WO2004096214A1 - A rapidly disintegrable composition for masking the bitter taste of ondansetron or a pharmaceutically acceptable salt thereof - Google Patents

A rapidly disintegrable composition for masking the bitter taste of ondansetron or a pharmaceutically acceptable salt thereof Download PDF

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Publication number
WO2004096214A1
WO2004096214A1 PCT/KR2004/000230 KR2004000230W WO2004096214A1 WO 2004096214 A1 WO2004096214 A1 WO 2004096214A1 KR 2004000230 W KR2004000230 W KR 2004000230W WO 2004096214 A1 WO2004096214 A1 WO 2004096214A1
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composition
ondansetron
sodium
pharmaceutically acceptable
acceptable salt
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PCT/KR2004/000230
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French (fr)
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Young-Joon Park
Dae-Sik Kang
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Yuhan Corporation
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • 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
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • the present invention relates to a composition for oral administration, which rapidly disintegrates in the oral cavity and masks the bitter taste of ondansetron or a pharmaceutically acceptable salt thereof, the composition comprising a therapeutically effective amount of ondansetron or a pharmaceutically acceptable salt thereof and an alkalizing agent.
  • Ondansetron or a pharmaceutically acceptable salt thereof is a selective
  • 5-hydroxytryptamine (5-HT) antagonist used in the treatment of emesis and anxiety, particularly nausea and vomiting associated with cancer chemotherapy and radiotherapy.
  • ondansetron is ondansetron hydrochloride dihydrate (European Pat. Publication No. 415,522).
  • Conventional compositions for oral administration e.g., tablet
  • ondansetron or a pharmaceutically acceptable salt thereof may be associated with certain disadvantages, particularly in the treatment of pediatric or geriatric patients, who may dislike or have difficulty in swallowing the composition, or patients having deglutition difficulties.
  • ondansetron or a pharmaceutically acceptable salt thereof disintegrated and dissolved by saliva in the oral, cavity exposes a bitter taste, which causes problems in drug-compliance of patients.
  • ondansetron hydrochloride dihydrate a preferable form of ondansetron, has even more bitter and irritating taste than the free base form. Therefore, there is a need to effectively mask bitter taste of ondansetron or a pharmaceutically acceptable salt thereof.
  • the present invention provides a rapidly disintegrable composition formulated by mixing both ondansetron or a pharmaceutically acceptable salt thereof and an alkalizing agent, using physicochemical properties that ondansetron or a pharmaceutically acceptable salt thereof has relatively lower water-solubility at higher pH.
  • the present invention provides a composition for oral administration, which disintegrates in the oral cavity rapidly (i.e., within about 60 seconds) and masks the bitter taste of ondansetron or a pharmaceutically acceptable salt thereof, the composition comprising a therapeutically effective amount of ondansetron or a pharmaceutically acceptable salt thereof and an alkalizing agent.
  • FIGs. 1 to 4 show dissolution profiles of Test tablet (Example 1 ) and Reference tablet (Zofran ® ) in pH 1.2 buffer solution, pH 4.0 buffer solution, water, and pH 6.8 buffer solution, respectively;
  • FIG. 5 shows blood concentration profiles of ondansetron in Test tablet (Example 1 ) and Reference tablet (Zofran ® ).
  • the present invention provides a composition for oral administration, which disintegrates in the oral cavity rapidly (i.e., within about 60 seconds) and masks the bitter taste, the composition comprising a therapeutically effective amount of ondansetron or a pharmaceutically acceptable salt thereof and an alkalizing agent.
  • ondansetron for the present invention is ondansetron hydrochloride dihydrate.
  • the term "therapeutically effective amount" refers to the amount that produces the desired therapeutic response upon oral administration and can be readily determined by one skilled in the art. In determining the therapeutically effective amount, a number of factors are considered, including but not limited to: the particular compound administered, the bioavailability characteristics of the pharmaceutical composition administered, the dose regimen selected, and other relevant factors.
  • Ondansetron or a pharmaceutically acceptable salt thereof has a relatively lower water-solubility at a higher pH. Therefore, when the composition of the present invention is orally administered, the alkalizing agent lowers solubility of the disintegrated ondansetron or a pharmaceutically acceptable salt thereof in the oral cavity, thereby masking the bitter taste caused by dissolution of ondansetron or a pharmaceutically acceptable salt thereof.
  • the alkalizing agent in the composition of the present invention raises the pH of the surroundings of the drug (i.e., ondansetron or a pharmaceutically acceptable salt thereof) to keep the disintegrated drug undissolved in the oral cavity, which results in masking a bitter taste to the tongue untill the drug is transferred with a saliva from the oral cavity to the gastrointestinal tract.
  • ondansetron or a pharmaceutically acceptable salt thereof is dissolved by a gastric juice in stomach to show pharmaceutical characteristics thereof.
  • composition of the present invention may be prepared in simple methods, without coating processes. Further, the rapidly disintegrable composition of the present invention may be administered to patients without help of water and may be applied preferably to patients having severe vomiting associated with cancer chemotherapy and radiotherapy.
  • the content of ondansetron or a pharmaceutically acceptable salt thereof may be in the ranges of 0.1 to 50 % by weight, preferably of 0.5 to 30 % by weight, based on total weight of the composition.
  • the alkalizing agent may be selected from the group consisting of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, magnesium carbonate, sodium citrate, sodium tartrate, sodium biphosphate, sodium phosphate, potassium phosphate, and magnesium trisilicate. Among them, sodium bicarbonate is preferably selected.
  • the alkalizing agent may be used in amounts ranging from 0.1 to 40 % by weight, based on total weight of the composition. In aspects of effective taste-masking and good stability and quality of the composition, the alkalizing agent may be preferably used in amounts ranging from 2 to 20 % by weight, based on total weight of the composition.
  • the composition of the present invention may further comprise one or more saccharides for rapidly disintegrating the composition in the oral cavity, as well as for increasing sweetness and feel thereof.
  • the saccharides may be selected from the group consisting of mannitol, sorbitol, lactose, dextrose, xylitol, glucose, dextrate, sugar, fructose, maltose, maltodextrin, levulose and erithrotol.
  • a spray-dried mannitol may be preferably used in the present invention.
  • the spray-dried mannitol may be prepared by spray-drying an aqueous solution of crystalline mannitol, having an average particle size of about from 10 to 200 ⁇ m.
  • a commercially available spray-dried mannitol powder (e.g., PEARLITOL SD ® 200, Roquette, France) may also be used in the present invention (WO 00/57857).
  • the content of the saccharide, including a spray-dried mannitol may be in the ranges of 10 to 95 % by weight, preferably 30 to 90 % by weight, based on total weight of the composition.
  • the composition of the present invention may further comprise one or more disintegrants such as a cross-linked polyvinylpyrolidone, croscarmellose sodium, calcium carboxyl methyl cellulose, low substituted hydroxy propyl cellulose and sodium starch glycolate.
  • a cross-linked polyvinylpyrolidone e.g., crospovidone
  • crospovidone a cross-linked polyvinylpyrolidone
  • composition of the present invention may further contain one or more pharmaceutically acceptable excipients, including a diluent such as microcrystalline cellulose, starch and cellulose; an organic acid such as citric acid, tartaric acid and malic acid; a sweetening agent such as aspartame, stevioside and saccharin; a lubricant such as silicon dioxide, colloidal silicon dioxide, magnesium stearate, talc, sodium stearyl fumarate, stearic acid, and polyethylene glycol; and a flavoring agent.
  • the excipients may be included in amounts ranging from 0.1 to 30 % by weight, based on total weight of the composition, preferably in amounts ranging from 0.5 to 10 % by weight.
  • composition of the present invention may be prepared according to a conventional method, such as a direct-compress method, a dry-granulation method and a wet-granulation method (Pharmaceutical Dosage forms, Tablet 2 nd edition, vol. 1-3).
  • the ingredients shown in Table 1 except for magnesium stearate and magnesium trisilicate, were mixed and passed through a 20-mesh sieve (U.S. standard) to obtain a mixture.
  • Magnesium stearate and magnesium trisilicate were passed through a 40-mesh sieve (U.S. standard) and then mixed with the mixture obtained in the above.
  • the resulting mixture was compressed into tablets to give rapidly disintegrable tablets, each weighing 220 mg (Hardness: about 5 - 6 Kp).
  • the resulting mixture was granulated, using purified water, with a fluid bed granulator at 80 ° C .
  • the granule was passed through a 20-mesh sieve (U.S. standard).
  • Magnesium stearate and magnesium trisilicate were passed through a 40-mesh sieve (U.S. standard) and then mixed with the granule obtained in the above.
  • the resulting mixture was compressed into tablets to give rapidly disintegrable tablets, each weighing 220 mg (Hardness: about 5 - 6 Kp).
  • the hardness of each tablet was measured with a tablet hardness tester (Schleuniger-2E, Dr. K. Schleuniger & Co.). The test was repeated 3-10 times for each sample and the results were averaged.
  • the organoleptic test was conducted according to the cross-over method, which is carried out with double blinded at random, of six male adults.
  • the mark * is directly proportional to unpleasant bitter taste.
  • Table 7 shows that there are no critical difference in the disintegration time between the tablets of Examples 1 - 3 and those of Comparative Examples 1 - 3. However, in case of the tablets of Examples 1 - 3, bitter tastes of the active ingredients are effectively masked.
  • Test Example 3 Comparative dissolution tests between the tablet prepared in Example 1 (hereinafter “Test tablet”) and a conventional rapidly disintegrable tablet containing ondansetron hydrochloride (Zofran ® 8mg, GSK; hereinafter “Reference tablet”) were carried out in water or buffer solutions of pH 1.2, pH 4.0 and pH 6.8, respectively (50rpm, medium: 900ml). The results were shown in Figs. 1 to 4 (Fig. 1 : dissolution in pH 1 .2 buffer solution, Fig. 2: dissolution in pH 4.0 buffer solution, Fig. 3: dissolution in water, and Fig. 4: dissolution in pH 6.8 buffer solution). As shown in Figs. 1 to 4, there is no significant difference in dissolution time between two tables.
  • test tablet Example 1
  • Reference tablet Zofran® 8mg, GSK
  • the test was carried out according to the cross-over method for twenty six healthy male volunteers.
  • Test tablet is biologically equivalent to

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Abstract

The present invention provides a composition for oral administration, which disintegrates in the oral cavitywithin about 60 seconds and masks a bitter taste of ondansetron or a pharmaceutically acceptable salt thereof, the composition comprising a therapeutically effective amount of ondansetron or a pharmaceuticallyacceptable salt thereof and an alkalizing agent.

Description

A RAPIDLY DISINTEGRABLE COMPOSITION FOR MASKING THE BITTER TASTE OF ONDANSETRON OR A PHARMACEUTICALLY ACCEPTABLE
SALT THEREOF
Technical Field
The present invention relates to a composition for oral administration, which rapidly disintegrates in the oral cavity and masks the bitter taste of ondansetron or a pharmaceutically acceptable salt thereof, the composition comprising a therapeutically effective amount of ondansetron or a pharmaceutically acceptable salt thereof and an alkalizing agent.
Background Art
Ondansetron or a pharmaceutically acceptable salt thereof is a selective
5-hydroxytryptamine (5-HT) antagonist and used in the treatment of emesis and anxiety, particularly nausea and vomiting associated with cancer chemotherapy and radiotherapy. It is known that a preferable form of ondansetron is ondansetron hydrochloride dihydrate (European Pat. Publication No. 415,522). Conventional compositions for oral administration (e.g., tablet) containing ondansetron or a pharmaceutically acceptable salt thereof may be associated with certain disadvantages, particularly in the treatment of pediatric or geriatric patients, who may dislike or have difficulty in swallowing the composition, or patients having deglutition difficulties. Accordingly, there have been efforts to develop a rapidly disintegrable formulation, which disintegrates rapidly and converts into a liquid form by saliva in the oral cavity, for example as described in WO 96/015785, Korean Pat. Publication No. 2001-107754, and WO 00/057857.
Meanwhile, in case of the rapidly disintegrable compositions (e.g., tablet), ondansetron or a pharmaceutically acceptable salt thereof disintegrated and dissolved by saliva in the oral, cavity exposes a bitter taste, which causes problems in drug-compliance of patients. Further, ondansetron hydrochloride dihydrate, a preferable form of ondansetron, has even more bitter and irritating taste than the free base form. Therefore, there is a need to effectively mask bitter taste of ondansetron or a pharmaceutically acceptable salt thereof.
In order to mask the bitter taste of drugs, several methods have been proposed, such as coating with a polymer (WO 99/01 1245, US Pat. No. 5,758,403, etc.); adding a sweetening agent (i.e., aspartame, etc.) (Korea Pat. Publication No. 1990-5890, etc.); preparing into a solid dispersion (Korea Pat. Publication No. 2002-74822, etc.); and microencapsulating a drug (European Pat. Publication No. 69097). However, the above methods involve complicated processes for the preparation and have difficulties in continuously masking a bitter taste.
Disclosure of the Invention
The present invention provides a rapidly disintegrable composition formulated by mixing both ondansetron or a pharmaceutically acceptable salt thereof and an alkalizing agent, using physicochemical properties that ondansetron or a pharmaceutically acceptable salt thereof has relatively lower water-solubility at higher pH. In accordance with an aspect of the present invention, the present invention provides a composition for oral administration, which disintegrates in the oral cavity rapidly (i.e., within about 60 seconds) and masks the bitter taste of ondansetron or a pharmaceutically acceptable salt thereof, the composition comprising a therapeutically effective amount of ondansetron or a pharmaceutically acceptable salt thereof and an alkalizing agent..
Brief Description of the Drawings
The above and other features and advantages of the present invention will become more apparent by describing in detail exemplary embodiments thereof with reference to the attached drawings in which:
FIGs. 1 to 4 show dissolution profiles of Test tablet (Example 1 ) and Reference tablet (Zofran®) in pH 1.2 buffer solution, pH 4.0 buffer solution, water, and pH 6.8 buffer solution, respectively;
FIG. 5 shows blood concentration profiles of ondansetron in Test tablet (Example 1 ) and Reference tablet (Zofran®).
Best mode for carrying out the Invention
The present invention provides a composition for oral administration, which disintegrates in the oral cavity rapidly (i.e., within about 60 seconds) and masks the bitter taste, the composition comprising a therapeutically effective amount of ondansetron or a pharmaceutically acceptable salt thereof and an alkalizing agent. The preferred form of ondansetron for the present invention is ondansetron hydrochloride dihydrate.
As used herein, the term "therapeutically effective amount " refers to the amount that produces the desired therapeutic response upon oral administration and can be readily determined by one skilled in the art. In determining the therapeutically effective amount, a number of factors are considered, including but not limited to: the particular compound administered, the bioavailability characteristics of the pharmaceutical composition administered, the dose regimen selected, and other relevant factors.
Ondansetron or a pharmaceutically acceptable salt thereof has a relatively lower water-solubility at a higher pH. Therefore, when the composition of the present invention is orally administered, the alkalizing agent lowers solubility of the disintegrated ondansetron or a pharmaceutically acceptable salt thereof in the oral cavity, thereby masking the bitter taste caused by dissolution of ondansetron or a pharmaceutically acceptable salt thereof. That is, when the composition (e.g., tablet) is disintegrated by saliva in the oral cavity, the alkalizing agent in the composition of the present invention raises the pH of the surroundings of the drug (i.e., ondansetron or a pharmaceutically acceptable salt thereof) to keep the disintegrated drug undissolved in the oral cavity, which results in masking a bitter taste to the tongue untill the drug is transferred with a saliva from the oral cavity to the gastrointestinal tract. Further, ondansetron or a pharmaceutically acceptable salt thereof is dissolved by a gastric juice in stomach to show pharmaceutical characteristics thereof.
The composition of the present invention may be prepared in simple methods, without coating processes. Further, the rapidly disintegrable composition of the present invention may be administered to patients without help of water and may be applied preferably to patients having severe vomiting associated with cancer chemotherapy and radiotherapy.
In the composition of the present invention, the content of ondansetron or a pharmaceutically acceptable salt thereof may be in the ranges of 0.1 to 50 % by weight, preferably of 0.5 to 30 % by weight, based on total weight of the composition.
The alkalizing agent may be selected from the group consisting of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, magnesium carbonate, sodium citrate, sodium tartrate, sodium biphosphate, sodium phosphate, potassium phosphate, and magnesium trisilicate. Among them, sodium bicarbonate is preferably selected. The alkalizing agent may be used in amounts ranging from 0.1 to 40 % by weight, based on total weight of the composition. In aspects of effective taste-masking and good stability and quality of the composition, the alkalizing agent may be preferably used in amounts ranging from 2 to 20 % by weight, based on total weight of the composition.
The composition of the present invention may further comprise one or more saccharides for rapidly disintegrating the composition in the oral cavity, as well as for increasing sweetness and feel thereof. The saccharides may be selected from the group consisting of mannitol, sorbitol, lactose, dextrose, xylitol, glucose, dextrate, sugar, fructose, maltose, maltodextrin, levulose and erithrotol. Among them, a spray-dried mannitol may be preferably used in the present invention. The spray-dried mannitol may be prepared by spray-drying an aqueous solution of crystalline mannitol, having an average particle size of about from 10 to 200 μm. A commercially available spray-dried mannitol powder (e.g., PEARLITOL SD® 200, Roquette, France) may also be used in the present invention (WO 00/57857). The content of the saccharide, including a spray-dried mannitol, may be in the ranges of 10 to 95 % by weight, preferably 30 to 90 % by weight, based on total weight of the composition.
For facilitating rapid-disintegrability, the composition of the present invention may further comprise one or more disintegrants such as a cross-linked polyvinylpyrolidone, croscarmellose sodium, calcium carboxyl methyl cellulose, low substituted hydroxy propyl cellulose and sodium starch glycolate. Among them, a cross-linked polyvinylpyrolidone (e.g., crospovidone) may be preferably used in the present invention. The composition of the present invention may further contain one or more pharmaceutically acceptable excipients, including a diluent such as microcrystalline cellulose, starch and cellulose; an organic acid such as citric acid, tartaric acid and malic acid; a sweetening agent such as aspartame, stevioside and saccharin; a lubricant such as silicon dioxide, colloidal silicon dioxide, magnesium stearate, talc, sodium stearyl fumarate, stearic acid, and polyethylene glycol; and a flavoring agent. The excipients may be included in amounts ranging from 0.1 to 30 % by weight, based on total weight of the composition, preferably in amounts ranging from 0.5 to 10 % by weight.
The composition of the present invention may be prepared according to a conventional method, such as a direct-compress method, a dry-granulation method and a wet-granulation method (Pharmaceutical Dosage forms, Tablet 2nd edition, vol. 1-3).
Hereinafter, the present invention will be described more specifically by examples. However, the following examples are provided only for illustrations and thus the present invention is not limited to or by them.
Examples 1 ~ 3
The ingredients shown in Table 1 , except for magnesium stearate and magnesium trisilicate, were mixed and passed through a 20-mesh sieve (U.S. standard) to obtain a mixture. Magnesium stearate and magnesium trisilicate were passed through a 40-mesh sieve (U.S. standard) and then mixed with the mixture obtained in the above. The resulting mixture was compressed into tablets to give rapidly disintegrable tablets, each weighing 220 mg (Hardness: about 5 - 6 Kp).
Table 1
Figure imgf000008_0001
Examples 4 - 6
The ingredients shown in Table 2 were passed through a 20-mesh sieve (U.S. standard) and mixed for 5 minutes. The mixture was compressed with 80 kgf/cii pressure by a roller compactor to obtain a granule. The resulting granule was passed through a 20-mesh sieve (U.S. standard) and then compressed into tablets to give rapidly disintegrable tablets, each weighing 220 mg (Hardness: about 4 - 5 Kp). Table 2
Figure imgf000009_0001
Examples 7 - 9
The ingredients shown in Table 3, except for magnesium stearate and magnesium trisilicate, were mixed and passed through a 20-mesh sieve (U.S. standard). The resulting mixture was granulated, using purified water, with a high-speed mixer. The granule was dried in 80 °C and passed through a 20-mesh sieve (U.S. standard). Magnesium stearate and magnesium trisilicate were passed through a 40-mesh sieve (U.S. standard) and then mixed with the granule obtained in the above. The resulting mixture was compressed into tablets to give rapidly disintegrable tablets, each weighing 220 mg (Hardness: about 5 - 6 Kp). Table 3
Figure imgf000010_0001
Examples 10 - 12
The ingredients shown in Table 4, except for magnesium stearate and magnesium trisilicate, were mixed and passed through a 20-mesh sieve (U.S. standard). The resulting mixture was granulated, using purified water, with a fluid bed granulator at 80 °C . The granule was passed through a 20-mesh sieve (U.S. standard). Magnesium stearate and magnesium trisilicate were passed through a 40-mesh sieve (U.S. standard) and then mixed with the granule obtained in the above. The resulting mixture was compressed into tablets to give rapidly disintegrable tablets, each weighing 220 mg (Hardness: about 5 - 6 Kp).
Table 4
Figure imgf000011_0001
Comparative Examples 1 - 3
As shown in Table 5, the procedures of Examples 1 - 3 were repeated, except for not using alkalizing agents (sodium bicarbonate, sodium carbonate, or potassium carbonate), to obtain rapidly disintegrable tablets.
Table 5
Figure imgf000012_0001
Comparative Examples 4 - 6
As shown in Table 6, the procedures of Examples 4 - 6 were repeated, except for not using alkalizing agents (sodium bicarbonate, sodium carbonate, or potassium carbonate), to obtain rapidly disintegrable tablets.
Table 6
Figure imgf000013_0001
Test Example 1
The hardnesses, disintegration times in the oral cavity and extent of the taste masking were measured by the following methods for the tablets obtained in Examples 1 - 6 and Comparative Examples 1 - 6. The results are shown in Table 7.
(1 ) Hardness
The hardness of each tablet was measured with a tablet hardness tester (Schleuniger-2E, Dr. K. Schleuniger & Co.). The test was repeated 3-10 times for each sample and the results were averaged.
(2) Disintegration time
The time for a sample to completely disintegrate by the action of saliva in the oral cavity of six male adults was measured. The test duplicated three times and the results were averaged. (3) Organoleptic test
The organoleptic test was conducted according to the cross-over method, which is carried out with double blinded at random, of six male adults.
Table 7
Figure imgf000014_0001
The mark * is directly proportional to unpleasant bitter taste.
Table 7 shows that there are no critical difference in the disintegration time between the tablets of Examples 1 - 3 and those of Comparative Examples 1 - 3. However, in case of the tablets of Examples 1 - 3, bitter tastes of the active ingredients are effectively masked.
Test Example 3 Comparative dissolution tests between the tablet prepared in Example 1 (hereinafter "Test tablet") and a conventional rapidly disintegrable tablet containing ondansetron hydrochloride (Zofran® 8mg, GSK; hereinafter "Reference tablet") were carried out in water or buffer solutions of pH 1.2, pH 4.0 and pH 6.8, respectively (50rpm, medium: 900ml). The results were shown in Figs. 1 to 4 (Fig. 1 : dissolution in pH 1 .2 buffer solution, Fig. 2: dissolution in pH 4.0 buffer solution, Fig. 3: dissolution in water, and Fig. 4: dissolution in pH 6.8 buffer solution). As shown in Figs. 1 to 4, there is no significant difference in dissolution time between two tables.
Test Example 3
The bioequivalence test was carried out for Test tablet (Example 1 ) and Reference tablet (Zofran® 8mg, GSK) in fast condition. The test was carried out according to the cross-over method for twenty six healthy male volunteers.
That is, after cross-administration of Test tablet and Reference tablet to the volunteers, the blood samples were taken every given period and blood concentrations thereof were measured. The blood concentration profiles of ondansetron in each tablet are shown in Fig. 5 and pharmacokinetic parameters thereof are shown in Table 8.
Table 8
Figure imgf000015_0001
As shown in Fig. 5 and Table 8, Test tablet is biologically equivalent to
Reference tablet.

Claims

What is claimed is:
1. A composition for oral administration, which disintegrates in the oral cavity within about 60 seconds and masks a bitter taste of ondansetron or a pharmaceutically acceptable salt thereof, the composition comprising a therapeutically effective amount of ondansetron or a pharmaceutically acceptable salt thereof and an alkalizing agent.
2. The composition of claim 1 , wherein the pharmaceutically acceptable salt of ondansetron is ondansetron hydrochloride dihydrate.
3. The composition of claim 1 , wherein the content of ondansetron or a pharmaceutically acceptable salt thereof is in the range of 0.1 to 50 % by weight, based on total weight of the composition.
4. The composition of claim 1 , wherein the alkalizing agent is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, magnesium carbonate, sodium citrate, sodium tartrate, sodium biphosphate, sodium phosphate, potassium phosphate and magnesium trisilicate.
5. The composition of claim 1 , wherein the content of the alkalizing agent is in the range of 0.1 to 40 % by weight, based on total weight of the tablet.
6. The composition of claim 1 , further comprising one or more saccharides selected from the group consisting of mannitol, sorbitol, lactose, dextrose, xylitol, glucose, dextrate, sugar, fructose, maltose, maltodextrin, levulose and erithrotol.
7. The composition of claim 6, wherein the saccharide is a spray-dried mannitol.
8. The composition of claim 6, wherein the content of the saccharide is in the range of 10 to 95 % by weight, based on total weight of the composition.
9. The composition of any one of claims 1 to 5, further comprising one or more disintegrants selected from the group consisting of a cross-linked polyvinylpyrolidone, croscarmellose sodium, calcium carboxyl methyl cellulose, low substituted hydroxy propyl cellulose and sodium starch glycolate.
10. The composition of any one of claims 6 to 8, further comprising one or more disintegrants selected from the group consisting of a cross-linked polyvinylpyrolidone, croscarmellose sodium, calcium carboxyl methyl cellulose, low substituted hydroxy propyl cellulose and sodium starch glycolate.
PCT/KR2004/000230 2003-04-28 2004-02-06 A rapidly disintegrable composition for masking the bitter taste of ondansetron or a pharmaceutically acceptable salt thereof WO2004096214A1 (en)

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KR10-2003-0026723A KR100503949B1 (en) 2003-04-28 2003-04-28 A composition of fast dissolving tablets effectively masked bitter taste of ondansetron hydrochloride

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WO2011160849A1 (en) * 2010-06-24 2011-12-29 Pharmatech Gmbh Taste-masked pharmaceutical formulation having accelerated onset of action
US8545890B2 (en) 2006-03-31 2013-10-01 Rubicon Research Private Limited Orally disintegrating tablets
US8663684B2 (en) 2008-09-19 2014-03-04 Molkerei Meggle Wasserburg Gmbh & Co. Kg Lactose and cellulose-based tableting aid
WO2017138645A1 (en) * 2016-02-12 2017-08-17 テイカ製薬株式会社 Dry-granulated material, solid preparation comprising dry-granulated material and method for manufacturing same
EP3263106B1 (en) 2015-02-25 2023-10-25 Eisai R&D Management Co., Ltd. Method for suppressing bitterness of quinoline derivative

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KR100701409B1 (en) * 2004-11-26 2007-03-30 한국유나이티드제약 주식회사 Pharmaceutical formulations containing sumatriptan succinate

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JPH0276826A (en) * 1988-06-27 1990-03-16 Dai Ichi Seiyaku Co Ltd Oral solid preparation
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WO2000057857A1 (en) * 1999-03-25 2000-10-05 Yuhan Corporation Rapidly disintegrable tablet for oral administration
WO2002047607A2 (en) * 2000-12-15 2002-06-20 Ranbaxy Laboratories Limited Process for the preparation of a fast dissolving dosage form

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EP0069097A2 (en) * 1981-06-18 1983-01-05 Astra Läkemedel Aktiebolag Pharmaceutical mixture
JPH0276826A (en) * 1988-06-27 1990-03-16 Dai Ichi Seiyaku Co Ltd Oral solid preparation
US5633006A (en) * 1992-07-30 1997-05-27 Pfizer Inc. Taste-masking composition of bitter pharmaceutical agents
WO2000057857A1 (en) * 1999-03-25 2000-10-05 Yuhan Corporation Rapidly disintegrable tablet for oral administration
WO2002047607A2 (en) * 2000-12-15 2002-06-20 Ranbaxy Laboratories Limited Process for the preparation of a fast dissolving dosage form

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8545890B2 (en) 2006-03-31 2013-10-01 Rubicon Research Private Limited Orally disintegrating tablets
US8663684B2 (en) 2008-09-19 2014-03-04 Molkerei Meggle Wasserburg Gmbh & Co. Kg Lactose and cellulose-based tableting aid
WO2011160849A1 (en) * 2010-06-24 2011-12-29 Pharmatech Gmbh Taste-masked pharmaceutical formulation having accelerated onset of action
JP2013529605A (en) * 2010-06-24 2013-07-22 ファーマテック・ゲーエムベーハー Taste masking pharmaceutical composition with accelerated onset of activity
EA031697B1 (en) * 2010-06-24 2019-02-28 Фарматек Гмбх Taste-masked pharmaceutical formulation having accelerated onset of action
EP3263106B1 (en) 2015-02-25 2023-10-25 Eisai R&D Management Co., Ltd. Method for suppressing bitterness of quinoline derivative
WO2017138645A1 (en) * 2016-02-12 2017-08-17 テイカ製薬株式会社 Dry-granulated material, solid preparation comprising dry-granulated material and method for manufacturing same
JP2018035132A (en) * 2016-02-12 2018-03-08 テイカ製薬株式会社 Dry granule, and solid formulation containing dry granule and method for producing the same
CN108601737A (en) * 2016-02-12 2018-09-28 特华制药株式会社 Dry granulation object and the solid formulation containing the dry granulation object and its manufacturing method

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KR100503949B1 (en) 2005-07-26

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