WO2013062498A1 - Solid oral formulations comprising ebastine - Google Patents

Solid oral formulations comprising ebastine Download PDF

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Publication number
WO2013062498A1
WO2013062498A1 PCT/TR2012/000170 TR2012000170W WO2013062498A1 WO 2013062498 A1 WO2013062498 A1 WO 2013062498A1 TR 2012000170 W TR2012000170 W TR 2012000170W WO 2013062498 A1 WO2013062498 A1 WO 2013062498A1
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Prior art keywords
pharmaceutical formulation
formulation according
diluent
formulations
particle size
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PCT/TR2012/000170
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French (fr)
Inventor
Mahmut Bilgic
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Mahmut Bilgic
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Publication of WO2013062498A1 publication Critical patent/WO2013062498A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to oral pharmaceutical formulations comprising ebastine as the active agent; preparation methods and area of use thereof.
  • Ebastine (Formula I) which was first disclosed in the patent numbered EP-A-0134124 is a non-sedative, selective, long-acting second generation antihistaminic agent. It has been found that 10 mg ebastine given once daily is as effective as other second generation antihistamines. 20 mg ebastine is used in the treatment of patients suffering moderate and severe allergic symptoms. Ebastine is acknowledged as a safe, effective and well-tolerated second generation antihistaminic agent in the treatment of allergic rhinitis and chronic idiopathic urticaria.
  • Kestine ® is in 10 and 20 mg tablet forms.
  • the first and most important problem encountered in preparation of oral formulations comprising ebastine is that water solubility of the active agent is low due to its hydrophobic characteristic. Low water solubility naturally leads to lower bioavailability of the formulations.
  • EP-A-0575481 discloses liquid ebastine formulations. According to the patent, solubility of ebastine is provided by use of polyethylene glycol as the solubility enhancing agent in the formulations.
  • ES-A-2107375 also discloses liquid ebastine formulations and use of hydroxylated carboxylic acids, non-ionic surfactants and medium-chain polyols in these formulations.
  • EP0614362 discloses oral formulations comprising ebastine as the active agent.
  • This patent claims that the problems such as low water solubility, therefore low bioavailability of ebastine can be solved by reducing particle size of the active agent, in other words by micronizing the active agent instead of using high doses of the active agent.
  • EP-A-0614362 discloses solid oral dosage forms comprising ebastine and use of micronized ebastine having a D (90) particle size less than 25 ⁇ in these dosage forms.
  • the oral dosage forms according to the patent are in tablet form.
  • micronization technique provided in order to improve active agent solubility in the prior art requires quite complicated and expensive devices. Since high production cost reflects in price of the active agent produced, it is not preferred.
  • particle size of the active agent is so small leads to other problems except for those listed above. While the active agent particles having a particle size in the range of 50-75 ⁇ on average provide free flow, the fact that particle size less than 50 ⁇ causes agglomeration tendency in the particles in dry powder form. The particles agglomerating (aggregating) during production cause inhomogeneous distribution of the active agent in the dosage form and therefore lower or higher dose amount than the required amount is taken by the patient. Furthermore, in the case that the oral dosage form is tablet, the particles agglomerating (aggregating) this way affect physical characteristics of the tablet obtained negatively. As a result of the studies he conducted, the inventor has found that tablet dosage forms prepared by the active agent having a particle size less than 50 ⁇ unexpectedly decompose in blisters during storage and distribution. This is an undesirable situation in terms of pharmaceutical technology.
  • the present invention provides new and improved ebastine formulations that can be produced without reducing the particle size of the active agent.
  • the present invention relates to pharmaceutical oral dosage forms comprising ebastine as the active agent.
  • One characteristic feature of oral dosage forms of the present invention is to 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.
  • D (90) particle size of ebastine comprised in said dosage forms is minimum 50 ⁇ , preferably in the range of 50 to 500 ⁇ , more preferably in the range of 50 to 350 ⁇ .
  • Oral dosage forms of the present invention comprise at least one pharmaceutically acceptable diluent and optionally at least one other excipient in addition to the active agent.
  • One characteristic feature of the formulations of the present invention is to comprise at least one diluent minimum in the percentage of 10% by weight, preferably in the range of 10 to 80% by weight, more preferably in the range of 10 to 70% by weight.
  • the diluents that can be used in the formulations of the present invention can be selected from a group comprising alkali metal carbonates such as calcium carbonate; alkaline metal phosphates such as calcium phosphate; alkaline metal sulphates such as calcium sulphate; cellulose derivatives such as cellulose, microcrystalline cellulose, cellulose acetate; magnesium oxide, dextrin, fructose, dextrose, glyceryl palmitostearate, lactitol, kaolin, lactose, maltose, mannitol, simethicone, sorbitol, starch, pregelatinized starch, talc, xylitol and/or anhydrates, hydrates and/or pharmaceutically acceptable derivatives or combinations thereof.
  • alkali metal carbonates such as calcium carbonate
  • alkaline metal phosphates such as calcium phosphate
  • alkaline metal sulphates such as calcium sulphate
  • cellulose derivatives such as
  • the diluent comprised in the formulations is preferably a cellulose derivative.
  • D(90) particle size of the cellulose derivative diluent used in the formulations of the present invention is minimum 120 ⁇ , preferably minimum 130 ⁇ , more preferably in the range of 140 ⁇ ⁇ 250 ⁇ .
  • D(50) particle size of the cellulose derivative diluent used in the formulations of the present invention is minimum 40 ⁇ , preferably minimum 50 ⁇ , more preferably in the range of 60 ⁇ to 120 ⁇ .
  • the term "D (90) particle size” used throughout the text refers to particle size of 90% of the particles by volume, “D (50) particle size” refers to particle size of 50% of the particles by volume.
  • excipients that can be used in addition to the diluent in the formulations according to the present invention can be selected from a group comprising pharmaceutically acceptable lubricants, disintegrants, anti-adhesive agents, coating agents, flavouring agents, sweeteners, effervescent acids, effervescent bases, binders, colorants or combinations thereof.
  • the disintegrants that can be used in the formulations of the present invention can be selected from a group comprising cellulose derivatives such as cross-linked carboxymethyl cellulose and/or its salts, microcrystalline cellulose, cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl 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.
  • cellulose derivatives such as cross-linked carboxymethyl cellulose and/or its salts, microcrystalline cellulose, cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, methyl cellulose
  • the lubricants that can be used in the formulations according to the present invention can be selected from metallic stearates (such as magnesium stearate, calcium stearate, aluminium stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated 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.
  • metallic stearates such as magnesium stearate, calcium stearate, aluminium stearate
  • fatty acid esters such as sodium stearyl fumarate
  • fatty acids such as stearic acid
  • fatty alcohols glyceryl behenate
  • mineral oil such as paraffins, hydrogenated vegetable oils, leucine
  • the anti-adhesive agents that can be used in the formulations according to the present invention can be selected from silicon dioxide, magnesium trisilicate, cellulose powder, starch, talc, tribasic calcium phosphate, metallic stearates, calcium silicate and metallic lauryl sulphates.
  • natural aroma oils such as peppermint oil, oil of wintergreen, clove bud oil, parsley oil, eucalyptus oil,
  • the sweeteners that can be used in the formulations according to the present invention can be selected from sucralose, sucrose, fructose, glucose, galactose, xylose, dextrose, laevulose, lactose, maltose, maltodextrin, mannitol, maltitol, maltol, sorbitol, xylitol, erythritol, lactitol, isomalt, corn syrup, saccharin, saccharin 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 according to the present 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 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 binders that can be used in the formulations according to the present invention can be selected from starches such as potato starch, corn starch, wheat starch; sugars such as sucrose, glucose, dextrose, lactose, maltodextrin; natural and synthetic gums; gelatine; cellulose derivatives such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose; polyvinylpyrrolidone (povidone); polyethylene glycol (PEG); waxes; calcium carbonate; calcium phosphate; alcohols such as sorbitol, xylitol, mannitol and water or a combination thereof.
  • starches such as potato starch, corn starch, wheat starch
  • sugars such as sucrose, glucose, dextrose, lactose, maltodextrin
  • natural and synthetic gums such as cellulose derivatives such
  • One characteristic feature of the formulations according to the present invention is to comprise ebastine as the active agent and at least one pharmaceutically acceptable diluent, a lubricant and optionally an anti-adhesive agent, disintegrant, binder and/or various coating agents as excipients.
  • At least one diluent minimum in the percentage of 10% preferably in the range of 10 to 80% by weight, more preferably in the range of 10 to 70% by weight,
  • the formulations according to the present invention can be in oral dosage forms such as solid, liquid, semi solid, water soluble, effervescent; though the preferred dosage forms are solid dosage forms.
  • solid oral dosage form used herein refers to dosage forms of tablet, film coated tablet, effervescent tablet, orodispersible tablet, capsule; though the more preferred dosage form in the scope of the present invention is film coated tablet.
  • the coating agents that can be used for film coating of tablet formulations prepared according to the present invention can be selected from lactose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, tiracetin, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate phthalate, polyvinyl acetate phthalate, diethyl phthalate, sugar derivatives, polyvinyl derivatives (for instance polyvinyl alcohol), polyethylene glycol, waxes, oils and gelatines, triethyl citrate, glyceride, titanium dioxide, yellow and/or black iron oxide, talc, sodium alginate, stearic acid, lecithin or a combination thereof.
  • the formulations according to the present invention can be produced by a production method existing in the prior art, for instance by dry granulation, wet granulation, dry blending methods.
  • the preferred production method can be dry blending or wet granulation.
  • a preferred method for production of the formulations according to the present invention is as follows:
  • the granules obtained are dried and sieved, 3. At least one diluent is added into the granules dried and they are mixed,
  • the final mixture is treated with the lubricant and optionally is compressed in tablet form and coated with film.
  • Another method preferred for production of the formulations according to the present invention is as follows: 1. Ebastine, at least one pharmaceutically acceptable diluent and a disintegrant are mixed until a homogeneous mixture is obtained and the mixture is sieved,
  • the mixture is mixed again with an anti-adhesive agent and then a lubricant, 3.
  • the mixture obtained is optionally compressed in tablet form and coated with film.
  • the method to be followed for production of the formulation is basically as follows:
  • the granules dried are mixed with microcrystalline cellulose in the amount given,
  • Example II The tablets compressed are coated with film.
  • the method to be followed for production of the formulation given above is composed of the following steps: 1. Ebastine, microcrystalline cellulose, diluent and disintegrant are mixed dryly and the mixture is sieved,

Abstract

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

Description

SOLID ORAL FORMULATIONS COMPRISING EBASTINE
The present invention relates to oral pharmaceutical formulations comprising ebastine as the active agent; preparation methods and area of use thereof.
Background of the Invention Ebastine (Formula I) which was first disclosed in the patent numbered EP-A-0134124 is a non-sedative, selective, long-acting second generation antihistaminic agent. It has been found that 10 mg ebastine given once daily is as effective as other second generation antihistamines. 20 mg ebastine is used in the treatment of patients suffering moderate and severe allergic symptoms. Ebastine is acknowledged as a safe, effective and well-tolerated second generation antihistaminic agent in the treatment of allergic rhinitis and chronic idiopathic urticaria.
Figure imgf000002_0001
Formula I: Ebastine
The commercial product called Kestine ® is in 10 and 20 mg tablet forms. In the prior art, the first and most important problem encountered in preparation of oral formulations comprising ebastine is that water solubility of the active agent is low due to its hydrophobic characteristic. Low water solubility naturally leads to lower bioavailability of the formulations.
The prior art offers various solutions for this problem of the active agent. The patent application numbered EP-A-0575481 discloses liquid ebastine formulations. According to the patent, solubility of ebastine is provided by use of polyethylene glycol as the solubility enhancing agent in the formulations. The patent application numbered ES-A-2107375 also discloses liquid ebastine formulations and use of hydroxylated carboxylic acids, non-ionic surfactants and medium-chain polyols in these formulations.
The European Patent Application numbered EP0614362 discloses oral formulations comprising ebastine as the active agent. This patent claims that the problems such as low water solubility, therefore low bioavailability of ebastine can be solved by reducing particle size of the active agent, in other words by micronizing the active agent instead of using high doses of the active agent.
The European Patent Application numbered EP-A-0614362 discloses solid oral dosage forms comprising ebastine and use of micronized ebastine having a D (90) particle size less than 25 μιτι in these dosage forms. The oral dosage forms according to the patent are in tablet form.
It is known that the process of particle size reduction (micronization) increases dissolution rate of low water soluble active agents significantly.
However, reducing the particle size of the active agent in order to increase its dissolution rate and therefore bioavailability may not always give the required results in terms of pharmaceutical technology. Small particles obtained by micronizing a hydrophobic active agent like ebastine forms larger hard-absorptive aggregates (micelles) in aqueous medium (for instance in stomach) due to thermodynamic repulsion; this reduces bioavailability of the active agent. In another aspect, micronization technique provided in order to improve active agent solubility in the prior art requires quite complicated and expensive devices. Since high production cost reflects in price of the active agent produced, it is not preferred.
The fact that particle size of the active agent is so small leads to other problems except for those listed above. While the active agent particles having a particle size in the range of 50-75 μηι on average provide free flow, the fact that particle size less than 50 μιη causes agglomeration tendency in the particles in dry powder form. The particles agglomerating (aggregating) during production cause inhomogeneous distribution of the active agent in the dosage form and therefore lower or higher dose amount than the required amount is taken by the patient. Furthermore, in the case that the oral dosage form is tablet, the particles agglomerating (aggregating) this way affect physical characteristics of the tablet obtained negatively. As a result of the studies he conducted, the inventor has found that tablet dosage forms prepared by the active agent having a particle size less than 50 μηι unexpectedly decompose in blisters during storage and distribution. This is an undesirable situation in terms of pharmaceutical technology.
Therefore, it is seen that there is need for new, easily producible ebastine formulations having sufficient solubility, high bioavailability without reducing the particle size of the active agent.
In line with this requirement, the present invention provides new and improved ebastine formulations that can be produced without reducing the particle size of the active agent.
Detailed Description of the Invention
The present invention relates to pharmaceutical oral dosage forms comprising ebastine as the active agent.
One characteristic feature of oral dosage forms of the present invention is to 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 feature of oral dosage forms of the present invention is that D (90) particle size of ebastine comprised in said dosage forms is minimum 50 μηι, preferably in the range of 50 to 500 μπι, more preferably in the range of 50 to 350 μηι. Oral dosage forms of the present invention comprise at least one pharmaceutically acceptable diluent and optionally at least one other excipient in addition to the active agent.
As a result of the development studies they conducted, the inventors have achieved to produce new, highly soluble pharmaceutical oral dosage forms with improved physical characteristics which do not carry the disadvantages existing in the prior art without the necessity to reduce the particle size of the active agent of hygroscopic ebastine formulations.
This effect has been surprisingly achieved by selecting type, amount and particle size of the excipients, particularly diluent, comprised in the formulations. One characteristic feature of the formulations of the present invention is to comprise at least one diluent minimum in the percentage of 10% by weight, preferably in the range of 10 to 80% by weight, more preferably in the range of 10 to 70% by weight.
The diluents that can be used in the formulations of the present invention can be selected from a group comprising alkali metal carbonates such as calcium carbonate; alkaline metal phosphates such as calcium phosphate; alkaline metal sulphates such as calcium sulphate; cellulose derivatives such as cellulose, microcrystalline cellulose, cellulose acetate; magnesium oxide, dextrin, fructose, dextrose, glyceryl palmitostearate, lactitol, kaolin, lactose, maltose, mannitol, simethicone, sorbitol, starch, pregelatinized starch, talc, xylitol and/or anhydrates, hydrates and/or pharmaceutically acceptable derivatives or combinations thereof.
One characteristic feature of the formulations of the present invention is that the diluent comprised in the formulations is preferably a cellulose derivative.
D(90) particle size of the cellulose derivative diluent used in the formulations of the present invention is minimum 120 μιη, preferably minimum 130 μιη, more preferably in the range of 140 μιη ίο 250 μπι.
D(50) particle size of the cellulose derivative diluent used in the formulations of the present invention is minimum 40 μηι, preferably minimum 50 μιη, more preferably in the range of 60 μιη to 120 μπι. The term "D (90) particle size" used throughout the text refers to particle size of 90% of the particles by volume, "D (50) particle size" refers to particle size of 50% of the particles by volume.
Other excipients that can be used in addition to the diluent in the formulations according to the present invention can be selected from a group comprising pharmaceutically acceptable lubricants, disintegrants, anti-adhesive agents, coating agents, flavouring agents, sweeteners, effervescent acids, effervescent bases, binders, colorants or combinations thereof.
The disintegrants that can be used in the formulations of the present invention can be selected from a group comprising cellulose derivatives such as cross-linked carboxymethyl cellulose and/or its salts, microcrystalline cellulose, cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl 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 lubricants that can be used in the formulations according to the present invention can be selected from metallic stearates (such as magnesium stearate, calcium stearate, aluminium stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated 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 according to the present invention can be selected from silicon dioxide, magnesium trisilicate, cellulose powder, starch, talc, tribasic calcium phosphate, metallic stearates, calcium silicate and metallic lauryl sulphates. The flavouring agents that can be used in the formulations according to the present invention can be selected from natural aroma oils (such as peppermint oil, oil of wintergreen, clove bud oil, parsley oil, eucalyptus oil, lemon oil, orange oil), menthol, menthane, anethole, methyl salicylate, eucalyptol, cinnamon, 1- methyl acetate, sage, eugenol, oxanon, alpha-irisone, marjoram, lemon, orange, blackberry, propenyl guaetol acetyl, cinnamon, vanilla, timole, linalol, cinnamaldehyde glycerol acetal, N-substituted p-menthane-3-carboxamide, 3,1- methoxy propane 1.2-diol a combination thereof.
The sweeteners that can be used in the formulations according to the present invention can be selected from sucralose, sucrose, fructose, glucose, galactose, xylose, dextrose, laevulose, lactose, maltose, maltodextrin, mannitol, maltitol, maltol, sorbitol, xylitol, erythritol, lactitol, isomalt, corn syrup, saccharin, saccharin 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 according to the present 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 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 binders that can be used in the formulations according to the present invention can be selected from starches such as potato starch, corn starch, wheat starch; sugars such as sucrose, glucose, dextrose, lactose, maltodextrin; natural and synthetic gums; gelatine; cellulose derivatives such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose; polyvinylpyrrolidone (povidone); polyethylene glycol (PEG); waxes; calcium carbonate; calcium phosphate; alcohols such as sorbitol, xylitol, mannitol and water or a combination thereof.
One characteristic feature of the formulations according to the present invention is to comprise ebastine as the active agent and at least one pharmaceutically acceptable diluent, a lubricant and optionally an anti-adhesive agent, disintegrant, binder and/or various coating agents as excipients.
One characteristic feature of the formulations of the present invention is to comprise
> Ebastine in the range of 5 to 30% by weight, preferably in the range of 5 to 27% by weight, more preferably in the range of 5 to 25% by weight,
> At least one diluent minimum in the percentage of 10%, preferably in the range of 10 to 80% by weight, more preferably in the range of 10 to 70% by weight,
> A lubricant minimum in the percentage of 1 % by weight, preferably in the range of 1 to 5% by weight, more preferably in the range of 1 to 4% by weight and Optionally an anti-adhesive agent, disintegrant, binder and/or various coating agents.
The formulations according to the present invention can be in oral dosage forms such as solid, liquid, semi solid, water soluble, effervescent; though the preferred dosage forms are solid dosage forms. The term "solid oral dosage form" used herein refers to dosage forms of tablet, film coated tablet, effervescent tablet, orodispersible tablet, capsule; though the more preferred dosage form in the scope of the present invention is film coated tablet.
The coating agents that can be used for film coating of tablet formulations prepared according to the present invention can be selected from lactose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, tiracetin, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate phthalate, polyvinyl acetate phthalate, diethyl phthalate, sugar derivatives, polyvinyl derivatives (for instance polyvinyl alcohol), polyethylene glycol, waxes, oils and gelatines, triethyl citrate, glyceride, titanium dioxide, yellow and/or black iron oxide, talc, sodium alginate, stearic acid, lecithin or a combination thereof.
The formulations according to the present invention can be produced by a production method existing in the prior art, for instance by dry granulation, wet granulation, dry blending methods.
The preferred production method can be dry blending or wet granulation. A preferred method for production of the formulations according to the present invention is as follows:
1. Ebastine and a pharmaceutically acceptable binder are mixed and granules are obtained,
2. The granules obtained are dried and sieved, 3. At least one diluent is added into the granules dried and they are mixed,
4. The final mixture is treated with the lubricant and optionally is compressed in tablet form and coated with film.
Another method preferred for production of the formulations according to the present invention is as follows: 1. Ebastine, at least one pharmaceutically acceptable diluent and a disintegrant are mixed until a homogeneous mixture is obtained and the mixture is sieved,
2. The mixture is mixed again with an anti-adhesive agent and then a lubricant, 3. The mixture obtained is optionally compressed in tablet form and coated with film.
The formulation examples according to the present invention are below. These examples are given in order to elucidate the subject of the present invention, yet the present invention is not limited to these examples.
EXAMPLES Example I:
Figure imgf000010_0001
D(90) particle size of microcrystalline cellulose comprised in the formulation given above 160 μπι, D(50) particle size is 80 μηι.
The method to be followed for production of the formulation is basically as follows:
1. Ebastine and binder in the amounts given are mixed and granulated,
2. The granules obtained are dried and sieved,
3. The granules dried are mixed with microcrystalline cellulose in the amount given,
4. The mixture is treated with the lubricant and compressed in tablet form,
5. The tablets compressed are coated with film. Example II:
Figure imgf000011_0001
The method to be followed for production of the formulation given above is composed of the following steps: 1. Ebastine, microcrystalline cellulose, diluent and disintegrant are mixed dryly and the mixture is sieved,
2. The mixture sieved is treated initially with anti-adhesive agent, then with lubricant,
3. The final mixture is compressed in tablet form and coated with film.

Claims

1. A pharmaceutical formulation for oral administration, characterized in that said formulation comprises ebastine in the range of 1-50 mg by weight, at least one pharmaceutically acceptable diluent 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 by weight, at least one pharmaceutically acceptable diluent and at least one other excipient per unit dosage form.
3. The pharmaceutical formulation according to claims 1-2, characterized in that said formulation comprises ebastine in the range of 10-30 mg by weight per unit dosage form, at least one pharmaceutically acceptable diluent and at least one other excipient.
4. The pharmaceutical formulation according to any preceding claims, characterized in that said formulation comprises at least one pharmaceutically acceptable diluent minimum in the percentage of 10% by weight.
5. The pharmaceutical formulation according to claim 4, characterized in that said formulation comprises at least one pharmaceutically acceptable diluent in the range of 10 to 80% by weight.
6. The pharmaceutical formulation according to claim 5, characterized in that said formulation comprises at least one pharmaceutically acceptable diluent in the range of 10 to 70% by weight.
7. The pharmaceutical formulation according to any preceding claims, characterized in that the diluent comprised in the formulations is selected from a group comprising alkali metal carbonates such as calcium carbonate; alkaline metal phosphates such as calcium phosphate; alkaline metal sulphates such as calcium sulphate; cellulose derivatives such as cellulose, microcrystalline cellulose, cellulose acetate; magnesium oxide, dextrin, fructose, dextrose, glyceryl palmitostearate, lactitol, kaolin, lactose, maltose, mannitol, simethicone, sorbitol, starch, pregelatinized starch, talc, xylitol and/or anhydrates, hydrates and/or pharmaceutically acceptable derivatives or combinations thereof.
8. The pharmaceutical formulation according to any preceding claims, characterized in that the diluent comprised in the formulations is a cellulose derivative.
9. The pharmaceutical formulation according to claim 8, characterized in that D(90) particle size of the cellulose derivative diluent is minimum 100 μιη.
10. The pharmaceutical formulation according to claim 9, characterized in that D(90) particle size of the cellulose derivative diluent is minimum 120 μπι.
11. The pharmaceutical formulation according to claim 10, characterized in that D(90) particle size of the cellulose derivative diluent is minimum in the range of 140 to 250 μηι.
12. The pharmaceutical formulation according to claims 8-11, characterized in that D(50) particle size of the cellulose derivative diluent is minimum 40 μιη.
13. The pharmaceutical formulation according to claim 12, characterized in that D(50) particle size of the cellulose derivative diluent is minimum 50 μπι.
14. The pharmaceutical formulation according to claim 13, characterized in that D(50) particle size of the cellulose derivative diluent is minimum in the range of 60 to 150 μιη.
15. The pharmaceutical formulation according to claim 1, characterized in that the excipients comprised in the formulations are selected from a group comprising lubricants, disintegrants, anti-adhesive agents, coating agents, flavouring agents, sweeteners, effervescent acids, effervescent bases, binders, colorants or combinations thereof.
16. The pharmaceutical formulation according to claim 1, characterized in that said formulations are prepared in solid oral dosage form.
17. The pharmaceutical formulation according to claim 16, characterized in that solid oral dosage forms are selected from a group comprising dosage forms of tablet, film coated tablet, effervescent tablet, orodispersible tablet or capsule.
18. The pharmaceutical formulation according to claim 17, characterized in that solid oral dosage form is film coated tablet.
19. The pharmaceutical formulation according to any preceding claims, characterized in that said formulations are produced by dry blending, wet granulation and/or dry blending methods.
20. The production method according to claim 19, characterized in that said method is dry blending or wet granulation.
PCT/TR2012/000170 2011-10-13 2012-10-12 Solid oral formulations comprising ebastine WO2013062498A1 (en)

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TR2011/10157 2011-10-13
TR201110157 2011-10-13

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0134124A1 (en) * 1983-08-05 1985-03-13 Fordonal, S.A. Piperidine derivatives
EP0614362A1 (en) * 1991-12-03 1994-09-14 Rhone Poulenc Rorer Sa Pharmaceutical compositions based on ebastime or analogues thereof.
DE102008000351A1 (en) * 2008-02-20 2009-08-27 Lindopharm Gmbh Preparing ebastine containing granules, useful to treat e.g. allergic rhinitis, comprises preparing granules from a solution of ebastine in cyclic ether solvent and a powder of one or more existing solid carrier materials, and drying
EP2210596A1 (en) * 2009-01-22 2010-07-28 Laboratorios Liconsa, S.A. Pharmaceutical composition of ibandronate sodium salt or a hydrate thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0134124A1 (en) * 1983-08-05 1985-03-13 Fordonal, S.A. Piperidine derivatives
EP0614362A1 (en) * 1991-12-03 1994-09-14 Rhone Poulenc Rorer Sa Pharmaceutical compositions based on ebastime or analogues thereof.
DE102008000351A1 (en) * 2008-02-20 2009-08-27 Lindopharm Gmbh Preparing ebastine containing granules, useful to treat e.g. allergic rhinitis, comprises preparing granules from a solution of ebastine in cyclic ether solvent and a powder of one or more existing solid carrier materials, and drying
EP2210596A1 (en) * 2009-01-22 2010-07-28 Laboratorios Liconsa, S.A. Pharmaceutical composition of ibandronate sodium salt or a hydrate thereof

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