KR20160043565A - A Pharmaceutical Composition comprising Montelukast and Antihistamine - Google Patents

Abstract

The present invention relates to a complex pharmaceutical composition containing montelukast and antihistamine. According to the present invention, the pharmaceutical composition formulates two ingredients by injecting a specific type of an elution controller in an adequate range, thereby improving the elution of each of the two ingredients to be normal. The complex pharmaceutical composition is capable of sufficiently achieving the elevated pharmacological effects of the two ingredients by reaching blood drug concentrations ultimately required for target treatment effects, alleviating the difficulties in a production process of the manufacture, and reducing production costs through improvement of yields.

Description

[0001] The present invention relates to montelukast and antihistamine-containing pharmaceutical compositions,

The present invention relates to a pharmaceutical composition containing a montelukast and an antihistamine. Specifically, the present invention relates to a pharmaceutical composition comprising montelukast and an antihistamine, wherein the two components are formulated together by injecting a certain kind of elution control agent in an appropriate range, , Ultimately reaching the blood drug concentration necessary for the desired therapeutic effect, not only can the synergistic pharmacological effect of the two components be sufficiently attained, but also the production cost is improved by improving the difficulty of the manufacturing process and improving the yield, ≪ / RTI >

In general, asthma is initially administered in the form of an inhalant, a beta-2 agonist or a steroid, to prevent or treat airway obstruction through bronchial dilation. In addition, an oral form of leukotriene antagonist may be used as adjunct therapy for bronchial inflammation inhibition .

However, in the case of a steroid preparation used as a first-line treatment, side effects such as poor growth of children, lowering of bone density, and immunodeficiency may occur as well as resistance to long-term use. In addition, although the beta-2 agonist exhibits a rapid effect, there is also a problem that the therapeutic effect is reduced when an emergency occurs due to resistance generation. In addition, these inhalants have a limitation in that they can not be sufficiently administered because of difficulties in delivering drugs to the human body, and long-term use or overuse of these inhalants has been undesirable.

Thus, leukotriene antagonists, bronchial inflammation-suppressing agents, have been used as adjunctive therapies to improve various problems of the inhalants and side effects due to excessive drug use. However, these leukotriene antagonists alone have not been effective in improving the bronchial inflammation, so that there is still a problem in that the efficacy of the monotherapy is still insufficient.

In accordance with this demand, WO999 / 32125 discloses that a pharmaceutical composition containing an leukotriene antagonist and an antihistamine agent as an active ingredient is expected to have a synergistic therapeutic effect on bronchial asthma. However, the above patent discloses that when leukotriene antagonists such as montelukast and antihistamine such as epinastine and azelastine are formulated together with leukotriene antagonist and antihistamine agent, various preparations which influence dissolution such as physicochemical interactions that may occur between the two components There is no specific reference to the problems of the present invention, and it is not recognized at all that the elution is reduced due to aggregation which may occur in simple mixing as in the present invention. In addition, the above patent discloses a variety of disintegrants that can be used in the case of combination formulation, such as starch, modified starches such as sodium carboxymethylstarch, natural and synthetic gums, celluloses such as methylcellulose and carboxymethylcellulose, croscarmellose sodium Such as microcrystalline cellulose and cross-linked microcrystalline cellulose, alginic acid, and clay such as bentonite, etc. These effects are not disclosed at all on the effect of each of these disintegrants, It is confirmed that there is a limit to improvement at the same time.

Accordingly, the inventors of the present invention have recognized such a problem and tried to solve the problem, and in June, 2012, they filed a separation-related patent for separating the two components in order to minimize the interaction between the two components [ Patent Application No. 2012-69220]. Despite these studies, however, the preparation through the separation phase requires the use of a multi-layer tablet machine, which is a special manufacturing facility, and it is difficult to use the production process even when the production process is complicated, And the need for further research was urgently needed.

           Montelukast Epinastine

Azelastine

Accordingly, a problem to be solved by the present invention is to provide a combination of montelukast and antihistamine together with a specific type of elution control agent in the form of a combination, and determine the most favorable conditions for the normal elution of the two active ingredients Thus, the dissolution of the two active ingredients is improved so that the concentration of the drug in the blood required for the desired therapeutic effect can be reached. Thus, the synergistic pharmacological effect of the two components can be sufficiently achieved, And to provide a combined pharmaceutical composition which simultaneously improves the production cost by improving the yield.

The present invention relates to a pharmaceutical composition comprising a montelukast and an antihistamine.

First, the pharmaceutical composition according to the present invention is a combination of montelukast and antihistamine, which comprises at least one elution regulator selected from crospovidone, carboxymethylcellulose calcium and sodium starch glycolate. As a usual release controlling agent, a binder capable of promoting disintegration including a disintegrant can be used, but the present invention is characterized in that it comprises at least one of crospovidone, carboxymethylcellulose calcium or sodium starch glycolate. In particular, in the case of crospovidone, it preferably contains the content of 0.01 to 10 parts by weight, or 0.03 to 7 parts by weight, or 0.1 to 3 parts by weight based on 1 part by weight of the main component. Also, it is preferable that the carboxymethyl cellulose calcium is contained in an amount of 0.01 to 10 parts by weight, or 0.03 to 7 parts by weight, and 0.1 to 3 parts by weight based on 1 part by weight of the main component. Finally, it is preferable that sodium starch glycolate is contained in an amount of 0.01 to 10 parts by weight, or 0.03 to 7 parts by weight, and 0.1 to 3 parts by weight based on 1 part by weight of the main component. In addition, the content of the elution regulator is 0.1 to 50% by weight, more preferably 0.5 to 30% by weight, and most preferably 1 to 20% by weight, based on the total composition, It is possible to control within. This is because, if these components are contained in too much or too small amounts, elution of both components is not preferable.

The montelukast, which is the active ingredient of the present invention, is preferably 4 to 20 mg, more preferably 4 to 10 mg, in a dose of 1 to 2 times per day. In addition, epinastine is preferably used in an amount of 1 to 2 times a day, preferably 5 to 40 mg, more preferably 5 to 20 mg. In the case of azelastine, it is preferably 0.5 to 2 mg, more preferably 1 to 1.4 mg.

The complex of the present invention as described above is preferably an oral formulation such as tablets, capsules, film, etc. in which the two main components are mixed, and can be manufactured by a conventional manufacturing method.

The present invention relates to a pharmaceutical composition containing a montelukast and an antihistamine, wherein the medicinal composition according to the present invention improves both of the two components so as to be a normal elution and ultimately reaches a blood drug concentration necessary for a desired therapeutic effect, Not only the synergistic pharmacological effect can be sufficiently achieved, but also the manufacturing difficulty and the production cost can be improved.

FIG. 1 is a graph comparing the dissolution rates of montelukast in each of Comparative Examples and Examples at the elapsed time of 30 minutes from the start of dissolution. FIG. 2 is a graph comparing the dissolution rates of epinastine in each of Comparative Examples and Examples at the elapsed time of 30 minutes from the start of elution.

Hereinafter, preferred embodiments and experimental examples are provided to facilitate understanding of the present invention. However, the following examples and experimental examples are provided only for the purpose of easier understanding of the present invention, and the scope of the present invention is not limited by these examples and experimental examples.

Example  1 ~ Example  2 and Comparative Example  1-5

The ingredients and the contents shown in Table 1 were mixed in a substantially uniform manner by a conventional method, followed by tableting using a tablet machine.

The raw drug contents used in Examples and Comparative Examples division Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Example 1 Example 2 function Raw material name mg / T mg / T mg / T mg / T mg / T mg / T mg / T chief ingredient Monterukast 10.4 10.4 10.4 10.4 10.4 10.4 10.4 chief ingredient Epinastine 20.0 20.0 20.0 20.0 20.0 20.0 20.0 Filler Lactose monohydrate 217.6 203.6 203.6 203.6 182.6 203.6 192.6 Elution control agent Sodium croscarmellose 14.0 Sodium carboxymethylcellulose 14.0 Bentonite 14.0 Microcrystalline cellulose 35.0 Crospovidone 14.0 Sodium starch glycolate 25.0 Lubricant Magnesium stearate 2.0 2.0 2.0 2.0 2.0 2.0 2.0 sub Total 250.0 250.0 250.0 250.0 250.0 250.0 250.0

Experimental Example

The tablets prepared in Examples and Comparative Examples were subjected to a dissolution test. The elution test was carried out with 900 mL of purified water, paddle method, and a rotation speed of 50 rpm as an eluent with one tablet each of the prepared tablets. Approximately 5 mL was taken 30 minutes after the initiation of the dissolution test, followed by filtration through a membrane filter. 3 mL was discarded and 1 mL was taken and tested according to a high-performance liquid chromatography method. The epinastine hydrochloride and montelukast sodium were sequentially separated according to the high performance liquid chromatography method and the area values of the respective peaks were integrated to calculate the concentration. The results are shown in Tables 2 and 3 and FIGS. 1 and 2 Respectively. When the concentration of montelukast sodium and epinastine in the eluate is 100%, the percentage of montelukast sodium and epinastine calculated at the time of collection is expressed as a percentage Respectively. Separately, a dissolution test was carried out on a commercially available drug containing both montelukast sodium-containing drugs Sincare and Epinastine hydrochloride. As a result, both of the ingredients were montelukast 70% or more, epinastine 85% Thus, preferred elution criteria were confirmed.

Leaching rate of montelukast after 30 minutes (%) Singular 75.4 Comparative Example 1 8.2 Comparative Example 2 64.5 Comparative Example 3 29.1 Comparative Example 4 39.4 Comparative Example 5 28.2 Example 1 75.1 Example 2 78.5

Elution rate of epinastine after 30 minutes elapsed (%) Allergy warmth 96.9 Comparative Example 1 21.2 Comparative Example 2 60.5 Comparative Example 3 41.2 Comparative Example 4 53.2 Comparative Example 5 38.6 Example 1 88.7 Example 2 92.6

Claims (6)

Wherein the composition comprises at least one elution regulator selected from the group consisting of crospovidone, carboxymethylcellulose calcium, and sodium starch glycolate.
The pharmaceutical composition according to claim 1, wherein the content of the elution regulator is 0.1 to 50% by weight of the total medicinal composition.
The pharmaceutical composition according to claim 1, wherein the crospovidone content is 0.01 to 10 parts by weight based on 1 part by weight of the main ingredient.
The pharmaceutical composition according to claim 1, wherein the carboxymethylcellulose calcium is 0.01 to 10 parts by weight based on 1 part by weight of the main ingredient.
The pharmaceutical composition according to claim 1, wherein the sodium starch glycolate is contained in an amount of 0.01 to 10 parts by weight based on 1 part by weight of the main ingredient.
The pharmaceutical composition according to any one of claims 1 to 5, wherein the antihistamine is selected from epinastine or azelastine.

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