WO2011139250A2 - Water dispersible formulation - Google Patents

Water dispersible formulation Download PDF

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Publication number
WO2011139250A2
WO2011139250A2 PCT/TR2011/000123 TR2011000123W WO2011139250A2 WO 2011139250 A2 WO2011139250 A2 WO 2011139250A2 TR 2011000123 W TR2011000123 W TR 2011000123W WO 2011139250 A2 WO2011139250 A2 WO 2011139250A2
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Prior art keywords
pharmaceutical composition
composition according
range
weight
betahistine
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PCT/TR2011/000123
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French (fr)
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WO2011139250A3 (en
Inventor
Mahmut Bilgic
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Mahmut Bilgic
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Publication of WO2011139250A3 publication Critical patent/WO2011139250A3/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
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Definitions

  • the present invention relates to new water dispersible pharmaceutical formulations comprising betahistine as the active agent.
  • the present invention relates to the water dispersible pharmaceutical formulation of betahistine that is effective in the treatment of Meniere's syndrome which has the symptoms of tinnitus, dizziness, deafness and which emerges with nausea, earache and headache.
  • Betahistine which has the chemical name 2-[2-(methylamino)ethyl]pyridin, is an active agent belonging to the group of central nervous system.
  • betahistine The molecule betahistine has been known since 1900s and various studies exist regarding said compound in the prior art. In Loffler, Ber. 37,161 (1904) and Walter et al. , J Am. Chem. Soc. 63, 2771 (1941), the molecule betahistine was described.
  • Betahistine is marketed as dihydrochloride salt under the name BETASERC.
  • BETASERC which is prepared in 8, 16 and 24 mg tablet forms, is used for the indications associated with Meniere's disease such as dizziness, tinnitus, hearing loss.
  • Meniere's disease gives loss of balance and hearing difficulty to the person as a result of excessive increase or decrease in endolymph.
  • the symptoms of the disease are tinnitus, diminishing hearing in low frequencies or hearing loss, occasional nausea and severe dizziness which may result in vomiting.
  • Meniere's disease can be seen at any age. The symptoms of Meniere's disease can be observed as attacks and this affects one's life rather negatively and complicates the daily life.
  • the medicament formulations comprising the molecule betahistine are formulated as tablets in the prior art. However, it appears as a disadvantage to use tablet dosage forms in children, elderly patients and people having swallowing difficulties.
  • the pharmaceutical formulation comprising betahistine methane sulfonate so as to be used in Meniere's disease was disclosed.
  • the invention relates to the preparation of said pharmaceutical formulation in capsule form.
  • the medicaments in capsule and tablet forms are not convenient for all patients.
  • the use of solid dosage forms such as tablets and capsules constitutes a problem in pediatric and geriatric patients and individuals with swallowing difficulties.
  • Formulating the pharmaceutical composition in suspension form may serve as an alternative to eliminate these problems.
  • the suspension forms may not be preferred as they have the potential of uncontrolled dose intake; they have high manufacture costs; they have physical and chemical stability problems; they cause problems in use and carrying. It is seen that the suspension forms are inconvenient in terms of stability and shelf life compared to solid dosage forms although they have higher bioavailability values than solid dosage forms. Water dispersible powder, tablet and granule formulations holds the advantages of both tablet and suspension forms, and eliminate the problems observed in these dosage forms.
  • the formulation pertaining to the present invention that is in the form of water dispersible powder, tablet and granule contain one dose of active agent.
  • the formulation pertaining to the present invention differs from suspension forms and eliminates the risk of decreased stabilization resulting from contact with water for a long time and taking excess or deficient dose.
  • betahistine is very hygroscopic. Stabilization problem is encountered in the dosage form comprising betahistine due to its hygroscopic character. However, a solution has not been suggested in the prior art to overcome stabilization problem of betahistine formulation.
  • the present invention is related to stable, water dispersible formulations comprising betahistine and their dosage forms in the form of powder, tablet and granule.
  • the inventors have surprisingly found that water dispersible powder, tablet and granule formulations comprising betahistine and a filler with low hygroscopicity do not show stabilization problem and said formulations can stand stable for 24 months.
  • the characteristic of the formulation pertaining to the present invention is that it comprises filler with low hygroscopicity in addition to betahistine and it is formulated in the form of water dispersible powder, tablet and granule.
  • Betahistine in the formulation pertaining to the present invention can be in free form or in the form of its pharmaceutically acceptable salt, enantiomer, racemate, solvate, hydrate, different polymorphic form and amorphous form.
  • the pharmaceutically acceptable salts of betahistine can be betahistine hydrochloride, betahistine dihydrochloride, betahistine fumarate, betahistine maleate, betahistine tartrate, betahistine citrate, betahistine succinate, betahistine phthalate and mesylate.
  • betahistine hydrochloride more preferably betahistine dihydrochloride is used.
  • the formulation pertaining to the present invention comprises the active agent in the range of
  • non-hygroscopic no increase in water content at ⁇ 90% RH, and increase after storage for one week above 90% RH is less than 20%.
  • moderately hygroscopic moisture increase ⁇ 5% after storage at below 60% RH, and after storage for one week at > 80% RH is less than 50% moisture.
  • the filler with low hygroscopicity that is used in the formulation pertaining to the present invention is in the class of 3, 2 or 1, preferably in class 2 or 1, more preferably in class 2 in terms of its hygroscopicity.
  • the filler with low hygroscopicity is selected from a group of excipients wherein the hygroscopicity of the said excipient it in the class of 3, 2 or 1, preferably in class 2 or 1, more preferably in class 2.
  • the pharmaceutically acceptable filler with low hygroscopicity pertaining to the present invention can be selected from a group comprising glucose, lactose, maltose, sucrose, sorbitol, mannitol, dextrin, maltodextrin or combination thereof.
  • maltodextrin is used as the filler with low hygroscopicity in the formulation pertaining to the present invention
  • the formulation pertaining to the present invention comprises the filler with low hygroscopicity in and amount in the range of 5-20%, preferably in the range of 7-15% by weight.
  • the ratio of active agent to filler with low hygroscopicity is in the range of 1:1 to 1 :10, preferably in the range of 1:3 to 1 :10, more preferably in the range of 1:5 to 1 :10 in the formulation pertaining to the present invention.
  • the pharmaceutical composition comprising betahistine can optionally comprise an effervescent couple, sweetener, binder, flavoring agent, lubricant, glidant, disintegrant, and other pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable effervescent couple pertaining to the present invention is comprised of a combination of the acidic agent and the basic agent.
  • the acidic agent can comprise organic and/or inorganic acids while the basic agent can be alkali carbonate or alkali bicarbonate.
  • the pharmaceutically acceptable acidic agent pertaining 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 pharmaceutically acceptable basic agent pertaining to the present invention can be selected from a group comprising potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate or combinations thereof.
  • the acidic agent composing the effervescent couple is preferably citric acid, more preferably citric acid anhydrous; while the basic agent is preferably sodium hydrogen carbonate.
  • the pharmaceutically acceptable sweetener pertaining to the present invention can be selected from a group comprising aspartame, acesulfame, acesulfame potassium, fructose, dextrose, glucose, lactitol, maltitol, xylitol, sorbitol, maltose, saccharine, saccharine sodium, sodium cyclamate, sucralose, sucrose or combinations thereof.
  • the pharmaceutically acceptable binder pertaining to the present invention can be selected from a group comprising starches such as potato starch, corn starch, wheat starch; sugars such as sucrose, glucose, dextrose, lactose, maltodextrin; natural and synthetic gums; gelatin; cellulose derivatives such as microcrystalline cellulose, HPC, HEC, HPMC, 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 as microcrystalline cellulose, HPC, HEC, HPMC, carboxymethyl
  • the pharmaceutically acceptable lubricant pertaining to the present invention can be selected from a group comprising sodium lauryl sulfate, calcium stearate, magnesium stearate, polyethylene glycol, polyvinyl alcohol, potassium benzoate, sodium benzoate, sodium chloride, carbowax 4000, talc or a combination thereof.
  • the pharmaceutically acceptable glidant pertaining to the present invention can be selected from a group comprising talc, magnesium stearate, stearic acid, sodium stearyl fumarate, polyoxyethylene glycol, leucine, alanine, glycine, sodium benzoate, sodium acetate, fumaric acid or a combination thereof.
  • the pharmaceutically acceptable disintegrant pertaining to the present invention can be selected from a group comprising starches such as potato starch, corn starch, wheat starch, pregelatinized starch, sodium starch glycolate; cellulose derivatives such as croscarmellose sodium or microcrystalline cellulose; polyvinylpyrrolidone; crospovidone; alginic acid and its salts; clays such as xanthan gum or Veegum; ion exchange resins or a combination thereof.
  • Wet or dry granulation method can be applied in order to prepare the formulation pertaining to the present invention.
  • the formulation pertaining to the present invention can be prepared by the wet granulation method having the following steps. 1. Mixing effective amount betahistine, filler with low hygroscopicity and optionally at least one excipient;
  • the pharmaceutical composition pertaining to the present invention comprises;
  • the active agent in the range of 0.1-50%, preferably in the range of 0.5-20%, more preferably in the range of 0.75-5% by weight,
  • the binder in the range of 1 -20% by weight
  • water dispersible powder, tablet and granule refers to effervescent tablets, effervescent granules, effervescent powders, water dispersible tablets, water dispersible powders and water dispersible granules.
  • the composition pertaining to the present invention can be used in attenuating the symptoms of Meniere's disease, decelerating the progress of Meniere's disease or in the treatment of the disease.
  • the composition pertaining to the present invention can be used in the treatment of Meniere's disease which has symptoms such as tinnitus, dizziness and deafness and which generally appears with symptoms such as nausea, earache and headache.
  • compositions pertaining to the present invention can be prepared as a medicament composition that is effective in the treatment of Meniere's disease which has symptoms such as tinnitus, dizziness and deafness and which generally appears with symptoms such as nausea, earache and headache.
  • EXAMPLE 1 Formulation preparation method for effervescent betahistine compositions
  • Betahistine, citric acid, sodium bicarbonate and filler with low hygroscopicity is mixed and granulated.
  • the granules are dried and then mixed with other excipients.
  • the final mixture is then compressed in the form of tablets.
  • Betahistine and filler with low hygroscopicity is mixed and granulated with a granulation solution comprising binder.
  • the granules are dried and then mixed with other excipients.
  • the final mixture is then filled into sachets.

Abstract

The present invention relates to new water dispersible pharmaceutical formulations comprising betahistine as the active agent.

Description

WATER DISPERSIBLE FORMULATION
The present invention relates to new water dispersible pharmaceutical formulations comprising betahistine as the active agent.
The present invention relates to the water dispersible pharmaceutical formulation of betahistine that is effective in the treatment of Meniere's syndrome which has the symptoms of tinnitus, dizziness, deafness and which emerges with nausea, earache and headache.
Betahistine (Formula 1), which has the chemical name 2-[2-(methylamino)ethyl]pyridin, is an active agent belonging to the group of central nervous system.
Figure imgf000002_0001
betahistine The molecule betahistine has been known since 1900s and various studies exist regarding said compound in the prior art. In Loffler, Ber. 37,161 (1904) and Walter et al. , J Am. Chem. Soc. 63, 2771 (1941), the molecule betahistine was described.
Betahistine is marketed as dihydrochloride salt under the name BETASERC. BETASERC, which is prepared in 8, 16 and 24 mg tablet forms, is used for the indications associated with Meniere's disease such as dizziness, tinnitus, hearing loss.
Meniere's disease gives loss of balance and hearing difficulty to the person as a result of excessive increase or decrease in endolymph. The symptoms of the disease are tinnitus, diminishing hearing in low frequencies or hearing loss, occasional nausea and severe dizziness which may result in vomiting. Meniere's disease can be seen at any age. The symptoms of Meniere's disease can be observed as attacks and this affects one's life rather negatively and complicates the daily life.
The medicament formulations comprising the molecule betahistine are formulated as tablets in the prior art. However, it appears as a disadvantage to use tablet dosage forms in children, elderly patients and people having swallowing difficulties. In the patent numbered US 4,229,428, the pharmaceutical formulation comprising betahistine methane sulfonate so as to be used in Meniere's disease was disclosed. The invention relates to the preparation of said pharmaceutical formulation in capsule form. However, the medicaments in capsule and tablet forms are not convenient for all patients. The use of solid dosage forms such as tablets and capsules constitutes a problem in pediatric and geriatric patients and individuals with swallowing difficulties.
Formulating the pharmaceutical composition in suspension form may serve as an alternative to eliminate these problems. Yet, the suspension forms may not be preferred as they have the potential of uncontrolled dose intake; they have high manufacture costs; they have physical and chemical stability problems; they cause problems in use and carrying. It is seen that the suspension forms are inconvenient in terms of stability and shelf life compared to solid dosage forms although they have higher bioavailability values than solid dosage forms. Water dispersible powder, tablet and granule formulations holds the advantages of both tablet and suspension forms, and eliminate the problems observed in these dosage forms.
The formulation pertaining to the present invention that is in the form of water dispersible powder, tablet and granule contain one dose of active agent. With this feature, the formulation pertaining to the present invention differs from suspension forms and eliminates the risk of decreased stabilization resulting from contact with water for a long time and taking excess or deficient dose.
It is indicated in the documents of The Japanese Pharmacopoeia, Fourteenth Edition, Part F and "Public Assessment Report of the Medicines Evaluation Board in the Netherlands ( Directive 2001/83/EC, Article 10(1))" and also in the label of SERC® that betahistine is very hygroscopic. Stabilization problem is encountered in the dosage form comprising betahistine due to its hygroscopic character. However, a solution has not been suggested in the prior art to overcome stabilization problem of betahistine formulation.
The present invention is related to stable, water dispersible formulations comprising betahistine and their dosage forms in the form of powder, tablet and granule. The inventors have surprisingly found that water dispersible powder, tablet and granule formulations comprising betahistine and a filler with low hygroscopicity do not show stabilization problem and said formulations can stand stable for 24 months.
The characteristic of the formulation pertaining to the present invention is that it comprises filler with low hygroscopicity in addition to betahistine and it is formulated in the form of water dispersible powder, tablet and granule. Betahistine in the formulation pertaining to the present invention can be in free form or in the form of its pharmaceutically acceptable salt, enantiomer, racemate, solvate, hydrate, different polymorphic form and amorphous form.
According to another aspect, the pharmaceutically acceptable salts of betahistine can be betahistine hydrochloride, betahistine dihydrochloride, betahistine fumarate, betahistine maleate, betahistine tartrate, betahistine citrate, betahistine succinate, betahistine phthalate and mesylate. Preferably betahistine hydrochloride, more preferably betahistine dihydrochloride is used.
The formulation pertaining to the present invention comprises the active agent in the range of
0.1.50%, preferably in the range of 0.5-20%, more preferably in the range of 0.75-5% by weight. Pharmaceutical excipients can be classified with respect to their hygroscopicity. Callahan et al. (1982) have classified the degree of hygroscopicity into four classes:
1. non-hygroscopic: no increase in water content at < 90% RH, and increase after storage for one week above 90% RH is less than 20%.
2. slightly hygroscopic: no moisture increase at < 80% RH and increase after one week storage is less than 40% at > 80% RH.
3. moderately hygroscopic: moisture increase < 5% after storage at below 60% RH, and after storage for one week at > 80% RH is less than 50% moisture.
4. very hygroscopic: moisture content increase may occur at 40-50% RH and increase may exceed 30% after storage for one week > 90% RH. The filler with low hygroscopicity that is used in the formulation pertaining to the present invention is in the class of 3, 2 or 1, preferably in class 2 or 1, more preferably in class 2 in terms of its hygroscopicity.
In other words the filler with low hygroscopicity is selected from a group of excipients wherein the hygroscopicity of the said excipient it in the class of 3, 2 or 1, preferably in class 2 or 1, more preferably in class 2.
The pharmaceutically acceptable filler with low hygroscopicity pertaining to the present invention can be selected from a group comprising glucose, lactose, maltose, sucrose, sorbitol, mannitol, dextrin, maltodextrin or combination thereof. Preferably maltodextrin is used as the filler with low hygroscopicity in the formulation pertaining to the present invention The formulation pertaining to the present invention comprises the filler with low hygroscopicity in and amount in the range of 5-20%, preferably in the range of 7-15% by weight.
The ratio of active agent to filler with low hygroscopicity is in the range of 1:1 to 1 :10, preferably in the range of 1:3 to 1 :10, more preferably in the range of 1:5 to 1 :10 in the formulation pertaining to the present invention.
According to the present invention, the pharmaceutical composition comprising betahistine can optionally comprise an effervescent couple, sweetener, binder, flavoring agent, lubricant, glidant, disintegrant, and other pharmaceutically acceptable excipients.
The pharmaceutically acceptable effervescent couple pertaining to the present invention is comprised of a combination of the acidic agent and the basic agent. The acidic agent can comprise organic and/or inorganic acids while the basic agent can be alkali carbonate or alkali bicarbonate.
The pharmaceutically acceptable acidic agent pertaining 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 pharmaceutically acceptable basic agent pertaining to the present invention can be selected from a group comprising potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate or combinations thereof.
The acidic agent composing the effervescent couple is preferably citric acid, more preferably citric acid anhydrous; while the basic agent is preferably sodium hydrogen carbonate.
When the formulation comprising filler with low hygroscopicity is formulated in effervescent form, C02 is produced when water is added into the composition pertaining to the present invention thanks to the effervescent couple in said pharmaceutical formulation and as a result, a solution that can easily be taken even by the patients experiencing swallowing difficulties is obtained. The fact that the active agent dissolves fast and it is taken in the form of a solution provides for observing the effect of the medicament fastly and this is particularly an advantage for the diseases that come as attacks.
The pharmaceutically acceptable sweetener pertaining to the present invention can be selected from a group comprising aspartame, acesulfame, acesulfame potassium, fructose, dextrose, glucose, lactitol, maltitol, xylitol, sorbitol, maltose, saccharine, saccharine sodium, sodium cyclamate, sucralose, sucrose or combinations thereof. The pharmaceutically acceptable binder pertaining to the present invention can be selected from a group comprising starches such as potato starch, corn starch, wheat starch; sugars such as sucrose, glucose, dextrose, lactose, maltodextrin; natural and synthetic gums; gelatin; cellulose derivatives such as microcrystalline cellulose, HPC, HEC, HPMC, 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.
The pharmaceutically acceptable lubricant pertaining to the present invention can be selected from a group comprising sodium lauryl sulfate, calcium stearate, magnesium stearate, polyethylene glycol, polyvinyl alcohol, potassium benzoate, sodium benzoate, sodium chloride, carbowax 4000, talc or a combination thereof.
The pharmaceutically acceptable glidant pertaining to the present invention can be selected from a group comprising talc, magnesium stearate, stearic acid, sodium stearyl fumarate, polyoxyethylene glycol, leucine, alanine, glycine, sodium benzoate, sodium acetate, fumaric acid or a combination thereof.
The pharmaceutically acceptable disintegrant pertaining to the present invention can be selected from a group comprising starches such as potato starch, corn starch, wheat starch, pregelatinized starch, sodium starch glycolate; cellulose derivatives such as croscarmellose sodium or microcrystalline cellulose; polyvinylpyrrolidone; crospovidone; alginic acid and its salts; clays such as xanthan gum or Veegum; ion exchange resins or a combination thereof.
Wet or dry granulation method can be applied in order to prepare the formulation pertaining to the present invention.
The formulation pertaining to the present invention can be prepared by the wet granulation method having the following steps. 1. Mixing effective amount betahistine, filler with low hygroscopicity and optionally at least one excipient;
2. Preparing granulation solution which may optionally comprise at least one excipient;
3. Granulating mixture prepared in the step 1, with the granulation solution prepared in the step 2;
4. Drying granule obtained in the step 3;
5. Optionally mixing dried granules obtained in the step 4 with at least one excipient; 6. Compressing final mixture in the form of tablets or filling the final mixture into single- dose packages.
In the case of preparing formulation pertaining to the present invention in the effervescent form, at least one excipient that is used in the step 1 is effervescent couple. According to the present invention, the pharmaceutical composition pertaining to the present invention comprises;
- the active agent in the range of 0.1-50%, preferably in the range of 0.5-20%, more preferably in the range of 0.75-5% by weight,
- the acidic agent in the range of 0-65% by weight,
- the basic agent in the range of 0-45% by weight,
- the filler in the range of 5-20% by weight,
- the binder in the range of 1 -20% by weight
- other excipients in the range of 1 -80% by weight.
The expression "water dispersible powder, tablet and granule" refers to effervescent tablets, effervescent granules, effervescent powders, water dispersible tablets, water dispersible powders and water dispersible granules.
According to another aspect, the composition pertaining to the present invention can be used in attenuating the symptoms of Meniere's disease, decelerating the progress of Meniere's disease or in the treatment of the disease. According to another aspect, the composition pertaining to the present invention can be used in the treatment of Meniere's disease which has symptoms such as tinnitus, dizziness and deafness and which generally appears with symptoms such as nausea, earache and headache.
According to another aspect, the compositions pertaining to the present invention can be prepared as a medicament composition that is effective in the treatment of Meniere's disease which has symptoms such as tinnitus, dizziness and deafness and which generally appears with symptoms such as nausea, earache and headache.
The pharmaceutical compositions pertaining to the present invention and the methods for the preparation of these can be explained with the examples below while the invention should not be limited to them. EXAMPLES:
EXAMPLE 1: Formulation preparation method for effervescent betahistine compositions
Figure imgf000008_0001
Betahistine, citric acid, sodium bicarbonate and filler with low hygroscopicity is mixed and granulated. The granules are dried and then mixed with other excipients. The final mixture is then compressed in the form of tablets.
EXAMPLE 2:
Figure imgf000008_0002
Betahistine and filler with low hygroscopicity is mixed and granulated with a granulation solution comprising binder. The granules are dried and then mixed with other excipients. The final mixture is then filled into sachets.

Claims

1. A formulation comprising betahistine characterized in that said formulation
• is in the water dispersible form
• comprises a filler with low hygroscopicity
· is stored in single-dose packages.
2. The pharmaceutical composition according to claim 1, wherein the active agent betahistine is in free form or in the form of its pharmaceutically acceptable salts, enantiomers, racemates, solvates, hydrates, different polymorphic forms or amorphous form.
3. The pharmaceutical composition according to claim 2 characterized in that betahistine is present as chloride, fumarate, maleate, tartrate, citrate, succinate, phthalate or mesylate salts.
4. The pharmaceutical composition according to claim 3 characterized in that betahistine is present as betahistine hydrochloride or betahistine dihydrochloride.
5. The pharmaceutical composition according to claim 4 characterized in that betahistine is present as betahistine dihydrochloride.
6. The pharmaceutical composition according to the claim 1 characterized in that the filler with low hygroscopicity is selected from a group which has hygroscopicity level of class 1, 2 or 3.
7. The pharmaceutical composition according to the claim 6 characterized in that the filler with low hygroscopicity is selected form a group comprising starch, glucose, lactose, maltose, sorbitol, mannitol, dextrin, maltodextrin or combination thereof.
8. The pharmaceutical composition according to the claim 7 characterized in that the filler with low hygroscopicity is maltodextrin.
9. The pharmaceutical composition according to the claim 1 characterized in that the amount of filler with low hygroscopicity is in the range of 5-20% by weight.
10. The pharmaceutical composition according to the claim 9 characterized in that the amount of filler with low hygroscopicity is in the range of 7-15% by weight.
11. The pharmaceutical composition according to the claim 1 characterized in that the ratio of betahistine to filler with low hygroscopicity is in the range of between 1 : 1 to 1 : 10 by weight.
12. The pharmaceutical composition accoridng to the claim 11 characterized in that the ratio of betahistine to filler with low hygroscopicity is in the range of between 1 :3 to 1 : 10 by weight.
13. The pharmaceutical composition according to the claim 12 characterized in that the ratio of betahistine to filler with low hygroscopicity is in the range of between 1 :5 to 1 : 10 by weight.
14. The pharmaceutical composition according to claim 1 characterized in that said formulation is prepared as effervescent tablets, effervescent granules, effervescent granules, effervescent powders, water dispersible tablets, water dispersible powders and water dispersible granules.
15. The pharmaceutical composition according to claim 1 characterized in that said formulation comprises pharmaceutically acceptable excipients in addition to betahistine which is used as the active agent.
16. The pharmaceutical composition according to claim 15 characterized in that said composition comprises effervescent couple, sweetener, binder, lubricant, glidant, disintegrant and other pharmaceutically acceptable excipients.
17. The pharmaceutical composition according to claim 16 characterized in that said formulation comprises
- the active agent in the range of 0.1 -50% by weight,
- the acidic agent in the range of 0-65% by weight,
- the basic agent in the range of 0-45% by weight,
- the filler in the range of 5-20% by weight,
- the binder in the range of 1 -20% by weight,
- the other excipients in the range of 1 -80%) by weigth.
18. The pharmaceutical composition according to claim 17 characterized in that said formulation comprises
- the active agent in the range of 0.5-20%) by weight,
- the acidic agent in the range of 0-65%> by weight,
- the basic agent in the range of 0-45% by weight,
- the filler in the range of 5-20% by weight,
- the binder in the range of 1 -20% by weight,
- the other excipients in the range of l-80%o by weigth.
19. The pharmaceutical composition according to claim 18 characterized in that said formulation comprises - the active agent in the range of 0.75-5%) by weight, - the acidic agent in the range of 0-65% by weight,
- the basic agent in the range of 0-45% by weight,
- the filler in the range of 5-20% by weight,
- the binder in the range of 1 -20% by weight,
- the other excipients in the range of 1-80% by weigth.
20. The pharmaceutical composition according to claim 16 characterized in that a combination of an acidic agent and a basic agent is used as the effervescent couple.
21. The pharmaceutical composition according to claim 20 characterized in that the acidic agent is selected from a group comprising acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, propionic acid, tartaric acid or combinations thereof.
22. The pharmaceutical composition according to claim 21 characterized in that the acidic agent is citric acid anhydrous and the ratio of citric acid anhydrous to the total weight of the formulation is in the range of 0-65%.
23. The pharmaceutical composition according to claim 20 characterized in that basic agent is selected from a group comprising potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate or combinations thereof.
24. The pharmaceutical composition according to claim 23 characterized in that basic agent is sodium hydrogen carbonate and the ratio of sodium hydrogen carbonate to the total weight of the formulation is in the range of 0-45%.
25. The pharmaceutical composition according to claim 16 characterized in that the sweetener is selected from a group comprising aspartame, acesulfame, acesulfame potassium, fructose, dextrose, glucose, lactitol, maltitol, xylitol, sorbitol, maltose, saccharine, saccharine sodium, sodium cyclamate, sucralose, sucrose or combinations thereof.
26. The pharmaceutical composition according to the claim 16 characterized in that the binder is selected from a group comprising starches such as potato starch, corn starch, wheat starch; sugars such as sucrose, glucose, dextrose, lactose, maltodextrin; natural and synthetic gums; gelatin; cellulose derivatives such as microcrystalline cellulose, HPC, HEC, HPMC, 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.
27. The pharmaceutical composition according to the claim 16 characterized in that the lubricant is selected from a group comprising sodium lauryl sulfate, calcium stearate, magnesium stearate, polyethylene glycol, polyvinyl alcohol, potassium benzoate, sodium benzoate, sodium chloride, carbowax 4000, talc or a combination thereof.
28. The pharmaceutical composition according to the claim 16 characterized in that the glidant is selected from a group comprising talc, magnesium stearate, stearic acid, sodium stearil fumarate, polyoxyethylene glycol, leucine, alanine, glycine, sodium benzoate, sodium acetate, fumaric acid or a combination thereof.
29. The pharmaceutical composition according to the claim 16 characterized in that the disintegrant is selected from a group comprising starches such as potato starch, corn starch, wheat starch, pregelatinized starch, sodium starch glycolate; cellulose derivatives such as croscarmellose sodium or microcrystalline cellulose; polyvinylpyrrolidone; crospovidone; alginic acid and its salts; clays such as xanthan gum or Veegum; ion exchange resins or a combination thereof.
30. A process for preparing pharmaceutical composition according to the claim 1 characterized in that said process comprises the following steps;
1. Mixing effective amount betahistine, filler with low hygroscopicity and optionally at least one excipient;
2. Preparing granulation solution optionally comprising at least one excipient;
3. Granulating mixture prepared in the step 1, by means of granulation solution prepared in the step 2;
4. Drying granule obtanied in the step 3;
5. Optionally mixing dried granule obtained in the step 4 with at least one excipient;
6. Compressing final mixture in the form of tablets or filling in single-dose packages.
PCT/TR2011/000123 2010-05-04 2011-05-02 Water dispersible formulation WO2011139250A2 (en)

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TR2010/03540 2010-05-04

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4229428A (en) 1977-07-22 1980-10-21 Cherqui Jean S Galenical form of administration of betahistine and its derivatives

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IT1229237B (en) * 1989-05-08 1991-07-26 Prodotti Formenti SALTS OF (2- (PYRIDYL) ETHYL) METHYLAMINE
GB2280604B (en) * 1993-07-02 1997-04-30 Resource Medical Limited Processing of active agents
US20050074489A1 (en) * 2003-10-01 2005-04-07 Pediamed Pharmaceuticals, Inc. Effervescent and effervescent-dispersion compositions for medicaments and methods of use thereof
EP2314296A1 (en) * 2009-10-22 2011-04-27 Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi Orally Disintegrating Tablets of Betahistine

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Publication number Priority date Publication date Assignee Title
US4229428A (en) 1977-07-22 1980-10-21 Cherqui Jean S Galenical form of administration of betahistine and its derivatives

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Title
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L6FFLER, BER., vol. 37, 1904, pages 161
PUBLIC ASSESSMENT REPORT OF THE MEDICINES EVALUATION BOARD IN THE NETHERLANDS ( DIRECTIVE 2001/83/EC, ARTICLE 10(1
WALTER ET AL., JAM. CHEM. SOC., vol. 63, 1941, pages 2771

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