KR20040095424A - A composition of fast dissolving tablets effectively masked bitter taste of ondansetron hydrochloride - Google Patents

Abstract

PURPOSE: Provided is a composition of a fast dissolving tablet which is effectively masks the bitter taste of ondansetron hydrochloride. The composition contains ondansetron hydrochloride or alkali antiemetic drugs and masks the bitter taste thereof effectively. Therefore, it is orally administered without water. CONSTITUTION: The composition of a fast dissolving tablet which masks the bitter taste of ondansetron hydrochloride is characterized by containing a therapeutically effective amount of ondansetron hydrochloride dihydrate, as an active ingredient, alkalizing agent, oral dissolving auxiliary agent, and/or at least one of pharmaceutically acceptable additive.

Description

Oral fast disintegrating composition for oral cavity which effectively hides bitter taste of hydrochloric acid ondansetron {A COMPOSITION OF FAST DISSOLVING TABLETS EFFECTIVELY MASKED BITTER TASTE OF ONDANSETRON HYDROCHLORIDE}

The present invention relates to oral fast disintegrating tablets containing oral hydrochloric acid on alkaline oral antiviral drugs, and more particularly, to the oral cavity without water and effectively masking the bitter taste of the drug while containing ondansetron hydrochloric acid or alkaline anti-jintomic drugs. Oral disintegrating tablet composition to increase the compliance of the patient can be dissolved quickly eat.

In general, ondansetron is a selective antagonist of 5-HT, which is used for the treatment of nausea and anxiety, and is particularly used for the treatment of nausea and vomiting caused by chemotherapy and radiation therapy for the treatment of cancer. It is known that ondansetron hydrochloride dihydrate is in the form of ondansetron hydrochloride dihydrate (Korean Patent No. 10-0182789).

Conventional ondansetron oral preparations are tablets, and such conventional tablets have a problem that is difficult to swallow in patients, children or elderly patients who complain of dysphagia by chemotherapy. In order to overcome this problem, many attempts have recently been made to develop orally dissolving tablets that can be rapidly disintegrated by intraoral saliva without taking water and can be taken like liquid formulations. Korean Patent Nos. 10-0262377, Korean Patent Publication Nos. 2001-0107754 and 2001-006835 refer to oral rapid tablets that contain ondansetron and can disintegrate rapidly in the oral cavity without water and can be taken as a liquid formulation. Doing. However, in the prior art, the base form of ondansetron is used, and ondansetron hydrochloride dihydrate, which is known as the most preferred form of medicine, is tasteless and irritating and has not yet been developed as a preparation for dissolution in the oral cavity.

On the other hand, various methods for concealing the bitter taste of drugs are known to date. Among them, Korean Patent Publication Nos. 2002-0002321 and 2001-0023384, and US Patent No. 5728403 disclose a method of coating a drug particle with a polymer material or a lipid component. Therefore, the prior art can cover up the bitter taste by coating the drug film, but the manufacturing process is very complicated and there is a problem that the release and absorption rate of the drug is delayed.

In addition, Korean Patent Publication No. 1990-0005890 discloses a method of concealing the bitter taste by adding artificial sweeteners (aspartame, amonium glycyrizinate, acesulfame potassium, sodium saccharin, etc.) having a sugar content of 200 to 300 times that of sugar. Presenting. However, this method has a strong sweetness at the beginning of the dose, but has a disadvantage in that it is not effective because it cannot continuously mask the bitter taste.

Korean Patent Publication No. 2002-0074822 discloses a method for preparing a solid dispersion of bitter acetaminophen and low molecular weight dextrin to mask the bitter taste of drugs. However, this method also has a disadvantage that the manufacturing process is not only cumbersome but also difficult to conceal the bitter taste because the solid dispersion must be prepared separately during the manufacturing process.

On the other hand, the Republic of Korea Patent No. 1988-0001752 is a base insoluble or poorly soluble drugs of chlorobutylolnium, northcapinium, bromine hexidinium, terbutalinium, cinidinium, promethagenium, diphenhydraminium, bromine Drugs can be obtained by microencapsulating peniraminium, solfadiazinium, tetracyclinium, erythromycinium, trimethoprinium, dextrosepropoxyphenium, and chloroquinium to add basic substances or by adding basic substances to capsules. It describes a method for preparing a dry powder to conceal the bitter taste of However, the prior art is not only difficult to effectively conceal the bitter taste of ondansetron or alkaline anti-jintomic acid hydrochloride, but also has a problem that the manufacturing process is cumbersome because the encapsulated fine encapsulation must be performed on the drug.

Accordingly, the present inventors have repeatedly studied to solve the problems of the prior art and to develop oral fast disintegrating tablets containing the most preferred form of hydrochloric acid onset dihydrate or alkaline antifungal drug, hydrochloric acid showing low solubility at high pH. The present invention has been completed by discovering that the physicochemical properties of ondansetron or alkaline anti-jintomic drugs can effectively mask the bitter taste of ondansetron dihydrate without hydrocoating the drug.

Accordingly, it is an object of the present invention to provide an oral fast disintegrating composition and a method for preparing the same, comprising a therapeutically effective amount of an active ingredient, an alkalizing agent, an oral dissolution aid, and one or more pharmaceutically acceptable additives.

It is also an object of the present invention to effectively mask the bitter taste of alkaline antifungal drugs, such as therapeutically effective amounts of ondansetron hydrochloride dihydrate, glanisetrone hydrochloride, or trocesetron hydrochloride, and to dissolve rapidly in the oral cavity. And to provide a method for producing the same.

1 to 4 are comparative dissolution test results of oral fast disintegrating tablets and control drugs (GlaxomiScleline's Zofran tablet, 8 mg) prepared according to an embodiment of the present invention at pH 1.2, pH 4.0, water and pH 6.8, respectively. The figure which shows.

Figure 5 is a view showing the bioequivalence test results of oral fast disintegrating tablet prepared in accordance with an embodiment of the present invention and the control drug (Grancose Mycline's Zofran tablet, 8mg).

The present invention relates to an oral fast disintegrating composition and a method for preparing the same, which contains ondansetron dihydrate or alkaline anti-jintomic acid hydrochloride, which is the most preferred form of ondansetron, as an active ingredient, effectively masking bitter taste and dissolving rapidly in the oral cavity.

In order to achieve the above object, in the present invention, ondansetron hydrochloride has a low solubility in physicochemical properties to show the solubility in the oral cavity, which can mask the bitter taste of ondansetron or alkaline anti-jintomic drugs without coating the drug. A composition and a method for preparing the same are provided. That is, the present invention is formulated with a component that can maintain a high pH in the oral cavity with hydrochloric acid ondansetron dihydrate or an alkaline anti-jinto drug, so that the stomach is rapidly dissolved by gastric acid, so that the solubility of the drug in the oral cavity without losing pharmacological properties Lower to provide a mouthwash disintegrating composition and a method for preparing the same so as to shield the bitter taste due to dissolution of the drug.

Accordingly, the oral quick disintegrating composition of the present invention is a therapeutically effective amount of ondansetron hydrochloric acid or alkaline anti-jintomic drug, an alkalizing agent capable of maintaining a high pH in the oral cavity, a dissolution aid to increase oral solubility, and one or more pharmaceutically acceptable Possible additives can be configured.

As the drug (or active ingredient) usable in the present invention, ondansetron dihydrate hydrochloride, or alkaline antifungal drug such as glanisetron hydrochloride or trocesetron hydrochloride can be used, and ondansetron dihydrate hydrochloride is most preferred. The drug may be used 0.1 to 50% by weight of the total weight of the tablet, preferably 0.5 to 30% by weight may be used.

The alkalizing agent plays the most important role in concealing the bitter taste of the drug, and serves to maintain a high pH around when the tablet is dissolved in the oral cavity. That is, when a tablet containing a drug such as ondansetron hydrochloric acid, which has a characteristic that the solubility rapidly decreases with increasing pH, is disintegrated by saliva in the oral cavity, the alkalizing agent is dispersed in saliva by elevating the surroundings to an alkaline pH. It prevents the drug from dissolving, so it doesn't feel bitter on the tongue and masks the bitter taste until it reaches the gastrointestinal tract with saliva in the oral cavity. The alkalizing agents that can be used include sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, sodium citrate, sodium stannate, sodium hydrogen phosphate, sodium phosphate, potassium phosphate, or magnesium trisilicate. It is preferable that it is sodium hydrogen. The alkalizing agent may be used in an amount of about 0.1 to 40% by weight based on the total weight of the tablet, and it is more preferable that 2 to 20% by weight is used to effectively conceal bitter taste while maintaining stability of the preparation and product quality.

In order to quickly disintegrate tablets in the oral cavity, oral dissolution aids must be included in the tablets, and it is most preferable to use sugars which can quickly dissolve in the mouth and improve sweetness and feel. Sugars that can be used include mannitol, sorbitol, lactose, dextrose, xyitol, sucrose, glucose, desrate, sucrose, fructose, maltose, maltidextrin, leblos, erythrotol and the like. In addition, in order to increase the solubility, the oral dissolution aid is preferably used by spray drying or commercially available spray drying raw materials. The oral dissolution aid may be 10 to 95% by weight based on the total weight of the tablet, preferably 30 to 90% by weight may be used.

The present invention relates to crosslinked polyvinylpyrrolidone, calcium carboxy methyl cellulose, low substituted hydroxy propyl cellulose, sodium starch glycolate, and the like as disintegrants; As excipients microcrystalline cellulose, starch, cellulose and the like; Citric acid, tartaric acid, malic acid and the like as the organic acid; As sweeteners, aspartame, stevioside, or saccharin; The lubricant may further include pharmaceutically acceptable additives such as silicon dioxide, colloidal silicon dioxide, magnesium stearyl acid, talc, sodium stearyl fumarate, stearyl acid, or polyethylene glycol. In addition, it may further comprise a pharmaceutically addable flavor to enhance the taste. The additive may be included in about 0.1 to 30% by weight based on the total weight of the tablet, it is more preferably used within 0.5 to 10%.

Oral fast disintegrating tablet containing hydrochloric acid ondansetron of the present invention can be prepared by direct tableting method, dry granulation method, wet granulation method and the like which is a conventional tablet manufacturing method. For example, ondansetron containing hydrochloric acid ondansetron of the present invention may be in the form of a tablet after mixing a therapeutically effective amount of an active ingredient, an alkalizing agent, an oral dissolution aid and / or one or more pharmaceutically acceptable additives. It can be tableted. In addition, oral fast disintegrating tablet containing hydrochloric acid ondansetron of the present invention is prepared by granulating a therapeutically effective amount of an active ingredient, an alkalizing agent, an oral dissolution adjuvant, or one or more pharmaceutically acceptable additives (disintegrant, etc.) The granules can then be prepared by further adding one or more pharmaceutically acceptable additives (such as disintegrants, lubricants or flavorings) to the granules, mixing and tableting them. In addition, in the case of the wet granulation method, a therapeutically effective amount of an active ingredient, an alkalizing agent, an oral dissolution aid, and a disintegrating agent is spray dried to prepare granules or a granule using a flu coater or a high intensive mixer. Pharmaceutically acceptable additives such as releases, glidants or flavorings can be added and mixed to form tablets.

Hereinafter, the present invention will be described in more detail according to Examples and Test Examples. However, this does not limit the present invention.

Examples 1 to 3

Of the components mentioned in Examples 1 to 3 in Table 1, all components except magnesium trisilicate and magnesium stearate were mixed and sieved to 20 sieves, and then mixed with magnesium trisilicate and magnesium stearate to 40 sieves. Mixed. The mixture was compressed to 220 mg per tablet to prepare a tablet. Hardness was prepared in the range of 5 kp to 6 kp.

Furtherance ratio(%) Example 1 Example 2 Example 3 Hydrochloric acid onsetsetron 4.55% 4.55% 4.55% Spray drying mannitol 79.77% 79.77% 79.77% Crospovidone 5.0% - - Sodium starch glycolate - 5.0% - Croscarmellose sodium - 5.0% Sodium bicarbonate 5.68% - - Sodium carbonate - 5.68% - Potassium bicarbonate - - 5.68% Aspartame 2.0% 2.0% 2.0% Colloidal Silicon Oxide 0.5% 0.5% 0.5% incense 1.0% 1.0% 1.0% Magnesium trisilicate 0.5% 0.5% 0.5% Magnesium stearate 1.5% 1.5% 1.5%

Examples 4-6

All components mentioned in Examples 4 to 6 of Table 2 were apples in a No. 20 sieve, and then uniformly mixed for 5 minutes, placed in a granular compressor, and compressed to a pressure of 80 kgf / cm 2 to prepare granules. The granules were sized in a No. 20 sieve and compressed to 220 mg per tablet to prepare tablets. Hardness was prepared in the range of 4 kp to 5 kp.

Furtherance ratio (%) Example 4 Example 5 Example 6 Hydrochloric acid onsetsetron 4.55% 4.55% 4.55% Di-mannitol 59.77% 59.77% 59.77% Lactose 20% 20% 20% Crospovidone 5.0% - - Sodium starch glycolate - 5.0% - Croscarmellose sodium - - 5.0% Sodium bicarbonate 5.68% 5.68% - Potassium bicarbonate - - 5.68% Aspartame 2.0% 2.0% 2.0% Colloidal Silicon Oxide 0.5% 0.5% 0.5% incense 1.0% 1.0% 1.0% Magnesium trisilicate 0.5% 0.5% 0.5% Magnesium stearate 1.5% 1.5% 1.5%

Examples 7-9

All ingredients except magnesium stearate and magnesium trisilicate among the components mentioned in Tables 7 to 9 of Table 3 were mixed with apples in a No. 20 sieve and placed in a high-speed granulator to prepare granules by adding purified water to 80 ° C. The dry granules were sized using No. 20 sieve network. Magnesium stearate and magnesium trisilicate were apple-mixed in a No. 40 sieve and mixed in the granular mixture. The mixture was compressed to 220 mg to make a tablet. Hardness was prepared in the range of 5 kp to 6 kp.

Furtherance ratio(%) Example 7 Example 8 Example 9 Hydrochloric acid onsetsetron 4.55% 4.55% 4.55% Di-mannitol 49.77% 49.77% 49.77% Microcrystalline cellulose 30% 30% 30% Crospovidone 5.0% - - Sodium starch glycolate - 5.0% - Croscarmellose sodium - - 5.0% Sodium bicarbonate 5.68% 5.68% 5.68% Aspartame 2.0% 2.0% 2.0% Colloidal Silicon Oxide 0.5% 0.5% 0.5% incense 1.0% 1.0% 1.0% Magnesium trisilicate 0.5% 0.5% 0.5% Magnesium stearate 1.5% 1.5% 1.5%

Examples 10-12

Of the components mentioned in Examples 10 to 12 of Table 4 except all components except magnesium stearate and magnesium trisilicate were mixed into a fluidized bed granulator, purified water was added to prepare granules, and then dried and dried granules It was established using the 20 network. Magnesium stearate and magnesium trisilicate were put into the No. 40 sieve and mixed with the fluidized bed granules. The mixture was compressed to 220 mg to make a tablet. The hardness of the tablet was prepared to have a hardness of 5kp ~ 6kp.

Furtherance ratio(%) Example 10 Example 11 Example 12 Hydrochloric acid onsetsetron 4.55% 4.55% 4.55% Erythritol 49.77% 49.77% 49.77% Microcrystalline cellulose 30% 30% 30% Crospovidone 5.0% - - Sodium starch glycolate - 5.0% - Croscarmellose sodium - - 5.0% Sodium bicarbonate 5.68% 5.68% 5.68% Aspartame 2.0% 2.0% 2.0% Colloidal Silicon Oxide 0.5% 0.5% 0.5% incense 1.0% 1.0% 1.0% Magnesium trisilicate 0.5% 0.5% 0.5% Magnesium stearate 1.5% 1.5% 1.5%

Examples 11-12

Of the components mentioned in Examples 11 and 12 of Table 5, all components except magnesium trisilicate and magnesium stearate were mixed and sieved to 20 sieves, and then mixed with trisilicate magnesium and magnesium stearate to 40 sieves. Mixed. The mixture was compressed to 220 mg per tablet to prepare a tablet. Hardness was prepared in the range of 5 kp to 6 kp.

Furtherance ratio(%) Example 11 Example 12 Hydrochloric acid tropesetron 4.55% - Hydrochloric acid hydrochloride - 4.55% Spray drying mannitol 79.77% 79.77% Crospovidone 5.0% - Sodium starch glycolate - 5.0% Croscarmellose sodium - Sodium bicarbonate 5.68% - Sodium carbonate - 5.68% Potassium bicarbonate - - Aspartame 2.0% 2.0% Colloidal Silicon Oxide 0.5% 0.5% incense 1.0% 1.0% Magnesium trisilicate 0.5% 0.5% Magnesium stearate 1.5% 1.5%

Test Example 1

The tablets prepared according to Examples 1 to 3 were placed in the mouths of six adult males, and the time when the tablets were completely disintegrated by the saliva of the oral cavity was measured and a sensory test (a degree of bitterness) was performed. The sensory test was performed in a crossover mode, which was randomly covered with two eyes. Comparative agent was used in the same manner as in Examples 1 to 3 (Comparative Examples 1, 2, and 3) except that no alkalizing agent was added, which is described in Table 6 below.

Furtherance ratio(%) Comparative Example 1 Comparative Example 2 Comparative Example 3 Hydrochloric acid onsetsetron 4.55% 4.55% 4.55% Spray drying mannitol 85.45% 85.45% 85.45% Crospovidone 5.0% - - Sodium starch glycolate - 5.0% - Croscarmellose sodium - - 5.0% Aspartame 2.0% 2.0% 2.0% Colloidal Silicon Oxide 0.5% 0.5% 0.5% incense 1.0% 1.0% 1.0% Magnesium trisilicate 0.5% 0.5% 0.5% Magnesium stearate 1.5% 1.5% 1.5%

As a result of performing the sensory test as described above, the oral disintegration time of the composition containing the alkalizing agent (Examples 1, 2 and 3) and the composition (Comparative Examples 1, 2 and 3) was not significantly different, but bitter taste The degree of shielding was confirmed that the composition containing the alkalizing agent is more excellent, it is described in Table 7 below.

Hardness (kp) (n = 6, RSD (%)) Oral Disintegration Time (sec) (n = 6, RSD (%)) Sensory test results (n = 6) Example 1 5.17 (RDS = 3.39) 20.17 (RDS = 10.15) * Comparative Example 1 5.13 (RDS = 6.12) 21.00 (RDS = 11.20) ****** Example 2 5.22 (RDS = 5.06) 34.67 (RDS = 14.49) * Comparative Example 2 5.17 (RDS = 5.83) 36.50 (RDS = 17.14) ****** Example 3 5.08 (RDS = 2.90) 34.33 (RDS = 13.43) * Comparative Example 3 5.03 (RDS = 3.91) 33.17 (RDS = 17.91) ******

In the above, bitter taste increases with increasing "*".

Test Example 2

The tablets prepared according to Examples 4 to 6 were placed in the mouths of six adult males, and the time when the tablets were completely disintegrated by the saliva of the oral cavity and the sensory test (blocking degree of bitterness) were measured. Sensory tests were carried out with crossovers. Comparative agent was used in the same manner as in Examples 4 to 6 except that the alkalizing agent was not added (Comparative Examples 4, 5 and 6), which are described in Table 8 below.

Furtherance ratio (%) Comparative Example 4 Comparative Example 5 Comparative Example 6 Hydrochloric acid onsetsetron 4.55% 4.55% 4.55% Di-mannitol 65.45% 65.45% 65.45% Lactose 20% 20% 20% Crospovidone 5.0% - - Sodium starch glycolate - 5.0% - Croscarmellose sodium - - 5.0% Aspartame 2.0% 2.0% 2.0% Colloidal Silicon Oxide 0.5% 0.5% 0.5% incense 1.0% 1.0% 1.0% Magnesium trisilicate 0.5% 0.5% 0.5% Magnesium stearate 1.5% 1.5% 1.5%

As a result of performing the sensory test as described above, the oral disintegration time of the composition containing the alkalizing agent (Examples 4, 5 and 6) and the composition (Comparative Examples 4, 5 and 6) was not significantly different, but the bitter taste Shielding degree was confirmed that the composition containing the alkalizing agent is more excellent, it is described in Table 9 below.

Hardness (kp) (n = 6, RSD (%)) Oral Disintegration Time (sec) (n = 6, RSD (%)) Sensory test results (n = 6) Example 4 4.58 (RDS = 6.82) 53.83 (RDS = 11.89) * Comparative Example 4 4.45 (RDS = 6.47) 55.50 (RDS = 9.03) ****** Example 5 4.73 (RDS = 7.98) 57.00 (RDS = 14.85) * Comparative Example 5 4.65 (RDS = 7.66) 60.00 (RDS = 13.74) ****** Example 6 4.53 (RDS = 6.19) 59.33 (RDS = 15.51) * Comparative Example 6 4.68 (RDS = 8.26) 56.50 (RDS = 21.291 ******

In the above, bitter taste increases with increasing "*"

Test Example 3

Comparison of the crude tablets of GlaxoSmithKline (GSK), a commercially available formulation containing ondansetron with hydrochloric acid, was prepared according to Example 1 of the present invention at pH 1.2, pH 4.0, water, and pH 6.8 according to the Notice of Food and Drug Administration. A dissolution test was performed, which is shown in FIGS. 1 to 4. As shown in the accompanying drawings, there was no dissolution difference between the two formulations, and in terms of dose compliance, the oral fast disintegrating tablet of the present invention effectively shielding bitter taste was better.

Test Example 4.

The bioequivalence evaluation was performed using the tablet prepared according to Example 1 of the present invention and Zofranc tablet from GlaxoSmithKline as a control. Twenty six healthy adult males were cross-administered with test drugs (oral disintegrating tablets in Example 1) and zofran tablets in a Latin square, and blood samples were taken at regular intervals, and the ondansetron concentrations in the blood were compared. As a result of the test as described above, oral quick disintegrating tablet of the present invention showed the same bioavailability as Zofran tablet, which is described in Figure 5 and Table 10 below.

AUC 0-24 hr (ng.hr/ml) Cmax (ng / ml) Tmax (hr) Test drug (Example 1) 195.28 ± 111.60 26.57 ± 9.57 1.71 ± 0.67 Reference medicine (zofran tablet) 182.68 ± 78.05 29.43 ± 8.34 1.65 ± 0.42 Difference in mean -6.90% 9.714% -3.507%

Oral fast disintegrating tablet containing hydrochloric acid ondansetron according to the present invention can effectively mask the bitter taste of ondansetron hydrochloric acid by a simple method without a separate coating process by mixing the alkalinizing agent in the drug can increase the patient's compliance with the drug, and in terms of drug efficacy Since it has the same effect as a general tablet, it can be used with confidence. In the manufacturing method of the tablet can be prepared according to an easy method such as direct tableting method, the oral disintegration rate is also very good and can be easily taken by the patient without water, especially for patients with severe vomiting.

Claims (10)

An oral disintegrating composition containing a therapeutically effective amount of ondansetron hydrochloride dihydrate, an alkalizing agent, an oral dissolution aid, and / or one or more pharmaceutically acceptable additives as an active ingredient. The composition of claim 1, wherein the active ingredient is 0.1-50% by weight based on the total weight. The composition according to claim 1, wherein the active ingredient is trophetrone hydrochloride or glanisetron hydrochloride. The method 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 stannate, sodium hydrogen phosphate, sodium phosphate, potassium phosphate, and magnesium trisilicate One or more compositions selected. The composition of claim 4, wherein the alkalizing agent is 0.1 to 40% by weight based on the total weight. According to claim 1, wherein the oral dissolution aid is one from the group consisting of mannitol, sorbitol, lactose, dextrose, xyitol, sucrose, glucose, destrate, sucrose, fructose, maltose, maltidextrin, leblos and erythrotol Or more selected. The composition of claim 6, wherein the oral dissolution aid is 10 to 95% by weight of the total weight. The composition of claim 1 wherein the additive comprises a pharmaceutically acceptable disintegrant, excipient, sweetener, organic acid, glidant or flavor. The composition of claim 8 wherein the disintegrant is crosslinked polyvinylpyrrolidone, calcium carboxy methylcellulose, low substituted hydroxy propylcellulose, or sodium starch glycolate. The composition of claim 8, wherein the excipient is microcrystalline cellulose, starch, or cellulose.