JP2015503549A - Film for oral administration containing montelukast or a pharmaceutically acceptable salt thereof - Google Patents

Abstract

The present invention provides an orally disintegrating film (ODF) comprising montelukast or a pharmaceutically acceptable salt thereof, desirably montelukast sodium. Moreover, this invention provides the manufacturing method of the montelukast orally disintegrating film which does not inhibit the stability of a montelukast and whose physical property is remarkably excellent.

Description

  The present invention relates to film dosage forms for oral administration and to those containing montelukast or a pharmaceutically acceptable salt thereof, preferably sodium montelukast. Since the film dosage form for oral administration according to the present invention disintegrates in the oral cavity at the time of taking, it can be taken easily without water.

  Montelukast is a leukotriene receptor antagonist (LTRA) and is used for asthma, allergic rhinitis and the like.

  Current oral dosage forms are marketed in tablets, capsules, granules and the like. These dosage forms are all inconvenient and difficult to administer unless taken with water.

  The film dosage form that is administered and dissolved in the oral cavity can be easily disintegrated and taken only with the saliva in the oral cavity, which is convenient for children who are difficult to swallow tablets, elderly patients, and bedridden patients for a long time. Can be provided. In addition, because of the characteristics of the thin film, it offers a convenient convenience for carrying in a wallet or notebook.

  Montelukast is known to be relatively easily denatured by moisture, heat and light. Therefore, in order to make montelukast into a film dosage form, stability must be ensured during production as well as during storage after production.

  The present invention has been made in view of the above-mentioned problems, and includes a film for oral administration which includes montelukast or a pharmaceutically acceptable salt thereof as an active ingredient, is easy to take, and ensures stability. The purpose is to provide.

  In order to achieve the above object, the present invention provides a film for oral administration comprising montelukast or a pharmaceutically acceptable salt thereof, desirably montelukast sodium. The film for oral administration of the present invention is taken in the mouth or dissolved finely. It is usually placed on the tongue and dissolved, but it can also be administered by adhering to the palate, sublingual or buccal cavity.

  Pharmaceutically acceptable salts of montelukast according to the present invention may be from lithium, sodium, potassium, calcium, ammonium, magnesium, dicyclohexylamine, amantadine, cyclopropylamine, or other organic amino acids. But not limited thereto.

  The film for oral administration of the present invention is also referred to as an oral disintegrable film (ODF), a strip, an oral dissolving film, etc., and is dissolved in the oral cavity. Take finely dispersed. Such a film is usually placed on the tongue and melted, but can also be administered by adhering to the palate, sublingual or oral vestibule. The film dosage form according to the present invention has the advantage that it can be taken without water.

  The film for oral administration according to the present invention contains 1 to 15 mg of montelukast, the weight per sheet is 20 to 200 mg, 5 to 20% by weight of the total weight is a plasticizer, and the film has a thickness of 500 μm or less. It is. Such a film preferably contains at least one of a flavoring agent, a coloring agent and a sweetening agent, and the content thereof is within 10% by weight relative to the total weight of the film. In addition, a thickener, a stabilizer, a pH adjuster, a disintegrant, an antibacterial agent, a saliva stimulant, a sour agent, an emulsifier, and the like can be further added as necessary. Most of the weight excluding such additives is occupied by substances involved in film formation.

  In the present specification, as the film forming agent, starch, water-soluble starch, modified starch, cellulose such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, pullulan, gelatin, alginic acid, guar gum One or more selected from xanthan gum, polyethylene glycol, acacia gum, gum arabic, polyacrylic acid, amylose, pectin, dextrin, chitin, chitosan, gelatin, gluten, casein, carrageenan, locust bean gum, etc. it can.

  As the plasticizer, one or more selected from glycerin, propylene glycol, polyethylene glycol, triacetin and the like can be used.

  As the flavoring agent, artificial flavoring, natural flavoring or a mixture thereof can be used, and various flavoring materials including lemon, peppermint, cherry, apple, grape, blueberry, orange, peach, pineapple, grapefruit, ginseng, etc. Can be used.

  As the colorant, an artificial pigment, a natural pigment or a mixture thereof can be used.

  As the sour agent, citric acid, malic acid, lactic acid, acetic acid, tartaric acid, fumaric acid or a mixture thereof can be used.

  In the film for oral administration according to the present invention, the above-described components are dissolved or dispersed in a single solvent or mixed solvent such as water, alcohols (for example, lower alcohols having 1 to 4 carbon atoms), acetone or the like. After the liquid is produced, the liquid or the mixed liquid is applied to a maximum of 1,000 μm or less, and dried to produce the liquid. Examples of the solvent that can be used for the production of the film for oral administration according to the present invention include acetone, heptane, butanol, propanol, pentanol, ethyl acetate and the like in addition to the above-mentioned solvents. It is not limited by the type, and for example, a solvent belonging to class 3 can be used from the description of the residual solvent in the International Conference on Harmonization (ICH) guidelines as necessary.

  In this invention, the manufacturing process made in the form of a film is included by apply | coating thinly the manufacturing stock solution mixed from said component to 1,000 micrometers or less, and applying heat to it and drying. In addition, the manufactured film is cut to have a desired size and weight, and packaged with a packaging material that blocks light and moisture, preferably an aluminum pouch film, to produce a final product.

  Further, the method for producing a film for oral administration containing montelukast with improved stability according to the present invention includes (S1) a liquid in which montelukast or a pharmaceutically acceptable salt thereof, a film forming agent and a plasticizer are dissolved or dispersed. A step of producing a composition, (S2) a step of applying the liquid composition, and (S3) an LOD of 1 to 8% by weight (preferably 2 to 7% by weight, more preferably 3 to 6% by weight).

  In the present invention, LOD can be measured using a moisture meter MX-50 model from AND. LOD means the weight% which is reduced with respect to the film weight before drying when about 1 g of film is dried at 105 ° C. when set to LO ACCURACY in standard mode.

  In the present invention, by adjusting the moisture content of the film dosage form containing montelukast, not only the stability of montelukast, but also various physical properties of the film (1% or less makes the film very prone to cracking, if it exceeds 8% It provides the advantage that it can be suitably adjusted (too sticky to handle the film).

  More desirably, a method for producing a montelukast-containing film according to the present invention, that is, a process of producing and drying a liquid composition which is a production stock solution, and a process of cutting and packaging the dried film into a desired size (weight), It is characterized by being carried out under an LED lamp, a sodium lamp or a fluorescent lamp for preventing fading (UV-blocking fluorescent lamp), more preferably under an LED lamp or a sodium lamp.

The UV-blocking fluorescent lamp is a lamp that blocks UV emitted from a general fluorescent lamp. Therefore, it can be said that this method is the same in principle as using a general fluorescent lamp and applying a UV blocking film in the direction of light irradiation. Therefore, using a general fluorescent lamp and blocking the UV in the direction of light irradiation. It is also included in the scope of the present invention to perform the above manufacturing process with the film attached.
In particular, when such illumination is used, the stability of montelukast can be maintained even under the same lux conditions.

  More preferably, in the method for producing a montelukast film according to the present invention, the exposed portion of the film is maintained at an illumination intensity of about 300 lux or less, and the time during which the film is exposed to light is adjusted within 2 hours. More desirable.

  Further, the present invention uses montelukast sodium as a main component, pregelatinized starch and / or hydroxypropylcellulose as a film forming agent, and a film for oral administration using glycerin as a plasticizer, This is based on the surprising finding that the film has superior stability and excellent physical properties as compared to the film for oral montelukast using other components. More desirably, the oral film according to the present invention contains sucralose as a sweetening agent and may further contain citric acid.

  The stability of the drug montelukast can be maintained for more than 2 weeks even in a liquid composition that is in a stock solution state containing water for producing an orally disintegrating film (ODF) according to the present invention. The montelukast-containing oral film is stable even when stored for 6 months under conditions of 40 ° C. and 75% RH in a state of being packaged with an aluminum pouch.

  In the present invention, “stable” means that MOK-3-sulfoxide is generated at 1.7% by weight or less and the total content of other impurities is 2.5% by weight or less.

  In the case of a montelukast sodium film preparation having such a formulation, the stability of the chemical is ensured during the production process, mass production is easy, it is appropriate in terms of sensory properties, and long-term stability as a chemical can be ensured. .

  According to the present invention, an orally disintegrating film (ODF) formulation comprising montelukast or a pharmaceutically acceptable salt thereof, preferably montelukast sodium, and such a formulation can be produced without inhibiting the stability of montelukast. it can.

  Hereinafter, in order to help understanding of the present invention, examples will be described in detail. However, the examples according to the present specification can be modified in many other forms, and the scope of the present invention should not be construed to be limited to the examples described below. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the concept of the invention to those skilled in the art.

<Example 1>
A film preparation containing montelukast sodium was produced according to the following formulation. All materials were dissolved in a solvent (water) and mixed uniformly. Although it was dried in an oven at 80 ° C., a film was produced so that LOD (loss on drying, 120 ° C., 10 minutes) was 1 to 3% by weight. The produced film was cut to an appropriate size so that the film weight was about 40.5 mg. Of these, montelukast sodium was about 5.2 mg. The thickness of the manufactured film was about 50 to 150 μm.

<Example 2>
The film was made as in Example 1, but with a LOD of 4 to 6% by weight.

<Experimental example 1>
After the films produced in Example 1 and Example 2 were stored under the same conditions, the degree of generation of montelukast impurities was compared. Specifically, the samples made in Example 1 and Example 2 were packaged with an aluminum pouch and stored in a chamber maintaining a relative humidity of 75% at 40 ° C. Table 2 below shows the results of comparing the degree of occurrence of impurities in the stored samples after storage for 6 months. The moisture content of the sample of Example 1 was about 2% by weight, and the moisture content of the sample of Example 2 was about 5% by weight.

  The impurity was analyzed using UPLC, and the analysis conditions were as follows.

Column: 2.1 mm x 100 mm, Waters ACQUITY UPLC (registered trademark) HSS C18 1.8 μm
Injection volume: 2 μl
Detector: UV spectrophotometer (wavelength 258 nm)
Column temperature: 40 ° C
Sample temperature: 5 ° C
Mobile phase A: 0.1% formic acid-water, mobile phase B: 100% 13 minutes from the start of acetonitrile: mobile top A: mobile top B = 35: 65
From 13 minutes to 13.1 minutes: moving up A: moving up B = 0: 100
13.1 to 15 minutes: Moving up A: Moving up B = 35: 65
Diluent: 100% methanol

  Here, MOK-3-sulfoxide is 2- (1-{(1R) -1- {3-[(E) -2- (7-chloro-2-quinolyl) -1-] which is an impurity of montelukast. Ethenyl] phenyl} -3- [2- (1-hydroxyl-1-methylethyl) phenyl] propylsulfinylmethyl) cyclopropyl} acetic acid.

<Example 3>
The film was produced in the same manner as in Example 1, but the LOD was 1% by weight or less.

<Example 4>
The film was produced in the same manner as in Example 1 except that the LOD exceeded 8% by weight.

<Experimental example 2>
The films produced in Examples 1, 2, 3 and 4 were wound on a rod having a diameter of about 10 mm while being pulled with a very weak force. When bent, in Examples 1, 2 and 4, it bent without problems, but the film of Example 3 cracked before bending to 90 degrees.

<Experimental example 3>
Two pieces of the produced film were stacked. The films made in Examples 1, 2, and 3 were able to pull apart from each other immediately, but the films in Example 4 were stuck together and could not be easily pulled apart.

<Example 5 and Example 6>
In the same manner as in Example 1, a stock solution in which the raw material was dissolved in a solvent was produced. The composition at this time is as shown in Table 3 (Example 5) and Table 4 (Example 6) below.

<Experimental example 4>
The stock solutions of Example 5 and Example 6 were placed in a light-shielded container and stored in a chamber maintained at 40 ° C. for 1 week, and then the impurities in the stock solution were analyzed. The amount of total impurity was maintained without significant change. Therefore, it was confirmed that the stability of the product could be maintained even when stored in a stock solution state during the process. The measurement results are shown in Table 5.

<Experimental example 5>
The film sample produced in Example 1 was placed in a transparent glass bottle and covered to prevent the sample from absorbing moisture in the air. Then, fluorescent lamps for general household / industrial lighting, LED lamps, sodium lamps, fading The bottle was inverted under a fluorescent lamp for prevention and stored for 2 hours, and then the impurities were analyzed. Experiments were performed in each case by adjusting the brightness of each lamp or adjusting the distance from the lamp so that the condition of each lamp was about 1,000 lux and about 200 lux. As a result, Table 6 and Table 7 show the degree of all impurities produced.

  As shown in Tables 6 and 7, under a general fluorescent lamp, about 0.63% impurity was generated when exposed to 1 hour even when the lamp was lowered to 200 lux. However, under an LED lamp or a fading-proof fluorescent lamp, a maximum of 0.51% impurity was generated in one hour even under a light source of about 1,000 lux.

  In the case of pharmaceuticals that generate impurities due to light, the exposure time must be reduced so as to suppress the generation of impurities as much as possible, but some exposure is inevitable through various processes such as molding and packaging. In addition, it is advantageous for the worker to have high illuminance so that the operator can visually recognize the presence or absence of abnormality of the product during the work. In the case of an LED lamp, a sodium lamp, or a fluorescent lamp for fading prevention, the impurity content does not increase up to 15 minutes even at 1,000 lux, and does not increase so much up to 30 minutes. However, in general fluorescent lamps, the impurity content starts to increase only after 15 minutes exposure, and the impurity content increases by 50% by weight or more after 30 minutes exposure.

<Example 7>
A film preparation containing montelukast sodium was produced according to the following formulation. All materials were dissolved in a solvent (water) and mixed uniformly. It was dried in an oven at 80 ° C., and a film was produced so that LOD (loss on drying, 120 ° C., 10 minutes) was 4 to 5% by weight. The manufactured film was cut to an appropriate size to be about 103.88 mg. Of these, montelukast sodium was about 10.4 mg. The thickness of the manufactured film was about 50 to 150 μm.

<Experimental example 6>
The film produced in Example 1 and Singlea ^™ 10 mg tablets (Comparative Example 1, Merck Sharp & Dohme Limited, UK) were stored under the same conditions, and the amount of impurities generated in Montelukast was compared. Specifically, the oral film sample and Singleah tablet produced in Example 1 were packaged with an aluminum pouch and stored in a chamber maintaining a relative humidity of 75% at 50 ° C. Table 9 shows the results of comparing the moisture content of the stored samples after 6 months storage.

  As shown in the experimental results of Table 9 and the various experimental results described above, in the case of a montelukast oral film preparation using starch, modified starch, hydroxypropyl cellulose, or a mixture thereof as the polymer, other polymers Compared to the above, the stability was remarkably good in terms of hygroscopicity and generation of impurities.

Claims (8)

An orally disintegrating film comprising montelukast or a pharmaceutically acceptable salt thereof; a polymer that is a film-forming agent; and a plasticizer,
A montelukast orally disintegrating film, wherein the loss on drying of the film is 1 to 8% by weight.   The montelukast orally disintegrating film according to claim 1, wherein the polymer is one or more selected from the group consisting of starch, modified starch, and hydroxypropylcellulose.   The montelukast orally disintegrating film according to claim 1, wherein the plasticizer is at least one selected from the group consisting of glycerin, propylene glycol, polyethylene glycol, and triacetin. (S1) a step of producing a liquid composition in which montelukast or a pharmaceutically acceptable salt thereof, a polymer as a film forming agent and a plasticizer are dissolved or dispersed;
(S2) applying the liquid composition for film formation; and (S3) drying the applied film until the loss on drying is 1 to 8% by weight. The manufacturing method of the Montelukast orally disintegrating film.   The said manufacturing method is performed under a LED lamp, a sodium lamp, or a UV block fluorescent lamp, The manufacturing method of the montelukast oral disintegration film of Claim 4 characterized by the above-mentioned.   The method for producing a montelukast orally disintegrating film according to claim 4, wherein the polymer is at least one selected from the group consisting of starch, modified starch, and hydroxypropylcellulose.   The method for producing a montelukast orally disintegrating film according to claim 4, wherein the plasticizer is at least one selected from the group consisting of glycerin, propylene glycol, polyethylene glycol, and triacetin.   The said plasticizer is glycerol, The manufacturing method of the montelukast orally disintegrating film of Claim 7 characterized by the above-mentioned.