WO2012002922A1

WO2012002922A1 - Synergistic pharmaceutical formulations of colesevelam and fenofibrate

Info

Publication number: WO2012002922A1
Application number: PCT/TR2011/000165
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Mahmut Bilgic
Priority date: 2010-06-30
Filing date: 2011-06-29
Publication date: 2012-01-05
Also published as: TR201005327A2

Abstract

The present invention relates to a new synergistic combination of active agents belonging to bile acid binding group and pharmaceutical compositions comprising said combination.

Description

SYNERGISTIC PHARMACEUTICAL FORMULATIONS OF COLESEVELAM AND FENOFIBRATE

The present invention particularly relates to pharmaceutical compositions comprising colesevelam as a bile acid binding active agent and fenofibrate as a lipid regulating agent and/or a pharmaceutically acceptable salt, free acid or base forms, solvates, polymorphs or hydrates and/or combinations thereof; preparation methods of said compositions and medical uses thereof.

Background of the Invention

As it is known, cardiovascular disease is one of the leading causes of death in the world. 17,5 million people die from cardiac diseases and heart attack every year. To this end, researchers have been trying new methods both for diagnosis and treatment of cardiovascular diseases.

This invention discloses a synergistic pharmaceutical formulation prepared so as to be used in the treatment of hyperlipoproteinemia alone (for instance primary and secondary hyperlipoproteinemia), hypertriglyceridemia alone (for instance type IV) or in cases that two of these are together (for instance type II b and III); diseases related to changing lipid levels such as hypercholesterolemia (for instance type II a), hyperlipidemia, mixed dislipidemia.

Colesevelam, which is a bile acid inhibitory active agent disclosed in the patent numbered US5693675 for the first time, is an aliphatic amine polymer generally used in the form of hydrochloride salt in the treatment of hypercholesterolemia and diabetes. This medicament used by the oral route is a hydrogel polymer which is not absorbed and have high bile acid binding capacity. Colesevelam binds to bile acid in the intestines and inhibits absorption of the bile acid. When the source of bile acid starts to be depleted, 7-alpha-hydroxylase which is a hepatic enzyme takes action and converts cholesterol into bile acid. The medication shows its effects by this mechanism described. When colesevelam is used alone, it reduces LDL cholesterol at 15-20%.

Fenofibrate, which is known with the chemical name 2-[4-(4-chlorobenzoyl) phenoxy]-2- methyl -propanoic acid, 1- methylethyl ester, is a fibric acid derivative lipid regulating agent firstly disclosed in the patent numbered US4058552 (A). Fenofibrate starts its action by being hydrolyzed to fenofibric acid and when considered from this aspect, it is a prodrug. It is used in the treatment of lipid diseases such as type IV and type V hyperlipoproteinemia which are related with extremely high levels of serum triglyceride and very high density lipoprotein (VHDL). It has been seen in treatments utilizing fenofibrate that triglyceride levels decrease approximately at 30%. Its non- micronized form has been used in the treatment of type Ila, type lib and type IV dislipidemia in various countries for more than 10 years. It is produced in micronized form in order to increase absorption and provide use of a single dose per day. It is hardly dissolved in water or does not dissolve at all.

In the treatment and prevention of diseases related to changing lipid levels, many active agents and combination product are used. However, as it is known, combination of two active agents is not possible most of the time even for treatment of a single disease due to problems such as active agent incompatibilities arising since the active agents have different physical and chemical characteristics; undesired drug interactions; increasing side effects; bioavailability remaining below the expected levels.

On the other hand, most of the combination products present in the prior art do not appeal to a wide range of patient profile. Especially diseases resulting from changing lipid levels are prevalent between 50-70 years of age and they progress along with other diseases. Patients use more than one medicament for more than one diseases they have; hence undesired adverse effects increase and the patients' adaptation to the treatment reduces.

For instance, formulations comprising at least one bile acid binder and ezetimibe as the second active agent in the European patent application numbered EP 1363668. In addition, various publications discuss use of bile acid binding active agents such as colesevelam in combination with statin group active agents.

However, both ezetimibe and statins are more potent drugs compared with lipid regulating active agents; thus their use in combined therapies creates a risky situation for patients.

To these respects, new approaches which can ensure high efficiency with less dosing; have high bioavailability; appeal to a wider range of patient profile are required in the treatment of diseases related to changing lipid levels.

During the studies they conducted taking these needs into consideration, the inventors have found that use of colesevelam and fenofibrate and/or their pharmaceutically acceptable salts, free acid or base forms, solvates, polymorphs and/or hydrates and/or combinations thereof in combination is more effective than the individual effects of drugs comprising the both active agents in the treatment of diseases related to changing lipid levels.

Furthermore, said combination do not hold the disadvantages mentioned above which may arise from use of the two active agents in combination.

Unexpected synergistic effect of these two active agents has enabled the development of a new medicament formulation in the treatment of diseases related with changing lipid levels.

In one aspect, the present invention discloses a combination product comprising the active agents colesevelam and fenofibrate separately or together in a single dosage form.

In another aspect, the present invention discloses pharmaceutical compositions belonging to this pharmaceutical formulation with synergistic effect.

In another aspect, the present invention discloses production methods for this pharmaceutical formulation with synergistic effect.

In another aspect, the present invention discloses use of this pharmaceutical formulation with synergistic effect in the treatment of diseases related with changing lipid levels.

In another aspect, the present invention discloses use of this pharmaceutical formulation with synergistic effect in the treatment of diseases related to changing lipid levels such as hyperlipoproteinemia alone (for instance primary and secondary hyperlipoproteinemia), hypertriglyceridemia alone (for instance type IV) or in cases that two of these are together (for instance type II b and III); hypercholesterolemia (for instance type II a), hyperlipidemia, mixed dislipidemia.

Detailed Description of the Invention

The present invention discloses synergistic pharmaceutical formulations comprising colesevelam as the bile acid binging agent and fenofibrate as the lipid regulating agent and/or their pharmaceutically acceptable salts, free acid or base forms, solvates, polymorphs or hydrates and/or combinations thereof.

In the formulations according to the present invention, fenofibrate and/or its free base form or a pharmaceutically acceptable salt of this acid form is preferred. The term "free acid form" used here refers to fenofibric acid and its pharmaceutically acceptable salts are selected from a group comprising salts such as choline, ethanolamine, diethanolamine, piperazine, calcium and/or tromethamine.

Colesevelam used in the formulations according to the present invention, on the other hand, is in the form of a pharmaceutically acceptable salt, preferably in the form of hydrochloride salt thereof.

The particle size of fenofibrate used in the formulations according to the present invention is preferably in the range of 1-500 μιη, more preferably in the range of 1-300 μηι, even more preferably in the range of 1-200 μπι.

Formulations of the present invention can be provided so as to be taken by the oral, enteral, parenteral route.

Oral dosage forms of the present invention can be in solid dosage forms such as tablet, film tablet, coated tablet, effervescent tablet, layered tablet; modified, fast, slow, controlled, prolonged release tablets; water soluble granules, effervescent granules, sachet formulations, powders and powder mixtures, orally disintegrated tablet, mini tablet, micro tablet, pellet while they can also be in multiple dosage forms comprising one or more of these together or in liquid dosage forms such as suspension dosage forms.

In the formulations of the present invention, active agents can be combined in a single dosage form or in a kit as being independent from each other. The combined drug produced this way can be taken simultaneously, sequentially or separately in different times.

The formulations of the present invention comprise colesevelam hydrochloride in the range of 1-20 gr., preferably in the range of 1-10 gr.; fenofibrate in the range of 100-500 mg, preferably in the range of 100-300 mg.

The expression "diseases related with changing lipid levels" used throughout the text refers to hyperlipoproteinemia alone (for instance primary and secondary hyperlipoproteinemia), hypertriglyceridemia alone (for instance type IV) or in cases that two of these are together (for instance type II b and III); hypercholesterolemia (for instance type II a), hyperlipidemia, mixed dislipidemia.

The formulations according to the invention can comprise additives selected from the group comprising binders, disintegrants, viscosity enhancing components, filling materials, drying agents, lubricants, diluents, binders, glidants, wetting agents, coating agents designed so as to provide various release characteristics, anti-adhesive agents, solvents, sweeteners or other pharmaceutically acceptable components such as excipients.

The filling materials used in the invention comprise one or more components selected from a group comprising lactose, sugar, starch, modified starch, mannitol, sorbitol, inorganic salts, microcrystalline cellulose, cellulose, calcium sulfate, xylitol and lactitol.

The disintegrant used in the present invention enables the dosage form to disperse in water easily and rapidly, and it is significant from this aspect. The disintegrants can be selected from a group comprising polymers having high dispersing characteristics for instance cross- linked hydroxypropyl cellulose, polyvinylpyrrolidone, high molecular weight polymers, microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, povidone; the products known under the trademarks Crospovidone®, Polyplasdone® or colloidal silicon dioxide, alginic acid, sodium alginate, corn starch.

The surfactants used in the present invention can be selected from a group comprising hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, vinyl acetate, sodium lauryl sulfate, dioctyl sulfosuccinate, gelatin, casein, lecithin, dextran, sorbitan esters, polyoxy ethylene alkyl ethers, polyethylene glycols, polyethylene stearates, collodial silicon dioxide, phosphates, carboxymethyl cellulose calcium, carboxy methyl cellulose sodium, triethanolamine, polyvinyl alcohol, hydroxy propyl methyl cellulose phthalate.

The anti-adhesive agents of the present invention are used in order to prevent the mixture comprising active agents to adhere onto device and machine surfaces and create rough surfaces. The substances used for this purpose can comprise one or more components selected from a group comprising talc, colloidal silicone dioxide (Aerosil, Syloid, Cab-OSil), magnesium stearate and corn starch.

The binders used in the present invention can comprise one or more components selected from a group comprising potato, wheat or corn starch; microcrystalline cellulose, for instance Avicel®, Filtrak®, Heweten® or Pharmacel®; hydroxypropyl cellulose, hydroxyethyl cellulose; hydroxypropylmethyl cellulose, for instance hydroxypropylmethyl cellulose-type 2910 USP; hypromellose and polyvinylpyrrolidone, for instance Povidone® K30(BASF), lactose, guar gum, pectin, gelatin, sodium alginate. The lubricants used in the present invention can comprise one or more components selected from a group comprising metallic stearates (such as magnesium stearate, calcium stearate, aluminum stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohol, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oil, leucine, polyethylene glycols (PEG), metallic lauryl sulfates (such as sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, colloidal silicon dioxide, sodium benzoate, sodium acetate, talc and/or hydrates thereof.

The diluents used in the present invention can comprise one or more components selected from a group comprising alkali metal carbonates, cellulose derivatives (microcrystalline cellulose, cellulose acetate, etc.), dextrin, fructose, dextrose, glyceryl palmitostearate, lactitol, lactose, direct compression lactose, maltose, mannitol, simethicone, sorbitol, starch, talc, xylitol and/or hydrates thereof and/or derivatives thereof.

The pharmaceutically acceptable emulsifying agents according to the present invention can be selected from the group comprising carbomer, cetostearyl alcohol, cetyl alcohol, cholesterol, dietanolamine, ethylene glycol, polmito stearate, glyceryl mono stearate, hydroxy propyl cellulose, lanoline, lecithine, methyl cellulose, monoethanol amine, oleic acid, polyoxy ethylene alkyl ester, prophylene glycol alginate, sodium citrate dihydrate, sodium lauryl sulfate, sorbitan esters, polysorbate.

The pharmaceutically acceptable carriers of the present invention can be selected from a group comprising polyether glycols, polypropylenes, xylitol, sorbitol, potassium sodium tartrate, sucrose tribehenate, glucose, lactitol, behenic acid, hydroquinone, monomethyl ether, sodium acetate, ethyl fumarate, myristic acid, citryl acid, saturated hydrocarbons, paraffins, sorbitan esters, fats, waxes, polyvinylpyrrolidone polymers, acrylic polymers and/or mixtures thereof.

The formulations according to the present invention can optionally be formulated so as to provide release characteristics such as fast, slow, delayed, prolonged release. To this respect, the release rate determinant polymers that can be used in scope of the present invention can be pH-dependant polymers, non pH-dependant polymers, swellable polymers, non-swellable polymers, hydrophilic polymers, hydrophobic polymers and/or one or more hydrophobic substances; ionic polymers such as sodium alginate, carbomer, calcium carboxy methyl cellulose or carboxy methyl cellulose; non-ionic polymers such as hydroxy propyl methyl cellulose; natural or/synthetic polysaccharides such as alkyl celluloses, hydroxyl alkyl celluloses, cellulose ethers, nitrocellulose, dextrin, agar, carrageenan, pectin, starch and starch derivatives or mixtures thereof; cellulosic polymers; methacrylate polymers, methacrylate copolymers, polyvinylpyrrolidone, polyvinylpyrrolidone-polyvinyl acetate copolymer, ethyl cellulose, cellulose acetate, cellulose propionate (high, medium and low molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, polyvinyl acetate, polyvinyl chloride.

In the formulations of the present invention; antioxidants, chelating agents, alkalinizing agents and photoprotective agents can be used as the stabilizer. The stabilizer/stabilizers that can be used in the formulations of the present invention are preferably alkalinizing agents and they can be selected from a group comprising alkaline metal salts such as sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate; alkaline earth metal salts such as calcium carbonate, calcium hydroxide, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, calcium acetate, calcium gluconate, calcium glycerophosphate, magnesium carbonate, magnesium hydroxide, magnesium sulfate, magnesium acetate, magnesium silicate, magnesium aluminate; and organic compounds such as primary, secondary and tertiary amines, cyclic amines, N,N'dibenzylethylendiamine, dietanolamine, ethylendiamine, meglumine, tromethamol, monosodium glutamate, polacrilline sodium, sodium alginate and/or pharmaceutically acceptable hydrates and/or derivatives thereof.

The film coating material of the present invention is composed of the following components and/or combinations thereof: lactose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, triacetine, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate phthalate, polyvinyl acetate phthalate, diethyl phthalate, sugar derivatives, polyvinyl derivatives, waxes, fats and gelatins, triethyl citrate, glyceride, titanium oxide, talc, sodium alginate, stearic acid, lecithin.

The solvents used in the present invention can comprise one or more components selected from a group comprising toluene, benzene, acetone, methyl acetate, tetrahydrofurane, heptane, hexane, acetonitrile, alcohol and/or alcohol mixtures.

Formulations of the present invention can be prepared by any methods in the prior art. These can be methods such as wet granulation, dry granulation, dry blending. EXAMPLES

1. Combined dosage form comprising colesevelam tablet and choline fenofibrate capsule

Combined dosage form comprising colesevelam capsule and fenoiibrate capsule

Combined dosage form comprising colesevelam sachet and choline fenofibrate capsule

Claims

1. A pharmaceutical composition characterized in that said composition comprises colesevelam and fenofibrate and/or their pharmaceutically acceptable salts, free acid or base forms, solvates, polymorphs or hydrates or combinations thereof in pharmaceutically effective amounts.

2. The formulation according to claim 1 , wherein colesevelam used in the formulations is in hydrochloride salt form.

3. The formulation according to claim 1, wherein fenofibrate used in the formulations is in the form of fenofibrate and/or a free acid form thereof or a pharmaceutically acceptable salt of said acid form.

4. The formulation according to claims 1-3, wherein the particle size of fenofibrate and/or its free acid form or a pharmaceutically acceptable salt of said acid form used in the formulations is in the range of 1 μιη to 500 μπι, more preferably in the range of 1 μπι to 300 μπι; even more preferably in the range of 1 μπι to 200 μπι.

5. The formulation according to any one of the preceding claims, wherein said formulation comprises colesevelam hydrochloride in the range of 1 gr. to 20 gr.; fenofibrate and/or its free acid form or a pharmaceutically acceptable salt of said acid form in the range of 100 mg to 500 mg.

6. The formulation according to claim 5, wherein said formulation comprises colesevelam hydrochloride in the range of 1 gr. to 10 gr; fenofibrate and/or its free acid form or a pharmaceutically acceptable salt of said acid form in the range of 100 mg to 300 mg.

7. The formulation according to any one of the preceding claims characterized in that said formulation is administered by one of the oral, parenteral or enteral routes.

8. The oral dosage form according to claim 7 characterized in that said oral dosage form is selected from a group comprising solid dosage forms such as tablet, film tablet, coated tablet, effervescent tablet, layered tablet; modified, fast, slow, controlled, prolonged release tablets; water soluble granules, effervescent granules, powders and powder mixtures, orally disintegrated tablet, mini tablet, micro tablet, pellet or multiple dosage forms comprising one or more of these together or liquid dosage forms such as suspension dosage forms.

9. The formulation according to any one of the preceding claims characterized in that said formulation comprises the active agents separately or in a single dosage form.

10. The formulation according to any one of the preceding claims characterized in that the active agents are taken simultaneously, separately or sequentially.

11. The formulation according to any one of the preceding claims characterized in that said formulation is used in the treatment of diseases related with changing lipid levels such as hyperlipoproteinemia alone (for instance primary and secondary hyperlipoproteinemia), hypertriglyceridemia alone (for instance type IV) or cases that two of these are together (for instance type II b and III); hypercholesterolemia (for instance type II a), hyperlipidemia, mixed dislipidemia.