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WO2011002424A2 - Solubility and stability enchancing pharmaceutical formulation - Google Patents

Solubility and stability enchancing pharmaceutical formulation Download PDF

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Publication number
WO2011002424A2
WO2011002424A2 PCT/TR2010/000125 TR2010000125W WO2011002424A2 WO 2011002424 A2 WO2011002424 A2 WO 2011002424A2 TR 2010000125 W TR2010000125 W TR 2010000125W WO 2011002424 A2 WO2011002424 A2 WO 2011002424A2
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
pharmaceutically acceptable
weight
ezetimibe
simvastatin
Prior art date
Application number
PCT/TR2010/000125
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French (fr)
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WO2011002424A3 (en
Inventor
Bilgic Mahmut
Original Assignee
Bilgic Mahmut
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Publication of WO2011002424A2 publication Critical patent/WO2011002424A2/en
Publication of WO2011002424A3 publication Critical patent/WO2011002424A3/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
    • A61K9/20—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Definitions

  • the present invention relates to pharmaceutical formulations comprising a therapeutically active agent with solubility problem in combination with a therapeutic agent with stability problem, and preparation methods thereof and medical uses thereof.
  • the present invention provides a combination effective in reducing elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and triglyceride (TG) levels, and in increasing high-density lipoprotein cholesterol (HDL-C) levels in patients with mixed hyperlipidemia or primary hypercholesterolemia (heterozygous familial and non-familial hypercholesterolemia); in reducing elevated total-C and LDL-C levels in patients with homozygous familial hypercholesterolemia (HoFH); and in reducing elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia.
  • This effect provided by the combination of the present invention is hereinafter referred as "the desired effect”.
  • the mentioned combination comprises ezetimibe as a cholesterol absorption inhibitor and simvastatin as an HMG-CoA reductase inhibitor.
  • Ezetimibe is a cholesterol absorption inhibitor with the chemical name of (3i?,4S) -1- (4- fluorophenyl) -3- [(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] -4- (4-hydroxyphenyl) -2- azetidinone (Formula I).
  • Ezetimibe is disclosed for the first time in the U.S. patent application of 5631365 A (USRE37721E, US5767115 A, US5846966 A, WO9508532 Al and EP0720599 B1 are also members of the same patent family).
  • Processes for preparation of ezetimibe, pharmaceutical compositions comprising ezetimibe and the use of ezetimibe as a hypocholesterolemic agent are also disclosed in the same prior art.
  • ezetimibe in combination with HMG-CoA reductase inhibitors, such as lovastatin, pravastatin, fluvastatin, simvastatin and atorvastatin, is effective in reducing the plasma cholesterol levels and in the treatment of atherosclerosis.
  • HMG-CoA reductase inhibitors such as lovastatin, pravastatin, fluvastatin, simvastatin and atorvastatin
  • Ezetimibe is an antilipidemic medication suitable for oral administration. It lowers serum cholesterol concentration by selectively inhibiting the absorption of phytosterols, such as cholesterol and the like, in the intestine. Its mechanism of action is complementary to that of HMG-CoA reductase inhibitors. Therefore, the cholesterol lowering effect of co-administered ezetimibe and HMG-CoA reductase inhibitors increases synergistically.
  • Simvastatin is an HMG-CoA reductase inhibitor with the chemical name of 2,2- dimethylbutanoic acid (lS,3R,7S,8S,8aR)-l,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-2R,4R)- tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-l-naphthalenyl ester (Formula II).
  • Simvastatin is disclosed for the first time in the U.S. patent application of 4444784 (EP0033538 Bl, US4293496 A and US4450171 A are also members of the same patent family). Processes ' for preparation of simvastatin and its use as a cholesterol biosynthesis inhibitor are disclosed in the same prior art.
  • Simvastatin being one of the inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG- CoA) reductase enzyme is an antilipidemic prodrug. It has a relatively high affinity for this enzyme. Simvastatin increases HDL levels as it reduces LDL, total cholesterol, triglyceride and apolipoprotein B levels. The synergistic cholesterol lowering effect of ezetimibe and HMG-CoA reductase inhibitors has been proved by various clinical trials:
  • Ezetimibe a first-in-class, novel cholesterol absorption inhibitor.
  • the present invention based on the synergistic cholesterol lowering effect of ezetimibe and HMG-CoA reductase inhibitors is directed to obtain a combination of ezetimibe as an effective hypocholesterolemic agent with simvastatin as a potent antilipemic agent that provides the desired effect.
  • the object of the invention is to provide a formulation of the invention comprising pharmaceutically acceptable, non-toxic and therapeutically effective amount of a combination of ezetimibe and simvastatin in a dosage form such as a tablet designed to achieve the desired effect.
  • particle size reduction might not be always effective in increasing the dissolution rate of a drug, because as the particles get bigger during the manufacturing process of the pharmaceutical dosage form, increase in the particle size results in the agglomeration of particles.
  • nanoparticulate technology Another technique applied to increase the surface area is nanoparticulate technology.
  • problems are faced during the nanoparticulate formation, such as technical and mechanical limitations that prevent the reduction of particle size to nanoparticulate measures, and stability issues of these small sized active agent particles.
  • simvastatin has a tendency for degradation caused by the oxidation of the dienin and hydroxyl groups found in its molecule structure. This issue creates the need to choose the appropriate excipient composition to ensure the stability of simvastatin present in the tablet.
  • a known method to increase the stability of simvastatin present in a tablet is the use of stabilizers. However, special attention must be paid while choosing the appropriate composition of these agents to the therapeutical effect and solubility besides stability.
  • first pharmacological moiety is selected from HMG-CoA reductase inhibitors and second pharmacological moiety is selected from the group of active agents including cholesterol absorption inhibitors such as ezetimibe.
  • HMG-CoA reductase inhibitors are defined as atorvastatin, pravastatin, simvastatin, lovastatin, fluvastatin, cerivastatin and rosuvastatin.
  • Stable antihyperlipoproteinemic oral pharmaceutical formulations which comprise ezetimibe, an HMG-CoA reductase inhibitor, disintegrants and glidants are disclosed in the International Patent Application with publication number 2006/134604.
  • HMG-CoA reductase inhibitors are defined to be atorvastatin, simvastatin and rosuvastatin.
  • This invention provides examples of formulations with known excipients.
  • the solubility problem of ezetimibe is not mentioned here, hence no solution for this problem was presented by this application.
  • a method for treating or preventing sitosterolemia comprising administering at least one sterol absorption inhibitor (ezetimibe), optionally in combination with at least one lipid lowering agent, is disclosed in the International Patent Application with publication number 2002/058696.
  • Lipid lowering agent is defined to be an HMG-CoA reductase inhibitor selected from atorvastatin, pravastatin, simvastatin, lovastatin, fluvastatin, pitavastatin and rosuvastatin.
  • This invention particularly relates to the medical use of ezetimibe.
  • the solubility problem of ezetimibe is not mentioned here, hence no solution for this problem was presented by this application.
  • European Patent No. 1531805 discloses pharmaceutical compositions comprising 1-20% by weight of a cholesterol absorption inhibitor, 1-80% by weight of simvastatin, 0.01-2% by weight of at least one stabilizer and citric acid up to a maximum of 10% by weight, with the proviso that ascorbic acid is not included.
  • Ezetimibe is defined as the cholesterol absorption inhibitor.
  • the invention only discloses formulations not comprising ascorbic acid. The solubility problem of ezetimibe is not mentioned here, hence no solution for this problem was presented by this application.
  • the present invention relates to a process for the preparation of a pharmaceutical composition
  • a pharmaceutical composition comprising therapeutically effective amount of ezetimibe or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of simvastatin for use in the manufacture of a medicament for the treatment of primary hypercholesterolemia (heterozygous familial and non-familial hypercholesterolemia), mixed hyperlipidemia, homozygous familial hypercholesterolemia and homozygous familial sitosterolemia, characterized in that ezetimibe or a pharmaceutically acceptable salt thereof and simvastatin are preformulated in a series of manufacturing process steps.
  • primary hypercholesterolemia heterozygous familial and non-familial hypercholesterolemia
  • mixed hyperlipidemia homozygous familial hypercholesterolemia and homozygous familial sitosterolemia
  • ezetimibe or a pharmaceutically acceptable salt thereof and simvastatin are preformulated in a series of manufacturing process steps.
  • the manufacturing process of the present invention which provides a formulation so as to obtain the desired effect is as follows:
  • Ezetimibe or a pharmaceutically acceptable salt is dissolved in 1-propanol, 2- propanol, acetone or a mixture of these to obtain a granulation solution;
  • a pharmaceutically acceptable diluent is granulated by spraying the granulation solution
  • the granules obtained in the previous step are dried and sieved, and optionally mixed with other pharmaceutically acceptable excipients, preferably a disintegrant, to obtain the first mixture;
  • simvastatin and the mixture of a stabilizer and/or stabilizers with at least one diluent are granulated by a granulation solution comprising an appropriate pure solvent or solvent mixture and optionally other pharmaceutically acceptable excipients, preferably a stabilizer and a diluent the granules obtained in the previous step are dried and sieved, and optionally mixed with other pharmaceutically acceptable excipients, preferably a disintegrant, to obtain the second mixture;
  • both of the mixtures are mixed to obtain a homogenous tablet, and the final mixture is optionally mixed with other pharmaceutically acceptable excipients, preferably a lubricant, and is finalized for tablet press;
  • both of the mixtures are fed separately to the tablet press machine to obtain a layered tablet;
  • tablets obtained in the previous step are film-coated.
  • the present invention based on the synergistic cholesterol lowering effect of ezetimibe and HMG-CoA reductase inhibitors is directed to obtain a combination of ezetimibe and simvastatin to provide the desired effect.
  • a solubility problem is encountered in these attempts.
  • To achieve the desired effect from the combination of ezetimibe and simvastatin there is the need to overcome the solubility problem of ezetimibe and stability problem of simvastatin, and also the need to find the appropriate amounts of active agents and excipients of the composition.
  • compositions comprising ezetimibe (or a pharmaceutically acceptable salt) and simvastatin, which are preformulated in a series of manufacturing steps, and at least one stabilizer, show the optimum efficiency in the treatment of various cardiovascular diseases.
  • compositions comprising specific amounts of ezetimibe (or a pharmaceutically acceptable salt) and simvastatin, at least one stabilizer in a sufficient amount, at least one diluent in an high amount and, optionally, at least one pharmaceutically acceptable excipient selected from the group of binders, disintegrants, lubricants and glidants, show the optimum efficiency in the treatment of various cardiovascular diseases.
  • ezetimibe or a pharmaceutically acceptable salt was dissolved in a granulation solution comprising 1-propanol, 2-propanol, acetone or a mixture of these.
  • the first mixture was obtained by optionally mixing the granules with other pharmaceutically acceptable excipients, preferably a disintegrant.
  • simvastatin and the mixture of a stabilizer and/or stabilizers with at least one diluent were granulated by a granulation solution comprising an appropriate pure solvent or solvent mixture and, optionally, other pharmaceutically acceptable excipients, preferably a stabilizer and a diluent.
  • a granulation solution comprising an appropriate pure solvent or solvent mixture and, optionally, other pharmaceutically acceptable excipients, preferably a stabilizer and a diluent.
  • the granules obtained after being dried and sieved were optionally mixed with other pharmaceutically acceptable excipients, preferably a disintegrant, and the second mixture is obtained.
  • tablets obtained in the previous step were optionally film-coated.
  • variable cardiovascular diseases refers to primary hypercholesterolemia (heterozygous familial and non-familial hypercholesterolemia), mixed hyperlipidemia, homozygous familial hypercholesterolemia and homozygous familial sitosterolemia.
  • ezetimibe or a pharmaceutically acceptable salt thereof in an amount of 0.1 to 20% by weight, simvastatin in an amount of 1 to 40% by weight, a pharmaceutically acceptable stabilizer in an amount of maximum 10% by weight, at least one pharmaceutically acceptable diluent in an amount of at least 60% by weight, preferably at least 70% by weight, more preferably at least 80% by weight and at least one diluent, and if needed at least one pharmaceutically acceptable excipient selected from excipients such as binders, disintegrants, lubricants and glidants, which all of them are used to obtain the desired effect.
  • excipients such as binders, disintegrants, lubricants and glidants, which all of them are used to obtain the desired effect.
  • Stabilizer and/or stabilizers can be selected from the group of antioxidants, chelating agents, alkalizing agents and photoprotectors.
  • Antioxidants can be selected from the group of butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulphite, gallates (e.g. propyl gallate), tocopherol, citric acid, malic acid and ascorbic acid.
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxytoluene
  • gallates e.g. propyl gallate
  • tocopherol citric acid, malic acid and ascorbic acid.
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxytoluene
  • gallates e.g. propyl gallate
  • tocopherol citric acid, malic acid and ascorbic acid.
  • Mentioned antioxidants prevent oxidation of simvastatin.
  • Chelating agents can be selected from the group of disodium EDTA, edetic acid, citric acid, sodium citrate,
  • Alkalizing agents can be selected from the group of alkali metal salts like sodium carbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate; and earth alkali metal salts like calcium carbonate, calcium hydroxide, tribasic calcium phosphate, calcium acetate, calcium gluconate, calcium glycerophosphate, magnesium carbonate, magnesium hydroxide, magnesium acetate, magnesium silicate and magnesium aluminate.
  • alkali metal salts like sodium carbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate
  • earth alkali metal salts like calcium carbonate, calcium hydroxide, tribasic calcium phosphate, calcium acetate, calcium gluconate, calcium glycerophosphate, magnesium carbonate, magnesium hydroxide, magnesium acetate, magnesium silicate and magnesium aluminate.
  • Photoprotectors can be selected from metal oxides such as titanium oxide, iron oxide and zinc. Preferably iron oxide is used.
  • Pharmaceutically acceptable diluents can be selected from the group of lactose, microcrystalline cellulose, starch, pregelatinized starch, modified starch, calcium phosphate (dibasic and/or tribasic), calcium sulphate trihydrate, calcium sulphate dihydrate, calcium carbonate, kaolin, lactitol, powdered cellulose, dextrose, dextrates, dextrin, sucrose, maltose, fructose, mannitol, sorbitol and xylitol.
  • lactose and microcrystalline cellulose is used.
  • binders can be selected from the group of starch (e.g. potato starch, cornstarch or wheat starch), sucrose, glucose, dextrose, lactose, sugars like maltodexrin, natural and synthetic gums (e.g. acacia tree), gelatin, cellulose derivatives (e.g. microcrystalline cellulose, HPC, HEC, HPMC, carboxymethylcellulose, methylcellulose, ethylcellulose), polyvinylpyrrolidone, polyethylene glycol, waxes, calcium carbonate, calcium phosphate, alcohols (e.g. sorbitol, xylitol and mannitol) and water.
  • the binder is present in the formulation preferably in a range of 0-10% by weight, more preferably in a range of 0.1-5% by weight.
  • the pharmaceutically acceptable disintegrants may be selected from the group of starch (e.g. potato starch, corn starch), sodium starch glycolate, pregelatinized starch, cellulose derivatives (e.g. croscarmellose sodium, microcrystalline cellulose), polyvinylpyrrolidone, crospovidone, alginic acid, sodium alginate, clays (e.g. xanthan gum or Veegum), ion- exchange resins, effervescent systems such as those utilizing food acids and alkaline carbonate components, and the like.
  • starch e.g. potato starch, corn starch
  • sodium starch glycolate e.g. croscarmellose sodium, microcrystalline cellulose
  • polyvinylpyrrolidone e.g. crospovidone
  • alginic acid sodium alginate
  • clays e.g. xanthan gum or Veegum
  • ion- exchange resins effervescent systems
  • Disintegrant is present in the formulation preferably in a range of 0-10% by weight, more preferably in a range of 1-5% by weight.
  • the pharmaceutically acceptable lubricants can be selected from the group of metallic stearates (e.g. magnesium stearate, calcium stearate, aluminum stearate), fatty acid esters (e.g. sodium stearyl fumarate), fatty acids (e.g. stearic acid), fatty alcohols, glyceryl behenate, mineral oils, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols (PEG), metallic lauryl sulfates (e.g.
  • Lubricant is present in the formulation preferably in a range of 0-10% by weight, more preferably in a range of 0.25-5% by weight.
  • the pharmaceutically acceptable glidants can be selected from the group of silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, metallic stearates, calcium silicate and metallic lauryl sulfate. The weight % of the glidant in the formulation is lower than 1%.
  • solubility enhancers can be used as other pharmaceutically acceptable excipients in the formulation.

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Abstract

The present invention relates to pharmaceutical formulations comprising a combination of a therapeutic agent with solubility problem (ezetimibe) and a therapeutic agent with stability problem (simvastatin), and the methods for the preparation thereof, and the use thereof.

Description

SOLUBILITY AND STABILITY ENCHANCING PHARMACEUTICAL
FORMULATION
Field of the Invention
The present invention relates to pharmaceutical formulations comprising a therapeutically active agent with solubility problem in combination with a therapeutic agent with stability problem, and preparation methods thereof and medical uses thereof.
Background of Invention
The present invention provides a combination effective in reducing elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and triglyceride (TG) levels, and in increasing high-density lipoprotein cholesterol (HDL-C) levels in patients with mixed hyperlipidemia or primary hypercholesterolemia (heterozygous familial and non-familial hypercholesterolemia); in reducing elevated total-C and LDL-C levels in patients with homozygous familial hypercholesterolemia (HoFH); and in reducing elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia. This effect provided by the combination of the present invention is hereinafter referred as "the desired effect". The mentioned combination comprises ezetimibe as a cholesterol absorption inhibitor and simvastatin as an HMG-CoA reductase inhibitor.
Ezetimibe is a cholesterol absorption inhibitor with the chemical name of (3i?,4S) -1- (4- fluorophenyl) -3- [(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] -4- (4-hydroxyphenyl) -2- azetidinone (Formula I).
Figure imgf000002_0001
Ezetimibe is disclosed for the first time in the U.S. patent application of 5631365 A (USRE37721E, US5767115 A, US5846966 A, WO9508532 Al and EP0720599 B1 are also members of the same patent family). Processes for preparation of ezetimibe, pharmaceutical compositions comprising ezetimibe and the use of ezetimibe as a hypocholesterolemic agent are also disclosed in the same prior art. It is also disclosed that use of ezetimibe in combination with HMG-CoA reductase inhibitors, such as lovastatin, pravastatin, fluvastatin, simvastatin and atorvastatin, is effective in reducing the plasma cholesterol levels and in the treatment of atherosclerosis.
Ezetimibe is an antilipidemic medication suitable for oral administration. It lowers serum cholesterol concentration by selectively inhibiting the absorption of phytosterols, such as cholesterol and the like, in the intestine. Its mechanism of action is complementary to that of HMG-CoA reductase inhibitors. Therefore, the cholesterol lowering effect of co-administered ezetimibe and HMG-CoA reductase inhibitors increases synergistically.
Simvastatin is an HMG-CoA reductase inhibitor with the chemical name of 2,2- dimethylbutanoic acid (lS,3R,7S,8S,8aR)-l,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-2R,4R)- tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-l-naphthalenyl ester (Formula II).
Figure imgf000003_0001
Simvastatin is disclosed for the first time in the U.S. patent application of 4444784 (EP0033538 Bl, US4293496 A and US4450171 A are also members of the same patent family). Processes' for preparation of simvastatin and its use as a cholesterol biosynthesis inhibitor are disclosed in the same prior art.
Simvastatin being one of the inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG- CoA) reductase enzyme is an antilipidemic prodrug. It has a relatively high affinity for this enzyme. Simvastatin increases HDL levels as it reduces LDL, total cholesterol, triglyceride and apolipoprotein B levels. The synergistic cholesterol lowering effect of ezetimibe and HMG-CoA reductase inhibitors has been proved by various clinical trials:
• Davis HR, PuIa KK, Alton KB, Burrier RE & Watkins RW. The Synergistic Hypocholesterolemic Activity of the Potent Cholesterol Absorption Inhibitor, Ezetimibe, in Combination With 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase
Inhibitors in Dogs. Metabolism 2001; 50(10):1234-1241
• Sudhop T, Von Bergmann K. Cholesterol absorption inhibitors for the treatment of hypercholesterolaemia. Drugs 2002; 62(16):2333-47
• Gagne C, MD; Gaudet D, MD PhD; Bruckert E, MD PhD. Efficacy and Safety of Ezetimibe Coadministered With Atorvastatin or Simvastatin in Patients With
Homozygous Familial Hypercholesterolemia. Circulation 2002; 105; 2469-2475
• Davidson M.H., Ballantyne CM., Kerzner B., Melani L., Sager P. T., Lipka L., Strony J., Suresh R., Veltri E., For Ezetimibe Study Group. Efficacy and safety of ezetimibe coadministered with statins: randomised, placebo-controlled, blinded experience in 2382 patients with primary hypercholesterolemia. Journal of Clinical Practice,
August 2004, 58(8): 746-755
• Gagne C; Bays H.E.; Weiss S.R.; Mata P.; Quinto K.; Melino M.; Cho M.; Musliner T. A.; Gumbiner B.I; Ezetimibe Study Group. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol 2002; 90: 1084-1091
• Christie M. Ballantyne, John Houri, Alberto Notarbartolo, Lorenzo Melani, Leslie J.
Lipka, Ramachandran Suresh, Steven Sun, Alexandre P. LeBeaut, Philip T. Sager ve Enrico P. Veltri. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation 2003 ; 107; 2490-2415
• Lipka LJ.. Ezetimibe: a first-in-class, novel cholesterol absorption inhibitor.
Cardiovascular Drug Reviews, 21(4); 293-312
• Kosoglu T, Meyer I, Veltri EP, et al. Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and simvastatin. Br J Clin Pharmacol. 2002
The present invention based on the synergistic cholesterol lowering effect of ezetimibe and HMG-CoA reductase inhibitors is directed to obtain a combination of ezetimibe as an effective hypocholesterolemic agent with simvastatin as a potent antilipemic agent that provides the desired effect.
The object of the invention is to provide a formulation of the invention comprising pharmaceutically acceptable, non-toxic and therapeutically effective amount of a combination of ezetimibe and simvastatin in a dosage form such as a tablet designed to achieve the desired effect.
Usually, when solid dosage forms such as tablets are administered orally, the drug must first dissolve in gastrointestinal fluids before exhibiting its effect. However dissolution problems arise with active agents such as ezetimibe with small particulate sizes. Low dissolution rates of these active agents affect their bioavailability adversely.
One of the known techniques applied to overcome the solubility problem of poorly soluble drugs is particle size reduction. Since the dissolution rate depends on the surface area of the particle directly, decreasing the size of the particles increases the total surface area, hence the dissolution rate.
However, particle size reduction might not be always effective in increasing the dissolution rate of a drug, because as the particles get bigger during the manufacturing process of the pharmaceutical dosage form, increase in the particle size results in the agglomeration of particles.
Another technique applied to increase the surface area is nanoparticulate technology. However some problems are faced during the nanoparticulate formation, such as technical and mechanical limitations that prevent the reduction of particle size to nanoparticulate measures, and stability issues of these small sized active agent particles.
Thus, there is a need for novel methods to overcome the solubility problem arisen from the combination of ezetimibe with other therapeutical agents, such as HMG-CoA reductase, which combination results in a synergistic effect.
In addition to the solubility problems, there is also stability problems of combination of ezetimib and simvastatin. Since simvastatin has a tendency for degradation caused by the oxidation of the dienin and hydroxyl groups found in its molecule structure. This issue creates the need to choose the appropriate excipient composition to ensure the stability of simvastatin present in the tablet. A known method to increase the stability of simvastatin present in a tablet is the use of stabilizers. However, special attention must be paid while choosing the appropriate composition of these agents to the therapeutical effect and solubility besides stability.
In the International Patent Application with publication number WO 2006/110882, compounds comprising a first pharmacological moiety covalently connected to a second pharmacological moiety through a physiologically labile linker are described. First pharmacological moiety is selected from HMG-CoA reductase inhibitors and second pharmacological moiety is selected from the group of active agents including cholesterol absorption inhibitors such as ezetimibe. HMG-CoA reductase inhibitors are defined as atorvastatin, pravastatin, simvastatin, lovastatin, fluvastatin, cerivastatin and rosuvastatin. The mechanism of action of ezetimibe and HMG-CoA reductase inhibitors are indicated as complementary in this patent application. It is also stated that this synergistic effect has been proven by clinical trials. So, this invention relates to novel compounds consisting of two pharmacological moieties and the use thereof. The solubility problem of ezetimibe is not mentioned here, hence no solution for this problem was presented by this application.
Stable antihyperlipoproteinemic oral pharmaceutical formulations which comprise ezetimibe, an HMG-CoA reductase inhibitor, disintegrants and glidants are disclosed in the International Patent Application with publication number 2006/134604. HMG-CoA reductase inhibitors are defined to be atorvastatin, simvastatin and rosuvastatin. This invention provides examples of formulations with known excipients. However, the solubility problem of ezetimibe is not mentioned here, hence no solution for this problem was presented by this application.
A method for treating or preventing sitosterolemia comprising administering at least one sterol absorption inhibitor (ezetimibe), optionally in combination with at least one lipid lowering agent, is disclosed in the International Patent Application with publication number 2002/058696. Lipid lowering agent is defined to be an HMG-CoA reductase inhibitor selected from atorvastatin, pravastatin, simvastatin, lovastatin, fluvastatin, pitavastatin and rosuvastatin. This invention particularly relates to the medical use of ezetimibe. The solubility problem of ezetimibe is not mentioned here, hence no solution for this problem was presented by this application.
European Patent No. 1531805 discloses pharmaceutical compositions comprising 1-20% by weight of a cholesterol absorption inhibitor, 1-80% by weight of simvastatin, 0.01-2% by weight of at least one stabilizer and citric acid up to a maximum of 10% by weight, with the proviso that ascorbic acid is not included. Ezetimibe is defined as the cholesterol absorption inhibitor. The invention only discloses formulations not comprising ascorbic acid. The solubility problem of ezetimibe is not mentioned here, hence no solution for this problem was presented by this application.
In the International Patent Application with the publication number 2007/003365, pharmaceutical formulations comprising ezetimibe and simvastatin, with the proviso that stabilizers or antioxidants are not included, are described. In the description part of this application, the use of micronized ezetimibe to overcome the problem of solubility is mentioned. However, this is a known method of prior art.
The above-mentioned patent applications are directed to the combination of ezetimibe and HMG-CoA reductase inhibitors because of their synergistic effect. However, the solubility problem that inhibits efficient work on this combination is not mentioned in these patents or patent applications. So, there is still need for various solutions which would allow formulators to combine ezetimibe and HMG-CoA reductase inhibitors to achieve the desired effect.
Summary of the Invention
The present invention relates to a process for the preparation of a pharmaceutical composition comprising therapeutically effective amount of ezetimibe or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of simvastatin for use in the manufacture of a medicament for the treatment of primary hypercholesterolemia (heterozygous familial and non-familial hypercholesterolemia), mixed hyperlipidemia, homozygous familial hypercholesterolemia and homozygous familial sitosterolemia, characterized in that ezetimibe or a pharmaceutically acceptable salt thereof and simvastatin are preformulated in a series of manufacturing process steps.
The manufacturing process of the present invention, which provides a formulation so as to obtain the desired effect is as follows:
Ezetimibe or a pharmaceutically acceptable salt is dissolved in 1-propanol, 2- propanol, acetone or a mixture of these to obtain a granulation solution;
a pharmaceutically acceptable diluent is granulated by spraying the granulation solution;
- the granules obtained in the previous step are dried and sieved, and optionally mixed with other pharmaceutically acceptable excipients, preferably a disintegrant, to obtain the first mixture;
simvastatin and the mixture of a stabilizer and/or stabilizers with at least one diluent are granulated by a granulation solution comprising an appropriate pure solvent or solvent mixture and optionally other pharmaceutically acceptable excipients, preferably a stabilizer and a diluent the granules obtained in the previous step are dried and sieved, and optionally mixed with other pharmaceutically acceptable excipients, preferably a disintegrant, to obtain the second mixture;
optionally, both of the mixtures are mixed to obtain a homogenous tablet, and the final mixture is optionally mixed with other pharmaceutically acceptable excipients, preferably a lubricant, and is finalized for tablet press;
optionally, both of the mixtures are fed separately to the tablet press machine to obtain a layered tablet;
Optionally, tablets obtained in the previous step are film-coated.
Detailed Description of the Invention
The present invention based on the synergistic cholesterol lowering effect of ezetimibe and HMG-CoA reductase inhibitors is directed to obtain a combination of ezetimibe and simvastatin to provide the desired effect. However, as mentioned before, a solubility problem is encountered in these attempts. To achieve the desired effect from the combination of ezetimibe and simvastatin, there is the need to overcome the solubility problem of ezetimibe and stability problem of simvastatin, and also the need to find the appropriate amounts of active agents and excipients of the composition.
Surprisingly, it was found that pharmaceutical compositions comprising ezetimibe (or a pharmaceutically acceptable salt) and simvastatin, which are preformulated in a series of manufacturing steps, and at least one stabilizer, show the optimum efficiency in the treatment of various cardiovascular diseases.
As another embodiment of the invention, it was found that pharmaceutical compositions comprising specific amounts of ezetimibe (or a pharmaceutically acceptable salt) and simvastatin, at least one stabilizer in a sufficient amount, at least one diluent in an high amount and, optionally, at least one pharmaceutically acceptable excipient selected from the group of binders, disintegrants, lubricants and glidants, show the optimum efficiency in the treatment of various cardiovascular diseases.
The problems of solubility and stability have been solved by applying a series of manufacturing steps to ezetimibe and simvastatin according to their specific characteristics.
- In the first step, ezetimibe or a pharmaceutically acceptable salt was dissolved in a granulation solution comprising 1-propanol, 2-propanol, acetone or a mixture of these.
Although ezetimibe usually tends to agglomerate, the granules obtained by spraying the granulation solution comprising ezetimibe onto a pharmaceutically acceptable diluent and after being dried and sieved, exhibited a dissolution rate greater than 90% in the first 10 minutes in the dissolution medium of ezetimibe. The first mixture was obtained by optionally mixing the granules with other pharmaceutically acceptable excipients, preferably a disintegrant.
In the second step, simvastatin and the mixture of a stabilizer and/or stabilizers with at least one diluent were granulated by a granulation solution comprising an appropriate pure solvent or solvent mixture and, optionally, other pharmaceutically acceptable excipients, preferably a stabilizer and a diluent. The granules obtained after being dried and sieved were optionally mixed with other pharmaceutically acceptable excipients, preferably a disintegrant, and the second mixture is obtained.
- Both of the mixtures were mixed together and this final mixture was optionally mixed with other pharmaceutically acceptable excipients, preferably a lubricant, and was finalized for tablet press or in order to obtain a layered tablet both of the mixtures they were fed separately to the tablet press machine.
- Finally, tablets obtained in the previous step were optionally film-coated.
The term "various cardiovascular diseases" as used herein refers to primary hypercholesterolemia (heterozygous familial and non-familial hypercholesterolemia), mixed hyperlipidemia, homozygous familial hypercholesterolemia and homozygous familial sitosterolemia.
The terms "in a specific amount", "in an high amount" and "optionally" as used herein refer to ezetimibe (or a pharmaceutically acceptable salt thereof) in an amount of 0.1 to 20% by weight, simvastatin in an amount of 1 to 40% by weight, a pharmaceutically acceptable stabilizer in an amount of maximum 10% by weight, at least one pharmaceutically acceptable diluent in an amount of at least 60% by weight, preferably at least 70% by weight, more preferably at least 80% by weight and at least one diluent, and if needed at least one pharmaceutically acceptable excipient selected from excipients such as binders, disintegrants, lubricants and glidants, which all of them are used to obtain the desired effect.
Stabilizer and/or stabilizers can be selected from the group of antioxidants, chelating agents, alkalizing agents and photoprotectors.
Antioxidants can be selected from the group of butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulphite, gallates (e.g. propyl gallate), tocopherol, citric acid, malic acid and ascorbic acid. Preferably BHA together with ascorbic acid is used. Mentioned antioxidants prevent oxidation of simvastatin. Chelating agents can be selected from the group of disodium EDTA, edetic acid, citric acid, sodium citrate, potassium citrate and combinations. Preferably citric acid is used. Citric acid inhibits oxidation by surrounding and masking metal ions that might catalyze the oxidation process from the environment.
Alkalizing agents can be selected from the group of alkali metal salts like sodium carbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate; and earth alkali metal salts like calcium carbonate, calcium hydroxide, tribasic calcium phosphate, calcium acetate, calcium gluconate, calcium glycerophosphate, magnesium carbonate, magnesium hydroxide, magnesium acetate, magnesium silicate and magnesium aluminate.
Photoprotectors can be selected from metal oxides such as titanium oxide, iron oxide and zinc. Preferably iron oxide is used.
Pharmaceutically acceptable diluents can be selected from the group of lactose, microcrystalline cellulose, starch, pregelatinized starch, modified starch, calcium phosphate (dibasic and/or tribasic), calcium sulphate trihydrate, calcium sulphate dihydrate, calcium carbonate, kaolin, lactitol, powdered cellulose, dextrose, dextrates, dextrin, sucrose, maltose, fructose, mannitol, sorbitol and xylitol. Preferably lactose and microcrystalline cellulose is used.
Pharmaceutically acceptable binders can be selected from the group of starch (e.g. potato starch, cornstarch or wheat starch), sucrose, glucose, dextrose, lactose, sugars like maltodexrin, natural and synthetic gums (e.g. acacia tree), gelatin, cellulose derivatives (e.g. microcrystalline cellulose, HPC, HEC, HPMC, carboxymethylcellulose, methylcellulose, ethylcellulose), polyvinylpyrrolidone, polyethylene glycol, waxes, calcium carbonate, calcium phosphate, alcohols (e.g. sorbitol, xylitol and mannitol) and water. The binder is present in the formulation preferably in a range of 0-10% by weight, more preferably in a range of 0.1-5% by weight.
The pharmaceutically acceptable disintegrants may be selected from the group of starch (e.g. potato starch, corn starch), sodium starch glycolate, pregelatinized starch, cellulose derivatives (e.g. croscarmellose sodium, microcrystalline cellulose), polyvinylpyrrolidone, crospovidone, alginic acid, sodium alginate, clays (e.g. xanthan gum or Veegum), ion- exchange resins, effervescent systems such as those utilizing food acids and alkaline carbonate components, and the like. Preferably croscarmellose sodium and starch is used. Disintegrant is present in the formulation preferably in a range of 0-10% by weight, more preferably in a range of 1-5% by weight. The pharmaceutically acceptable lubricants can be selected from the group of metallic stearates (e.g. magnesium stearate, calcium stearate, aluminum stearate), fatty acid esters (e.g. sodium stearyl fumarate), fatty acids (e.g. stearic acid), fatty alcohols, glyceryl behenate, mineral oils, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols (PEG), metallic lauryl sulfates (e.g. sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, sodium benzoate, sodium acetate and talk. Lubricant is present in the formulation preferably in a range of 0-10% by weight, more preferably in a range of 0.25-5% by weight. The pharmaceutically acceptable glidants can be selected from the group of silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, metallic stearates, calcium silicate and metallic lauryl sulfate. The weight % of the glidant in the formulation is lower than 1%.
In addition, solubility enhancers, electrolytes, sweeteners, colorants, coating agents can be used as other pharmaceutically acceptable excipients in the formulation.
The formulation examples of the invention are given below. These examples are given only to explain the invention and the scope of the invention is not limited to these examples.
EXAMPLES Exam le 1.
Figure imgf000012_0001
Example 3.
Figure imgf000013_0001

Claims

1. A process for the preparation of a pharmaceutical composition comprising therapeutically effective amount of ezetimibe or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of simvastatin for use in the manufacture of a medicament for the treatment of primary hypercholesterolemia (heterozygous familial and non-familial hypercholesterolemia), mixed hyperlipidemia, homozygous familial hypercholesterolemia and homozygous familial sitosterolemia, characterized in that ezetimibe or a pharmaceutically acceptable salt thereof and simvastatin are preformulated in a series of manufacturing process steps.
2. The process according to claim 1, characterized in that ezetimibe or a pharmaceutically acceptable salt is dissolved in solution comprising 1-propanol, 2- propanol, acetone or a mixture of these to obtain a granulation solution; granulation is achieved by spraying the granulation solution onto a pharmaceutically acceptable diluent and after the granules are dried and sieved, they are optionally mixed with other pharmaceutically acceptable excipients, preferably a disintegrant, to obtain the first mixture.
3. The process according to claim 1, characterized in that simvastatin and the mixture of a stabilizer and/or stabilizers with at least one diluent is granulated by a granulation solution comprising an appropriate pure solvent or solvent mixture and, optionally, other pharmaceutically acceptable excipients, preferably a stabilizer and a diluent and the granules obtained after being dried and sieved are then optionally mixed with other pharmaceutically acceptable excipients, preferably a disintegrant, to obtain the second mixture.
4. The process according to claim 1, characterized in that both of the mixtures are optionally mixed together and this final mixture is optionally mixed with other pharmaceutically acceptable excipients, preferably a lubricant, and finalized for tablet press or to obtain a layered tablet optionally both of the mixtures are fed separately to the tablet press machine. The pharmaceutical composition prepared according to any one of the claims between 1 and 4, characterized in that the pharmaceutical composition comprises, based on the weight of the core tablet,
- ezetimibe or a pharmaceutically acceptable salt thereof in an amount of 0.1 to 20% by weight,
simvastatin in an amount of 1 to 40% by weight,
- at least one pharmaceutically acceptable stabilizer in an amount of less than 10% by weight, and
at least one pharmaceutically acceptable excipient selected from excipients such as binders, disintegrants, diluents, lubricants and glidants.
5. The pharmaceutical composition prepared according to any one of the claims between 1 and 4, characterized in that the pharmaceutical composition comprises, based on the weight of the core tablet,
- ezetimibe or a pharmaceutically acceptable salt thereof in an amount of 0.1 to
20% by weight,
simvastatin in an amount of 1 to 40% by weight,
at least one pharmaceutically acceptable stabilizer in an amount of less than
10% by weight, and
- at least one pharmaceutically acceptable diluent in an amount of at least 60% by weight, preferably at least 70%, more preferably at least 80% by weight, and,
at least one pharmaceutically acceptable excipient selected from excipients such as binders, disintegrants, diluents, lubricants and glidants.
6. The pharmaceutical composition prepared according to any one of the claims between 1 and 4, characterized in that the pharmaceutical composition comprises an antioxidant as a stabilizer, preferably BHA, ascorbic acid or a combination of these.
7. The pharmaceutical composition prepared according to any one of the claims between 1 and 4, characterized in that the pharmaceutical composition comprises a chelating agent as a stabilizer, preferably citric acid.
8. The pharmaceutical composition prepared according to any one of the claims between 1 and 4, characterized in that the pharmaceutical composition comprises a photoprotector agent as a stabilizer, preferably iron oxide.
9. The pharmaceutical composition prepared according to any one of the claims between 1 and 4, characterized in that the pharmaceutical composition comprises a diluent, preferably lactose, microcrystalline cellulose or a combination of these.
10. The pharmaceutical composition prepared according to any one of the claims between
1 and 4, characterized in that the pharmaceutical composition comprises a disintegrant, preferably croscarmellose sodium, starch or a combination of these.
11. The pharmaceutical composition according to claim 11 characterized in that the disintegrant is present in the formulation preferably in a range of 0-10% by weight, more preferably in a range of 1-5% by weight.
12. The pharmaceutical composition prepared according to any one of the claims between 1 and 4, characterized in that the pharmaceutical composition comprises a lubricant, preferably magnesium stearate.
13. The pharmaceutical composition according to claim 13 characterized in that the lubricant is present in the formulation preferably in a range of 0-10% by weight, more preferably in a range of 0.25-5% by weight.
14. The pharmaceutical composition prepared according to any one of the claims between 1 and 4, characterized in that the pharmaceutical composition comprises a glidant, preferably silicon dioxide.
15. The pharmaceutical composition according to claim 15 characterized in that the weight % of the glidant in the formulation is lower than 1%.
16. The pharmaceutical composition according to any one of the previous claims, characterized in that the pharmaceutical composition is in solid dosage form for oral administration.
17. The pharmaceutical composition according to claim 17, characterized in that the solid dosage form is a tablet, preferably a film tablet.
PCT/TR2010/000125 2009-07-02 2010-06-25 Solubility and stability enchancing pharmaceutical formulation WO2011002424A2 (en)

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