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    • 专利摘要:
    Pharmaceutical composition comprising 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof in the form of individualized delivery units and corresponding manufacturing process. Pharmaceutical composition comprising 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof in the form of individualized delivery units, in which a part of the 2,5-dihydroxybenzenesulfonic acid is in the form of an immediate release composition and another part of the acid 2,5-dihydroxybenzenesulfonic is in the form of an extended release composition. This allows administration of the composition only once every 24 hours to the patient. It can be used for the treatment of primary varicose conditions, chronic venous insufficiency, phlebitis, thrombophlebitis, post-thrombotic syndrome, leg ulcers, varices of pregnancy, adjuvant varicectomy, sclerotherapy or adjuvant in the treatment of diabetic retinopathy. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2680293A1
    申请号:ES201730225
    申请日:2017-02-22
    公开日:2018-09-05
    发明作者:Alfredo José INATTI MARTINEZ
    申请人:Belac Invest S L；Belac Invest SL；
    IPC主号:
    专利说明:

            DESCRIPTION Pharmaceutical composition comprising 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof in the form of individualized delivery units and corresponding manufacturing process. Field of the Invention The present invention relates to a pharmaceutical composition for oral administration of programmed action. for a dual, immediate and prolonged release, comprising 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts, for the reduction of fibrinogen in human blood, as well as for the prophylaxis and treatment of diseases caused by elevated levels of fibrinogen.   The invention also relates to a method of manufacturing a composition according to the invention.   Background of the Invention 20 2,5-Dihydroxybenzenesulfonic acid and / or its salts (dobesilate, for example calcium dobesilate), is a regulator of capillary functions and was described in patent ES 335. 945  The formula of calcium dobesilate is: 25 This principle has an elective action on the capillary wall, whose physiological properties of resistance and permeability are regularized by the preparation.  In other words, calcium dobesilate acts by increasing venous, venular and       decreasing the permeability of the capillary wall.  This action finds its application in all cases of hair fragility.    2,5-Dihydroxybenzenesulfonic acid or its pharmaceutically acceptable salts are generally administered orally in the form of tablets and capsules.  It is very soluble in water, soluble in ethanol, very slightly soluble in 2-propanol and practically insoluble in methylene chloride.   The present invention comprises 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts or preferably calcium dihydroxybenzenesulfonate 10 (calcium dobesilate).  It is incorporated into pellets, granules or tablets, which for dosing are located in hard gelatin capsules, hydroxypropyl methylcellulose, tablets, bilayer tablets, modified-release tablets, extended-release tablets, etc. , so that they can be swallowed easily.   In patent application EP 2 208 498 A1, which is incorporated by reference, a pharmaceutical formulation of calcium dobesilate, in capsule or tablet form, having a concentration of 250 mg of active ingredient is described.   In patent application ES 2 229 902 A1, a pharmaceutical formulation of calcium dobesilate in tablets is disclosed, which has a polymeric coating that transfers enteric properties to the pharmaceutical formulation and the concentration of active ingredient is less than 500 mg. .   The rate of gastric emptying of pellets, spherical units or coated microgranules is less dependent on the presence or absence of food in the stomach, which in some cases allows to reduce intra and interindividual variability in the absorption profiles of the active substance.  In addition, the pellets, spherical units or coated microgranules are dispersed as individualized units in the gastrointestinal tract, significantly reducing the high local concentrations of calcium dobesilate.  In this way its absorption is facilitated, fluctuations in plasma concentration are reduced and certain side effects are minimized.           Transport is the movement of a drug from one place to another within the body.  The drug can be released freely in a form not combined with an appropriate kinetic energy for its thermal environment or move in combination with extracellular or cellular constituents, sometimes in connection with 5 energy producing processes that allow the molecule or complex to overcome barriers Against simple diffusion.    There are currently pharmaceutical formulations for calcium dobesilate on the market.  But none of them incorporates a loading dose similar to a conventional dose (which is 500 mg), with which the immediate effect required by certain pathologies can be guaranteed.   It is thus necessary to have a pharmaceutical composition, administered once a day, which provides therapeutic levels of 2,5-15 dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts (preferably calcium dihydroxybenzenesulfonate) for 24 hours.   There are several methodologies for the manufacture of pellets, spherical units or microgranules.  One of them consists in preparing the spherical pellets or microgranules 20 by extrusion or spheronization, this methodology allows the obtaining of spherical particles that comprise the active principle, from a wetted paste, using a Equipment known as Marumerizer (Luwa) or the CF -Granulator (Vector).   A second method of manufacturing pellets, spherical units or microgranules, consists in using neutral particles (nuclei), the content of which can be sugar and / or starch, sugar and / or microcrystalline cellulose.  The cores are coated with the active substance by atomization or dusting.    In the present invention, the instantaneous effect can be observed with the incorporation, in the same dose, of an immediate action composition and another prolonged action composition, thus becoming a novel formulation with a prolonged type of programmed action.           In the present invention its dosage form may optionally be in pellets, granules, tablets, hard gelatin capsules, hydroxypropyl methylcellulose, tablets, bilayer tablets, modified-release tablets or extended-release tablets.   5 In different patent documents mention is made of the use of prolonged release formulations, however, there is a risk of not guaranteeing the immediate effect that this type of pharmacological agent deserves, which is of paramount importance especially for the reduction of Fibrinogen in human blood, as well as for the prophylaxis and treatment of diseases caused by elevated levels of fibrinogen.   Thus, it becomes necessary to have a pharmaceutical composition in the form of dual action, consisting of a part of the active ingredient in an immediate action formulation, and another part of the active ingredient in a prolonged action formulation.  This guarantees the rapid therapeutic effect and prolonging the action of the active substance over several hours, thus avoiding a multiplicity of daily dosages during the time the medication is prolonged.  It is thus necessary to have a pharmaceutical composition, administered once a day, which provides therapeutic levels of 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts (preferably calcium dihydroxybenzenesulfonate) for 24 hours.   DISCLOSURE OF THE INVENTION Surprisingly, the authors of the present invention have found that it is feasible to obtain a pharmaceutical formulation, in individualized units (ie to be administered once a day) that combines pharmacologically useful amounts of 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts (preferably calcium dihydroxybenzenesulfonate) that provide, by means of a dual action (immediate and prolonged), its properties for the reduction of fibrinogen in blood, instantaneously, said effects being prolonged in plasma levels along 24 hours.  For this the pharmaceutical composition that       comprising 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof in the form of individual delivery units, is characterized in that a part of said 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof is in the form of a release composition immediate and another part of said 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof is in the form of a prolonged release composition.   The novel programmed release galenic formulation, which provides therapeutically acceptable amounts of 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts (preferably calcium dihydroxybenzenesulfonate) in the form of pellets, spherical units or microgranules of immediate release or microgranules of prolonged release, dual-release tablets or extended-release tablets, acts effectively in the indication for the treatment of fibrinogen reduction in human blood, as well as for the prophylaxis and treatment of diseases caused by elevated levels of fibrinogen and diseases related.   A subject of the invention is also the use of a pharmaceutical composition comprising 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof in the form of individual delivery units, in which a portion of said 2,5-dihydroxybenzenesulfonic acid or one of its pharmaceutically acceptable salts is in the form of immediate release composition and another part of said 2,5-dihydroxybenzenesulfonic acid or one of its pharmaceutically acceptable salts is in the form of prolonged release composition for the manufacture of a medicament.  Preferably the medicament is for the treatment of fibrinogen reduction in human blood, prophylaxis and treatment of diseases caused by elevated fibrinogen levels, to increase venous tone, to decrease the permeability of the capillary wall, for the treatment of all primary varicose states (pain, heaviness of legs, 30 night cramps, paraesthesia), chronic venous insufficiency, phlebitis, thrombophlebitis, post-thrombotic syndrome, leg ulcers, varicose veins of pregnancy, adjuvant of varicectomy, sclerotherapy, adjuvant in the retinopathy treatment       diabetic (in particular micro-aneurysms, exudates, intra and extra retinal hemorrhages, proliferative vascular and conjunctival lesions), inhibition of vasoactive substances responsible for the contracture or shrinking of endothelial cells (bradykinin, histamine, serotonin), enzyme inhibition they degrade mucopolysaccharides, prevent the destruction of platelet membranes and their thrombogenic effect, improve blood viscosity (for example, increasing the elasticity and deformability of red blood cells, reducing the level of high-density plasma proteins (decreasing the partial viscosity of plasma), and / or chronic venous insufficiency.   Preferably the composition according to the invention is for use in the treatment of primary varicose conditions, chronic venous insufficiency, phlebitis, thrombophlebitis, post-thrombotic syndrome, leg ulcers, varicose veins of pregnancy, varicectomy adjuvant, sclerotherapy or adjuvant in the treatment of diabetic retinopathy.  Preferably the primary varicose states are pains, heaviness of legs, night cramps or paraesthesia.   Advantageously, an individualized delivery unit is administered only once every 24 hours or, alternatively, two individualized delivery units are administered simultaneously only once every 24 hours.  In general, preferably the composition according to the invention is administered only once every 24 hours.    Preferably, the individual delivery units are tablets, capsules or sachets, and most preferably are tablets or sachets.  Advantageously, the tablets are bilayer tablets, wherein one layer comprises said immediate release composition and the other layer comprises said prolonged release composition.   Another object of the present invention is a process for producing a pharmaceutical composition of 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts or preferably 30-calcium dihydroxybenzenesulfonate, by suitable processes from (Neutral) nuclei or Microgranules already made. .  The manufacturing process of the pharmaceutical composition according to the invention is characterized in that it comprises the following steps:        [a] manufacture the immediate release composition part, [b] manufacture the extended release composition part, and 5 [c] manufacture individualized delivery units comprising both immediate release composition and extended release composition.   Preferably in step [c] tablets are manufactured (which will thus be dual-release) and very preferably bilayer tablets are manufactured.   Advantageously in step [a] the immediate release composition is manufactured dry and in step [b] the extended release composition part is manufactured wet.   Preferably in step [a] 55.5% w / w or 85% w / w of 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof, 8% w / w and 28% w / w microcrystalline cellulose are used , 1% w / w 6% w / w sodium starch glycolate, 0.6% w / w 5% w / w magnesium stearate and 0.6% w / w 5.5% w / w talc , said% being referred to the total weight of the immediate release composition part 20.   Advantageously in step [b] 25% w / w or 75% w / w of 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof, 10% w / w or 45% w / w hydroxypropyl methylcellulose, 6.1 are used. % w / w 20% w / w hydroxypropylcellulose, 25 0.05% w / w 3% w / w dye, 0.6% w / w 5% w / w talc and 0.6% w / pa 5% w / w magnesium stearate, said% being referred to the total weight of the prolonged release composition part.   Preferably in step [c] the ratio between immediate release composition 30 and said prolonged release composition is between 12:88 and 52:48, and most preferably between 24:76 and 40:60.           Preferably, the individualized delivery units are bilayer tablets, wherein one layer comprises said immediate release composition and the other layer comprises said prolonged release composition.   A particularly advantageous form of the process according to the invention is that in which: step [a] comprises: [a. 1] Sift through a # 20 mesh, 55.5% w / w 85% w / w of 2.5-10 dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof, 8% w / w 28% w / w microcrystalline cellulose and 1% w / w 6% w / w sodium starch glycolate, said% being referred to the total weight of the immediate release composition part, [a. 2] mix the obtained in [a. 1], between a time range of 1 min to 30 min, [a. 3] sift through a # 30 mesh, 0.6% w / w 5% w / w magnesium stearate and 0.6% w / w 5.5% w / w talc, these% being referred to the total weight of the immediate release composition part, 20 [a. 4] mix the obtained in [a. 2] and [a. 3], between a time range of 1 min to 15 min, and step [b] comprises: 25 [b. 1] micronize, 25% w / w to 75% w / w 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof, said% being referred to the total weight of said part of the extended release composition, 30 [b. 2] dissolve, 0.1% w / w to 5% w / w hydroxypropylcellulose in a sufficient amount of purified water, said% being referred to the total weight of said part of the extended release composition,        [b. 3] mix the obtained in [b. 1], with 10% w / w 45% w / w hydroxypropylmethylcellulose, 6% w / w 15% w / w hydroxypropylcellulose and 0.05% w / w 3% w / w red lacquer, between a range of time from 1 min to 15 min, said% being referred to the total weight of said part of the extended release composition, 5 [b. 4] granulate what is obtained in [b. 3] with the solution obtained in [b. 2], [b. 5] dry the obtained in [b. 4], between a temperature range of 45 ºC to 70 ºC and a time range of 10 min to 60 min, 10 [b. 6] sift through a 062R mesh the obtained in [b. 5], [b. 7] sift through a # 30 mesh, 0.6% w / w 5% w / w talc and 0.6% w / w 5% w / w magnesium stearate, said% being referred to the total weight of said part of prolonged release composition, [b. 8] mix the obtained in [b. 6] and [b. 7], between a time range of 1 min to 15 min.   BRIEF DESCRIPTION OF FIGURES 20 Other advantages and features of the invention can be seen from the following description, in which, without any limitation, preferred embodiments of the invention are described, mentioning the accompanying drawings .  The figures show: 25 Figure 1 schematically shows a dual-action tablet.   Figures 2A and 2B show the immediate release stage.   30 Figures 3A and 3B show the extended release stage.   Figure 4 shows the release profile of example 1.          Figure 5 shows the release profile of example 3.   Figure 6 shows the release profile of example 5.   5 Figure 7 shows the release profile of example 6.   DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION The present invention relates to a pharmaceutical composition comprising an agent with properties for the reduction of fibrinogen in blood, specifically 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts or preferably calcium dihydroxybenzenesulfonate.   It is the purpose of the present invention to provide a pharmaceutical composition, to be delivered orally in the form of doses prepared from the combination of 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts or preferably calcium dihydroxybenzenesulfonate with materials or pharmaceutically acceptable excipients.   In the present invention the pharmaceutical composition can be provided in oral dosage form in dual-acting tablets.   Preferably each individual delivery unit of the composition has a content of 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof between 50 mg and 2. 500 mg in its immediate release form and between 50 mg and 2. 500 mg in its prolonged release form, more preferably each individual delivery unit has a content of 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof between 100 mg and 2. 000 mg in its immediate release form and between 100 mg and 30 2. 000 mg in its prolonged release form, and most preferably each individual delivery unit has a content of 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof.       150 mg and 1. 000 mg in its immediate release form and between 150 mg and 1. 000 mg in its prolonged release form.   Advantageously, each individual unit comprises between 400 mg to 2200 mg, of 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof.   The pharmaceutical composition of the present invention can be prepared by the procedures described below, optionally using excipients such as: plasticizers, diluent, adherents, retardants, gastro-resistant, colorants, surfactants or surfactants, binder, glidants, lubricants, disintegrants , conveyors and other additives of known use in the pharmaceutical industry.    Preferably the pharmaceutical composition of the present invention is provided as an oral dosage form comprising 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts or preferably calcium dihydroxybenzenesulfonate, in a pharmaceutical release, scheduled release preparation. dual.  The oral dose form may preferably take the form of tablets (or tablets), granules, capsules, etc.  and more preferably the tablet form.   In the present invention, the immediate release composition may preferably contain excipients such as: solubilizers, disintegrants, plasticizers, retardants, gastro-resistant material, colorants, surfactants or surfactants, glidants, lubricants, diluents and binders.   As used in the present invention the term "diluents" (for immediate release composition) comprises those agents that are used to give fluidity and compressibility to the pharmaceutical formulation.  Such compounds include, as an example and without limitation, dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, powdered sugar, sorbitol, inositol, bentonite, dextrose, sucrose, maltose , microcrystalline cellulose,       Starch such as Avicel, dicalcium phosphate dihydrate, calcium phosphate, lactose monohydrate, pregelatinized starch, hydrolyzed starch, compressible sugar, hydroxypropyl methyl cellulose, calcium monohydrate sulfate, calcium sulfate dihydrate, calcium lactose trihydrate, amylose , cellulose, calcium carbonate, kaolin, sodium chloride, fructose, xylitol, dextrose monohydrate, calcium lactose 5 trihydrate, polyvinylpyrrolidone, dicalcium phosphate, cellulose, silicon dioxide, titanium oxide, alumina, talc, lactose 80, etc. .  Preferably the diluent (in the immediate release composition) is a diluent of the group consisting of dicalcium phosphate, lactose, cellulose, microcrystalline cellulose, dicalcium phosphate dihydrate, lactose monohydrate, pregelatinized starch, hydroxypropyl methyl cellulose, cellulose, 10 Calcium carbonate, polyvinylpyrrolidone, alumina, talc and lactose 80, and most preferably it is microcrystalline cellulose.  Advantageously, microcrystalline cellulose is in a proportion of 8% w / w at 28% w / w, based on the total weight of the immediate release composition part.   As used in the present invention, the term "disintegrants" (in the immediate release composition) means "the agents used to facilitate breakage or disintegration of the dosage form after administration".  Such compounds include, as an example and without limitation, starch, celluloses, corn starch, potato starch, croscarmellose, croscarmellose sodium, crospovidone, sodium starch glycolate, colloidal silicon dioxide, magnesium silicate, aluminum silicate, microcrystalline cellulose, pregelatinized starch, sodium alginate, methylcellulose, agar, bentonite, alginic acid, gum agar, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, sodium lauryl sulfate, sodium bicarbonate, sodium chloride, etc.  Preferably the disintegrant is a disintegrant of the group consisting of starch, cellulose, corn starch, croscarmellose, croscarmellose sodium, crospovidone, sodium starch glycolate, microcrystalline cellulose, pregelatinized starch, sodium alginate, gum agar, carboxymethylcellulose and lauryl sulfate sodium, and most preferably is sodium starch glycolate.  Advantageously, the sodium starch glycolate is in a proportion of 1% w / w to 6% w / w, based on the total weight of the immediate release composition part.          As used in the present invention, the term "lubricants" (in the immediate release composition) means "the agents used to reduce friction between the particles and adhere to the surface of the drugs."  Such compounds include, as an example and without being limiting, talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils such as hydrogenated soybean oil, polyethylene glycol, sodium benzoate, sodium fumarate, calcium hydroxide, glycerol, boric acid, sodium acetate, sodium chloride, glyceryl behenate, magnesium or sodium lauryl sulfate, colloidal silicone, corn starch, etc.  Preferably the lubricant is a lubricant of the group consisting of talc, magnesium stearate, calcium stearate, stearic acid, sodium stearate fumarate and lauryl magnesium sulfate or sodium, and most preferably it is magnesium stearate, talc or a mixture of both .  Advantageously, the lubricant is magnesium stearate and magnesium stearate is in a proportion of 0.6% w / w to 5% w / w, based on the total weight of the immediate release composition part.  Alternatively, or additionally, advantageously the lubricant is talc and the talc is in a proportion of 0.6% w / w to 5.5% w / w, based on the total weight of the immediate release composition part.   It is particularly advantageous that the immediate release composition part comprises 55.5% w / w 85% w / w 2,5-dihydroxybenzenesulfonic acid or one of its pharmaceutically acceptable salts, 8% w / w 28% w / w of microcrystalline cellulose, 1% w / w 6% w / w sodium starch glycolate, 0.6% w / w 5% w / w magnesium stearate and 0.6% w / w 5.5% w / p of talc, said% being referred to the total weight of the immediate release composition part.   In the present invention, the extended release composition may preferably contain excipients such as: sulubilizers, disintegrants, plasticizers, retardants, gastro-resistant material, colorants, surfactants or surfactants, glidants, lubricants, diluents and binders.   As used in the present invention, the term "retarders" (in the delayed or prolonged release composition) means "those agents that are used so that the active ingredient is gradually released over time.       determined after administration ”.  Such retarding agents include, as an example and without being limiting, bentonite, carbomers, carrageenans, cellulose acetate, ethyl cellulose, cetyl alcohol, cetyl ester, chitosan, glyceryl behenate, glyceryl monooleate, glyceryl monostearate, glyceryl palmostearate, agar gum, hydroxypropyl cellulose, methylcellulose, polyethylene oxide, povidone, stearic acid, stearyl alcohol, xanthan gum, algic acid, carnauba wax, hypromellose, hypromellose phthalate, sodium alginate, sodium hyaluronate, stearic acid, hydroxyethylcellulose, polyamide , ethyl cellulose, hydroxypropyl methylcellulose, ammonium methacrylate copolymer, etc.  Preferably the retardant is a retardant of the group consisting of ethyl cellulose, agar gum, hydroxypropyl cellulose, methylcellulose, povidone, xanthan gum, hypromellose, hypromellose phthalate, sodium alginate, hydroxyethylcellulose, hydroxypropyl methylcellulose and methacrylate copolymer, preferably very methacrylate, It is hydroxypropyl methylcellulose.  Advantageously, hydroxypropylmethylcellulose is in a proportion of 10% w / w to 45% w / w, based on the total weight of the prolonged release composition part.  As used in the present invention, the term "binders" (in the extended release composition) means the agents used to impart cohesive qualities to the powdered materials.  Such compounds include, as an example and without limitation, starch, gelatin, sugars such as sucrose, glucose, dextrose, molasses, lactose, natural gums, synthetic gums, gum arabic, sodium alginate, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, Veegum, polyethylene glycol, ethyl cellulose, water, alcohol, pregelatinized starches, microcrystalline dextrose, amylase, polyvinylpyrrolidone, microcrystalline cellulose, cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, agar, methylcellulose, carboxamic acid, cellulose cellulose dextrin, glyceryl behenate, gum agar, hydroxyethylmethyl cellulose, hypromellose, lactose, spray dried lactose monohydrate, liquid glucose, maltodextrin, maltose, polydextrose, methacrylic acid, povidone, stearic acid, hydroxypropyl methylcellulose, etc.  Preferably the binder is a binder of the group consisting of starch, lactose, gum arabic, sodium alginate, carboxymethyl cellulose, methyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, ethyl cellulose, water, alcohol, pregelatinized starches, microcrystalline cellulose, dextrosecrystalline, dextrosecrystalline cellulose, dextrosecrystalline cellulose       cellulose, hydroxyethylcellulose, hydroxypropylcellulose, algic acid, sodium carboxymethylcellulose, cellulose phthalate acetate, dextrin, glyceryl behenate, agar gum, hydroxyethylmethyl cellulose, hypromellose, lactose, atomized dried lactose monohydrate, maltodextrin, acrylate acrylate, acrylate acrylate stearic and hydroxypropylmethylcellulose, and most preferably it is hydroxypropylcellulose.  Advantageously, hydroxypropyl cellulose is in a proportion of 6.1% w / w at 20% w / w, based on the total weight of the extended release composition part.   As used in the present invention the term "dyes" (in the extended release composition) means "the agents used to improve the aesthetic appearance of the pharmaceutical form".  Such compounds include, as an example and without limitation FD&C Red 40, D&C Red 33, D&C Red 36, D&C Red 22, D&C Red 28, D&C Red 3, Iron Oxide - red, FD & C Yellow 6, FD & C Yellow 5, D&C Yellow 10, Iron oxide - yellow, FD & C Blue 1, FD & C 15 Blue 2, FD & C Green 3, Iron oxide - black , Red Lacquer, Titanium Dioxide, etc.  Preferably the dye is a dye from the group consisting of FD&C Red 40, D&C Red 33, D&C Red 36, D&C Red 22, D&C Red 28, D&C Red 3, iron oxide - red, FD&C Yellow 6, FD&C Yellow 5, D&C Yellow 10, iron oxide - yellow, FD&C Blue 1, FD&C Blue 2, FD&C Green 3, iron oxide - black, 20 red lacquer and titanium dioxide, and most preferably it is red lacquer.  Advantageously, the red lacquer is in a proportion of 0.05% w / w at 3% w / w, based on the total weight of the prolonged release composition part.   As used in the present invention the term "lubricants" (in the extended release composition) means "the agents used to reduce friction between the particles and adhere to the surface of the drugs".  Such compounds include, as an example and without being limiting, talc, magnesium stearate, calcium stearate, stearic acid, polyethylene glycol, sodium benzoate, sodium stearate, calcium hydroxide, mineral oil, fatty acids, sodium stearate, glycerol, boric acid, sodium acetate, glyceryl behenate, magnesium or sodium lauryl sulfate, corn starch, etc.  Preferably the lubricant is a lubricant of the group consisting of talc, magnesium stearate, calcium stearate, acid       stearic acid, sodium sterate fumarate, calcium hydroxide, sodium stearate, boric acid, magnesium or sodium lauryl sulfate, and corn starch, and most preferably it is talc, magnesium stearate or a mixture of both.  Advantageously, the lubricant is talc and is in a proportion of 0.6% w / w to 5% w / w, based on the total weight of the prolonged release composition part.  Alternatively, or additionally, the lubricant is advantageously magnesium stearate and is in a proportion of 0.6% w / w to 5% w / w, based on the total weight of the extended release composition part.   It is particularly advantageous that the prolonged release composition portion 10 comprises 25% w / w 75% w / w 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof, 10% w / w or 45% w / w hydroxypropyl methylcellulose , 6.1% w / w 20% w / w hydroxypropylcellulose, 0.05% w / w 3% w / w dye, 0.6% w / w 5% w / w talc and 0.6 % w / w 5% w / w magnesium stearate, said% being referred to the total weight of said part of the prolonged release composition.   The pharmaceutical formulation of the present invention is presented in the form of programmed, sustained or controlled release and is administered in a single dose once a day.   Preferably the composition according to the invention has a proportion between the immediate release composition part and the extended release composition part between 12:88 and 52:48, and most preferably between 24:76 and 40:60 .  These proportions are those that best allow the equilibrium between immediate and prolonged release of 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts or preferably calcium dihydroxybenzenesulfonate.   Preferred dosage forms are those containing between 10 mg and 3500 mg of the 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts or preferably calcium dihydroxybenzenesulfonate, preferably between 40 mg and       2500 mg, preferably between 60 mg and 1800 mg, and more preferably between 400 mg and 2200 mg.  It is particularly advantageous that they have between 400 and 1200 mg.   Manufacturing procedure 5 There are several methodologies for manufacturing a dual-acting tablet of 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts or preferably calcium dihydroxybenzenesulfonate.    A) Wet granulometry method 10 This methodology, with the use of a solvent, allows the obtaining of a granulate comprising the active ingredient, using various equipment that are known by the pharmaceutical industry such as a Mixer, a Fluid Bed Dryer and a sieve.   15 The application of this process has as stages: STAGE A1: Manufacture of the Immediate Release layer 20 A1a) Preparation of a dough, consisting of the mixture of 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable or preferably salts calcium dihydroxybenzenesulfonate, with or without plasticizing agents, retarders, gastro-resistant material, colorants, surfactants or surfactants, glidants, lubricants, binders, diluents, disintegrants and other 25 additives for use known in the pharmaceutical industry and with the use of a solvent which can be distilled water or ethyl alcohol at 95 °.   A1b) Granulation of the mixture.    30 A1c) Drying of the granulate.   A1d) Screening of the granulate.          A1e) Granulate mixing, optionally with or without plasticizing agents, retardants, gastro-resistant material, colorants, surfactants or surfactants, glidants, lubricants, binders, diluents, disintegrants and other additives used in the pharmaceutical industry.  5 A1f) Screening of the granulate.   A1g) Mixing of the granulate, optionally with or without plasticizing agents, retarders, gastro-resistant material, colorants, surfactants or surfactants, 10 glidants, lubricants, binders, diluents, disintegrants and other additives for use known in the pharmaceutical industry.    STAGE A2: Manufacture of the Prolonged Release layer 15 A2a) Preparation of a dough, consisting of the mixture of 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts or preferably calcium dihydroxybenzenesulfonate, with or without plasticizing agents, retardants, gastro-resistant material, colorants, surfactants or surfactants, glidants, lubricants, binders, diluents, disintegrants and other 20 additives of known use in the pharmaceutical industry and with the use of a solvent that can be distilled water or ethyl alcohol of 95 ° .   A2b) Granulation of the mixture.   25 A2c) Drying the granulate.   A2d) Screening of the granulate.   A2e) Mixing of the granulate, optionally with or without plasticizing agents, retarders, gastro-resistant material, colorants, surfactants or surfactants, glidants, lubricants, binders, diluents, disintegrants and other additives used in the pharmaceutical industry.          A2f) Screening of the granulate.   A2g) Mixing of the granulate, optionally with or without plasticizing agents, retardants, gastro-resistant material, colorants, surfactants or surfactants, glidants, lubricants, binders, diluents, disintegrants and other additives used in the pharmaceutical industry.    STAGE A3: Pressing a tablet 10 A bilayer tablet is pressed, which has a layer of the product obtained in A1g) and a layer of the product obtained in A2g).    B) Dry mixture method 15 A second method of manufacturing a dual-acting tablet of 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts or preferably calcium dihydroxybenzenesulfonate consists in the realization of a dry mixture, this It allows the obtaining of a granulate comprising the active ingredient, using several equipment that are well known in the pharmaceutical industry such as a mixer and a sieve.   The application of this process has as stages: STEP B1: Manufacturing of the Immediate Release layer 25 B1a) Preparation of a dry mass, consisting of the mixture of 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts or preferably calcium dihydroxybenzenesulfonate, with or without plasticizers, retardants, gastro-resistant material, colorants, surfactants or surfactants, glidants, lubricants, binders, diluents, disintegrants and other additives used in the pharmaceutical industry.          B1b) Screening of the granulate.    STAGE B2: Manufacture of the Prolonged Release Layer B2a) Preparation of a dry mass, consisting of the mixture of 2.5-5 dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts or preferably calcium dihydroxybenzenesulfonate, with or without plasticizers, retardants, gastro-resistant material, colorants, surfactants or surfactants, glidants, lubricants, binders, diluents, disintegrants and other additives for use known in the pharmaceutical industry.  10 B2b) Screening of the granulate.    STEP B3: Pressing a tablet 15 A bilayer tablet is pressed, which has a layer of the product obtained in B1b) and a layer of the product obtained in B2b).    C) Combined method 20 A third method of manufacturing a dual-acting tablet of 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts or preferably calcium dihydroxybenzenesulfonate consists in the production of a dry mixture for the layer of Immediate release and use the wet granulation method, for the prolonged release layer, which allows obtaining a granulate comprising the active ingredient, using various equipment that are known to the pharmaceutical industry such as a Mixer and a Sifter.    The application of this process has as stages: 30 STAGE C1: Manufacturing of the Immediate Release layer       C1a) Sift and prepare a dry mass, consisting of the mixture of 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts or preferably calcium dihydroxybenzenesulfonate, with or without plasticizers, retardants, colorants, surfactants or surfactants, glidants, lubricants, binders, diluents, disintegrants and other additives of known use in the pharmaceutical industry.   STAGE C2: Manufacture of the Prolonged Release C2a) Micronize layer, 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts or preferably calcium dihydroxybenzenesulfonate.    C2b) Preparation of a dry mass, consisting of the mixture of 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts or preferably calcium dihydroxybenzenesulfonate, with or without plasticizing agents, retarders, gastro-resistant material, colorants, surfactants or surfactants, glidants, lubricants, binders, diluents, disintegrants and other additives of known use in the pharmaceutical industry and with the use of a solvent that can be distilled water or 95 ° ethyl alcohol.  20 C2c) Granulation of the mixture.    C2d) Drying of the granulate.   25 C2e) Screening of the granulate.   C2f) Granulate mixing, optionally with or without plasticizing, retarding, gastro-resistant agents, colorants, surfactants or surfactants, glidants, lubricants, binders, diluents, disintegrants and other additives of known use in the pharmaceutical industry.    STAGE C3: Pressing a tablet        A bilayer tablet is pressed, which has a layer of the product obtained in C1a) and a layer of the product obtained in C2f).    The best method for the preparation of this novel medicine is from the use of the dry granulation method for immediate release and the moisture granulation method for prolonged release.    EXAMPLES 10 The following examples of manufacturing processes, of the pharmaceutical composition of the present invention, are provided for the purpose of better illustrating said invention, and they should not be considered as limiting the invention whose scope is set out in the claims.   15 STAGE 1: Manufacture of the Immediate Release layer a) Sift through a # 20 mesh, 55.5% w / w 85% w / w calcium dobesilate, 8% w / w 28% w / w Microcrystalline Cellulose and 1% w / w 6% w / w Sodium Starch Glycolate.  All ranges are referred to the total weight of the Immediate Release Stage 20.     b) Mix the obtained in a), between a time range of 1 min to 30 min.    c) Sift through a # 30 mesh, 0.6% w / w at 5% w / w Magnesium Stearate and 0.6% 25 w / w at 5.5% w / w Talc.  All ranges are referred to the total weight of the Immediate Release Stage.   d) Mix the obtained in b) and c), between a time range of 1 min to 15 min.   30 STAGE 2: Manufacturing of the Extended Release layer       a) Micronize, 25% w / w to 75% w / w calcium dobesilate.  All ranges are referred to the total weight of the Prolonged Release Stage.   b) Dissolve, 0.1% w / w to 5% w / w Hydroxypropylcellulose in a sufficient amount of Purified Water.  All ranges are referred to the total weight of the Stage 5 Prolonged Release.   c) Mix the obtained in a), with 10% w / w 45% w / w Hydroxypropylmethylcellulose, 6% w / w 15% w / w Hydroxypropylcellulose and 0.05% w / w 3% w / w Lacquer Red, between a time range of 1 min to 15 min.  All ranges are referred to total weight 10 of the Prolonged Release Stage.   d) Granulate the obtained in c) with the solution obtained in b).   e) Dry the obtained in d), between a temperature range of 45 ºC to 70 ºC and a time range of 10 min to 60 min.   f) Sift through a 062R mesh the obtained in e).   g) Sift through a # 30 mesh, 0.6% w / w at 5% w / w talc and 0.6% w / w at 5% w / w of 20 Magnesium Stearate.  All ranges are referred to the total weight of the Prolonged Release Stage.   h) Mix the obtained in f) and g), between a time range of 1 min to 15 min.   25 EXAMPLE 1 Next, the pharmaceutical release preparation process will be divided into two stages.   30 STAGE 1: Manufacture of the Immediate Release layer       a) Sift through a # 20 mesh, 74.07% w / w calcium dobesilate, 20.74% w / w Microcrystalline Cellulose and 2.07% w / w Sodium Starch Glycolate.  All ranges are referred to the total weight of the Immediate Release Stage.   b) Mix the obtained in a), between a time range of 1 min to 30 min.   5 c) Sift through a # 30 mesh, 1.33% w / w Magnesium Stearate and 1.78% w / w Talc.  All ranges are referred to the total weight of the Immediate Release Stage.   10 d) Mix the obtained in b) and c), between a time range of 1 min to 15 min.   Materials Weight [%] Calcium Dobesilate 74.07 Microcrystalline Cellulose 20.74 Sodium Starch Glycolate 2.07 Magnesium Stearate 1.33 Talc 1.79 STAGE 2: Manufacture of the Prolonged Release Layer 15 a) Micronize 53.76 % w / w calcium dobesilate.  All ranges are referred to the total weight of the Prolonged Release Stage.   b) Dissolve 0.81% w / w Hydroxypropylcellulose and a sufficient amount of Purified Water.  All ranges are referred to the total weight of the Prolonged Release Stage.   c) Mix the obtained in a) with 32.15% w / w Hydroxypropyl methylcellulose, 9.68% w / w Hydroxypropylcellulose and 0.12% w / w Red Lacquer, between a time range of 1 min 25 a 15 min.  All ranges are referred to the total weight of the Prolonged Release Stage.          d) Granulate the obtained in c) with the solution obtained in b).   e) Dry the obtained in d), between a temperature range of 45 ºC to 70 ºC and a time range of 10 min to 60 min.  5 f) Sift through a 062R mesh the obtained in e).   g) Sift through a # 30 mesh, 1.97% w / w talc and 1.51% w / w Magnesium Stearate.  All ranges are referred to the total weight of the Prolonged Release Stage 10.   h) Mix the obtained in f) and g), between a time range of 1 min to 15 min.   Materials Weight [%] Calcium Dobesilate 53.76 Hydroxypropylmethylcellulose 32.15 Hydroxypropylcellulose 10.49 Red Lacquer 0.12 Talc 1.97 Magnesium Stearate 1.51 Purified water * c. s.  * It evaporates during the process 15 Both phases are compressed in an elongated punch.   An example of a bilayer tablet is shown in Figure 1 in which the immediate release layer 1 is represented in a gray color, while the prolonged release layer 20 is represented in a white color.  Figures 2A, 2B and 3A, 3B schematically show the dual action of the tablets according to the invention, where, in the first place, the immediate release layer 1 (Figures 2A and 2B) is dissolved and, subsequently, the delayed release layer 2 (Figures 3A and 3B).   25        The release profile of the bilayer tablet of example 1 is shown in Figure 4.   For examples 2, 3 and 4 the previous technique already mentioned in example 1 is used.   5 EXAMPLE 2 STAGE 1: Manufacture of the Immediate Release layer Materials Weight [%] Calcium Dobesilate 76.45 Microcrystalline Cellulose 18.84 Sodium Starch Glycolate 1.88 Magnesium Sterate 1.21 Talc 1.62 10 STAGE 2: Manufacturing of the Prolonged Release Layer Materials Weight [%] Calcium Dobesilate 55.22 Hydroxypropylmethylcellulose 31.14 Hydroxypropylcellulose 10.15 Red Lacquer 0.12 Talc 1.91 Magnesium Stearate 1.46 Purified water * c. s.  * It evaporates during the process 15 Both phases are compressed in an elongated punch.   EXAMPLE 3       STAGE 1: Manufacturing of the Immediate Release layer Materials Weight [%] Calcium Dobesilate 78.13 Microcrystalline Cellulose 17.5 Sodium Starch Glycolate 1.75 Magnesium Stearate 1.12 Talc 1.5 STAGE 2: Layer Manufacturing Prolonged Release 5 Materials Weight [%] Calcium Dobesilate 56.37 Hydroxypropylmethylcellulose 30.34 Hydroxypropylcellulose 9.89 Red Lacquer 0.12 Talc 1.86 Magnesium Stearate 1.42 Purified water * c. s.  * It evaporates during the process Both phases are compressed in an elongated punch.   10 Figure 5 shows the release profile of the bilayer tablet.          EXAMPLE 4 STAGE 1: Manufacturing of the Immediate Release layer Materials Weight [%] Calcium Dobesilate 72.82 Microcrystalline Cellulose 21.75 Sodium Starch Glycolate 2.17 Magnesium Stearate 1.4 Talc 1.86 5 STAGE 2: Manufacturing of the Prolonged Release layer Materials Weight [%] Calcium Dobesilate 54.78 Hydroxypropylmethylcellulose 31.45 Hydroxypropylcellulose 10.25 Red Lacquer 0.12 Talc 1.93 Magnesium Stearate 1.47 Purified water * c. s.  * It evaporates during the process Both phases are compressed in an elongated punch.  10       EXAMPLE 5 STAGE 1: Manufacture of the Immediate Release layer Materials Weight [%] Calcium Dobesilate 79.5 Microcrystalline Cellulose 12.75 Sodium Starch Glycolate 4 Magnesium Stearate 1.75 Talc 2 5 STAGE 2: Manufacture of the layer Prolonged Release Materials Weight [%] Calcium Dobesilate 58.4 Hydroxypropylmethylcellulose 28.35 Hydroxypropylcellulose 8.75 Red Lacquer 0.1 Talc 2.1 Magnesium Stearate 2.3 Purified water * c. s.  * It evaporates during the process 10 Both phases are compressed in an elongated punch.   Figure 6 shows the release profile of the bilayer tablet.   fifteen       EXAMPLE 6 STAGE 1: Manufacturing of the Immediate Release layer Materials Weight [%] Calcium Dobesilate 72.3 Microcrystalline Cellulose 20.45 Sodium Starch Glycolate 3.75 Magnesium Stearate 1.6 Talc 1.9 5 STAGE 2: Manufacturing of the Prolonged Release layer Materials Weight [%] Calcium Dobesilate 51.18 Hydroxypropylmethylcellulose 33.46 Hydroxypropylcellulose 11.08 Red Lacquer 0.08 Talc 2.2 Magnesium Stearate 2 Purified water * c. s.  * It evaporates during the process 10 Both phases are compressed in an elongated punch.   Figure 7 shows the release profile of the bilayer tablet.    To evaluate the dissolution profile of the pharmaceutical composition in the form of a tablet 15 of the present invention, a type II dissolution apparatus (Pallets) was used, using a buffer solution at pH 5.5 as the dissolution medium.           The experiment was carried out in sextuplicate at a temperature of 37 ° C, 60 rpm and a volume of 1. 000 ml of a buffer solution at pH 5.5.  Samples were taken at different time intervals with medium replacement and the amount of calcium dobesilate was determined, dissolved by a UV-Vis spectrophotometer at 308 nm wavelength.  5 It can be concluded that the present pharmaceutical formulation shows a dual action profile in pH 5.5 buffer solution.   The first phase is immediate release, lasts approximately 1 hour, 10 during that time between 20% and 70% of the total calcium dobesilate corresponding to this stage is released.   For the second phase which is prolonged release, the corresponding total release time between 35% and 100% of the total calcium dobesilate corresponding to this stage is 24 hours.   The combination of both stages promotes that the total in vivo release of the active substance be prolonged over 24 hours.   20 Pharmacokinetic Data Plasma levels for the pharmaceutical formulation of dual-release calcium dobesilate were obtained through a clinical study of 14 volunteers in good health of both sexes, with an age range between 21 and 25 54 years, whose Average data are shown in Table No. 1.  Where pharmacokinetic variables such as: Maximum Concentration (Cmax), Area Under the Curve (ABC) and Maximum Time (Tmax) are reflected.           Table Nº 1: Pharmacokinetic Variables Pharmacokinetic Variables Calcium Dobesilate Dual Release c / 24 h Calcium Dobesilate Immediate Release c / 12h P LN transformed Cmax 10. 15 +/- 1. 94 μ / mL8. 96 +/- 1. 88 μ / mL 0. 09 ABC 0-24 92. 84 +/- 15. 96 μ / mL / h 88. 74 +/- 12. 86μ / mL / h 0. 26 ABC 0-∞ 96. 57 +/- 16. 28μ / mL / h 93. 35 +/- 15. 28μ / mL / h 0. 33 Tmax 4. 79 +/- 0. 2 h 4. 68 +/- +/- 0. 36 0. 8 It can be seen in Table Nº 1, that there are no statistically significant differences between the two formulations in any of the parameters evaluated in the 24 hours (therapeutic interval).   5 Table Nº 2: Relationship of the arithmetic means and their 95% confidence intervals Average 95% CI minimum 95% CI maximum Cmax 105. 81% 103. 67% 107. 93% ABC 0-24 100. 47% 104. 61% 108. 75% ABC 0-∞ 105. 81% 103. 67% 107. 93% It can be seen in Table Nº 2, that the relationships between the averages of both 10 products and their 95% confidence intervals remain within the accepted limits for similar products (80% -125%).  No significant adverse effects related to medication were reported.   In the data reflected in Tables Nº 1 and 2, it was found that dobesilate 15 L. P supplied in a daily dose of 1000 mg is absorbed at the same rate       measured by Cmax and in an amount measured by similar ABCs, so we must expect similar therapeutic effects.   Surprisingly, the authors of the present invention have found the need to innovate with a new pharmaceutical formulation for dual release of calcium dobesilate.  This new formulation guarantees the optimal therapeutic effects of calcium dobesilate in the first minutes, after the intake of the formulation.      
    权利要求:
    Claims (1)
    [1]
    CLAIMS 1 - Pharmaceutical composition comprising 2,5-dihydroxybenzenesulfonic acid or one of its pharmaceutically acceptable salts in the form of individualized delivery units, characterized in that a part of said 2,5-5-dihydroxybenzenesulfonic acid or one of its pharmaceutically acceptable salts is in the form of an immediate release composition and another part of said 2,5-dihydroxybenzenesulfonic acid or one of its pharmaceutically acceptable salts is in the form of a prolonged release composition. 10 2 - Composition according to claim 1, characterized in that it is for use in the treatment of primary varicose states, chronic venous insufficiency, phlebitis, thrombophlebitis, post-thrombotic syndrome, leg ulcers, varicose veins of pregnancy, adjuvant to varicectomy , sclerotherapy or adjuvant in the treatment of diabetic retinopathy. 3 - Composition according to one of claims 1 or 2, characterized in that said primary varicose states are pain, heavy legs, night cramps or paresthesia. 4 - Composition according to any of claims 1 to 3, characterized in that an individualized unit of supply is administered only once every 24 hours. 5 - Composition according to any of claims 1 to 3, characterized in that two individualized units of supply are administered simultaneously once every 24 hours. 6 - Composition according to any of claims 1 to 5, characterized in that each individualized supply unit has a content of 2,5-dihydroxybenzenesulfonic acid or one of its pharmaceutically acceptable salts of between 30-50 mg and 2,500 mg in its release form immediate and between 50 mg and 2,500 mg in its prolonged release form, preferably each individualized delivery unit has a content of 2,5-dihydroxybenzenesulfonic acid or one of its pharmaceutically acceptable salts of between 100 mg and 2,000 mg in their immediate release form and between 100 mg and 2,000 mg in their prolonged release form, and most preferably each individualized delivery unit has a content of 2,5-dihydroxybenzenesulfonic acid or one of its pharmaceutically acceptable salts of between 150 mg and 1,000 mg in its immediate release form and between 150 mg and 1,000 mg in its prolonged release form. 7 - Composition according to any of claims 1 to 6, characterized in that each individualized unit comprises between 400 mg to 2200 mg, of 2,5-dihydroxybenzenesulfonic acid or one of its pharmaceutically acceptable salts. 8 - Composition according to any of claims 1 to 7, characterized in that said pharmaceutically acceptable salt is calcium dobesilate. 9 - Composition according to any of claims 1 to 8, characterized in that said individualized supply units are tablets, capsules or sachets, preferably they are tablets or sachets. 10 - Composition according to claim 9, characterized in that said individualized units are tablets, and said tablets are bilayer tablets, where one layer 20 comprises said immediate release composition and the other layer comprises said prolonged release composition. 11 - Composition according to any of claims 1 to 10, characterized in that the immediate release composition part additionally comprises at least one excipient from the group of excipients consisting of solubilizers, disintegrants, plasticizers, retardants, gastro-resistant material, colorants , surfactants or surfactants, glidants, lubricants, diluents and binders. 12 - Composition according to claim 11, characterized in that said diluent is a diluent from the group consisting of dicalcium phosphate, lactose, cellulose, microcrystalline cellulose, dicalcium phosphate dihydrate, lactose monohydrate, starch pregelatinized, hydroxy-propyl-methyl-cellulose, cellulose, calcium carbonate, polyvinylpyrrolidone, alumina, talc and lactose 80. 13 - Composition according to claim 12, characterized in that said diluent is microcrystalline cellulose. 14 - Composition according to claim 13, characterized in that said microcrystalline cellulose is in a proportion of 8% w / w to 28% w / w, with respect to the total weight of the immediate release composition part. 10 15 - Composition according to claim 11, characterized in that said disintegrant is a disintegrant from the group consisting of starch, cellulose, corn starch, croscarmellose, croscarmellose sodium, crospovidone, sodium starch glycolate, microcrystalline cellulose, pregelatinized starch, alginate sodium, gum agar, carboxymethylcellulose, and sodium lauryl sulfate. 15 16 - Composition according to claim 15 characterized in that said disintegrant is sodium starch glycolate. 17 - Composition according to claim 16, characterized in that said sodium starch glycolate is in a proportion of 1% w / w to 6% w / w, with respect to the total weight of the immediate release composition part. 18 - Composition according to claim 11, characterized in that said lubricant is a lubricant from the group consisting of talc, magnesium stearate, calcium stearate, stearic acid, sodium sterate fumarate and magnesium or sodium lauryl sulfate. 19 - Composition according to claim 18, characterized in that said lubricant is magnesium stearate, talc or a mixture of both. 30 20 - Composition according to claim 19, characterized in that said lubricant is magnesium stearate and the magnesium stearate is in a proportion of 0.6% w / w to 5% w / w, relative to the total weight of the immediate release composition part. 21 - Composition according to one of claims 19 or 20, characterized in that said lubricant is talc and the talc is in a proportion of 0.6% w / w to 5.5% w / w, with respect to the total weight of the immediate release composition part. 22 - Composition according to any of claims 1 to 21, characterized in that said part of the prolonged release composition additionally comprises at least one excipient from the group of excipients consisting of solubilizers, 10 disintegrants, plasticizers, retardants, gastro-resistant material, colorants , surfactants or surfactants, glidants, lubricants, diluents and binders. 23 - Composition according to claim 22, characterized in that said retardant is a retardant from the group formed by ethyl cellulose, agar gum, hydroxypropyl cellulose, methylcellulose, povidone, xanthan gum, hypromellose, hypromellose phthalate, sodium alginate, hydroxyethylcellulose, hydroxypropylmethyl and ammonium methacrylate copolymer. 24 - Composition according to claim 23, characterized in that said retardant 20 is hydroxypropylmethylcellulose. 25 - Composition according to claim 24, characterized in that said hydroxypropylmethylcellulose is in a proportion of 10% w / w to 45% w / w, with respect to the total weight of the part of the prolonged release composition. 25 26 - Composition according to claim 22, characterized in that said binder is a binder from the group consisting of starch, lactose, gum arabic, sodium alginate, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, polyethylene glycol, ethylcellulose, water, alcohol, celluloselatinized starches, microcrystalline, 30 microcrystalline dextrose, polyvinylpyrrolidone, cellulose, hydroxyethylcellulose, hydroxypropylcellulose, alginic acid, sodium carboxymethylcellulose, cellulose acetate phthalate, dextrin, glyceryl behenate, agar gum, hydroxyethylmethyl cellulose, hypromellose, lactose, spray-dried lactose monohydrate, maltodextrin, maltose, methacrylic acid, povidone, stearic acid, and hydroxypropylmethylcellulose. 27 - Composition according to claim 26, characterized in that said binder is hydroxypropylcellulose. 28 - Composition according to claim 27, characterized in that said hydroxypropylcellulose is in a proportion of 6.1% w / w to 20% w / w, with respect to the total weight of the part of the prolonged release composition. 29 - Composition according to claim 22, characterized in that said dye is a dye from the group formed by FD & C Red 40, D & C Red 33, D & C Red 36, D & C Red 22, D & C Red 28 , D&C Red 3, Iron Oxide - Red, FD&C Yellow 6, FD&C Yellow 5, D&C Yellow 10, Iron Oxide - Yellow, FD&C Blue 1, FD&C Blue 2, FD & C Green 3, iron oxide - black, red lacquer and titanium dioxide. 15 30 - Composition according to claim 29, characterized in that said colorant is red lacquer. 31 - Composition according to claim 30, characterized in that said red lacquer is in a proportion of 0.05% w / w to 3% w / w, with respect to the total weight of the part of the prolonged release composition. 32 - Composition according to claim 22, characterized in that said lubricant is a lubricant from the group consisting of talc, magnesium stearate, calcium stearate, stearic acid, sodium stearate fumarate, calcium hydroxide, sodium stearate, boric acid, magnesium or sodium lauryl sulfate, and corn starch. 33 - Composition according to claim 32, characterized in that said lubricant is talc, magnesium stearate or a mixture of both. 30 34 - Composition according to claim 33, characterized in that said lubricant is talc and is in a proportion of 0.6% w / w to 5% w / w, with respect to the total weight of the part of the prolonged release composition. 35 - Composition according to one of claims 33 or 34, characterized in that said lubricant is magnesium stearate and is in a proportion of 0.6% w / p to 5% w / w, with respect to the total weight of the part of extended release composition. 36 - Composition according to any of claims 1 to 35, characterized in that said part of the immediate release composition comprises 55.5% w / w to 85% w / w of 2,5-dihydroxybenzenesulfonic acid or one of its pharmaceutically acceptable salts , 8% w / w, 28% w / w microcrystalline cellulose, 1% w / w, 6% w / w sodium starch glycolate, 0.6% w / w, 5% w / w magnesium stearate and 0, 6% w / w to 5.5% w / w talc, said% being referred to the total weight of the part of immediate release composition. 37 - Composition according to any of claims 1 to 36, characterized in that said part of the prolonged release composition comprises 25% w / w to 75% w / w of 2,5-dihydroxybenzenesulfonic acid or one of its pharmaceutically acceptable salts, 10 % w / w 45% w / w of hydroxypropylmethylcellulose, 6.1% w / w, 20% w / w of hydroxypropylcellulose, 0.05% w / w, 3% w / w of a dye, 0.6% w / w 5% w / w talc and 0.6% w / w to 5% w / w magnesium stearate, said% being referred to the total weight of said part of the prolonged release composition. 38 - Composition according to any of claims 1 to 37, characterized in that it has a ratio between said part of immediate release composition and said part of prolonged release composition comprised between 12:88 and 52:48. 39 - Composition according to claim 38, characterized in that it has a ratio between said part of immediate release composition and said part of prolonged release composition comprised between 24:76 and 40:60. 40 - Process for manufacturing a pharmaceutical composition according to any of claims 1 to 39, characterized in that it comprises the following steps: [a] manufacturing said part of immediate release composition, 5 [b] manufacturing said part of prolonged release composition , and [c] manufacturing individualized delivery units comprising both immediate release composition and extended release composition. 41 - Method according to claim 40, characterized in that in said step [c] tablets are manufactured. 42 - Process according to one of claims 40 or 41, characterized in that in said step [a] said immediate release composition is manufactured by dry means and in said step [b] said part of the prolonged release composition is manufactured by damp. 43 - Process according to any of claims 40 to 42, characterized in that in said step [a] 55.5% w / w to 85% w / w of 2,5-20 dihydroxybenzenesulfonic acid or one of its pharmaceutically acceptable salts is used , 8% w / w, 28% w / w microcrystalline cellulose, 1% w / w, 6% w / w sodium starch glycolate, 0.6% w / w, 5% w / w magnesium stearate and 0, 6% w / w to 5.5% w / w talc, said% being referred to the total weight of the immediate release composition part. 44 - Process according to any of claims 40 to 43, characterized in that in said step [b] 25% w / w to 75% w / w of 2,5-dihydroxybenzenesulfonic acid or one of its pharmaceutically acceptable salts is used, 10 % w / w 45% w / w of hydroxypropylmethylcellulose, 6.1% w / w, 20% w / w of hydroxypropylcellulose, 30 0.05% w / w, 3% w / w of a dye, 0.6% w / p to 5% w / w talc and 0.6% w / w to 5% w / w magnesium stearate, said% being referred to the total weight of said part of the prolonged release composition.45 - Method according to any of claims 40 to 44, characterized in that in said step [c] the ratio between said immediate release composition and said prolonged release composition is between 12:88 and 52:48. 46 - Method according to claim 45, characterized in that in said step [c] the ratio between said immediate release composition and said prolonged release composition is between 24:76 and 40:60. 47 - Method according to any of claims 40 to 46, characterized in that said individualized delivery units are bilayer tablets, where one layer comprises said immediate release composition and the other layer comprises said prolonged release composition. 48 - Process according to any of claims 40 to 47, characterized in that said step [a] comprises: [a.1] sieving through a # 20 mesh, 55.5% w / w to 85% w / w of acid 2 , 5-dihydroxybenzenesulfonic acid or one of its pharmaceutically acceptable salts, 8% w / w 20 to 28% w / w of microcrystalline cellulose and 1% w / w to 6% w / w of sodium starch glycolate, said% being referred to by weight total of the immediate release composition part, [a.2] mix the obtained in [a.1], between a time range of 1 min to 30 min, 25 [a.3] sieve through a # 30 mesh, 0.6% w / w to 5% w / w of magnesium stearate and 0.6% w / w to 5.5% w / w of talc, said% being referred to the total weight of the immediate release composition part, 30 [a.4] mix the obtained in [a.2] and [a.3], between a time range of 1 min to 15 min, and said step [b] comprises: [b.1] micronizing, 25% w / pa 75% w / w of 2,5-dihydroxybenzenesulfonic acid or one of its pharmaceutically acceptable salts, said% being referred to the total weight of said part of prolonged release composition, 5 [b.2] dissolve 0.1% w / p to 5% w / w of hydroxypropylcellulose in a sufficient quantity of purified water, said% being referred to the total weight of said part of the release composition prolonged, 10 [b.3] mix the obtained in [b.1], with 10% w / w to 45% w / w of hydroxypropylmethylcellulose, 6% w / w to 15% w / w of hydroxypropylcellulose and 0.05% w / pa 3% w / w of red lacquer, between a time range of 1 min to 15 min, said% being referred to the total weight of said part of the prolonged release composition, 15 [b.4] granulate the obtained in [ b.3] with the solution obtained in [b.2], [b.5] dry the obtained in [b.4], between a temperature range of 45 ºC to 70 ºC and a time range of 10 min to 60 min, 20 [b.6] sieve by a 062R mesh obtained in [b.5], [b.7] sieve through a # 30 mesh, 0.6% w / w to 5% w / w talc and 0.6% w / w to 5% w / p of magnesium stearate, said% being referred to the total weight of said part of the prolonged release composition, 25 [b.8] mix the obtained in [b.6] and [b.7], within a time range of 1 min to 15 min.
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    同族专利:
    公开号 | 公开日
    WO2018154161A1|2018-08-30|
    BR112019016778A2|2020-03-31|
    CN110290784A|2019-09-27|
    ES2680293B1|2019-08-22|
    PE20191465A1|2019-10-16|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US20070010581A1|2002-11-29|2007-01-11|Jose Esteve-Soler|Use of 2,5-dihydroxybenzenesulfonic compounds for the treatment of disorders based on an impairment of no production and/or of regulation of edhf function|
    CN1939291A|2006-09-29|2007-04-04|何岩|Hydroxyphenyl sulfonated calcium slow-releasing preparation|
    CN103169679A|2011-12-26|2013-06-26|上海复星医药产业发展有限公司|Calcium dobesilate medical composition with high drug loading capacity|
    CN103271895A|2012-03-14|2013-09-04|南京先宇科技有限公司|Stable calcium dobesilate containing pharmaceutical composition and preparation method thereof|
    WO2016092560A2|2014-12-09|2016-06-16|Eris Lifesciences Pvt Ltd.|Dual release bilayer tablets comprising metformin|
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    ES201730225A|ES2680293B1|2017-02-22|2017-02-22|Pharmaceutical composition comprising 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof in the form of individualized delivery units and corresponding manufacturing process|ES201730225A| ES2680293B1|2017-02-22|2017-02-22|Pharmaceutical composition comprising 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof in the form of individualized delivery units and corresponding manufacturing process|
    BR112019016778-1A| BR112019016778A2|2017-02-22|2018-02-20|PHARMACEUTICAL COMPOSITION UNDERSTANDING 2,5- DIHYDROBENZENOSULPHONIC ACID OR ONE OF ITS ACCEPTABLE PHARMACEUTICAL SALTS IN THE FORM OF INDIVIDUALIZED SUPPLY UNITS AND THEIR MANUFACTURING METHOD|
    PE2019001494A| PE20191465A1|2017-02-22|2018-02-20|PHARMACEUTICAL COMPOSITION INCLUDING 2,5-DIHYDROXYBENZENOSULPHONIC ACID OR ONE OF ITS PHARMACEUTICALLY ACCEPTABLE SALTS IN THE FORM OF INDIVIDUALIZED SUPPLY UNITS AND RELATED MANUFACTURING PROCEDURES|
    PCT/ES2018/070123| WO2018154161A1|2017-02-22|2018-02-20|Pharmaceutical composition comprising 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof in the form of personalised supply units and the corresponding manufacturing method|
    CN201880010868.6A| CN110290784A|2017-02-22|2018-02-20|In the pharmaceutical composition and corresponding manufacturing method comprising 2,5- dihydroxy benzenes sulfonic acid or its pharmaceutically acceptable salt of personalized supply unit form|
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