WO2012050539A1 - Pharmaceutical composition comprising eplerenone - Google Patents

Pharmaceutical composition comprising eplerenone Download PDF

Info

Publication number
WO2012050539A1
WO2012050539A1 PCT/TR2011/000210 TR2011000210W WO2012050539A1 WO 2012050539 A1 WO2012050539 A1 WO 2012050539A1 TR 2011000210 W TR2011000210 W TR 2011000210W WO 2012050539 A1 WO2012050539 A1 WO 2012050539A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
composition according
range
eplerenone
cellulose
Prior art date
Application number
PCT/TR2011/000210
Other languages
French (fr)
Inventor
Mahmut Bilgic
Original Assignee
Mahmut Bilgic
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 Mahmut Bilgic filed Critical Mahmut Bilgic
Publication of WO2012050539A1 publication Critical patent/WO2012050539A1/en

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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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

Definitions

  • the present invention relates to new, soluble and easily-produceable pharmaceutical formulations comprising eplerenone.
  • the present invention relates to eplerenone formulation which is effective in the treatment of cardiovascular diseases such as congestive heart failure, congestive heart failure after myocardial infarction, heart disorders, and hypertension.
  • Eplerenone, 9a, 11 -epoxy-7a-(methoxycarbonyl)-3 -oxo, 17a-pregn-4-ene-21 , 17-carbolactone is an antihypertensive agent which is an aldosterone antagonist.
  • Eplerenone is described in the patent numbered US 4559332 (A) in detail.
  • the molecule eplerenone, synthesis method for the molecule eplerenone and pharmaceutical compositions comprising eplerenone are disclosed in the molecule patent.
  • Eplerenone is an aldosterone antagonist which can be used in the treatment of cardiovascular diseases, and hyperaldosteronism-related diseases such as hypertension.
  • Eplerenone is sparingly soluble in water. This brings along some problems during production. Eplerenone which has lipophilic nature does not dissolve well in gastrointestinal channel. This solubility problem complicates to formulate eplerenone.
  • Purpose of the invention is to eliminate the existing problems by formulating eplerenone which has low water solubility and poses disadvantages during production due to its lipophilic nature with effective amounts of appropriate excipients.
  • the pharmaceutical formulation comprising eplerenone provides the required solubility without decreasing the particle size of the active agent eplerenone therefore encountering the problem of agglomeration in the present invention.
  • the inventors Using the active agent and the other excipients in specified ranges, the inventors have obtained therapeutically effective compositions which have far better solubility than expected.
  • composition of the present invention is characterized by comprising;
  • Microcrystalline cellulose in the range of 15-50%, preferably in the range of 26-36%) by weight;
  • the characteristic feature of the composition of the present invention is that the ratio of eplerenone to microcrystalline cellulose by weight varies in the range of 1 :2 to 1 :0.5.
  • the characteristic feature of the composition of the present invention is that the ratio of eplerenone to the diluent by weight varies in the range of 1 : 1.5 to 1 :0.4.
  • the pharmaceutical composition obtained in the case that the diluent in the composition of the present invention is direct compression lactose (which will henceforward be called “lactose D.C.") have better solubility characteristics.
  • Avicel PH 102 is preferably used in the pharmaceutical composition as microcrystalline cellulose, which is present in the composition as a disintegrant.
  • the most soluble composition has been obtained by using the diluent which has the average particle size in the range of 50 and 200 ⁇ , preferably 50 and 175 ⁇ and microcrystalline cellulose which has the average particle size in the range of 50 and 200 ⁇ , preferably 50 and 150 ⁇ .
  • compositions of the present invention can be selected from a group comprising sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid esters (polysorbates), polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene castor oil derivatives, docusate sodium, quaternary ammonium compounds; sugar esters and glycerides of fatty acids.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising eplerenone.
  • pharmaceutically acceptable excipients can optionally be used in the composition of the present invention.
  • eplerenone in the composition of the present invention can be in free form or pharmaceutically acceptable salt, enantiomer, racemate, solvate, hydrate, different polymorphic form and amorphous form thereof.
  • Particle size of the active agent eplerenone in the pharmaceutical composition of the present invention is in the range of 10-300 ⁇ , preferably in the range of 10-25 ⁇ .
  • composition of the present invention can be used in the treatment, alleviation of the symptoms or slowing the progression of cardiovascular diseases, hyperaldosteronism-related diseases such as hypertension.
  • compositions of the present invention can be used in people suffering from heart failure, systolic function disorder of left ventricle and in the treatment of cardiovascular diseases such as congestive heart failure after myocardial infarction, diseases such as hypertension, edema associated with hepatic impairment and hepatic cirrhosis.
  • compositions of the present invention can be prepared as a medicament composition effective in the treatment of people suffering from heart failure, systolic function disorder of left ventricle and in the treatment of cardiovascular diseases such as congestive heart failure after myocardial infarction, diseases such as hypertension, edema associated with hepatic impairment and hepatic cirrhosis.
  • the present invention relates to administration of the pharmaceutical formulation on mammals including human in the treatment of cardiovascular diseases and hypertension.
  • composition of the present invention which relates to a pharmaceutical composition for use in the production of a medicament effective in the treatment of diseases such as cardiovascular diseases and hypertension is characterized by comprising the active agent eplerenone.
  • compositions comprising the active agent eplerenone and effective amounts of excipients to reduce the symptoms of diseases such as cardiovascular diseases and hypertension, slowing the progression of the disease and treatment of the disease.
  • reducing the symptoms refers to reducing the number of the symptoms observed in the patients who are diagnosed with said disease by administration of the pharmaceutical combination comprising eplerenone.
  • slowing the progression of the disease refers to the administration of the pharmaceutical combination comprising eplerenone to the patients who are at the first stage of the disease and diagnosed with said disease.
  • treatment of the disease refers to administration of the pharmaceutical composition comprising eplerenone in the treatment of people diagnosed with said disease or in any stage of said disease.
  • dose of the active agent in the composition of the present invention depends on factors such as status of the disease to be treated; patient's state of health, age, weight, gender.
  • the active agent in said composition can be in the range of 10-100 mg, preferably in the range of 13.5-72 mg, more preferably in the range of 18-54 mg.
  • composition of the present invention can be prepared as administrable by the oral route.
  • compositions of the present invention can comprise oral dosage forms and pharmaceutical formulations with pharmaceutically acceptable excipients.
  • Oral dosage forms can be in solid forms such as tablets; capsules; enteric-coated or modified release tablets; prolonged release tablets; delayed release tablet; fast soluble tablets; effervescent tablets; effervescent granules; fast soluble powder mixture; granule; pellet, minitablet; granule capsule; pellet capsule; minitablet capsule; microtablet capsule; dry powder mixture for syrup preparation; dragee; orally disintegrated tablets; water-soluble powder, tablet or granule or in liquid form such as suspension.
  • oral dosage form is in tablet form and optionally coated by a film coating composition.
  • the film coating composition according to the invention can comprise the following components lactose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, triacetin, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate phthalate, polyvinyl acetatae phthalate, diethyl phthalate, sugar derivatives, polyvinyl derivatives (such as polyvinyl alcohol), polyethylene glycol, waxes, oils and gelatins, triethyl citrate, glyceride, titanium oxide, red and/or black iron oxide, talc, sodium alginate, stearic acid, lecitine or mixtures thereof.
  • the film coating composition comprises polyvinyl alcohol, polyethylene glycol, lecitine, yellow and/or black iron oxide and at least one other component.
  • the film coating composition is in the range of 1 and 5 %, preferably 1 and 4 % by total weight of the composition.
  • composition of the present invention is produced by conventional methods.
  • pharmaceutically acceptable excipients can also be used in addition to the active agents used in the oral formulations comprising the present invention.
  • These excipients can be selected from a group comprising substances such as pharmaceutically acceptable disintegrant, binder, lubricant, glidant and/or coating material.
  • Preffered excipient composition according to the invention does not comprise binder.
  • Pharmaceutically acceptable disintegrants of the present invention can be selected from a group comprising microcrystalline cellulose, croscarmellose sodium (such as Ac-Di-Sol), starch, clay, methyl cellulose, carboxymethylcellulose, sodium carboxymethyl cellulose, alginate, crospovidone; gums such as agar, guar, pectin and tragant; pregelatinized starch, starch.
  • croscarmellose sodium such as Ac-Di-Sol
  • starch such as Ac-Di-Sol
  • clay methyl cellulose, carboxymethylcellulose, sodium carboxymethyl cellulose, alginate, crospovidone
  • gums such as agar, guar, pectin and tragant
  • pregelatinized starch starch.
  • the composition can comprise croscarmellose sodium as another disintegrant together with microcrystalline cellulose.
  • the amount of croscarmellose sodium in the composition is in the range of 1 and 4 %, preferably 1 and 3.5 %.
  • the ratio of microcrystalline cellulose to croscarmellose sodium by weight is at least 10, preferably between 10 and 20, more preferably between 12 and 17.5.
  • Pharmaceutically acceptable diluents of the present invention can be selected from a group comprising lactose, dry lactose, lactose monohydrate, direct compression lactose (lactose D.C.), starch, hydrolyzed starch, mannitol, sorbitol, xylitol, dextrose, dextrose monohydrate, dibasic calcium phosphate dihydrate, monobasic calcium, sulphate monohydrate, calcium sulphate dihydrate, amylose, cellulose and cellulose derivatives, calcium carbonate, glycine, bentonite, polyvinylpyrrolidone.
  • binders of the present invention can be selected from a group comprising ethyl cellulose, hydroxyethyl cellulose, methylcellulose, microcrystalline cellulose (such as Avicel PH 101, Avicel PH 102), hydroxymethyl cellulose, hydroxypropyl cellulose, gelatin, hypromellose, magnesium aluminum silicate, maltodextrin, polyethylene oxide, povidone, sorbitol and water or a combination thereof.
  • Pharmaceutically acceptable lubricants of the present invention can be selected from a group comprising metallic stearates (such as magnesium stearate, calcium stearate, aluminum stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oil, leucine, polyethylene glycols, metallic lauryl sulfates (such as sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, sodium benzoate, sodium acetate and talc.
  • metallic stearates such as magnesium stearate, calcium stearate, aluminum stearate
  • fatty acid esters such as sodium stearyl fumarate
  • fatty acids such as stearic acid
  • fatty alcohols such as sodium stearic acid
  • fatty alcohols such as sodium stearyl fumarate
  • fatty alcohols
  • Pharmaceutically acceptable glidants of the present invention can be selected from a group comprising talc, silicon dioxide, magnesium trisilicate, cellulose powder, starch, tribasic calcium phosphate, metallic stearates, calcium silicate and metallic lauryl sulfate.
  • the formulation can further comprise other pharmaceutically acceptable excipients such as solubility enhancers, electrolytes, sweeteners, coloring agents and coating agents.
  • composition of the present invention can be produced by conventional methods in the prior art.
  • Eplerenone, Avicel PH 102, lactose D.C. and sodium lauryl sulfate are mixed in a container for some time. Afterwards, sufficient amounts of glidant and lubricant are added into this mixture. Mixing goes on until a homogeneous mixture is obtained. The final mixture is loaded into tablet compression machine and tablets are compressed. Compressed tablets are coated with a film coating solution prepared by dissolving in a sufficient amount of deionized water and the tablets formulations are finalized.

Abstract

The present invention relates to new, soluble and easily-produceable pharmaceutical formulations comprising eplerenone.

Description

PHARMACEUTICAL COMPOSITION COMPRISING EPLERENONE
The present invention relates to new, soluble and easily-produceable pharmaceutical formulations comprising eplerenone.
The present invention relates to eplerenone formulation which is effective in the treatment of cardiovascular diseases such as congestive heart failure, congestive heart failure after myocardial infarction, heart disorders, and hypertension.
Eplerenone, 9a, 11 -epoxy-7a-(methoxycarbonyl)-3 -oxo, 17a-pregn-4-ene-21 , 17-carbolactone is an antihypertensive agent which is an aldosterone antagonist.
Figure imgf000002_0001
eplerenone
Eplerenone is described in the patent numbered US 4559332 (A) in detail. The molecule eplerenone, synthesis method for the molecule eplerenone and pharmaceutical compositions comprising eplerenone are disclosed in the molecule patent.
Eplerenone is an aldosterone antagonist which can be used in the treatment of cardiovascular diseases, and hyperaldosteronism-related diseases such as hypertension.
Eplerenone is sparingly soluble in water. This brings along some problems during production. Eplerenone which has lipophilic nature does not dissolve well in gastrointestinal channel. This solubility problem complicates to formulate eplerenone.
Purpose of the invention is to eliminate the existing problems by formulating eplerenone which has low water solubility and poses disadvantages during production due to its lipophilic nature with effective amounts of appropriate excipients.
There exist various studies relating to formulations comprising the active agent eplerenone. For instance, it is aimed to improve solubility of the active agent eplerenone by decreasing its particle size in the patent numbered EP 1175220. Said patent relates to D90 particle size of eplerenone being smaller than 10 μηι, preferably smaller than 5 μπι. However, small particle size may lead to undesirable consequences such as agglomeration.
Most of the studies in the prior art depend on particle size of the active agent eplerenone. However, decreasing the particle size may not always be effective in improving dissolution rate of the drug because most of the lipophilic active agents turn into larger particles due to thermodynamic reasons during production of the formulation. Agglomeration is observed as a result of increased particle size, therefore reduced surface area. At this point; new, soluble and easily-produceable pharmaceutical formulations are required.
It has been surprisingly seen that the pharmaceutical formulation comprising eplerenone provides the required solubility without decreasing the particle size of the active agent eplerenone therefore encountering the problem of agglomeration in the present invention.
Using the active agent and the other excipients in specified ranges, the inventors have obtained therapeutically effective compositions which have far better solubility than expected.
The composition of the present invention is characterized by comprising;
- Eplerenone in the range of 10-50%, preferably in the range of 20-30% by weight;
- Microcrystalline cellulose in the range of 15-50%, preferably in the range of 26-36%) by weight;
- Diluent in the range of 12-60%, preferably in the range of 24-38%) by weight;
- Surfactant in the range of 0.5-10%, preferably in the range of 1.5-4% by weight and optionally at least one pharmaceutically acceptable excipient.
In another aspect, the characteristic feature of the composition of the present invention is that the ratio of eplerenone to microcrystalline cellulose by weight varies in the range of 1 :2 to 1 :0.5.
In another aspect, the characteristic feature of the composition of the present invention is that the ratio of eplerenone to the diluent by weight varies in the range of 1 : 1.5 to 1 :0.4.
In another aspect, it has been seen that the pharmaceutical composition obtained in the case that the diluent in the composition of the present invention is direct compression lactose (which will henceforward be called "lactose D.C.") have better solubility characteristics. According to the present invention, Avicel PH 102 is preferably used in the pharmaceutical composition as microcrystalline cellulose, which is present in the composition as a disintegrant.
It has also been seen that the particle size distribution of the pharmaceutical excipients in the composition plays an important role onto the solubility characteristic of the composition.
According to the present invention, the most soluble composition has been obtained by using the diluent which has the average particle size in the range of 50 and 200 μιη, preferably 50 and 175 μιη and microcrystalline cellulose which has the average particle size in the range of 50 and 200 μιη, preferably 50 and 150 μηι.
Pharmaceutically acceptable surfactants of the present invention can be selected from a group comprising sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid esters (polysorbates), polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene castor oil derivatives, docusate sodium, quaternary ammonium compounds; sugar esters and glycerides of fatty acids.
It has been seen that the pharmaceutical composition of the present invention obtained by using sodium lauryl sulfate as surfactant presents better solubility characteristics than expected.
The present invention relates to a pharmaceutical composition comprising eplerenone. At the same time, pharmaceutically acceptable excipients can optionally be used in the composition of the present invention.
In another aspect, eplerenone in the composition of the present invention can be in free form or pharmaceutically acceptable salt, enantiomer, racemate, solvate, hydrate, different polymorphic form and amorphous form thereof.
Particle size of the active agent eplerenone in the pharmaceutical composition of the present invention is in the range of 10-300 μπι, preferably in the range of 10-25 μπι.
In another aspect, the composition of the present invention can be used in the treatment, alleviation of the symptoms or slowing the progression of cardiovascular diseases, hyperaldosteronism-related diseases such as hypertension. In another aspect, the compositions of the present invention can be used in people suffering from heart failure, systolic function disorder of left ventricle and in the treatment of cardiovascular diseases such as congestive heart failure after myocardial infarction, diseases such as hypertension, edema associated with hepatic impairment and hepatic cirrhosis.
According to the present invention, the compositions of the present invention can be prepared as a medicament composition effective in the treatment of people suffering from heart failure, systolic function disorder of left ventricle and in the treatment of cardiovascular diseases such as congestive heart failure after myocardial infarction, diseases such as hypertension, edema associated with hepatic impairment and hepatic cirrhosis.
In another aspect, the present invention relates to administration of the pharmaceutical formulation on mammals including human in the treatment of cardiovascular diseases and hypertension.
In another aspect, the composition of the present invention which relates to a pharmaceutical composition for use in the production of a medicament effective in the treatment of diseases such as cardiovascular diseases and hypertension is characterized by comprising the active agent eplerenone.
In another aspect, it is aimed with the pharmaceutical compositions comprising the active agent eplerenone and effective amounts of excipients to reduce the symptoms of diseases such as cardiovascular diseases and hypertension, slowing the progression of the disease and treatment of the disease.
The expression "reducing the symptoms" refers to reducing the number of the symptoms observed in the patients who are diagnosed with said disease by administration of the pharmaceutical combination comprising eplerenone. The expression "slowing the progression of the disease" refers to the administration of the pharmaceutical combination comprising eplerenone to the patients who are at the first stage of the disease and diagnosed with said disease. The expression "treatment of the disease" refers to administration of the pharmaceutical composition comprising eplerenone in the treatment of people diagnosed with said disease or in any stage of said disease.
In another aspect, dose of the active agent in the composition of the present invention depends on factors such as status of the disease to be treated; patient's state of health, age, weight, gender. The active agent in said composition can be in the range of 10-100 mg, preferably in the range of 13.5-72 mg, more preferably in the range of 18-54 mg.
According to the present invention, the composition of the present invention can be prepared as administrable by the oral route.
Pharmaceutical compositions of the present invention can comprise oral dosage forms and pharmaceutical formulations with pharmaceutically acceptable excipients.
Oral dosage forms can be in solid forms such as tablets; capsules; enteric-coated or modified release tablets; prolonged release tablets; delayed release tablet; fast soluble tablets; effervescent tablets; effervescent granules; fast soluble powder mixture; granule; pellet, minitablet; granule capsule; pellet capsule; minitablet capsule; microtablet capsule; dry powder mixture for syrup preparation; dragee; orally disintegrated tablets; water-soluble powder, tablet or granule or in liquid form such as suspension. According to the present invention, oral dosage form is in tablet form and optionally coated by a film coating composition.
The film coating composition according to the invention can comprise the following components lactose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, triacetin, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate phthalate, polyvinyl acetatae phthalate, diethyl phthalate, sugar derivatives, polyvinyl derivatives ( such as polyvinyl alcohol), polyethylene glycol, waxes, oils and gelatins, triethyl citrate, glyceride, titanium oxide, red and/or black iron oxide, talc, sodium alginate, stearic acid, lecitine or mixtures thereof.
According to the present invention, the film coating composition comprises polyvinyl alcohol, polyethylene glycol, lecitine, yellow and/or black iron oxide and at least one other component. The film coating composition is in the range of 1 and 5 %, preferably 1 and 4 % by total weight of the composition.
According to an aspect, the composition of the present invention is produced by conventional methods.
In another aspect, pharmaceutically acceptable excipients can also be used in addition to the active agents used in the oral formulations comprising the present invention. These excipients can be selected from a group comprising substances such as pharmaceutically acceptable disintegrant, binder, lubricant, glidant and/or coating material. Preffered excipient composition according to the invention does not comprise binder.
Pharmaceutically acceptable disintegrants of the present invention can be selected from a group comprising microcrystalline cellulose, croscarmellose sodium (such as Ac-Di-Sol), starch, clay, methyl cellulose, carboxymethylcellulose, sodium carboxymethyl cellulose, alginate, crospovidone; gums such as agar, guar, pectin and tragant; pregelatinized starch, starch.
According to the invention, the composition can comprise croscarmellose sodium as another disintegrant together with microcrystalline cellulose.
The amount of croscarmellose sodium in the composition is in the range of 1 and 4 %, preferably 1 and 3.5 %.
The ratio of microcrystalline cellulose to croscarmellose sodium by weight is at least 10, preferably between 10 and 20, more preferably between 12 and 17.5.
Pharmaceutically acceptable diluents of the present invention can be selected from a group comprising lactose, dry lactose, lactose monohydrate, direct compression lactose (lactose D.C.), starch, hydrolyzed starch, mannitol, sorbitol, xylitol, dextrose, dextrose monohydrate, dibasic calcium phosphate dihydrate, monobasic calcium, sulphate monohydrate, calcium sulphate dihydrate, amylose, cellulose and cellulose derivatives, calcium carbonate, glycine, bentonite, polyvinylpyrrolidone.
Pharmaceutically acceptable binders of the present invention can be selected from a group comprising ethyl cellulose, hydroxyethyl cellulose, methylcellulose, microcrystalline cellulose (such as Avicel PH 101, Avicel PH 102), hydroxymethyl cellulose, hydroxypropyl cellulose, gelatin, hypromellose, magnesium aluminum silicate, maltodextrin, polyethylene oxide, povidone, sorbitol and water or a combination thereof.
Pharmaceutically acceptable lubricants of the present invention can be selected from a group comprising metallic stearates (such as magnesium stearate, calcium stearate, aluminum stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oil, leucine, polyethylene glycols, metallic lauryl sulfates (such as sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, sodium benzoate, sodium acetate and talc. Pharmaceutically acceptable glidants of the present invention can be selected from a group comprising talc, silicon dioxide, magnesium trisilicate, cellulose powder, starch, tribasic calcium phosphate, metallic stearates, calcium silicate and metallic lauryl sulfate.
In addition to these, the formulation can further comprise other pharmaceutically acceptable excipients such as solubility enhancers, electrolytes, sweeteners, coloring agents and coating agents.
The composition of the present invention can be produced by conventional methods in the prior art.
The combination of the present invention and pharmaceutical formulations comprising this combination and their preparation methods can be explained by examples below, yet the invention cannot be limited to these.
EXAMPLES
EXAMPLE 1:
Eplerenone, Avicel PH 102, lactose D.C. and sodium lauryl sulfate are mixed in a container for some time. Afterwards, sufficient amounts of glidant and lubricant are added into this mixture. Mixing goes on until a homogeneous mixture is obtained. The final mixture is loaded into tablet compression machine and tablets are compressed. Compressed tablets are coated with a film coating solution prepared by dissolving in a sufficient amount of deionized water and the tablets formulations are finalized.
Figure imgf000009_0001

Claims

1. A pharmaceutical formulation characterized in that said formulation comprises eplerenone, disintegrant, diluent, surfactant and optionally at least one pharmaceutically acceptable excipient in effective amounts.
2. The pharmaceutical composition according to claim 1 characterized in that said composition comprises;
- eplerenone in the range of 10-50% by weight;
- microcrystalline cellulose as disintegrant in the range of 15-50% by weight;
- diluent in the range of 12-60% by weight;
- surfactant in the range of 0.5-10% by weight and optionally at least one pharmaceutically acceptable excipients.
3. The pharmaceutical composition according to claim 2 characterized in that said composition comprises;
- eplerenone in the range of 20-30% by weight;
- microcrystalline cellulose as disintegrant in the range of 26-36% by weight;
- diluent in the range of 24-38% by weight;
- surfactant in the range of 1.5-4% by weight and optionally at least one pharmaceutically acceptable excipients.
4. The pharmaceutical composition according to claims 2 and 3 characterized in that the ratio of eplerenone to microcrystalline cellulose by weight is in the range of 1:2 to 1:0,5.
5. The pharmaceutical composition according to claims 2 and 3 characterized in that the ratio of eplerenone to diluent by weight is in the range of 1 : 1,5 to 1 :0,4.
6. The pharmaceutical composition according to claim 1-3, wherein the diluent used in said composition is selected from a group comprising lactose, dry lactose, lactose monohydrate, direct compression lactose, starch, hydrolyzed starch, mannitol, sorbitol, xylitol, dextrose, dextrose monohydrate, dibasic calcium phosphate dihydrate, monobasic calcium, sulphate monohydrate, calcium sulphate dihydrate, amylose, cellulose and cellulose derivatives, calcium carbonate, glycine, bentonite, polyvinylpyrrolidone.
7. The pharmaceutical composition according to claim 6 characterized in that the diluent used in said composition is direct compression lactose.
8. The pharmaceutical composition according to claim 1 to 3, wherein the surfactant used in said composition is selected from a group comprising sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid esters (polysorbates), polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene castor oil derivatives, docusate sodium, quaternary ammonium compounds; sugar esters and glycerides of fatty acids.
9. The pharmaceutical composition according to claim 8 characterized in that the surfactant used in said composition is sodium lauryl sulfate.
10. The pharmaceutical composition according to any of the preceding claims characterized in that the active agent eplerenone is in free form or in the form of pharmaceutically acceptable salt, enantiomers, racemate, solvate, hydrate, different polymorphic form and amorphous form thereof.
11. The pharmaceutical composition according to according to any of the preceding claims characterized in that the active agent eplerenone in said composition has a particle size in the range of 10-300 μπι
12. The pharmaceutical composition according to claim 11 characterized in that the active agent eplerenone in said composition has a particle size in the range of in the range of 10-25 μηι.
13. The pharmaceutical composition according to any of the preceding claims characterized in that the active agent eplerenone in said composition weights in the range of 10-100 mg.
14. The pharmaceutical composition according to claim 13 characterized in that the active agent eplerenone in said composition weights in the range of 13,5-72 mg.
15. The pharmaceutical composition according to claim 14 characterized in that the active agent eplerenone in said composition weights in the range of 18-54 mg.
16. The pharmaceutical composition according to any of the preceding claims characterized in that said composition is prepared so as to be administered by the oral route.
17. The pharmaceutical composition according to claim 16 characterized in that the composition to be administered by the oral route is in solid forms such as tablets; capsules; enteric-coated or modified release tablets; prolonged release tablets; delayed release tablet; fast soluble tablets; effervescent tablets; effervescent granules; fast soluble powder mixture; granule; pellet, minitablet; granule capsule; pellet capsule; minitablet capsule; microtablet capsule; dry powder mixture for syrup preparation; dragee; orally disintegrated tablets; water-soluble powder, tablet or granule or in liquid form such as suspension.
18. The pharmaceutical composition according to claim 1 to 3 characterized in that the pharmaceutically acceptable excipients comprise substances such as disintegrant, binder, lubricant, glidant and coating material.
19. The pharmaceutical composition according to claim 18, wherein the disintegrant used in said composition is selected from a group comprising microcrystalline cellulose, croscarmellose sodium (such as Ac-Di-Sol), starch, clay, methyl cellulose, carboxymethylcellulose, sodium carboxymethyl cellulose, alginate, crospovidone; gums such as agar, guar, pectin and tragant; pregelatinized starch, starch.
20. The pharmaceutical composition according to claim 18, wherein the binder used in said composition is selected from a group comprising ethyl cellulose, hydroxyethyl cellulose, methylcellulose, microcrystalline cellulose (Avicel PH 101, Avicel PH 102), hydroxymethyl cellulose, hydroxypropyl cellulose, gelatin, hypromellose, magnesium aluminum silicate, maltodextrin, polyethylene oxide, povidone, sorbitol and water or a combination thereof.
21. The pharmaceutical composition according to claim 18, wherein the lubricant used in said composition is selected from a group comprising metallic stearates (magnesium stearate, calcium stearate, aluminum stearate), fatty acid esters (sodium stearyl fumarate), fatty acids (stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oil, leucine, polyethylene glycols, metallic lauryl sulfates (sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, sodium benzoate, sodium acetate and talc.The pharmaceutical composition according to claim 18, wherein the glidant used in said composition is selected from a group comprising talc, silicon dioxide, magnesium trisilicate, cellulose powder, starch, tribasic calcium phosphate, metallic stearates, calcium silicate and metallic lauryl sulfate.
PCT/TR2011/000210 2010-09-20 2011-09-19 Pharmaceutical composition comprising eplerenone WO2012050539A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2010/07653 2010-09-20
TR2010/07653A TR201007653A2 (en) 2010-09-20 2010-09-20 Pharmaceutical composition containing eplerenone

Publications (1)

Publication Number Publication Date
WO2012050539A1 true WO2012050539A1 (en) 2012-04-19

Family

ID=45524932

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2011/000210 WO2012050539A1 (en) 2010-09-20 2011-09-19 Pharmaceutical composition comprising eplerenone

Country Status (2)

Country Link
TR (4) TR201007653A2 (en)
WO (1) WO2012050539A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109925293A (en) * 2019-03-15 2019-06-25 南京卡文迪许生物工程技术有限公司 Eplerenone oral solid formulation and preparation method thereof
CN113995719A (en) * 2021-10-19 2022-02-01 河南中盛动物药业有限公司 Application of sodium carboxymethylcellulose in improvement of amoxicillin and colistin sulfate injection

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4559332A (en) 1983-04-13 1985-12-17 Ciba Geigy Corporation 20-Spiroxanes and analogues having an open ring E, processes for their manufacture, and pharmaceutical preparations thereof
WO2000033847A1 (en) * 1998-12-09 2000-06-15 G.D. Searle & Co. Micronized eplerenone compositions
EP1175220A2 (en) 1999-12-08 2002-01-30 Pharmacia Corporation Nanoparticulate eplerenone compositions
US20020132001A1 (en) * 2000-05-11 2002-09-19 Garthwaite Susan M. Aldosterone antagonist composition for release during aldosterone acrophase
WO2007012960A1 (en) * 2005-07-29 2007-02-01 Glenmark Pharmaceuticals Limited Pharmaceutical compositions of eplerenone
WO2008074098A1 (en) * 2006-12-21 2008-06-26 Alphapharm Pty Ltd Pharmaceutical composition

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4559332A (en) 1983-04-13 1985-12-17 Ciba Geigy Corporation 20-Spiroxanes and analogues having an open ring E, processes for their manufacture, and pharmaceutical preparations thereof
WO2000033847A1 (en) * 1998-12-09 2000-06-15 G.D. Searle & Co. Micronized eplerenone compositions
EP1175220A2 (en) 1999-12-08 2002-01-30 Pharmacia Corporation Nanoparticulate eplerenone compositions
EP1175220B1 (en) * 1999-12-08 2005-04-27 Pharmacia Corporation Nanoparticulate eplerenone compositions
US20020132001A1 (en) * 2000-05-11 2002-09-19 Garthwaite Susan M. Aldosterone antagonist composition for release during aldosterone acrophase
WO2007012960A1 (en) * 2005-07-29 2007-02-01 Glenmark Pharmaceuticals Limited Pharmaceutical compositions of eplerenone
WO2008074098A1 (en) * 2006-12-21 2008-06-26 Alphapharm Pty Ltd Pharmaceutical composition

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109925293A (en) * 2019-03-15 2019-06-25 南京卡文迪许生物工程技术有限公司 Eplerenone oral solid formulation and preparation method thereof
CN113995719A (en) * 2021-10-19 2022-02-01 河南中盛动物药业有限公司 Application of sodium carboxymethylcellulose in improvement of amoxicillin and colistin sulfate injection
CN113995719B (en) * 2021-10-19 2023-06-23 河南中盛生物工程有限公司 Application of sodium carboxymethyl cellulose in improving amoxicillin and colistin sulfate injection

Also Published As

Publication number Publication date
TR201109158A2 (en) 2012-04-24
TR201109160A2 (en) 2012-04-24
TR201007653A2 (en) 2012-04-24
TR201109159A2 (en) 2012-04-24

Similar Documents

Publication Publication Date Title
US20200000726A1 (en) Gastroresistant pharmaceutical formulations containing rifaximin
US20100098759A1 (en) Controlled-release preparation containing cilostazol and process for the preparation thereof
JP2015506377A5 (en)
JP5351490B2 (en) Nifedipine-containing nucleated tablet and method for producing the same
KR20160101720A (en) Pharmaceutical compositions comprising azd9291
JP2011513391A (en) Sustained release pharmaceutical composition containing mycophenolate and method thereof
US11819577B2 (en) Fixed dose pharmaceutical composition of valsartan and sacubitril
CA2644179C (en) Novel pharmaceutical composition comprising a disintegration matrix
WO2012156981A1 (en) Pharmaceutical compositions of lurasidone
JP2015500853A (en) Immediate release multi-unit pellet system
AU2019280026A1 (en) Galenic formulations of organic compounds
JP2010519200A (en) Controlled release formulation containing cilostazol and method for producing the same
JP7021108B2 (en) Oral pharmaceutical composition of nicotinamide
JP2012516299A (en) Organic galenic formulation
US11576917B2 (en) Pharmaceutical compositions comprising Ibrutinib
US20110086102A1 (en) Delayed release compositions
US9561242B2 (en) Doxycycline composition
WO2012050539A1 (en) Pharmaceutical composition comprising eplerenone
JP2010535212A (en) Improved candesartan formulation
US20220273619A1 (en) Pharmaceutical formulations comprising sodium palmitoyl-l-prolyl-l-prolylglycyl-l-tyrosinate and methods for preparing the same
KR102081095B1 (en) Enteric coated formulation comprising fenofibric acid a or pharmaceutically acceptable salts thereof
US11260055B2 (en) Oral pharmaceutical composition of lurasidone and preparation thereof
EP3157526A1 (en) Oral pharmaceutical composition of tofacitinib
US9566287B2 (en) Pharmaceutical composition of doxycycline with reduced food effect
KR102216579B1 (en) Enteric coated formulation comprising fenofibric acid a or pharmaceutically acceptable salts thereof

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: 11811437

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: 11811437

Country of ref document: EP

Kind code of ref document: A1