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.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Medicinal Preparation (AREA)

Priority Applications (3)

Applications Claiming Priority (2)

Publications (1)

Family

ID=63252461

Family Applications (1)

Country Status (5)

Families Citing this family (2)

Citations (5)

• 2017
  • 2017-02-22 ES ES201730225A patent/ES2680293B1/es active Active
• 2018
  • 2018-02-20 WO PCT/ES2018/070123 patent/WO2018154161A1/es active Application Filing
  • 2018-02-20 PE PE2019001494A patent/PE20191465A1/es unknown
  • 2018-02-20 BR BR112019016778-1A patent/BR112019016778A2/pt unknown
  • 2018-02-20 CN CN201880010868.6A patent/CN110290784A/zh active Pending

Patent Citations (5)

Non-Patent Citations (4)

Also Published As

Similar Documents

Legal Events