WO2013081562A1

WO2013081562A1 - Oral formulations comprising ebastine

Info

Publication number: WO2013081562A1
Application number: PCT/TR2012/000171
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Mahmut Bilgic
Priority date: 2011-10-13
Filing date: 2012-10-12
Publication date: 2013-06-06

Abstract

The present invention relates to oral pharmaceutical formulations comprising ebastine as active agent; and preparation methods and fields of use thereof.

Description

ORAL FORMULATIONS COMPRISING EBASTINE

The present invention relates to oral pharmaceutical formulations comprising ebastine; and preparation methods and fields of use thereof.

Background of the Invention Ebastine (Formula I) is a non-sedative, selective, long-acting, second generation antihistaminic agent, which was first disclosed in the patent numbered EP-A-0134124. Ebastine which is given in 10 mg doses daily has been found to be as effective as the other second generation antihistamines. It is used in 20 mg doses in the treatment of patients with mild and severe symptoms. Ebastine is acknowledged to be a safe, effective and well-tolerable second generation antihistaminic agent used in the treatment of allergic rhinitis and chronic idiopathic urticaria.

Formula I: Ebastine

The commercial product named Kestine ® is in 10 and 20 mg doses and in tablet form. In the prior art, the first and most important problem faced in the production of oral formulations comprising ebastine is the low water-solubility of the active agent due to its hydrophobic characteristic. This low water-solubility naturally causes low levels of bioavailability in the formulations.

The prior art suggests various solutions for this problem of the active agent. The patent application numbered EP-A-0575481 discloses liquid ebastine formulations. According to said patent, the solubility of ebastine is provided by use of polyethylene glycol as solubility improving agent in the formulations. The patent application numbered ES-A-2107375 also discloses liquid ebastine formulations and the use of hydroxilated carboxylic acids, non-ionic surfactants and medium-chain-length polyols in these formulations.

The European patent application numbered EP0614362 discloses oral formulations comprising ebastine. Said patent claims to suggest solutions for the problems of ebastine like low water-solubility and consequently low bioavailability by reducing the particle size of the active agent, in other words micronizing the active agent, instead of using it in high doses.

The European Patent Application numbered EP-A-0614362 discloses solid oral dosage forms comprising ebastine and the use of micronized ebastine having a D (90) particle size smaller than 25 μηι. The oral dosage forms of this patent are in tablet form.

It is known that the process of reducing the particle size (micronization) increases the water- solubility rate of low water-soluble active agents.

However, reducing the particle size of an active agent to increase solubility rate and consequently bioavailability may not always give the desired results in terms of pharmaceutical technology. Particularly the small particles obtained through micronizing a hydrophobic active agent like ebastine turn into bigger masses with difficult absorption properties in aqueous media (e.g. in stomach) due to thermodynamic impulse; this case reduces the bioavailability of the active agent.

In another aspect, the micronization technique used to improve the solubility of active agents in the prior art requires highly complicated and expensive devices. Since such high costs of production are reflected on the prices of the produced active agents, said technique is not preferred.

Very small particle size of the active agent also causes other problems apart from those mentioned above. While the active agent particles with a particle size in the range of 50-75 μπι in average provide free flow during the production process, particles with a particle size smaller than 50 μπι causes the particles to tend to agglomerate in dry form. The particles agglomerating (aggregating) during the production process reduces the homogeneous distribution of the active agent in the dosage form, thus decreasing the dose amount taken by the patient. At the same time, the particles agglomerating (aggregating this way) also negatively affects the physical properties of the obtained tablet, in the case that the oral dosage form is tablet. As a result of the studies conducted within the scope of the invention, the inventor has found that the tablet dosage forms prepared with an active agent having a particle size smaller than 50 μηι surprisingly disintegrate in the blister during storage and delivery. This is an undesirable case in terms of pharmaceutical technology.

Consequently, it is seen that there is a need for easily producible, new ebastine formulations with adequate solubility and high bioavailability properties, without decreasing the particle size. In accordance with this need, the present invention provides new and improved ebastine formulations that can be produced without decreasing the particle size of the active agent.

Detailed Description of the Invention

The present invention relates to pharmaceutical formulations comprising ebastine as active agent. A characteristic of the formulations of the invention is that said formulations comprise ebastine in the range of 1 to 50 mg, preferably in the range of 1 to 40 mg, more preferably in the range of 10 to 30 mg per unit dosage form.

Another characteristic of the formulations of the invention is that the particle size of ebastine comprised in them is at least 50 μηι, preferably in the range of 50 to 500 μιτι, more preferably in the range of 50 to 350 μη .

The formulations of the invention comprise at least one pharmaceutically acceptable diluent and optionally another excipient in addition to the active agent.

As a result of the development studies conducted, the inventors have achieved to produce highly soluble and physically improved new pharmaceutical formulations that do not have the disadvantages in the prior art, eliminating the need for decreasing the particle size of the ebastine formulations known for their hygroscopic properties.

Surprisingly, this effect was achieved through the choice of the types, amounts and the particle sizes of the excipients, particularly the diluent, comprised in the formulations. A characteristic of the formulations of the invention is that said formulations comprise at least one diluent at least at 10%, preferably in the range of 10 to 80%, more preferably at the range of 10 to 70% by weight.

The diluents that can be used in the formulations of the invention can be selected from a group comprising alkali metal carbonates such as calcium carbonate; alkali metal phosphates such as calcium phosphate; alkali metal sulphates such as calcium sulphate; cellulose derivatives such as cellulose, microcrystalline cellulose, cellulose acetate; magnesium oxide, dextrin, fructose, dextrose, glyceryl palmitostearate, lactitol, kaolinite, lactose, maltose, mannitol, simethicone, sorbitol, starch, pregelatinized starch, talc, xylitol and/or anhydrates, hydrates and/or pharmaceutically acceptable derivatives or combinations thereof.

A characteristic of the formulations of the invention is that the diluent comprised in said formulations is a cellulose derivative.

D(90) particle size of the cellulose derivative diluent used in the formulations of the invention is at least 120 μηι, preferably at least 130 μηι, more preferably in the range of 140 μπι to 250 μηι.

D(50) particle size of the cellulose derivative diluent used in the formulations of the invention is at least 40 μπι, preferably at least 50 μιη, more preferably in the range of 60 μπι to 120 μηι.

The formulations of the invention can optionally comprise another diluent selected from the given group, in addition to the cellulose derivative diluent. In this case, the ratio of the cellulose derivative diluent comprised in the formulations to the second diluent selected is in the range of 1 to 5, preferably in the range of 1 to 4, more preferably in the range of 1 to 3 by weight.

In the case that the formulations of the invention comprise a second diluent in addition to the cellulose derivative diluent, the particle size of the second diluent should also be selected from a specific interval so as to obtain the desired properties in the formulations.

According to this, the D(90) particle size of the second diluent should be smaller than 200 μηι, preferably smaller than 160 μιη, more preferably smaller than 150 μιη; and D(50) particle size of the second diluent should be smaller than 80 μιη, preferably smaller than 75 μηι, more preferably smaller than 70 μπι. The second diluent that can be used in addition to the cellulose derivative diluent in the formulations of the invention is preferably pregelatinized starch.

The other excipients that can be used in addition to the diluent in the formulations of the invention can be selected from a group comprising pharmaceutically acceptable lubricants, disintegrants, anti-adhesive agents, coating agents, flavoring agents, sweeteners, effervescent acids, effervescent bases, binders, coloring agents or combinations thereof.

The disintegrants that can be used in the formulations of the invention can be selected from a group comprising cellulose derivatives such as cross-linked carboxy methyl cellulose and/or its salts, microcrystalline cellulose, cellulose, hydroxypropyl cellulose, hydroxy ethyl cellulose, hydroxy propyl methyl cellulose, hydroxy propyl ethyl cellulose, methyl cellulose; sodium starch glycolate, alginic acid, sodium alginate, chitosan, colloidal silicone dioxide, starch, pregelatinized starch, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone or combinations thereof.

The lubricant that can be used in the formulations of the invention can be selected from a group comprising metallic stearates (such as magnesium stearate, calcium stearate, aluminium stearate), oil acid esters (such as sodium stearyl fumarate), oil acids (such as stearic acid), oil alcohols, glyceryl behenate, mineral oil, paraffins, hydrogen vegetable oils, leucine, polyethylene glycols (PEG), metallic lauryl sulphates (such as sodium lauryl sulphate, magnesium lauryl sulphate), sodium chloride, sodium benzoate, sodium acetate and talc. The anti-adhesive agents that can be used in the formulations of the invention can be selected from a group comprising silicone dioxide, magnesium trisilicate, cellulose powder, starch, talc, tribasic calcium phosphate, metallic stearates, calcium silicate and metallic lauryl sulphates.

The flavoring agents that can be used in the formulations of the invention can be selected from a group comprising natural flavoring oils (such as 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 guaethol acetyl, cinnamon, vanilla, thymol, linalool, cinnamaldehyde glycerol acetal, N-substituted pmentane-3carboxamide, 3,1- methoxy propane 1,2-diol or combinations thereof. The sweeteners that can be used in the formulations of the invention can be selected from a group comprising sucralose, sucrose, fructose, glucose, galactose, xylose, dextrose, laevulose, lactose, maltose, maltodextrin, mannitol, maltitol, maltol, sorbitol, xylitol, erythritol, lactitol, isomalt, corn syrup, saccharine, saccharine salts, acesulfame potassium, aspartame, D- tryptophane, monoammonium glycyrrhizinate, neohesperidine dihydrochalcone, thaumatin, neotame, alitame, stevioside and cyclamates or a combination thereof.

The effervescent acids that can be used in the formulations of the invention can be selected from a group comprising acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, propionic acid, tartaric acid or combinations thereof. The effervescent bases that can be used in the formulations of the invention can be selected from a group comprising potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium hydrogen sulfate or combinations thereof.

The binders that can be used in the formulations of the invention can be selected from a group comprising starches such as potato starch, corn starch, wheat starch; sugars such as sucrose, glycose, dextrose, lactose, maltodextrin; natural and synthetic gums; gelatin; cellulose derivatives such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethylcellulose, methylcellulose, ethylcellulose; polyvinylpyrrolidone (povidone); polyethylene glycol (PEG); waxes; calcium carbonate; calcium phosphate; alcohols such as sorbitol, xylitol, mannitol; and water; or combinations thereof.

A characteristic of the formulations of the invention is that said formulations comprise ebastine as active agent and at least one pharmaceutically acceptable diluent, one lubricant and optionally an anti-adhesive agent, disintegrant, binder and/or various coating agents as excipients.

A characteristic of the formulations of the invention is that said formulations comprise Ebastine in the range of 5 to 30%, preferably in the range of 5 to 27%, more preferably in the range of 5 to 25% by weight, > At least one diluent at least at 10%, preferably in the range of 10 to 80%, more preferably in the range of 10 to 70% by weight, A lubricant at least at 1%, preferably in the range of 1 to 5%, more preferably in the range of 1 to 4% by weight and > Optionally an anti-adhesive agent, disintegrant, binder and/or various coating agents.

While the formulations of the invention can be in oral dosage forms such as solid, liquid, semi-solid, water-soluble, effervescent forms; the preferred dosage forms are solid dosage forms.

The phrase "solid oral dosage form" refers to tablet, film-coated tablet, effervescent tablet, orodispersible tablet, capsule dosage forms; the particularly preferred dosage form within the scope of the invention is film-coated tablet.

The coating-agents that can be used for film-coating the tablet formulations of the invention can be selected from a group comprising lactose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, triacetin, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate phthalate, polyvinyl acetate phthalate, diethyl phthalate, sugar derivatives, polyvinyl derivatives (e.g. polyvinyl alcohol), polyethylene glycol, waxes, oils and gelatins, triethyl citrate, glyceride, titanium dioxide, yellow and/or black iron oxide, talc, sodium alginate, stearic acid, lecithin or combinations thereof.

The preferred coating agent is selected from a group comprising polyvinyl alcohol, polyethylene glycol, titanium dioxide, lecithin, hydroxypropyl methyl cellulose or combinations thereof.

The formulations of the invention can be produced by any one of the production methods of the prior art, e.g. dry granulation, wet granulation, dry mixing methods.

The preferred production method can be dry mixing or wet granulation methods. A preferred method for the production of the formulations of the invention is as follows:

1. Ebastine and a pharmaceutically acceptable binder are mixed and the granules are obtained, 2. The obtained granules are dried and sieved,

3. At least one diluent is added into the dried granules and mixed,

4. The final mixture is treated with lubricant and optionally compressed into tablets and film-coated.

Another method preferred for the production of the formulations of the invention is as follows:

1. Ebastine, at least one pharmaceutically acceptable diluent and a disintegrant are mixed until obtaining a homogeneous mixture and the obtained mixture is sieved,

2. The mixture is mixed again with an anti-adhesive agent at first and then with a lubricant,

3. The obtained mixture is optionally compressed into tablets and film-coated.

The examples for the formulations of the invention are presented below. These examples are given to explain the scope of the invention; the invention is not limited to these examples.

EXAMPLES Example I:

The production method for film-coated tablet formulation to be produced in accordance with the formulation given above is as follows:

1. Given amounts of ebastine and binder are mixed and granulated,

2. The obtained granules are mixed and sieved,

3. The dried granules are mixed with the given amount of microcrystalline cellulose,

4. The mixture is treated with the lubricant and compressed into tablets,

5. The compressed tablets are film-coated. Example II:

The particle sizes (μηι) of microcrystalline cellulose and pregelatinized starch in the given formulation are as follows:

The method for the production of the formulations comprises the following steps:

1. Ebastine, microcrystalline cellulose, pregelatinized starch and the disintegrant are dry- mixed and the mixture is sieved, he sieved mixture was treated with the anti-adhesive agent at first, and then with the lubricant,

The final mixture is compressed into tablets and film-coated.

Claims

1. A pharmaceutical formulation for oral administration, characterized in that said formulation comprises ebastine in the range of 1-50 mg, a cellulose derivative diluent having a D(90) particle size of at least 120 μιη and at least one other excipient per unit dosage form.

2. The pharmaceutical formulation according to claim 1, characterized in that said formulation comprises ebastine in the range of 1-40 mg, a cellulose derivative diluent having a D(90) particle size of at least 120 μιη and at least one other excipient per unit dosage form.

3. The pharmaceutical formulation according to claims 1 and 2, characterized in that said formulation comprises ebastine in the range of 10-30 mg, a cellulose derivative diluent having a D(90) particle size of at least 120 μπι and at least one other excipient per unit dosage form.

4. The pharmaceutical formulation according to claims 1 to 3, characterized in that the D(90) particle size of the cellulose derivative diluent is at least 130 μπι.

5. The pharmaceutical formulation according to claim 4, characterized in that the D(90) particle size of the cellulose derivative diluent is in the range of 140 to 250 μηι.

6. The pharmaceutical formulation according to claims 1 to 3, characterized in that the D(50) particle size of the cellulose derivative diluent is at least 40 μιη.

7. The pharmaceutical formulation according to claim 6, characterized in that the D(50) particle size of the cellulose derivative diluent is at least 50 μπι.

8. The pharmaceutical formulation according to claim 7, characterized in that the D(50) particle size of the cellulose derivative diluent is at least in the range of 60 to 120 μπι.

9. The pharmaceutical formulation according to any one of the preceding claims, characterized in that the ratio of the cellulose derivative diluent comprised in said formulation to the second diluent selected is in the range of 1 to 5 by weight.

10. The pharmaceutical formulation according to claim 9, characterized in that the ratio of the cellulose derivative diluent comprised in said formulation to the second diluent selected is in the range of 1 to 4 by weight.

11. The pharmaceutical formulation according to claim 10, characterized in that the ratio of the cellulose derivative diluent comprised in said formulation to the second diluent selected is in the range of 1 to 3 by weight.

12. The pharmaceutical formulation according to claim 11, characterized in that the D(90) particle size of the second diluent comprised in said formulation is smaller than 200 μηι.

13. The pharmaceutical formulation according to claim 12, characterized in that the D(90) particle size of the second diluent comprised in said formulation is smaller than 160 μηι.

14. The pharmaceutical formulation according to claims 13, characterized in that the D(90) particle size of the second diluent comprised in said formulation is smaller than 150 μηι.

15. The pharmaceutical formulation according to claim 11, characterized in that the D(50) particle size of the second diluent comprised in said formulation is smaller than 80 μιη.

16. The pharmaceutical formulation according to claim 15, characterized in that the D(50) particle size of the second diluent comprised in said formulation is smaller than 75 μιτι.

17. The pharmaceutical formulation according to claim 16, characterized in that the D(50) particle size of the second diluent comprised in said formulation is smaller than 70 μηι.

18. The pharmaceutical formulation according to any one of the preceding claims, characterized in that the diluent comprised in said formulation is selected from a group comprising alkali metal carbonates such as calcium carbonate; alkali metal phosphates such as calcium phosphate; alkali metal sulphates such as calcium sulphate; cellulose derivatives such as cellulose, microcrystalline cellulose, cellulose acetate; magnesium oxide, dextrin, fructose, dextrose, glyceryl palmitostearate, lactitol, kaolinite, lactose, maltose, mannitol, simethicone, sorbitol, starch, pregelatinized starch, talc, xylitol and/or anhydrates, hydrates and/or pharmaceutically acceptable derivatives or combinations thereof.

19. The pharmaceutical formulation according to claim 18, characterized in that the second diluent is pregelatinized starch.

20. The pharmaceutical formulation according to claim 1, characterized in that the excipients comprised in said formulation are selected from a group comprising lubricants, disintegrants, anti-adhesive agents, coating agents, flavoring agents, sweeteners, effervescent acids, effervescent bases, binders, coloring agents or combinations thereof.

21. The pharmaceutical formulation according to any one of the preceding claims, characterized in that said formulation is prepared as solid oral dosage form.

22. The pharmaceutical formulation according to claim 21, characterized in that the solid oral dosage forms are selected from a group comprising tablet, film-coated tablet, effervescent tablet, orodispersible tablet or capsule dosage forms.

23. The pharmaceutical formulation according to claim 22, characterized in that the solid oral dosage form is film-coated tablet.

24. The pharmaceutical formulation according to any one of the preceding claims, characterized in that said formulation is produced through dry granulation, wet granulation and/or dry mixing methods.

25. The production method according to claim 24, characterized in that said method is dry mixing method or wet granulation method.