WO2012064300A2

WO2012064300A2 - Desloratadine granules

Info

Publication number: WO2012064300A2
Application number: PCT/TR2011/000242
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Mahmut Bilgic
Priority date: 2010-11-11
Filing date: 2011-11-03
Publication date: 2012-05-18
Also published as: TR201009396A2; WO2012064300A3

Abstract

The present invention relates to granules comprising a therapeutically effective amount of desloratadine or a pharmaceutically acceptable salt, solvate, derivative, polymorph, hydrate or enantiomer thereof and production method thereof.

Description

DESLORATADINE GRANULES

The present invention relates to granules comprising desloratadine or a pharmaceutically acceptable salt, solvate, derivative, polymorph, hydrate or enantiomer thereof in a therapeutically effective amount and production methods thereof.

Background of the Invention

Desloratadine (Formula I), which was first disclosed in the patent numbered US4659716 A and has the chemical name of (8-chloro-6,l l-dihydro-l l-(4-piperidylidene)-5H-benzo[5,6]- cyclohepta[l,2-b]pyridine, is a non-sedating, long-acting Hl-histaminic.

Desloratadine which is an active metabolite of loratadine is an orally administered Hl- receptor antagonist. Desloratadine is a new antihistaminic which binds to HI receptors with a higher affinity as compared to other HI receptor antagonists. Desloratadine 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 muscles. The blockage of HI receptors suppresses histaminic activities such as edema, flare and itching.

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

The pharmaceutical formulations comprising desloratadine are prone to degrade easily due to light, heat, moisture and other chemicals. Mostly, the formulations degrade during shelf-life. Active agent degradation is mostly not realized by the patient. However, effects of degradation are big, even lethal in vivo. The products which are released with degradation of desloratadine are desloratadine, dehydro desloratadine, N-formyldesloratadine though the most degration product is N-formyldesloratadine presented in Formula (II) below.

In the prior art, various studies have been conducted related to stable desloratadine formulations and production methods thereof.

For instance, the patent numbered US6100274 discloses formulations comprising desloratadine or a pharmaceutically acceptable salt, basic salt thereof and a pharmaceutically acceptable disintegrant. Said patent discloses that desloratadine is degraded when interacted with higly acidic excipients.

Another example is the patent numbered US6979463. In this patent, formulations comprising a separation layer to prevent desloratadine from interacting with the acidic excipients are disclosed.

In the patent numbered US20020123504, stable desloratadine formulations which do not comprise lactose are disclosed.

When the prior art is taken into consideration, it has been thought that generally, acidic excipients cause degradation of desloratadine and solutions have been suggested for this problem. Most of these solution offers relate to use of basic substances in desloratadine formulations.

However, the inventors have found that possible degradations of desloratadine formulations not only result from chemical characteristics of excipients but also the formulations are affected by production method and physical conditions during production.

Wet granulation method which is frequently used in the prior art refers to blending active agents and various pharmaceutically acceptable excipients and obtaining granules by spraying granulation solution prepared with substances such as solvent, binder on this mixture. Wet granules that are prepared by this method are mostly dried in a dryer called "fluid bed dryer" in specific temparature ranges such that they have desired moisture content.

Desloratadine granules are usually prepared by wet granulation method due to nonhygroscopic nature of desloratadine and wet granules are generally dried approximately at 60°C.

The patent numbered US 2007014855 (Al) discloses stable desloratadine formulations which comprise an alkaline stabilizing agent; preparation of these formulations by wet granulation method and drying granules which are obtained by this method at 60-75°C.

However, after the studies they conducted, the inventors have found that the moisture content of the granules produced by the method specified above is not at a desired level.

For this purpose, they have developed a new production method for desloratadine formulations.

Desloratadine granule formulations which were produced by said new method could remain stable much longer than the formulations in the prior art and formulations which were obtained by said method had longer shelf life as compared to the formulations in the prior art. Granule formulations of the present invention could be produced without any need for using basic excipients in order to provide enough stability.

The characteristic feature of granule formulations according to the invention is that moisture content of granules is in the range of 1 to 5 % by weight.

Other characteristic feature of granule formulations according to the invention is that granule formulation comprises desloratadine in the range of 0.01 to 10 by weight.

Other characteristic feature of granule formulations according to the invention is that granule formulation comprises desloratadine in the range of 0.01 to 8 by weight.

Other characteristic feature of granule formulations according to the invention is that granule formulation comprises desloratadine in the range of 0.01 to 5 by weight. Other characteristic feature of granule formulations according to the invention is that granule formulations can comprise at least one pharmaceutically acceptable excipient.

The pharmaceutically acceptable excipients that can be used in the granule formulations of the present invention can be selected from the group comprising binders, disintegrants, viscosity increasing components, filling agents, drying agents, flavouring agents, lubricants, diluents, binders, glidants, wetting agents, anti-adhesive agents, effervescent couples, solvents, sweeteners or combinations thereof.

The filling agents that can be used in the invention can comprise one or more components selected from a group comprising lactose, sugar, starch, modified starch, mannitol, sorbitol, inorganic salts, microcrystalline cellulose, cellulose, calcium sulphate, xylitol and/ or lactitol or their combinations.

The disintegrants that can be used in the invention provide the dosage form to disintegrate in water easily and fast. In this respect, disintegrant is important. Disintegrants can be selected from higly dispersive polymers for instance; cross-linked hydroxypropyl cellulose, polyvinylpyrrolidone, high-molecular-weight polymers, microcrystalline cellulose, sodium starch glycolate, povidone, colloidal silicon dioxide, alginic acid, sodium alginate, corn starch.

The anti-adhesion agents of the present invention are used in order to prevent the mixture which comprises active agent from forming rough surfaces by adhering to device and machine surfaces during the process. Substances which are used for this purpose can comprise one or more components selected from the following group: talc, coloidal silicon dioxide, magnesium stearate and corn starch.

The binders that can be used in the invention can comprise one or more components selected from a group comprising potato, wheat or corn starch; microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose; hydroxypropyl methylcellulose, hypromellose and polyvinylpyrrolidone, lactose, guar gam, pectin, gelatine, sodium alginate.

The lubricants that can be used in the invention can comprise one or more components selected from the group comprising 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 glicols (PEG), metallic lauryl sulphates (sodium lauryl sulphate, magnesium lauryl sulphate), sodium chloride, sodium benzoate, sodium acetate and talc and/or hydrates thereof.

The diluents that can be used in the invention can comprise one or more components selected from the group comprising alkali metal carbonates, cellulose derivatives (microcrystalline cellulose, cellulose acetate etc.), dextrine, fructose, dextrose, glyceryl palmito stearate, lactitol, lactose, directly compressed lactose, lactose, maltose, mannitol, simethicone, sorbitol, starch, talc, xylitol and/or hydrates and/or derivatives thereof.

The term "effervescent couple" stated in the invention refers to use of an acidic agent and a basic agent together.

Pharmaceutically acceptable acidic agent of the invention can be selected from a group comprising acetic acid, fumaric acid, citric acid, lactic acid, malic acid, phosphoric acid, propionic acid, tartaric acid or pharmaceutically acceptable salts, hydrates, anhydrate or preferably a combination thereof.

Pharmaceutically acceptable basic agent of the present invention can be selected from a group comprising potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium hydrogen citrate or combinations thereof.

The solvents of the present invention comprises one or more components selected from, but not limited to, the group comprising toluene, benzene, acetone, methylacetate, tetrahydrofurane, heptane, hexane, acetonitrile, alcohol and/or alcohol combinations.

The film coating agent of the present invention is composed of, but not limited to, the following components and/or combinations thereof such as lactose, hydroxypropyl methylcellulose, triacetine titanium dioxide, polyvinyl alcohol, talc, lecithin, polyethylene glycol.

The flavoring agent of the present invention can be selected from a group comprising natural aroma oils (peppermint oil, wintergreen oil, clove bud oil, parsley oil, eucalyptus oil, lemon oil, orange oil), menthol, menthane, anethole, methyl salicylate, eucalyptol, cinnamon, 1- methyl acetate, sage, eugenol, oxanone, alpha irisone, marjoram, lemon, orange, blackberry, propenyl guaetol acetyl, cinnamon, vanilla, thymol, linalol, cinnamaldehyde glycerol acetal, N-substituted p-menthane-3-carboxamide, 3,1-methoxy propane 1,2-diol or a combination thereof. The characteristic feature of the present invention is that the granules can be manufactured by the method below:

I. Obtaining active agent combination by blending an effective amount of desloratadine and at least one pharmaceutical excipient,

II. Preparing granulation solution by blending deionised water and at least one pharmaceutically acceptable excipient,

III. Preparing desloratadine granules by spraying granulation solution on the active agent combination obtained in the first step,

IV. Drying the active agent granules which are obtained in a fluid bed dryer.

Characteristic feature of the production method of the present invention is that the drying process is implemented gradually.

The gradual drying process stated herein comprises drying wet granules at 70-90°C initially, and then at 40-70°C.

However, the inventors have faced an another unexpectable problem in the granule formulations produced by the method above.

The granules which are produced by this method adhere with each other and than agglomerate before the drying process and this condition adversely effects the quality of end product.

The problem has been solved by the granule formulations of the present invention by adjustment the active agent particle size.

Accordingly, the granule formulations which are produced by the method above are highly stable.

Characteristic feature of the granule formulation according to the present invention is that D (90) particle size of desloratadine is in the range of 1 and 70 μηι.

Other characteristic feature of the granule formulation according to the present invention is that D (90) particle size of desloratadine is in the range of 1 and 60 μιη.

Other characteristic feature of the granule formulation according to the present invention is that D (90) particle size of desloratadine is in the range of 1 and 50 μηι. Characteristic feature of the granule formulation according to the present invention is that D (50) particle size of desloratadine is in the range of 1 and 40 μηι.

Other characteristic feature of the granule formulation according to the present invention is that D (50) particle size of desloratadine is in the range of 1 and 30 μηι.

Other characteristic feature of the granule formulation according to the present invention is that D (50) particle size of desloratadine is in the range of 1 and 25 μηι.

Characteristic feature of the granule formulation according to the present invention is that the ratio of D (50) / D (90) particle size of desloratadine is between 0.1 and 1.

Other characteristic feature of the granule formulation according to the present invention is that the ratio of D (50) / D (90) particle size of desloratadine is between 0.1 and 0.9.

Other characteristic feature of the granule formulation according to the present invention is that the ratio of D (50) / D (90) particle size of desloratadine is between 0.1 and 0.7.

The granules produced according to the invention was kept at 60% relative humidity and at 25 °C for 12 weeks, and it was seen that granules comprise N-formyl desloratadine which is one of the major degradation products of formulations in the range of 0.01% to 0.50% by weight, more preferably in the range of 0.01% to 0.10% by weight as a result of HPLC analyses run using samples that are taken intermittently.

Granules produced according to the invention can be used for production of any dosage forms in the prior art.

Granules of the present invention can be effervescent or noneffervescent.

Oral dosage forms of the present invention can be in the form of solid oral dosage forms such as tablet, film-coated tablet, coated tablet, effervescent tablet, laminated tablet; modified, fast, slow, controlled, prolonged release tablet; orodispersible tablet, mini tablet, micro tablet, pellet; multiple dosage forms comprising one or more thereof or liquid dosage forms such as suspension dosage forms.

Granules of the present invention is preferably in effervescent form.

The formulations of the present invention can be combined with a second active agent. Nasal decongestants, leukotriene receptor antagonists, antihistaminics, antidepressants can be used as the second active agent. The antihistaminics that can be used in the formulations of the present invention can be selected from a group comprising diphenhydramine, dimenhydrinate, carbinoxamine, chlorphenoxamine, mepyramine, antazoline, triple amine, dexchlorpheniramine, dexbrompheniramine, pheniramine, buclizine, hydroxyzin, 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 leukotriene receptor antagonists that can be used in the formulations of the present invention can be selected from a group comprising montelukast, zafirlukast and zileuton or pharmaceutically acceptable salts, solvates, derivatives, polymorphs, hydrates or enantiomers thereof. Preferably, montekulast sodium is used.

The nasal decongestants used in the formulations of the present invention are preferably pseudoephedrine.

In case of the combination therapy, the dosage forms can be administered separately, together or sequentially or levosetirizine can combine with the other active agent in a single dosage form.

Pharmaceutical formulation examples of the present invention are presented below. These examples are given to clarify the present invention; yet, the scope of the invention is not limited to these examples.

EXAMPLES

Example 1: Effervescant Desloratadine Granules

The production method proposed for aforementioned formulation is as follows:

Granulation solution which comprises an effective amount of deionised water and at least one other pharmaceutically acceptable excipient is prepared.

Active agent combination which comprises desloratadine or a pharmaceutically acceptable salt thereof and at least one other pharmaceutically acceptable excipient are wet granulated with the granulation solution prepared.

The wet granules are dried gradually at an air intake temperature of 70-90°C initially, and then of 40-70°C in a fluid bed dryer. Water content of the granules prepared in this way was measured with a Karl Fischer device and water content of the granules was measured to be approximetly 2.65 %.

Effervescent desloratadine granules produced according to the invention were kept at 60% of relative humidity and at 25°C for 12 weeks, and it was seen that granules comprise N-formyl desloratadine which is one of the major degradation products in the range of 0.01% to 0.50 % by weight as a result of HPLC analyses of samples taken intermittently.

Results are presented below (see Table 1).

Table 1: Stability Parameters for Desloratadine Effervescent Granules (example 1)

Example 2. Desloratadine and Pseudoephedrine Containing Effervescent Granules

The production method proposed for aforementioned formulation is as follows:

Desloratadin wherein D (90) particle size of the active agent is 40 μηι, D (50) particle size of the active agent is 15 μπι and other excipients are wet granulated by the granulation solution comprising binder and deionised water.

The wet granules are dried gradually at an air intake temperature of 65 °C initially, and then of 45°C in a fluid bed dryer and sieved.

Pseudoephedrine is added to the dried granules and mixed to obtain final granule composition.

Claims

1. Granule formulation comprising desloratadine characterised in that moisture content of said granules is in the range of 1 % to 5 % by weight.

2. The granule formulation according to claim 1 characterised in that the granule formulation comprises desloratadine in the range of 0.01 to 10 by weight.

3. The granule formulation according to claims 1 to 2 characterised in that the granule formulation comprises desloratadine in the range of 0.01 to 8 by weight.

4. The granule formulation according to claims 1 to 3 characterised in that the granule formulation comprises desloratadine in the range of 0.01 to 5 by weight.

5. The granule formulation according to any one of the preceding claims characterised in that the formulation comprises at least one pharmaceutically acceptable excipient.

6. The granule formulation according to claim 5 characterised in that pharmaceutically acceptable excipients can be selected from the group comprising binders, disintegrants, viscosity increasing components, filling agents, drying agents, flavouring agents, lubricants, diluents, binders, glidants, wetting agents, anti- adhesive agents, effervescent couples, solvents, sweeteners or combinations thereof.

7. The granule formulation according to any one of the preceding claims characterised in that D (90) particle size of desloratadine is in the range of 1 and 70 μπι.

8. The granule formulation according to claim 7 characterised in that D (90) particle size of desloratadine is in the range of 1 and 60 μπι.

9. The granule formulation according to claims 8 to 9 characterised in that D (90) particle size of desloratadine is in the range of 1 and 50 μηι.

10. The granule formulation according to any one of the preceding claims characterised in that D (50) particle size of desloratadine is in the range of 1 and 40 μπι.

11. The granule formulation according to claim 10 characterised in that D (50) particle size of desloratadine is in the range of 1 and 30 μιη.

12. The granule formulation according to claims 10 to 11 characterised in that D (50) particle size of desloratadine is in the range of 1 and 25 μιη.

13. The granule formulation according to claims 10 to 15 characterised in that the ratio of D (50) / D (90) particle size of desloratadine is between 0.1 and 1.

14. The granule formulation according to claim 14 characterised in that the ratio of D (50) / D (90) particle size of desloratadine is between 0.1 and 0.9.

15. The granule formulation according to claims 13 to 14 characterised in that the ratio of D (50) / D (90) particle size of desloratadine is between 0.1 and 0.7.

16. The manufacturing method of the granules according to any one of the preceding claims in which the granules has moisture content in the range of 1 to 5 % by weight characterised in that said granules are produced by the following method: a) Obtaining active agent combination by blending an effective amount of desloratadine and at least one pharmaceutical excipient, b) Preparing granulation solution by blending deionised water and at least one pharmaceutically acceptable excipient. c) Preparing desloratadine granules by spraying the granulation solution on the active agent combination obtained in the first step. d) Drying the obtained active agent granules in a fluid bed dryer.

17. The manufacturing method according to claim 16 characterised in that drying process is implemented gradually.

18. The manufacturing method according to claims 16 to 17 characterised in that said granules are dried at 70-90°C initially, then at 40-70°C.

19. The granule formulation according to claims 1 to 15 characterised in that said formulation comprises at least one other pharmaceutically acceptable active agent.

20. The granule formulation according to claim 17 characterised in that the second active agent is selected from a group comprising nasal decongestants, leukotriene receptor antagonists, antihistaminics, antidepressants.

21. The granule formulation according to claim 18 characterised in that the second active agent is a leukotriene receptor antagonist.

22. The granule formulation according to claim 21 characterised in that leukotriene receptor antagonist can be selected from a group comprising montelukast, zafirlukast and zileuton or pharmaceutically acceptable salts, solvates, derivatives, polymorphs, hydrates or enantiomers thereof.

23. The granule formulation according to claim 22 characterised in that leukotriene receptor antagonist montekulast sodium is used.

24. The granule formulation according to claim 20 characterised in that the second active agent is a nasal decongestant.

25. The granule formulation according to claim 24 characterised in that nasal decongestant is pseudoephedrine.

26. The granule formulation according to any one of preceding claims characterised in that said granules are used for production of a drug for remotion, prevention and/or treatment of seasonal allergic rhinitis, perennial allergic rhinitis, chronic idiopathic urticaria and symptoms thereof.