WO2011152803A1 - Water soluble formulation comprising a combination of amlodipine and a statin - Google Patents

Water soluble formulation comprising a combination of amlodipine and a statin Download PDF

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Publication number
WO2011152803A1
WO2011152803A1 PCT/TR2011/000140 TR2011000140W WO2011152803A1 WO 2011152803 A1 WO2011152803 A1 WO 2011152803A1 TR 2011000140 W TR2011000140 W TR 2011000140W WO 2011152803 A1 WO2011152803 A1 WO 2011152803A1
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Prior art keywords
pharmaceutical composition
composition according
amlodipine
effervescent
acid
Prior art date
Application number
PCT/TR2011/000140
Other languages
French (fr)
Inventor
Mahmut Bilgic
Original Assignee
Mahmut Bilgic
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Publication date
Application filed by Mahmut Bilgic filed Critical Mahmut Bilgic
Priority to EP11745588.1A priority Critical patent/EP2575757A1/en
Publication of WO2011152803A1 publication Critical patent/WO2011152803A1/en

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    • 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
    • A61K31/435—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
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent

Definitions

  • the present invention relates to novel, stable and easily produceable water soluble pharmaceutical compositions of a combination of a calcium channel blocker and a 3-hydroxy- 3-methylglutaryl-coenzyme A reductase inhibitor.
  • Amlodipine (Formula I), chemical name of which is 3-ethyl 5-methyl (+/-)-2-[(2- aminoethoxy)methyl] -4-(o-chlorophenyl)- 1 ,4-dihydropyridine-6-methyl-3 ,5 - pyridinedicarboxylate, was disclosed in the patent numbered EP 0089167 in detail.
  • HMG-CoA reductase inhibitors competitively inhibit the activation of the enzyme named HMG-CoA reductase.
  • This enzyme is in HMG-CoA reductase pathway where it is used for cholesterol synthesis of the body.
  • Rosuvastatin, atorvastatin, cerivastatin, lovastatin, fluvastatin, mevastatin, pravastatin and pitavastatin are HMG-CoA reductase inhibitors, in other terms, statin group compounds.
  • Rosuvastatin having the chemical name (3i?,5S,6E)-7-[4-(4-fluorophenyl)-6-(l-methylethyl)- 2[methyl(methylsulphonyl)amino]-5-pyrimidinyl]-3,5-dihydroxy-6-heptenoic acid is a HMG CoA enzyme inhibitor which was first disclosed in the patent numbered US 5260440 is displayed in formula (II):
  • rosuvastatin inhibits the activation of the enzyme named HMG-CoA reductase that is responsible for cholesterol synthesis in the body and prevents cholesterol formation and it is effective in the treatment of cardiovascular diseases such as hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.
  • Atorvastatin ⁇ Formula III which has the chemical name ( R, (Si?,)-2-(4-fluorophenyl)- ⁇ , ⁇ - dihydroxy-5 -( 1 -methylethyl)-3 -phenyl-4- [(phenylamino)carbanoyl] - 1 H-pyrrol- 1 -heptanoic acid is a HMG CoA reductase inhibitor.
  • Atorvastatin was first disclosed in the patent numbered EP 409281. There exist processes for preparation of atorvastatin and its use as cholesterol biosynthesis inhibitor in said patent.
  • Atorvastatin is a hypolipidemic drug which is a selective competitive inhibitor of HMG CoA reductase enzyme. It has the indication of lowering increased LDL cholesterol and triglyceride levels.
  • the product marketed under the trademark CADUET® comprises the combination of atorvastatin and amlodipine.
  • the product in tablet form is formulated in 5/10 mg, 5/20 mg, 10/10 mg and 10/20 mg doses of amlodipine/atorvastatin.
  • Rosuvastatin on the other hand, is marketed under the trademark Crestor®. Rosuvastatin in the composition formulated as film tablet is in calcium salt form.
  • formulations comprising amlodipine and statins separately or in combination are formulated in tablet form which is a solid dosage form.
  • one of the disadvantages of tablet dosage forms that they have lower bioavailability compared with suspension dosage forms.
  • the highest bioavailability can be obtained from oral solutions among all dosage forms.
  • dosage forms such as tablet and capsule leads to swallowing difficulties for some patients, especially for elderly and physically handicapped patients as they are difficult to be swallowed and have unpleasant taste even taken with liquids. In parallel with this, the patients do not take the drugs regularly and this substantially affects the efficiency of the treatment.
  • Use of solid dosage forms such as tablet or capsule poses problems in pediatric and geriatric patients, people having swallowing difficulties.
  • suspension forms may not be preferred since they have the possibility of high and/or uncontrolled dose intake; high manufacture costs; problems in physical and chemical stability; problems in use and carrying.
  • suspension forms have higher bioavailability values compared with solid dosage forms, they are more inconvenient in comparison to solid dosage forms in terms of stability and shelf life.
  • the inventors have surprisingly found new, user-friendly, therapeutically advantageous and stable water soluble powder, tablet and granule formulations comprising amlodipine and a statin group compound.
  • the characteristic feature of the present invention is that water soluble powder, tablet and granule formulations carry the advantages of both tablet and suspension forms together and eliminate the problems observed in these dosage forms.
  • the present invention relates to pharmaceutical formulations comprising therapeutically effective amounts of amlodipine and a statin group compound.
  • amlodipine can be in free form, in the form of a pharmaceutically acceptable salt, crystalline form, amorphous form, enantiomer, racemate, solvate, hydrate thereof.
  • amlodipine is in the form of a pharmaceutically acceptable salt thereof; preferably in besylate, mesylate or maleate salts form, more preferably in besylate salt form.
  • the statin group compound can be in free form, in the form of a pharmaceutically acceptable salt, crystalline form, amorphous form, enantiomer, racemates, solvate, hydrate thereof.
  • the statin group compound is preferably used in the form of a pharmaceutically salt thereof, more preferably in calcium salt form.
  • the characteristic feature of the formulation of the present invention is that said formulation is in powder, tablet or granule form.
  • water soluble powder, tablet and granule refers to effervescent tablets, effervescent granules, effervescent powders, water soluble powders, water soluble tablets, water soluble granules and sachet forms. It has been observed that the composition of the present invention provides a more effective use when said composition is formulated as effervescent formulations in the form of effervescent tablet, effervescent granule or effervescent powder. Medicament compositions comprising effervescent formulations suitable for single dose use provide ease of use for patients requiring special consideration.
  • Effervescent formulations disperse very fast; they rapidly and simultaneously release the active agent/agents into the aqueous liquid. At this point, effervescent tablet forms are more advantageous than solid dosage forms.
  • the time passing between the addition of the formulation into water and swallowing the obtained solution is relatively short. Consumption of the formulation in a short time impedes the degradation of the active agent with water.
  • pharmaceutical formulations in effervescent form are particularly preferred by patients in terms of ease of use and carrying.
  • the formulation disperses in aqueous liquid rapidly and it can be administered by the oral route, with a spoon or as a drop when necessary. Such formulations are more advantageous especially for elderly and physically handicapped patients.
  • the formulations of the present invention comprise amlodipine in a therapeutically effective amount, a statin group compound in a therapeutically effective amount and at least one excipient.
  • a solution which can easily be taken even by patients with swallowing difficulties is produced, owing to the fact that the composition of the present invention comprises an effervescent couple. Dissolution of the active agent rapidly and being taken as a solution enables to obtain the effect of the medicament relatively fast.
  • the term "effervescent couple” refers to use of an acidic agent and a basic agent together.
  • Said basic agent can be alkaline earth carbonate or alkaline earth bicarbonate. Earth alkaline carbonate/bicarbonate in the effervescent couple provides C0 2 production in the pharmaceutical composition.
  • Said acidic agent can be selected from organic and/or inorganic acids such as acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, fumaric acid, propionic acid, tartaric acid; or their pharmaceutically acceptable salts, hydrates, anhydrates or a combination thereof.
  • the pharmaceutical composition is produced by dry granulation method.
  • amlodipine which is one of the active agents composing the composition of the present invention, is a quite hygroscopic compound. There observed degradation as it absorbs the humidity in its environment.
  • composition of the present invention comprises the following steps:
  • Step 1
  • statin group compound is subjected to wet granulation in the presence of at least one effervescent base.
  • statin granules obtained are dried such that their moisture rate is 5% and they are sieved.
  • the active agent amlodipine is treated with at least one effervescent acid in non-aqueous environment.
  • the mixtures obtained in the second and the third steps are mixed until the required homogeneity is attained to.
  • the final mixture is prepared ready for tablet compression optionally after the other pharmaceutically acceptable excipients are added. Tablets are coated as required.
  • the problems experienced in water soluble powder, tablet and granule formulations are overcome and a far more stable product is obtained in comparison with the compositions produced by conventional methods since the pharmaceutical composition comprising amlodipine and a statin group compound is subjected to the production method according to the present invention.
  • statin group compound By subjecting the statin group compound to wet granulation in the presence of the effervescent base; fluidity, dispersion and solubility characteristics of said compound is provided to be as required.
  • the amount of the active agent in the pharmaceutical formulation of the present invention can vary in the range of 0.5% to 95%, preferably in the range of 1% to 90% according to total amount of substance in the pharmaceutical formulation. Dosage of the active agent in the pharmaceutical formulation may change according to the route of administration; users' age and state of health.
  • the pharmaceutical formulation comprising the present invention can comprise 1-40 mg amlodipine and 0,1-160 mg statin group compound in one dose.
  • Statin group compounds can be selected from the group comprising rosuvastatin, atorvastatin, cerivastatin, lovastatin, fluvastatin, mevastatin, pravastatin and pitavastatin.
  • compositions are obtained in the treatment of the disease by formulating amlodipine in combination with rosuvastatin or atorvastatin.
  • compositions comprising the present invention are indicated in diseases comprising dyslipidemia, hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, angina, variant angina, prophylaxis of myocardial infarction, prophylaxis of stroke, atherosclerosis and hypertension.
  • the pharmaceutical formulations of the present invention are administered by the oral route.
  • the pharmaceutical formulation comprising the use of amlodipine and a statin group compound in combination can also optionally comprise excipients such as effervescent couple, binder, sweetener, flavoring agent, diluent, lubricant, taste regulating agent, viscosity enhancing components, surfactants, filling materials, drying agents, glidants, anti-foam agents, wetting agents.
  • excipients such as effervescent couple, binder, sweetener, flavoring agent, diluent, lubricant, taste regulating agent, viscosity enhancing components, surfactants, filling materials, drying agents, glidants, anti-foam agents, wetting agents.
  • the pharmaceutically acceptable effervescent couple of the present invention is composed of the combination of an acidic agent and a basic agent.
  • the acidic agent comprises organic and/or inorganic acids; the basic agent can be alkaline earth carbonate or alkaline earth bicarbonate.
  • the pharmaceutically acceptable acidic agent of the present invention can be selected from, but not limited to, a group comprising acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, fumaric acid, propionic acid, tartaric acid and/or pharmaceutically acceptable salts, hydrates, anhydrates or preferably a combination thereof.
  • the pharmaceutically acceptable basic agent of the present invention can be selected from, but not limited to, the group comprising potassium carbonate, potassium bicarbonate, sodium carbonate, sodium hydrogen carbonate or combinations thereof.
  • the pharmaceutically acceptable binder of the present invention can be selected from, but not limited to, a group comprising ethyl cellulose, hydroxyethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, gelatin, hypromellose, magnesium aluminum silicate, maltodextrin, polyethylene oxide, povidone, polyvinylpyrrolidone, sorbitol and water or combinations thereof.
  • stability characteristic of the pharmaceutical formulation is positively affected when the binder is polyvinylpyrrolidone.
  • the pharmaceutically acceptable sweetener of the present invention can be selected from, but not limited to, a group comprising aspartame, acesulfame, acesulfame potassium, fructose, dextrose, glucose, lactitol, maltitol, xylitol, sorbitol, maltose, saccharine, saccharine sodium, sodium cyclamate, sucralose, sucrose or combinations thereof.
  • the pharmaceutically acceptable flavoring agent of the present invention can be selected from, but not limited to, the group comprising sour cherry flavor, blackberry flavor, grapefruit flavor, grape flavor, pear flavor, orange flavor, apricot flavor or combinations thereof.
  • the pharmaceutically acceptable diluent of the present invention can be selected from, but not limited to, the group comprising lactose, dry lactose, lactose monohydrate, directly compressed lactose (lactose D.C.), starch, hydrolyzed starch, mannitol, sorbitol, xylitol, dextrose, dextrose monohydrate, dibasic calcium phosphate dihydrate, monobasic calcium, sulfate monohydrate, calcium sulfate dihydrate, amylose, calcium carbonate, glycine, bentonite.
  • the pharmaceutically acceptable lubricant of the present invention can be selected from, but not limited to, the group comprising metallic stearates (e.g. magnesium stearate, calcium stearate, aluminum stearate), fatty acid esters (e.g. sodium stearil fumarate), fatty acids (e.g. stearic acid), fatty alcohols, polyethylene glycol, glyceryl behenate, mineral oil, paraffines, hydrogenated vegetable oil, leucine, polyethylene glycols (PEG), metallic lauryl sulfates (e.g. sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, sodium benzoate, sodium acetate and talc.
  • metallic stearates e.g. magnesium stearate, calcium stearate, aluminum stearate
  • fatty acid esters e.g. sodium stearil fumarate
  • fatty acids e.g. stearic acid
  • the pharmaceutically acceptable surfactant can be selected from, but not limited to, the 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 of fatty acids and glycerides of fatty acids.
  • the pharmaceutically acceptable glidant of the present invention can be selected from, but not limited to, the group comprising talc, silicone dioxide, magnesium trisilicate, cellulose powder, starch, tribasic calcium phosphate, metallic stearates, calcium silicate and metallic lauryl sulfate.
  • Atorvastatin is subjected to wet granulation in the presence of at least one effervescent base.
  • the granules obtained are dried such that their moisture rate is maximum 5%, then they are sieved.
  • Amlodipine is mixed with at least one effervescent acid and the binder in nonaqueous environment. Then, the mixtures belonging to the active agents atorvastatin and amlodipine are mixed until the required homogeneity is attained to.
  • the mixture is prepared ready for tablet compression after the other pharmaceutically acceptable excipient are added. Said mixture is shaped.
  • Rosuvastatin is subjected to wet granulation in the presence of at least one effervescent base.
  • the granules obtained are dried such that their moisture rate is maximum 5%, then they are sieved.
  • Amlodipine is mixed with at least one effervescent acid and the binder in nonaqueous environment. Then, the mixtures belonging to the active agents atorvastatin and amlodipine are mixed until the required homogeneity is attained to.
  • the mixture is prepared ready for tablet compression after other pharmaceutically acceptable excipient are added. Said mixture is shaped.

Abstract

The present invention relates to novel, stable and easily produceable water soluble pharmaceutical compositions of a combination of a calcium channel blocker and a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor.

Description

WATER SOLUBLE FORMULATION COMPRISING A COMBINATION OF
AMLODIPINE AND A STATIN
The present invention relates to novel, stable and easily produceable water soluble pharmaceutical compositions of a combination of a calcium channel blocker and a 3-hydroxy- 3-methylglutaryl-coenzyme A reductase inhibitor.
Amlodipine (Formula I), chemical name of which is 3-ethyl 5-methyl (+/-)-2-[(2- aminoethoxy)methyl] -4-(o-chlorophenyl)- 1 ,4-dihydropyridine-6-methyl-3 ,5 - pyridinedicarboxylate, was disclosed in the patent numbered EP 0089167 in detail. There exist synthesis methods related with amlodipine and pharmaceutical compositions comprising amlodipine in the prior art. It is known that the molecule amlodipine is indicated in the treatment of hypertension, cardiovascular diseases such as angina.
Figure imgf000002_0001
amlodipine
3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (which will henceforward be called "HMG-CoA reductase inhibitors") competitively inhibit the activation of the enzyme named HMG-CoA reductase. This enzyme is in HMG-CoA reductase pathway where it is used for cholesterol synthesis of the body.
Rosuvastatin, atorvastatin, cerivastatin, lovastatin, fluvastatin, mevastatin, pravastatin and pitavastatin are HMG-CoA reductase inhibitors, in other terms, statin group compounds.
Rosuvastatin having the chemical name (3i?,5S,6E)-7-[4-(4-fluorophenyl)-6-(l-methylethyl)- 2[methyl(methylsulphonyl)amino]-5-pyrimidinyl]-3,5-dihydroxy-6-heptenoic acid is a HMG CoA enzyme inhibitor which was first disclosed in the patent numbered US 5260440 is displayed in formula (II):
Figure imgf000003_0001
It is indicated in the patent numbered US5260440 that rosuvastatin inhibits the activation of the enzyme named HMG-CoA reductase that is responsible for cholesterol synthesis in the body and prevents cholesterol formation and it is effective in the treatment of cardiovascular diseases such as hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.
Atorvastatin {Formula III) which has the chemical name ( R, (Si?,)-2-(4-fluorophenyl)- β,δ- dihydroxy-5 -( 1 -methylethyl)-3 -phenyl-4- [(phenylamino)carbanoyl] - 1 H-pyrrol- 1 -heptanoic acid is a HMG CoA reductase inhibitor.
Figure imgf000003_0002
Atorvastatin was first disclosed in the patent numbered EP 409281. There exist processes for preparation of atorvastatin and its use as cholesterol biosynthesis inhibitor in said patent.
Atorvastatin is a hypolipidemic drug which is a selective competitive inhibitor of HMG CoA reductase enzyme. It has the indication of lowering increased LDL cholesterol and triglyceride levels.
Use of calcium channel blockers including amlodipine in the treatment of atherosclerosis was disclosed in Kramsch et al., Journal of Human Hypertension, 1995; (Suppl. 1): 53-59. In this literature, use of the active agent amlodipine in combination with lipid lowering compounds was also explained. In Jukema et al., Circulation, 1995; (Suppl. 1): 1-197, it was indicated that calcium channel blockers and lipid lowering agents induce synergistic effect. In Orekhov et al., Cardiovascular Drugs and Therapy, 1997; 11 :350, on the other hand, use of the combination of amlodipine and lovastatin in the treatment of atherosclerosis was described.
The product marketed under the trademark CADUET® comprises the combination of atorvastatin and amlodipine. The product in tablet form is formulated in 5/10 mg, 5/20 mg, 10/10 mg and 10/20 mg doses of amlodipine/atorvastatin.
Rosuvastatin, on the other hand, is marketed under the trademark Crestor®. Rosuvastatin in the composition formulated as film tablet is in calcium salt form.
When the prior art is taken into consideration, it is seen that formulations comprising amlodipine and statins separately or in combination are formulated in tablet form which is a solid dosage form.
However, compounds of statin group are influenced by external factors such as moisture and light and they are easily disintegrated. This poses a problem in formulating compounds of statin group. Lactone is produced as a result of "intramolecular esterification" reaction which occurs between carboxylic acid in the structure of statins and hydroxyl groups on β and δ carbons of this carboxylic acid. This characteristic reduces the stability of the substance and therefore, shortens the shelf life.
In another aspect, one of the disadvantages of tablet dosage forms that they have lower bioavailability compared with suspension dosage forms. The highest bioavailability can be obtained from oral solutions among all dosage forms. Furthermore, dosage forms such as tablet and capsule leads to swallowing difficulties for some patients, especially for elderly and physically handicapped patients as they are difficult to be swallowed and have unpleasant taste even taken with liquids. In parallel with this, the patients do not take the drugs regularly and this substantially affects the efficiency of the treatment. Use of solid dosage forms such as tablet or capsule poses problems in pediatric and geriatric patients, people having swallowing difficulties.
An alternative to eliminate these problems can be formulating the pharmaceutical composition in suspension form. However, suspension forms may not be preferred since they have the possibility of high and/or uncontrolled dose intake; high manufacture costs; problems in physical and chemical stability; problems in use and carrying. Although suspension forms have higher bioavailability values compared with solid dosage forms, they are more inconvenient in comparison to solid dosage forms in terms of stability and shelf life.
When the prior art is taken into consideration, there seems need to develop different dosage forms of the composition comprising amlodipine and a statin group compound which are user-friendly and have long shelf life. At this point, it is considered that there is need for novel dosage forms which would be effective in the treatment of hypertension and cardiovascular diseases, and provide an alternative method for patients requiring special consideration such as pediatric, geriatric patients and people having swallowing difficulties.
The inventors have surprisingly found new, user-friendly, therapeutically advantageous and stable water soluble powder, tablet and granule formulations comprising amlodipine and a statin group compound.
The characteristic feature of the present invention is that water soluble powder, tablet and granule formulations carry the advantages of both tablet and suspension forms together and eliminate the problems observed in these dosage forms.
The present invention relates to pharmaceutical formulations comprising therapeutically effective amounts of amlodipine and a statin group compound.
According to the invention, amlodipine can be in free form, in the form of a pharmaceutically acceptable salt, crystalline form, amorphous form, enantiomer, racemate, solvate, hydrate thereof. In the composition of the present invention, amlodipine is in the form of a pharmaceutically acceptable salt thereof; preferably in besylate, mesylate or maleate salts form, more preferably in besylate salt form.
According to the present invention, the statin group compound can be in free form, in the form of a pharmaceutically acceptable salt, crystalline form, amorphous form, enantiomer, racemates, solvate, hydrate thereof. The statin group compound is preferably used in the form of a pharmaceutically salt thereof, more preferably in calcium salt form.
The characteristic feature of the formulation of the present invention is that said formulation is in powder, tablet or granule form.
The expression "water soluble powder, tablet and granule" refers to effervescent tablets, effervescent granules, effervescent powders, water soluble powders, water soluble tablets, water soluble granules and sachet forms. It has been observed that the composition of the present invention provides a more effective use when said composition is formulated as effervescent formulations in the form of effervescent tablet, effervescent granule or effervescent powder. Medicament compositions comprising effervescent formulations suitable for single dose use provide ease of use for patients requiring special consideration.
Effervescent formulations disperse very fast; they rapidly and simultaneously release the active agent/agents into the aqueous liquid. At this point, effervescent tablet forms are more advantageous than solid dosage forms. The time passing between the addition of the formulation into water and swallowing the obtained solution is relatively short. Consumption of the formulation in a short time impedes the degradation of the active agent with water. In addition, pharmaceutical formulations in effervescent form are particularly preferred by patients in terms of ease of use and carrying.
It is one of the purposes of the present invention to produce tablets which ease use when dispersed or in aqueous solution. The formulation disperses in aqueous liquid rapidly and it can be administered by the oral route, with a spoon or as a drop when necessary. Such formulations are more advantageous especially for elderly and physically handicapped patients.
The formulations of the present invention comprise amlodipine in a therapeutically effective amount, a statin group compound in a therapeutically effective amount and at least one excipient. When added water, a solution which can easily be taken even by patients with swallowing difficulties is produced, owing to the fact that the composition of the present invention comprises an effervescent couple. Dissolution of the active agent rapidly and being taken as a solution enables to obtain the effect of the medicament relatively fast.
The term "effervescent couple" refers to use of an acidic agent and a basic agent together. Said basic agent can be alkaline earth carbonate or alkaline earth bicarbonate. Earth alkaline carbonate/bicarbonate in the effervescent couple provides C02 production in the pharmaceutical composition. Said acidic agent, on the other hand, can be selected from organic and/or inorganic acids such as acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, fumaric acid, propionic acid, tartaric acid; or their pharmaceutically acceptable salts, hydrates, anhydrates or a combination thereof. In the patent application numbered WO 2004/110406, the pharmaceutical composition is produced by dry granulation method. However, there exist some problems resulting from dry granulation method. First of them is the problems resulting from compactor use. This method leading to high levels of powder production causes the active agent to leave the process in powder form and therefore results in active agent loss. Furthermore, temperature rise during the process negatively affects the stability of some active agents. At this point, it has been considered to produce the effervescent formulation of the present invention by wet granulation method instead of dry granulation method. Due to wet granulation method, compressibility of the active agent in powder form is increased; the granules comprising the active agent are ensured to be homogeneous; the segregation problem is impeded; and good fluidity is attained to.
In course of production of the composition of the present invention by wet granulation method, there observed a compatibility problem between amlodipine and the statin group compound. In addition, some problems resulting from preparation of the composition of the present invention in effervescent form have been experienced. Moreover, amlodipine, which is one of the active agents composing the composition of the present invention, is a quite hygroscopic compound. There observed degradation as it absorbs the humidity in its environment.
According to this, production of the composition of the present invention comprises the following steps:
Step 1 :
The statin group compound is subjected to wet granulation in the presence of at least one effervescent base.
Step 2:
The statin granules obtained are dried such that their moisture rate is 5% and they are sieved. Step 3:
The active agent amlodipine is treated with at least one effervescent acid in non-aqueous environment. Step 4:
The mixtures obtained in the second and the third steps are mixed until the required homogeneity is attained to.
Step 5:
The final mixture is prepared ready for tablet compression optionally after the other pharmaceutically acceptable excipients are added. Tablets are coated as required.
In consequence of production of the pharmaceutical formulation of the present invention as mentioned above, both the incompatibility between the active agents is prevented and it has been observed that the amount of the lacton impurity occurring as a result of degradation of statin group compounds is far less than the expected amount.
According to the present invention, the problems experienced in water soluble powder, tablet and granule formulations are overcome and a far more stable product is obtained in comparison with the compositions produced by conventional methods since the pharmaceutical composition comprising amlodipine and a statin group compound is subjected to the production method according to the present invention.
By subjecting the statin group compound to wet granulation in the presence of the effervescent base; fluidity, dispersion and solubility characteristics of said compound is provided to be as required.
In another aspect, it has been observed that there is increase in the stability of the final compound in consequence of all these steps when the binder is mixed with amlodipine in nonaqueous environment instead of being given with the statin group compound in the present invention. The binder being comprised in the process in the same step with amlodipine has both brought a solution to solubility problem in amlodipine and improved the stability characteristic of the final product.
In another aspect, an unexpected stability increase is obtained; the obtained product is enabled to remain almost fully undisintegrated during its shelf life; drug-drug interactions are minimized; and the bioavailability is improved by formulating the composition of the present invention by the production method according to the present invention. According to the present invention, the amount of the active agent in the pharmaceutical formulation of the present invention can vary in the range of 0.5% to 95%, preferably in the range of 1% to 90% according to total amount of substance in the pharmaceutical formulation. Dosage of the active agent in the pharmaceutical formulation may change according to the route of administration; users' age and state of health.
In another aspect, the pharmaceutical formulation comprising the present invention can comprise 1-40 mg amlodipine and 0,1-160 mg statin group compound in one dose.
Statin group compounds can be selected from the group comprising rosuvastatin, atorvastatin, cerivastatin, lovastatin, fluvastatin, mevastatin, pravastatin and pitavastatin.
In another aspect, it has been seen that more effective compositions are obtained in the treatment of the disease by formulating amlodipine in combination with rosuvastatin or atorvastatin.
Pharmaceutical compositions comprising the present invention are indicated in diseases comprising dyslipidemia, hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, angina, variant angina, prophylaxis of myocardial infarction, prophylaxis of stroke, atherosclerosis and hypertension.
In another aspect, the pharmaceutical formulations of the present invention are administered by the oral route.
According to the present invention, the pharmaceutical formulation comprising the use of amlodipine and a statin group compound in combination can also optionally comprise excipients such as effervescent couple, binder, sweetener, flavoring agent, diluent, lubricant, taste regulating agent, viscosity enhancing components, surfactants, filling materials, drying agents, glidants, anti-foam agents, wetting agents.
The pharmaceutically acceptable effervescent couple of the present invention is composed of the combination of an acidic agent and a basic agent. The acidic agent comprises organic and/or inorganic acids; the basic agent can be alkaline earth carbonate or alkaline earth bicarbonate.
The pharmaceutically acceptable acidic agent of the present invention can be selected from, but not limited to, a group comprising acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, fumaric acid, propionic acid, tartaric acid and/or pharmaceutically acceptable salts, hydrates, anhydrates or preferably a combination thereof.
The pharmaceutically acceptable basic agent of the present invention can be selected from, but not limited to, the group comprising potassium carbonate, potassium bicarbonate, sodium carbonate, sodium hydrogen carbonate or combinations thereof.
The pharmaceutically acceptable binder of the present invention can be selected from, but not limited to, a group comprising ethyl cellulose, hydroxyethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, gelatin, hypromellose, magnesium aluminum silicate, maltodextrin, polyethylene oxide, povidone, polyvinylpyrrolidone, sorbitol and water or combinations thereof.
According to the present invention, stability characteristic of the pharmaceutical formulation is positively affected when the binder is polyvinylpyrrolidone.
The pharmaceutically acceptable sweetener of the present invention can be selected from, but not limited to, a group comprising aspartame, acesulfame, acesulfame potassium, fructose, dextrose, glucose, lactitol, maltitol, xylitol, sorbitol, maltose, saccharine, saccharine sodium, sodium cyclamate, sucralose, sucrose or combinations thereof.
The pharmaceutically acceptable flavoring agent of the present invention can be selected from, but not limited to, the group comprising sour cherry flavor, blackberry flavor, grapefruit flavor, grape flavor, pear flavor, orange flavor, apricot flavor or combinations thereof.
The pharmaceutically acceptable diluent of the present invention can be selected from, but not limited to, the group comprising lactose, dry lactose, lactose monohydrate, directly compressed lactose (lactose D.C.), starch, hydrolyzed starch, mannitol, sorbitol, xylitol, dextrose, dextrose monohydrate, dibasic calcium phosphate dihydrate, monobasic calcium, sulfate monohydrate, calcium sulfate dihydrate, amylose, calcium carbonate, glycine, bentonite.
The pharmaceutically acceptable lubricant of the present invention can be selected from, but not limited to, the group comprising metallic stearates (e.g. magnesium stearate, calcium stearate, aluminum stearate), fatty acid esters (e.g. sodium stearil fumarate), fatty acids (e.g. stearic acid), fatty alcohols, polyethylene glycol, glyceryl behenate, mineral oil, paraffines, hydrogenated vegetable oil, leucine, polyethylene glycols (PEG), metallic lauryl sulfates (e.g. sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, sodium benzoate, sodium acetate and talc.
The pharmaceutically acceptable surfactant can be selected from, but not limited to, the 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 of fatty acids and glycerides of fatty acids.
The pharmaceutically acceptable glidant of the present invention can be selected from, but not limited to, the group comprising talc, silicone dioxide, magnesium trisilicate, cellulose powder, starch, tribasic calcium phosphate, metallic stearates, calcium silicate and metallic lauryl sulfate.
The combination of the present invention and the pharmaceutical compositions comprising this combination and their preparation methods can be explained by the examples below, yet the invention should not be limited to them.
EXAMPLES
EXAMPLE 1:
Figure imgf000011_0001
Atorvastatin is subjected to wet granulation in the presence of at least one effervescent base. The granules obtained are dried such that their moisture rate is maximum 5%, then they are sieved. Amlodipine is mixed with at least one effervescent acid and the binder in nonaqueous environment. Then, the mixtures belonging to the active agents atorvastatin and amlodipine are mixed until the required homogeneity is attained to. The mixture is prepared ready for tablet compression after the other pharmaceutically acceptable excipient are added. Said mixture is shaped.
EXAMPLE 2:
Figure imgf000012_0001
Rosuvastatin is subjected to wet granulation in the presence of at least one effervescent base. The granules obtained are dried such that their moisture rate is maximum 5%, then they are sieved. Amlodipine is mixed with at least one effervescent acid and the binder in nonaqueous environment. Then, the mixtures belonging to the active agents atorvastatin and amlodipine are mixed until the required homogeneity is attained to. The mixture is prepared ready for tablet compression after other pharmaceutically acceptable excipient are added. Said mixture is shaped.

Claims

1. A pharmaceutical composition characterized in that the combination of amlodipine and a statin group compound is formulated in water soluble powder, tablet or granule form.
2. The pharmaceutical composition according to claim 1 characterized in that the active agent amlodipine is in free form, in the form of a pharmaceutically acceptable salt, crystalline form, amorphous form, enantiomer, racemate, solvate, hydrate thereof.
3. The pharmaceutical composition according to claim 2 characterized in that the active agent amlodipine is in the form of pharmaceutically acceptable salt thereof.
4. The pharmaceutical composition according to claim 3 characterized in that the active agent amlodipine used in said composition is in besylate, mesylate or maleate salt form.
5. The pharmaceutical composition according to claim 4 characterized in that the active agent amlodipine used in said composition is in besylate salt.
6. The pharmaceutical composition according to claim 1 characterized in that the statin group compound is in free form, in the form of a pharmaceutically acceptable salt, crystalline form, amorphous form, enantiomer, racemate, solvate, hydrate thereof.
7. The pharmaceutical composition according to claim 6 characterized in that the statin group compound used in said composition is the form of pharmaceutically acceptable salt thereof.
8. The pharmaceutical composition according to claim 7 characterized in that the statin group compound used in said composition is the form of calcium salt.
9. The pharmaceutical composition according to claim 1 characterized in that the statin group compound used in combination with amlodipine is selected from the group comprising rosuvastatin, atorvastatin, cerivastatin, lovastatin, fluvastatin, mevastatin, pravastatin and pitavastatin.
10. The pharmaceutical composition according to claim 9 characterized in that the statin group compound is rosuvastatin.
11. The pharmaceutical composition according to claim 9 characterized in that the statin group compound is atorvastatin.
12. The pharmaceutical composition composed of the combination of amlodipine and a statin group compound characterized in that the pharmaceutical composition is prepared by wet granulation method.
13. The production method according to claim 12 characterized in that said method is composed of the steps that;
- the statin group compound is subjected to wet granulation in the presence of at least one effervescent base;
- the granules obtained are dried such that their moisture rate is 5% and they are sieved; and the active agent amlodipine is treated with at least one effervescent acid in non-aqueous environment;
- the both mixtures obtained are mixed until the required homogeneity is attained to;
- the final mixture is prepared ready for tablet compression optionally after the other pharmaceutically acceptable excipients are added, and the tablets are optionally coated.
14. The production method according to claim 12 characterized in that the binder is not subjected to wet granulation; it is mixed with the active agent amlodipine in the presence of the effervescent base in non-aqueous environment.
15. The pharmaceutical composition according to claim 1 characterized in that the formulation is prepared in tablet, effervescent granule, effervescent powder, water soluble powder, water soluble tablet, water soluble granule and sachet form.
16. The pharmaceutical composition according to claim 15 characterized in that the formulation is in effervescent tablet, effervescent powder or effervescent granule form.
17. The pharmaceutical composition according to claim 1 characterized in that the active agent combination comprises at least one effervescent couple, binder, sweetener, flavoring agent, diluent, lubricant, taste regulating agent, viscosity enhancing components, surfactants, filling materials, drying agents, glidants, anti-foam agents, wetting agents as excipients.
18. The pharmaceutical composition according to claim 17 characterized in that the acidic agent in the effervescent couple is composed of organic and/or inorganic acids; the basic agent is composed of alkaline earth carbonate and/or alkaline earth bicarbonate.
19. The pharmaceutical composition according to claim 18 characterized in that the acidic agent used in said composition is selected from the group comprising acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, fumaric acid, propionic acid, tartaric acid and/or pharmaceutically acceptable salts, hydrates, anhydrates or preferably a combination thereof.
20. The pharmaceutical composition according to claim 18 characterized in that the basic agent used in said composition is selected from the group comprising potassium carbonate, potassium bicarbonate, sodium carbonate, sodium hydrogen carbonate or combinations thereof.
21. The pharmaceutical composition according to claim 17 characterized in that the binder used in said composition is selected from the group comprising ethyl cellulose, hydroxyethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, gelatin, hypromellose, magnesium aluminum silicate, maltodextrin, polyethylene oxide, povidone, polyvinylpyrrolidone, sorbitol and water or combinations thereof.
22. The pharmaceutical composition according to claim 22 characterized in that the binder used in said composition is preferably polyvinylpyrrolidone.
23. The pharmaceutical composition according to claim 17 characterized in that the sweetener used in said composition is selected from the group comprising aspartame, acesulfame, acesulfame potassium, fructose, dextrose, glucose, lactitol, maltitol, xylitol, sorbitol, maltose, saccharine, saccharine sodium, sodium cyclamate, sucralose, sucrose or combinations thereof.
24. The pharmaceutical composition according to claim 17 characterized in that the flavoring agent used in said composition is selected from the group comprising sour cherry flavor, blackberry flavor, grapefruit flavor, grape flavor, pear flavor, orange flavor, apricot flavor or combinations thereof.
25. The pharmaceutical composition according to claim 17 characterized in that the diluent used in said composition is selected from the group comprising lactose, dry lactose, lactose monohydrate, directly compressed lactose (lactose D.C.), starch, hydrolyzed starch, mannitol, sorbitol, xylitol, dextrose, dextrose monohydrate, dibasic calcium phosphate dihydrate, monobasic calcium, sulfate monohydrate, calcium sulfate dihydrate, amylose, calcium carbonate, glycine, bentonite.
26. The pharmaceutical composition according to claim 17 characterized in that the lubricant used in said composition is selected from the group comprising metallic stearates (such as magnesium stearate, calcium stearate, aluminum stearate), fatty acid esters (such as sodium stearil fumarate), fatty acids (such as stearic acid), fatty alcohols, polyethylene glycol, glyceryl behenate, mineral oil, paraffines, hydrogenated vegetable oil, leucine, polyethylene glycols (PEG), metallic lauryl sulfates (such as sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, sodium benzoate, sodium acetate and talc.
27. The pharmaceutical composition according to claim 17 characterized in that the surfactant used in said composition is selected from the 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 of fatty acids and glycerides of fatty acids.
28. The pharmaceutical composition according to claim 17 characterized in that the glidant used in said composition is selected from the group comprising talc, silicone dioxide, magnesium trisilicate, cellulose powder, starch, tribasic calcium phosphate, metallic stearates, calcium silicate and metallic lauryl sulfate.
29. The pharmaceutical composition according to claim 1 characterized in that said pharmaceutical composition comprises 1-40 mg amlodipine; 0,1-160 mg a statin group compound in one dose.
PCT/TR2011/000140 2010-06-03 2011-06-02 Water soluble formulation comprising a combination of amlodipine and a statin WO2011152803A1 (en)

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WO2012093971A3 (en) * 2011-01-06 2012-09-20 Mahmut Bilgic Effervescent compositions comprising amlodipine
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