Classifications

• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
• • 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
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
• • 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
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine 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
• • 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

Definitions

• the present invention relates to a composition for oral administration in the form of microparticles, for example microspheres or pellets, as well as the process for their preparation.
• the invention also relates to a composition containing a diuretic and the use of the composition for the treatment of edema, cardiovascular disorders, hypertension, kidney damage, liver damage, among others.
• Diuretics are a group of drugs used to treat various medical conditions, including edema, heart failure, hypertension, certain types of kidney and liver diseases, and increased infraocular pressure among others.
• the substance that causes the elimination of water and sodium in the body through urine is called diuretics, these can be classified as diuretics, loop (by acting in the loop of renal Henle), Thiazides (thiazide derivatives), Carbonic anhydrase inhibitors, potassium-sparing, which can be of two kinds: Sodium channel inhibitors and aldosterone antagonists, osmotic diuretics.
• Hydrochlorothiazide (HCTZ) is a diuretic agent commonly used in the treatment of edema and hypertension. It is a white, odorless, crystalline powder. Its chemical name is 6-chloro-3, 4-dihydro-2H-l, 2, 4- benzothiadiazin-7-sulfonamide-1, 1-dioxide. Its structural formula is:
• Hydrochlorothiazide is stable under conditions of neutral and relatively acidic pH, but it is not very stable in alkaline environments. Practically insoluble in water, poorly soluble in methanol and ethanol and soluble in sodium hydroxide.
• telmisartan a synergistic effect has been reported to treat blood pressure with the combination of thiazide diuretics such as hydrochlorothiazide and an antagonist of angiotensin II receptor (ARB), resulting in virtually no additional side effects.
• ARB angiotensin II receptor
• this approach is not feasible due to the incompatibility of HCTZ with basic compounds such as meglumine, which is a usual component of conventional telmisartan formulations.
• the processes of formation of microspheres and pellets from inert cores commonly involve spraying on the inert core of a solution formed by an adhesive or binder polymer and the active principle.
• hydrochlorothiazide oxidizes very easily under these spray conditions.
• the present invention successfully solves the aforementioned problem, thanks to an optimization of the spray conditions and the formation of an active principle suspension with a homogeneous particle size.
• the present invention provides a pharmaceutical composition in the form of hydrochlorothiazide microspheres, optionally coated with one or more layers of modified release polymers, or polymeric shells that They provide protection to the microsphere of factors such as humidity and light, among others.
• the present invention provides a pharmaceutical composition in the form of hydrochlorothiazide pellets, optionally coated with one or more layers of modified release polymers, or polymeric shells that confer protection to the microsphere of factors such as moisture and light, among others.
• the present invention provides a pharmaceutical composition in the form of microspheres or hydrochlorothiazide pellets that may contain layers of other drugs including, but not limited to, cardiovascular, antihypertesive or lipid lowering agents.
• the present invention provides a pharmaceutical composition in the form of microparticles (microspheres or pellets) of hydrochlorothiazide in combination with other dosage units including, for example, granules, microspheres, powders, pellets, solutions, suspensions and microtablets, which contain other additional drugs including, but not limited to, cardiovascular, antihypertesive or lipid lowering agents.
• the present invention provides methods for treating and / or preventing a cardiovascular disease comprising administering to a subject in need thereof, a pharmaceutical composition containing hydrochlorothiazide and optionally one or more cardiovascular, lipid lowering or antihypertensive agents.
• Another characteristic of the process that allows to reduce the risk of oxidation is that the suspension that is applied has such a concentration of active ingredient, which allows the coverage to be applied very quickly, which reduces the exposure time of the active substance to the conditions that promote oxidation.
• a second layer consisting of a coating can be included to improve the durability, appearance and / or handling of the composition of the pellets.
• polymers used in this second layer include, but are not limited to hydroxypropyl methylcellulose (HPMC) and Opadry®.
• the additional layer (s) can also be formed with polymer (s) for modified release (immediate or delayed) using, for example, acrylic polymers or cellulose derivatives.
• An effective amount of one or more plasticizers may be included in the release modification layer, to improve the physical properties of said layer.
• plasticizers include, but are not limited to, citric acid esters, propylene glycol, HPC, HPMC, glycerin and diethyl phthalate.
• compositions of the present invention may include additional excipients to improve handling, processing properties and / or dissolution properties of the active ingredient.
• Additional excipients contemplated in the present invention include, but are not limited to, vehicles, diluents, solubilizers, lubricants or glidants, surfactants, disintegrants and / or anti-sticks.
• solubilizers include alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, butanediols, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl, polyethylene glycol, propylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose derivatives , cyclodextrins and cyclodextrin derivatives; polyethylene glycol ethers such as methoxy PEG; amides, such as ⁇ -caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, polyvinylpyrrolidone; esters, such as ethyl propionate, tributyl citrate, acetyl triethyl
• Possible lubricating or sliding agents include, but are not limited to, glyceryl behenate, metal stearates (e.g., magnesium stearate, calcium and sodium), stearic acid, hydrogenated vegetable oils, talc, waxes, boric acid, benzoate. sodium, sodium acetate, sodium chloride, DL-leucine, polyethylene glycol, sodium acetate, SDS, magnesium lauryl sulfate, starch, calcium carbonate, calcium phosphate, titanium dioxide or combinations thereof.
• metal stearates e.g., magnesium stearate, calcium and sodium
• stearic acid e.g., hydrogenated vegetable oils, talc, waxes, boric acid, benzoate.
• the surfactants of the present invention include but are not limited to: sodium lauryl sulfate, poloxamers (copolymers of polyoxyethylene and polyoxypropylene), natural or synthetic lecithins, sorbitan esters and fatty acids, polyoxyethylene sorbitan esters and fatty acids, Cremophor ® , polyoxyethylene stearates, or combinations thereof.
• Dyes, flavorings, sweeteners, antioxidants, preservatives, chelating agents, opacifiers and / or viscomodulators can also be used in the preparation of the pharmaceutical compositions of the present invention.
• microspheres and pellets of the present invention allows to obtain a product with a very good solution unlike commercial tablets. This is due to the fact that the contact area of the active ingredient available is larger than in the case of a tablet, which allows to improve the dissolution of the drug. This property is particularly useful when it comes to active ingredients with low solubility, such as lercanidipine and telmisartan.
• An additional advantage of the microparticles of the present invention is that the release of the active ingredients can be handled independently even when they are in the same dose unit.
• microparticles of the present application consists in the versatility to form virtually any combination with other active principle (s) generating stable compositions.
• Hydrochlorothiazide and the additional drug (s) may be co-formulated as a single dose unit or may be formulated as two or more dose units for coordinated, combined or concomitant administration.
• microspheres and pellets of the present invention can be placed in a pharmaceutical form suitable for oral administration, for example, hard or soft capsules.
• the microspheres can also be compressed to form tablets (coated tablets, bilayer, multilayer), or placed in sachets or processed to form granules, dispersions or suspensions.
• the capsules can be formed, for example, from gelatin or HPMC.
• microparticles of the present invention can be combined with pharmaceutically acceptable carriers or excipients selected from solvents, diluents, solubilizers, lubricants or glidants, disintegrants, surfactants, anti-adherent, dyes, flavorings, sweeteners, antioxidants, preservatives, chelating agents, opacifiers, viscomodulators and mixtures thereof.
• a dispersion or suspension of microspheres can be formed in water-miscible but non-aqueous liquid vehicles, such as alcohols, oils and polyethylene glycol, among others, and combinations thereof.
• Another example is the combination of microspheres with powders such as talc or other solid excipients.
• the dispersion, suspension or mixture of microspheres with powders can be placed in a gelatin capsule, HPMC capsule, sachet or other suitable dosage form.
• microparticles of the present invention can be formulated in a dose unit, or they can be formulated with other active ingredients in the same dose unit, or even formulated individually in separate dose units as a pharmaceutical kit.
• the microspheres or pellets in one embodiment may be coated with layers of another active ingredient (s).
• the microspheres or pellets of the present invention can be combined with other pharmaceutical compositions in the form of suspensions, solutions, dispersions, pellets, granules, microspheres, powders, microcapsules etc. containing another active ingredient (s) and placed in the same dose unit; in another mode, when it is desired to co-administer two or more separate units, the HCTZ microparticles are present in a first unit, for example a capsule or tablet, and another active principle (s) are present in another dose unit, for example, tablet, capsule, sachet , suspension, solution or dispersion.
• the microparticles of the present invention are formulated with another active principle in the same dose unit and other active principle (s) are present in another dose unit.
• active ingredients that can be used in combination with the microparticles of the present invention are one or more of: cholesterol absorption inhibitors such as ezetimibe, and simvastatin; aldosterone antagonists such as eplerenone and aldactone; acyl-CoA cholesteryl transferase inhibitors such as CI-1011 (Avasimibe, Pfizer) and CS-505 (Pactimibe sulfate, Sankyo Pharma); beta receptor blockers such as atenolol, acebutolol, carvediol, nadolol, nevibolol, pindolol and propranolol; ACE inhibitors such as enalapril, lisinopril, benazepril, captopril, cilazapril,
• microparticles of the present invention can also be combined with other active principle (s) such as those described above, in kit form.

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

Priority Applications (1)

Applications Claiming Priority (2)

Publications (2)

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Cited By (9)

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• 2012
  • 2012-08-17 MX MX2012009583A patent/MX351059B/es active IP Right Grant
• 2013
  • 2013-08-16 PE PE2015000210A patent/PE20150710A1/es active IP Right Grant
  • 2013-08-16 WO PCT/IB2013/056690 patent/WO2014027334A2/fr not_active Ceased
• 2015
  • 2015-02-13 CR CR20150077A patent/CR20150077A/es unknown
  • 2015-02-16 GT GT201500035A patent/GT201500035A/es unknown
  • 2015-02-16 DO DO2015000028A patent/DOP2015000028A/es unknown
  • 2015-02-17 CL CL2015000375A patent/CL2015000375A1/es unknown
  • 2015-03-04 CO CO15048826A patent/CO7310526A2/es unknown

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