Classifications

• • 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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • 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
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • 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
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

• 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.
• Tolvaptan is an orally bioavailable, selective, arginine vasopressin receptor 2 (V2, AVPR2) antagonist that can be used to treat hyponatremia.
• V2 arginine vasopressin receptor 2
• 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.
• 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
• 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.
• Tolvaptan is a class IV drug in the BCS classification, that is, a low-soluble and hypotonic drug.
• BCS BCS classification
• 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.
• CN102366412 discloses a preparation method of a tolvaptan tablet. The method is wet granulation without water.
• WO2008156217 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.
• 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.
• 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.
• 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.
• Tolvaptan Amorphous is better solubility than Tolvaptan Crystalline.
• 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.
• 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.
• a tablet comprises an intragranular composition comprising amorphous tolvaptan and at least one binder, wherein the intragranular composition obtained by wet-granulation using water.
• 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.
• 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.
• 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.
• binders having low viscosity are used.
• 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.
• the amount of binder is between 1.0% and 20.0%, between 1.0% and 15.0% by weight of the total composition.
• the amount of binder is between 3.0% and 10.0% by weight of the total composition.
• 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.
• 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.
• 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
• d (0.5) means that the size at which 50% by volume of the particles are finer.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• an intragranular composition further comprises at least one pharmaceutically acceptable excipient selected from the group comprising disintegrants, fillers or mixtures thereof.
• 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.
• the disintegrant is croscarmellose sodium.
• 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.
• 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.
• 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.
• 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.
• 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.
• FD&C Drug & Cosmetic
• 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.
• the tablet comprises;
• 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.
• the lubricant is magnesium stearate.
• 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.
• 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.
• Example 1 Example 2:
• 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.

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• 2023
  • 2023-02-15 EP EP23756751.6A patent/EP4479057A4/de active Pending

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