A tablet of tolvaptan and at least one binder processed with wet granulation

Abstract

The present invention relates to a tablet comprising an intragranular composition comprising amorphous tolvaptan and at least one binder, wherein the intragranular composition is obtained by wet-granulation using water.

Description

[0001] A TABLET OF TOLVAPTAN AND AT LEAST ONE BINDER PROCESSED WITH WET GRANULATION

[0002] Field of the Invention

[0003] The present invention relates to a tablet comprising an intragranular composition comprising amorphous tolvaptan and at least one binder, wherein the intragranular composition is obtained by wet-granulation using water.

[0004] Background of the Invention

[0005] Tolvaptan is an orally bioavailable, selective, arginine vasopressin receptor 2 (V2, AVPR2) antagonist that can be used to treat hyponatremia. Upon oral administration, tolvaptan selectively and competitively binds to and blocks the V2 receptor located in the walls of the vasculature and luminal membranes of renal collecting ducts, thereby preventing the binding of vasopressin to the V2 receptor. This prevents water absorption in the kidneys and increases the excretion of electrolyte- free water via the kidneys. This reduces intravascular volume and increases serum sodium concentrations and osmolality.

[0006] Tolvaptan is chemically described as N-(4-(7-Chloro-5-hydroxy-2,3,4,5-tetrahydro-lH- benzo[b]azepine-l-carbonyl)-3-methylphenyl)-2-methylbenzamide. Its empirical formula is

[0007] C26H25CIN2O3, with structural formula as follows:

[0008] Tolvaptan is available as oral tablets containing 15 mg and 30 mg of tolvaptan, with trade name SAMSCA® by Otsuka America Pharmaceutical for the treatment of clinically significant hypervolemic and euvolemic hyponatremia.

[0009] Tolvaptan is a class IV drug in the BCS classification, that is, a low-soluble and hypotonic drug. For poorly soluble drugs, its dissolution is the rate-limiting process of absorption, and is often the most important factor affecting its bioavailability. U.S. Pat. No. 5,258,510 disclose tolvaptan.

[0010] CN102366412 (A) discloses a preparation method of a tolvaptan tablet. The method is wet granulation without water.

[0011] WO2008156217 (A2) discloses a pharmaceutical solid preparation comprising tolvaptan and hydroxypropylcellulose containing a hydroxypropoxyl group in an amount of 50 wt.% or greater. Also, a method for preparing the pharmaceutical solid preparation discloses. The method is wet or dry granulation.

[0012] In prior art, there are also several patents which disclose tolvaptan in oral pharmaceutical dosage forms. However, despite the dissolution problem of tolvaptan, an effective formulation and method has not been disclosed.

[0013] There still remains a need in the art to provide an improved a tablet comprising tolvaptan having high solubility, excellent pharmacomechanic properties and accordingly a high bioavailability and a long-term stability which is also obtained by using wet granulation.

[0014] Detailed Description of the Invention

[0015] The main object of the present invention is to provide a tablet comprising amorphous tolvaptan with having desired level of dissolution rate and high stability and excellent pharmacomechanic properties, such as flowability, compressibility and content uniformity which overcomes the abovedescribed problems in the prior art and have additive advantages over them.

[0016] Another object of the present invention is to provides a process for a tablet composition comprising tolvaptan or crystalline polymorph thereof. The process is a simple, rapid, cost effective, time-saving and industrially convenient method.

[0017] Tolvaptan is poorly soluble in water. This causes problems of dissolution profile and bioavailability. In the present invention, some studies have been done so that these problems do not appear.

[0018] It was seen that Tolvaptan Amorphous is better solubility than Tolvaptan Crystalline. In addition to solubility in the pharmaceutical composition, stability is also very important. It is very important for its stability that amorphous tolvaptan can be produced without turning into crystals and that it remains amorphous throughout its shelf life. To achieve this, it is found that for a tablet comprising amorphous tolvaptan, using wet granulation method with water is used and both the desired dissolution profile and stability is achieved. As used herein, the term "intragranular composition" refers to a population of granules that are wetted with solvent and then dried and granulated. Intragranular composition can be called also "granulate" or "granulate component". The "extragranular composition" refers is the part that does not participate in wet granulation.

[0019] According to this embodiment of the present invention, a tablet comprises an intragranular composition comprising amorphous tolvaptan and at least one binder, wherein the intragranular composition obtained by wet-granulation using water. These properties provide the desired dissolution profile and stability. Also, these provide the desired hardness and compressibility.

[0020] When amorphous tolvaptan treated with water, transition from amorphous to crystalline has not been observed. We found that when using else a solvent (for example ethyl alcohol and water mixture) during process, transition from amorphous form to crystalline form is seen.

[0021] Also, tolvaptan is used small proportion that can lead to considerable problems during the manufacture of the composition with regard to the uniformity of the content of active agent in the individual composition units. Because of problems uniformity of the content, the active substance may interact with several excipients. It reflects that content uniformity play important role in the dissolution of the drug. In this invention, to eliminate this problem, wet granulation is preferred in terms of pharmacotechnical properties, such as flowability, compressibility and content uniformity of tolvaptan.

[0022] Suitable binders are selected from the group comprising polyvinylpyrrolidone, sodium carboxymethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, starch, pregelatinized starch, sodium alginate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose, polymethacrylates, methacrylate polymers, hyaluronic acid, pectin, polysaccharides, polyacrylamide, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof.

[0023] The viscosity of a binder is a measure of its flow characteristics, and the performance of a bituminous mix is greatly affected by its viscosity. In the present invention, binders having low viscosity are used.

[0024] According to one embodiment of the present invention, the binder is polyvinylpyrrolidone. Polymer having low viscosity is povidone with a dynamic viscosity of 10% aqueous solution at 25°C up to about 10 mPa.s. Povidone is selected from the consisting of K12, K17, K25,K30, VA 64 and mixture thereof, more preferably VA 64. We saw that the use of the binder surprisingly achieved content uniformity, the desired flowabilirty and homogeneity of active agent. According to one embodiment of this invention, the amount of binder is between 1.0% and 20.0%, between 1.0% and 15.0% by weight of the total composition.

[0025] According to one embodiment of this invention, the amount of binder is between 3.0% and 10.0% by weight of the total composition.

[0026] According to one embodiment of this invention, the amount of amorphous tolvaptan is between 5.0% and 25.0%, between 8.0% and 25.0%, between 10.0% and 20.0% by weight of the total composition.

[0027] We have found that amorphous tolvaptan having the following particle sizes is important for formulation. Too small particle sizes influence the manufacturability, for example by sticking or filming. On the other hand too large particles negatively affect the dissolution properties of the pharmaceutical composition and dosage form and thus the bioavailability. In the following preferred ranges of the particle size distribution are described.

[0028] As used here in, "particle size distribution" is defined by the cumulative volume size distribution as tested by a conventionally accepted method which is the laser diffraction method determined by the equipment of Malvern Mastersizer 2000 laser diffraction particle size analyzer analyzer. "D (0.9)" or "d90" means that the size at which %90 by volume of the particles are finer, d (0.1) means that the size at which 10% by volume of the particles are finer and d (0.5) means that the size at which 50% by volume of the particles are finer. In this invention, particle size distribution of d (0.9) or d (0.5) or D(0.1) value of tolvaptan has been measured with solid samples and these values have been identified by Malvern Mastersizer 2000 laser diffraction particle size analyzer.

[0029] According to this embodiment of the present invention, amorphous tolvaptan has a d (0.9) particle size between 2 pm and 100 pm or between 3 pm and 50 pm or between 3 pm and 30 pm.

[0030] According to this embodiment of the present invention, amorphous tolvaptan has a d (0.9) particle size between 3 pm and 30 pm or between 3 pm and 25 pm or between 3 pm and 20 pm.

[0031] According to this embodiment of the present invention, amorphous tolvaptan has a d (0.5) particle size between 1 pm and 25 pm or between 1 pm and 15 pm or between 1 pm and 8 pm.

[0032] According to this embodiment of the present invention, amorphous tolvaptan has a d (0.5) particle size between 1 pm and 5 pm. According to this embodiment of the present invention, amorphous tolvaptan has a d (0.1) particle size between 0.1 pm and 20 pm or between 0.1 pm and 12 pm or between 0.1 pm and 8 pm.

[0033] According to this embodiment of the present invention, amorphous tolvaptan has a d (0.9) particle size between 2 pm and 100 pm, amorphous tolvaptan has a d (0.5) particle size between 1 pm and 30 pm, amorphous tolvaptan has a d (0.1) particle size between 0.1 pm and 12 pm. These particle size of amorphous tolvaptan helps to provide the desired dissolution profile by dissolving tolvaptan.

[0034] According to this embodiment of the present invention, a tablet comprises an intragranular composition comprising amorphous tolvaptan having a d (0.9) particle size between 2 pm and 100 pm and polyvinylpyrrolidone, wherein the intragranular composition is obtained by wet-granulation using water.

[0035] According to one embodiment of the present invention, an intragranular composition further comprises at least one pharmaceutically acceptable excipient selected from the group comprising disintegrants, fillers or mixtures thereof.

[0036] Suitable disintegrants are selected from the group comprising croscarmellose sodium, corn starch, starch, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, hydroxymethyl starch or mixtures thereof.

[0037] According to one embodiment of the present invention, the disintegrant is croscarmellose sodium.

[0038] According to one embodiment of this invention, the amount of disintegrant is between 1.0% and 20.0%, preferably between 3.0% and 15.0%, more preferably between 3.0% and 10.0% by weight of the total composition.

[0039] Suitable fillers are selected from the group comprising microcrystalline cellulose, lactose monohydrate, ammonium alginate, calcium carbonate, calcium phosphate, calcium phosphate dehydrate, neutral pellets, calcium sulfate, cellulose, cellulose acetate, compressible sugar, ethylcellulose, fructose, glyceryl palmitostearate, lactitol, lactose, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides, polydextrose, polymethacrylates, simethicone, sodium alginate, sodium chloride, sorbitol, sucrose, sugar spheres, sulfobutylether beta-cyclodextrin, talc, tragacanth, trehalose, xylitol or mixtures thereof.

[0040] According to one embodiment of the present invention, the filler is microcrystalline cellulose or lactose monohydrate or mixtures thereof. According to one embodiment of this invention, the amount of filler is between 55.0% and 90.0%, between 60.0% and 80.0% by weight of the total composition.

[0041] According to one embodiment of this invention, the tablet further comprises an extragranular composition comprising at least one pharmaceutically acceptable excipient selected from the group comprising coloring agents, lubricants or mixtures thereof.

[0042] Suitable coloring agents are selected from the group comprising indigo carmin aliminium lake, ferric oxide, titanium dioxide, Food, Drug & Cosmetic (FD&C) dyes (such as; FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C lakes), poncau, indigo Drug & Cosmetic (D&C) blue, indigotine FD&C blue, carmoisine indigotine (indigo Carmine); iron oxides (such as; iron oxide red, yellow, black), quinoline yellow, flaming red, carmine, carmoisine, sunset yellow or mixtures thereof.

[0043] According to one embodiment of the present invention, the coloring agent is indigo carmin aliminium lake. This excipient is known as redox indicator. It prevents the active substance from being degraded by giving its own reversible reaction against oxidative and reducing substances (stress factors). Since the reaction is reversible, it is not completely depleted by its own degradation, and the raw material is protected from stress factors (oxidative and reducing species). This contributes positively to the shelf life of the product. This coloring agent provides the desired stability.

[0044] According to one embodiment of the present invention, the tablet comprises;

[0045] — Amorphous tolvaptan

[0046] — Croscarmellose sodium

[0047] — Polyvinylpyrrolidone VA 64

[0048] — Lactose Monohydrate

[0049] — Microcrystalline cellulose

[0050] — Indigo carmin aliminium lake

[0051] Suitable lubricants are selected from the group comprising magnesium stearate, calcium stearate, sodium stearyl fumarate, potassium stearate, stearic acid, sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols or mixtures thereof.

[0052] According to one embodiment of the present invention, the lubricant is magnesium stearate.

[0053] According to this embodiment of the invention, a process for preparing a tablet comprises the following steps: a) Dissolving polyvinylpyrrolidone VA 64 in water, b) Mixing amorphous tolvaptan, at least one disintegrant and at least one filler, c) Granulating the dry mixture at step (b) with the mixture step (a) and obtained wet granule, d) Drying the wet granule and then sieving, e) Adding indigo carmin aliminium lake and then mixing, f) Adding at least one lubricant and then mixing, g) Compressing the mixture into tablets.

[0054] According to this embodiment of the invention, a process for preparing a tablet comprises the following steps: a) Dissolving polyvinylpyrrolidone VA 64 in water, b) Mixing amorphous tolvaptan, lactose monohydrate, croscarmellose sodium and microcystralline cellulose, c) Granulating the dry mixture at step (b) with the mixture step (a) and obtained wet granule, d) Drying the wet granule and then sieving, e) Adding indigo carmin aliminium lake and then mixing, f) Adding magnesium stearate and then mixing, g) Compressing the mixture into tablets.

[0055] Example 1: Example 2:

[0056] A process for example 1 or 2; a) Dissolving polyvinylpyrrolidone VA 64 in water, b) Mixing amorphous tolvaptan, lactose monohydrate, croscarmellose sodium and microcystralline cellulose, c) Granulating the dry mixture at step (b) with the mixture step (a) and obtained wet granule, d) Drying the wet granule and then sieving, e) Adding indigo carmin aliminium lake and then mixing, f) Adding magnesium stearate and then mixing, g) Compressing the mixture into tablets.

Claims

CLAIMS1) A tablet comprises an intragranular composition comprising amorphous tolvaptan and at least one binder, wherein the intragranular composition obtained by wet-granulation using water.2) The tablet according to claim 1, wherein binders are selected from the group comprising polyvinylpyrrolidone, sodium carboxymethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, starch, pregelatinized starch, sodium alginate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose, polymethacrylates, methacrylate polymers, hyaluronic acid, pectin, polysaccharides, polyacrylamide, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof.3) The tablet according to claim 2, wherein the binder is polyvinylpyrrolidone.4) The tablet according to claim 1, wherein amorphous tolvaptan has a d (0.9) particle size between 2 pm and 100 pm or between 3 pm and 50 pm or between 3 pm and 30 pm.5) The tablet according to claim 1, wherein amorphous tolvaptan has a d (0.5) particle size between 1 pm and 25 pm or between 1 pm and 15 pm or between 1 pm and 8 pm.6) The tablet according to claim 1, wherein amorphous tolvaptan has a d (0.1) particle size between 0.1 pm and 20 pm or between 0.1 pm and 12 pm or between 0.1 pm and 8 pm.7) The tablet according to claim 1, wherein an intragranular composition further comprises at least one pharmaceutically acceptable excipient selected from the group comprising disintegrants, fillers or mixtures thereof.8) The tablet according to claim 7, wherein disintegrants are selected from the group comprising croscarmellose sodium, corn starch, starch, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, hydroxymethyl starch or mixtures thereof.9) The tablet according to claim 7, wherein fillers are selected from the group comprising microcrystalline cellulose, lactose monohydrate, ammonium alginate, calcium carbonate, calcium phosphate, calcium phosphate dehydrate, neutral pellets, calcium sulfate, cellulose, cellulose acetate, compressible sugar, ethylcellulose, fructose, glyceryl palmitostearate,lactitol, lactose, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides, polydextrose, polymethacrylates, simethicone, sodium alginate, sodium chloride, sorbitol, sucrose, sugar spheres, sulfobutylether beta-cyclodextrin, talc, tragacanth, trehalose, xylitol or mixtures thereof.10) The tablet according to claim 9, wherein the filler is microcrystalline cellulose or lactose monohydrate or mixtures thereof.11) The tablet according to claim 1, wherein further comprises an extragranular composition comprising at least one pharmaceutically acceptable excipient selected from the group comprising coloring agents, lubricants or mixtures thereof.12) The tablet according to claim 11, wherein the coloring agent is indigo carmin aliminium lake.13) The tablet according to claim 11, wherein lubricants are selected from the group comprising magnesium stearate, calcium stearate, sodium stearyl fumarate, potassium stearate, stearic acid, sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols or mixtures thereof.14) The tablet according to claim 1, wherein the tablet comprises;— Amorphous tolvaptan— Croscarmellose sodium— Polyvinylpyrrolidone VA 64— Lactose Monohydrate— Microcrystalline cellulose— Indigo carmin aliminium lake15) A process for preparing a tablet comprises the following steps: a) Dissolving polyvinylpyrrolidone VA 64 in water, b) Mixing amorphous tolvaptan, at least one disintegrant and at least one filler, c) Granulating the dry mixture at step (b) with the mixture step (a) and obtained wet granule, d) Drying the wet granule and then sieving, e) Adding indigo carmin aliminium lake and then mixing, f) Adding at least one lubricant and then mixing, g) Compressing the mixture into tablets.

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