WO2013117793A1 - Solid cilostazol pharmaceutical composition - Google Patents

Solid cilostazol pharmaceutical composition 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
Prior art date
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PCT/ES2013/070072
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Spanish (es)
French (fr)
Inventor
Jesús GRANDÍO TIERNO
Antonio FERNÁNDEZ AIJÓN
Carlos Govantes Esteso
María de los Angeles BUENO SÁNCHEZ
Original Assignee
Laboratorios Normon S.A.
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Application filed by Laboratorios Normon S.A. filed Critical Laboratorios Normon S.A.
Publication of WO2013117793A1 publication Critical patent/WO2013117793A1/en

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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.

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Abstract

The present invention relates to a solid cilostazol pharmaceutical composition that comprises cilostazol as active principle, a binder that contains a mixture of a sugar alcohol and talc, and, optionally, a disintegrant. Said combination of excipients confers appropriate solubility on the active principle. The present invention also relates to the use of said composition for preparing pharmaceutical forms of cilostazol for oral administration. The invention also relates to tablets prepared with the composition of the invention, which exhibit appropriate properties in terms of solubility and bioavailability of the cilostazol. The present invention also relates to methods for preparing the cilostazol tablets and composition, and also to the use thereof as drugs.

Description

COMPOSICIÓN FARMACÉUTICA SÓLIDA DE CILOSTAZOL  SOLID PHARMACEUTICAL COMPOSITION OF CILOSTAZOL
DESCRIPCION DESCRIPTION
Campo de la técnica Technical field
La presente invención se refiere a composiciones farmacéuticas sólidas de cilosta- zol que presentan una solubilidad apropiada del principio activo, y que se pueden emplear para preparar formas farmacéuticas de cilostazol para su administración por vía oral.  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.
Estado de la técnica anterior Prior art
El cilostazol es la D.C.I. del compuesto químico 6-[4-(1 -ciclohexil-1 -/-tetrazol-5- il)butoxi-3,4-dihidro-2(1 H)-quinolinona, que responde a la siguiente fórmula: 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:
Figure imgf000003_0001
Figure imgf000003_0001
El cilostazol fue descrito por primera vez en 1979 por la compañía Otsuka en la patente belga BE878548. Cilostazol was first described in 1979 by the Otsuka company in the Belgian patent BE878548.
El cilostazol es un inhibidor de la enzima fosfodiesterasa III (PDE III) y se emplea en medicina como antitrombótico para mejorar la distancia máxima y exenta de dolor que pueden caminar pacientes que padecen de claudicación intermitente, que no padecen de dolor en estado de reposo y que no presentan indicios de necrosis tisular periférica (estadio II de la clasificación de Fontaine de enfermedad arterial periférica). 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).
El cilostazol es un principio activo prácticamente insoluble en agua, y se considera que su biodisponibilidad a partir de composiciones farmacéuticas está limitada por la velocidad de disolución. En la solicitud de patente norteamericana US-A-2005/0255155 se describe que en el Biopharmaceutics Classification System el cilostazol está clasificado como fármaco de Clase II, caracterizado por una baja solubilidad y una elevada permeabilidad. También se describe que la absorción oral del cilostazol es rápida y completa, y que los perfiles cinéticos de cilostazol muestran que, cuando la disolución in vivo es completa, no hay limitación a la absorción. 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. In 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.
Por ello en el estado de la técnica se encuentran diferentes aproximaciones dirigidas a solucionar el problema de la solubilidad del cilostazol, mejorando la velocidad de disolución y, en consecuencia, su biodisponibilidad.  Therefore, in the state of the art there are different approaches aimed at solving the problem of the solubility of cilostazol, improving the dissolution rate and, consequently, its bioavailability.
En la ficha técnica del medicamento Pletal® se describe un comprimido que comprende 100 mg de cilostazol como principio activo y como excipientes: almidón de maíz, celulosa microcristalina, carmelosa cálcica, hipromelosa y estearato magnésico. 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.
En la solicitud de patente internacional WO-A-00/57881 se describen composicio- nes que comprenden cilostazol como principio activo y que presentan una disper- sabilidad y/o solubilidad mejorada del principio activo. En dichas composiciones el cilostazol, con un tamaño de partícula de 10 μηι o menos, se incorpora a un agente solubilizante y/o dispersante seleccionado de entre el grupo formado por un polímero hidrosoluble, un tensioactivo, o mezcla de los mismos. De acuerdo con la des- cripción y los ejemplos que figuran en la misma el agente solubilizante preferido es el laurilsulfato sódico, solo o en combinación con polímeros hidrosolubles como, por ejemplo, la hidroxipropilcelulosa, o la hidroxipropilmetilcelulosa.  In the international patent application WO-A-00/57881, compositions comprising cilostazol as an active ingredient and having an improved dispersibility and / or solubility of the active ingredient are described. In said compositions cilostazol, with a particle size of 10 μηι 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. According to the description and examples given therein, 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.
En el marco del desarrollo de nuevas formas polimórficas de cilostazol, en la Formulación 3 de la solicitud de patente WO-A-03/002121 se describen comprimidos de cilostazol que comprenden como excipientes: almidón, celulosa microcristalina, polivinilpirrolidona, carboximetilalmidón sódico, estearato magnésico y talco. Según el procedimiento descrito, los tres últimos componentes se añaden a la fase extra- granular antes de efectuar la compresión. Within the framework of the development of new polymorphic forms of cilostazol, 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.
En la solicitud de patente internacional WO-A-2005/023225 se describe una solu- ción técnica para mejorar la velocidad de disolución del cilostazol mediante la formación de un adsorbato del mismo sobre un soporte inerte como, por ejemplo, ma- nitol, polivinilpirrolidona o polietilenglicol. El procedimiento para la preparación del adsorbato comprende disolver el principio activo en cloruro de metileno, añadir el soporte inerte para formar una suspensión y evaporar el disolvente. In the international patent application WO-A-2005/023225 a technical solution is described to improve the dissolution rate of cilostazol by forming an adsorbate thereof on an inert support such as, for example, nylon, polyvinylpyrrolidone or polyethylene glycol. The procedure for the preparation of Adsorbate comprises dissolving the active substance in methylene chloride, adding the inert support to form a suspension and evaporating the solvent.
La solicitud de patente internacional WO-A-2006/030301 está dirigida al desarrollo de composiciones de cilostazol bioequivalentes a las composiciones comerciales del mismo. En dicho documento se describe una composición farmacéutica en forma de comprimidos que comprende cilostazol, con un tamaño medio de partícula específico de modo que el 90% de las partículas presentan un tamaño inferior a 50 μηι, y como excipientes: almidón, hidroxipropilmetilcelulosa, carboximetilcelulosa cálcica, celulosa microcristalina, y estearato magnésico. International patent application WO-A-2006/030301 is directed to the development of bioequivalent cilostazol compositions to commercial compositions thereof. Said document describes a pharmaceutical composition in the form of tablets comprising cilostazol, with a specific average particle size so that 90% of the particles have a size less than 50 μηι, and as excipients: starch, hydroxypropylmethylcellulose, calcium carboxymethylcellulose , microcrystalline cellulose, and magnesium stearate.
En la solicitud de patente internacional WO-A-2008/030209 se describen composiciones nanoparticuladas de cilostazol que incluyen un agente estabilizante de superficie, de modo que se mejora la baja biodisponibilidad del principio activo y se evita tener que tomarlo durante las comidas. También se describe que los agentes estabilizantes de superficie pueden ser polímeros, oligómeros de bajo peso molecu- lar, productos naturales y tensioactivos, y se cita a un número considerable de ejemplos. También se describen composiciones de cilostazol en forma de comprimidos que comprenden como excipientes: hipromelosa, docusato sódico, sacarosa, lauril sulfato sódico, lactosa monohidrato, celulosa microcristalina silicificada, cros- povidona y estearato magnésico. In the international patent application WO-A-2008/030209 nanoparticulate cilostazol compositions are described 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.
Existe pues la necesidad de disponer de composiciones sólidas de cilostazol alternativas que sean bioequivalentes a las composiciones comerciales existentes, fáciles de preparar, y que, al mismo tiempo, presenten un perfil de disolución reprodúcele. Objeto de la invención There is therefore a need to have alternative solid cilostazole compositions that are bioequivalent to existing commercial compositions, easy to prepare, and which, at the same time, have a reproductive dissolution profile. Object of the invention
El objeto de la invención es una composición farmacéutica sólida que comprende cilostazol como principio activo.  The object of the invention is a solid pharmaceutical composition comprising cilostazol as active ingredient.
También es objeto de la invención un comprimido que comprende dicha composición.  Also subject to the invention is a tablet comprising said composition.
Forma parte también del objeto de la invención la utilización de dicha composición para la preparación de formas sólidas de cilostazol para su administración por vía oral. También forma parte del objeto de la invención un procedimiento para la preparación de dicha composición y dicho comprimido. The use of said composition for the preparation of solid forms of cilostazol for oral administration is 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.
Forma parte también del objeto de la invención la utilización de dicha composición para la preparación de un medicamento para mejorar la distancia máxima y exenta de dolor que pueden caminar pacientes que padecen de claudicación intermitente, que no padecen de dolor en estado de reposo y que no presentan indicios de necrosis tisular periférica (estadio II de la clasificación de Fontaine de enfermedad arterial periférica).  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).
También forma parte del objeto de la invención la utilización de dicho comprimido para la preparación de un medicamento para mejorar la distancia máxima y exenta de dolor que pueden caminar pacientes que padecen de claudicación intermitente, que no padecen de dolor en estado de reposo y que no presentan indicios de necrosis tisular periférica (estadio II de la clasificación de Fontaine de enfermedad arterial periférica).  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).
Figuras Figures
En la Figura 1 se representa el perfil de disolución de los comprimidos obtenidos en el Ejemplo 1 y del medicamento comercial Pletal® empleando como medio de diso- lución ácido clorhídrico 0,1 N. En ordenadas se representa el porcentaje de principio activo disuelto y en abscisas se representa el tiempo en minutos. 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.
En la Figura 2 se representa el perfil de disolución de los comprimidos obtenidos en el Ejemplo 1 y del medicamento comercial Pletal® empleando como medio de disolución tampón de acetato sódico 0,05 M (pH=4,5). En ordenadas se representa el porcentaje de principio activo disuelto y en abscisas se representa el tiempo en minutos. Figure 2 shows the dissolution profile of the tablets obtained in Example 1 and of the commercial drug Pletal ® using 0.05 M sodium acetate buffer (pH = 4.5) as the dissolution medium. In ordinates the percentage of dissolved active substance is represented and in abscissa the time in minutes is represented.
En la Figura 3 se representa el perfil de disolución de los comprimidos obtenidos en el Ejemplo 1 y del medicamento comercial Pletal® empleando como medio de disolución tampón de fosfato potásico 0,05 M (pH=6,8). En ordenadas se representa el porcentaje de principio activo disuelto y en abscisas se representa el tiempo en minutos. Figure 3 shows the dissolution profile of the tablets obtained in Example 1 and the commercial drug Pletal ® using 0.05 M potassium phosphate buffer as a dissolution medium (pH = 6.8). In ordinates the percentage of dissolved active substance is represented and in abscissa the time in minutes is represented.
En la Figura 4 se representa el perfil de disolución de los comprimidos obtenidos en el Ejemplo 1 y del medicamento comercial Pletal® empleando como medio de diso- lución tampón de fosfato potásico 0,05 M (pH=6,8) que contiene laurilsulfato sódico al 0,5%. En ordenadas se representa el porcentaje de principio activo disuelto y en abscisas se representa el tiempo en minutos. 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. In ordinates the percentage of dissolved active substance is represented and in abscissa the time in minutes is represented.
En la Figura 5 se representa el perfil de disolución de los comprimidos obtenidos en el Ejemplo 1 y del medicamento comercial Pletal® empleando como medio de disolución agua con laurilsulfato sódico al 0,3 %. En ordenadas se representa el porcentaje de principio activo disuelto y en abscisas se representa el tiempo en minutos. En estas condiciones se consigue un grado de liberación del principio activo próximo al 80%, que permite efectuar una buena comparación entre los perfiles de las dos composiciones y, en este caso, comprobar la similitud significativa que existe entre ambas. 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.
Descripción detallada de la invención Detailed description of the invention
La composición farmacéutica sólida objeto de la invención comprende: The solid pharmaceutical composition object of the invention comprises:
a) una cantidad farmacéuticamente efectiva de cilostazol o una sal farmacéuticamente aceptable, solvato o hidrato del mismo,  a) a pharmaceutically effective amount of cilostazol or a pharmaceutically acceptable salt, solvate or hydrate thereof,
b) un agente aglutinante que consiste esencialmente de una mezcla de un alcohol de azúcar y talco, y  b) a binding agent consisting essentially of a mixture of a sugar alcohol and talc, and
c) opcionalmente un agente disgregante.  c) optionally a disintegrating agent.
Los autores de esta invención han desarrollado una nueva composición farmacéutica sólida de cilostazol que presenta una solubilidad bioequivalente al medicamento comercial y que, cuando se emplea para la preparación de comprimidos, no presenta dificultades de compresión.  The authors of this invention have developed a new solid pharmaceutical composition of cilostazol that presents a bioequivalent solubility to the commercial medicine and which, when used for the preparation of tablets, does not present compression difficulties.
Dichos comprimidos contienen una fase intragranular que comprende la composición farmacéutica de la invención, cuya combinación de principio activo, agente aglutinante formado por un alcohol de azúcar y talco, y opcionalmente, un agente disgregante, facilita de forma sorprendente la disolución del principio activo y permite obtener un perfil de disolución equivalente al del medicamento comercial En el contexto de la invención, la expresión "una cantidad farmacéuticamente efectiva" significa una cantidad de un principio activo, que cuando es administrada a un mamífero para tratar una enfermedad o trastorno, es suficiente para conseguir una acción terapéutica. La "cantidad farmacéuticamente efectiva" puede variar en fun- ción del principio activo, la enfermedad y la severidad de la misma, y de la edad, peso, condición física y respuesta del mamífero a ser tratado. 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 In the context of the invention, the expression "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.
La composición sólida de cilostazol The solid composition of cilostazol
La composición sólida de cilostazol comprende una cantidad farmacéuticamente efectiva de cilostazol, un agente aglutinante que consiste esencialmente de una mezcla de un alcohol de azúcar y talco, y, opcionalmente, un agente disgregante. En dicha composición la suma de los porcentajes de los diferentes componentes (principio activo, alcohol de azúcar, talco y, opcionalmente, agente disgregante) es el 100%. 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. In said composition the sum of the percentages of the different components (active ingredient, sugar alcohol, talc and, optionally, disintegrating agent) is 100%.
El cilostazol es el principio activo de la composición farmacéutica sólida objeto de la invención.  Cilostazol is the active substance of the solid pharmaceutical composition object of the invention.
El cilostazol puede prepararse por ejemplo de acuerdo con el procedimiento descri- to en la patente española ES483792.  Cilostazol can be prepared, for example, in accordance with the procedure described in Spanish patent ES483792.
En el contexto de la invención el término cilostazol incluye cilostazol, así como las sales farmacéuticamente aceptables, los solvatos e hidratos del mismo.  In the context of the invention the term cilostazol includes cilostazol, as well as pharmaceutically acceptable salts, solvates and hydrates thereof.
Entre las sales farmacéuticamente aceptables se pueden mencionar, por ejemplo, acetato, besilato, citrato, fumarato, lactato, maleato, mesilato, tartrato, tosilato, bi- sulfato, hidrobromuro, hidrocloruro, y sulfato. Among the pharmaceutically acceptable salts there may be mentioned, for example, acetate, besylate, citrate, fumarate, lactate, maleate, mesylate, tartrate, tosylate, bi- sulfate, hydrobromide, hydrochloride, and sulfate.
Si bien no es descartable la inclusión de un segundo principio activo, preferiblemente la composición comprende cilostazol como único principio activo.  Although the inclusion of a second active ingredient is not disposable, preferably the composition comprises cilostazol as the only active ingredient.
Dada la baja solubilidad en agua del cilostazol, preferiblemente se emplea cilostazol en forma micronizada, de manera que al menos el 50%, preferiblemente el 75% y aún más preferiblemente el 90% de las partículas de cilostazol presentan un tamaño medio de partícula no superior a 10 mieras. Given the low water solubility of cilostazol, 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
Dicho tamaño de partícula puede ser obtenido mediante el control del proceso de reducción del tamaño de partícula que se puede efectuar, por ejemplo, con un molino cerámico o por chorro de aire.  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.
En la composición de la invención el cilostazol habitualmente representa entre el 35% y el 90% en peso sobre el total del peso de la composición, preferiblemente entre el 45% y el 85%, y más preferiblemente entre el 60% y el 70%. In the composition of the invention 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% .
La composición de la invención comprende un agente aglutinante. Los agentes aglutinantes se emplean en tecnología farmacéutica para causar la adhesión de las partículas pulverulentas en los procesos de granulación. The 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.
El agente aglutinante que forma parte de la composición de la invención consiste esencialmente de una mezcla de un alcohol de azúcar y talco. The binding agent that is part of the composition of the invention consists essentially of a mixture of a sugar alcohol and talc.
El alcohol de azúcar es una forma hidrogenada de un hidrato de carbono, cuyo grupo carbonilo ha sido reducido a un grupo hidroxilo primario o secundario, dependiendo de si el hidrato de carbono contenía un grupo aldehido o un grupo ceto- na respectivamente. 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.
El alcohol de azúcar apropiado para la composición de la invención se puede se- leccionar entre los derivados de monosacáridos como, por ejemplo, sorbitol, mani- tol, dulcitol, fucitol, iditol, arabitol, xilitol o ribitol, o entre los derivados de disacáridos como, por ejemplo, maltitol, lactitol, isomalt o poliglicitol.  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.
Preferiblemente el alcohol de azúcar se selecciona de entre el grupo formado por sorbitol, manitol, xilitol, isomalt, maltitol y lactitol, más preferiblemente es sorbitol, isomalt, manitol, o maltitol, y aún más preferiblemente es sorbitol.  Preferably 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.
En la composición de la invención el alcohol de azúcar habitualmente representa entre el 10% y el 45% en peso sobre el peso total de la composición, preferiblemente 15% y el 40%, y más preferiblemente entre el 25 % y el 30%.  In the composition of the invention, 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%.
El talco es un silicato magnésico hidratado que se emplea habitualmente en com- posiciones farmacéuticas como agente antiapelmazante, deslizante, diluyente o lubrificante. Talc is a hydrated magnesium silicate that is commonly used in pharmaceutical compositions as an anti-caking agent, slider, diluent or lubricant.
En la composición de la invención el talco forma parte del agente aglutinante y queda incorporado en la fase intragranular de la composición.  In the composition of the invention, talc is part of the binding agent and is incorporated into the intragranular phase of the composition.
En la composición de la invención el talco habitualmente representa entre el 0,1 % y el 5% en peso sobre el peso total de la composición, preferiblemente entre el 0,5% y el 3%, y más preferiblemente entre el 1 % y el 2%. In the composition of the invention 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%.
La composición de la invención comprende opcionalmente un agente disgregante. Preferiblemente, la composición de la invención comprende un agente disgregante. El agente disgregante que preferiblemente forma parte de la composición de la invención es un componente que se incluye en la formulación para garantizar que la composición se rompa en fragmentos pequeños cuando entre en contacto con un líquido, favoreciendo la dispersión y disolución del principio activo. Entre los agentes disgregantes apropiados para ser incorporados en la composición de la invención se encuentran, por ejemplo, ácido algínico, agar, alginato sódico, almidón de maíz, almidón de patata, almidón glicolato sódico, almidón pregela- tinizado, celulosa microcristalina, carboximetilcelulosa cálcica, croscarmelosa sódi- ca, crospovidona, dióxido de silicio coloidal, fosfato cálcico dibásico, fosfato cálcico tribásico, goma guar, hidroxipropilcelulosa de bajo grado de sustitución, poliacrilina potásica, silicato alumínico y magnésico, y mezclas de los mismos. The composition of the invention optionally comprises a disintegrating agent. Preferably, 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. Among the appropriate disintegrating agents to be incorporated into the composition of the invention are, 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.
Preferiblemente el agente disgregante se selecciona de entre el grupo formado por almidón de maíz, almidón de patata, almidón glicolato sódico, almidón pregelatini- zado, celulosa microcristalina, carboximetilcelulosa cálcica, crospovidona, dióxido de silicio coloidal, fosfato cálcico dibásico, fosfato cálcico tribásico, y mezclas de los mismos; más preferiblemente entre carboximetilcelulosa cálcica, celulosa microcristalina, crospovidona, dióxido de silicio coloidal, y mezclas de los mismos; y aún más preferiblemente entre carboximetilcelulosa cálcica, crospovidona, y mezclas de los mismos. Preferably 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.
En la composición de la invención el agente disgregante habitualmente representa entre el 2% y el 20% en peso sobre el peso total de la composición, más preferiblemente entre el 4% y el 1 5%, y más preferiblemente entre el 5% y el 10%.  In the composition of the invention 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%
Forma parte del objeto de la invención un procedimiento para preparar la composi- ción de la invención que comprende: A process for preparing the composition of the invention comprising:
a) disolver el alcohol de azúcar en agua, un disolvente orgánico, o mezclas de los mismos,  a) dissolve sugar alcohol in water, an organic solvent, or mixtures thereof,
b) dispersar el talco en la solución obtenida en la etapa a),  b) dispersing the talc in the solution obtained in step a),
c) amasar el cilostazol y, opcionalmente, el agente disgregante con la disper- sión obtenida en la etapa b), y  c) kneading the cilostazol and, optionally, the disintegrating agent with the dispersion obtained in step b), and
d) granular y secar hasta obtener una humedad inferior al 10%.  d) granulate and dry until a humidity of less than 10% is obtained.
La composición de la invención puede prepararse por métodos bien conocidos por el experto en la materia, como la granulación por vía húmeda, que se encuentran bien descritos en manuales de tecnología farmacéutica como el libro Remington: The Science and Practice of Pharmacy, 20th Edition, The 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,
Philadelphia, Lippincott, Williams & Wilkins, 2000 [ISBN 0 683 306472] o en M. Aulton, Farmacia: La ciencia del diseño de las formas farmacéuticas, 2- edición, Elsevier, Madrid, 2004 [ISBN 84-8174-728-9]. Una forma preferida de preparar la composición de la invención es la siguiente. En primer lugar se prepara una solución del alcohol de azúcar en agua y en la misma se dispersa el talco. Philadelphia, Lippincott, Williams & Wilkins, 2000 [ISBN 0 683 306472] or in M. Aulton, Pharmacy: The science of design of pharmaceutical forms, 2- edition, Elsevier, Madrid, 2004 [ISBN 84-8174-728-9 ]. A preferred way of preparing the composition of the invention is as follows. First, a solution of the sugar alcohol in water is prepared and the talc is dispersed therein.
El cilostazol y el agente disgregante se mezclan y tamizan, y se granula dicha mez- da por vía húmeda mediante la aplicación de la dispersión del agente aglutinante consistente en un alcohol de azúcar y talco.  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.
La composición de la invención obtenida en forma de granulado se seca por sistema de aire caliente hasta una humedad inferior al 10%, preferiblemente inferior al 5%, obteniéndose de este modo la composición de la invención que resulta apro- piada para la preparación de formas farmacéuticas orales de cilostazol.  The 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.
Por ello, forma parte también del objeto de la invención la utilización de dicha composición para la preparación de formas sólidas de cilostazol para su administración por vía oral. Formas farmacéuticas orales  Therefore, the use of said composition for the preparation of solid forms of cilostazol for oral administration is also part of the object of the invention. Oral Pharmaceutical Forms
La composición de la invención resulta apropiada para preparar formas farmacéuticas orales, por ejemplo, comprimidos, cápsulas o polvos dosificados en sobres. Entre ellas resultan preferidos los comprimidos, que pueden obtenerse mediante el mezclado y homogeneizado de las composiciones objeto de la invención con agentes auxiliares adecuados, y posterior compresión. The composition of the invention is suitable for preparing oral pharmaceutical forms, for example, tablets, capsules or powders dosed in sachets. Among them, tablets are preferred, which can be obtained by mixing and homogenizing the compositions object of the invention with suitable auxiliary agents, and subsequent compression.
Se ha visto que con la composición de la invención se pueden preparar formas farmacéuticas sólidas orales que presentan un perfil de disolución del cilostazol apropiado y que en el caso de comprimidos, no se observan dificultades en la eta- pa de compresión.  It has been found that 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.
Por ello, también forma parte del objeto de la invención un comprimido de cilostazol que comprende:  Therefore, a cilostazol tablet comprising:
a) una cantidad de la composición de la invención que sea suficiente como para proporcionar una dosis unitaria efectiva de cilostazol, y  a) an amount of the composition of the invention that is sufficient to provide an effective unit dose of cilostazol, and
b) al menos un agente auxiliar.  b) at least one auxiliary agent.
Preferiblemente los comprimidos de la invención consisten en entre un 35% y un 90% en peso de la composición de la invención, y entre un 10% y un 65% en peso de al menos un agente auxiliar. Más preferiblemente los comprimidos consisten en entre un 50% y un 75% en peso de la composición de la invención, y en entre un 25% y un 45% en peso de al menos un agente auxiliar. Aún más preferiblemente los comprimidos consisten en entre un 60% y un 70% en peso de la composición de la invención, y en entre un 30% y un 40% en peso de al menos un agente auxi- liar. Preferably 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.
Como ya se ha mencionado anteriormente, el cilostazol es un principio activo efectivo para tratar la claudicación intermitente.  As already mentioned above, cilostazol is an effective active substance to treat intermittent claudication.
Para mantener el efecto terapéutico habitualmente se administra a los adultos en dosis diarias comprendidas entre 100 mg y 300 mg, repartidas en dos dosis. Prefe- riblemente los comprimidos de la invención contienen una dosis unitaria que está comprendida entre los 50 mg y los 150 mg de cilostazol, más preferiblemente contienen 100 mg de cilostazol.  To maintain the therapeutic effect, it is usually administered to adults in daily doses between 100 mg and 300 mg, divided into two doses. Preferably 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.
Se ha comprobado que en los comprimidos que comprenden las formulaciones de la invención, no es crítica la selección del agente auxiliar.  It has been found that in the tablets comprising the formulations of the invention, the selection of the auxiliary agent is not critical.
El agente auxiliar se puede seleccionar entre el grupo formado por diluyentes, disgregantes, lubrificantes, antiadherentes, edulcorantes, saborizantes, aromatizantes, y/o mezclas de los mismos. The auxiliary agent can be selected from the group consisting of diluents, disintegrants, lubricants, non-sticks, sweeteners, flavorings, flavorings, and / or mixtures thereof.
El agente auxiliar se puede incorporar tanto en la etapa de granulación para preparar la composición de la invención, como en la etapa de mezclado de la misma con la fase extragranular, o bien en las dos etapas. Preferiblemente el agente auxiliar se incorpora en la etapa de mezclado de la composición de la invención con la fase extragranular.  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. Preferably the auxiliary agent is incorporated in the mixing stage of the composition of the invention with the extragranular phase.
Los diluyentes son excipientes inertes que facilitan la compresión de materiales pulverulentos y dotan de resistencia a los comprimidos. Se pueden incorporar tanto a la fase intragranular como a la fase extragranular. Preferiblemente se incorporan a la fase extragranular. Entre los diluyentes que se pueden emplear, se encuentran: celulosa microcristalina, celulosa en polvo, celulosa silicificada, lactosa monohidra- to, lactosa anhidra, manitol, sorbitol, sacarosa, fructosa, dextrosa, fosfato cálcico dibásico, almidón, almidón pregelatinizado, hidroxipropilcelulosa de bajo grado de sustitución, y/o mezclas de los mismos. Preferiblemente el diluyente empleado en los comprimidos de la invención es celulosa microcristalina.  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. Among 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. Preferably the diluent used in the tablets of the invention is microcrystalline cellulose.
Los agentes disgregantes son excipientes que provocan una rápida rotura del comprimido cuando éste se introduce en medio acuoso, y también una rápida disgrega- - l i ción de los gránulos, de manera que se produce una rápida liberación del principio activo. 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.
El comprimido de la invención, además de incluir opcionalmente un agente disgregante en la fase intragranular, también incorpora al menos un agente disgregante en la fase extragranular. Los disgregantes se pueden seleccionar entre el grupo formado por: hidroxipropilcelulosa de bajo grado de sustitución, almidón glicolato sódico, carboximetilcelulosa cálcica, crospovidona, croscarmelosa sódica, y/o sus mezclas. Preferiblemente el agente disgregante empleado es carboximetilcelulosa cálcica, crospovidona, o mezclas de las mismas.  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. Preferably the disintegrating agent employed is calcium carboxymethyl cellulose, crospovidone, or mixtures thereof.
Los lubrificantes y antiadherentes son excipientes que reducen las tensiones interparticulares, impiden la adhesión de las partículas, y mejoran la fluidez de las composiciones granuladas o pulverulentas. Los lubrificantes se pueden seleccionar entre el grupo formado por talco, sílice coloidal, sales alcalinotérreas del ácido esteárico, especialmente los estearatos magnésico y cálcico, ácido esteárico, palmi- toestearato de glicerina, fumarato de estearilo, monoestearato de glicerina, y/o sus mezclas. Uno de los antiadherentes más empleados es la sílice coloidal. Preferiblemente se emplea estearato magnésico, ácido esteárico, sílice coloidal, o sus mezclas, como lubrificante extragranular. 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. Preferably, magnesium stearate, stearic acid, colloidal silica, or mixtures thereof are used as extragranular lubricant.
Como ya se ha descrito anteriormente, en los comprimidos de la invención se em- plea talco como agente lubrificante en la fase intragranular en combinación con el alcohol de azúcar.  As already described above, in the tablets of the invention talc is used as a lubricating agent in the intragranular phase in combination with the sugar alcohol.
Los comprimidos de esta invención pueden contener además edulcorantes, aromatizantes y saborizantes, con el objeto de conseguir unas características organolépticas (aroma y sabor) adecuadas que sean aceptables por los pacientes. Entre los edulcorantes pueden citarse sacarina sódica, aspartamo, manitol, xilitol, sacarosa, sorbitol y glicirricinato amónico, y entre los aromatizantes y saborizantes aromas de frutas y plantas, por ejemplo naranja, anís, menta, etc.  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. Among the 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.
Los nombres de los productos comerciales correspondientes a los distintos tipos de excipientes mencionados se pueden encontrar en Rowe et al., Handbook of Phar- maceutical Excipients, Fourth Edition, London, 2003 (ISBN 0-85369-472-9).  The names of commercial products corresponding to the different types of excipients mentioned can be found in Rowe et al., Handbook of Pharmaceutical Excipients, Fourth Edition, London, 2003 (ISBN 0-85369-472-9).
La cantidad de agente auxiliar presente en los comprimidos de la invención depende de la funcionalidad del mismo. Por ejemplo la cantidad de diluyente puede estar comprendida entre el 10% y el 30% sobre el peso total del comprimido, preferible- mente entre el 15% y el 25% sobre el peso total del comprimido; la cantidad de agente disgregante puede estar comprendida entre el 2% y el 25% sobre el peso total del comprimido, preferiblemente entre el 7% y el 17% sobre el peso total del comprimido; y la cantidad de agente lubrificante puede estar comprendida entre el 0,5% y el 6% sobre el peso total del comprimido, preferiblemente entre el 2% y el 4% sobre el peso total del comprimido. The amount of auxiliary agent present in the tablets of the invention depends on the functionality thereof. For example, 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; and 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.
Estos porcentajes del agente auxiliar se refieren al agente auxiliar que forma parte del componente extragranular del comprimido de cilostazol. Dicho comprimido comprende además, como componente intragranular, la composición de la inven- ción que comprende el principio activo, agente aglutinante (alcohol de azúcar y talco) y el agente disgregante.  These percentages of the auxiliary agent refer 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.
En una realización preferida los comprimidos de la invención comprenden entre un 20% y un 80% en peso de cilostazol, preferiblemente entre el 35% y el 65%, y más preferiblemente entre el 40% y el 50%; entre un 10% y un 30% en peso de alcohol de azúcar, preferiblemente entre un 12% y un 25%, y más preferiblemente entre un 15% y un 20%; entre el 10% y el 30% en peso de un diluyente, preferiblemente entre el 15% y el 25%, más preferiblemente entre el 17% y el 22%; entre un 2% y un 25% en peso de un agente disgregante, preferiblemente entre un 10% y un 20%, y más preferiblemente entre un 12% y un 18%; entre 0,1 % y 5% en peso de talco, preferiblemente entre 0,4% y 2%, y más preferiblemente entre 0,6% y 1 %; entre 0,5% y 6% de lubrificante extragranular, preferiblemente entre 1 ,5% y 4,5%, y más preferiblemente entre 2% y 4%, de modo que la suma de los porcentajes en peso de los componentes sobre el total de la composición es igual al 100%. En otra realización más preferida el alcohol de azúcar es seleccionado entre sorbitol, malti- tol, manitol e isomalt; el diluyente es celulosa microcristalina; el disgregante se selecciona de carboximetilcelulosa cálcica, crospovidona y sus mezclas; y el lubrificante extragranular se selecciona de entre el grupo formado por estearato magnésico, ácido esteárico, sílice coloidal y sus mezclas.  In a preferred embodiment 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%. In another more preferred embodiment 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; and the extragranular lubricant is selected from the group consisting of magnesium stearate, stearic acid, colloidal silica and mixtures thereof.
El agente disgregante que forma parte del comprimido de la invención se encuentra opcionalmente dividido en dos fracciones: una fracción intragranular que se granula opcionalmente conjuntamente con el principio activo con la dispersión de talco en la solución de sorbitol, y una fracción extragranular que se añade al granulado junta- mente con el diluyente y los lubrificantes extragranulares antes de preparar el comprimido. 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.
Preferiblemente la fase intragranular incluye un agente disgregante. En este caso preferido, la fracción de agente disgregante intragranular representa generalmente entre el 10% y el 90% en peso del total de agente disgregante que forma parte del comprimido, preferiblemente entre el 20% y el 80%, más preferiblemente entre el 30% y el 70%, aún más preferiblemente entre el 40% y el 60%, y todavía más preferiblemente entre el 52% y el 57%.  Preferably the intragranular phase includes a disintegrating agent. In this preferred case, 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%.
En una realización preferida los comprimidos de la invención comprenden:  In a preferred embodiment the tablets of the invention comprise:
a) entre 50 mg y 150 mg de cilostazol,  a) between 50 mg and 150 mg of cilostazol,
b) entre 20 mg y 60 mg de un alcohol de azúcar seleccionado entre sorbitol, isomalt, manitol, o maltitol,  b) between 20 mg and 60 mg of a sugar alcohol selected from sorbitol, isomalt, mannitol, or maltitol,
c) entre 20 mg y 60 mg de celulosa microcristalina,  c) between 20 mg and 60 mg of microcrystalline cellulose,
d) entre 9 mg y 27 mg de carboximetilcelulosa cálcica,  d) between 9 mg and 27 mg of calcium carboxymethylcellulose,
e) entre 8 mg y 24 mg de crospovidona,  e) between 8 mg and 24 mg of crospovidone,
f) entre 1 mg y 4 mg de talco,  f) between 1 mg and 4 mg of talc,
g) entre 2 mg y 8 mg de estearato magnésico,  g) between 2 mg and 8 mg of magnesium stearate,
h) entre 0,8 mg y 2,4 mg de sílice coloidal, y  h) between 0.8 mg and 2.4 mg of colloidal silica, and
i) entre 1 ,2 mg y 3,6 mg de ácido esteárico.  i) between 1.2 mg and 3.6 mg of stearic acid.
En una realización más preferida los comprimidos de la invención comprenden: a) entre 50 mg y 150 mg de cilostazol, In a more preferred embodiment the tablets of the invention comprise: a) between 50 mg and 150 mg of cilostazol,
b) entre 20 mg y 60 mg de sorbitol,  b) between 20 mg and 60 mg of sorbitol,
c) entre 20 mg y 60 mg de celulosa microcristalina,  c) between 20 mg and 60 mg of microcrystalline cellulose,
d) entre 9 mg y 27 mg de carboximetilcelulosa cálcica,  d) between 9 mg and 27 mg of calcium carboxymethylcellulose,
e) entre 8 mg y 24 mg de crospovidona,  e) between 8 mg and 24 mg of crospovidone,
f) entre 1 mg y 4 mg de talco,  f) between 1 mg and 4 mg of talc,
g) entre 2 mg y 8 mg de estearato magnésico,  g) between 2 mg and 8 mg of magnesium stearate,
h) entre 0,8 mg y 2,4 mg de sílice coloidal, y  h) between 0.8 mg and 2.4 mg of colloidal silica, and
i) entre 1 ,2 mg y 3,6 mg de ácido esteárico.  i) between 1.2 mg and 3.6 mg of stearic acid.
Un comprimido particularmente preferido comprende: A particularly preferred tablet comprises:
a) 100 mg de cilostazol,  a) 100 mg cilostazol,
b) 40 mg de sorbitol,  b) 40 mg of sorbitol,
c) 45 mg de celulosa microcristalina, d) 18 mg de carboximetilcelulosa cálcica, c) 45 mg of microcrystalline cellulose, d) 18 mg of calcium carboxymethylcellulose,
e) 16 mg de crospovidona,  e) 16 mg of crospovidone,
f) 2 mg de talco,  f) 2 mg of talc,
g) 4 mg de estearato magnésico,  g) 4 mg magnesium stearate,
h) 1 ,6 mg de sílice coloidal, y  h) 1.6 mg of colloidal silica, and
i) 2,4 mg de ácido esteárico.  i) 2.4 mg stearic acid.
Forma parte del objeto de la invención un procedimiento para preparar un comprimido que comprende: A process for preparing a tablet comprising:
a) disolver el alcohol de azúcar en agua, un disolvente orgánico, o mezclas de los mismos,  a) dissolve sugar alcohol in water, an organic solvent, or mixtures thereof,
b) dispersar el talco en la solución obtenida en la etapa a),  b) dispersing the talc in the solution obtained in step a),
c) amasar el cilostazol y, opcionalmente, el agente disgregante con la dispersión obtenida en la etapa b),  c) knead the cilostazol and, optionally, the disintegrating agent with the dispersion obtained in step b),
d) granular y secar hasta obtener una humedad inferior al 10%,  d) granulate and dry until a humidity of less than 10% is obtained,
e) añadir al menos un agente auxiliar, mezclar y comprimir.  e) add at least one auxiliary agent, mix and compress.
Una forma de preparar el comprimido puede ser por ejemplo la siguiente. En primer lugar se prepara la composición de la invención por mezclado y tamizado del principio activo y una parte del agente disgregante, y granulación de dicha mezcla por vía húmeda mediante la aplicación de una dispersión de un agente aglutinante con- sistente en un alcohol de azúcar y talco, en un agua. La mezcla granulada se seca en un lecho fluido hasta obtener una humedad inferior al 10%, preferiblemente inferior al 5%, y se tamiza. A continuación se agrega el agente auxiliar, se mezcla y se procede a la compresión en una máquina convencional.  One way to prepare the tablet may be for example the following. First, 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.
En la fabricación de los comprimidos de la invención no se han observado proble- mas de adherencia significativos en los punzones de la máquina de comprimir. In the manufacture of the tablets of the invention no significant adhesion problems have been observed in the punches of the compressing machine.
Una vez obtenido el comprimido, si se desea puede aplicarse una capa exterior de recubrimiento protector utilizando técnicas también convencionales, por ejemplo mediante grageado o pulverización. Once the tablet is obtained, if desired, an outer layer of protective coating can be applied using conventional techniques, for example by means of dredging or spraying.
En una realización preferida, el comprimido incluye además una capa exterior de recubrimiento.  In a preferred embodiment, the tablet further includes an outer coating layer.
En este caso pueden emplearse los recubrimientos disponibles comercialmente. Con las composiciones de la invención también pueden prepararse cápsulas o polvos dosificados en sobres que comprenden una cantidad de la composición suficiente como para proporcionar una dosis unitaria efectiva de cilostazol. In this case, commercially available coatings can be used. With the 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.
En el caso de una cápsula o sobre la dosis unitaria de cilostazol está comprendida entre 50 mg y 150 mg, preferiblemente la dosis unitaria es 100 mg. In the case of a capsule or about the unit dose of cilostazol is between 50 mg and 150 mg, preferably the unit dose is 100 mg.
Las cápsulas pueden prepararse por métodos bien conocidos por el experto en la materia, y que se encuentran bien descritos en el libro Remington anteriormente citado. Por ejemplo mediante una máquina de encapsulacion en la que se dosifica la composición de la invención en cápsulas de gelatina dura.  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.
Los sobres se rellenan con la cantidad de composición de la invención que contiene la dosis unitaria deseada de cilostazol. Envelopes are filled with the amount of composition of the invention that contains the desired unit dose of cilostazol.
Forma parte también del objeto de la invención la utilización de la composición de la invención para la preparación de un medicamento para mejorar la distancia máxima y exenta de dolor que pueden caminar pacientes que padecen de claudicación intermitente, que no padecen de dolor en estado de reposo y que no presentan indicios de necrosis tisular periférica (estadio II de la clasificación de Fontaine de enfermedad arterial periférica).  The use of the 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).
También forma parte del objeto de la invención la composición de la invención para mejorar la distancia máxima y exenta de dolor que pueden caminar pacientes que padecen de claudicación intermitente, que no padecen de dolor en estado de reposo y que no presentan indicios de necrosis tisular periférica (estadio II de la clasificación de Fontaine de enfermedad arterial periférica).  Also part of the object of the invention is the 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).
Forma parte también del objeto de la invención la utilización del comprimido de la invención para la preparación de un medicamento para mejorar la distancia máxima y exenta de dolor que pueden caminar pacientes que padecen de claudicación intermitente, que no padecen de dolor en estado de reposo y que no presentan indicios de necrosis tisular periférica (estadio II de la clasificación de Fontaine de enfermedad arterial periférica).  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).
También forma parte del objeto de la invención el comprimido de la invención para mejorar la distancia máxima y exenta de dolor que pueden caminar pacientes que padecen de claudicación intermitente, que no padecen de dolor en estado de reposo y que no presentan indicios de necrosis tisular periférica (estadio II de la clasificación de Fontaine de enfermedad arterial periférica). Perfiles de disolución 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
En estos ensayos se compararon los perfiles de disolución de los comprimidos de la invención frente a comprimidos del medicamento comercial Pletal® 100 mg en las condiciones experimentales que se describen en los Ejemplos. In these tests, the dissolution profiles of the tablets of the invention were compared against tablets of the commercial drug Pletal ® 100 mg under the experimental conditions described in the Examples.
Para ello se emplearon cinco medios de disolución: For this, five dissolution media were used:
1 ) ácido clorhídrico 0,1 H,  1) 0.1 H hydrochloric acid,
2) tampón acetato sódico 0,05 M (pH = 4,5),  2) 0.05 M sodium acetate buffer (pH = 4.5),
3) tampón fosfato potásico 0,05 M (pH = 6,8),  3) 0.05 M potassium phosphate buffer (pH = 6.8),
4) tampón fosfato potásico 0,05 M (pH = 6,8), con laurilsulfato sódico al 0,5% y 4) 0.05 M potassium phosphate buffer (pH = 6.8), with 0.5% sodium lauryl sulfate and
5) agua con laurilsulfato sódico al 0,3 %. 5) water with 0.3% sodium lauryl sulfate.
Los resultados ponen de manifiesto que, de acuerdo con las directrices de EMA, los perfiles de disolución de los comprimidos de la invención comparados con el medicamento de referencia Pletal® 100 mg son similares. The results show that, according to EMA guidelines, the dissolution profiles of the tablets of the invention compared to the reference drug Pletal ® 100 mg are similar.
Los ensayos con los comprimidos obtenidos en los ejemplos de referencia descritos más adelante, no condujeron a la obtención de perfiles de disolución equivalentes a los del medicamento de referencia, a pesar de incluir cantidades considerables de alcohol de azúcar, pero sin talco en la fase intragranular (ver Ejemplo de Referencia 3), o incluyendo talco en la fase extragranular (ver Ejemplo de Referencia 2).  The tests with the tablets obtained in the reference examples described below, did not lead to the obtaining of dissolution profiles equivalent to those of the reference medicine, despite including considerable amounts of sugar alcohol, but without talc in the intragranular phase (see Reference Example 3), or including talc in the extragranular phase (see Reference Example 2).
Solamente cuando se han preparado comprimidos que comprenden la composición de la invención se obtiene un perfil de disolución apropiado, es decir, solamente cuando se ha granulado el principio activo, opcionalmente mezclado con un agente disgregante, con un agente aglutinante que consiste esencialmente en una mezcla de un alcohol de azúcar y talco se ha obtenido un perfil de disolución de cilostazol análogo al del medicamento de referencia, y no se han observado dificultades en el procedimiento de compresión.  Only when tablets comprising the composition of the invention have been prepared an appropriate dissolution profile is obtained, that is, only when the active ingredient has been granulated, optionally mixed with a disintegrating agent, with a binding agent consisting essentially of a mixture From a sugar alcohol and talc, a dissolution profile of cilostazol similar to that of the reference medicine has been obtained, and no difficulties have been observed in the compression procedure.
Así pues, se ha comprobado sorprendentemente que los comprimidos que com- prenden la composición de la invención presentan una solubilidad bioequivalente al medicamento comercial, y que no presentan dificultades en la etapa de compresión. Ejemplos Thus, it has been surprisingly found that 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. Examples
Ejemplo de referencia 1 .- Reference Example 1 .-
Preparación de comprimidos de cilostazol con sorbitol en la fase intraqranular Preparation of cilostazol tablets with sorbitol in the intraqranular phase
Se prepararon comprimidos de cilostazol, con la siguiente composición por comprimido: Cilostazol tablets were prepared, with the following composition per tablet:
Figure imgf000019_0001
Figure imgf000019_0001
Para la manufactura de los comprimidos se preparó una solución de sorbitol en agua. A solution of sorbitol in water was prepared for the manufacture of the tablets.
A continuación se tamizó el cilostazol y la mitad de carmelosa cálcica, se premezcló y se amasó con la solución de sorbitol.  The cilostazol and half of calcium carmellose were then screened, premixed and kneaded with the sorbitol solution.
Se granuló la mezcla y se secó por aire hasta obtener una humedad inferior al 5%. Seguidamente se calibró el granulado obtenido junto con la celulosa microcristalina, el resto de la carmelosa sódica y la crospovidona, y se mezcló hasta obtener una mezcla homogénea.  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.
Finalmente se incorporó por tamiz la sílice coloidal y el estearato magnésico, y se comprimió en máquina rotativa. Se observaron problemas durante la compresión, ya que la composición se adhería a los punzones de la máquina. Finally, the 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.
Ejemplo de referencia 2.- Preparación de comprimidos de cilostazol con maltitol en la fase intraqranular y talco en la fase extraqranular Reference example 2.- Preparation of cilostazol tablets with maltitol in the intraqranular phase and talc in the extraqranular phase
Se prepararon comprimidos de cilostazol, con la siguiente composición por comprimido:  Cilostazol tablets were prepared, with the following composition per tablet:
Figure imgf000020_0001
Figure imgf000020_0001
Para la manufactura de los comprimidos se preparó una solución de maltitol en agua. A solution of maltitol in water was prepared for the manufacture of the tablets.
A continuación se tamizó el cilostazol y la mitad de la carmelosa cálcica, se pre- mezcló y se amasó con la solución de maltitol.  The cilostazol and half of the calcium carmellose were then screened, pre-mixed and kneaded with the maltitol solution.
Se granuló la mezcla y se secó por aire hasta obtener una humedad inferior al 5%. Seguidamente se calibró el granulado obtenido junto con la celulosa microcristalina, el resto de la carmelosa sódica y la crospovidona, y se mezcló hasta obtener una mezcla homogénea. 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.
Finalmente se incorporó por tamiz el talco, la sílice coloidal y el estearato magnési- co, y se comprimió en máquina rotativa.  Finally, talc, colloidal silica and magnesium stearate were sieved and compressed in a rotary machine.
A pesar de incluir un contenido de agente lubrificante extragranular superior al del Ejemplo de Referencia 1 , durante la compresión se observaron problemas de adherencia, ya que la composición se adhería a los punzones de la máquina.  Despite including an extragranular lubricating agent content greater than that of Reference Example 1, adhesion problems were observed during compression, since the composition adhered to the machine punches.
La disolución de los comprimidos en el medio agua con 0,3% de lauriisulfato sódico quedó un 7% por debajo del medicamento de referencia. The dissolution of the tablets in the water medium with 0.3% sodium lauriisulfate was 7% below the reference medicine.
Ejemplo de referencia 3.-Reference Example 3.-
Preparación de comprimidos de cilostazol con sorbitol en la fase intraqranular Preparation of cilostazol tablets with sorbitol in the intraqranular phase
Se prepararon comprimidos de cilostazol, con la siguiente composición por com- primido:  Cilostazol tablets were prepared, with the following composition as a whole:
Figure imgf000021_0001
Figure imgf000021_0001
Para la manufactura de los comprimidos se preparó una solución de sorbitol en agua. A continuación se tamizó el cilostazol y la mitad de carmelosa cálcica, se premezcló y se amasó con la solución de sorbitol. 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.
Se granuló la mezcla y se secó por aire hasta obtener una humedad inferior al 5%. Seguidamente se calibró el granulado obtenido junto con la celulosa microcristalina, el resto de la carmelosa sódica, y se mezcló hasta obtener una mezcla homogénea.  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.
Finalmente se incorporó por tamiz la sílice coloidal y el estearato magnésico, y se comprimió en máquina rotativa.  Finally, the colloidal silica and magnesium stearate were sieved and compressed in a rotary machine.
Durante la compresión se observaron problemas de adherencia en los punzones. La disolución de los comprimidos en el medio agua con 0,3% de laurilsulfato sódico quedó un 15% por debajo del medicamento de referencia.  During the compression there were adhesion problems in the punches. The dissolution of the tablets in the water medium with 0.3% sodium lauryl sulfate was 15% below the reference medicine.
Ejemplo 1 .- Preparación de comprimidos de cilostazol con sorbitol y talco en la fase intraqranu- lar Example 1 .- Preparation of cilostazol tablets with sorbitol and talc in the intraqranular phase
Se prepararon comprimidos de cilostazol que contenían sorbitol y talco en la fase intragranular y que tenían la siguiente composición cuantitativa:  Cilostazol tablets containing sorbitol and talc in the intragranular phase and having the following quantitative composition were prepared:
Componente Cantidad Component Quantity
(mg/comprimido)  (mg / tablet)
Cilostazol 100 Cilostazol 100
Sorbitol 40 Sorbitol 40
Celulosa microcris45 talina Talc microcris cellulose45
Carmelosa cálcica 18 Calcium Carmellose 18
Crospovidona 16 Crospovidone 16
Sílice coloidal 1 ,6 Estearato magnési4 co Colloidal silica 1, 6 Magnesium Stearate 4 co
Ácido esteárico 2,4 Stearic Acid 2,4
Talco 2 Talc 2
Para la manufactura de los comprimidos se preparó una solución de sorbitol en agua y se dispersó el talco en la misma. For the manufacture of the tablets a solution of sorbitol in water was prepared and the talc was dispersed therein.
A continuación se tamizó el cilostazol y el 50% de carmelosa cálcica, se premezcló y se amasó con la dispersión de talco en la solución de sorbitol.  The cilostazol and 50% calcium carmellose were then screened, premixed and kneaded with the talc dispersion in the sorbitol solution.
Se granuló la mezcla y se secó por aire hasta obtener una humedad inferior al 5%. Seguidamente se calibró el granulado obtenido junto con la celulosa microcristalina, el resto de la carmelosa sódica y la crospovidona, y se mezcló hasta obtener una mezcla homogénea.  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.
Finalmente se incorporó por tamiz la sílice coloidal, el estearato magnésico y el ácido esteárico, y se comprimió en máquina rotativa. Finally, the colloidal silica, magnesium stearate and stearic acid were incorporated by sieve and compressed in a rotary machine.
Se obtuvieron comprimidos, cada uno de los cuáles contenía 100 mg de cilostazol.  Tablets were obtained, each containing 100 mg of cilostazol.
Ejemplo 2 .- Preparación de comprimidos de cilostazol con sorbitol y talco en la fase intraqranu- lar Example 2 .- Preparation of cilostazol tablets with sorbitol and talc in the intraqranular phase
Siguiendo un procedimiento análogo al del Ejemplo 1 , se prepararon comprimidos de cilostazol que se diferencian de los de dicho Ejemplo 1 en que la composición por comprimido es la siguiente:  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:
Componente Cantidad Component Quantity
(mg/comprimido)  (mg / tablet)
Cilostazol 100 Cilostazol 100
Sorbitol 40 Sorbitol 40
Celulosa microcris- 45 talina Microcris cellulose- 45 talina
Carmelosa cálcica 18 Calcium Carmellose 18
Crospovidona 1 1 Crospovidone 1 1
Sílice coloidal 1 ,6 Colloidal silica 1, 6
Estearato magnési4 co Magnesium Stearate 4 co
Ácido esteárico 2,4 Stearic Acid 2,4
Talco 2 Talc 2
Ejemplo 3 .-Example 3 .-
Preparación de comprimidos de cilostazol con maltitol v talco en la fase intragranu- lar Preparation of cilostazol tablets with maltitol v talc in the intragranular phase
Siguiendo un procedimiento análogo al del Ejemplo 1 , se prepararon comprimidos de cilostazol que se diferencian de los de dicho Ejemplo 1 en que la composición por comprimido es la siguiente:  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:
Componente Cantidad Component Quantity
(mg/comprimido)  (mg / tablet)
Cilostazol 100 Cilostazol 100
Maltitol 40 Maltitol 40
Celulosa microcris- 45 talina Microcrystalline cellulose-45 talin
Carmelosa cálcica 18 Calcium Carmellose 18
Crospovidona 16 Crospovidone 16
Sílice coloidal 1 ,6 Estearato magnési4 co Colloidal silica 1, 6 Magnesium Stearate 4 co
Ácido esteárico 2,4 Stearic Acid 2,4
Talco 2 Talc 2
Ejemplo 4 .-Example 4 .-
Preparación de comprimidos de cilostazol con manitol y talco en la fase intraqranu- lar Preparation of cilostazol tablets with mannitol and talc in the intraqranular phase
Siguiendo un procedimiento análogo al del Ejemplo 1 , se prepararon comprimidos de cilostazol que se diferencian de los de dicho Ejemplo 1 en que la composición por comprimido es la siguiente: 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:
Componente Cantidad Component Quantity
(mg/comprimido)  (mg / tablet)
Cilostazol 100 Cilostazol 100
Manitol 40 Mannitol 40
Celulosa microcris- 45 talina Microcrystalline cellulose-45 talin
Carmelosa cálcica 18 Calcium Carmellose 18
Crospovidona 16 Crospovidone 16
Sílice coloidal 1 ,6 Colloidal silica 1, 6
Estearato magnési4 co Magnesium Stearate 4 co
Ácido esteárico 2,4 Stearic Acid 2,4
Talco 2 Ejemplo 5 .-Talc 2 Example 5 .-
Preparación de comprimidos de cilostazol con isomalt y talco en la fase intraqranu- lar Preparation of cilostazol tablets with isomalt and talc in the intraqranular phase
Siguiendo un procedimiento análogo al del Ejemplo 1 , se prepararon comprimidos de cilostazol que se diferencian de los de dicho Ejemplo 1 en que la composición por comprimido es la siguiente: 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:
Figure imgf000026_0001
Ejemplo 6.-
Figure imgf000026_0001
Example 6.-
Perfil de liberación de comprimidos de cilostazol Cilostazol tablet release profile
En estos ensayos se compararon los perfiles de disolución de los comprimidos preparados en el Ejemplo 1 , como representativos de los comprimidos de la invención, frente a comprimidos del medicamento comercial Pletal 100 mg en las condiciones experimentales que se describen a continuación. In these tests the dissolution profiles of the tablets prepared in Example 1 were compared, as representative of the tablets of the invention, against tablets of the commercial drug Pletal 100 mg under the experimental conditions described below.
Los ensayos de disolución del principio activo se efectuaron en un baño de disolución ERWEKA, modelo DT800.  Dissolution tests of the active substance were carried out in an ERWEKA dissolution bath, model DT800.
La concentración del principio activo se determinó mediante el empleo de un espec- trofotómetro diodo array AGILENT, modelo 8453, y el programa informático UV- Visible Chemstation Rev.A.09.01 (AGILENT). 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.
Se emplearon cuatro medios de disolución, según se muestra en la siguiente tabla:  Four dissolution media were used, as shown in the following table:
Figure imgf000027_0001
Figure imgf000027_0001
En todos los métodos se emplearon las siguientes condiciones experimentales: Número de comprimidos: 12 The following experimental conditions were used in all methods: Number of tablets: 12
Volumen: 900 mi Volume: 900 mi
Temperatura: 37 ± 0,5eC Temperature: 37 ± 0.5 e C
Aparato: modelo 2, paletas (USP) Device: model 2, pallets (USP)
Velocidad de agitación: 50 rpm Stirring speed: 50 rpm
Análisis de cilostazol disuelto a los tiempos estipulados: medida de D.O. a 258 nm En las Tablas I a IV y en las Figuras 1 a 4 se presentan los resultados de los ensayos de disolución en los diferentes medios 1 a 4 respectivamente: TABLA I Analysis of cilostazol dissolved at the stipulated times: OD measurement at 258 nm Tables I to IV and Figures 1 to 4 show the results of dissolution tests in different media 1 to 4 respectively: TABLE I
Medio 1: HCI 0,1 N  Medium 1: 0.1 N HCI
Tiempo EjemPletal® Exemplary Time ®
(minutos) plo 1 (minutes) plo 1
0,0 0,00.0 0.0
0 0
0,6 1,1 0.6 1.1
5 5
1,7 3,9 1.7 3.9
7,5 7.5
2,8 5,0 2.8 5.0
10 10
4,1 6,0 4.1 6.0
15 fifteen
4,9 6,7 4.9 6.7
20 twenty
5,3 6,9 5.3 6.9
22,5 22.5
5,5 7,0 5.5 7.0
25 25
5,9 7,3 5.9 7.3
30 30
TABLA II TABLE II
Medio 2: Tampón acetato sódico 0,05 M (pH = 4,5) Medium 2: 0.05 M sodium acetate buffer (pH = 4.5)
Tiempo EjemPletal® Exemplary Time ®
(minutos) plo 1 (minutes) plo 1
0,0 0,00.0 0.0
0 0
0,7 1 ,4 0.7 1, 4
5 5
2,0 3,6 2.0 3.6
7,5 7.5
3,0 4,6 3.0 4.6
1 0 1 0
4,2 5,7 4.2 5.7
1 5 fifteen
5,1 5,8 5.1 5.8
20 twenty
5,5 6,1 5.5 6.1
22,5 22.5
5,8 5,9 5.8 5.9
25 25
6,2 6,1 6.2 6.1
30 30
TABLA III TABLE III
Medio 3: Tampón fosfato potásico 0,05 M (pH Medium 3: 0.05 M potassium phosphate buffer (pH
Tiempo EjemPletal® Exemplary Time ®
(minutos) plo 1 (minutes) plo 1
0,0 0,00.0 0.0
0 0
0,8 2,5 0.8 2.5
5 5
2,1 4,1 2.1 4.1
7,5 7.5
3,1 4,8 3.1 4.8
1 0 1 0
4,2 5,5 4.2 5.5
1 5 fifteen
5,0 5,8 5.0 5.8
20 twenty
5,3 6,0 5.3 6.0
22,5 22.5
5,5 6,0 5.5 6.0
25 25
5,8 6,2 5.8 6.2
TABLA IV TABLE IV
Medio 4: Tampón fosfato potásico 0,05 M (pH = 6,8) con lauriisulfato sódico al 0,5% Medium 4: 0.05 M potassium phosphate buffer (pH = 6.8) with 0.5% sodium lauriisulfate
Tiempo EjemPletal® Exemplary Time ®
(minutos) plo 1 (minutes) plo 1
0,0 0,0 0.0 0.0
0  0
36,9 32,3  36.9 32.3
5  5
56,9 47,8  56.9 47.8
7,5  7.5
66,3 57,8  66.3 57.8
1 0  1 0
74,4 69,7  74.4 69.7
1 5  fifteen
78,9 77,0  78.9 77.0
20  twenty
80,5 79,8  80.5 79.8
22,5  22.5
81 ,8 82,0  81, 8 82.0
25  25
83,7 85,6 83.7 85.6
TABLA V TABLE V
Medio 5: Agua con lauriisulfato sódico al 0,3 % Medium 5: Water with 0.3% sodium lauriisulfate
Tiempo EjemPletal® Exemplary Time ®
(minutos) plo 1 (minutes) plo 1
0,0 0,00.0 0.0
0 0
26,5 33,0 26.5 33.0
5 5
42,5 44,5 42.5 44.5
7,5 7.5
51 ,5 51 ,5 51, 5 51, 5
10 10
60,5 59,7 60.5 59.7
15 fifteen
66,1 65,3 66.1 65.3
20 twenty
68,3 67,6 68.3 67.6
22,5 22.5
70,0 69,6 70.0 69.6
25 25
72,7 72,9 72.7 72.9
30 30
74,9 75,4 74.9 75.4
35 35
76,6 77,5 76.6 77.5
40 40
78,1 79,2 78.1 79.2
45 Se puede observar que los perfiles de disolución de los comprimidos de la invención comparados con el medicamento de referencia Pletal® 100 mg son similares, de acuerdo con las directrices de EMA Note for Guidance on The Investigation of Bioavailability and Bioequivalence. The European Agency for the Evaluation of Medicinal Products; CPMP/EWP/QWP/1401/98; Rev. 1 2010. Four. Five It can be seen that the dissolution profiles of the tablets of the invention compared to the reference drug Pletal ® 100 mg are similar, in accordance with the guidelines of EMA Note for Guidance on The Investigation of Bioavailability and Bioequivalence. The European Agency for the Evaluation of Medicinal Products; CPMP / EWP / QWP / 1401/98; Rev. 1 2010.
También se ha comprobado que los coeficientes de variación del porcentaje de principio activo disuelto a cada tiempo correspondiente a los comprimidos de la invención son sustancialmente análogos a los coeficientes de variación correspon- dientes a los comprimidos del medicamento de referencia.  It has also been found that the coefficients of variation of the percentage of active ingredient dissolved at each time corresponding to the tablets of the invention are substantially analogous to the coefficients of variation corresponding to the tablets of the reference medicine.

Claims

REIVINDICACIONES
1 . - Composición farmacéutica sólida caracterizada porque comprende: a) una cantidad farmacéuticamente efectiva de cilostazol o una sal farmacéuticamente aceptable, solvato o hidrato del mismo, one . - Solid pharmaceutical composition characterized in that it comprises: a) a pharmaceutically effective amount of cilostazol or a pharmaceutically acceptable salt, solvate or hydrate thereof,
b) un agente aglutinante que consiste esencialmente de una mezcla de un alcohol de azúcar y talco, y  b) a binding agent consisting essentially of a mixture of a sugar alcohol and talc, and
c) opcionalmente un agente disgregante.  c) optionally a disintegrating agent.
2. - Composición según la reivindicación 1 , caracterizada porque el cilostazol se emplea en forma micronizada de manera que al menos el 50% de las partículas presentan un tamaño medio de partícula no superior a 10 mieras. 2. - Composition according to claim 1, characterized in that the cilostazol is used in a micronized form so that at least 50% of the particles have an average particle size not exceeding 10 microns.
3.- Composición según la reivindicación 1 ó 2, caracterizada porque el cilostazol representa entre el 35% y el 90% en peso sobre el peso total de la composición. 3. Composition according to claim 1 or 2, characterized in that cilostazol represents between 35% and 90% by weight over the total weight of the composition.
4. - Composición según cualquiera de las reivindicaciones 1 a 3, caracterizada porque el alcohol de azúcar se selecciona de entre el grupo formado por sorbitol, ma- nitol, xilitol, isomalt, maltitol y lactitol. 4. - Composition according to any one of claims 1 to 3, characterized in that the sugar alcohol is selected from the group consisting of sorbitol, mammol, xylitol, isomalt, maltitol and lactitol.
5. - Composición según la reivindicación 4, caracterizada porque el alcohol azúcar se selecciona entre sorbitol, isomalt, manitol, o maltitol. 5. - Composition according to claim 4, characterized in that the sugar alcohol is selected from sorbitol, isomalt, mannitol, or maltitol.
6.- Composición según la reivindicación 5, caracterizada porque el alcohol azúcar es sorbitol. 6. Composition according to claim 5, characterized in that the sugar alcohol is sorbitol.
7.- Composición según cualquiera de las reivindicaciones 1 a 6, caracterizada porque el alcohol de azúcar representa entre el 10% y el 45% en peso sobre el peso total de la composición. 7. Composition according to any of claims 1 to 6, characterized in that the sugar alcohol represents between 10% and 45% by weight over the total weight of the composition.
8.- Composición según cualquiera de las reivindicaciones 1 a 7, caracterizada porque el talco representa entre el 0,1 % y el 5% en peso sobre el peso total de la composición. 8. Composition according to any of claims 1 to 7, characterized in that the talc represents between 0.1% and 5% by weight over the total weight of the composition.
9.- Composición según cualquiera de las reivindicaciones 1 a 8, caracterizada porque comprende un agente disgregante. 9. Composition according to any of claims 1 to 8, characterized in that it comprises a disintegrating agent.
10. - Composición según la reivindicación 9, caracterizada porque el agente disgregante se selecciona de entre el grupo formado por almidón de maíz, almidón de patata, almidón glicolato sódico, almidón pregelatinizado, celulosa microcristalina, carboximetilcelulosa cálcica, crospovidona, dióxido de silicio coloidal, fosfato cálcico dibásico, fosfato cálcico tribásico, y mezclas de los mismos. 10. - Composition according to claim 9, characterized in that 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, and mixtures thereof.
1 1 . - Composición según la reivindicación 10, caracterizada porque el agente dis- gregante se selecciona de entre carboximetilcelulosa cálcica, celulosa microcristalina, crospovidona, dióxido de silicio coloidal, y mezclas de los mismos. eleven . - Composition according to claim 10, characterized in that the disintegrating agent is selected from calcium carboxymethylcellulose, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and mixtures thereof.
12. - Composición según la reivindicación 1 1 , caracterizada porque el agente disgregante se selecciona de entre carboximetilcelulosa cálcica, crospovidona, y mez- das de los mismos. 12. - Composition according to claim 1, characterized in that the disintegrating agent is selected from calcium carboxymethylcellulose, crospovidone, and mixtures thereof.
13. - Composición según cualquiera de las reivindicaciones 9 a 12, caracterizada porque el agente disgregante representa entre el 2% y el 20% en peso sobre el peso total de la composición. 13. - Composition according to any of claims 9 to 12, characterized in that the disintegrating agent represents between 2% and 20% by weight over the total weight of the composition.
14. - Procedimiento para preparar la composición según cualquiera de las reivindicaciones 1 a 13, caracterizado porque comprende: a) disolver el alcohol de azúcar en agua, un disolvente orgánico, o mezclas de los mismos, 14. - Method for preparing the composition according to any of claims 1 to 13, characterized in that it comprises: a) dissolving the sugar alcohol in water, an organic solvent, or mixtures thereof,
b) dispersar el talco en la solución obtenida en la etapa a),  b) dispersing the talc in the solution obtained in step a),
c) amasar el cilostazol y, opcionalmente, el agente disgregante con la dispersión obtenida en la etapa b), y d) granular y secar hasta obtener una humedad inferior al 10%. c) knead the cilostazol and, optionally, the disintegrating agent with the dispersion obtained in step b), and d) granulate and dry until a humidity of less than 10% is obtained.
15.- Comprimido de cilostazol caracterizado porque comprende: a) una cantidad de la composición según cualquiera de las reivindicaciones 1 a 13 que sea suficiente como para proporcionar una dosis unitaria efectiva de cilostazol, y 15. Cilostazol tablet characterized in that it comprises: a) an amount of the composition according to any one of claims 1 to 13 that is sufficient to provide an effective unit dose of cilostazol, and
b) al menos un agente auxiliar.  b) at least one auxiliary agent.
16.- Comprimido según la reivindicación 15, caracterizado porque consiste en entre un 35% y un 90% en peso de la composición según cualquiera de las reivindicaciones 1 a 12, y entre un 10% y un 65% en peso de al menos un agente auxiliar. 16. Tablet according to claim 15, characterized in that it consists of between 35% and 90% by weight of the composition according to any of claims 1 to 12, and between 10% and 65% by weight of at least one auxiliary agent
17. - Comprimido según la reivindicación 15 ó 16, caracterizado porque contiene una dosis unitaria de cilostazol comprendida entre los 50 mg y los 150 mg. 17. - Tablet according to claim 15 or 16, characterized in that it contains a unit dose of cilostazol between 50 mg and 150 mg.
18. - Comprimido según la reivindicación 17, caracterizado porque contiene una dosis unitaria de cilostazol de 100 mg. 18. - Tablet according to claim 17, characterized in that it contains a unit dose of cilostazol of 100 mg.
19.- Comprimido según cualquiera de las reivindicaciones 15 a 18, caracterizado porque el agente auxiliar se selecciona de entre el grupo formado por diluyentes, disgregantes, lubrificantes, antiadherentes, edulcorantes, saborizantes, aromatizantes, y/o mezclas de los mismos. 19. Tablet according to any of claims 15 to 18, characterized in that the auxiliary agent is selected from the group consisting of diluents, disintegrants, lubricants, non-sticks, sweeteners, flavorings, flavorings, and / or mixtures thereof.
20.- Comprimido según cualquiera de las reivindicaciones 15 a 19, caracterizado porque comprende entre un 20% y un 80% en peso de cilostazol; entre un 10% y un 30% en peso de alcohol de azúcar; entre el 10% y el 30% en peso de un dilu- yente; entre un 2% y un 25% en peso de un agente disgregante; entre 0,1 % y 5% en peso de talco; y entre 0,5% y 6% de lubrificante extragranular, de modo que la suma de los porcentajes en peso de los componentes sobre el total de la composición es igual al 100%. 20. Tablet according to any of claims 15 to 19, characterized in that it comprises between 20% and 80% by weight of cilostazol; between 10% and 30% by weight of sugar alcohol; between 10% and 30% by weight of a diluent; between 2% and 25% by weight of a disintegrating agent; between 0.1% and 5% by weight of talc; and between 0.5% and 6% extragranular lubricant, so that the sum of the weight percentages of the components over the total composition is equal to 100%.
21 . - Comprimido según la reivindicación 20, caracterizado porque el alcohol de azúcar es seleccionado entre sorbitol, maltitol, manitol e isomait; el diluyente es celulosa microcristalina; el agente disgregante se selecciona de carboximetilcelulo- sa cálcica, crospovidona y sus mezclas; y el lubrificante extragranular se selecciona de entre el grupo formado por estearato magnésico, ácido esteárico, sílice coloidal y sus mezclas. twenty-one . - Tablet according to claim 20, characterized in that the sugar alcohol is selected from sorbitol, maltitol, mannitol and isomait; the diluent is microcrystalline cellulose; the disintegrating agent is selected from calcium carboxymethylcellulose, crospovidone and mixtures thereof; and the extragranular lubricant is selected from the group consisting of magnesium stearate, stearic acid, colloidal silica and mixtures thereof.
22. - Comprimido según la reivindicación 13, caracterizado porque comprende: a) entre 50 mg y 150 mg de cilostazol, 22. - Tablet according to claim 13, characterized in that it comprises: a) between 50 mg and 150 mg of cilostazol,
b) entre 20 mg y 60 mg de un alcohol de azúcar seleccionado entre sorbitol, isomait, manitol, o maltitol,  b) between 20 mg and 60 mg of a sugar alcohol selected from sorbitol, isomait, mannitol, or maltitol,
C) entre 20 mg y 60 mg de celulosa microcristalina,  C) between 20 mg and 60 mg of microcrystalline cellulose,
d) entre 9 mg y 27 mg de carboximetilcelulosa cálcica,  d) between 9 mg and 27 mg of calcium carboxymethylcellulose,
e) entre 8 mg y 24 mg de crospovidona,  e) between 8 mg and 24 mg of crospovidone,
f) entre 1 mg y 4 mg de talco,  f) between 1 mg and 4 mg of talc,
g) entre 2 mg y 8 mg de estearato magnésico,  g) between 2 mg and 8 mg of magnesium stearate,
h) entre 0,8 mg y 2,4 mg de sílice coloidal, y  h) between 0.8 mg and 2.4 mg of colloidal silica, and
i) entre 1 ,2 mg y 3,6 mg de ácido esteárico.  i) between 1.2 mg and 3.6 mg of stearic acid.
23. - Comprimido según la reivindicación 22, caracterizado porque el alcohol de azúcar es sorbitol. 23. - Tablet according to claim 22, characterized in that the sugar alcohol is sorbitol.
24. - Comprimido según la reivindicación 22, caracterizado porque comprende: a) 100 mg de cilostazol 24. - Tablet according to claim 22, characterized in that it comprises: a) 100 mg cilostazol
b) 40 mg de sorbitol  b) 40 mg sorbitol
c) 45 mg de celulosa microcristalina  c) 45 mg of microcrystalline cellulose
d) 18 mg de carboximetilcelulosa cálcica  d) 18 mg calcium carboxymethyl cellulose
e) 16 mg de crospovidona  e) 16 mg crospovidone
f) 2 mg de talco,  f) 2 mg of talc,
g) 4 mg de estearato magnésico,  g) 4 mg magnesium stearate,
h) 1 ,6 mg de sílice coloidal, y i) 2,4 mg de ácido esteárico. h) 1.6 mg of colloidal silica, and i) 2.4 mg stearic acid.
25.- Procedimiento para preparar un comprimido según cualquiera de las reivindi- caciones 15 a 24 que comprende: a) disolver el alcohol de azúcar en agua, un disolvente orgánico, o mezclas de los mismos, 25. Process for preparing a tablet according to any of claims 15 to 24 comprising: a) dissolving the sugar alcohol in water, an organic solvent, or mixtures thereof,
b) dispersar el talco en la solución obtenida en la etapa a),  b) dispersing the talc in the solution obtained in step a),
c) amasar el cilostazol y, opcionalmente, el agente disgregante con la dispersión obtenida en la etapa b),  c) knead the cilostazol and, optionally, the disintegrating agent with the dispersion obtained in step b),
d) granular y secar hasta obtener una humedad inferior al 10%,  d) granulate and dry until a humidity of less than 10% is obtained,
e) añadir al menos un agente auxiliar, mezclar y comprimir.  e) add at least one auxiliary agent, mix and compress.
26.- Utilización de una composición de cualquiera de las reivindicaciones 1 a 13 para preparar formas farmacéuticas sólidas de cilostazol para su administración por vía oral. 26.- Use of a composition of any of claims 1 to 13 to prepare solid pharmaceutical forms of cilostazol for oral administration.
27. - Utilización según la reivindicación 26, caracterizada porque la forma farmacéu- tica sólida de cilostazol es un comprimido. 27. - Use according to claim 26, characterized in that the solid pharmaceutical form of cilostazol is a tablet.
28. - Utilización de la composición según cualquiera de las reivindicaciones 1 a 13 para la preparación de un medicamento para mejorar la distancia máxima y exenta de dolor que pueden caminar pacientes que padecen de claudicación intermitente, que no padecen de dolor en estado de reposo y que no presentan indicios de necrosis tisular periférica (estadio II de la clasificación de Fontaine de enfermedad arterial periférica). 28. - Use of the composition according to any one of claims 1 to 13 for the preparation of a medicament for improving the maximum and pain-free distance that patients suffering from intermittent claudication may 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).
29.- Utilización del comprimido según cualquiera de las reivindicaciones 15 a 24 para la preparación de un medicamento para mejorar la distancia máxima y exenta de dolor que pueden caminar pacientes que padecen de claudicación intermitente, que no padecen de dolor en estado de reposo y que no presentan indicios de necrosis tisular periférica (estadio II de la clasificación de Fontaine de enfermedad arterial periférica). 29.- Use of the tablet according to any of claims 15 to 24 for the preparation of a medicament to improve the maximum and pain-free distance that patients suffering from intermittent claudication may walk, who do not suffer from pain at rest and who they have no evidence of peripheral tissue necrosis (stage II of Fontaine's classification of peripheral arterial disease).
PCT/ES2013/070072 2012-02-10 2013-02-08 Solid cilostazol pharmaceutical composition WO2013117793A1 (en)

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Citations (3)

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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 (en) * 2008-02-29 2009-09-03 Otsuka Pharmaceutical Co., Ltd. An orally disintegrating tablet

Patent Citations (3)

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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 (en) * 2008-02-29 2009-09-03 Otsuka Pharmaceutical Co., Ltd. An orally disintegrating tablet

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