidone hydrochloride has a d (0.9) particle size between 15 and 0.5 pm and the weight ratio of lurasidone hydrochloride to binders is between 1.0 and 2.0.2) The tablet according to claim 1, wherein hydrochloride has a d (0.9) particle size between 13 and 2 pm or between 10 and 3 pm or between 8 and 4 pm.3) The tablet according to claim 1, wherein the weight ratio of lurasidone hydrochloride to binders is between 1.1 and 1.7.4) The tablet according to claim 1, wherein binder is selected from the group comprising copovidone, copolyvidone, polyvinylpyrrolidone, povidone K30, hydroxypropyl methyl cellulose (HPMC), pullulan, polymethacrylate, glyceryl behenate, hydroxypropyl cellulose (HPC), carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, ethyl cellulose, polymetacrylates, polyethylene oxide, polyvinyl alcohol, starch, pregelatinized starch, cellulose acetate phthalate, hydroxypropyl starch, hydroxyethyl methyl cellulose, polyethylene glycol, polyoxyethylene-alkyl ethers, polydextrose or mixtures thereof.5) The tablet according to claim 1 or 4, wherein binder is pregelatinized starch or polyvinylpyrrolidone or mixtures thereof, preferably, pregelatinized starch and polyvinylpyrrolidone are used together.6) The tablet according to claim 5, wherein the amount of pregelatinized starch is between 3.0% and 15.0%, preferably 6.0 -11.0 % by weight of the total composition.7) The tablet according to claim 5, wherein the amount of polyvinylpyrrolidone is between 2.0% and 10.0% by weight of the total composition.8) The tablet according to claim 1, wherein further comprises at least one pharmaceutically acceptable excipient selected from diluents, disintegrants, lubricants or mixtures thereof.9) The tablet according to claim 8, wherein diluent is selected from the group comprising lactose monohydrate, lactose, dibasic calcium phosphate, microcrystalline cellulose, mannitol, spray-dried mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodiumchloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.10) The tablet according to claim 9, wherein diluent is mannitol or microcrystalline cellulose or mixtures thereof, preferably, mannitol and microcrystalline cellulose are used together.11) The tablet according to claim 8, wherein disintegrant is selected from the group comprising croscarmellose sodium, sodium carbonate, hydroxypropyl cellulose (HPC), cross-linked polyvinylpyrrolidone, copovidon, sodium starch glycolate, starch, alginic acid and alginates, ion-exchange resins, magnesium aluminum silica, sodium dodecyl sulphate, sodium carboxy methyl cellulose, carboxy methyl cellulose calcium, guar gum, polyacrylic potassium, sodium alginate, sodium lauryl sulphate or mixtures thereof.12) The tablet according to claim 11, wherein the disintegrant is croscarmellose sodium.13) The tablet according to claim 8, wherein lubricant is selected from the group comprising sodium lauryl sulphate, sodium stearyl fumarate, magnesium stearate, zinc stearate, calcium stearate, talc, polyethylene glycol, glyceryl monostearate, glyceryl palmitostearate, magnesium lauryl sulphate, fumaric acid, zinc stearate, stearic acid, hydrogenated natural oils, or mixtures thereof.14) The tablet according to claim 1, wherein the tablet comprises,- lurasidone hydrochloride having a d (0.9) particle size between 15 and 0.5 pm- pregelatinized starch- polyvinylpyrrolidone.15) The tablet according to claim 1 or 8, wherein the tablet comprises;- the amount of lurasidone hydrochloride is between 8-25%- the amount of pregelatinized starch is between 3-15%,- the amount of polyvinylpyrrolidone is between 2-10%,- the amount of microcrystalline cellulose is between 20-35%,- the amount of croscarmellose sodium is between 5-12%,- the amount of mannitol is between 25-40%,- the amount of magnesium stearate is between 0.1-2%,- the amount of the coating layer is between 1-5%, by weight of the total composition.

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