WO2013117793A1 - Composition pharmaceutique solide de cilostazol - Google Patents

Composition pharmaceutique solide de cilostazol Download PDF

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Publication number
WO2013117793A1
WO2013117793A1 PCT/ES2013/070072 ES2013070072W WO2013117793A1 WO 2013117793 A1 WO2013117793 A1 WO 2013117793A1 ES 2013070072 W ES2013070072 W ES 2013070072W WO 2013117793 A1 WO2013117793 A1 WO 2013117793A1
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Prior art keywords
cilostazol
composition
weight
composition according
sugar alcohol
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PCT/ES2013/070072
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English (en)
Spanish (es)
Inventor
Jesús GRANDÍO TIERNO
Antonio FERNÁNDEZ AIJÓN
Carlos Govantes Esteso
María de los Angeles BUENO SÁNCHEZ
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Laboratorios Normon S.A.
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Publication of WO2013117793A1 publication Critical patent/WO2013117793A1/fr

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention relates to solid pharmaceutical compositions of cilostazol which have an appropriate solubility of the active ingredient, and which can be used to prepare pharmaceutical forms of cilostazol for oral administration.
  • Cilostazol is the D.C.I. of the chemical compound 6- [4- (1-cyclohexyl-1 - / - tetrazol-5- yl) butoxy-3,4-dihydro-2 (1 H) -quinolinone, which responds to the following formula:
  • Cilostazol was first described in 1979 by the Otsuka company in the Belgian patent BE878548.
  • Cilostazol is a phosphodiesterase III (PDE III) enzyme inhibitor and is used in medicine as an antithrombotic to improve the maximum and pain-free distance that patients suffering from intermittent claudication can walk, who do not suffer from pain at rest and who have no evidence of peripheral tissue necrosis (stage II of Fontaine's classification of peripheral arterial disease).
  • PDE III phosphodiesterase III
  • Cilostazol is an active substance practically insoluble in water, and its bioavailability from pharmaceutical compositions is considered to be limited by the rate of dissolution.
  • US patent application US-A-2005/0255155 it is described that in the Biopharmaceutics Classification System cilostazol is classified as a Class II drug, characterized by low solubility and high permeability. It is also described that the oral absorption of cilostazol is rapid and complete, and that the kinetic profiles of cilostazol show that when the dissolution in vivo is complete, there is no limitation to absorption.
  • a tablet containing 100 mg of cilostazol as an active ingredient and as excipients is described in the medicinal product sheet Pletal ® : corn starch, microcrystalline cellulose, calcium carmellose, hypromellose and magnesium stearate.
  • compositions comprising cilostazol as an active ingredient and having an improved dispersibility and / or solubility of the active ingredient are described.
  • cilostazol with a particle size of 10 ⁇ or less, is incorporated into a solubilizing and / or dispersing agent selected from the group consisting of a water-soluble polymer, a surfactant, or mixture thereof.
  • the preferred solubilizing agent is sodium lauryl sulfate, alone or in combination with water-soluble polymers such as, for example, hydroxypropyl cellulose, or hydroxypropyl methylcellulose.
  • Formulation 3 of patent application WO-A-03/002121 describes cilostazol tablets comprising as excipients: starch, microcrystalline cellulose, polyvinylpyrrolidone, sodium carboxymethyl starch, magnesium stearate and talcum powder According to the described procedure, the last three components are added to the extra-granular phase before compression.
  • nanoparticulate cilostazol compositions which include a surface stabilizing agent, so that the low bioavailability of the active ingredient is improved and it is avoided having to take it during meals. It is also described that surface stabilizing agents can be polymers, low molecular weight oligomers, natural products and surfactants, and a considerable number of examples are cited. Also described are cilostazol compositions in the form of tablets comprising as excipients: hypromellose, sodium docusate, sucrose, sodium lauryl sulfate, lactose monohydrate, silicified microcrystalline cellulose, crospovidone and magnesium stearate.
  • the object of the invention is a solid pharmaceutical composition comprising cilostazol as active ingredient.
  • Also subject to the invention is a tablet comprising said composition.
  • compositions for the preparation of solid forms of cilostazol for oral administration are also part of the object of the invention. Also part of the object of the invention is a process for the preparation of said composition and said tablet.
  • Also part of the object of the invention is the use of said composition for the preparation of a medicament to improve the maximum and pain-free distance that patients suffering from intermittent claudication, who do not suffer from pain at rest, and who do not present evidence of peripheral tissue necrosis (stage II of the Fontaine classification of peripheral arterial disease).
  • Also part of the object of the invention is the use of said tablet for the preparation of a medicament to improve the maximum and pain-free distance that patients suffering from intermittent claudication, who do not suffer from pain at rest, and who do not present evidence of peripheral tissue necrosis (stage II of the Fontaine classification of peripheral arterial disease).
  • Figure 1 shows the dissolution profile of the tablets obtained in Example 1 and of the commercial drug Pletal ® using 0.1 N hydrochloric acid as the dissolution medium.
  • the percentage of dissolved active substance is represented in ordinates and in Abscissa represents time in minutes.
  • Figure 4 shows the dissolution profile of the tablets obtained in Example 1 and of the commercial drug Pletal ® using as a dissolution medium.
  • 0.05 M potassium phosphate buffer solution (pH 6.8) containing 0.5% sodium lauryl sulfate.
  • pH 6.8
  • sodium lauryl sulfate 0.5% sodium lauryl sulfate
  • Figure 5 shows the dissolution profile of the tablets obtained in Example 1 and the commercial drug Pletal ® using as a dissolution medium water with 0.3% sodium lauryl sulfate. In ordinates the percentage of dissolved active substance is represented and in abscissa the time in minutes is represented. Under these conditions, a degree of release of the active ingredient close to 80% is achieved, which allows a good comparison between the profiles of the two compositions and, in this case, to verify the significant similarity between the two.
  • the solid pharmaceutical composition object of the invention comprises:
  • a binding agent consisting essentially of a mixture of a sugar alcohol and talc
  • Said tablets contain an intragranular phase comprising the pharmaceutical composition of the invention, whose combination of active ingredient, binding agent formed by a sugar alcohol and talc, and optionally a disintegrating agent, surprisingly facilitates the dissolution of the active ingredient and allows obtain a dissolution profile equivalent to that of the commercial medicament
  • a pharmaceutically effective amount means an amount of an active ingredient, which when administered to a mammal to treat a disease or disorder, is sufficient to Get a therapeutic action.
  • the “pharmaceutically effective amount” may vary depending on tion of the active substance, the disease and its severity, and the age, weight, physical condition and response of the mammal to be treated.
  • the solid composition of cilostazol comprises a pharmaceutically effective amount of cilostazol, a binding agent consisting essentially of a mixture of a sugar alcohol and talc, and, optionally, a disintegrating agent.
  • a pharmaceutically effective amount of cilostazol a pharmaceutically effective amount of cilostazol, a binding agent consisting essentially of a mixture of a sugar alcohol and talc, and, optionally, a disintegrating agent.
  • a binding agent consisting essentially of a mixture of a sugar alcohol and talc
  • a disintegrating agent consisting essentially of a mixture of a sugar alcohol and talc
  • Cilostazol is the active substance of the solid pharmaceutical composition object of the invention.
  • Cilostazol can be prepared, for example, in accordance with the procedure described in Spanish patent ES483792.
  • cilostazol includes cilostazol, as well as pharmaceutically acceptable salts, solvates and hydrates thereof.
  • salts there may be mentioned, for example, acetate, besylate, citrate, fumarate, lactate, maleate, mesylate, tartrate, tosylate, bi- sulfate, hydrobromide, hydrochloride, and sulfate.
  • composition comprises cilostazol as the only active ingredient.
  • cilostazol is preferably used in a micronized form, so that at least 50%, preferably 75% and even more preferably 90% of the cilostazol particles have an average particle size not exceeding 10 microns
  • Said particle size can be obtained by controlling the process of reducing the particle size that can be carried out, for example, with a ceramic mill or by air jet.
  • cilostazol usually represents between 35% and 90% by weight over the total weight of the composition, preferably between 45% and 85%, and more preferably between 60% and 70% .
  • composition of the invention comprises a binding agent.
  • the binding agents are used in pharmaceutical technology to cause adhesion of the powder particles in the granulation processes.
  • the binding agent that is part of the composition of the invention consists essentially of a mixture of a sugar alcohol and talc.
  • Sugar alcohol is a hydrogenated form of a carbohydrate, whose carbonyl group has been reduced to a primary or secondary hydroxyl group, depending on whether the carbohydrate contained an aldehyde group or a keto group respectively.
  • the sugar alcohol suitable for the composition of the invention can be selected from monosaccharide derivatives such as, for example, sorbitol, mannol, dulcitol, fucitol, iditol, arabitol, xylitol or ribitol, or between disaccharide derivatives such as maltitol, lactitol, isomalt or polyglicitol.
  • monosaccharide derivatives such as, for example, sorbitol, mannol, dulcitol, fucitol, iditol, arabitol, xylitol or ribitol, or between disaccharide derivatives such as maltitol, lactitol, isomalt or polyglicitol.
  • the sugar alcohol is selected from the group consisting of sorbitol, mannitol, xylitol, isomalt, maltitol and lactitol, more preferably it is sorbitol, isomalt, mannitol, or maltitol, and even more preferably it is sorbitol.
  • sugar alcohol usually represents between 10% and 45% by weight over the total weight of the composition, preferably 15% and 40%, and more preferably between 25% and 30%.
  • Talc is a hydrated magnesium silicate that is commonly used in pharmaceutical compositions as an anti-caking agent, slider, diluent or lubricant.
  • talc is part of the binding agent and is incorporated into the intragranular phase of the composition.
  • the talc usually represents between 0.1% and 5% by weight over the total weight of the composition, preferably between 0.5% and 3%, and more preferably between 1% and the 2%.
  • composition of the invention optionally comprises a disintegrating agent.
  • the composition of the invention comprises a disintegrating agent.
  • the disintegrating agent that is preferably part of the composition of the invention is a component that is included in the formulation to ensure that the composition is broken into small fragments when in contact with a liquid, favoring the dispersion and dissolution of the active ingredient.
  • disintegrating agents for example, alginic acid, agar, sodium alginate, corn starch, potato starch, sodium starch glycolate, pregelatinized starch, microcrystalline cellulose, calcium carboxymethylcellulose , croscarmellose sodium, crospovidone, colloidal silicon dioxide, dibasic calcium phosphate, tribasic calcium phosphate, guar gum, low-grade hydroxypropylcellulose, potassium polyacryl, alumina and magnesium silicate, and mixtures thereof.
  • the disintegrating agent is selected from the group consisting of corn starch, potato starch, sodium starch glycolate, pregelatinized starch, microcrystalline cellulose, calcium carboxymethyl cellulose, crospovidone, colloidal silicon dioxide, dibasic calcium phosphate, tribasic calcium phosphate, tribasic calcium phosphate, tribasic calcium phosphate and mixtures thereof; more preferably between calcium carboxymethyl cellulose, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and mixtures thereof; and even more preferably between calcium carboxymethyl cellulose, crospovidone, and mixtures thereof.
  • the disintegrating agent usually represents between 2% and 20% by weight over the total weight of the composition, more preferably between 4% and 1-5%, and more preferably between 5% and 10%
  • a process for preparing the composition of the invention comprising:
  • composition of the invention can be prepared by methods well known to those skilled in the art, such as wet granulation, which are well described in pharmaceutical technology manuals such as the Remington book: The Science and Practice of Pharmacy, 20th Edition,
  • composition of the invention is as follows. First, a solution of the sugar alcohol in water is prepared and the talc is dispersed therein.
  • the cilostazol and the disintegrating agent are mixed and screened, and said mixture is granulated in a wet way by applying the dispersion of the binding agent consisting of a sugar alcohol and talc.
  • composition of the invention obtained in the form of granules is dried by hot air system to a humidity of less than 10%, preferably less than 5%, thus obtaining the composition of the invention that is suitable for the preparation of shapes.
  • Cilostazol oral pharmaceuticals Cilostazol oral pharmaceuticals.
  • compositions for the preparation of solid forms of cilostazol for oral administration are also part of the object of the invention.
  • Oral Pharmaceutical Forms are also part of the object of the invention.
  • composition of the invention is suitable for preparing oral pharmaceutical forms, for example, tablets, capsules or powders dosed in sachets.
  • tablets are preferred, which can be obtained by mixing and homogenizing the compositions object of the invention with suitable auxiliary agents, and subsequent compression.
  • oral solid pharmaceutical forms can be prepared with the composition of the invention that have an appropriate cilostazole dissolution profile and that in the case of tablets, no difficulties are observed in the compression stage.
  • a cilostazol tablet comprising:
  • composition of the invention a) an amount of the composition of the invention that is sufficient to provide an effective unit dose of cilostazol, and
  • the tablets of the invention consist of between 35% and 90% by weight of the composition of the invention, and between 10% and 65% by weight of at least one auxiliary agent. More preferably the tablets consist of between 50% and 75% by weight of the composition of the invention, and in between 25% and 45% by weight of at least one auxiliary agent. Even more preferably the tablets consist of between 60% and 70% by weight of the composition of the invention, and between 30% and 40% by weight of at least one auxiliary agent.
  • cilostazol is an effective active substance to treat intermittent claudication.
  • the tablets of the invention contain a unit dose that is between 50 mg and 150 mg of cilostazol, more preferably they contain 100 mg of cilostazol.
  • the auxiliary agent can be selected from the group consisting of diluents, disintegrants, lubricants, non-sticks, sweeteners, flavorings, flavorings, and / or mixtures thereof.
  • the auxiliary agent can be incorporated both in the granulation stage to prepare the composition of the invention, and in the stage of mixing it with the extragranular phase, or in both stages.
  • the auxiliary agent is incorporated in the mixing stage of the composition of the invention with the extragranular phase.
  • Diluents are inert excipients that facilitate the compression of pulverulent materials and provide resistance to tablets. They can be incorporated into both the intragranular phase and the extragranular phase. Preferably they are incorporated into the extragranular phase.
  • the diluents that can be used are: microcrystalline cellulose, powdered cellulose, silicified cellulose, lactose monohydrate, anhydrous lactose, mannitol, sorbitol, sucrose, fructose, dextrose, dibasic calcium phosphate, starch, pregelatinized starch, hydroxypropylcellulose low degree of substitution, and / or mixtures thereof.
  • the diluent used in the tablets of the invention is microcrystalline cellulose.
  • Disintegrating agents are excipients that cause a rapid breakage of the tablet when it is introduced into an aqueous medium, and also a rapid disintegration. - granulation, so that rapid release of the active ingredient occurs.
  • the tablet of the invention in addition to optionally including a disintegrating agent in the intragranular phase, also incorporates at least one disintegrating agent in the extragranular phase.
  • the disintegrants can be selected from the group consisting of: low-grade hydroxypropyl cellulose, sodium starch glycolate, calcium carboxymethyl cellulose, crospovidone, croscarmellose sodium, and / or mixtures thereof.
  • the disintegrating agent employed is calcium carboxymethyl cellulose, crospovidone, or mixtures thereof.
  • Lubricants and non-sticks are excipients that reduce interparticular stresses, prevent adhesion of particles, and improve the fluidity of granulated or powdery compositions.
  • the lubricants can be selected from the group consisting of talc, colloidal silica, alkaline earth salts of stearic acid, especially magnesium and calcium stearates, stearic acid, glycerin palmitate stearate, stearyl fumarate, glycerin monostearate, and / or mixtures thereof .
  • One of the most commonly used non-sticks is colloidal silica.
  • magnesium stearate, stearic acid, colloidal silica, or mixtures thereof are used as extragranular lubricant.
  • talc is used as a lubricating agent in the intragranular phase in combination with the sugar alcohol.
  • the tablets of this invention may also contain sweeteners, flavorings and flavorings, in order to achieve suitable organoleptic characteristics (aroma and taste) that are acceptable to patients.
  • sweeteners there may be mentioned sodium saccharin, aspartame, mannitol, xylitol, sucrose, sorbitol and ammonium glycyrrhizinate, and among the flavoring and flavoring aromas of fruits and plants, for example orange, anise, mint, etc.
  • the amount of auxiliary agent present in the tablets of the invention depends on the functionality thereof.
  • the amount of diluent may be between 10% and 30% of the total weight of the tablet, preferably mind between 15% and 25% on the total weight of the tablet;
  • the amount of disintegrating agent may be between 2% and 25% on the total weight of the tablet, preferably between 7% and 17% on the total weight of the tablet;
  • the amount of lubricating agent may be between 0.5% and 6% on the total weight of the tablet, preferably between 2% and 4% on the total weight of the tablet.
  • auxiliary agent refers to the auxiliary agent that is part of the extragranular component of the cilostazol tablet.
  • Said tablet further comprises, as an intragranular component, the composition of the invention comprising the active ingredient, binding agent (sugar alcohol and talc) and the disintegrating agent.
  • the tablets of the invention comprise between 20% and 80% by weight of cilostazol, preferably between 35% and 65%, and more preferably between 40% and 50%; between 10% and 30% by weight of sugar alcohol, preferably between 12% and 25%, and more preferably between 15% and 20%; between 10% and 30% by weight of a diluent, preferably between 15% and 25%, more preferably between 17% and 22%; between 2% and 25% by weight of a disintegrating agent, preferably between 10% and 20%, and more preferably between 12% and 18%; between 0.1% and 5% by weight of talc, preferably between 0.4% and 2%, and more preferably between 0.6% and 1%; between 0.5% and 6% extragranular lubricant, preferably between 1.5% and 4.5%, and more preferably between 2% and 4%, so that the sum of the weight percentages of the components over the total of the composition is equal to 100%.
  • the sugar alcohol is selected from sorbitol, maltol, mannitol and isomalt;
  • the diluent is microcrystalline cellulose;
  • the disintegrant is selected from calcium carboxymethylcellulose, crospovidone and mixtures thereof;
  • the extragranular lubricant is selected from the group consisting of magnesium stearate, stearic acid, colloidal silica and mixtures thereof.
  • the disintegrating agent that is part of the tablet of the invention is optionally divided into two fractions: an intragranular fraction that is optionally granulated together with the active ingredient with the talc dispersion in the sorbitol solution, and an extragranular fraction that is added to the granulated board- Mind the diluent and extragranular lubricants before preparing the tablet.
  • the intragranular phase includes a disintegrating agent.
  • the intragranular disintegrating agent fraction generally represents between 10% and 90% by weight of the total disintegrating agent that is part of the tablet, preferably between 20% and 80%, more preferably between 30%. and 70%, even more preferably between 40% and 60%, and still more preferably between 52% and 57%.
  • a sugar alcohol selected from sorbitol, isomalt, mannitol, or maltitol
  • the tablets of the invention comprise: a) between 50 mg and 150 mg of cilostazol,
  • a particularly preferred tablet comprises:
  • a process for preparing a tablet comprising:
  • the composition of the invention is prepared by mixing and sieving the active ingredient and a part of the disintegrating agent, and granulating said mixture by wet route by applying a dispersion of a binding agent consisting of a sugar alcohol and talc, in a water.
  • the granulated mixture is dried in a fluid bed until a humidity of less than 10%, preferably less than 5%, is obtained and sieved.
  • the auxiliary agent is then added, mixed and compressed in a conventional machine.
  • an outer layer of protective coating can be applied using conventional techniques, for example by means of dredging or spraying.
  • the tablet further includes an outer coating layer.
  • compositions of the invention capsules or powders dosed in sachets comprising an amount of the composition sufficient to provide an effective unit dose of cilostazol can also be prepared.
  • a capsule or about the unit dose of cilostazol is between 50 mg and 150 mg, preferably the unit dose is 100 mg.
  • the capsules can be prepared by methods well known to the person skilled in the art, and which are well described in the aforementioned Remington book. For example by an encapsulation machine in which the composition of the invention is dosed in hard gelatin capsules.
  • Envelopes are filled with the amount of composition of the invention that contains the desired unit dose of cilostazol.
  • composition of the invention for the preparation of a medicament to improve the maximum and pain-free distance that patients suffering from intermittent claudication, who do not suffer from pain at rest, is also part of the object of the invention. and that do not show signs of peripheral tissue necrosis (stage II of Fontaine's classification of peripheral arterial disease).
  • composition of the invention to improve the maximum and pain-free distance that patients suffering from intermittent claudication, who do not suffer from pain at rest and who do not show signs of peripheral tissue necrosis can walk (stage II of the Fontaine classification of peripheral arterial disease).
  • Also part of the object of the invention is the use of the tablet of the invention for the preparation of a medicament to improve the maximum and pain-free distance that patients suffering from intermittent claudication, who do not suffer from pain at rest and can walk. who have no evidence of peripheral tissue necrosis (stage II of Fontaine's classification of peripheral arterial disease).
  • Also part of the object of the invention is the tablet of the invention to improve the maximum and pain-free distance that patients suffering from intermittent claudication, who do not suffer from pain at rest and who do not show signs of peripheral tissue necrosis can walk (stage II of the Fontaine classification of peripheral arterial disease). Dissolution profiles
  • the tablets comprising the composition of the invention have a bioequivalent solubility to the commercial medicament, and that they do not present difficulties in the compression stage.
  • Cilostazol tablets were prepared, with the following composition per tablet:
  • a solution of sorbitol in water was prepared for the manufacture of the tablets.
  • the cilostazol and half of calcium carmellose were then screened, premixed and kneaded with the sorbitol solution.
  • the mixture was granulated and air dried to obtain a humidity of less than 5%. Then the granulate obtained was calibrated together with the microcrystalline cellulose, the rest of the sodium carmellose and the crospovidone, and mixed until a homogeneous mixture was obtained.
  • colloidal silica and magnesium stearate were sieved and compressed in a rotary machine. Problems were observed during compression, since the composition adhered to the machine's punches.
  • Cilostazol tablets were prepared, with the following composition per tablet:
  • a solution of maltitol in water was prepared for the manufacture of the tablets.
  • the cilostazol and half of the calcium carmellose were then screened, pre-mixed and kneaded with the maltitol solution.
  • the mixture was granulated and air dried to obtain a humidity of less than 5%. Then the granulate obtained was calibrated together with the microcrystalline cellulose, the rest of the sodium carmellose and the crospovidone, and mixed until a homogeneous mixture was obtained.
  • talc, colloidal silica and magnesium stearate were sieved and compressed in a rotary machine.
  • Cilostazol tablets were prepared, with the following composition as a whole:
  • a solution of sorbitol in water was prepared for the manufacture of the tablets.
  • the cilostazol and half of calcium carmellose were then screened, premixed and kneaded with the sorbitol solution.
  • the mixture was granulated and air dried to obtain a humidity of less than 5%. Then the granulate obtained was calibrated together with the microcrystalline cellulose, the rest of the sodium carmellose, and mixed until a homogeneous mixture was obtained.
  • colloidal silica and magnesium stearate were sieved and compressed in a rotary machine.
  • Example 1 Preparation of cilostazol tablets with sorbitol and talc in the intraqranular phase
  • Cilostazol tablets containing sorbitol and talc in the intragranular phase and having the following quantitative composition were prepared:
  • a solution of sorbitol in water was prepared and the talc was dispersed therein.
  • the cilostazol and 50% calcium carmellose were then screened, premixed and kneaded with the talc dispersion in the sorbitol solution.
  • the mixture was granulated and air dried to obtain a humidity of less than 5%. Then the granulate obtained was calibrated together with the microcrystalline cellulose, the rest of the sodium carmellose and the crospovidone, and mixed until a homogeneous mixture was obtained.
  • colloidal silica, magnesium stearate and stearic acid were incorporated by sieve and compressed in a rotary machine.
  • Tablets were obtained, each containing 100 mg of cilostazol.
  • Example 2 Preparation of cilostazol tablets with sorbitol and talc in the intraqranular phase
  • Example 1 Following a procedure analogous to that of Example 1, cilostazol tablets were prepared which differ from those of said Example 1 in that the composition per tablet is as follows:
  • Example 1 Following a procedure analogous to that of Example 1, cilostazol tablets were prepared which differ from those of said Example 1 in that the composition per tablet is as follows:
  • Example 1 Following a procedure analogous to that of Example 1, cilostazol tablets were prepared which differ from those of said Example 1 in that the composition per tablet is as follows:
  • Example 1 Following a procedure analogous to that of Example 1, cilostazol tablets were prepared which differ from those of said Example 1 in that the composition per tablet is as follows:
  • Dissolution tests of the active substance were carried out in an ERWEKA dissolution bath, model DT800.
  • the concentration of the active substance was determined by the use of an AGILENT array diode spectrophotometer, model 8453, and the UV-Visible Chemstation Rev.A.09.01 (AGILENT) software.

Abstract

La présente invention concerne une composition pharmaceutique solide de cilostazol qui comprend du cilostazol en tant que principe actif, un agent agglutinant qui contient un mélange d'alcool de sucre et de talc, et, éventuellement, un agent de désagrégation. La combinaison d'excipients confère la solubilité appropriée au principe actif. L'invention porte également sur l'utilisation de ladite composition pour la préparation de formes pharmaceutiques de cilostazol destinées à l'administration par voie orale. L'invention concerne également des comprimés préparés avec la composition de l'invention qui présentent des propriétés appropriées du point de vue de la solubilité et de la biodisponibilité du cilostazol. Enfin, l'invention concerne des procédés de préparation de la composition et des comprimés de cilostazol ainsi que leur utilisation en tant que médicaments.
PCT/ES2013/070072 2012-02-10 2013-02-08 Composition pharmaceutique solide de cilostazol WO2013117793A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ESP201230213 2012-02-10
ES201230213A ES2422657B1 (es) 2012-02-10 2012-02-10 Composición farmacéutica sólida de cilostazol

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020058066A1 (en) * 2000-09-22 2002-05-16 Otsuka Pharmaceutical Co., Ltd. Cilostazol dry coated tablet
US7144585B1 (en) * 1999-03-25 2006-12-05 Otsuka Pharmaceutical Co., Ltd. Cilostazol preparation
WO2009107864A2 (fr) * 2008-02-29 2009-09-03 Otsuka Pharmaceutical Co., Ltd. Comprimé à désintégration orale

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7144585B1 (en) * 1999-03-25 2006-12-05 Otsuka Pharmaceutical Co., Ltd. Cilostazol preparation
US20020058066A1 (en) * 2000-09-22 2002-05-16 Otsuka Pharmaceutical Co., Ltd. Cilostazol dry coated tablet
WO2009107864A2 (fr) * 2008-02-29 2009-09-03 Otsuka Pharmaceutical Co., Ltd. Comprimé à désintégration orale

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JINNO, JUN-ICHI ET AL.: "In vitro-in vivo correlation for wet-milled tablet of poorly water-soluble cilostazol", JOURNAL OF CONTROLLED RELEASE, vol. 130, no. 1, 2008, pages 29 - 37, XP023781293 *

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