WO2012064301A2

WO2012064301A2 - Physically improved tablet formulations

Info

Publication number: WO2012064301A2
Application number: PCT/TR2011/000243
Authority: WO
Inventors: Bilgic Mahmut
Original assignee: Bilgic Mahmut
Priority date: 2010-11-11
Filing date: 2011-11-03
Publication date: 2012-05-18
Also published as: WO2012064305A3; TR201009398A2; WO2012064305A2; WO2012064301A3

Abstract

The present invention relates to physically improved tablet formulations of a leukotriene receptor antagonist and combinations of the leukotriene receptor antagonist with an H1- antihistaminic which are effective in prevention and/or treatment of allergic and inflammatory diseases of the skin or upper and lower respiratory tracts and relieving the symptoms thereof.

Description

PHYSICALLY IMPROVED TABLET FORMULATIONS

The present invention relates to physically improved tablet formulations of a leukotriene receptor antagonist and combinations of the leukotriene receptor antagonist with an Hl- antihistaminic which are effective in prevention and/or treatment of allergic and inflammatory diseases of the skin or upper and lower respiratory tracts and relieving the symptoms thereof.

Montelukast (Formula I), chemical name of which is l-[[[(lR)-l-[3-[(lE)-2-(7-chloro-2- quinolinyl)ethenyl]phenyl3-[2-( 1 -hydroxy- 1 -methyl-ethyl)phenyl]propyl]thio]methyl] cyclopropane acetic acid, is a leukotrine receptor antagonist.

Formula (I)

Montelukast was first disclosed in the patent numbered EP480717 Al . Processes for preparation of montelukast and also use of montelukast as leukotriene antagonist are clarified in the patent.

Montelukast is a potent and selective antagonist of leukotriene D4 (LTD₄) which is administered by the oral route and is effective on cysteinyl leukotriene receptor (CysLT in the respiratory tract. Cysteinyl leukotrienes (LTC₄, LTD₄, LTE₄) are powerful inflammatory eicosanoids which are secreted by various cells including mast cell and eosinophils. These important pro-asthmatics mediators bind to cysteinyl leukotriene receptors (CysLTi) in the respiratory tract and cause a range of respiratory activities such as bronchoconstruction, intensive mucus secretion, vascular permeability and eosinophil accumulation.

Montelukast is a powerful compound which treats asthma inflammation parameters significantly. Montelukast binds to CysLTj receptor with a high affinity and selectivity and strongly inhibits physiological effects of LTC₄, LTD₄, LTE₄ in CysLTi receptor without any agonist activity. Levocetirizine (Formula II), chemical name of which is 2-[2-[4-[(R)-(4- chlorophenyl)- phenyl- methyl]piperazin-l-yl] ethoxy] acetic acid, is a non-sedating, long-acting Hl- histaminic.

Formula (II)

Cetirizine was first disclosed in the patent numbered EP0058146 Al. The patent numbered GB2225321 A for preparation process of levocetirizine and the patent numbered WO9406429 Al for use of levocetirizine in treatment of allergic diseases are among the first patents related to levocetirizine which is the R-enantiomer of cetirizine. Piperazine derivative of levocetirizin which is the R-enantiomer of cetirizine is a potent and selective HI receptor antagonist. Levocetirizine is a new antihistaminic which binds to HI receptors with high affinity, even two times higher as compared to cetirizine. Levocetirizine competes with histamine and inhibits histamine from binding to HI receptors. This antagonism blocks the effects of antihistamine on the gastrointestinal tract, uterus, large blood vessels, bronchial smooth muscle. The blockage of HI receptors suppresses histaminic activities such as edema, flare and itching. The facts that levocetirizine enters the central nervous system in little amounts and has little affinity to HI receptors explain its non-sedative nature to some extent.

Levocetirizine has anti-allergic and anti-inflammatory activity. The studies have shown that levocetirizine inhibits a comprehensive series of reactions that induce and disseminate allergic inflammation.

Use of levocetirizine and montekulast together is explained in the prior art. For instance, the patent numbered WO2003101434 discloses intranasal use of an antihistamine and a leukotriene inhibitor for treatment and prevention of allergic rhinitis and symptoms thereof. The antihistaminic active agent given is loratadine or desloratadine while the leukotriene inhibitor is montelukast in said patent.

However, as a result of the studies conducted, the inventor have found that the combination product in the prior art does not have enough hardness in some cases; for instance, when said product is produced in tablet dosage form or when the product is required to be used as stored in blisters.

As it is known, tablet hardness relates to resistance of tablets against corrosion- breakage before storing, carrying, coating and use. Low-hardness tablets are exposed to corrosion, disintegration or breakage more. Such situations cause active agent loss. Furthermore, there is a close correlation between tablet hardness and dispersibility. Since extra hard tablets cannot disintegrate and dissolve as required, the bioavailability of these tablets shall decrease and therefore duration of getting the desired biological response shall be longer. When all these parameters are taken into consideration, it is aimed that tablet hardness is low enough to enable the tablet to disintegrate fast in stomach while it is high enough to preserve tablet integrity from production to patients' use; during packing, carrying and storing.

There are many patent applications that disclose montelukast formulations and production method thereof. For instance, the patent numbered WO2007092031 (Al) discloses montelukast formulations which have less than 1% of sulphoxide impurity and do not comprise microcrystalline cellulose, and processes for production thereof. Production of montelukast tablet formulations by wet granulation method is also clarified in this patent.

However, it has been seen that the tablet obtained when the formulation and production method of said patent are applied to montelukast and combinations thereof does not have desired mechanical properties.

As montelukast is prone to degrade easily, production method and formulation to be used for tablet production should be selected quite carefully in order to provide adequate mechanical properties. In addition to this, although use of different amounts of various pharmaceutically acceptable excipients in order to improve mechanical properties of the tablet is available in the prior art, this is quite a hard solution to be implemented for active agents which are affected from environmental conditions easily and incompatible with most of the pharmaceutical excipients.

When the prior art is taken into consideration, hardness problem of tablet formulations comprising montelukast and combinations thereof has not been mentioned and therefore, no solution has been suggested.

The present invention aims to provide a pharmaceutical formulation that can be used for preparation of tablets which are hard enough, also dispersible and soluble enough and highly stable.

As a result of the studies they conducted, the inventors have surprisingly achieved to produce stable pharmaceutical tablets which have sufficient hardness value and are also sufficiently well dispersible and soluble by using two different diluents at different rates and qualities in montelukast formulations and combinations of these formulations with at least one pharmaceutical excipient.

The diluents in the formulations of the present invention comprises one or more components selected from the group comprising alkaline metal carbonates, cellulose derivatives (microcrystalline cellulose, cellulose acetate etc.) dextrin, fructose, dextrose, glyceryl palmito stearate, lactitol, lactose, directly compressible lactose, maltose, mannitol, simethicone, sorbitol, starch, talc, xylitol and/or pharmaceutically acceptable derivatives thereof.

A characteristic feature of the formulations according to the invention is that said formulations comprise lactose or pharmaceutically acceptable derivatives thereof and mannitol as diluents.

The term "lactose or pharmaceutically acceptable derivatives thereof which is said to be used as one of diluents in the formulations according to the present invention refers to lactose and pharmaceutically acceptable hydrates and /or anhydrates thereof. Possible derivatives of lactose that can be used in the formulations of the present invention can be lactose, lactose anhydrate and/ or lactose monohydrate.

The other characteristic feature of the formulations according to the invention is that the ratio of the diluents to each other (lactose or pharmaceutically acceptable derivatives thereof : mannitol) is in the range of 0.1 to 5 by weight. The other characteristic feature of the formulations according to the invention is that the ratio of the diluents to each other (lactose or pharmaceutically acceptable derivatives thereof : mannitol) is in the range of 0.1 to 1 by weight.

The other characteristic feature of the formulations according to the invention is that the ratio of the diluents to each other (lactose or pharmaceutically acceptable derivatives thereof : mannitol) is in the range of 0.6 to 1 by weight.

The other characteristic feature of the formulations according to the invention is that the average particle size (D50) of lactose or pharmaceutically acceptable derivatives thereof and mannitol which are used in the formulations as diluents is maximum 150 μιη. The other characteristic feature of the formulations according to the invention is that the average particle size (D50) of lactose or pharmaceutically acceptable derivatives thereof and mannitol which are used in the formulations as diluents is maximum 130 μπι.

The other characteristic feature of the formulations according to the invention is that the average particle size (D50) of lactose or pharmaceutically acceptable derivatives thereof and mannitol which are used in the formulations as diluents is maximum 120 μπι.

The term "average particle size (D50)" used herein refers to the particle size of 50% of the particles by volume.

A characteristic feature of the formulations according to the invention is that said formulations are in the form of tablet, film coated tablet or bilayer tablet. Montelukast formulations of the present invention are used as combined with at least one other active agent.

The second active agent stated herein is preferably an antihistaminic and selected from a group comprising diphenhydramine, carbinoxamine, chlorphenoxamine, mepyramine, antazoline, triple amine, dexchlorpheniramine, dexbrompheniramine, pheniramine, buclizine, hydroxyzine, cinnarizine, meclizine, alimemazine, promethazine, cyproheptadine, ebastine, astemizole, acrivastine, loratadine, desloratadine, ketotifen, cetirizine, levocetirizine or pharmaceutically acceptable salts, solvates, derivatives, polymorphs, hydrates or enantiomers thereof.

The second active agent used in the formulations is levocetrizine dihydrochloride. The second active agent can be used with montekulast simultaneously, sequentially or separately. However, the two active agents are combined in a single dosage form in the preferred embodiment of the present invention.

The term "montelukast" stated in the text refers to montelukast and its pharmaceutically acceptable salts, solvates, derivatives, polymorphs, hydrates or enantiomers. Preferably, montelukast used in the formulations of the present invention is in the form of sodium salt.

Formulations according to the present invention can comprise other pharmaceutically suitable components such as additives and excipients selected from disintegrants, viscosity enhancing components, filling agents, drying agents, stabilizing agents, lubricants, diluents, binders, glidants, anti-foam agents, wetting agents, effervescent mixtures, sweeteners and flavouring agents.

The disintegrant that can be used in formulations of the present invention can be selected from highly dispersive polymers, for instance cross-linked hydroxypropyl cellulose, polyvinylpyrrolidone, high-molecular-weight polymers, microcrystalline cellulose, sodium starch glycolate, povidone, alginic acid, sodium alginate.

The binders that can be used in formulations of the present invention comprise one or more components selected from the group comprising potato, wheat or corn starch; microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hypromellose and polyvinylpyrrolidone.

The lubricants that can be used in formulations of the present invention comprise one or more components selected from the group comprising highly metallic stearates (magnesium stearate, calcium stearate, aluminium stearate etc), fatty acid esters (sodium stearyl fumarate etc), fatty acids (stearic acid etc), fatty alcohols, glyceryl behenate, mineral oil, paraffins, L- Leucine, hydrogenated vegetable oil, leucine, polyethylene glycols (PEG), metallic lauryl sulphates (sodium lauryl sulphate, magnesium lauryl sulphate), sodium chloride, sodium benzoate, sodium acetate and talc and/or hydrates thereof.

The stabilizing agent that can be used in formulations of the present invention can be selected from 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 sulphate, calcium acetate, calcium gluconate, calcium glycerophosphate, magnesium carbonate, magnesium hydroxide, magnesium sulphate, magnesium acetate, magnesium silicate, magnesium aluminate; organic components such as primary, secondary and tertiary amines, cyclic amines, Ν,Ν'-dibenzyl ethylenediamine, diethanolamine, ethylenediamine, meglumine, monosodium glutamate, polacrilin sodium, sodium alginate and/or pharmaceutically acceptable hydrates and/or derivatives thereof.

The filling agent that can be used in formulations of the present invention comprises one or more components selected from the group comprising lactose, sugar, starch, modified starch, mannitol, sorbitol, inorganic salts, microcrystalline cellulose, cellulose, calcium sulphate, xylitol and lactitol.

The film coating agent that can be used in formulations of the present invention comprises components such as lactose, hydroxypropyl methyl cellulose, triacetine, titanium dioxide, polyvinyl alcohol, talc, lecithin, polyethylene glycol and/or combinations thereof. Said film coating composition can comprise one or more pharmaceutically acceptable solvent or solvent mixtures. The solvents that can be used in formulations of the present invention comprise one or more components selected from the group comprising ethyl alcohol, methyl alcohol, isopropyl alcohol, deionised water or combinations thereof.

The sweeteners that can be used in formulations of the present invention comprise one or more components selected from the group comprising aspartam, dextrose, fructose, sucralose, sodium cyclamate, mannitol, maltose, saccharine and/or pharmaceutically accaptable salts thereof.

Combination product of the present invention comprising levocetirizine dihydrochloride along with an effective amount of montelukast sodium is preferably in the form of bilayer tablet and basically composed of two formulations; the first formulation comprises an effective amount of levocetirizine dihydrochloride and a specific amount of lactose or pharmaceutically acceptable derivatives thereof as diluent; and the second formulation comprises an effective amount of montelukast sodium and a specific amount of mannitol as diluent.

The ratio of the diluents to each other (lactose or pharmaceutically acceptable derivatives thereof : mannitol) in these two phases is in the range of 0.1 to 5 by weight, preferably in the range of 0.1 to 1 by weight, more preferably in the range of 0.6 to 1 by weight.

Tablets which have enough breaking load and hardness can be produced by direct compression method. Hardness value of the bilayer tablets produced according to the invention is at least 10 kP, preferably in the range of 10-50 kP, more preferably in the range of 10-20 kP.

Substantial tablet hardness value of the formulations according to the invention has been achieved bu adjusting amount, type and also particle size of the diluents which are used in the formulations.

The present invention also provides a production method for production of tablet formulations given above.

Tablet formulations of the present invention can also be produced with any method in the prior art; for instance, wet granulation, dry granulation, dry blending though said production method preferably comprises the following steps:

1. Preparation of the first formulation

a. Mixing and sieving montelukast or a pharmaceutically acceptable salt, ester, solvate, derivative, polymorph or hydrate thereof, mannitol and at least one other pharmaceutically acceptable excipient,

b. Adding a pharmaceutically acceptable lubricant into the mixture obtained in the first step and blending the mixture so as to obtain the first formulation,

2. Preparation of the second formulation

c. Mixing and sieving levocetirizine or a pharmaceutically acceptable salt, ester, solvate, derivative, polymorph or hydrate thereof, a specific amount of lactose or pharmaceutically acceptable derivatives thereof and at least one other pharmaceutical excipient,

d. Adding a pharmaceutically acceptable lubricant into the mixture obtained in the first step and blending the mixture so as to obtain the second formulation.

3. Preparation of bilayer tablet dosage form

Preparation of bilayer dosage form by feeding the two formulations which are produced in the steps above to the tablet compression machine consecutively,

4. Coating

Prepared bilayer dosage form can optionally be coated.

On the other hand, the inventors have seen that the lubricants and mixing times in step "b" and "d" of the bilayer tablet formulation which is prepared according to the production method clarified above affect mechanical properties of the end production. Mixing time for montelukast formulation in step "b" is preferably 1-10 minutes, more preferably 1-5 minutes; mixing time for levocetirizine formulation in step "d" is preferably 1- 20 minutes, more preferably 1-15 minutes in production of the formulations of the present invention.

Examples of pharmaceutical tablet formulations of the present invention are presented below. Examples are given in order to clarify the subject of the invention; yet the subject of the invention is not limited to these examples.

EXAMPLES

Example 1: Film Coated Tablet Formulation

The film coated tablet formulation given above is prepared according to the production explained in detail in description.

Example 2: Film Coated Bilayer Tablet Formulation

The formulation given above is prepared according to the production explained in detail in description.

Values of tablet hardness analysis which was run at approximately 15 kN pressure using 10 samples taken from different production lines of the bilayer tablets produced this way are identified and showed in the table below.

Table I. Tablet hardness data

As clearly seen from the data, the bilayer dosage form produced with said formulation and also production method has enough tablet hardness.

Claims

Tablet formulations comprising montelukast and/or a pharmaceutically acceptable salt thereof characterised in that at least two different diluents are used in said formulations. The tablet formulation according to claim 1 characterised in that said diluents used in the formulations are selected from a group comprising alkaline metal carbonates, cellulose derivatives, dextrin, fructose, dextrose, glycerol palmito-stearate, lactitol, directly compressible lactose, maltose, mannitol, simethicone, sorbitol, starch, talc, xylitol and/or pharmaceutically acceptable derivatives thereof.

The tablet formulation according to claim 2 characterised in that said diluents used in the formulations are lactose or pharmaceutically acceptable derivatives thereof and mannitol.

The tablet formulation according to any of the preceding claims characterised in that the ratio of the diluents to each other (lactose or pharmaceutically acceptable derivatives thereof : mannitol ) is in the range of 0.1 to 5 by wieight.

The tablet formulation according to claim 4 characterised in that the ratio of the diluents to each other (lactose or pharmaceutically acceptable derivatives thereof : mannitol ) is in the range of 0.1 to 1.

The tablet formulation according to claims 4 to 5 characterised in that the ratio of the diluents to each other (lactose or pharmaceutically acceptable derivatives thereof : mannitol ) is in the range of 0.6 to 1.

The tablet formulation according to any of the preceding claims characterised in that said formulations are in the form of tablet, film coated tablet or bilayer tablet.

The tablet formulation according to claim 7 characterised in that said formulations are in bilayer tablet form.

The tablet formulation according to any one of the preceding claims characterised in that said formulation comprises at least one other active agent.

The tablet formulation according to claim 9 characterised in that said second active agent is preferably an antihistaminic and selected from the group comprising diphenhydramine, dimenhydrinate, carbinoxamine, chlorphenoxamine, mepyramine, antazoline, triple amine, dexchlorpheniramine, dexbrompheniramine, pheniramine, buclizine, hydroxyzine, cinnarizine, meclizine, alimemazine, promethazine, cyproheptadine, ebastine, astemizole, acrivastine, loratadine, desloratadine, ketotifen, cetirizine, levocetirizine or pharmaceutically acceptable salts, solvates, derivatives, polymorphs, hydrates or enantiomers thereof.

11. The tablet formulation according to claim 10 characterised in that said second active agent is levocetirizine dihydrochloride.

12. Production method for preparing the tablet formulation according to claim 11 characterised in that said method comprises the following steps;

• Preparation of the first formulation

a) Mixing and sieving montelukast or a pharmaceutically acceptable salt, ester, solvate, derivative, polymorph or hydrate thereof, mannitol and at least one other pharmaceutically acceptable excipient.

b) Adding a pharmaceutically acceptable lubricant into the mixture obtained in the first step and blending the mixture so as to obtain the first formulation

• Preparation of the second formulation

c) Mixing and sieving levocetirizine or a pharmaceutically acceptable salt, ester, solvate, derivative, polymorph or hydrate thereof, a specific amount of lactose lactose or pharmaceutically acceptable derivatives thereof and at least one other pharmaceutical excipient.

d) Adding a pharmaceutically acceptable lubricant into the mixture obtained in the first step and blending the mixture so as to obtain the second formulation.

• Preparation of bilayer tablet dosage form

Preparation of bilayer dosage form by feeding the two formulations which are produced in the steps above to the tablet compression machine consecutively.

• Coating

Prepared bilayer dosage form can optionally be coated.

13. The production method according to claim 14 characterised in that the mixing time in step "b" is 1-10 minutes.

14. The production method according to claim 15 characterised in that the mixing time in step "b" is 1-5 minutes.

15. The production method according to claim 14 characterised in that the mixing time in step "d" is 1-20 minutes.

16. The production method according to claim 17 characterised in that the mixing time in step "d" is 1-15 minutes.

17. The tablet formulation according to claim 1 characterised in that said formulation is used in prevention and/or treatment of allergic and inflammatory diseases of the skin or upper and lower respiratory tract diseases such as seasonal allergic rhinitis, perennial allergic rhinitis, allergic sinusitis, atopic dermatitis, urticaria, allergic asthma, aspirin induced asthma, exercise induced asthma and in relieving the symptoms thereof.