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WO2018154161A1 - 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 - Google Patents

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 Download PDF

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Publication number
WO2018154161A1
WO2018154161A1 PCT/ES2018/070123 ES2018070123W WO2018154161A1 WO 2018154161 A1 WO2018154161 A1 WO 2018154161A1 ES 2018070123 W ES2018070123 W ES 2018070123W WO 2018154161 A1 WO2018154161 A1 WO 2018154161A1
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WIPO (PCT)
Prior art keywords
composition
composition according
pharmaceutically acceptable
total weight
immediate release
Prior art date
Application number
PCT/ES2018/070123
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Spanish (es)
French (fr)
Inventor
Alfredo José INATTI MARTINEZ
Original Assignee
Belac Invest, S.L.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Belac Invest, S.L. filed Critical Belac Invest, S.L.
Priority to CN201880010868.6A priority Critical patent/CN110290784A/en
Priority to BR112019016778-1A priority patent/BR112019016778B1/en
Priority to PE2019001494A priority patent/PE20191465A1/en
Publication of WO2018154161A1 publication Critical patent/WO2018154161A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Definitions

  • the present invention relates to an orally administered pharmaceutical composition of programmed action for dual, immediate and prolonged release, comprising 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts, for fibrinogen reduction in human blood, as well as for the prophylaxis and treatment of diseases caused by elevated fibrinogen levels.
  • a part of 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof is in the form of an immediate release composition and another part of 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof is in the form of a prolonged release composition.
  • the invention also relates to a method of manufacturing a composition according to the invention.
  • This principle has an elective action on the capillary wall, whose physiological properties of resistance and permeability are regularized by the preparation.
  • calcium dobesilate acts by increasing venous, venular tone 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.
  • 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 combination with a kinetic energy appropriate for its thermal environment or move in combination with extracellular or cellular constituents, sometimes in connection with energy producing processes that allow the molecule or complex to overcome barriers against Simple diffusion
  • compositions 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.
  • 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 long-term programmed action.
  • a pharmaceutical formulation in individualized units (i.e. 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, through a dual action (immediate and prolonged), its properties for the reduction of fibrinogen in blood, instantaneously, prolonging said effects at plasma levels over 24 hours.
  • the pharmaceutical composition comprising 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof in the form of individual delivery units, wherein a part of the 2,5-dihydroxybenzenesulfonic acid or one of its pharmaceutically acceptable salts is in the form of a composition.
  • Immediate release and another part of 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof is in the form of a prolonged release composition, it is characterized in that the immediate release composition part further comprises between 8% w / w 28% w / w, with respect to the total weight of the immediate release composition part, of microcrystalline cellulose, the extended release composition part further comprises between 10% w / w and 45% w / w, relative to the total weight of the prolonged release composition part of hydroxypropyl methylcellulose, and between 6.1% p / pa 20% w / w, with respect to the total weight of the extended release composition part of hydroxypropyl cellulose, and why it has a proportion between the immediate release composition part and the extended release composition part comprised between 24: 76 and 40:60.
  • novel galenic formulation of programmed release 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 release prolonged, dual-release tablets or extended-release tablets, acts effectively on the indication for the treatment of reduction of human blood fibrinogen, as well as for the prophylaxis and treatment of diseases caused by high levels of fibrinogen and related diseases.
  • pharmaceutically acceptable salts preferably calcium dihydroxybenzenesulfonate
  • hydroxypropylmethylcellulose as a retarding agent is based on in vitro tests carried out with the different materials, in which it was demonstrated that it has a better capacity to delay the release of the active substance, guaranteeing an ideal zero order reaction for the new formulation. In the tests carried out with the other retarding agents, it was not possible to obtain the ideal dissolution profile that would guarantee the action for 24 hours. Additionally, the proportion between the immediate release composition part and the extended release composition part between 24:76 and 40:60 allows to obtain the most suitable dissolution profile to guarantee the required absorption and obtain the required plasma concentrations for 24 hours. These proportions are the ones that best allow a balance between immediate and prolonged release of 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts. Other proportions do not allow to obtain a dissolution profile of 24 hours.
  • the object of the invention is also the use of a pharmaceutical composition according to the invention for the manufacture of a medicament.
  • the medicament is for the treatment of human fibrinogen reduction in 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, night cramps, paraesthesia), chronic venous insufficiency, phlebitis, thrombophlebitis, post-thrombotic syndrome, leg ulcers, varicose veins of pregnancy, adjuvant varicectomy, sclerotherapy, adjuvant in treatment of diabetic retinopathy (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, his
  • 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.
  • primary varicose states are pains, heaviness of legs, night cramps or paraesthesia.
  • 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.
  • the composition according to the invention is preferably administered only once every 24 hours.
  • the individual delivery units are tablets, capsules or sachets, and most preferably are tablets or sachets.
  • the tablets are bilayer tablets, wherein one layer comprises said immediate release composition and the other layer comprises said prolonged release composition.
  • step [a] manufacture the immediate release composition part dry, using 55.5% w / w 85% w / w 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof and 8% w / w 28% w / w microcrystalline cellulose, the% being referred to the total weight of the immediate release composition part
  • step [b] manufacture the wet-release prolonged composition part, using 25% w / w 75% w / w 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof, 10% w / w 45% w / p of hydroxypropylmethylcellulose and 6.1% w / w 20% w / w of hydroxypropylcellulose, the% being referred to the total weight of said part of the extended release composition
  • step [b] includes a step [b.1] of micronization of 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof, and
  • step [b.1] the micronization process of the raw material used guarantees the appropriate release and reproducibility required batch by batch. With larger particle sizes, reproducibility problems are obtained in the dissolution profiles obtained.
  • step [c] tablets are manufactured (which will thus be dual-release) and very preferably bilayer tablets are manufactured.
  • step [a] in addition, 1% w / w 6% w / w sodium starch glycolate, 0.6% w / w 5% w / w magnesium stearate and 0.6% w are used / pa 5.5% w / w talc, said% being referred to the total weight of the immediate release composition part.
  • step [b] additionally, 0.05% w / w and 3% w / w of a dye, 0.6% w / w 5% w / w talc and 0.6% w / w are used 5% w / w magnesium stearate, said% being referred to the total weight of the prolonged release composition part.
  • the individualized delivery units are bilayer tablets, wherein one layer comprises said immediate release composition and the other layer comprises said prolonged release composition.
  • step [a] comprises: [a.1] sieving through a # 20 mesh, 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof , 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,
  • stage [b] includes, after step [b.1], :
  • [b.2] dissolve, 0.1% w / w 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 hydroxypropylmethylcellulose, 6% w / w 15% w / w hydroxypropylcellulose and 0.05% w / w 3% w / w red lacquer, between a time range of 1 min to 15 min, said% being referred to the total weight of said part of extended release composition, [b.4] granulate what is obtained in [b.3] with the solution obtained in [b.2],
  • Figure 1 schematically shows a dual action tablet.
  • Figures 2A and 2B show the immediate release stage.
  • 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.
  • Figure 7 shows the release profile of example 6.
  • Figure 8 shows the release profile of example 7.
  • Figure 9 shows the release profile of example 8.
  • Figure 10 shows the release profile of example 9.
  • Figure 1 1 shows the release profile of example 10.
  • Figure 12 shows the release profile of example 1 1.
  • Figure 13 shows the release profile of example 12.
  • Figure 14 shows the release profile of example 13.
  • Figure 15 shows the release profile of example 14.
  • Figure 16 shows the release profile of example 15.
  • Figure 17 shows the release profile of example 16.
  • the present invention relates to a pharmaceutical composition
  • 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.
  • 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 form. with prolonged release, 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 2,000 mg in its 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 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.
  • 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.
  • 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 dual-release, scheduled release pharmaceutical preparation.
  • the oral dose form may preferably take the form of tablets (or tablets), granules, capsules, etc. and more preferably the tablet form.
  • the immediate release composition may preferably contain excipients such as: solubilizers, disintegrants, plasticizers, retardants, gastro-resistant material, colorants, surfactants or surfactants, glidants, lubricants and binders.
  • disintegrants in the immediate release composition
  • agents used to facilitate breakage or disintegration of the dosage form after administration 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, cellulose microcrystalline, pregelatinized starch, sodium alginate, methylcellulose, agar, bentonite, alginic acid, gum agar, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, sodium lauryl sulfate, sodium bicarbonate, sodium chloride, etc.
  • 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, agar gum, carboxymethylcellulose and sodium lauryl sulfate , and most preferably is sodium starch glycolate.
  • 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.
  • Such compounds include, as an example and without limitation, talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils such as hydrogenated soybean oil, polyethylene glycol, sodium benzoate, sodium stearate fumarate, calcium hydroxide, glycerol, boric acid, sodium acetate, sodium chloride, glyceryl behenate, lauryl magnesium or sodium sulfate, colloidal silicone, corn starch, etc.
  • the lubricant is talc and the talc is in a proportion of 0.6% w / w 5.5% w / w, based on the total weight of the immediate release composition part.
  • the immediate release composition part comprises 55.5% w / w 85% w / w 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof, 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 5.5% w / w of talc, said% being referred to the total weight of the immediate release composition part.
  • the prolonged release composition may preferably contain excipients such as: sulubilizers, disintegrants, plasticizers, gastro-resistant material, colorants, surfactants or surfactants, glidants, lubricants and diluents.
  • excipients such as: sulubilizers, disintegrants, plasticizers, gastro-resistant material, colorants, surfactants or surfactants, glidants, lubricants and diluents.
  • 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 Blue 2, FD&C Green 3, Iron Oxide - Black, Red lacquer, Titanium dioxide, etc.
  • 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, red lacquer and titanium dioxide, and most preferably it is red lacquer.
  • the red lacquer is in a proportion of 0.05% w / w to 3% w / w, based on the total weight of the prolonged release composition part.
  • lubricants in the prolonged release composition
  • lubricants 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.
  • the lubricant is a lubricant of 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 , and most preferably it is talc, magnesium stearate or a mixture of both.
  • 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.
  • the lubricant is 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.
  • Preferred dosage forms are those containing between 10 mg and 3,500 mg of 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.
  • This methodology with the use of a solvent allows the obtaining of a granulate comprising the active ingredient, using several equipment that are known by the pharmaceutical industry such as a Mixer, a Fluid Bed Dryer and a Sifter.
  • STAGE A1 Manufacture of the Immediate Release layer
  • A1 e 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.
  • A2e 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 for use known 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 for use known in the pharmaceutical industry.
  • STAGE A3 Pressing a tablet
  • a bilayer tablet is pressed, which has a layer of the product obtained in A1 g) and a layer of the product obtained in A2g).
  • 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 production of a dry mixture, this allows obtaining 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
  • B2a 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 of known use in the pharmaceutical industry.
  • a bilayer tablet is pressed, which has a layer of the product obtained in B1 b) and a layer of the product obtained in B2b).
  • 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 making a dry mixture, for the immediate release layer and using 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 sieve.
  • STAGE C2 Manufacture of the Prolonged Release C2a) Micronize layer, 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts or preferably calcium dihydroxybenzenesulfonate.
  • C2e Screening of the granulate.
  • C2f Mixing of the granulate, optionally with or without plasticizing agents, retarders, gastro resistant, colorants, surfactants or surfactants, glidants, lubricants, binders, diluents, disintegrants and other additives for use known in the pharmaceutical industry.
  • STAGE C3 Pressing a tablet
  • a bilayer tablet is pressed, which has a layer of the product obtained in C1 a) 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.
  • 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 Glycolate Starch. All percentages refer 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.
  • STAGE 2 Manufacture of the Prolonged Release layer a) Micronize, 25% w / w 75% w / w calcium dobesilate. All percentages refer to the total weight of the Prolonged Release Stage. b) Dissolve 0.1% w / w 5% w / w Hydroxypropylcellulose in a sufficient amount of Purified Water. All percentages refer to the total weight of the Prolonged Release Stage.
  • 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 Starch Sodium Glycolate. All percentages refer 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. c) Sift through a # 30, 1, 33% w / w mesh of Magnesium Stearate and 1.78% w / w Talc. All percentages refer 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. Materials Weight [%]
  • STAGE 2 Manufacture of the Prolonged Release layer a) Micronize 53.76% w / w calcium dobesilate. All percentages refer to the total weight of the Prolonged Release Stage. b) Dissolve 0.81% w / w Hydroxypropylcellulose and a sufficient amount of Purified Water. All percentages refer to the total weight of the Prolonged Release Stage. c) Mix the obtained in a) with 32.15% w / w Hydroxypropylmethylcellulose, 9.68% w / w Hydroxypropylcellulose and 0.12% w / w Red Lacquer, between a time range of 1 min to 15 min. All percentages refer to the total weight of the Prolonged Release Stage.
  • Purified water * is.
  • FIG. 1 An example of a bilayer tablet in which the immediate release layer 1 is represented in a gray color is shown in Figure 1, while the extended release layer 2 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 prolonged release layer 2 ( Figures 3A and 3B).
  • Purified water * is.
  • Purified water * is.
  • Both phases are compressed in an elongated punch.
  • the ratio between the immediate release layer and the extended release layer is 34:66.
  • Figure 5 shows the release profile of the bilayer tablet.
  • Purified water * is.
  • Purified water * is.
  • Both phases are compressed in an elongated punch.
  • the ratio between the immediate release layer and the extended release layer is 39:61.
  • Figure 6 shows the release profile of the bilayer tablet.
  • Purified water * is.
  • Figure 7 shows the release profile of the bilayer tablet.
  • Purified water * is.
  • Both phases are compressed in an elongated punch.
  • the ratio between the immediate release layer and the extended release layer is 30:70.
  • Figure 8 shows the release profile of the bilayer tablet.
  • Purified water * is.
  • Figure 9 shows the release profile of the bilayer tablet.
  • Purified water * is.
  • Both phases are compressed in an elongated punch.
  • the ratio between the immediate release layer and the extended release layer is 30:70.
  • the release profile of the bilayer tablet is shown in Figure 10.
  • Purified water * is.
  • Both phases are compressed in an elongated punch.
  • the ratio between the immediate release layer and the extended release layer is 27:73.
  • Figure 1 1 shows the release profile of the bilayer tablet.
  • Purified water * is.
  • Both phases are compressed in an elongated punch.
  • the ratio between the immediate release layer and the extended release layer is 25:75.
  • Figure 12 shows the release profile of the bilayer tablet.
  • the release profile of the bilayer tablet is shown in Figure 13.
  • Purified water * is.
  • Both phases are compressed in an elongated punch.
  • the ratio between the immediate release layer and the extended release layer is 36:64.
  • the release profile of the bilayer tablet is shown in Figure 14.
  • the solution shows an accelerated release profile, which does not allow 24-hour maintenance of the action.
  • Purified water * is.
  • Both phases are compressed in an elongated punch.
  • the ratio between the immediate release layer and the extended release layer is 28:72.
  • the solution shows a slow release profile, which does not allow maintenance of suitable levels for 24 hours.
  • Purified water * is.
  • Both phases are compressed in an elongated punch.
  • the ratio between the immediate release layer and the extended release layer is 22:78.
  • Figure 16 shows the release profile of the bilayer tablet.
  • the solution shows a slow release profile, which does not allow maintenance of suitable levels for 24 hours.
  • Purified water * is.
  • Both phases are compressed in an elongated punch.
  • the ratio between the immediate release layer and the extended release layer is 41: 59.
  • the experiment was carried out in sextuplicate at a temperature of 37 ° C, 60 rpm and a volume of 1000 ml of a buffer solution at pH 5.5. Samples were taken at different time intervals with media replacement and the amount of calcium dobesilate was determined, dissolved by a UV-Vis spectrophotometer at 308 nm wavelength.
  • the present pharmaceutical formulation shows a dual action profile in pH 5.5 buffer solution.
  • the first phase is immediate release, has an approximate duration of 1 hour, during that time between 20% and 70% of the total calcium dobesilate corresponding to this stage is released.
  • the second phase which is extended release, the corresponding total release time between 35% and 100% of the total calcium dobesilate corresponding to this stage is 24 hours.
  • the authors of the present invention have found a new pharmaceutical dual-release formulation of calcium dobesilate with which the optimal therapeutic effects of calcium dobesilate are guaranteed in the first minutes, after the intake of the formulation, and throughout 24 hours. Therefore, the new formulation allows to supply in a single dose the amount necessary for a whole day, which will be released gradually over the next 24 hours of intake. This offers a great advantage to the patient in terms of compliance with the necessary treatment.

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Abstract

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. Pharmaceutical composition comprising 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof in the form of personalised supply units, in which part of the 2,5-dihydroxybenzenesulfonic acid is in the form of an immediate-release composition additionally comprising between 8% and 28% microcrystalline cellulose, and the other part of which is in the form of a prolonged-release composition additionally comprising between 10% and 45% hydroxypropylmethylcellulose and between 6.1% and 20% hydroxypropylcellulose. The proportion between the two parts is between 24:76 and 40:60. This allows administration of the composition to the patient once every 24 hours. The composition can be used to treat primary varicose states, chronic venous insufficiency, phlebitis, thrombophlebitis, post-thrombotic syndrome, leg ulcers, pregnancy-related varicose veins. as a coadjuvant for varicectomy, sclerotherapy or as a coadjuvant in the treatment of diabetic retinopathy.

Description

COMPOSICIÓN FARMACÉUTICA QUE COMPRENDE ÁCIDO 2,5 - DIHIDROXIBENCENOSULFÓNICO O UNA DE SUS SALES FARMACÉUTICAMENTE ACEPTABLES EN FORMA DE UNIDADES INDIVIDUALIZADAS DE SUMINISTRO Y PROCEDIMIENTO DE FABRICACIÓN CORRESPONDIENTE  PHARMACEUTICAL COMPOSITION THAT INCLUDES ACID 2,5 - DIHYDROXIBENCENOSULPHONIC OR ONE OF ITS PHARMACEUTICALLY ACCEPTABLE SALTS IN THE FORM OF INDIVIDUALIZED SUPPLY UNITS AND CORRESPONDING MANUFACTURING PROCEDURE
DESCRIPCIÓN DESCRIPTION
Campo de la Invención La presente invención se refiere a una composición farmacéutica de administración oral de acción programada para una liberación dual, inmediata y liberación prolongada, que comprende ácido 2,5 - dihidroxibencenosulfónico y/o sus sales farmacéuticamente aceptables, para la reducción de fibrinógeno en sangre de humanos, así como para la profilaxis y tratamiento de enfermedades causadas por niveles elevados de fibrinógeno. Una parte del ácido 2,5 - dihidroxibencenosulfónico o una de sus sales farmacéuticamente aceptables está en forma de composición de liberación inmediata y otra parte del ácido 2,5 - dihidroxibencenosulfónico o una de sus sales farmacéuticamente aceptables está en forma de composición de liberación prolongada. Field of the Invention The present invention relates to an orally administered pharmaceutical composition of programmed action for dual, immediate and prolonged release, comprising 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts, for fibrinogen reduction in human blood, as well as for the prophylaxis and treatment of diseases caused by elevated fibrinogen levels. A part of 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof is in the form of an immediate release composition and another part of 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof is in the form of a prolonged release composition.
La invención también se refiere a un procedimiento de fabricación de una composición de acuerdo con la invención. The invention also relates to a method of manufacturing a composition according to the invention.
Antecedentes de la Invención Background of the Invention
El ácido 2,5 - dihidroxibencenosulfónico y/o sus sales (dobesilato, por ejemplo dobesilato de calcio), es un regulador de las funciones capilares y fue descrito en la patente ES 335.945. La fórmula del dobesilato de calcio es: 2,5-Dihydroxybenzenesulfonic acid and / or its salts (dobesilate, for example calcium dobesilate), is a regulator of capillary functions and was described in the patent ES 335.945. The formula of calcium dobesilate is:
Figure imgf000004_0001
Figure imgf000004_0001
Este principio posee una acción electiva sobre la pared capilar, cuyas propiedades fisiológicas de resistencia y permeabilidad son regularizadas por el preparado. En otras palabras, el dobesilato de calcio actúa aumentando el tono venoso, venular y disminuyendo la permeabilidad de la pared capilar. Esta acción encuentra su aplicación en todos los casos de fragilidad capilar. 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 tone and decreasing the permeability of the capillary wall. This action finds its application in all cases of hair fragility.
El ácido 2,5 - dihidroxibencenosulfónico o sus sales farmacéuticamente aceptables generalmente son administrados por vía oral en la forma de tabletas y cápsulas. Es muy soluble en agua, soluble en etanol, muy ligeramente soluble en 2-propanol y prácticamente insoluble en cloruro de metileno. 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.
La presente invención comprende el ácido 2,5 - dihidroxibencenosulfónico y/o sus sales farmacéuticamente aceptables o preferentemente el dihidroxibencenosulfonato de calcio (dobesilato de calcio). Es incorporado en pellets, granulados o tabletas, los que para su dosificación se ubican en cápsulas de gelatina dura, hidroxipropilmetilcelulosa, tabletas, tabletas bicapa, tabletas de liberación modificada, tabletas de liberación prolongada, etc., de forma tal que puedan ingerirse con facilidad. The present invention comprises 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts or preferably calcium dihydroxybenzenesulfonate (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 easily ingested .
En la solicitud de patente EP 2 208 498 A1 , que se incorpora como referencia, se describe una formulación farmacéutica del dobesilato de calcio, en forma de capsula o tabletas, que posee una concentración de 250 mg de principio activo. En la solicitud de la patente ES 2 229 902 A1 , se revela una formulación farmacéutica de dobesilato de calcio en tabletas, que posee un recubrimiento polimérico que le transfiere propiedades entéricas a la formulación farmacéutica y la concentración de principio activo es menor a 500 mg. La velocidad de vaciamiento gástrico de los pellets, unidades esféricas o microgránulos recubiertos resulta menos dependiente de la presencia o ausencia de alimentos en el estómago, lo que en algunos casos permite reducir la variabilidad intra e interindividual en los perfiles de absorción del principio activo. Además, los pellets, unidades esféricas o microgránulos recubiertos se dispersan como unidades individualizadas en el tracto gastrointestinal, reduciendo de forma significativa las elevadas concentraciones locales de la dobesilato de calcio. De este modo se facilita su absorción, se reducen las fluctuaciones en la concentración plasmática y se minimizan ciertos efectos secundarios. In the patent application EP 2 208 498 A1, which is incorporated by reference, a pharmaceutical formulation of calcium dobesilate, in the form of a capsule or tablets, having a concentration of 250 mg of active ingredient is described. In the 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 the pellets, spherical units or coated microgranules is less dependent on the presence or absence of food in the stomach, which in some cases makes it possible to reduce intra and inter-individual 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.
El transporte es el movimiento de una droga de un lugar a otro dentro del organismo. La droga se puede difundir con libertad en forma no combinada con una energía cinética apropiada para su medio térmico o desplazarse en combinación con constituyentes extracelulares o celulares, algunas veces en conexión con procesos productores de energía que permiten que la molécula o el complejo superen barreras contra la difusión simple. Transport is the movement of a drug from one place to another within the body. The drug can be released freely in combination with a kinetic energy appropriate for its thermal environment or move in combination with extracellular or cellular constituents, sometimes in connection with energy producing processes that allow the molecule or complex to overcome barriers against Simple diffusion
En la actualidad existen en el mercado formulaciones farmacéuticas para el dobesilato de calcio. Pero en ninguna de ellas se incorpora una dosis de carga similar a una dosis convencional (que es de 500 mg), con la cual se pueda garantizar el efecto inmediato que requieren ciertas patologías. 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.
Se hace necesario así disponer de una composición farmacéutica, de administración una vez al día, que provea niveles terapéuticos del ácido 2,5 - dihidroxibencenosulfónico y/o sus sales farmacéuticamente aceptables (preferentemente el dihidroxibencenosulfonato de calcio) durante las 24 horas. 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.
Existen varias metodologías para la manufactura de los pellets, unidades esféricas o microgránulos. Una de ellas consiste en elaborar los pellets esféricos o microgránulos por extrusión o esferonización, esta metodología permite la obtención de partículas esféricas que comprenden el principio activo, a partir de una pasta humectada, utilizando un Equipo conocido como Marumerizer (Luwa) o el CF-Granulator (Vector). Un segundo método de manufactura de los pellets, unidades esféricas o microgránulos, consiste en utilizar partículas neutras (núcleos), cuyo contenido puede ser de azúcar y/o almidón, azúcar y/o celulosa microcristalina. Los núcleos se recubren con el principio activo por atomización o espolvoreado. There are several methodologies for the manufacture of pellets, spherical units or microgranules. One of them consists in preparing the spherical pellets or microgranules by extrusion or spheronization, this methodology allows the obtaining of spherical particles that comprise the active principle, from a moisturized paste, using a Equipment known as Marumerizer (Luwa) or the CF- Granulator (Vector). A second method of manufacturing pellets, spherical units or microgranules, is to use neutral particles (nuclei), the content of which may be sugar and / or starch, sugar and / or microcrystalline cellulose. The cores are coated with the active substance by atomization or dusting.
En la presente invención el efecto instantáneo se puede observar con la incorporación, en una misma dosis, de una composición de acción inmediata y otra composición de acción prolongada, constituyéndose así en una novedosa formulación con acción programada de tipo prolongado. 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 long-term programmed action.
En la presente invención su forma de dosificación puede ser opcionalmente en pellets, granulados, tabletas, cápsulas de gelatina dura, hidroxipropilmetilcelulosa, tabletas, tabletas bicapa, tabletas de liberación modificada o tabletas de liberación prolongada. En distintos documentos de patente se hace mención al uso de formulaciones de liberación prolongada, sin embargo, se corre el riesgo de no garantizar el efecto inmediato que amerita este tipo de agente farmacológico, el cual es de suma importancia sobre todo para la reducción de fibrinógeno en sangre de humanos, así como para la profilaxis y tratamiento de enfermedades causadas por niveles elevados de fibrinógeno. 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. In different patent documents mention is made of the use of extended-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 fibrinogen levels.
Es así como se hace necesario disponer de una composición farmacéutica en forma de acción dual, constituido por una parte del principio activo en una formulación de acción inmediata, y por otra parte del principio activo en una formulación de acción prolongada. Así se garantiza el efecto terapéutico rápido y prolongando la acción del principio activo a lo largo de varias horas, evitando de este modo una multiplicidad de dosificaciones diarias durante el tiempo que se prolongue la medicación. Se hace necesario así disponer de una composición farmacéutica, de administración una vez al día, que provea niveles terapéuticos de ácido 2,5 - dihidroxibencenosulfónico y/o sus sales farmacéuticamente aceptables (preferentemente de dihidroxibencenosulfonato de calcio) durante las 24 horas. Exposición de la invención It is thus 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 long-acting 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, that provides therapeutic levels of 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts (preferably calcium dihydroxybenzenesulfonate) for 24 hours. Exhibition of the invention
Sorprendentemente los autores de la presente invención han encontrado que es factible obtener una formulación farmacéutica, en unidades individualizadas (es decir para ser administrada una vez al día) que combine cantidades farmacológicamente útiles de ácido 2,5 - dihidroxibencenosulfónico y/o sus sales farmacéuticamente aceptables (preferentemente el dihidroxibencenosulfonato de calcio) que provean, mediante una acción dual (inmediata y prolongada), sus propiedades para la reducción de fibrinógeno en sangre, en forma instantánea, prolongándose dichos efectos en niveles plasmáticos a lo largo de 24 horas. Para ello la composición farmacéutica que comprende ácido 2,5 - dihidroxibencenosulfónico o una de sus sales farmacéuticamente aceptables en forma de unidades individualizadas de suministro, donde una parte del ácido 2,5 - dihidroxibencenosulfónico o una de sus sales farmacéuticamente aceptables está en forma de composición de liberación inmediata y otra parte del ácido 2,5 - dihidroxibencenosulfónico o una de sus sales farmacéuticamente aceptables está en forma de composición de liberación prolongada, está caracterizada por que la parte de composición de liberación inmediata comprende, adicionalmente entre un 8 % p/p a 28 % p/p, respecto del peso total de la parte de composición de liberación inmediata, de celulosa microcristalina, la parte de composición de liberación prolongada comprende, adicionalmente entre un 10 % p/p a 45 % p/p, respecto del peso total de la parte de composición de liberación prolongada, de hidroxipropilmetilcelulosa, y entre un 6,1 % p/p a 20 % p/p, respecto del peso total de la parte de composición de liberación prolongada, de hidroxipropilcelulosa, y por que tiene una proporción entre la parte de composición de liberación inmediata y la parte de composición de liberación prolongada comprendida entre 24:76 y 40:60. Surprisingly, the authors of the present invention have found that it is feasible to obtain a pharmaceutical formulation, in individualized units (i.e. 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, through a dual action (immediate and prolonged), its properties for the reduction of fibrinogen in blood, instantaneously, prolonging said effects at plasma levels over 24 hours. For this, the pharmaceutical composition comprising 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof in the form of individual delivery units, wherein a part of the 2,5-dihydroxybenzenesulfonic acid or one of its pharmaceutically acceptable salts is in the form of a composition. Immediate release and another part of 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof is in the form of a prolonged release composition, it is characterized in that the immediate release composition part further comprises between 8% w / w 28% w / w, with respect to the total weight of the immediate release composition part, of microcrystalline cellulose, the extended release composition part further comprises between 10% w / w and 45% w / w, relative to the total weight of the prolonged release composition part of hydroxypropyl methylcellulose, and between 6.1% p / pa 20% w / w, with respect to the total weight of the extended release composition part of hydroxypropyl cellulose, and why it has a proportion between the immediate release composition part and the extended release composition part comprised between 24: 76 and 40:60.
La novedosa formulación galénica de liberación programada, que provee cantidades terapéuticamente aceptables del ácido 2,5 - dihidroxibencenosulfónico y/o sus sales farmacéuticamente aceptables (preferentemente el dihidroxibencenosulfonato de calcio) en forma de pellets, unidades esféricas o microgránulos de liberación inmediata o microgránulos de liberación prolongada, tabletas de liberación dual o tabletas de liberación prolongada, actúa con eficacia en la indicación para el tratamiento de la reducción de fibrinogeno en sangre de humanos, así como para la profilaxis y tratamiento de enfermedades causadas por niveles elevados de fibrinogeno y enfermedades relacionadas. El uso de hidroxipropilmetilcelulosa como agente retardante se basa en pruebas in vitro efectuadas con los distintos materiales, en las cuales se demostró que posee una mejor capacidad de retardo en la liberación del principio activo, garantizando una reacción de orden cero ideal para la nueva formulación. En las pruebas realizadas con los otros agentes retardantes, no se logró obtener el perfil de disolución idóneo que garantizara la acción por 24 horas. Adicionalmente, la proporción entre la parte de composición de liberación inmediata y la parte de composición de liberación prolongada comprendida entre 24:76 y 40:60 permite obtener el perfil de disolución más adecuado para garantizar la absorción requerida y obtener las concentraciones plasmáticas requeridas durante 24 horas. Estas proporciones son las que mejor permiten alcanzar el equilibrio entre la liberación inmediata y la liberación prolongada del ácido 2,5 - dihidroxibencenosulfónico y/o sus sales farmacéuticamente aceptables. Otras proporciones no permiten obtener un perfil de disolución de 24 horas. The novel galenic formulation of programmed release, 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 release prolonged, dual-release tablets or extended-release tablets, acts effectively on the indication for the treatment of reduction of human blood fibrinogen, as well as for the prophylaxis and treatment of diseases caused by high levels of fibrinogen and related diseases. The use of hydroxypropylmethylcellulose as a retarding agent is based on in vitro tests carried out with the different materials, in which it was demonstrated that it has a better capacity to delay the release of the active substance, guaranteeing an ideal zero order reaction for the new formulation. In the tests carried out with the other retarding agents, it was not possible to obtain the ideal dissolution profile that would guarantee the action for 24 hours. Additionally, the proportion between the immediate release composition part and the extended release composition part between 24:76 and 40:60 allows to obtain the most suitable dissolution profile to guarantee the required absorption and obtain the required plasma concentrations for 24 hours. These proportions are the ones that best allow a balance between immediate and prolonged release of 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts. Other proportions do not allow to obtain a dissolution profile of 24 hours.
La invención también tiene por objeto el uso de una composición farmacéutica de acuerdo con la invención para la fabricación de un medicamento. Preferentemente el medicamento es para el tratamiento de la reducción de fibrinogeno en sangre de humanos, la profilaxis y tratamiento de enfermedades causadas por niveles elevados de fibrinogeno, para aumentar el tono venoso, para disminuir la permeabilidad de la pared capilar, para el tratamiento de todos los estados varicosos primarios (dolores, pesadez de piernas, calambres nocturnos, parestesias), insuficiencia venosa crónica, flebitis, tromboflebitis, síndrome post-trombótico, ulceras de las piernas, várices del embarazo, coadyuvante de la varicectomía, escleroterapia, coadyuvante en el tratamiento de la retinopatía diabética (en particular micro-aneurismas, exudados, hemorragias intra y extra retinianas, lesiones proliferativas vasculares y conjuntivales), inhibición de las sustancias vasoactivas responsables de la contractura o encogimiento de las cédulas endoteliales (bradiquinina, histamina, serotonina), inhibición de enzimas que degradan mucopolisacáridos, evitar la destrucción de membranas plaquetarias y su efecto trombogénico, mejorar la viscosidad de la sangre (por ejemplo, aumentando la elasticidad y deformabilidad de los glóbulos rojos, reducir el nivel de proteínas plasmáticas de alta densidad (disminuyendo la viscosidad parcial del plasma), y/o la insuficiencia venosa crónica. The object of the invention is also the use of a pharmaceutical composition according to the invention for the manufacture of a medicament. Preferably the medicament is for the treatment of human fibrinogen reduction in 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, night cramps, paraesthesia), chronic venous insufficiency, phlebitis, thrombophlebitis, post-thrombotic syndrome, leg ulcers, varicose veins of pregnancy, adjuvant varicectomy, sclerotherapy, adjuvant in treatment of diabetic retinopathy (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), inhibition of enzymes that degrade mucopolysaccharides, avoid 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 proteins High density plasma (decreasing partial plasma viscosity), and / or chronic venous insufficiency.
Preferentemente la composición de acuerdo con la invención es para el uso en el tratamiento de estados varicosos primarios, insuficiencia venosa crónica, flebitis, tromboflebitis, síndrome post-trombótico, ulceras de las piernas, várices del embarazo, coadyuvante de la varicectomía, escleroterapia o coadyuvante en el tratamiento de la retinopatía diabética. Preferentemente los estados varicosos primarios son dolores, pesadez de piernas, calambres nocturnos o parestesias. 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.
Ventajosamente se administra una unidad individualizada de suministro una sola vez cada 24 horas o, alternativamente, se administran dos unidades individualizadas de suministro simultáneamente una sola vez cada 24 horas. En general, preferentemente se administra la composición de acuerdo con la invención una sola vez cada 24 horas. 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, the composition according to the invention is preferably administered only once every 24 hours.
Preferentemente las unidades individualizadas de suministro son tabletas, cápsulas o sobres, y muy preferentemente son tabletas o sobres. Ventajosamente las tabletas son tabletas bicapa, donde una capa comprende dicha composición de liberación inmediata y la otra capa comprende dicha composición de liberación prolongada. 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.
Es otro objeto de la presente invención un procedimiento para producir una composición farmacéutica del ácido 2,5 - dihidroxibencenosulfónico y/o sus sales farmacéuticamente aceptables o preferentemente el dihidroxibencenosulfonato de calcio, por procedimientos adecuados a partir de núcleos (Neutros) o Microgránulos ya elaborados. El procedimiento de fabricación de la composición farmacéutica de acuerdo con la invención se caracteriza por que comprende las siguientes etapas: 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 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] fabricar la parte de composición de liberación inmediata por vía seca, empleándose 55,5 % p/p a 85 % p/p de ácido 2,5 - dihidroxibencenosulfónico o una de sus sales farmacéuticamente aceptables y 8 % p/p a 28 % p/p de celulosa microcristalina, estando los % referidos al peso total de la parte de composición de liberación inmediata, [b] fabricar la parte de composición de liberación prolongada por vía húmeda, empleándose 25 % p/p a 75 % p/p de ácido 2,5 - dihidroxibencenosulfónico o una de sus sales farmacéuticamente aceptables, 10 % p/p a 45 % p/p de hidroxipropilmetilcelulosa y 6,1 % p/p a 20 % p/p de hidroxipropilcelulosa, estando los % referidos al peso total de dicha parte de composición de liberación prolongada, donde la etapa [b] incluye una etapa [b.1 ] de micronización del ácido 2,5 - dihidroxibencenosulfónico o una de sus sales farmacéuticamente aceptables, y [a] manufacture the immediate release composition part dry, using 55.5% w / w 85% w / w 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof and 8% w / w 28% w / w microcrystalline cellulose, the% being referred to the total weight of the immediate release composition part, [b] manufacture the wet-release prolonged composition part, using 25% w / w 75% w / w 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof, 10% w / w 45% w / p of hydroxypropylmethylcellulose and 6.1% w / w 20% w / w of hydroxypropylcellulose, the% being referred to the total weight of said part of the extended release composition, where step [b] includes a step [b.1] of micronization of 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof, and
[c] fabricar unas unidades individualizadas de suministro que comprenden tanto composición de liberación inmediata como composición de liberación prolongada donde la proporción entre la composición de liberación inmediata y la composición de liberación prolongada está comprendida entre 24:76 y 40:60. [c] manufacturing individualized delivery units comprising both immediate release composition and prolonged release composition where the ratio between immediate release composition and extended release composition is between 24:76 and 40:60.
En la etapa [b.1 ], el proceso de micronización de la materia prima utilizada, garantiza la liberación apropiada y la reproducibilidad requerida lote a lote. Con tamaños de partícula superiores se tienen problemas de reproducibilidad en los perfiles de disolución obtenidos. In step [b.1], the micronization process of the raw material used guarantees the appropriate release and reproducibility required batch by batch. With larger particle sizes, reproducibility problems are obtained in the dissolution profiles obtained.
Preferentemente en la etapa [c] se fabrican unas tabletas (que serán, así, de liberación dual) y muy preferentemente se fabrican unas tabletas bicapa. Preferably in step [c] tablets are manufactured (which will thus be dual-release) and very preferably bilayer tablets are manufactured.
Preferentemente en la etapa [a] se emplea, adicionalmente, 1 % p/p a 6 % p/p de glicolato sódico de almidón, 0,6 % p/p a 5 % p/p de estearato de magnesio y 0,6 % p/p a 5,5 % p/p de talco, estando dichos % referidos al peso total de la parte de composición de liberación inmediata. Preferably in step [a], in addition, 1% w / w 6% w / w sodium starch glycolate, 0.6% w / w 5% w / w magnesium stearate and 0.6% w are used / pa 5.5% w / w talc, said% being referred to the total weight of the immediate release composition part.
Ventajosamente en la etapa [b] se emplea, adicionalmente, 0,05 % p/p a 3 % p/p de un colorante, 0,6 % p/p a 5 % p/p de talco y 0,6 % p/p a 5 % p/p de estearato de magnesio, estando dichos % referidos al peso total de la parte de composición de liberación prolongada. Preferentemente las unidades individualizadas de suministro son tabletas bicapa, donde una capa comprende dicha composición de liberación inmediata y la otra capa comprende dicha composición de liberación prolongada. Una forma particularmente ventajosa del procedimiento de acuerdo con la invención es aquella en la que: la etapa [a] comprende: [a.1 ] tamizar por una malla # 20, el ácido 2,5 - dihidroxibencenosulfónico o una de sus sales farmacéuticamente aceptables, la celulosa microcristalina y 1 % p/p a 6 % p/p de glicolato sódico de almidón, estando dichos % referidos al peso total de la parte de composición de liberación inmediata, [a.2] mezclar lo obtenido en [a.1 ], entre un rango de tiempo de 1 min a 30 min, Advantageously in step [b], additionally, 0.05% w / w and 3% w / w of a dye, 0.6% w / w 5% w / w talc and 0.6% w / w are used 5% w / w magnesium stearate, said% being referred to the total weight of the prolonged release composition part. 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] sieving through a # 20 mesh, 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof , 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] tamizar por una malla # 30, 0,6 % p/p a 5 % p/p de estearato de magnesio y 0,6 % p/p a 5,5 % p/p de talco, estando dichos % referidos al peso total de la parte de composición de liberación inmediata, [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, said% being referred to the total weight of the immediate release composition part,
[a.4] mezclar lo obtenido en [a.2] y [a.3], entre un rango de tiempo de 1 min a 15 min, y la etapa [b] comprende, tras la etapa [b.1 ],: [a.4] mix the results obtained in [a.2] and [a.3], between a time range of 1 min to 15 min, and stage [b] includes, after step [b.1], :
[b.2] disolver, 0,1 % p/p a 5 % p/p de hidroxipropilcelulosa en una cantidad suficiente de agua purificada, estando dichos % referidos al peso total de dicha parte de composición de liberación prolongada, [b.3] mezclar lo obtenido en [b.1 ], con la hidroxipropilmetilcelulosa, 6 % p/p a 15 % p/p de hidroxipropilcelulosa y 0,05 % p/p a 3 % p/p de laca roja, entre un rango de tiempo de 1 min a 15 min, estando dichos % referidos al peso total de dicha parte de composición de liberación prolongada, [b.4] granular lo obtenido en [b.3] con la solución obtenida en [b.2], [b.2] dissolve, 0.1% w / w 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 hydroxypropylmethylcellulose, 6% w / w 15% w / w hydroxypropylcellulose and 0.05% w / w 3% w / w red lacquer, between a time range of 1 min to 15 min, said% being referred to the total weight of said part of extended release composition, [b.4] granulate what is obtained in [b.3] with the solution obtained in [b.2],
[b.5] secar lo obtenido en [b.4], entre un rango de temperatura de 45 eC a 70 eC y un rango de tiempo de 10 min a 60 min, [b.5] dry the obtained in [b.4], between a temperature range of 45 e C to 70 e C and a time range of 10 min to 60 min,
[b.6] tamizar por una malla 062R lo obtenido en [b.5], [b.6] sift through a 062R mesh what was obtained in [b.5],
[b.7] tamizar por una malla # 30, 0,6 % p/p a 5 % p/p de talco y 0,6 % p/p a 5 % p/p de estearato de magnesio, estando dichos % referidos al peso total de dicha parte de composición de liberación prolongada, [b.7] sieve 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 weight total of said part of extended release composition,
[b.8] mezclar lo obtenido en [b.6] y [b.7], entre un rango de tiempo de 1 min a 15 min. [b.8] mix the results obtained in [b.6] and [b.7], between a time range of 1 min to 15 min.
Breve descripción de las figuras Brief description of the figures
Otras ventajas y características de la invención se aprecian a partir de la siguiente descripción, en la que, sin ningún carácter limitativo, se relatan unos modos preferentes de realización de la invención, haciendo mención de los dibujos que se acompañan. Las figuras muestran: 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 mentioned, mentioning the accompanying drawings. The figures show:
La figura 1 muestra esquemáticamente una tableta de acción dual. Las figuras 2A y 2B muestra la etapa de liberación inmediata. Las figuras 3A y 3B muestra la etapa de liberación prolongada. La figura 4 muestra el perfil de liberación del ejemplo 1 . Figure 1 schematically shows a dual action tablet. Figures 2A and 2B show the immediate release stage. Figures 3A and 3B show the extended release stage. Figure 4 shows the release profile of example 1.
La figura 5 muestra el perfil de liberación del ejemplo 3. La figura 6 muestra el perfil de liberación del ejemplo 5. La figura 7 muestra el perfil de liberación del ejemplo 6. La figura 8 muestra el perfil de liberación del ejemplo 7. La figura 9 muestra el perfil de liberación del ejemplo 8. La figura 10 muestra el perfil de liberación del ejemplo 9. La figura 1 1 muestra el perfil de liberación del ejemplo 10. La figura 12 muestra el perfil de liberación del ejemplo 1 1 . La figura 13 muestra el perfil de liberación del ejemplo 12. Figure 5 shows the release profile of example 3. Figure 6 shows the release profile of example 5. Figure 7 shows the release profile of example 6. Figure 8 shows the release profile of example 7. Figure 9 shows the release profile of example 8. Figure 10 shows the release profile of example 9. Figure 1 1 shows the release profile of example 10. Figure 12 shows the release profile of example 1 1. Figure 13 shows the release profile of example 12.
La figura 14 muestra el perfil de liberación del ejemplo 13. La figura 15 muestra el perfil de liberación del ejemplo 14. La figura 16 muestra el perfil de liberación del ejemplo 15. La figura 17 muestra el perfil de liberación del ejemplo 16. Figure 14 shows the release profile of example 13. Figure 15 shows the release profile of example 14. Figure 16 shows the release profile of example 15. Figure 17 shows the release profile of example 16.
Descripción detallada de unas formas de realización de la invención Detailed description of embodiments of the invention
La presente invención se refiere a una composición farmacéutica que comprende un agente con propiedades para la reducción de fibrinogeno en sangre, específicamente ácido 2,5 - dihidroxibencenosulfónico y/o sus sales farmacéuticamente aceptables o preferentemente el dihidroxibencenosulfonato de calcio. 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.
Es propósito de la presente invención proveer una composición farmacéutica, para ser suministrada por vía oral en forma de dosis preparadas a partir de la combinación del ácido 2,5 - dihidroxibencenosulfonico y/o sus sales farmacéuticamente aceptables o preferentemente el dihidroxibencenosulfonato de calcio con materiales o excipientes farmacéuticamente aceptables. En la presente invención la composición farmacéutica puede ser provista en forma de dosificación oral en tabletas de acción dual. 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 the 2,5-dihydroxybenzenesulfonic acid and / or its pharmaceutically acceptable salts or preferably calcium dihydroxybenzenesulfonate with pharmaceutically acceptable materials or excipients. In the present invention the pharmaceutical composition can be provided in oral dosage form in dual-action tablets.
Preferentemente cada unidad individualizada de suministro de la composición tiene un contenido de ácido 2,5 - dihidroxibencenosulfonico o una de sus sales farmacéuticamente aceptables de entre 50 mg y 2.500 mg en su forma de liberación inmediata y de entre 50 mg y 2.500 mg en su forma de liberación prolongada, más preferentemente cada unidad individualizada de suministro tiene un contenido de ácido 2,5 - dihidroxibencenosulfonico o una de sus sales farmacéuticamente aceptables de entre 100 mg y 2.000 mg en su forma de liberación inmediata y de entre 100 mg y 2.000 mg en su forma de liberación prolongada, y muy preferentemente cada unidad individualizada de suministro tiene un contenido de ácido 2,5 dihidroxibencenosulfonico o una de sus sales farmacéuticamente aceptables de entre 150 mg y 1 .000 mg en su forma de liberación inmediata y de entre 150 mg y 1 .000 mg en su forma de liberación prolongada. 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 form. with prolonged release, 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 2,000 mg in its 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 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.
Ventajosamente cada unidad individualizada comprende entre 400 mg a 2200 mg, de ácido 2,5 - dihidroxibencenosulfonico o una de sus sales farmacéuticamente aceptables. La composición farmacéutica de la presente invención puede ser preparada mediante los procedimientos que se describen a continuación, utilizando opcionalmente excipientes tales como: plastificantes, diluyente, adherentes, retardantes, gastro resistente, colorantes, tensoactivos o surfactantes, aglutinante, deslizantes, lubricantes, desintegrantes, transportadores y otros aditivos de uso conocido en la industria farmacéutica. 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.
Preferentemente la composición farmacéutica de la presente invención se provee como una forma de dosis oral que comprende el ácido 2,5 - dihidroxibencenosulfonico y/o sus sales farmacéuticamente aceptables o preferentemente el dihidroxibencenosulfonato de calcio, en una preparación farmacéutica de liberación programada, de liberación dual. La forma de dosis oral puede adoptar preferentemente forma de tabletas (o comprimidos), gránulos, cápsulas, etc. y más preferiblemente la forma de tabletas. 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 dual-release, scheduled release pharmaceutical preparation. The oral dose form may preferably take the form of tablets (or tablets), granules, capsules, etc. and more preferably the tablet form.
En la presente invención, la composición de liberación inmediata puede contener preferentemente excipientes tales como: solubilizantes, desintegrantes, plastificantes, retardantes, material gastro resistente, colorantes, tensoactivos o surfactantes, deslizantes, lubricantes y aglutinantes. 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 and binders.
Tal como es utilizado en la presente invención el término "desintegrantes" (en la composición de liberación inmediata) significa "los agentes utilizados para facilitar la rotura o desintegración de la forma de dosificación después de su administración". Tales compuestos incluyen, como ejemplo y sin ser limitantes, almidón, celulosas, almidón de maíz, almidón de papa, croscarmelosa, croscarmelosa de sodio, crospovidona, glicolato sódico de almidón, dióxido de silicio coloidal, silicato de magnesio, silicato de aluminio, celulosa microcristalina, almidón pregelatinizado, alginato de sodio, metilcelulosa, agar, bentonita, ácido algínico, goma agar, carboximetilcelulosa, carboximetilcelulosa de calcio, carboximetilcelulosa de sodio, lauril sulfato de sodio, bicarbonato de sodio, cloruro de sodio, etc. Preferentemente el desintegrante es un desintegrante del grupo formado por almidón, celulosa, almidón de maíz, croscarmelosa, croscarmelosa de sodio, crospovidona, glicolato sódico de almidón, celulosa microcristalina, almidón pregelatinizado, alginato de sodio, goma agar, carboximetilcelulosa y lauril sulfato de sodio, y muy preferentemente es glicolato sódico de almidón. Ventajosamente el glicolato sódico de almidón se encuentra en una proporción de 1 % p/p a 6 % p/p, respecto del peso total de la parte de composición de liberación inmediata. Tal como es utilizado en la presente invención el término "lubricantes" (en la composición de liberación inmediata) significa "los agentes utilizados para reducir la fricción entre las partículas y adherirse a la superficie de los fármacos". Tales compuesto incluyen, como ejemplo y sin ser limitantes, talco, estearato de magnesio, estearato de calcio, ácido esteárico, aceites vegetales hidrogenados como el aceite de soja hidrogenado, polietilenglicol, benzoato de sodio, fumarato estearato de sodio, hidróxido de calcio, glicerol, ácido bórico, acetato de sodio, cloruro de sodio, behenato de glicerilo, lauril sulfato de magnesio o sodio, silicona coloidal, almidón de maíz, etc. Preferentemente el lubricante es un lubricante del grupo formado por talco, estearato de magnesio, estearato de calcio, ácido esteárico, fumarato estérate de sodio y lauril sulfato de magnesio ó sodio, y muy preferentemente es estearato de magnesio, talco o una mezcla de ambos. Ventajosamente el lubricante es estearato de magnesio y el estearato de magnesio se encuentra en una proporción de 0,6 % p/p a 5 % p/p, respecto del peso total de la parte de composición de liberación inmediata. Alternativamente, o adicionalmente, ventajosamente el lubricante es talco y el talco se encuentra en una proporción de 0,6 % p/p a 5,5 % p/p, respecto del peso total de la parte de composición de liberación inmediata. Es particularmente ventajoso que la parte de composición de liberación inmediata comprenda 55,5 % p/p a 85 % p/p de ácido 2,5 - dihidroxibencenosulfónico o una de sus sales farmacéuticamente aceptables, 8 % p/p a 28 % p/p de celulosa microcristalina, 1 % p/p a 6 % p/p de glicolato sódico de almidón, 0,6 % p/p a 5 % p/p de estearato de magnesio y 0,6 % p/p a 5,5 % p/p de talco, estando dichos % referidos al peso total de la parte de composición de liberación inmediata. As used in the present invention, the term "disintegrants" (in the immediate release composition) means "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, cellulose microcrystalline, 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, agar gum, carboxymethylcellulose and sodium lauryl sulfate , 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 limitation, talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils such as hydrogenated soybean oil, polyethylene glycol, sodium benzoate, sodium stearate fumarate, calcium hydroxide, glycerol, boric acid, sodium acetate, sodium chloride, glyceryl behenate, lauryl magnesium or sodium 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 sterate fumarate and magnesium or sodium lauryl sulfate, 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 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 a pharmaceutically acceptable salt thereof, 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 5.5% w / w of talc, said% being referred to the total weight of the immediate release composition part.
En la presente invención, la composición de liberación prolongada puede contener preferentemente excipientes tales como: sulubilizantes, desintegrantes, plastificantes, material gastro resistente, colorantes, tensoactivos o surfactantes, deslizantes, lubricantes y diluyentes. In the present invention, the prolonged release composition may preferably contain excipients such as: sulubilizers, disintegrants, plasticizers, gastro-resistant material, colorants, surfactants or surfactants, glidants, lubricants and diluents.
Tal como es utilizado en la presente invención el término "colorantes" (en la composición de liberación prolongada) significa "los agentes utilizados para mejorar la apariencia estética de la forma farmacéutica". Tales compuesto incluyen, como ejemplo y sin ser limitantes FD & C Rojo 40, D & C Rojo 33, D & C Rojo 36, D & C Rojo 22, D & C Rojo 28, D & C Rojo 3, Óxido de hierro - rojo, FD & C Amarillo 6, FD & C Amarillo 5, D & C Amarillo 10, Óxido de hierro - amarillo, FD & C Azul 1 , FD & C Azul 2, FD & C Verde 3, Óxido de hierro - negro, Laca Roja, Dióxido de titanio, etc. Preferentemente el colorante es un colorante del grupo formado por FD & C Rojo 40, D & C Rojo 33, D & C Rojo 36, D & C Rojo 22, D & C Rojo 28, D & C Rojo 3, óxido de hierro - rojo, FD & C Amarillo 6, FD & C Amarillo 5, D & C Amarillo 10, óxido de hierro - amarillo, FD & C Azul 1 , FD & C Azul 2, FD & C Verde 3, óxido de hierro - negro, laca roja y dióxido de titanio, y muy preferentemente es laca roja. Ventajosamente la laca roja se encuentra en una proporción de 0,05 % p/p a 3 % p/p, respecto del peso total de la parte de composición de liberación prolongada. 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 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, 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 to 3% w / w, based on the total weight of the prolonged release composition part.
Tal como es utilizado en la presente invención el término "lubricantes" (en la composición de liberación prolongada) significa "los agentes utilizados para reducir la fricción entre las partículas y adherirse a la superficie de los fármacos". Tales compuesto incluyen, como ejemplo y sin ser limitantes, talco, estearato de magnesio, estearato de calcio, ácido esteárico, polietilenglicol, benzoato de sodio, fumarato estearato de sodio, hidróxido de calcio, aceite mineral, ácidos grasos, estearato de sodio, glicerol, ácido bórico, acetato de sodio, behenato de glicerilo, lauril sulfato de magnesio o sodio, almidón de maíz, etc. Preferentemente el lubricante es un lubricante del grupo formado por talco, estearato de magnesio, estearato de calcio, ácido esteárico, fumarato esterato de sodio, hidróxido de calcio, estearato de sodio, ácido bórico, lauril sulfato de magnesio ó sodio, y almidón de maíz, y muy preferentemente es talco, estearato de magnesio o una mezcla de ambos. Ventajosamente, el lubricante es talco y se encuentra en una proporción de 0,6 % p/p a 5 % p/p, respecto del peso total de la parte de composición de liberación prolongada. Alternativamente, o adicionalmente, ventajosamente el lubricante es estearato de magnesio y se encuentra en una proporción de 0,6 % p/p a 5 % p/p, respecto del peso total de la parte de composición de liberación prolongada. As used in the present invention, the term "lubricants" (in the prolonged 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, stearic acid, sodium stearate 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, advantageously the lubricant is 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.
Es particularmente ventajoso que la parte de composición de liberación prolongada comprenda 25 % p/p a 75 % p/p de ácido 2,5 - dihidroxibencenosulfónico o una de sus sales farmacéuticamente aceptables, 10 % p/p a 45 % p/p de hidroxipropilmetilcelulosa, 6,1 % p/p a 20 % p/p de hidroxipropilcelulosa, 0,05 % p/p a 3 % p/p de un colorante, 0,6 % p/p a 5 % p/p de talco y 0,6 % p/p a 5 % p/p de estearato de magnesio, estando dichos % referidos al peso total de dicha parte de composición de liberación prolongada. La formulación farmacéutica de la presente invención se presenta bajo la forma de liberación programada, sostenida o controlada y se administra en una única dosis una vez al día. It is particularly advantageous that the prolonged release composition part 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 extended 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.
Formas de dosis preferidas son aquellas que contienen entre 10 mg y 3500 mg el ácido 2,5 - dihidroxibencenosulfónico y/o sus sales farmacéuticamente aceptables o preferentemente el dihidroxibencenosulfonato de calcio, preferiblemente entre 40 mg y 2500 mg, preferiblemente entre 60 mg y 1800 mg, y más preferiblemente entre 400 mg y 2200 mg. Es particularmente ventajoso que tengan entre 400 y 1200 mg. Preferred dosage forms are those containing between 10 mg and 3,500 mg of 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.
Procedimiento de fabricación Existen varias metodologías para manufacturar una tableta de acción dual del ácido 2,5 - dihidroxibencenosulfónico y/o sus sales farmacéuticamente aceptables o preferentemente el dihidroxibencenosulfonato de calcio. Manufacturing procedure 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) Método de la qranulometría húmeda A) Wet Qranulometry Method
Esta metodología con la utilización de un solvente, permite la obtención de un granulado que comprende el principio activo, utilizando varios equipos que son conocidos por la industria farmacéutica tales como un Mezclador, un Secador de lecho Fluido y un Tamizador. This methodology with the use of a solvent, allows the obtaining of a granulate comprising the active ingredient, using several equipment that are known by the pharmaceutical industry such as a Mixer, a Fluid Bed Dryer and a Sifter.
La aplicación de este proceso, tiene como etapas: The application of this process has as stages:
ETAPA A1 : Fabricación de la capa de Liberación Inmediata A1 a) Preparación de una masa, que consiste en la mezcla del ácido 2,5 - dihidroxibencenosulfónico y/o sus sales farmacéuticamente aceptables o preferentemente el dihidroxibencenosulfonato de calcio, con o sin agentes plastificantes, retardantes, material gastro resistente, colorantes, tensoactivos o suríactantes, deslizantes, lubricantes, aglutinantes, diluyentes, desintegrantes y otros aditivos de uso conocido en la industria farmacéutica y con la utilización de un solvente que puede ser agua destilada o alcohol etílico a 95°. A1 b) Granulación de la mezcla. STAGE A1: Manufacture of the Immediate Release layer A1 a) 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, dyes, 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 ethyl alcohol at 95 °. A1 b) Granulation of the mixture.
A1 c) Secado del granulado. A1 c) Drying the granulate.
A1 d) Tamizado del granulado. A1 d) Screening of the granulate.
A1 e) Mezclado del granulado, opcionalmente con o sin agentes plastificantes, retardantes, material gastro resistente, colorantes, tensoactivos o suríactantes, deslizantes, lubricantes, aglutinantes, diluyentes, desintegrantes y otros aditivos de uso conocido en la industria farmacéutica. A1 e) 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.
A1 f) Tamizado del granulado. A1 f) Screening of the granulate.
A1 g) Mezclado del granulado, opcionalmente con o sin agentes plastificantes, retardantes, material gastro resistente, colorantes, tensoactivos o suríactantes, deslizantes, lubricantes, aglutinantes, diluyentes, desintegrantes y otros aditivos de uso conocido en la industria farmacéutica. A1 g) 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.
ETAPA A2: Fabricación de la capa de Liberación Prolongada STAGE A2: Manufacturing of the Prolonged Release layer
A2a) Preparación de una masa, que consiste en la mezcla del ácido 2,5 - dihidroxibencenosulfónico y/o sus sales farmacéuticamente aceptables o preferentemente el dihidroxibencenosulfonato de calcio, con o sin agentes plastificantes, retardantes, material gastro resistente, colorantes, tensoactivos o suríactantes, deslizantes, lubricantes, aglutinantes, diluyentes, desintegrantes y otros aditivos de uso conocido en la industria farmacéutica y con la utilización de un solvente que puede ser agua destilada o alcohol etílico de 95°. A2b) Granulación de la mezcla. 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, 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 ethyl alcohol of 95 °. A2b) Granulation of the mixture.
A2c) Secado del granulado. A2c) Drying of the granulate.
A2d) Tamizado del granulado. A2d) Screening of the granulate.
A2e) Mezclado del granulado, opcionalmente con o sin agentes plastificantes, retardantes, material gastro resistente, colorantes, tensoactivos o surfactantes, deslizantes, lubricantes, aglutinantes, diluyentes, desintegrantes y otros aditivos de uso conocido en la industria farmacéutica. A2e) 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 for use known in the pharmaceutical industry.
A2f) Tamizado del granulado. A2g) Mezclado del granulado, opcionalmente con o sin agentes plastificantes, retardantes, material gastro resistente, colorantes, tensoactivos o surfactantes, deslizantes, lubricantes, aglutinantes, diluyentes, desintegrantes y otros aditivos de uso conocido en la industria farmacéutica. ETAPA A3: Prensado de una tableta 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 for use known in the pharmaceutical industry. STAGE A3: Pressing a tablet
Se prensa una tableta bicapa, que tiene una capa de del producto obtenido en A1 g) y una capa del producto obtenido en A2g). A bilayer tablet is pressed, which has a layer of the product obtained in A1 g) and a layer of the product obtained in A2g).
B) Método de la mezcla seca B) Dry mix method
Un segundo método de manufactura de una tableta de acción dual del ácido 2,5 - dihidroxibencenosulfónico y/o sus sales farmacéuticamente aceptables o preferentemente el dihidroxibencenosulfonato de calcio, consiste en la realización de una mezcla seca, esta permite la obtención de un granulado que comprende el principio activo, utilizando varios equipos que son muy conocidos en la industria farmacéutica tales como un Mezclador y un Tamizador. La aplicación de este proceso, tiene como etapas: ETAPA B1 : Fabricación de la capa de Liberación Inmediata 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 production of a dry mixture, this allows obtaining 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
B1 a) Preparación de una masa seca, que consiste en la mezcla del ácido 2,5 - dihidroxibencenosulfónico y/o sus sales farmacéuticamente aceptables o preferentemente el dihidroxibencenosulfonato de calcio, con o sin plastificantes, retardantes, material gastro resistente, colorantes, tensoactivos o surfactantes, deslizantes, lubricantes, aglutinantes, diluyentes, desintegrantes y otros aditivos de uso conocido en la industria farmacéutica. B1 a) 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.
B1 b) Tamizado del granulado. ETAPA B2: Fabricación de la capa de Liberación Prolongada B1 b) Screening of the granulate. STAGE B2: Manufacturing of the Prolonged Release layer
B2a) Preparación de una masa seca, que consiste en la mezcla del ácido 2,5 - dihidroxibencenosulfónico y/o sus sales farmacéuticamente aceptables o preferentemente el dihidroxibencenosulfonato de calcio, con o sin plastificantes, retardantes, material gastro resistente, colorantes, tensoactivos o surfactantes, deslizantes, lubricantes, aglutinantes, diluyentes, desintegrantes y otros aditivos de uso conocido en la industria farmacéutica. B2a) 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 of known use in the pharmaceutical industry.
B2b) Tamizado del granulado. B2b) Screening of the granulate.
ETAPA B3: Prensado de una tableta STAGE B3: Pressing a tablet
Se prensa una tableta bicapa, que tiene una capa de del producto obtenido en B1 b) y una capa del producto obtenido en B2b). C) Método combinado A bilayer tablet is pressed, which has a layer of the product obtained in B1 b) and a layer of the product obtained in B2b). C) Combined method
Un tercer método de manufactura de una tableta de acción dual del ácido 2,5 - dihidroxibencenosulfónico y/o sus sales farmacéuticamente aceptables o preferentemente el dihidroxibencenosulfonato de calcio, consiste en la realización de una mezcla seca, para la capa de liberación inmediata y utilizar el método de granulación húmeda, para la capa de liberación prolongada, lo que permite la obtención de un granulado que comprende el principio activo, utilizando varios equipos que son conocidos por la industria farmacéutica tales como un Mezclador y un Tamizador. 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 making a dry mixture, for the immediate release layer and using 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 sieve.
La aplicación de este proceso, tiene como etapas: The application of this process has as stages:
ETAPA C1 : Fabricación de la capa de Liberación Inmediata STAGE C1: Manufacturing of the Immediate Release layer
C1 a) Tamizar y preparar una masa seca, que consiste en la mezcla del ácido 2,5 - dihidroxibencenosulfónico y/o sus sales farmacéuticamente aceptables o preferentemente el dihidroxibencenosulfonato de calcio, con o sin plastificantes, retardantes, colorantes, tensoactivos o surfactantes, deslizantes, lubricantes, aglutinantes, diluyentes, desintegrantes y otros aditivos de uso conocido en la industria farmacéutica. C1 a) 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.
ETAPA C2: Fabricación de la capa de Liberación Prolongada C2a) Micronizar, el ácido 2,5 - dihidroxibencenosulfónico y/o sus sales farmacéuticamente aceptables o preferentemente el dihidroxibencenosulfonato de calcio. 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) Preparación de una masa seca, que consiste en la mezcla del ácido 2,5 - dihidroxibencenosulfónico y/o sus sales farmacéuticamente aceptables o preferentemente el dihidroxibencenosulfonato de calcio, con o sin agentes plastificantes, retardantes, material gastro resistente, colorantes, tensoactivos o surfactantes, deslizantes, lubricantes, aglutinantes, diluyentes, desintegrantes y otros aditivos de uso conocido en la industria farmacéutica y con la utilización de un solvente que puede ser agua destilada o alcohol etílico de 95°. 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 others 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 °.
C2c) Granulación de la mezcla. C2c) Granulation of the mixture.
C2d) Secado del granulado. C2d) Drying of the granulate.
C2e) Tamizado del granulado. C2f) Mezclado del granulado, opcionalmente con o sin agentes plastificantes, retardantes, gastro resistente, colorantes, tensoactivos o surfactantes, deslizantes, lubricantes, aglutinantes, diluyentes, desintegrantes y otros aditivos de uso conocido en la industria farmacéutica. ETAPA C3: Prensado de una tableta C2e) Screening of the granulate. C2f) Mixing of the granulate, optionally with or without plasticizing agents, retarders, gastro resistant, colorants, surfactants or surfactants, glidants, lubricants, binders, diluents, disintegrants and other additives for use known in the pharmaceutical industry. STAGE C3: Pressing a tablet
Se prensa una tableta bicapa, que tiene una capa de del producto obtenido en C1 a) y una capa del producto obtenido en C2f). El mejor método para la elaboración de este novedoso medicamento es partir de la utilización del método de la granulación seca para liberación inmediata y el método de la granulación humedad para la liberación prolongada. A bilayer tablet is pressed, which has a layer of the product obtained in C1 a) 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.
EJEMPLOS EXAMPLES
Los siguientes ejemplos de procedimientos de fabricación, de la composición farmacéutica de la presente invención, se proveen con la finalidad de ilustrar mejor dicha invención, no debiéndose considerar a los mismos como limitantes de la invención cuyo alcance se establece en las reivindicaciones. ETAPA 1 : Fabricación de la capa de Liberación Inmediata a) Tamizar por una malla # 20, 55,5 % p/p a 85 % p/p de dobesilato de calcio, 8 % p/p a 28 % p/p de Celulosa Microcristalina y 1 % p/p a 6 % p/p de Glicolato Sódico de Almidón. Todos los porcentajes están referidos al peso total de la Etapa de Liberación Inmediata. b) Mezclar lo obtenido en a), entre un rango de tiempo de 1 min a 30 min. c) Tamizar por una malla # 30, 0,6 % p/p a 5 % p/p de Estearato de Magnesio y 0,6 % p/p a 5,5 % p/p de Talco. Todos los porcentajes están referidos al peso total de la Etapa de Liberación Inmediata. d) Mezclar lo obtenido en b) y c), entre un rango de tiempo de 1 min a 15 min. 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. 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 Glycolate Starch. All percentages refer 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. c) Sift through a # 30 mesh, 0.6% w / w 5% w / w Magnesium Stearate and 0.6% w / w 5.5% w / w Talc. All percentages refer 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.
ETAPA 2: Fabricación de la capa de Liberación Prolongada a) Micronizar, 25 % p/p a 75 % p/p de dobesilato de calcio. Todos los porcentajes están referidos al peso total de la Etapa de Liberación Prolongada. b) Disolver, 0,1 % p/p a 5 % p/p de Hidroxipropilcelulosa en una cantidad suficiente de Agua Purificada. Todos los porcentajes están referidos al peso total de la Etapa de Liberación Prolongada. c) Mezclar lo obtenido en a), con 10 % p/p a 45 % p/p de Hidroxipropilmetilcelulosa, 6 % p/p a 15 % p/p de Hidroxipropilcelulosa y 0,05 % p/p a 3 % p/p de Laca Roja, entre un rango de tiempo de 1 min a 15 min. Todos los porcentajes están referidos al peso total de la Etapa de Liberación Prolongada. d) Granular lo obtenido en c) con la solución obtenida en b). e) Secar lo obtenido en d), entre un rango de temperatura de 45 eC a 70 eC y un rango de tiempo de 10 min a 60 min. f) Tamizar por una malla 062R lo obtenido en e). g) Tamizar por una malla # 30, 0,6 % p/p a 5 % p/p de talco y 0,6 % p/p a 5 % p/p de Estearato de Magnesio. Todos los porcentajes están referidos al peso total de la Etapa de Liberación Prolongada. h) Mezclar lo obtenido en f) y g), entre un rango de tiempo de 1 min a 15 min. EJEMPL0 1 STAGE 2: Manufacture of the Prolonged Release layer a) Micronize, 25% w / w 75% w / w calcium dobesilate. All percentages refer to the total weight of the Prolonged Release Stage. b) Dissolve 0.1% w / w 5% w / w Hydroxypropylcellulose in a sufficient amount of Purified Water. All percentages refer to the total weight of the Prolonged Release Stage. 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 percentages refer 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 e C to 70 e C 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 5% w / w talc and 0.6% w / w 5% w / w Magnesium Stearate. All percentages refer 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. EXAMPLE 1
A continuación, el proceso de preparación farmacéutica de liberación programada se va a dividir en dos etapas. ETAPA 1 : Fabricación de la capa de Liberación Inmediata a) Tamizar por una malla # 20, 74,07 % p/p de dobesilato de calcio, 20,74 % p/p de Celulosa Microcristalina y 2,07 % p/p de Glicolato Sódico de Almidón. Todos los porcentajes están referidos al peso total de la Etapa de Liberación Inmediata. b) Mezclar lo obtenido en a), entre un rango de tiempo de 1 min a 30 min. c) Tamizar por una malla # 30, 1 ,33 % p/p de Estearato de Magnesio y 1 ,78 % p/p de Talco. Todos los porcentajes están referidos al peso total de la Etapa de Liberación Inmediata. d) Mezclar lo obtenido en b) y c), entre un rango de tiempo de 1 min a 15 min. Materiales Peso [%] Next, the process of pharmaceutical preparation for scheduled release will be divided into two stages. 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 Starch Sodium Glycolate. All percentages refer 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. c) Sift through a # 30, 1, 33% w / w mesh of Magnesium Stearate and 1.78% w / w Talc. All percentages refer 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. Materials Weight [%]
Dobesilato de Calcio 74,07  Calcium Dobesilate 74.07
Celulosa Microcristalina 20,74  Microcrystalline Cellulose 20.74
Glicolato Sódico de Almidón 2,07  Starch Sodium Glycolate 2.07
Estearato de Magnesio 1 ,33  Magnesium Stearate 1, 33
Talco 1 ,79  Talc 1, 79
ETAPA 2: Fabricación de la capa de Liberación Prolongada a) Micronizar 53,76 % p/p de dobesilato de calcio. Todos los porcentajes están referidos al peso total de la Etapa de Liberación Prolongada. b) Disolver 0,81 % p/p de Hidroxipropilcelulosa y una cantidad suficiente de Agua Purificada. Todos los porcentajes están referidos al peso total de la Etapa de Liberación Prolongada. c) Mezclar lo obtenido en a) con 32,15 % p/p de Hidroxipropilmetilcelulosa, 9,68 % p/p de Hidroxipropilcelulosa y 0,12 % p/p de Laca Roja, entre un rango de tiempo de 1 min a 15 min. Todos los porcentajes están referidos al peso total de la Etapa de Liberación Prolongada. d) Granular lo obtenido en c) con la solución obtenida en b). e) Secar lo obtenido en d), entre un rango de temperatura de 45 eC a 70 eC y un rango de tiempo de 10 min a 60 min. f) Tamizar por una malla 062R lo obtenido en e). g) Tamizar por una malla # 30, 1 ,97 % p/p de talco y 1 ,51 % p/p de Estearato de Magnesio. Todos los porcentajes están referidos al peso total de la Etapa de Liberación Prolongada. h) Mezclar lo obtenido en f) y g), entre un rango de tiempo de 1 min a 15 min. STAGE 2: Manufacture of the Prolonged Release layer a) Micronize 53.76% w / w calcium dobesilate. All percentages refer to the total weight of the Prolonged Release Stage. b) Dissolve 0.81% w / w Hydroxypropylcellulose and a sufficient amount of Purified Water. All percentages refer to the total weight of the Prolonged Release Stage. c) Mix the obtained in a) with 32.15% w / w Hydroxypropylmethylcellulose, 9.68% w / w Hydroxypropylcellulose and 0.12% w / w Red Lacquer, between a time range of 1 min to 15 min. All percentages refer 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 e C to 70 e C 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, 1, 97% w / w talcum powder and 1.51% w / w Magnesium Stearate. All percentages refer 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.
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 53,76  Calcium Dobesilate 53.76
Hidroxipropilmetilcelulosa 32,15  Hydroxypropyl methylcellulose 32.15
Hidroxipropilcelulosa 10,49  Hydroxypropylcellulose 10.49
Laca Roja 0,12  Red Lacquer 0.12
Talco 1 ,97  Talc 1, 97
Estearato de Magnesio 1 ,51  Magnesium Stearate 1, 51
Agua purificada* es. Purified water * is.
* Se evapora durante el proceso  * It evaporates during the process
Se comprimen ambas fases en un punzón alargado. Both phases are compressed in an elongated punch.
En la figura 1 se muestra un ejemplo de tableta bicapa en la que la capa de liberación inmediata 1 está representada en un color gris, mientras que la capa de liberación prolongada 2 está representada en un color blanco. Las figuras 2A, 2B y 3A, 3B muestran esquemáticamente la acción dual de las tabletas de acuerdo con la invención, donde, en primer lugar, se disuelve la capa de liberación inmediata 1 (figuras 2A y 2B) y, posteriormente, se disuelve la capa de liberación prolongada 2 (figuras 3A y 3B). An example of a bilayer tablet in which the immediate release layer 1 is represented in a gray color is shown in Figure 1, while the extended release layer 2 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 prolonged release layer 2 (Figures 3A and 3B).
En la figura 4 se muestra el perfil de liberación de la tableta bicapa del ejemplo 1 . La proporción entre la capa de liberación inmediata y la capa de liberación prolongada es de 33:67. The release profile of the bilayer tablet of example 1 is shown in Figure 4. The ratio between the immediate release layer and the extended release layer is 33:67.
Para los ejemplos 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 y 12 se utiliza la anterior técnica ya mencionada en el ejemplo 1 . EJEMPLO 2 For examples 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 and 12 the previous technique already mentioned in example 1 is used. EXAMPLE 2
ETAPA 1 : Fabricación de la capa de Liberación Inmediata STAGE 1: Manufacturing of the Immediate Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 76,45  Calcium Dobesilate 76.45
Celulosa Microcristalina 18,84  Microcrystalline Cellulose 18.84
Glicolato Sódico de Almidón 1 ,88  Starch Sodium Glycolate 1, 88
Esterato de Magnesio 1 ,21  Magnesium Sterate 1, 21
Talco 1 ,62  Talc 1, 62
ETAPA 2: Fabricación de la capa de Liberación Prolongada STAGE 2: Manufacturing of the Prolonged Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 55,22  Calcium Dobesilate 55.22
Hidroxipropilmetilcelulosa 31 ,14  Hydroxypropyl methylcellulose 31, 14
Hidroxipropilcelulosa 10,15  Hydroxypropylcellulose 10.15
Laca Roja 0,12  Red Lacquer 0.12
Talco 1 ,91  Talc 1, 91
Estearato de Magnesio 1 ,46  Magnesium Stearate 1, 46
Agua purificada* es. Purified water * is.
* Se evapora durante el proceso  * It evaporates during the process
Se comprimen ambas fases en un punzón alargado. La proporción entre la capa de liberación inmediata y la capa de liberación prolongada es de 31 :69. EJEMPLO 3 Both phases are compressed in an elongated punch. The ratio between the immediate release layer and the extended release layer is 31: 69. EXAMPLE 3
ETAPA 1 : Fabricación de la capa de Liberación Inmediata STAGE 1: Manufacturing of the Immediate Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 78,13  Calcium Dobesilate 78.13
Celulosa Microcristalina 17,5  17.5 Microcrystalline Cellulose
Glicolato Sódico de Almidón 1 ,75  Starch Sodium Glycolate 1, 75
Estearato de Magnesio 1 ,12  Magnesium Stearate 1, 12
Talco 1 ,5  Talc 1, 5
ETAPA 2: Fabricación de la capa de Liberación Prolongada STAGE 2: Manufacturing of the Prolonged Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 56,37  Calcium Dobesilate 56.37
Hidroxipropilmetilcelulosa 30,34  Hydroxypropyl methylcellulose 30.34
Hidroxipropilcelulosa 9,89  Hydroxypropylcellulose 9.89
Laca Roja 0,12  Red Lacquer 0.12
Talco 1 ,86  Talc 1, 86
Estearato de Magnesio 1 ,42  Magnesium Stearate 1, 42
Agua purificada* es. Purified water * is.
* Se evapora durante el proceso  * It evaporates during the process
Se comprimen ambas fases en un punzón alargado. La proporción entre la capa de liberación inmediata y la capa de liberación prolongada es de 34:66. Both phases are compressed in an elongated punch. The ratio between the immediate release layer and the extended release layer is 34:66.
En la figura 5 se muestra el perfil de liberación de la tableta bicapa. EJEMPLO 4 Figure 5 shows the release profile of the bilayer tablet. EXAMPLE 4
ETAPA 1 : Fabricación de la capa de Liberación Inmediata STAGE 1: Manufacturing of the Immediate Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 72,82  Calcium Dobesilate 72.82
Celulosa Microcristalina 21 ,75  Microcrystalline Cellulose 21, 75
Glicolato Sódico de Almidón 2,17  Sodium Glycolate Starch 2.17
Estearato de Magnesio 1 ,4  Magnesium Stearate 1, 4
Talco 1 ,86  Talc 1, 86
ETAPA 2: Fabricación de la capa de Liberación Prolongada STAGE 2: Manufacturing of the Prolonged Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 54,78  Calcium Dobesilate 54.78
Hidroxipropilmetilcelulosa 31 ,45  Hydroxypropyl methylcellulose 31, 45
Hidroxipropilcelulosa 10,25  Hydroxypropylcellulose 10.25
Laca Roja 0,12  Red Lacquer 0.12
Talco 1 ,93  Talc 1, 93
Estearato de Magnesio 1 ,47  Magnesium Stearate 1, 47
Agua purificada* es. Purified water * is.
* Se evapora durante el proceso  * It evaporates during the process
Se comprimen ambas fases en un punzón alargado. La proporción entre la capa de liberación inmediata y la capa de liberación prolongada es de 37:63. EJEMPLO 5 Both phases are compressed in an elongated punch. The ratio between the immediate release layer and the extended release layer is 37:63. EXAMPLE 5
ETAPA 1 : Fabricación de la capa de Liberación Inmediata STAGE 1: Manufacturing of the Immediate Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 79,5  Calcium Dobesilate 79.5
Celulosa Microcristalina 12,75  Microcrystalline Cellulose 12.75
Glicolato Sódico de Almidón 4  Starch Sodium Glycolate 4
Estearato de Magnesio 1 ,75  Magnesium Stearate 1, 75
Talco 2  Talc 2
ETAPA 2: Fabricación de la capa de Liberación Prolongada STAGE 2: Manufacturing of the Prolonged Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 58,4  Calcium Dobesilate 58.4
Hidroxipropilmetilcelulosa 28,35  Hydroxypropyl methylcellulose 28.35
Hidroxipropilcelulosa 8,75  Hydroxypropylcellulose 8.75
Laca Roja 0,1  Red Lacquer 0,1
Talco 2,1  Talc 2.1
Estearato de Magnesio 2,3  Magnesium Stearate 2.3
Agua purificada* es. Purified water * is.
* Se evapora durante el proceso  * It evaporates during the process
Se comprimen ambas fases en un punzón alargado. La proporción entre la capa de liberación inmediata y la capa de liberación prolongada es de 39:61 . Both phases are compressed in an elongated punch. The ratio between the immediate release layer and the extended release layer is 39:61.
En la figura 6 se muestra el perfil de liberación de la tableta bicapa. EJEMPLO 6 Figure 6 shows the release profile of the bilayer tablet. EXAMPLE 6
ETAPA 1 : Fabricación de la capa de Liberación Inmediata STAGE 1: Manufacturing of the Immediate Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 72,3  Calcium Dobesilate 72.3
Celulosa Microcristalina 20,45  Microcrystalline Cellulose 20.45
Glicolato Sódico de Almidón 3,75  Sodium Glycolate Starch 3.75
Estearato de Magnesio 1 ,6  Magnesium Stearate 1, 6
Talco 1 ,9  Talc 1, 9
ETAPA 2: Fabricación de la capa de Liberación Prolongada STAGE 2: Manufacturing of the Prolonged Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 51 ,18  Calcium Dobesilate 51, 18
Hidroxipropilmetilcelulosa 33,46  Hydroxypropyl methylcellulose 33.46
Hidroxipropilcelulosa 1 1 ,08  Hydroxypropylcellulose 1 1, 08
Laca Roja 0,08  Red Lacquer 0,08
Talco 2,2  Talc 2.2
Estearato de Magnesio 2  Magnesium Stearate 2
Agua purificada* es. Purified water * is.
* Se evapora durante el proceso  * It evaporates during the process
Se comprimen ambas fases en un punzón alargado. La proporción entre la capa de liberación inmediata y la capa de liberación prolongada es de 28:72. Both phases are compressed in an elongated punch. The ratio between the immediate release layer and the extended release layer is 28:72.
En la figura 7 se muestra el perfil de liberación de la tableta bicapa. Figure 7 shows the release profile of the bilayer tablet.
Los ejemplos 1 a 6 son formas particularmente ventajosas de realización de la invención. EJEMPLO 7 Examples 1 to 6 are particularly advantageous embodiments of the invention. EXAMPLE 7
ETAPA 1 : Fabricación de la capa de Liberación Inmediata STAGE 1: Manufacturing of the Immediate Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 78,13  Calcium Dobesilate 78.13
Celulosa Microcristalina 17,50  Microcrystalline Cellulose 17.50
Glicolato Sódico de Almidón 1 ,75  Starch Sodium Glycolate 1, 75
Esterato de Magnesio 1 ,12  Magnesium Sterate 1, 12
Talco 1 ,50  Talc 1, 50
ETAPA 2: Fabricación de la capa de Liberación Prolongada STAGE 2: Manufacturing of the Prolonged Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 56,37  Calcium Dobesilate 56.37
Etilcelulosa 30,34  Ethyl Cellulose 30.34
Hidroxipropilcelulosa 9,89  Hydroxypropylcellulose 9.89
Laca Roja 0,12  Red Lacquer 0.12
Talco 1 ,86  Talc 1, 86
Estearato de Magnesio 1 ,42  Magnesium Stearate 1, 42
Agua purificada* es. Purified water * is.
* Se evapora durante el proceso  * It evaporates during the process
Se comprimen ambas fases en un punzón alargado. La proporción entre la capa de liberación inmediata y la capa de liberación prolongada es de 30:70. Both phases are compressed in an elongated punch. The ratio between the immediate release layer and the extended release layer is 30:70.
En la figura 8 se muestra el perfil de liberación de la tableta bicapa. Figure 8 shows the release profile of the bilayer tablet.
EJEMPLO 8 EXAMPLE 8
ETAPA 1 : Fabricación de la capa de Liberación Inmediata Materiales Peso [%] STAGE 1: Manufacturing of the Immediate Release layer Materials Weight [%]
Dobesilato de Calcio 78,13  Calcium Dobesilate 78.13
Celulosa Microcristalina 17,50  Microcrystalline Cellulose 17.50
Glicolato Sódico de Almidón 1 ,75  Starch Sodium Glycolate 1, 75
Esterato de Magnesio 1 ,12  Magnesium Sterate 1, 12
Talco 1 ,50  Talc 1, 50
ETAPA 2: Fabricación de la capa de Liberación Prolongada STAGE 2: Manufacturing of the Prolonged Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 50,71  Calcium Dobesilate 50.71
Etilcelulosa 36,00  Ethyl Cellulose 36.00
Hidroxipropilcelulosa 9,89  Hydroxypropylcellulose 9.89
Laca Roja 0,12  Red Lacquer 0.12
Talco 1 ,86  Talc 1, 86
Estearato de Magnesio 1 ,42  Magnesium Stearate 1, 42
Agua purificada* es. Purified water * is.
* Se evapora durante el proceso  * It evaporates during the process
Se comprimen ambas fases en un punzón alargado. La proporción entre la capa de liberación inmediata y la capa de liberación prolongada es de 29:71 . Both phases are compressed in an elongated punch. The ratio between the immediate release layer and the extended release layer is 29:71.
En la figura 9 se muestra el perfil de liberación de la tableta bicapa. Figure 9 shows the release profile of the bilayer tablet.
EJEMPLO 9 EXAMPLE 9
ETAPA 1 : Fabricación de la capa de Liberación Inmediata STAGE 1: Manufacturing of the Immediate Release layer
Materiales Peso [%] Dobesilato de Calcio 78,13 Materials Weight [%] Calcium Dobesilate 78.13
Celulosa Microcristalina 17,50  Microcrystalline Cellulose 17.50
Glicolato Sódico de Almidón 1 ,75  Starch Sodium Glycolate 1, 75
Esterato de Magnesio 1 ,12  Magnesium Sterate 1, 12
Talco 1 ,50  Talc 1, 50
ETAPA 2: Fabricación de la capa de Liberación Prolongada STAGE 2: Manufacturing of the Prolonged Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 61 ,98 Calcium Dobesilate 61, 98
Copolimero de Metacrilato de Amonio 24,80Ammonium Methacrylate Copolymer 24.80
Hidroxipropilcelulosa 9,82Hydroxypropylcellulose 9.82
Laca Roja 0,12Red Lacquer 0.12
Talco 1 ,86Talc 1, 86
Estearato de Magnesio 1 ,42Magnesium Stearate 1, 42
Agua purificada* es. Purified water * is.
* Se evapora durante el proceso  * It evaporates during the process
Se comprimen ambas fases en un punzón alargado. La proporción entre la capa de liberación inmediata y la capa de liberación prolongada es de 30:70. Both phases are compressed in an elongated punch. The ratio between the immediate release layer and the extended release layer is 30:70.
En la figura 10 se muestra el perfil de liberación de la tableta bicapa. The release profile of the bilayer tablet is shown in Figure 10.
EJEMPLO 10 ETAPA 1 : Fabricación de la capa de Liberación Inmediata EXAMPLE 10 STAGE 1: Manufacture of the Immediate Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 78,13  Calcium Dobesilate 78.13
Celulosa Microcristalina 17,50  Microcrystalline Cellulose 17.50
Glicolato Sódico de Almidón 1 ,75 Esterato de Magnesio 1 ,12 Starch Sodium Glycolate 1, 75 Magnesium Sterate 1, 12
Talco 1 ,50  Talc 1, 50
ETAPA 2: Fabricación de la capa de Liberación Prolongada STAGE 2: Manufacturing of the Prolonged Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 50,94 Calcium Dobesilate 50.94
Copolimero de Metacrilato de Amonio 35,84Ammonium Methacrylate Copolymer 35.84
Hidroxipropilcelulosa 9,82Hydroxypropylcellulose 9.82
Laca Roja 0,12Red Lacquer 0.12
Talco 1 ,86Talc 1, 86
Estearato de Magnesio 1 ,42Magnesium Stearate 1, 42
Agua purificada* es. Purified water * is.
* Se evapora durante el proceso  * It evaporates during the process
Se comprimen ambas fases en un punzón alargado. La proporción entre la capa de liberación inmediata y la capa de liberación prolongada es de 27:73. Both phases are compressed in an elongated punch. The ratio between the immediate release layer and the extended release layer is 27:73.
En la figura 1 1 se muestra el perfil de liberación de la tableta bicapa. Figure 1 1 shows the release profile of the bilayer tablet.
EJEMPLO 11 ETAPA 1 : Fabricación de la capa de Liberación Inmediata EXAMPLE 11 STAGE 1: Manufacture of the Immediate Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 72,82  Calcium Dobesilate 72.82
Celulosa Microcristalina 21 ,75  Microcrystalline Cellulose 21, 75
Glicolato Sódico de Almidón 2,17  Sodium Glycolate Starch 2.17
Esterato de Magnesio 1 ,40  Magnesium Sterate 1, 40
Talco 1 ,86 ETAPA 2: Fabricación de la capa de Liberación Prolongada Talc 1, 86 STAGE 2: Manufacturing of the Prolonged Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 52,83 Calcium Dobesilate 52.83
Alginato de Sodio 33,40Sodium Alginate 33.40
Hidroxipropilcelulosa 10,25Hydroxypropylcellulose 10.25
Laca Roja 0,12Red Lacquer 0.12
Talco 1 ,93Talc 1, 93
Estearato de Magnesio 1 ,47Magnesium Stearate 1, 47
Agua purificada* es. Purified water * is.
* Se evapora durante el proceso  * It evaporates during the process
Se comprimen ambas fases en un punzón alargado. La proporción entre la capa de liberación inmediata y la capa de liberación prolongada es de 25:75. Both phases are compressed in an elongated punch. The ratio between the immediate release layer and the extended release layer is 25:75.
En la figura 12 se muestra el perfil de liberación de la tableta bicapa. Figure 12 shows the release profile of the bilayer tablet.
EJEMPLO 12 EXAMPLE 12
ETAPA 1 : Fabricación de la capa de Liberación Inmediata STAGE 1: Manufacturing of the Immediate Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 72,82  Calcium Dobesilate 72.82
Celulosa Microcristalina 21 ,75  Microcrystalline Cellulose 21, 75
Glicolato Sódico de Almidón 2,17  Sodium Glycolate Starch 2.17
Esterato de Magnesio 1 ,40  Magnesium Sterate 1, 40
Talco 1 ,86  Talc 1, 86
ETAPA 2: Fabricación de la capa de Liberación Prolongada Materiales Peso [%] STAGE 2: Manufacturing of the Prolonged Release layer Materials Weight [%]
Dobesilato de Calcio 56,59 Calcium Dobesilate 56.59
Alginato de Sodio 29,64Sodium Alginate 29.64
Hidroxipropilcelulosa 10,25Hydroxypropylcellulose 10.25
Laca Roja 0,12Red Lacquer 0.12
Talco 1 ,93Talc 1, 93
Estearato de Magnesio 1 ,47Magnesium Stearate 1, 47
Agua purificada* es. Purified water * is.
* Se evapora durante el proceso  * It evaporates during the process
Se comprimen ambas fases en un punzón alargado. La proporción entre la capa de liberación inmediata y la capa de liberación prolongada es de 29:71 . Both phases are compressed in an elongated punch. The ratio between the immediate release layer and the extended release layer is 29:71.
En la figura 13 se muestra el perfil de liberación de la tableta bicapa. The release profile of the bilayer tablet is shown in Figure 13.
EJEMPLO 13 EXAMPLE 13
ETAPA 1 : Fabricación de la capa de Liberación Inmediata STAGE 1: Manufacturing of the Immediate Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 79,5  Calcium Dobesilate 79.5
Celulosa Microcristalina 12,75  Microcrystalline Cellulose 12.75
Glicolato Sódico de Almidón 4  Starch Sodium Glycolate 4
Estearato de Magnesio 1 ,75  Magnesium Stearate 1, 75
Talco 2  Talc 2
ETAPA 2: Fabricación de la capa de Liberación Prolongada STAGE 2: Manufacturing of the Prolonged Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 78,25 Hidroxipropilmetilcelulosa 8,5 Calcium Dobesilate 78.25 Hydroxypropyl methylcellulose 8.5
Hidroxipropilcelulosa 8,75  Hydroxypropylcellulose 8.75
Laca Roja 0,1  Red Lacquer 0,1
Talco 2,1  Talc 2.1
Estearato de Magnesio 2,3  Magnesium Stearate 2.3
Agua purificada* es. Purified water * is.
* Se evapora durante el proceso  * It evaporates during the process
Se comprimen ambas fases en un punzón alargado. La proporción entre la capa de liberación inmediata y la capa de liberación prolongada es de 36:64. Both phases are compressed in an elongated punch. The ratio between the immediate release layer and the extended release layer is 36:64.
En la figura 14 se muestra el perfil de liberación de la tableta bicapa. The release profile of the bilayer tablet is shown in Figure 14.
La disolución muestra un perfil acelerado en liberación, lo cual no permite un mantenimiento de 24 horas de la acción. The solution shows an accelerated release profile, which does not allow 24-hour maintenance of the action.
EJEMPLO 14 EXAMPLE 14
ETAPA 1 : Fabricación de la capa de Liberación Inmediata STAGE 1: Manufacturing of the Immediate Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 79,5  Calcium Dobesilate 79.5
Celulosa Microcristalina 12,75  Microcrystalline Cellulose 12.75
Glicolato Sódico de Almidón 4  Starch Sodium Glycolate 4
Estearato de Magnesio 1 ,75  Magnesium Stearate 1, 75
Talco 2  Talc 2
ETAPA 2: Fabricación de la capa de Liberación Prolongada STAGE 2: Manufacturing of the Prolonged Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 40,75 Hidroxipropilmetilcelulosa 46,0 Calcium Dobesilate 40.75 Hydroxypropyl methylcellulose 46.0
Hidroxipropilcelulosa 8,75  Hydroxypropylcellulose 8.75
Laca Roja 0,1  Red Lacquer 0,1
Talco 2,1  Talc 2.1
Estearato de Magnesio 2,3  Magnesium Stearate 2.3
Agua purificada* es. Purified water * is.
* Se evapora durante el proceso  * It evaporates during the process
Se comprimen ambas fases en un punzón alargado. La proporción entre la capa de liberación inmediata y la capa de liberación prolongada es de 28:72. Both phases are compressed in an elongated punch. The ratio between the immediate release layer and the extended release layer is 28:72.
En la figura 15 se muestra el perfil de liberación de la tableta bicapa. Figure 15 shows the release profile of the bilayer tablet.
La disolución muestra un perfil lento en liberación, lo cual no permite un mantenimiento de niveles idóneos durante las 24 horas. The solution shows a slow release profile, which does not allow maintenance of suitable levels for 24 hours.
EJEMPLO 15 EXAMPLE 15
ETAPA 1 : Fabricación de la capa de Liberación Inmediata STAGE 1: Manufacturing of the Immediate Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 72,3  Calcium Dobesilate 72.3
Celulosa Microcristalina 20,45  Microcrystalline Cellulose 20.45
Glicolato Sódico de Almidón 3,75  Sodium Glycolate Starch 3.75
Estearato de Magnesio 1 ,6  Magnesium Stearate 1, 6
Talco 1 ,9  Talc 1, 9
ETAPA 2: Fabricación de la capa de Liberación Prolongada STAGE 2: Manufacturing of the Prolonged Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 51 ,18 Hidroxipropilmetilcelulosa 33,46 Calcium Dobesilate 51, 18 Hydroxypropyl methylcellulose 33.46
Hidroxipropilcelulosa 1 1 ,08  Hydroxypropylcellulose 1 1, 08
Laca Roja 0,08  Red Lacquer 0,08
Talco 2,2  Talc 2.2
Estearato de Magnesio 2  Magnesium Stearate 2
Agua purificada* es. Purified water * is.
* Se evapora durante el proceso  * It evaporates during the process
Se comprimen ambas fases en un punzón alargado. La proporción entre la capa de liberación inmediata y la capa de liberación prolongada es de 22:78. Both phases are compressed in an elongated punch. The ratio between the immediate release layer and the extended release layer is 22:78.
En la figura 16 se muestra el perfil de liberación de la tableta bicapa. Figure 16 shows the release profile of the bilayer tablet.
La disolución muestra un perfil lento en liberación, lo cual no permite un mantenimiento de niveles idóneos durante las 24 horas. The solution shows a slow release profile, which does not allow maintenance of suitable levels for 24 hours.
EJEMPLO 16 EXAMPLE 16
ETAPA 1 : Fabricación de la capa de Liberación Inmediata STAGE 1: Manufacturing of the Immediate Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 72,3  Calcium Dobesilate 72.3
Celulosa Microcristalina 20,45  Microcrystalline Cellulose 20.45
Glicolato Sódico de Almidón 3,75  Sodium Glycolate Starch 3.75
Estearato de Magnesio 1 ,6  Magnesium Stearate 1, 6
Talco 1 ,9  Talc 1, 9
ETAPA 2: Fabricación de la capa de Liberación Prolongada STAGE 2: Manufacturing of the Prolonged Release layer
Materiales Peso [%] Materials Weight [%]
Dobesilato de Calcio 51 ,18 Hidroxipropilmetilcelulosa 33,46 Calcium Dobesilate 51, 18 Hydroxypropyl methylcellulose 33.46
Hidroxipropilcelulosa 1 1 ,08  Hydroxypropylcellulose 1 1, 08
Laca Roja 0,08  Red Lacquer 0,08
Talco 2,2  Talc 2.2
Estearato de Magnesio 2  Magnesium Stearate 2
Agua purificada* es. Purified water * is.
* Se evapora durante el proceso  * It evaporates during the process
Se comprimen ambas fases en un punzón alargado. La proporción entre la capa de liberación inmediata y la capa de liberación prolongada es de 41 :59. Both phases are compressed in an elongated punch. The ratio between the immediate release layer and the extended release layer is 41: 59.
En la figura 17 se muestra el perfil de liberación de la tableta bicapa. The release profile of the bilayer tablet is shown in Figure 17.
La disolución muestra un perfil acelerado en liberación, lo cual no permite un mantenimiento de 24 horas de la acción. The solution shows an accelerated release profile, which does not allow 24-hour maintenance of the action.
Para evaluar el perfil de disolución de la composición farmacéutica en forma de tableta de la presente invención, se utilizó un aparato de disolución tipo II (Paletas), empleando como medio de disolución una solución buffer a pH 5,5. To evaluate the dissolution profile of the pharmaceutical composition in tablet form of the present invention, a type II dissolution apparatus (Pallets) was used, using a buffer solution at pH 5.5 as the dissolution medium.
El experimento se realizó por sextuplicado a una temperatura de 37 °C, 60 rpm y un volumen de 1 .000 mi de una solución buffer a pH 5,5. Se extrajeron muestras a distintos intervalos de tiempos con reposición de medio y se determinó la cantidad de dobesilato de calcio, disuelto mediante un espectrofotometro UV-Vis a 308 nm de longitud de onda. The experiment was carried out in sextuplicate at a temperature of 37 ° C, 60 rpm and a volume of 1000 ml of a buffer solution at pH 5.5. Samples were taken at different time intervals with media replacement and the amount of calcium dobesilate was determined, dissolved by a UV-Vis spectrophotometer at 308 nm wavelength.
Se puede concluir que la presente formulación farmacéutica muestra un perfil de acción dual en solución buffer pH 5,5. La primera fase es de liberación inmediata, tiene una duración aproximada de 1 hora, a lo largo de ese tiempo se libera entre 20 % y 70 % del total del dobesilato de calcio correspondiente a esta etapa. Para la segunda fase que es de liberación prolongada, el tiempo de liberación total correspondiente entre 35 % y 100 % del total del dobesilato de calcio correspondiente a esta etapa, es de 24 horas. 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, has an approximate duration of 1 hour, during that time between 20% and 70% of the total calcium dobesilate corresponding to this stage is released. For the second phase, which is extended release, the corresponding total release time between 35% and 100% of the total calcium dobesilate corresponding to this stage is 24 hours.
El conjunto de ambas etapas promueve que la liberación total in vivo del principio activo se prolongue a lo largo de 24 horas. The combination of both stages promotes that the total in vivo release of the active substance be prolonged over 24 hours.
Datos Farmacocinéticos Pharmacokinetic Data
Los niveles plasmáticos para la formulación farmacéutica de dobesilato de calcio de liberación dual, se obtuvieron mediante un estudio clínico realizado a 14 voluntarios con buena salud de ambos sexos, con un rango de edad comprendido entre los 21 a 54 años, cuyos datos promedios figuran en la Tabla Ne 1 . A donde están reflejados variables farmacocinéticas tales como: Concentración Máxima (Cmax), Área Bajo la Curva (ABC) y Tiempo Máximo (Tmax). 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 54 years, whose average data are in Table N e 1. Where pharmacokinetic variables such as: Maximum Concentration (Cmax), Area Under the Curve (ABC) and Maximum Time (Tmax) are reflected.
Tabla Ns 1 : Variables Farmacocinéticas Table N s 1: Pharmacokinetic Variables
Dobesilato de Dobesilato de Dobesilate Dobesilate
Variables Calcio Calcio P LN Farmacocinéticas Liberación Dual Liberación transformados  Variables Calcium Calcium P LN Pharmacokinetics Dual release Transformed release
c/24 h Inmediata c/12h  c / 24 h Immediate c / 12h
Cmax 10.15+/-1 .94 μ/mL 8.96+/-1 .88 μ/mL 0.09  Cmax 10.15 +/- 1 .94 μ / mL 8.96 +/- 1 .88 μ / mL 0.09
92.84+/-15.96 88.74+/- 92.84 +/- 15.96 88.74 +/-
ABC 0 24 0.26 ABC 0 24 0.26
μ/mL/h 12.86μ/ηι ι  μ / mL / h 12.86μ / ηι ι
96.57+/- 93.35+/- 96.57 +/- 93.35 +/-
ABC 0■" 0.33 ABC 0 ■ " 0.33
16.28μ/ηι ι 15.28M/mL/h  16.28μ / ηι ι 15.28M / mL / h
Tmax 4.79+/-0.2 h 4.68+/- +/- 0.36 0.8 Se puede observar en la Tabla Ne 1 , que no existen diferencias estadísticamente significativas entre las dos formulaciones en ninguno de los parámetros evaluados en las 24 horas (intervalo terapéutico). Tabla Ns 2: Relación de las medias aritméticas v sus intervalos de confianza al 95 % Tmax 4.79 +/- 0.2 h 4.68 +/- +/- 0.36 0.8 It can be seen in Table N e 1, that there are no statistically significant differences between the two formulations in any of the parameters evaluated in the 24 hours (therapeutic interval). Table N s 2: Ratio of arithmetic means and their 95% confidence intervals
Figure imgf000044_0001
Figure imgf000044_0001
Se puede observar en la Tabla Ne 2, que las relaciones entre las medias de ambos productos y sus intervalos de confianza al 95 % se mantienen dentro de los límites aceptados para productos similares (80% -125%). No se reportaron efectos adversos de importancia relacionados con la medicación. It can be seen in Table N e 2, that the relationships between the averages of both 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.
En los datos reflejados en las Tablas Ne 1 y 2, se pudo comprobar que el dobesilato L.P suministrado en una dosis diaria de 1000 mg se absorbe a una misma velocidad medida por la Cmax y en una cantidad medida por las ABC, similares, por lo cual debemos esperar efectos terapéuticos similares. In the data reflected in Tables N e 1 and 2, it was found that LP dobesilate supplied in a daily dose of 1000 mg is absorbed at the same rate measured by Cmax and in an amount measured by ABCs, similar, by which we should expect similar therapeutic effects.
Sorprendentemente los autores de la presente invención han encontrado una nueva formulación farmacéutica de liberación dual de dobesilato de calcio con la que se garantizan los efectos terapéuticos óptimos de dobesilato de calcio en los primeros minutos, después de la ingesta de la formulación, y a lo largo de 24 horas. Por lo tanto, la nueva formulación permite suministrar en una sola dosis la cantidad necesaria para todo un día, que se irá liberando de una forma gradual a lo largo de las siguientes 24 horas de la ingesta. Esto ofrece una gran ventaja al paciente en términos de cumplimiento del tratamiento necesario. Surprisingly, the authors of the present invention have found a new pharmaceutical dual-release formulation of calcium dobesilate with which the optimal therapeutic effects of calcium dobesilate are guaranteed in the first minutes, after the intake of the formulation, and throughout 24 hours. Therefore, the new formulation allows to supply in a single dose the amount necessary for a whole day, which will be released gradually over the next 24 hours of intake. This offers a great advantage to the patient in terms of compliance with the necessary treatment.

Claims

REIVINDICACIONES 1 - Composición farmacéutica que comprende ácido 2,5 - dihidroxibencenosulfónico o una de sus sales farmacéuticamente aceptables en forma de unidades individualizadas de suministro, donde una parte de dicho ácido 2,5 - dihidroxibencenosulfónico o una de sus sales farmacéuticamente aceptables está en forma de composición de liberación inmediata y otra parte de dicho ácido 2,5 - dihidroxibencenosulfónico o una de sus sales farmacéuticamente aceptables está en forma de composición de liberación prolongada caracterizada por que dicha parte de composición de liberación inmediata comprende, adicionalmente entre un 8 % p/p a 28 % p/p, respecto del peso total de la parte de composición de liberación inmediata, de celulosa microcristalina, dicha parte de composición de liberación prolongada comprende, adicionalmente entre un 10 % p/p a 45 % p/p, respecto del peso total de la parte de composición de liberación prolongada, de hidroxipropilmetilcelulosa, y entre un 6,1 % p/p a 20 % p/p, respecto del peso total de la parte de composición de liberación prolongada, de hidroxipropilcelulosa, y por que tiene una proporción entre dicha parte de composición de liberación inmediata y dicha parte de composición de liberación prolongada comprendida entre 24:76 y 40:60. 2 - Composición según la reivindicación 1 , caracterizada por que es para el uso en el tratamiento de estados varicosos primarios, insuficiencia venosa crónica, flebitis, tromboflebitis, síndrome post-trombótico, ulceras de las piernas, várices del embarazo, coadyuvante de la varicectomía, escleroterapia o coadyuvante en el tratamiento de la retinopatía diabética. 3 - Composición según una de las reivindicaciones 1 ó 2, caracterizada por que dichos estados varicosos primarios son dolores, pesadez de piernas, calambres nocturnos o parestesias. 4 - Composición según cualquiera de las reivindicaciones 1 a 3, caracterizada por que se administra una unidad individualizada de suministro una sola vez cada 24 horas. 5 - Composición según cualquiera de las reivindicaciones 1 a 3, caracterizada por que se administran dos unidades individualizadas de suministro simultáneamente una sola vez cada 24 horas. 6 - Composición según cualquiera de las reivindicaciones 1 a 5, caracterizada por que cada unidad individualizada de suministro tiene un contenido de ácido 2,5 - dihidroxibencenosulfonico o una de sus sales farmacéuticamente aceptables de entre 50 mg y 2.500 mg en su forma de liberación inmediata y de entre 50 mg y 2.500 mg en su forma de liberación prolongada, preferentemente cada unidad individualizada de suministro tiene un contenido de ácido 2,5 - dihidroxibencenosulfonico o una de sus sales farmacéuticamente aceptables de entre 100 mg y 2.000 mg en su forma de liberación inmediata y de entre 100 mg y 2.000 mg en su forma de liberación prolongada, y muy preferentemente cada unidad individualizada de suministro tiene un contenido de ácido 2,5 - dihidroxibencenosulfonico o una de sus sales farmacéuticamente aceptables de entre 150 mg y 1 .000 mg en su forma de liberación inmediata y de entre 150 mg y 1 .000 mg en su forma de liberación prolongada. 7 - Composición según cualquiera de las reivindicaciones 1 a 6, caracterizada por que cada unidad individualizada comprende entre 400 mg a 2200 mg, de ácido 2,5 - dihidroxibencenosulfonico o una de sus sales farmacéuticamente aceptables. 8 - Composición según cualquiera de las reivindicaciones 1 a 7, caracterizada por que dicha sal farmacéuticamente aceptable es dobesilato de calcio. 9 - Composición según cualquiera de las reivindicaciones 1 a 8, caracterizada por que dichas unidades individualizadas de suministro son tabletas, cápsulas o sobres, preferentemente son tabletas o sobres. 10 - Composición según la reivindicación 9, caracterizada por que dichas unidades individualizadas son tabletas, y dichas tabletas son tabletas bicapa, donde una capa comprende dicha composición de liberación inmediata y la otra capa comprende dicha composición de liberación prolongada. 1 1 - Composición según cualquiera de las reivindicaciones 1 a 10, caracterizada por que la parte de composición de liberación inmediata comprende, adicionalmente por lo menos un excipiente del grupo de excipientes formado por solubilizantes, desintegrantes, plastificantes, retardantes, material gastro resistente, colorantes, tensoactivos ó surfactantes, deslizantes, lubricantes y aglutinantes. 12 - Composición según la reivindicación 1 1 , caracterizada por que dicho desintegrante es un desintegrante del grupo formado por almidón, celulosa, almidón de maíz, croscarmelosa, croscarmelosa de sodio, crospovidona, glicolato sódico de almidón, celulosa microcristalina, almidón pregelatinizado, alginato de sodio, goma agar, carboximetilcelulosa y lauril sulfato de sodio. 13 - Composición según la reivindicación 12 caracterizada por que dicho desintegrante es glicolato sódico de almidón. 14 - Composición según la reivindicación 13, caracterizada por que dicho glicolato sódico de almidón se encuentra en una proporción de 1 % p/p a 6 % p/p, respecto del peso total de la parte de composición de liberación inmediata. 15 - Composición según la reivindicación 1 1 , caracterizada por que dicho lubricante es un lubricante del grupo formado por talco, estearato de magnesio, estearato de calcio, ácido esteárico, fumarato esterato de sodio y lauril sulfato de magnesio ó sodio. 16 - Composición según la reivindicación 15, caracterizada por que dicho lubricante es estearato de magnesio, talco o una mezcla de ambos. 17 - Composición según la reivindicación 16, caracterizada por que dicho lubricante es estearato de magnesio y el estearato de magnesio se encuentra en una proporción de0,6 % p/p a 5 % p/p, respecto del peso total de la parte de composición de liberación inmediata. 18 - Composición según una de las reivindicaciones 16 ó 17, caracterizada por que dicho lubricante es talco y el talco se encuentra en una proporción de 0,6 % p/p a 5,5% p/p, respecto del peso total de la parte de composición de liberación inmediata. 19 - Composición según cualquiera de las reivindicaciones 1 a 18, caracterizada por que dicha parte de composición de liberación prolongada comprende, adicionalmente por lo menos un excipiente del grupo de excipientes formado por solubilizantes, desintegrantes, plastificantes, material gastro resistente, colorantes, tensoactivos ó suríactantes, deslizantes, lubricantes y diluyentes. 20 - Composición según la reivindicación 19, caracterizada por que dicho colorante es un colorante del grupo formado por FD & C Rojo 40, D & C Rojo 33, D & C Rojo 36, D& C Rojo 22, D & C Rojo 28, D & C Rojo 3, óxido de hierro - rojo, FD & C Amarillo 6, FD & C Amarillo 5, D & C Amarillo 10, óxido de hierro - amarillo, FD & C Azul 1 , FD & C Azul 2, FD & C Verde 3, óxido de hierro - negro, laca roja y dióxido de titanio. 21 - Composición según la reivindicación 20, caracterizada por que dicho colorante es laca roja. 22 - Composición según la reivindicación 21 , caracterizada por que dicha laca roja se encuentra en una proporción de 0,05 % p/p a 3 % p/p, respecto del peso total de la parte de composición de liberación prolongada. 23 - Composición según la reivindicación 19, caracterizada por que dicho lubricante es un lubricante del grupo formado por talco, estearato de magnesio, estearato de calcio, ácido esteárico, fumarato esterato de sodio, hidróxido de calcio, estearato de sodio, ácido bórico, lauril sulfato de magnesio ó sodio, y almidón de maíz. 24 - Composición según la reivindicación 23, caracterizada por que dicho lubricante es talco, estearato de magnesio o una mezcla de ambos. 25 - Composición según la reivindicación 24, caracterizada por que dicho lubricante es talco y se encuentra en una proporción de 0,6 % p/p a 5 % p/p, respecto del peso total de la parte de composición de liberación prolongada. 26 - Composición según una de las reivindicaciones 24 ó 25, caracterizada por que dicho lubricante es estearato de magnesio y se encuentra en una proporción de 0,6 % p/p a 5 % p/p, respecto del peso total de la parte de composición de liberación prolongada. 27 - Composición según cualquiera de las reivindicaciones 1 a 26, caracterizada por que dicha parte de composición de liberación inmediata comprende 55,5 % p/p a 85 % p/p de ácido 2,5 - dihidroxibencenosulfónico o una de sus sales farmacéuticamente aceptables, 8 % p/p a 28 % p/p de celulosa microcristalina, 1 % p/p a 6 % p/p de glicolato sódico de almidón, 0,6 % p/p a 5 % p/p de estearato de magnesio y 0,6 % p/p a 5,5 % p/p de talco, estando dichos % referidos al peso total de la parte de composición de liberación inmediata. 28 - Composición según cualquiera de las reivindicaciones 1 a 27, caracterizada por que dicha parte de composición de liberación prolongada comprende 25 % p/p a 75 % p/p de ácido 2,5 - dihidroxibencenosulfónico o una de sus sales farmacéuticamente aceptables, 10 % p/p a 45 % p/p de hidroxipropilmetilcelulosa, 6,1 % p/p a 20 % p/p de hidroxipropilcelulosa, 0,05 % p/p a 3 % p/p de un colorante, 0,6 % p/p a 5 % p/p de talco y 0,6 % p/p a 5 % p/p de estearato de magnesio, estando dichos % referidos al peso total de dicha parte de composición de liberación prolongada. 29 - Procedimiento de fabricación de una composición farmacéutica según cualquiera de las reivindicaciones 1 a 28, caracterizado por que comprende las siguientes etapas: [a] fabricar dicha parte de composición de liberación inmediata por vía seca, empleándose 55,5 % p/p a 85 % p/p de ácido 2,5 - dihidroxibencenosulfónico o una de sus sales farmacéuticamente aceptables y 8 % p/p a 28 % p/p de celulosa microcristalina, estando dichos % referidos al peso total de la parte de composición de liberación inmediata, [b] fabricar dicha parte de composición de liberación prolongada por vía húmeda, empleándose 25 % p/p a 75 % p/p de ácido 2,5 - dihidroxibencenosulfónico o una de sus sales farmacéuticamente aceptables, 10 % p/p a 45 % p/p de hidroxipropilmetilcelulosa y 6,1 % p/p a 20 % p/p de hidroxipropilcelulosa, estando dichos % referidos al peso total de dicha parte de composición de liberación prolongada, donde dicha etapa [b] incluye una etapa [b.1 ] de micronización de dicho ácido 2,5 - dihidroxibencenosulfónico o una de sus sales farmacéuticamente aceptables, y [c] fabricar unas unidades individualizadas de suministro que comprenden tanto composición de liberación inmediata como composición de liberación prolongada, donde la proporción entre dicha composición de liberación inmediata y dicha composición de liberación prolongada está comprendida entre 24:76 y 40:60. 30 - Procedimiento según la reivindicación 29, caracterizado por que en dicha etapa [c] se fabrican unas tabletas. 31 - Procedimiento según cualquiera de las reivindicaciones 29 a 30, caracterizado por que en dicha etapa [a] se emplea, adicionalmente, 1 % p/p a 6 % p/p de glicolato sódico de almidón, 0,6 % p/p a 5 % p/p de estearato de magnesio y 0,6 % p/p a 5,5 % p/p de talco, estando dichos % referidos al peso total de la parte de composición de liberación inmediata. 32 - Procedimiento según cualquiera de las reivindicaciones 29 a 31 , caracterizado por que en dicha etapa [b] se emplea, adicionalmente, 0,05 % p/p a 3 % p/p de un colorante, 0,6 % p/p a 5 % p/p de talco y 0,6 % p/p a 5 % p/p de estearato de magnesio, estando dichos % referidos al peso total de dicha parte de composición de liberación prolongada. 33 - Procedimiento según cualquiera de las reivindicaciones 29 a 32, caracterizado por que dichas unidades individualizadas de suministro son tabletas bicapa, donde una capa comprende dicha composición de liberación inmediata y la otra capa comprende dicha composición de liberación prolongada. 34 - Procedimiento según cualquiera de las reivindicaciones 29 a 33, caracterizado por que dicha etapa [a] comprende: CLAIMS 1 - Pharmaceutical composition comprising 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof in the form of individualized delivery units, where a portion of said 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof is in the form of immediate release composition and another part of said 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof is in the form of an extended release composition characterized in that said immediate release composition part further comprises between 8% w / w 28% w / w, with respect to the total weight of the immediate release composition part, of microcrystalline cellulose, said extended release composition part further comprises between 10% w / w and 45% w / w, relative to the total weight of the extended release composition part of hydroxypropyl methylcellulose, and between 6.1% w / w and 20% w / w, with respect to the total weight of the extended release composition part of hydroxypropyl cellulose, and why it has a proportion between said immediate release composition part and said composition part extended release between 24:76 and 40:60. 2 - Composition according to claim 1, characterized in that it 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. 3 - Composition according to one of claims 1 or 2, characterized in that said primary varicose states are pains, heaviness of legs, night cramps or paraesthesia. 4 - Composition according to any one of claims 1 to 3, characterized in that an individualized delivery unit is administered only once every 24 hours. 5 - Composition according to any one of claims 1 to 3, characterized in that two individualized delivery units are administered simultaneously only once every 24 hours. 6 - Composition according to any one of claims 1 to 5, characterized in that each individual delivery unit 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, preferably each individual delivery unit has a content of 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt of between 100 mg and 2,000 mg in its release form immediately and between 100 mg and 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 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 one of claims 1 to 6, characterized in that each individual unit comprises between 400 mg to 2200 mg, 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof. 8 - Composition according to any one of claims 1 to 7, characterized in that said pharmaceutically acceptable salt is calcium dobesilate. Composition according to any one of claims 1 to 8, characterized in that said individualized delivery 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, wherein one layer comprises said immediate release composition and the other layer comprises said prolonged release composition. 1 - Composition according to any one of claims 1 to 10, characterized in that the immediate release composition part further comprises at least one excipient of the group of excipients formed by solubilizers, disintegrants, plasticizers, retardants, gastro-resistant material, colorants , surfactants or surfactants, glidants, lubricants and binders. Composition according to claim 1, characterized in that said disintegrant is a disintegrant of the group consisting of starch, cellulose, corn starch, croscarmellose, sodium croscarmellose, crospovidone, sodium starch glycolate, microcrystalline cellulose, pregelatinized starch, alginate sodium, gum agar, carboxymethyl cellulose and sodium lauryl sulfate. 13 - Composition according to claim 12 characterized in that said disintegrant is sodium starch glycolate. 14 - Composition according to claim 13, characterized in that said starch sodium glycolate is in a proportion of 1% w / w to 6% w / w, based on the total weight of the immediate release composition part. Composition according to claim 1, characterized in that said lubricant is a lubricant of the group consisting of talc, magnesium stearate, calcium stearate, stearic acid, sodium sterate fumarate and magnesium or sodium lauryl sulfate. 16 - Composition according to claim 15, characterized in that said lubricant is magnesium stearate, talc or a mixture of both. 17 - Composition according to claim 16, characterized in that said 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 composition part of immediate release 18 - Composition according to one of claims 16 or 17, characterized in that said lubricant is talc and the talc is in a proportion of 0.6% w / w 5.5% w / w, based on the total weight of the part of immediate release composition. Composition according to any one of claims 1 to 18, characterized in that said part of the extended-release composition further comprises at least one excipient of the group of excipients formed by solubilizers, disintegrants, plasticizers, gastro-resistant material, colorants, surfactants or surfactants, glidants, lubricants and diluents. Composition according to claim 19, characterized in that said dye is a dye of 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, red lacquer and titanium dioxide. 21 - Composition according to claim 20, characterized in that said dye is red lacquer. 22 - Composition according to claim 21, characterized in that said red lacquer is in a proportion of 0.05% w / w to 3% w / w, based on the total weight of the prolonged release composition part. 23 - Composition according to claim 19, characterized in that said lubricant is a lubricant of the group consisting of talc, magnesium stearate, calcium stearate, stearic acid, sodium sterate fumarate, calcium hydroxide, sodium stearate, boric acid, lauryl magnesium or sodium sulfate, and corn starch. 24 - Composition according to claim 23, characterized in that said lubricant is talc, magnesium stearate or a mixture of both. 25 - Composition according to claim 24, characterized in that said lubricant is talc and is in a proportion of 0.6% w / w at 5% w / w, based on the total weight of the prolonged release composition part. 26 - Composition according to one of claims 24 or 25, characterized in that said lubricant is magnesium stearate and is in a proportion of 0.6% w / w to 5% w / w, based on the total weight of the composition part extended release. 27 - Composition according to any one of claims 1 to 26, characterized in that said immediate release composition part comprises 55.5% w / w 85% w / w 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof, 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 5.5% w / w talc, said% being referred to the total weight of the immediate release composition part. Composition according to any one of claims 1 to 27, characterized in that said part of the extended-release composition comprises 25% w / w 75% w / w 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof, 10% p / pa 45% w / w hydroxypropylmethylcellulose, 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 extended release composition. 29 - Method of manufacturing a pharmaceutical composition according to any one of claims 1 to 28, characterized in that it comprises the following steps: [a] manufacturing said part of immediate release composition by dry route, using 55.5% w / w 85 % w / w 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof and 8% w / w 28% w / w microcrystalline cellulose, said% being referred to the total weight of the immediate release composition part, [ b] manufacturing said part of the wet-release prolonged composition, using 25% w / w 75% w / w 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof, 10% w / w 45% w / w of hydroxypropyl methylcellulose and 6.1% w / w at 20% w / w hydroxypropylcellulose, said% being referred to the total weight of said part of the extended release composition, wherein said step [b] includes a micronization stage [b.1] From d io 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof, and [c] manufacturing individualized delivery units comprising both immediate release composition and prolonged release composition, wherein the ratio between said immediate release composition and said composition Prolonged release is between 24:76 and 40:60. 30 - Method according to claim 29, characterized in that said step [c] produces tablets. 31 - Method according to any one of claims 29 to 30, characterized in that said step [a] additionally uses 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. 32 - Method according to any one of claims 29 to 31, characterized in that said step [b] additionally uses 0.05% w / w 3% w / w of a 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 extended release composition. 33 - Method according to any of claims 29 to 32, characterized in that said individualized delivery units are bilayer tablets, wherein one layer comprises said immediate release composition and the other layer comprises said prolonged release composition. 34 - Method according to any of claims 29 to 33, characterized in that said step [a] comprises:
[a.1 ] tamizar por una malla # 20, dicho ácido 2,5 - dihidroxibencenosulfónico o una de sus sales farmacéuticamente aceptables, dicha celulosa microcristalina y 1 % p/p a 6 % p/p de glicolato sódico de almidón, estando dichos % referidos al peso total de la parte de composición de liberación inmediata, [a.1] screen through a # 20 mesh, said 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof, said 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] mezclar lo obtenido en [a.1 ], entre un rango de tiempo de 1 min a 30 min, [a.2] mix the results obtained in [a.1], between a time range of 1 min to 30 min,
[a.3] tamizar por una malla # 30, 0,6 % p/p a 5 % p/p de estearato de magnesio y 0,6 % p/p a 5,5 % p/p de talco, estando dichos % referidos al peso total de la parte de composición de liberación inmediata, [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, said% being referred to the total weight of the immediate release composition part,
[a.4] mezclar lo obtenido en [a.2] y [a.3], entre un rango de tiempo de 1 min a 15 min, y dicha etapa [b] comprende, tras dicha etapa [b.1 ],: [a.4] mix the results obtained in [a.2] and [a.3], between a time range of 1 min to 15 min, and said stage [b] comprises, after said stage [b.1], :
[b.2] disolver 0,1 % p/p a 5 % p/p de hidroxipropilcelulosa en una cantidad suficiente de agua purificada, estando dichos % referidos al peso total de dicha parte de composición de liberación prolongada, [b.2] dissolve 0.1% w / w at 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] mezclar lo obtenido en [b.1 ], con dicha hidroxipropilmetilcelulosa, 6 % p/p a 15 % p/p de hidroxipropilcelulosa y 0,05 % p/p a 3 % p/p de laca roja, entre un rango de tiempo de 1 min a 15 min, estando dichos % referidos al peso total de dicha parte de composición de liberación prolongada, [b.3] mix the obtained in [b.1], with said hydroxypropylmethylcellulose, 6% w / w 15% w / w hydroxypropylcellulose and 0.05% w / w 3% w / w red lacquer, between rank of time of 1 min to 15 min, said% being referred to the total weight of said part of prolonged release composition,
[b.4] granular lo obtenido en [b.3] con la solución obtenida en [b.2], [b.4] granulate what is obtained in [b.3] with the solution obtained in [b.2],
[b.5] secar lo obtenido en [b.4], entre un rango de temperatura de 45 eC a 70 eC y un rango de tiempo de 10 min a 60 min, [b.5] dry the obtained in [b.4], between a temperature range of 45 e C to 70 e C and a time range of 10 min to 60 min,
[b.6] tamizar por una malla 062R lo obtenido en [b.5], [b.6] sift through a 062R mesh what was obtained in [b.5],
[b.7] tamizar por una malla # 30, 0,6 % p/p a 5 % p/p de talco y 0,6 % p/p a 5 % p/p de estearato de magnesio, estando dichos % referidos al peso total de dicha parte de composición de liberación prolongada, [b.8] mezclar lo obtenido en [b.6] y [b.7], entre un rango de tiempo de 1 min a 15 min. [b.7] sieve 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 weight total of said part of extended release composition, [b.8] mix the obtained in [b.6] and [b.7], between a time range of 1 min to 15 min.
PCT/ES2018/070123 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 WO2018154161A1 (en)

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CN201880010868.6A CN110290784A (en) 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
BR112019016778-1A BR112019016778B1 (en) 2017-02-22 2018-02-20 PHARMACEUTICAL COMPOSITION 1/51 2,5-DIHYDROBENZENESULPHONIC ACID OR ONE OF ITS PHARMACEUTICALLY ACCEPTABLE SALTS IN THE FORM OF INDIVIDUALIZED UNITS AND ITS METHOD OF MANUFACTURING
PE2019001494A PE20191465A1 (en) 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

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CN114601816B (en) * 2021-10-09 2022-09-02 北京惠之衡生物科技有限公司 Calcium dobesilate capsule composition and preparation method thereof
CN115581681A (en) * 2022-06-10 2023-01-10 海南林恒制药股份有限公司 Novel calcium dobesilate capsule and preparation method thereof

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ES2680293B1 (en) 2019-08-22
ES2680293A1 (en) 2018-09-05

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