WO2013159166A1 - Forme pharmaceutique orale pour la prévention de maladies vasculaires, comprimé utilisé comme forme pharmaceutique et capsule gélatineuse utilisée comme forme pharmaceutique - Google Patents

Forme pharmaceutique orale pour la prévention de maladies vasculaires, comprimé utilisé comme forme pharmaceutique et capsule gélatineuse utilisée comme forme pharmaceutique Download PDF

Info

Publication number
WO2013159166A1
WO2013159166A1 PCT/BR2013/000129 BR2013000129W WO2013159166A1 WO 2013159166 A1 WO2013159166 A1 WO 2013159166A1 BR 2013000129 W BR2013000129 W BR 2013000129W WO 2013159166 A1 WO2013159166 A1 WO 2013159166A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydrochlorothiazide
losartan
rpm
tablet
rotating
Prior art date
Application number
PCT/BR2013/000129
Other languages
English (en)
Portuguese (pt)
Inventor
Walker Magalhães LAHMANN
Hilton Oliveira dos Santos FILHO
Thiago Rennó Dos Mares GUIA
Aguinaldo Campos JÚNIOR
Original Assignee
Hypermarcas S.A.
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 Hypermarcas S.A. filed Critical Hypermarcas S.A.
Publication of WO2013159166A1 publication Critical patent/WO2013159166A1/fr

Links

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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone

Definitions

  • the present invention broadly relates to oral dosage forms for the prevention of cardio and cerebrovascular diseases in mammals, particularly humans.
  • the invention relates to pharmaceutical forms comprising (a) one or more HMG-CoA reductase inhibitors, (b) one or more angiotensin II receptor antagonists and (c) one or more thiazide class diuretics where (a) is not in substantial physical contact with (b) or (c).
  • oral dosage forms comprise combinations of (a) HMG-CoA reductase inhibitors, particularly stabilized statins, (b) particularly stabilized angiotensin II receptor antagonists and (c) one or more diuretics of class of thiazides which, surprisingly, offer performance of their components as obtained individually in comparative bioequivalence assays.
  • class of thiazides refers to the structure of benzothiadiazines, which are benzene-derived heterocyclic bicyclic compounds with the heterocycle having 2 nitrogen atoms and one sulfur atom.
  • a particular aspect of maintaining the individual performance of the active ingredients comprising the pharmaceutical form of the invention is to prevent or minimize direct physical contact of the HMG-CoA reductase inhibitors with the other two actives, which are preferably mixed together.
  • a particularly preferred embodiment of the invention is a two-layer physical separation tablet, one layer containing one or more HMG-CoA reductase inhibitors, and another layer containing a mixture of one or more HMG receptor antagonists. angiotensin II with one or more thiazide class diuretics.
  • Optimum conditions obtained by the invention are understood to be the release of drugs according to the dissolution profile of the reference assets, that is, the individualized compounds, as well as the robust and reproducible industrial production.
  • a specific formulation for oral solid dosage forms of active ingredients in fixed dose combinations requires specific formulations for the joining of two or three layers, or for the inclusion of pellets in tablets or capsules, or for deposit of pharmaceutical assets in coating polymers.
  • formulations made according to the invention exhibit in vitro and in vivo behavior of their active constituents similar to the performance obtained by the simple forms of the isolated products.
  • the isolated products are single tablets, that is, especially simple dosage forms compared to the active combination dosage forms.
  • the pharmaceutical forms of the invention are directed to the prevention of cardio and cerebrovascular diseases, particularly high blood pressure, coronary artery disease, acute coronary syndrome and stroke.
  • cardio and cerebrovascular diseases particularly high blood pressure, coronary artery disease, acute coronary syndrome and stroke.
  • active principles of the preparation of the invention are commented below.
  • Statins are known as inhibitors of HMG-CoA (where HMG-CoA is an acronym for "3-hydroxy-3-methylglutaryl coenzyme A”), an enzyme located in liver tissue that produces mevalonate, a small molecule used in synthesis. of cholesterol and other mevalonate derivatives. Its inhibition reduces the amount of cholesterol produced which, in turn, reduces the total amount of LDL ("low density lipoprotein”) cholesterol. Because high LDL cholesterol rates are associated with morbidity and mortality from cardio and cerebrovascular events, the effect of constant statin use is particularly suited to preventing such events.
  • HMG-CoA is an acronym for "3-hydroxy-3-methylglutaryl coenzyme A”
  • Statins are known to have low acid stability, benefiting from a clearly alkaline environment to minimize their degradation, for example by using calcium carbonate, sodium hydroxide, sodium phosphate, potassium hydroxide, phosphate dibasic calcium, tribasic calcium phosphate, potassium carbonate, etc.
  • the alkaline environment favors the dissolution of this active, enabling its adequate absorption by the gastrointestinal tract.
  • the angiotensin receptor antagonist (ARA) class is useful in the treatment of hypertension.
  • losartan the first ARA to be commercially available, acts by blocking angiotensin II ATI receptors. Its effects are: direct vasodilation, preventing the increase of aldosterone production by the adrenal glands, decreasing sodium and water retention, thus preventing hypervolemia and consequent hypertension.
  • Diuretics reduce blood pressure by reducing plasma volume and extracellular volume.
  • Thiazides were originally synthesized to be inhibitors of carbonic anhydrase (a class of diuretics that decreases the resorption of HCO 3 " and, indirectly, of Na + ).
  • thiazides (including hydrochlorothiazide) are very weak inhibitors of anhydrase.
  • hydrochlorothiazide belongs to the group of saluretics and acts on the nephron distal tubule at the level of the thiazide sensitive cotransporter (TSC) which is a Na + / Cl support channel " .
  • TSC thiazide sensitive cotransporter
  • hydrochlorothiazide is not only as effective as other drugs, but also prevents more cardiovascular complications than other drugs. Coupled with its low cost, an important factor in lifelong therapy, it makes it a first-line drug in the control of hypertension.
  • the present invention aims at combining the above three actives in oral dosage forms, with specific physical separation of the pharmaceutical actives, favoring stability, dissolution and compatibility aspects between them. DESCRIPTION OF THE FIGURES
  • Figure 1 Double-layer tablet, where a layer with one or two pharmaceutical assets is compressed over another layer, with one or two assets, totaling three assets.
  • Figure 2 Triple layer tablet, where each layer with a pharmaceutical active is sequentially compressed, totaling three layers and three actives.
  • Figure 3 Multi-unit pellet tablet of a pharmaceutical active.
  • Figure 4 Monobloc tablet containing multi-units (pellets) with one or two pharmaceutical actives.
  • Figure 5 Polymer coated tablet in which one or two pharmaceutical actives are included.
  • Figure 7 Hard gelatin capsule containing multiparticulate forms in three active pellets.
  • FIG 8 Dissolution profile of atorvastatin, obtained by the invention, in pH 6.8 phosphate buffer medium, pharmacopoeic apparatus (American Pharmacopoeia number 31) with paddles rotating 50 rpm at 37 degrees in 900 ml.
  • Figure 9 Dissolution profile of hydrochlorothiazide, obtained by the invention, in 0.1N HCl medium, pharmacopoeic apparatus (American Pharmacopoeia number 31) with paddles rotating 50 rpm at 37 degrees in 1000 ml.
  • FIG 10 Dissolution profile of hydrochlorothiazide, obtained by the invention, in pH 6.8 phosphate buffer medium, pharmacopoeic apparatus (American Pharmacopoeia number 31) with paddles rotating 50 rpm at 37 degrees in 1000 ml.
  • pharmacopoeic apparatus American Pharmacopoeia number 31
  • Figure 11 Dissolution profile of hydrochlorothiazide, obtained by the invention, in purified water, apparatus Pharmacopeic (American Pharmacopoeia number 31) basket, rotating 100 rpm, at 37 ° degrees, in 1000 mL.
  • Pharmacopeic American Pharmacopoeia number 31
  • Figure 12 Dissolution profile of hydrochlorothiazide, obtained by the invention, in Fessif medium, pharmacopoeic apparatus (American Pharmacopoeia number 31) rotating blades 50 rpm at 37 degrees in 1000 ml.
  • Figure 13 Dissolution profile of the losartan obtained by the invention in HCl 0.1 IN pharmacopoeic apparatus (American Pharmacopoeia number 31) with paddles rotating 50 rpm at 37 degrees in 1000 ml.
  • Figure 14 Dissolution profile of the losartan, obtained by the invention, in pH 6.8 phosphate buffer medium, pharmacopoeic apparatus (American Pharmacopoeia number 31) with paddles rotating 50 rpm at 37 degrees in 1000 ml.
  • pharmacopoeic apparatus American Pharmacopoeia number 31
  • Figure 15 Dissolution profile of the losartan, obtained by the invention, in purified water, pharmacopeic apparatus (American Pharmacopoeia number 31) basket, rotating 100 rpm at 37 degrees in 1000 mL.
  • pharmacopeic apparatus American Pharmacopoeia number 31
  • FIG 17 Dissolution profile of atorvastatin in phosphate buffer pH 6.8, paddle apparatus, rotating 50 rpm at 37 degrees in 900 mL - curve obtained with Citalor 10 mg product containing only this active ingredient.
  • Figure 18 Graph of the behavior during the 12 month stability test of atorvastatin, losartan and hydrochlorothiazide actives comprised in tablets according to the invention, described below in an example embodiment.
  • Fessif (Fed state simulated intestinal fluid) medium is an in vitro tablet dissolving medium that simulates in many respects the composition of intestinal fluid, such as pH, osmolarity, presence of surfactants, viscosity and other characteristics. See description, for example at: http: // biorelevant. com / site media / upload / literature / Marques Dissolution Media 2004.pdf
  • the invention relates to oral pharmaceutical forms comprising (a) one or more HMG-CoA reductase inhibitors, particularly alkalinizing stabilized statins, (b) one or more angiotensin II receptor antagonists and (c) one or more thiazide diuretics, (a) not in substantial physical contact with (b) or (c).
  • Oral forms are preferably solid oral forms, for example, double layer tablets, triple layer tablets, physically separated active inclusion monobloc tablets, coated tablets, active additive coated tablets and capsules containing multiparticulate forms, or pellets, of two or three assets.
  • HMG-CoA reductase inhibitors suitable for the invention are one or more statins, particularly chosen from atorvastatin, simvastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, cerivastatin and their pharmaceutically acceptable salts. Particularly atorvastatin or pharmaceutically acceptable salts thereof is used.
  • said statins are stabilized by one or more alkalizing agents, for example calcium carbonate, sodium hydroxide, sodium phosphate, potassium hydroxide, dibasic calcium phosphate, tribasic calcium phosphate, and potassium carbonate, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, aluminum magnesium hydroxide.
  • alkalizing agents for example calcium carbonate, sodium hydroxide, sodium phosphate, potassium hydroxide, dibasic calcium phosphate, tribasic calcium phosphate, and potassium carbonate, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, aluminum magnesium hydroxide.
  • said ARA or angiotensin II receptor antagonists suitable for the invention are one or more of losartan, irbesartan, valsartan, olmesartan, telmisartan, azilsartan, eprosartan, candesartan and their pharmaceutically acceptable salts.
  • losartan or pharmaceutically acceptable salts thereof are used.
  • any other thiazide class diuretics suitable for the invention are one or more of cyclothiazide, trichloromethiazide, cyclopentiazide, polythiazide, bendroflumetiazide, hydroflumetiazide, chlorothiazide, hydrochlorothiazide, benzothiazide, flumetiazide, methylcyclothiazide, butiazide, In particular hydrochlorothiazide or pharmaceutically acceptable salts thereof is used.
  • a particular embodiment of the invention is a tablet containing between 2 and 50 mg atorvastatin, between 5 and 120 mg losartan and between 5 and 75 mg hydrochlorothiazide.
  • a particular embodiment of the solid oral preparation of the invention is a tablet, containing (a) granulate or simple admixture with excipients containing an HMG-CoA reductase inhibitor, particularly a stabilized statin, (b) a simple granulate or admixture with excipients containing an ARA , (c) granulated or with thiazide diuretic excipients, in which (a) is not in substantial physical contact with (b) or (c).
  • a particular embodiment of the invention is a two-layer tablet (as seen in Figure 1), wherein one layer is of granulate formulated comprising one or more HMG-CoA reductase inhibitors, particularly stabilized atorvastatin, and the other layer is a combination of (a) formulated granules comprising one or more ARAs, particularly stabilized losartan, and (b) solid solution granules of one or more thiazide class diuretics, particularly hydrochlorothiazide.
  • the three actives may be distributed in three different layers, constituting a triple layer tablet, as can be seen in Figure 2.
  • Granules or simple mixtures with excipients of the three essential components of the solid oral forms of the invention may be produced separately. This way, the specific aspects related to the stability and solubility of each asset are advantageously respected, allowing the best use of its characteristics - that is, a simple mixture of excipients to thiazide diuretic, particularly hydrochlorothiazide, the alkaline pH applicable to HMG-CoA inhibitors. acid-sensitive reductase, particularly atorvastatin and the desired additive of ARA, particularly losartan. In particular the pH of a granulate with HMG-CoA reductase inhibitors must be above 6.
  • the actives may be combined into a monoblock tablet with pellets or granules inserted therein as can be seen in Figures 3 and 4.
  • Pellets are understood as agglomeration of fine powders containing one or more active substances and their excipient (s) in small spheroidal units. These spheroidal units, produced by spheronization or addition, are independent units that do not necessarily contain the required full dose of the active, but the pellet set has the required dose. Tablets containing pellets exhibit physical separation of assets. In monobloc tablets, the actives may be present in one or more different pellet types, immersed in the compressed mixture.
  • the invention contemplates, in a particular example, pellets together comprising ARA and thiazide diuretics.
  • monobloc or pellet tablets, with or without pellets, with a coating containing one or more of the pharmaceutical actives are produced.
  • one of the assets is mixed with the coating material and sprayed onto the tablet, providing physical separation of the assets, as can be seen in Figure 5.
  • Particular non-limiting examples of embodiments of this alternative follow below:
  • One coating contains atorvastatin and a core containing a mixture of losartan and hydrochlorothiazide;
  • a coating containing mixture of losartan and hydrochlorothiazide coats a core containing atorvastatin
  • a two-layer tablet one hydrochlorothiazide and one atorvastatin, has a losartan-containing coating
  • the tablets are constructed in the tablet-on-tablet system where a granulate or simple blend is contained within another tablet, as can be seen in Figure 6.
  • the assets are combined into small tablets, powders or pellets, which fill gelatin capsules, maintaining the physical separation of the assets, as can be seen in Figure 7.
  • Immediate or prolonged release coated tablets are orally administrable solid dosage forms which can be produced by physical compression of the active ingredient and excipients, ie the set of substances that form, compressibility, mechanical strength and modulate the release of the active ingredient.
  • active principle There is a core, which is the set consisting of excipients and active ingredients, coated with a film that offers isolation of the core from contact with atmospheric air, but soluble in contact with the gastrointestinal environment.
  • the cores can be produced by dry or wet granulometry.
  • Granules may be produced, for example, with the aid of silicon dioxide, microcrystalline cellulose, for example Avicel®, carbohydrates, starches, and others.
  • binders gelatin, alginate, cellulose ethers such as CMC (carboxymethyl cellulose) and HPMC (hydroxypropyl methyl cellulose), polyethylene glycols, ethylene oxide in polymerized form, polyvinylpyrrolidones, povidones may be used.
  • Detergent products such as sodium lauryl sulfate or dodecyl sulfate may also be used.
  • the mass formed for example, of the solid dispersion of the active ingredient mixture, microcrystalline cellulose and colloidal silicon dioxide, is mixed in a rotary mill.
  • the mass is then transferred to a granulator - eg GLATT®, by adding solvents such as ethyl alcohol or povidone until dispersed. complete.
  • the granules are dried by placing the mass composed of active and excipients in a fluidized bed, and then compressing them, which can be done in compressing machines, for example, FETTE®.
  • the mass of the mixture prior to compression may receive spheronized or addition-constructed pellets.
  • the active-containing small beads can be actively mixed with the excipient mass while maintaining a uniform pellet distribution aspect within the monoblock or double layer tablet.
  • Compression can be done on rotary compressing machines, for example, FETTE®, the shape of the cores (convex, cylindrical, oblong biplanes, etc.) and sizes can be varied, in monobloc tablets, or with two or three layers.
  • the coating of a tablet aims at preserving the stability of the active principle (s), by protecting the core from the outer environment.
  • the coating is hydrophilic, permeable to water and the moist environment of the gastrointestinal tract.
  • the coating-forming materials are, for example, mixtures of polyvinylpyrrolidone or polyvinylpyrrolidone and polyvinyl acetate copolymer with hydroxypropyl methylcellulose (HPMC) or mixtures of cellulose derivatives such as hydroxypropyl methylcellulose and ethylcellulose.
  • HPMC hydroxypropyl methylcellulose
  • cellulose derivatives such as hydroxypropyl methylcellulose and ethylcellulose.
  • These polymers are dispersed in ethyl alcohol or water. to constitute the vehicle of application.
  • To the solution of polymers in water or alcohol may be added pigments, talc or wetting agents. Dyes and pigments may also be added for pleasant and differentiated coloring of the pharmaceutical form, such as titanium dioxide and ferric oxide.
  • the tablet coating may receive pharmaceutical actives.
  • tablets with one or more active, layered or pelleted, or separately produced granules may receive polymeric additives coated with pharmaceutical actives.
  • the coating is a polymer such as a polycarboxylic acid, for example hydroxypropyl methyl cellulose phthalate, polyvinyl pyrrolidone or polymers called "enteric polymers” such as Eudragit L30D, dispersed in water with ammonium addition or other alkaline agent.
  • a polymer such as a polycarboxylic acid, for example hydroxypropyl methyl cellulose phthalate, polyvinyl pyrrolidone or polymers called “enteric polymers” such as Eudragit L30D, dispersed in water with ammonium addition or other alkaline agent.
  • the coating former may be sprayed onto the tablet in aqueous or alcoholic dispersion using rotary coating equipment such as GLATT® or ACCELA COTA®.
  • Plasticizers such as triethyl acetate, other phthalates, or polyethylene glycols may be added to the dispersion.
  • the dosage forms of the present invention may contain a variety of known excipients, such as disintegrants, diluents, glidants and colorants.
  • disintegrants can be used those with high coefficient of expansion, such as crospovidone, croscarmellose and starch glycolate.
  • Diluents may be sucrose, dextrose, mannitol, sorbitol, starch, microcrystalline cellulose and other excipients known in the art.
  • Lubricants and glidants can be employed in tablet production.
  • lubricants and glidants may be hydrogenated vegetable oils, magnesium stearate, stearic acid, sodium lauryl sulfate, magnesium lauryl sulfate, colloidal silica, talc or mixtures of the above excipients.
  • a preferred lubricant is magnesium stearate or mixtures of magnesium stearate with colloidal silica.
  • the excipients used for compression are preferably binders such as starches from various sources, eg from corn, microcrystalline cellulose such as Avicel® product, silicon dioxide such as Aerosil®, mannitol, lactose and polyethylene glycol. molecular weight 400 to 6,000 Da, polyvinylpyrrolidone such as Polyplasdone®, carboxymethylcellulose, hypromellose, carboxymethyl starch, dicalcium phosphate, talc and lubricants such as stearate.
  • Various dyes may also be added, especially for differentiating between different dosages.
  • Dissolution Profiles means the determination of various drug concentrations in the dissolution medium at different collection times in order to determine the dissolved drug percentage versus time curve in standardized apparatus such as the American Pharmacopoeia. number 31.
  • An orally administered drug can only be absorbed if it is dissolved in the media. gastrointestinal tract, which occurs only after its release from the pharmaceutical form.
  • Dissolution profile graphs are plots of the nominal percentage of the pharmaceutically included pharmaceutical form collected in the dissolution medium, that is, dissolved versus the time of each collection.
  • Dissolution profiles have a direct influence on the in vivo performance of the dosage forms. At the theoretical limit, if there is no dissolution or is insignificant, there will be no absorption of the drug and consequently it will have no biological effect. On the other hand, dissolution indicates that an insoluble drug, treated by excipients, becomes soluble.
  • the construction of the pharmaceutical form has a direct effect on the dissolution profile.
  • a tablet with higher compressive strength may retain the drug longer, impacting the biological effect of the drug.
  • the dissolution profile is a typical expression of the drug in a particular pharmaceutical form, with a direct impact on its clinical performance.
  • dissolution efficiency is the area under the dissolution profile curve in relation to the total plot area plotted as a percentage.
  • a dissolution efficiency of 50% means that, over the total experiment time, the area under the dissolution profile curve represents 50% of the total graph area. In a hypothetical situation, if a tablet dissolves 100% of the drug instantly, the dissolution efficiency would be 100%. On the other hand, if a tablet did not release any percentage of the drug, it would be totally inefficient. that is, the dissolution efficiency would be 0%.
  • the core assembly plus coating or capsule allows stability of the active ingredient for a minimum of 1 years. Stability can be defined as the absence of degradation within legally acceptable limits, ie, having active principle content of 90 to 110% over a period of at least 1 year.
  • Figure 18 shows the behavior of atorvastatin, losartan and hydrochlorothiazide actives during the 12-month stability. Atorvastatin maintains the content above 98%, with 2.0% of impurities and degradants allowed. Losartan and hydrochlorothiazide have maximum impurities of: benzothiadiazine below 1%, 1-H dimmer below 0.5% and 2-H dimmer below 0.5%, totaling a maximum of 2% for the two combined assets, measured by high performance liquid chromatography.
  • Microcrystalline Cellulose (Avicel® PH 302) - 50 mg
  • Potassium losartan, hydrochlorothiazide and colloidal silicon dioxide were passed through a 1.0 mm mesh, transferred to the mixer and homogenized for 5 minutes.
  • Microcrystalline cellulose 200 and fully pregelatinized starch previously knitted 1.0 mm were added to the mixer. Homogenized for 10 minutes.
  • To the mixer was added the previously magnesium vegetable stearate 0.250 mm mesh. It was mixed for 5 minutes. After double layer compression of layers 1 and 2, the coating was performed by means of a circular Accela-Cota perforated bucket equipment.
  • the coating used was a commercial blend from Colorcon, called Opadry II, composed of polyvinyl alcohol, titanium dioxide, macrogol and talc.
  • Atorvastatin in pH 6.8 phosphate buffer medium, paddle apparatus, rotating 50 rpm at 37 degrees in 900 mL between 65% and 95% - Figure 8;
  • Dissolution curves represent the expression of the release mechanism of the active ingredients within the pharmaceutical form. Thus, it is possible to modulate the release for protection of the pharmaceutical active, in addition to improving the solubilization conditions.
  • the excipients have the exact function of optimizing the behavior of the pharmaceutical active.
  • the atorvastatin and hydrochlorothiazide actives are water-insoluble and sparingly soluble losartan actives.
  • Dissolution curves express, as shown in Figures 8 to 16, the interaction between actives and excipients - dissolution efficiency is therefore an expression of the pharmaceutical composition per se and manufacturing process.
  • hydrochlorothiazide alone without the presence of excipients has approximately zero solubility.
  • composition object of this invention provides similar dissolution of the actives both in the combined form and in individual tablets. Compare, for example, the dissolution curves observed in Figures 8 and 17 for atorvastatin in the reference tablet (Citalor, from Pfizer, 10 mg) and for the combined form of actives of the invention.

Landscapes

  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne généralement des formes pharmaceutiques orales à usage thérapeutique pour la prévention de maladies cardiovasculaires et cérébrovasculaires chez des mammifères, de préférence chez l'homme. Plus particulièrement, l'invention concerne un comprimé qui comprend (a) un ou plusieurs inhibiteurs de HMG-CoA réductase, (b) un ou plusieurs antagonistes de récepteurs de l'angiotensine II, et (c) un ou plusieurs diurétiques de la classe des thiazides.
PCT/BR2013/000129 2012-04-26 2013-04-18 Forme pharmaceutique orale pour la prévention de maladies vasculaires, comprimé utilisé comme forme pharmaceutique et capsule gélatineuse utilisée comme forme pharmaceutique WO2013159166A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
BRBR1020120097354 2012-04-26
BR102012009735-4A BR102012009735A2 (pt) 2012-04-26 2012-04-26 Forma farmacêutica oral para a prevenção de doenças vasculares, comprimido como forma farmacêutica e cápsula gelatinosa como forma farmacêutica

Publications (1)

Publication Number Publication Date
WO2013159166A1 true WO2013159166A1 (fr) 2013-10-31

Family

ID=49482044

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/BR2013/000129 WO2013159166A1 (fr) 2012-04-26 2013-04-18 Forme pharmaceutique orale pour la prévention de maladies vasculaires, comprimé utilisé comme forme pharmaceutique et capsule gélatineuse utilisée comme forme pharmaceutique

Country Status (4)

Country Link
AR (1) AR090865A1 (fr)
BR (1) BR102012009735A2 (fr)
UY (1) UY34769A (fr)
WO (1) WO2013159166A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015066785A1 (fr) * 2013-11-08 2015-05-14 Hypermarcas S.A. Forme pharmaceutique à usage oral pour prévenir les maladies vasculaires, comprimé et capsule en gélatine à titre de forme pharmaceutique
EP3090744A4 (fr) * 2013-12-30 2017-06-14 Alvogen Korea Co., Ltd. Formulation complexe pharmaceutique comprenant un inhibiteur de récepteur d'angiotensine ii et un inhibiteur de réductase hmg-coa

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005039637A2 (fr) * 2003-10-17 2005-05-06 Novartis Ag Combinaisons
WO2005053687A1 (fr) * 2003-11-25 2005-06-16 Novartis Ag Combinaison de composes organiques
WO2010092450A1 (fr) * 2009-02-11 2010-08-19 Khamar, Balukesh, Mafatlal Composition pharmaceutique stable pour l'athérosclérose

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005039637A2 (fr) * 2003-10-17 2005-05-06 Novartis Ag Combinaisons
WO2005053687A1 (fr) * 2003-11-25 2005-06-16 Novartis Ag Combinaison de composes organiques
WO2010092450A1 (fr) * 2009-02-11 2010-08-19 Khamar, Balukesh, Mafatlal Composition pharmaceutique stable pour l'athérosclérose

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RUILOPE LM ET AL.: "Fixed-dose valsartan+HCTZ combination vs' amlodipine monotherapy in hypertensive patients with additional cardiovascular risk factors with and without concomitant use of statins.", J.HYPERTENS., vol. 24, no. SUPPL., 2006, pages 1 - 19 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015066785A1 (fr) * 2013-11-08 2015-05-14 Hypermarcas S.A. Forme pharmaceutique à usage oral pour prévenir les maladies vasculaires, comprimé et capsule en gélatine à titre de forme pharmaceutique
EP3065737A1 (fr) * 2013-11-08 2016-09-14 Hypermarcas S.A. Forme pharmaceutique à usage oral pour prévenir les maladies vasculaires, comprimé et capsule en gélatine à titre de forme pharmaceutique
EP3065737A4 (fr) * 2013-11-08 2017-03-29 Hypermarcas S.A. Forme pharmaceutique à usage oral pour prévenir les maladies vasculaires, comprimé et capsule en gélatine à titre de forme pharmaceutique
EP3090744A4 (fr) * 2013-12-30 2017-06-14 Alvogen Korea Co., Ltd. Formulation complexe pharmaceutique comprenant un inhibiteur de récepteur d'angiotensine ii et un inhibiteur de réductase hmg-coa

Also Published As

Publication number Publication date
UY34769A (es) 2013-11-29
BR102012009735A2 (pt) 2014-04-15
AR090865A1 (es) 2014-12-10

Similar Documents

Publication Publication Date Title
CN110548149B (zh) 含葡萄糖激酶激活剂和α-葡萄糖苷酶抑制剂的药物组合及其制备方法和用途
ES2307463T3 (es) Forma de dosificación de combinación que contiene un agente reductor del colesterol, un inhibidor de la renina-angiotensina, y aspirina.
ES2587912T3 (es) Composición farmacéutica que comprende olmesartán medoxomilo y rosuvastatina o su sal
KR100253824B1 (ko) Hmg-coa 환원효소 억제제 화합물을 포함하는 안정화된 약학 조성물
US20100247649A1 (en) Pharmaceutical formulations comprising telmisartan and hydrochlorothiazide
BRPI0510419B1 (pt) Comprimido revestido e método para preparar um comprimido revestido.
ES2435240T3 (es) Composiciones de dosis fija farmacéuticas sólidas que comprenden irbesartán y amlodipina, su preparación y su aplicación terapéutica
PT1441713E (pt) Comprimidos de tamsulosina de libertação modificada.
HUT62488A (en) Process for producing orally administrable pharmaceutical compositions comprising coagulation and platelet function inhibiting active ingredients in small dose
BRPI0806713A2 (pt) composições de tiacumicinas estáveis
WO2014027334A2 (fr) Composition pharmaceutique orale sous forme de microsphères et procédé de préparation
US20070104789A1 (en) Gastro-resistant and ethanol-resistant controlled-release formulations comprising hydromorphone
CA2764172A1 (fr) Antagoniste du recepteur de la thrombine et comprime de clopidogrel a dose fixe
ES2483154T3 (es) Formulaciones farmacéuticas sólidas de ramipril y besilato de amlodipino y su preparación
ES2620078T3 (es) Formulación oral para el tratamiento de enfermedades cardiovasculares
ES2402865T3 (es) Formulación farmacéutica que contiene fluvastatina
WO2013159166A1 (fr) Forme pharmaceutique orale pour la prévention de maladies vasculaires, comprimé utilisé comme forme pharmaceutique et capsule gélatineuse utilisée comme forme pharmaceutique
BR102013028883A2 (pt) forma farmacêutica oral para a prevenção de doenças vasculares, comprimido como forma farmacêutica e cápsula gelatinosa como forma farmacêutica
WO2016012898A1 (fr) Composition pharmaceutique orale de lurasidone
EA029586B1 (ru) Фармацевтическая композиция для лечения вич-инфекций
ES2299157T3 (es) Formulacion estable que comprende un farmaco sensible a la humedad y procedimiento de preparacion del mismo.
WO2014026261A1 (fr) Préparation pharmaceutique orale solide pour la prévention de maladies cardiovasculaires et cérébrovasculaires, et comprimé
BRPI0621739A2 (pt) formulação estável que consiste em drogas sensìveis à umectação e seu procedimento de fabricação
ES2313578T3 (es) Formulacion estable que comprende una combinacion de un farmaco sensible a la humedad y un segundo farmaco y procedimiento de preparacion de la misma.
KR20110031226A (ko) 에프로사르탄 조성물

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13782627

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13782627

Country of ref document: EP

Kind code of ref document: A1