KR20100086140A - A composition of fast dissolving tablets containing montelukast and it's manufacturing thereof - Google Patents

Abstract

PURPOSE: A rapidly disintegrating tablet composition in oral cavity containing montelukast is provided to disintegrate in a short time without foreign feeling and to easily administer without water or beverage. CONSTITUTION: A rapidly disintegrating tablet composition in oral cavity contains montelukast as a pharmacologically active ingredient or pharmaceutically acceptable salt. The active ingredient is contained in 1-30 weight%. The composition additionally contains 20-90 weight% of excipient. The excipient is mannitol having a particle size of 50-500 micron. The composition also contains sweetener, lubricating agent, acidizing and alkalizing agents, foaming agent, aromatic agent, coloring agent, or stabilizer.

Description

Fast dissolving tablet composition in oral cavity containing montelukast as an active ingredient and a method for manufacturing the same

The present invention relates to a fast disintegrating tablet composition in the oral cavity containing montelukast and montelukast sodium salt as an active ingredient, and to the fast disintegrating tablet in the oral cavity obtained from the composition. Fast disintegrating tablets with less foreign body feel and hardness than the product's easy handling can be easily manufactured by using general solid preparation equipment.

Montelukast is an antagonist that inhibits cysteinyl leukotriene CysLT ₁ receptor and is used for the prevention and treatment of leukotriene-mediated diseases and disorders. Leukotriene is associated with inflammation and contraction of the airway muscles and accumulation of fluid in the lungs. In particular, montelukast is known to be effective in allergic rhinitis, atopic dermatitis, chronic urticaria, sinusitis, bipolar, chronic obstructive pulmonary disease, conjunctivitis including nasal conjunctivitis, migraine, cystic fibrosis and viral bronchiolitis (DahlSE. asthma with antileukotrienes: first line or last resort therapy, Eur J Pharmacol 2006; 533 (1-3): 4056).

General oral formulations are divided into tablets, capsules, granules, powders and the like. A problem with many oral pharmaceutical formulations is that some water is required for administration. If there is no water, or if it is impossible to drink or obtain water or a drink due to the condition of the patient, there are many difficulties when taking a drug to alleviate and prevent symptoms. In addition, tablets and capsules show a number of disadvantages in the administration of patients who are not cooperative in medication, such as patients with reduced swallowing ability, the elderly, infants and psychiatric diseases. Granules and powders, which are oral pharmaceutical formulations other than tablets, are inconvenient to administer the correct dosage and, in the case of bitter medicines, cause significant inconvenience due to residual in the mouth. Currently sold formulations have the same problem.

Regarding fast disintegrating preparations in oral cavity, patent 10-0457458 discloses fast disintegrating formulations containing pamotidine, loratadine, cetirizine hydrochloride, domperidone or lovastatin as active ingredients.

Patent registration No. 10-0762598 discloses an orally dispersible pharmaceutical composition containing as an active ingredient a compound protected in EP 648,741.

Patent No. 0503949 discloses an orally disintegrating composition containing ondansetron hydrochloride as an active ingredient and concealing the bitter taste of ondansetron.

Patent No. 10-0604034 discloses oral disintegrating tablets containing amlodipine free base and compositions thereof.

However, no orally disintegrating composition containing montelukast or a derivative thereof as an active ingredient has been disclosed or suggested.

The montelukast sodium formulation was developed by Merck, USA, and is commercially available in adult 10 mg skin tablets and pediatric 4 mg and 5 mg chewable tablets. In the case of commercially available tablets, it is difficult to take it without water, and it is difficult to apply to elderly people who have insufficient swallowing ability and patients who are difficult to take oral preparations. It is difficult to chew.

Antagonists that inhibit the cysteinyl leukotriene CysLT ₁ receptor are used for the prevention and treatment of leukotriene and mediated diseases and disorders, and leukotriene is associated with inflammation and contraction of the airway muscles and accumulation of fluid in the lungs, especially montelukast is an allergy. It is known to be effective in rhinitis, atopic dermatitis, chronic urticaria, sinusitis, nonpolyps, chronic obstructive pulmonary disease, conjunctivitis including nonconjunctivitis, migraine, cystic fibrosis and viral bronchiolitis. Formulations having this effect have been required for the drug to disintegrate and be absorbed very quickly and to develop fast efficacy.

The inventors of the present invention show a fast disintegration in the oral cavity using montelukast or montelukast sodium salt as an active ingredient as a pharmaceutically acceptable active ingredient, does not cause any residual residue in the mouth, and will not cause damage during transportation and storage. Research efforts have been made to produce tablets of degree.

Surprisingly, the present invention, when formulated with montelukast fast disintegrating tablets, can rapidly disintegrate within 30 seconds, preferably within 20 seconds, and very preferably within 15 seconds in the oral cavity, thereby rapidly expressing the medicinal effect and taking without water even when taken. Therefore, it has considerable convenience compared with the conventional formulation.

The fast disintegrating tablet in the oral cavity of the present invention can be easily prepared by using conventional excipients such as montelukast and its salts and water-soluble sugars, and pharmaceutically acceptable additives, using conventional production equipment for solid preparations. Because it disintegrates very quickly within, it is possible to produce faster drug expression than conventional formulations. In addition, it has the advantage that there is almost no foreign body feeling and residual feeling in taking oral.

The montelukast sokbung tablet prepared according to the present invention has little residual feeling and foreign body ingestion at the time of ingestion, and may simultaneously exert the effect of shielding the taste of the drug by using a saccharide as an excipient. In addition, the mechanical strength is sufficient to prevent breakage of tablets in general handling and distribution.

Oral disintegrating tablets described in the present invention, because they disintegrate rapidly in the oral cavity once taken, so to carry out according to the Korean Pharmacopoeia General Test Method Disintegration Test section, because the amount of test solution is extremely large compared to the general saliva amount in the oral cavity, sokbung tablet We judged it as inappropriate to evaluate. Therefore, in order to measure the disintegration time was tested by citing the disintegration test method described in Patent Publication No. 10-2005-0062467. In addition, in order to clearly disintegrate in the oral cavity, the disintegration time and the degree of residual feeling after the actual dose were specifically evaluated.

It is known to have a hardness of at least 3 kp to have mechanical strength that will not cause damage during transportation and storage of the product. Thus, each tablet hardness was measured.

Hereinafter, the fast disintegrating pharmaceutical composition of the present invention will be described in detail for each component.

As a pharmaceutically effective fast-acting active ingredient used as the fast disintegrating pharmaceutical composition of the present invention, general salts such as montelukast and montelukast sodium can be used, and both amorphous and crystalline forms can be used as the physical crystal form. Although the active ingredient is not particularly limited, it is preferable to include 1 to 30% by weight of the total weight of the composition for stable oral disintegration.

In addition to the active ingredient in the fast disintegrating composition of the present invention, water-soluble carbohydrates such as mannitol, sorbitol, dextrose, maltose, erythritol, sucrose, maltitol, lactose, maltose, trihalose, glucose, xylitol, and F-melt are used.

F-melt is available in two types, F-melt type M and type C. It is a mixture of D-mannitol, xylitol, microcrystalline cellulose, crospovidone and magnesium aluminometal silicate and calcium phosphate, supplied by Fuji Chemical of Japan. .

Pharmaceutically acceptable as disintegration aids such as crosslinked polyvinylpyrrolidone, low substituted hydroxypropyl cellulose, pregelatinized starch, croscarmellose sodium, sodium starch glycolate or corn starch used in solid preparations common in the art. Possible disintegrants can be used, and the amount of the disintegrating agent can be used to be 10% or less, preferably 3 to 7% of the total weight of the tablet in consideration of the residual in the oral cavity when taking, but the amount is not limited.

The fast disintegrating pharmaceutical composition of the present invention can use pharmaceutically acceptable additives in the art in addition to the above components by the choice of those skilled in the art. Such pharmaceutically acceptable additives are not particularly limited, but one or two or more mixtures may be used in sweeteners, lubricants, acids and alkalizing agents, micropore-forming agents and blowing agents, and may be used in amounts of 1 to 10% of the total weight of the tablet. It is correct to use. In particular, among the additives used, sweeteners may include aspartame, saccharin, acesulfame potassium, steviosides, sucrose, sucralose and the like, and lubricants include talc, stearic acid, magnesium stearate, colloidal silicon dioxide, and the like. Sodium stearyl fumarate, glyceryl behenate and glyceryl distearate are used, and as acid and alkalizing agent, organic acids such as ascorbic acid, citric acid, tartaric acid, succinic acid, malic acid can be used, and sodium hydroxide, ammonium hydroxide, Potassium hydroxide may be used, and the blowing agent may be sodium hydrogen carbonate, sodium carbonate, calcium carbonate, or the like, but its use is not limited.

In particular, the acidifying agent that can stimulate the salivary glands to promote disintegration is not particularly limited in use, but it is preferably used at 5% or less of the total weight of the tablet, more preferably 1 to 3%, more preferably 2% use.

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 and 2

As a method for preparing the composition mentioned in Examples 1 to 2 of Table 1, after putting montelukast sodium as an active ingredient, F-melt as an excipient, spray-dried mannitol, crospovidone as a disintegrant, and citric acid as an acidifying agent in a drum mixer Mix thoroughly for 10 minutes. After the addition of sodium stearyl fumarate as a lubricant, the same mixture is carried out for 5 minutes and then tableting using a conventional tableting method using a rotary tableting machine. The mixture is 250 mg per tablet, and the hardness is prepared in the range of 4-5kp.

Table 1.

Furtherance ratio(%) Example 1 Example 2 Montelukast Sodium 2.08 2.08 F-melt 57.92 57.92 Spray Dried Mannitol 100mesh 30.00 - Spray Dry Mannitol 200mesh - 30.00 Crospovidone 6.00 6.00 Citric acid 2.00 2.00 Sodium stearyl fumarate 2.00 2.00

Examples 3 to 5

Examples 3 to 5 are prepared in the same manner as in Examples 1 to 2 to prepare the compositions mentioned in Examples 3 to 5 of Table 2 as an example for identifying the difference between the disintegrants added to the fast disintegrating tablet.

Table 2.

Furtherance ratio(%) Example 3 Example 4 Example 5 Montelukast Sodium 2.08 2.08 2.08 F-melt 57.92 57.92 57.92 Spray Dried Mannitol 100mesh 30.00 30.00 30.00 Corn starch 6.00 - - Croscarmellose Sodium - 6.00 - Sodium starch glycolate - - 6.00 Citric acid 2.00 2.00 2.00 Sodium stearyl fumarate 2.00 2.00 2.00

Examples 6-7

The compositions mentioned in Examples 6-7 of Table 3 below are prepared in the same manner as in Examples 1-2. Separately, magnesium stearate in Example 6 is added in place of sodium stearyl fumarate, and aspartame in Example 7 is prepared by adding simultaneously with a disintegrant.

Table 3.

Furtherance ratio(%) Example 6 Example 7 Montelukast Sodium 2.08 2.08 F-melt 57.92 57.42 Spray Dried Mannitol 100mesh 30.00 30.00 Crospovidone 6.00 6.00 Citric acid 2.00 2.00 Aspartame 0.50 0.50 Sodium stearyl fumarate - 2.00 Magnesium stearate 2.00 -

Example 8.

In the preparation method of the composition mentioned in Example 8 of Table 4, after putting montelukast sodium as an active ingredient, spray-dried mannitol as an excipient, crospovidone as a disintegrant, sodium bicarbonate as a foaming agent and citric acid as an acidifying agent in a drum mixer Mix thoroughly for 10 minutes. After the addition of sodium stearyl fumarate as a lubricant, the same mixture is carried out for 5 minutes and then tableting using a conventional tableting method using a rotary tableting machine. The mixture is 250 mg per tablet, and the hardness is prepared in the range of 4-5kp.

Table 4.

Furtherance ratio(%) Example 8 Montelukast Sodium 2.08 Sodium bicarbonate 56.00 Citric acid 28.00 Spray Dried Mannitol 100mesh 9.52 Crospovidone 2.40 Magnesium stearate 2.00

Experimental Example 1.  Confirmation of physical properties of Montelukast Sokcho

C50 tablet hardness tester (HOLLAND, England) was used to evaluate the hardness of the montelukast fast disintegrating tablet of the present invention. As a result, in Experimental Examples 1 to 8, all tablets having a physical strength of 4 kp or more were confirmed.

Experimental Example 2.  Measurement of Disintegration of Montelukast Sorbent Tablets

In vitro and in vivo evaluations were simultaneously performed on the tablets of Examples 1 to 8.

In vitro disintegration experiment was carried out on a glass Petri dish (100x10 mm), a 90 mm diameter filter paper (Reference WH1442090), and disintegrating medium [cobalt (II) 6-chloride 10% (w / w) aqueous solution] 9-10 mL at room temperature. Pour the volume into the dish. After soaking all the papers, the tablets are placed on a plate, and the time until the water is wetted to the end of the tablet surface by capillary action is measured as the completion time.

In vivo disintegration experiments measure the time until complete disintegration of tablets by saliva in the oral cavity of 10 adult males. The test is repeated three times and the mean value is displayed.

 Table 5.

Hardness (kp) Disintegration time (seconds) in vitro in vivo Experimental Example 1 6.2 8 sec 12 seconds Experimental Example 2 6.8 10 sec 13 seconds Experimental Example 3 4.7 20 seconds 30 seconds Experimental Example 4 5.8 15 seconds 22 seconds Experimental Example 5 4.3 17 seconds 23 seconds Experimental Example 6 6.1 9 sec 13 seconds Experimental Example 7 5.2 9 sec 14 sec Experimental Example 8 6.0 18 seconds 25 sec

Experimental Example 3.  Dissolution Rate Measurement of Montelukast Sorbent Tablets

The dissolution rate of the drug was measured in accordance with the comparative dissolution test in the pharmacokinetic test management regulation notification of the Food and Drug Administration of Montelukast intraoral disintegrating tablet prepared in Example 1 and Singular rare tablet of Merck Co., Ltd. The initial dissolution rate was faster than that of the reference drug, and the total amount of drug released after completion of dissolution was the same.

As a result, as shown in Figure 1 showed a faster initial dissolution pattern than the reference drug. Since regular film tablets and fast disintegrating tablets differ in the first application of the drug, it is difficult to evaluate the two formulations in general.However, since tablets are released at the same time as the disintegration, the drug is released at the same time. Can replace the effect. In the present invention, since the release amount of the drug is almost similar after 30 minutes, the pharmacological effects of the two formulations can be regarded as equivalent. However, in the case of the definition of fast disintegration as in Example 2, it disintegrates quickly using only a small amount of saliva in the oral cavity, and thus can be used more quickly than general film-coated formulations through convenience and fast drug release. Will also have at the same time. In addition, since the disintegration time is much faster than the chewable tablets, the initial drug release pattern is also confirmed to be fast, and unlike the chewable tablets that require chewing during the high mechanical strength, they do not require any physical force other than a small amount of saliva. It is a great advantage to take for children or elderly patients who have a lot of swallowing effects and patients in special situations.

From these results, the fast disintegrating tablet in the oral cavity of the present invention is faster disintegration in the oral cavity than the conventional formulation, maximizing the convenience of taking, it can be seen that the product is sufficiently secured in ease of storage and handling.

1 is a view showing a comparative dissolution test results of oral disintegrating tablets and a control agent in the oral cavity according to the present invention.

Claims (8)

Fast disintegrating tablet in oral cavity of montelukast comprising montelukast or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient. The fast disintegrating pharmaceutical composition of claim 1, wherein the bioactive component is 1-30 wt% of the total weight of the preparation. The orally disintegrating pharmaceutical composition according to claim 1, wherein the particle size of mannitol used as an excipient is 50 to 500 microns. The orally disintegrating pharmaceutical composition according to claim 1, wherein the excipient is 20 to 90% by weight of the total weight of the composition. The method according to claim 1, which is prepared by further mixing one or more pharmaceutically acceptable additives selected from the group consisting of disintegration aids, sweeteners, lubricants, acids and alkalizing agents, microporous agents, foaming agents, fragrances, coloring agents and stabilizers. Fast disintegrating pharmaceutical composition in the oral cavity, characterized in that. The orally disintegrating pharmaceutical composition according to claim 1, wherein the disintegration aid is 1 to 20% by weight of the total weight of the composition. The disintegration aid according to claim 6, wherein the disintegration aid is one selected from crosslinked polyvinylpyrrolidone, low substituted hydroxypropyl cellulose, pregelatinized starch, croscarmellose sodium, sodium starch glycolate and corn starch and F-melt. Or oral disintegrating pharmaceutical composition, characterized in that the mixture of two or more. The orally disintegrating pharmaceutical composition according to claim 1, wherein the oral disintegration is terminated within 3 minutes.

Images