WO2013066279A1

WO2013066279A1 - Solid dosage forms comprising ezetimibe

Info

Publication number: WO2013066279A1
Application number: PCT/TR2012/000173
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Mahmut Bilgic
Priority date: 2011-10-13
Filing date: 2012-10-12
Publication date: 2013-05-10

Abstract

The present invention relates to pharmaceutical formulations comprising an active agent having solubility problems; and the production methods and use of these formulations.

Description

SOLID DOSAGE FORMS COMPRISING EZETIMIBE

The present invention relates to pharmaceutical formulations comprising an active agent having solubility problem; and to the production method and use of these formulations. Background of the Invention

Ezetimibe is a cholesterol absorption inhibitor, chemical name of which is (3R,45)-l-(4- Fluorophenyl)-3-[(3S]-3- 4-fluorophenyl]-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2- azetidinone (Formula I):

Ezetimibe was first described in the patent numbered US5631365 A. In the prior art, there are methods for preparation of ezetimibe; pharmaceutical compositions comprising ezetimibe; and use of ezetimibe as a hypocholesterolemic agent. Besides, it was stated that use of ezetimibe in combination with HMG-CoA reductase inhibitors such as lovastatin, pravastatin, fluvastatin, simvastatin and atorvastatin is effective in reducing the cholesterol level in blood; and in the treatment of arteriosclerosis.

An essential problem regarding ezetimibe in the prior art is its highly low solubility. When the solid dosage forms such as tablet are used via the oral route, the drug should be dissolved in the gastrointestinal fluid before it shows its effect. However, at this point, solubility problem arises for drugs like ezetimibe which have small particle sizes. Low solubility of these drugs also affects their bioavailability negatively. The PCT application numbered WO 2006060808 searches for a solution for this low solubility problem, using micronized ezetimibe particles having higher surface area values. The particle size of the micronized particles in said patent is lower than 30 μπι.

The patent numbered EP1849459 explains the formulations in which ezetimibe is used as milled together with a hydrophilic agent. It is said that the average size of the ezetimibe particles, which are also present in this patent, is 5 μπι or less.

The patent numbered WO 2009077573 explains suspension formulations comprising ezetimibe with a particle size lower than 30 μπι. It was stated in the application that the preferred particle size is smaller than 5 μπι and larger than 0.5 μπι. As can be seen, most of the solutions in the prior art are intended for increasing the solubility of the active agent via adjusting the particle size of ezetimibe to be smaller than 10 μηι in average. However, decreasing the particle size is not an appropriate solution offer to increase the solubility of the active agents with hydrophobic chemical structures like ezetimibe. Due to thermodynamic propulsion in aqueous media, small particles of hydrophobic active agents turn into big masses called "micelle", absorption of which is harder. For this reason, small particles of ezetimibe do not dissolve well in gastrointestinal channel. This complicates formulating ezetimibe.

Another problem is about the production methods of active agents with very small particle sizes. In the formulations where active agents with small particle sizes are generally used, homogeneous mixing cannot be performed as the particles scatter around during the production process; and this leads to a decrease in the amount of active agent in the final product. Therefore, the production method should be carefully chosen for the active agents with small particle sizes. When the prior art is considered, there is a need for determining the particle size that can provide appropriate solubility and thus bioavailability in ezetimibe formulations; and a production method for formulations comprising ezetimibe with this particle size.

The inventors have achieved to produce formulations with adequate solubility via using specific formulation components and a production method instead of decreasing the particle size of the active agent to provide solubility of ezetimibe. The characteristic of the formulations of the invention is that said formulations comprise ezetimibe which has a D(90) particle size in the range of 10 and 50 μπι, at least 1% of disintegrant by weight and at least another excipient; and are produced by wet granulation method. Detailed Description of the Invention

The present invention relates to pharmaceutical formulations comprising ezetimibe and/or a pharmaceutically acceptable salt thereof; their production method and fields of use.

According to the first embodiment of the invention, ezetimibe in the formulations is polymorphically in crystalline form. The formulations of the invention comprise ezetimibe in the range of 1-20% by weight.

According to the second embodiment of the invention, D(90) particle size of the ezetimibe particles in the formulations is in the range of 10 and 50 μιη.

According to the third embodiment of the invention, D(90) particle size of the ezetimibe particles in the formulations is in the range of 15 and 45 μπι.

The statement "D(90) particle size" mentioned through the text refers to the particle size which comprises 90% of the particles by volume; and it was measured by wet method in Malvern Mastersizer 2000 S [Hydro 2000) device.

According to the forth embodiment of the invention, the formulations are used in the treatment of hypercholesterolemia and /or hyperlipoproteinemia.

The oral dosage forms of the invention are the forms present in the prior art and they can be solid dosage forms such as tablet, film tablet, coated tablet, effervescent tablet, layered tablet; modified-, fast-, slow-, controlled-, delayed-release tablets; orodispersible tablet, bilayer tablet, mini tablet, micro tablet, pellet; multi-dosage forms comprising one or more of these forms; or liquid dosage forms such as suspension dosage forms.

A characteristic of the formulations of the invention is that said formulations are formulated as solid dosage forms, preferably as tablet dosage form.

Tablet dosage forms preferred in the invention are film-coated tablet or bilayer tablet. The oral dosage forms of the invention can comprise an HMG CoA enzyme inhibitor as a second active agent.

The second active agent that can be used in the formulations of the invention can be selected from this group: rosuvastatin, lovastatin, atorvastatin, pravastatin, fluvastatin, pitavastatin, simvastatin or pharmaceutically acceptable salts, solvates, derivatives, polymorphs, hydrates or enantiomers thereof.

The formulations of the invention comprise the second active agent preferably in the range of 1 and 10% by weight.

D(90) particle size of the second active agent used in the formulations of the invention is preferably in the range of 1 and 200 μπι. These formulations of the invention can comprise other pharmaceutically acceptable components such as additives and excipients selected from a group comprising pharmaceutically acceptable binders, disintegrants, viscosity enhancing components, filling agents, drying agents, lubricants, sweeteners, flavoring agents, taste masking agents, diluents, binders, glidants, wetting agents, stabilizers, effervescent acid-base couple, anti-adhesive agents, solvents, sweeteners.

In the formulations of the invention, agents such as antioxidants, chelating agents, alkalizing agents and photoprotectors can be used as stabilizer.

The stabilizer/stabilizers that can be used in the formulations of the invention can be selected from alkali 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 sulphate, calcium acetate, calcium gluconate, calcium glycerophosphate, magnesium carbonate, magnesium hydroxide, magnesium sulphate, magnesium acetate, magnesium silicate, magnesium aluminate; and organic compounds such as primary, secondary and tertiary amines, cyclic amines, Ν,Ν'-dibenzylethylenediamine, diethanolamine, ethylenediamine, meglumine, monosodium glutamate, polacryline sodium, sodium alginate and/or pharmaceutically acceptable hydrates and/or derivatives thereof. The filling agents that can be comprised in the invention can comprise one or more components from this group: lactose, sugar, starch, modified-starch, mannitol, sorbitol, inorganic salts, microcrystalline cellulose, cellulose, calcium sulphate, xylitol and lactitol.

The disintegrants that can be comprised in the invention can be selected from highly dispersive polymers, for example from the group comprising cross-linked hydroxypropyl cellulose, polyvinylpyrrolidone, high molecular-weight polymers, microcrystalline cellulose, sodium starch glycolate, povidone, carboxymethyl cellulose, carboxymethyl cellulose sodium, colloidal silicone dioxide, alginic acid, sodium alginate, corn starch or combinations thereof. The inventors have discovered that the amount and type of the disintegrant used in the formulations developed within the scope of the invention have a positive effect on the solubility of the formulations.

According to this, the formulations comprise carboxymethyl cellulose sodium at least at 1%, preferably in the range of 1 to 10%, more preferably in the range of 1 to 8% by weight.

The formulations can optionally comprise at least another disintegrant.

The formulations of the invention can comprise one or more binders selected from the group comprising potato, wheat or corn starch; microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone, lactose, guar gum, pectin, gelatin, sodium alginate or combinations thereof.

The binder used in the formulations of the invention is preferably hydroxypropyl methyl cellulose; and comprised in an amount in the range of 0.5 to 5%, preferably in the range of 0.5 to 3%, more preferably in the range of 0.5 to 2% by weight in the formulations. The formulations can optionally comprise at least another binder.

The formulations of the invention can comprise one or more diluents selected from the group comprising alkali metal carbonates, cellulose derivatives (microcrystalline cellulose, cellulose acetate etc.), dextrin, fructose, dextrose, glyceryl palmitostearate, lactitol, lactose, directly compressible lactose, maltose, mannitol, simethicone, sorbitol, starch, talc, xylitol and/or hydrates and/or combinations thereof. The diluent used in the formulations of the invention is lactose and/or a derivative thereof; and is comprised at least at 50%, preferably in the range of 50 to 95%, more preferably in the range of 50 to 90% by weight in the formulations.

Lactose and/or lactose derivative diluent used in the formulations of the invention is selected from the group comprising lactose, directly compressible lactose, lactose anhydrate, lactose monohydrate or combinations thereof.

The formulations of the invention can optionally comprise at least another diluent.

The anti-adhesive agents that can be comprised in the invention are used to prevent the mixture comprising active agent from forming a rough surface by sticking onto device and machine parts during the process.

The agents used for this purpose can comprise one or more components selected from this group: talc, colloidal silicone dioxide, magnesium stearate and corn starch.

The formulations of the invention comprise at least one anti-adhesive agent in the range of 0.01 to 1% by weight. The preferred anti-adhesive agent is colloidal silicone dioxide. The lubricants that can be comprised in the invention can comprise one or more components selected from this group: highly metallic stearates (magnesium stearate, calcium stearate, aluminum stearate etc.), fatty acid esters (sodium stearyl fumarate etc.), fatty acids ( stearic acid etc.), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oil, leucine, polyethylene glycols (PEG), metallic lauryl sulphate (sodium lauryl sulphate, magnesium lauryl sulphate etc.), sodium chloride, sodium benzoate, sodium acetate and talc and/or hydrates thereof.

The formulations of the invention preferably comprise magnesium stearate as lubricant.

The solvents that can be comprised in the invention can comprise one or more components selected from this group: toluene, benzene, acetone, methyl acetate, tetrahydrofurane, heptane, hexane, acetonitrile, alcohol and/or alcohol mixtures.

The film-coating agent that can be comprised in the invention comprises these components and/or combinations thereof: lactose, hydroxypropyl methyl cellulose, triacetin, titanium dioxide, polyvinyl alcohol, talc, lecithin, polyethylene glycol.

Other additives and excipients apart from the given ones can be added to the formulations of the invention depending on the desire and purpose. The ezetimibe formulations of the invention can be produced by any one of the methods in the prior art. These methods can be dry granulation, wet granulation, direct compression or dry blending.

The method to be used in the production of the ezetimibe formulation of the invention is preferably wet granulation method described below:

1. Obtaining a granulation solution by mixing an effective amount of ezetimibe, at least one pharmaceutically acceptable solvent or solvent mixture and at least one excipient,

2. Performing granulation by spraying the obtained granulation solution onto the mixture comprising at least one pharmaceutically acceptable diluent and at least another excipient and optionally another active agent,

3. Drying the obtained granules,

4. Treating the dry granules with lubricant and preferably taking them into the tablet compression machine to be compressed into tablets. Another method to be used for the production of the ezetimibe formulations of the invention is as following:

1. Obtaining a granulation solution by mixing an effective amount of ezetimibe, at least one pharmaceutically acceptable solvent or solvent mixture,

2. Performing granulation by spraying the obtained granulation solution onto at least one diluent,

3. Drying the obtained granules and adding at least one pharmaceutically acceptable excipient and optionally another active agent into the dry granules,

4. Treating the granules with lubricant and preferably taking them into the tablet compression machine to be compressed into tablets. Another method to be used for the production of the ezetimibe formulations of the invention is as follows:

1. Mixing effective amounts of ezetimibe and diluent,

2. Obtaining a granulation solution by mixing at least one pharmaceutically acceptable solvent or solvent mixture, at least one excipient and optionally another active agent, 3. Granulating the mixture obtained in the first step with the granulation solution obtained in the second step,

4. Drying the obtained granules,

5. Treating the dry granules optionally with another pharmaceutical excipient and then with lubricant and preferably taking them into the tablet compression machine to be compressed into tablets.

A characteristic of the methods given above based on wet granulation and used for the production of the formulations of the invention comprising ezetimibe, D(90) particle size of which varies in the range of 10 and 80 μπ\, preferably in the range of 10 and 50 μιτι, is that the pharmaceutically acceptable solvent comprised in the granulation solution comprises ethyl alcohol and/or propyl alcohol.

The granulation solution comprised in the ezetimibe tablet formulations of the invention is granulated with a granulation solution comprising ethyl alcohol and/or propyl alcohol in the range of 1-50% by weight. The inventors have found that small ezetimibe particles are effectively produced without causing any micelle formation in the case that the ezetimibe particles of the present invention are granulated with a granulation solution comprising ethyl alcohol and/or propyl alcohol in the range of 1-50% by weight.

The pharmaceutical tablet formulations of the invention are given below. These examples are given to explain the scope of the invention; yet the scope of the invention is not limited to these examples.

EXAMPLES

Example 1. Film-coated tablet formulation comprising ezetimibe

Any of the methods given within the scope of the invention can be used for the production of the formulation given above; however, the preferred method is as follows:

1. Ezetimibe, D (90) particle size of which is 35 μιτι, and the diluent are mixed,

2. The obtained mixture is granulated with at least one pharmaceutically acceptable solvent or solvent mixture,

3. The obtained granules are dried,

4. The dry granules are mixed with the pharmaceutically acceptable diluent and finally taken to the tablet compression machine after being treated with the lubricant.

5. The obtained tablets are coated with film.

Example 2. Bilayer tablet formulation comprising ezetimibe and rosuvastatin

Any of the methods given within the scope of the invention can be used for the production of the formulation given above; however, the preferred method is as follows: 1. A granulation solution is obtained by mixing ezetimibe, D (90) particle size of which is 25 μιη, and an adequate amount of 1-propanol,

2. Granulation is performed by spraying the obtained granulation solution onto the filling agent.

3. The obtained granules are dried and effective amounts of rosuvastatin calcium, binder, disintegrant and at least another pharmaceutically acceptable excipient are added into the dry granules,

4. The final granules are treated with the lubricant and taken into the tablet compression machine to be compressed into tablets. Example 3. Biiayer tablet formulation comprising ezetimibe and atorvastatin

1. Obtaining a granulation solution by mixing ezetimibe, D (90) particle size of which is 15 μπι, adequate amounts of ethyl alcohol and water,

2. Performing granulation by spraying the obtained granulation solution onto the dry mixture comprising atorvastatin calcium, diluent, disintegrant and optionally at least another excipient,

3. Drying the obtained granules,

4. Treating the dry granules with the lubricant and preferably taking them into the tablet compression machine to be compressed into tablets.

Claims

1. A pharmaceutical formulation comprising ezetimibe, characterized in that said formulation comprises ezetimibe with a particle size in the range of 10 and 50 μπι, at least one pharmaceutically acceptable disintegrant at least at 1% by weight, and another excipient.

2. The pharmaceutical formulation according to claim 1, characterized in that D(90] particle size of ezetimibe is in the range of 15 and 45 μπι.

3. The pharmaceutical formulation according to claim 1, characterized in that said formulation comprises at least one pharmaceutically acceptable disintegrant in the range of 1 and 10% by weight.

4. The pharmaceutical formulation according to claim 3, characterized in that said formulation comprises at least one pharmaceutically acceptable disintegrant in the range of 1 and 8% by weight.

5. The pharmaceutical formulation according to claim 4, characterized in that the disintegrant is selected from a group comprising cross-linked hydroxypropyl cellulose, polyvinylpyrrolidone, high molecular-weight polymers, microcrystalline cellulose, sodium starch glycolate, povidone, carboxymethyl cellulose, carboxymethyl cellulose sodium, colloidal silicone dioxide, alginic acid, sodium alginate, corn starch or combinations thereof.

6. The pharmaceutical formulation according to claim 5, characterized in that the disintegrant is carboxymethyl cellulose sodium.

7. The pharmaceutical formulation according to claim 1, characterized in that said formulation comprises at least one excipient selected from pharmaceutically acceptable binders, disintegrants, viscosity enhancing components, filling agents, drying agents, lubricants, sweeteners, flavoring agents, taste masking agents, diluents, binders, glidants, wetting agents, stabilizers, effervescent acid-base couple, anti-adhesive agents, solvents, sweeteners.

8. The pharmaceutical formulation according to claim 7, characterized in that said formulation comprises at least one pharmaceutically acceptable binder.

9. The pharmaceutical formulation according to claim 8, characterized in that said formulation comprises at least one binder selected from a group comprising potato, wheat or corn starch; microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone, lactose, guar gum, pectin, gelatin, sodium alginate or combinations thereof.

10. The pharmaceutical formulation according to claim 9, characterized in that the binder is hydroxypropyl methyl cellulose.

11. The pharmaceutical formulation according to claim 10, characterized in that said formulation comprises hydroxypropyl methyl cellulose in the range of 0.5 to 5% by weight.

12. The pharmaceutical formulation according to claim 11, characterized in that said formulation comprises hydroxypropyl methyl cellulose in the range of 0.5 to 3% by weight.

13. The pharmaceutical formulation according to claim 12, characterized in that said formulation comprises hydroxypropyl methyl cellulose in the range of 0.5 to 2% by weight.

14. The pharmaceutical formulation according to claim 7, characterized in that said formulation comprises at least one pharmaceutically acceptable diluent.

15. The pharmaceutical formulation according to claim 14, characterized in that the pharmaceutically acceptable diluent is selected from the group comprising alkali metal carbonates, cellulose derivatives (microcrystalline cellulose, cellulose acetate etc.], dextrin, fructose, dextrose, glyceryl palmitostearate, lactitol, lactose, directly compressible lactose, maltose, mannitol, simethicone, sorbitol, starch, talc, xylitol and/or hydrates, anhydrates or combinations thereof.

16. The pharmaceutical formulation according to claim 15, characterized in that the pharmaceutically acceptable diluent is lactose and/or lactose derivative.

17. The pharmaceutical formulation according to claim 16, characterized in that lactose and/or lactose derivative diluent is selected from the group comprising lactose, directly compressible lactose, lactose anhydrate, lactose monohydrate or combinations thereof.

18. The pharmaceutical formulation according to claim 17, characterized in that said formulation comprises at least 50% of lactose and/or lactose derivative diluent by weight.

19. The pharmaceutical formulation according to claim 18, characterized in that said formulation comprises lactose and/or lactose derivative diluent in the range of 50 to 95% by weight.

20. The pharmaceutical formulation according to claim 19, characterized in that said formulation comprises lactose and/or lactose derivative diluent in the range of 50 to 90% by weight.

21. The formulation according to claim 1, characterized in that said formulation comprises ezetimibe in the range of 1-20% by weight.

22. The formulation according to claim 1, characterized in that said formulation is used in the production of a pharmaceutical dosage form suitable for oral intake.

23. The formulation according to claim 22, characterized in that the pharmaceutical oral dosage form is preferably selected from this group: tablet, film tablet, coated tablet, bilayer tablet, effervescent tablet, layered tablet; modified-, fast-, slow-, controlled-, delayed-release tablets; orodispersible tablet, mini tablet, micro tablet, pellet; or multi-dosage forms comprising one or more of these forms; or suspension dosage forms.

24. The formulation according to claim 23, characterized in that the pharmaceutical oral dosage form is preferably film-coated tablet.

25. The pharmaceutical formulation according to claim 1, characterized in that said formulation comprises a second active agent in the range of 1 to 10% by weight.

26. The pharmaceutical formulation according to claim 25, characterized in that the second active agent is preferably an HMG CoA enzyme inhibitor.

27. The pharmaceutical formulation according to claim 8, characterized in that the HMG CoA enzyme inhibitor is selected from a group comprising rosuvastatin, lovastatin, atorvastatin, pravastatin, fluvastatin, pitavastatin, simvastatin or pharmaceutically acceptable salts, solvates, derivatives, polymorphs, hydrates or enantiomers thereof.

28. The pharmaceutical formulation according to claim 27, characterized in that the HMG CoA enzyme inhibitor is preferably rosuvastatin or atorvastatin or pharmaceutically acceptable salts, solvates, derivatives, polymorphs, hydrates or enantiomers thereof.

29. A production method for the pharmaceutical formulation according to any one of the preceding claims, characterized in that said method is one of wet granulation, dry granulation, dry blending or direct compression methods.

30. The method according to claim 29, characterized in that said method is wet granulation method.

31. The method according to claim 30, characterized in that said method comprises the following steps:

• Obtaining a granulation solution by mixing an effective amount of ezetimibe, at least one pharmaceutically acceptable solvent or solvent mixture and at least one excipient,

• Performing granulation by spraying the obtained granulation solution onto the mixture comprising at least one pharmaceutically acceptable diluent and at least another excipient and optionally another active agent,

• Drying the obtained granules,

· Treating the dry granules with lubricant and preferably taking them into the tablet compression machine to be compressed into tablets.

32. The method according to claim 30, characterized in that said method comprises the following steps:

• Obtaining a granulation solution by mixing an effective amount of ezetimibe, at least one pharmaceutically acceptable solvent or solvent mixture,

• Performing granulation by spraying the obtained granulation solution onto at least one diluent,

• Drying the obtained granules and adding at least one pharmaceutically acceptable excipient and optionally another active agent into the dry granules,

• Treating the granules with lubricant and preferably taking them into the tablet compression machine to be compressed into tablets.

33. The method according to claims 31 and 32, characterized in that the solution used in the granulation comprises ethyl alcohol and/or propyl alcohol in the range of 1-50% by weight.

34. The formulation according to claim 1, characterized in that said formulation is used in the treatment of hypercholesterolemia and/or hyperlipoproteinemia.