KR20130074766A - Film for oral cavity administration containing montelukast or its pharmaceutically acceptable salt - Google Patents

Abstract

PURPOSE: An oral disintegrating film (ODF) containing montelukast or a pharmaceutically acceptable salt thereof, preferably montelukast sodium, is provided to improve montelukast stability. CONSTITUTION: A montelukast ODF contains ODF or a pharmaceutically acceptable salt thereof, a polymer which is a film forming agent, and a plasticizer. The loss on drying of the film is 1-8 wt%. A method for manufacturing the montelukast ODF comprises the steps of: preparing a liquid composition containing dissolved or dispersed montelukast ODF or a pharmaceutically acceptable salt thereof, the polymer, and the plasticizer; applying the liquid composition for forming a film; and drying the film.

Description

Film for oral administration containing montelukast or its pharmaceutically acceptable salts {Film for oral cavity administration containing montelukast or its pharmaceutically acceptable salt}

The present invention relates to a film dosage form for oral administration, containing montelukast or a pharmaceutically acceptable salt thereof, preferably montelukast sodium. Film dosage form for oral administration according to the present invention is disintegrated in the oral cavity during administration, and can be easily taken without water.

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

Current oral formulations are available in tablets, capsules, granules and the like. All of these formulations are inconvenient to administer unless taken with water.

Film formulations that are taken by dissolving and dissolving in the oral cavity are easily disintegrated and can be taken only by saliva in the oral cavity, and thus can provide convenience for children, the elderly, patients lying for a long time, etc. who are difficult to swallow tablets. In addition, the thin film provides convenience for carrying around in a purse or a notebook.

Montelukast, on the other hand, is known to be relatively easily denatured by moisture, heat and light. Therefore, in order to make montelukast into a film formulation, stability must be ensured during storage as well as during storage.

Therefore, the problem to be solved by the present invention is to provide a montelukast or a pharmaceutically acceptable salt thereof as an active ingredient, easy to take, the stability of the oral administration film and a method for producing the same.

In order to solve the above problems, the present invention provides oral administration film containing montelukast or a pharmaceutically acceptable salt thereof, preferably montelukast sodium. The film for oral administration of the present invention is to be dissolved or finely dispersed in the oral cavity. It is usually placed on the tongue to melt, but can also be attached to the palate, sublingual, buccal, etc.

Pharmaceutically acceptable salts of montelukast according to the invention consist of lithium, sodium, potassium, calcium, ammonium, magnesium, dicyclohexylamine, amantadine, cyclopropylamine or other organic amino Salts include, but are not limited to.

The oral administration film of the present invention is also referred to as oral dispersible film (ODF), strip, orally dissolving film, etc., and is taken by dissolving or finely dispersing in oral cavity Done. These films are usually placed on the tongue to melt, but can also be administered by adhering to the palate, sublingual, buccal, or the like. Film formulations according to the invention have the advantage that they can be taken without water.

Oral administration film according to the present invention is a film containing a montelukast 1 ~ 15mg and the weight per sheet 20 ~ 200mg, 5 ~ 20% by weight of the total weight of the plasticizer, having a thickness of less than 500um. Preferably such films may comprise any one or more of flavoring agents, colorants and sweeteners, the content of which is within 10% by weight of the total weight of the film, respectively. In addition, additional thickeners, stabilizers, pH adjusting agents, disintegrants, antibacterial agents, saliva irritants, acidulants, emulsifiers and the like may be added as necessary. Most of the weight, with the exception of the additives mentioned, accounts for the material involved in film formation.

Examples of the film-forming agent include cellulose such as starch, water-soluble starch, modified starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose carboxymethyl cellulose and hydroxyethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, pullulan, gelatin, One or more selected from alginic acid, guar gum, xanthan gum, polyethylene glycol, acacia gum, arabian gum, polyacrylic acid, amylose, pectin, dextrin, chitin, chitosan, gelatin, glycene, casein, carrageenan, lobbyist gum, etc. Can be.

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

Artificial flavors, natural flavors or mixtures thereof may be used as the flavoring agent, and various flavoring materials including lemon, peppermint, cherry, apple, grape, blueberry, orange, peach, pineapple, grapefruit, ginseng, etc. may be used. have.

As the colorant, artificial dyes, natural dyes or mixtures thereof can be used.

The acidulant may be citric acid, malic acid, lactic acid, acetic acid, tartaric acid, fumaric acid or a mixture thereof.

The oral administration film according to the present invention is prepared by dissolving or dispersing the above-mentioned components in a single solvent or a mixed solvent such as water, alcohols (for example, lower alcohol having 1 to 4 carbon atoms), acetone, or the like to prepare a solution or mixed solution. It is prepared by applying this solution or mixed solution up to 1000 μm and drying it. Solvents that can be used in the preparation of the oral administration film according to the present invention include acetone, leptane, butanol, propanol, pentanol, ethyl acetate, etc., in addition to the above-mentioned solvents, but the present invention is not limited to these types of solvents. For example, if necessary, a solvent belonging to class 3 may be used in the description of the residual solvent in the ICH guideline.

The present invention includes a manufacturing process of making a film form by applying a thin film to the manufacturing stock solution mixed with the above components to less than 1000um to dry by heating it. In addition, the produced film is cut to have a desired size and weight, and made into a final product by including the cut film as a packaging material, preferably an aluminum pouch film, which blocks light and moisture.

The present invention also provides a method of preparing a liquid composition comprising (S1) montelukast or a pharmaceutically acceptable salt thereof, a film former, and a lysozyme dissolved or dispersed, (S2) applying the liquid composition, and (S3) applying the liquid. And the resulting formed film is dried until the LOD is 1-8% by weight (preferably 2-7% by weight, more preferably 3-6% by weight). It provides a method for producing.

In the present invention, LOD can be measured by using a moisture analyzer MX-50 model of AND. When set to LO ACCURACY in the Standard mode, it means a weight percent that is reduced by weight of the film before drying when about 1 g of the film is dried at a temperature of 105 ° C.

The present invention not only provides stability of montelukast by controlling the moisture content of montelukast-containing film formulations, but also the physical properties of the film (below 1%, the film may break too easily, and if it exceeds 8%, the film may be too tacky. Difficulties in dealing with this).

More preferably, the present invention is a manufacturing method according to the present invention, that is, the process of preparing and drying the liquid composition as a stock solution and the process of cutting and packaging the dried film to a desired size (weight) to prevent LED lamp, sodium lamp or fading Provided is a method for producing a montelukast-containing film, which is carried out under a fluorescent lamp (UV-blocking fluorescent lamp), preferably under an LED lamp or a sodium lamp.

UV-blocking fluorescent light is to block the UV from ordinary fluorescent lights. Therefore, the use of ordinary fluorescent lamps, but the UV light blocking film in the direction of the light irradiation can be said to be the same method in principle, so using the normal fluorescent lamps, but the UV film is attached in the direction of the light irradiation process is also performed. It is included in the scope of the present invention.

Specifically, the use of such illumination can maintain the stability of montelukast even under the same lux conditions.

More preferably, in the production of the montelukast film of the present invention, the degree of illumination is maintained such that the portion of the film is exposed to about 300 lux or less, and the time for which the film is exposed to light is adjusted to be within 2 hours.

Preferably, the present invention also uses montelukast sodium as the main component, pregelatinized starch and / or hydroxypropylcellulose as the film former, and other components in the case of oral administration films using glycerin as the plasticizer. It is based on the surprising discovery that the montelukast mouth film used is more stable than the montelukast mouth film used, and the film has good physical properties. More preferably, such oral films according to the invention contain sucralose as a sweetener and may further comprise citric acid.

In order to prepare the ODF according to the present invention, the stability of the drug montelukast can be maintained without changing the stability of the drug montelukast even in a liquid composition containing water, and the montelukast-containing oral film made by the present invention is placed in an aluminum pouch. It is stable even if it is stored for 6 months under the condition of 40 ℃ and 75% RH in a packaged state.

In the present invention, "stable" means that the MOK-3-sulphoxide is generated in less than 1.7% by weight, the total content of the other flexible material is 2.5% by weight or less.

In the case of the montelukast sodium film formulation having such a prescription, the stability of the drug was secured during the production process, the mass productivity was easy, the sensory properness, and the long-term stability as the drug was secured.

Oral disintegrating film (ODF) formulations comprising montelukast or a pharmaceutically acceptable salt thereof, preferably montelukast sodium, of the present invention and methods for preparing such formulations without compromising the stability of montelukast.

Hereinafter, embodiments of the present invention will be described in detail to facilitate understanding of the present invention. However, the embodiments according to the present invention can be modified into various other forms, and the scope of the present invention should not be construed as being limited to the following embodiments. Embodiments of the invention are provided to more fully describe the present invention to those skilled in the art.

≪ Example 1 >

A film formulation comprising montelukast sodium was prepared according to the formula below. All materials were dissolved in solvent (water) and then mixed uniformly. This was dried in an oven at 80 ° C., but a film was prepared such that LOD (loss on drying, 120 ° C., 10 minutes) was 1 to 3 wt%. The film produced was cut to an appropriate size such that the film weight was about 40.5 mg. In it, montelukast sodium was about 5.2 mg. The thickness of the produced film was about 50 ~ 150um.

Ingredients Input (g) Montelukast Sodium 5.2 Pregelatinized starch 8.8 Hydroxypropylcellulose 21 glycerin 4 Sucralose One Citric acid 0.5 water 120

<Example 2>

The film was prepared in the same manner as in Example 1 so that the LOD was 4-6 wt%.

<Experimental Example 1>

After storing the films prepared in Examples 1 and 2 under the same conditions, the degree of occurrence of the flexible material of montelukast was compared. Specifically, the samples made in Examples 1 and 2 were packaged in aluminum pouches and stored in a chamber maintaining a temperature of 40 degrees Celsius, 75% relative humidity. Table 2 shows the result of comparing the degree of occurrence of the flexible material of the sample stored after 6 months storage. 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.

Analysis of the analog was performed using UPLC, the analysis conditions were as follows.

Column: 2.1 mm x 100 mm, Waters ACQUITY UPLC® HSS C18 1.8 μm

Injection volume: 2 μl

Detector: ultraviolet absorbance photometer (wavelength 258 nm)

Column temperature: 40 ° C

Sample temperature: 5 ° C

Mobile phase A: 0.1% Formic acid in Water, mobile phase B: 100% Acetonitrile

    Start-13 minutes: Mobile phase A: Mobile phase B = 35: 65

    13 minutes ~ 13.1 minutes: Mobile phase A: Mobile phase B = 0: 100

    13.1 to 15 minutes: Mobile phase A: Mobile phase B = 35: 65

Diluent: 100% Methanol

MOK-3-sulphoxide Unknown flexible material Total flexible material Example One 2 One 2 One 2 Early 0.19% 0.13% 0% 0.05% 0.24% 0.18% 6 months 0.64% 1.02% 0.15% 0.17% 1.01% 1.34%

MOK-3-sulphoxide is 2- (1-{(1R) -1- {3-[(E) -2- (7-chloro-2-quinolyl) -1-ethenyl, which is a flexible substance of montelukast ] phenyl} -3- [2- (1-hydroxy-1-methylethyl) phenyl] propylsulfinylmethyl) cyclopropyl} acetic acid.

<Example 3>

The film was prepared in the same manner as in Example 1 so that the LOD was 1 wt% or less.

<Example 4>

The film was prepared in the same manner as in Example 1 but with an LOD exceeding 8 wt%.

<Experimental Example 2>

The films prepared in Examples 1, 2, 3 and 4 were wound on a rod of about 10 mm in diameter while pulling with very weak force. According to the bending of Examples 1, 2, and 4, the film of Example 3 was broken before the angle of 90 degrees was bent.

<Experimental Example 3>

Two sheets of film were piled up. The films made in Examples 1, 2 and 3 could straighten the film, but the films of Example 4 stuck together and did not easily fall off.

<Examples 5 and 6>

In the same manner as in Example 1, a stock solution obtained by dissolving a raw material in a solvent was prepared. At this time, the composition is shown in Table 3 (Example 5) and 4 (Example 6).

Ingredients Input (g) Montelukast Sodium 5.2 Starch 10 Hydroxypropylcellulose 21.43 glycerin 4.8 Sucralose 0.77 Lemon incense 3 Citric acid 0.8 water 20 ethanol 50

Ingredients Input (g) Montelukast Sodium 5.2 Pregelatinized starch 10 Hydroxypropylcellulose 21.7 glycerin 4.7 Acesulfame potassium 1.4 Lemon incense 3 water 70

<Experimental Example 4>

The stock solution of Examples 5 and 6 was placed in a light-blocked container and stored in a chamber maintained at 40 degrees Celsius for 1 week, and then analyzed for the flexible material of the stock solution. The sum of the total lead remained unchanged. Therefore, it was confirmed that the stability of the product can be maintained even when stored in the undiluted state during the process. The measurement results are shown in Table 5 below.

Example 5 Example 6 Early 0.5% 0.5% One week 0.4% 0.6%

<Experimental Example 5>

The film sample prepared in Example 1 was placed in a transparent glass bottle and the lid was closed so that the sample did not absorb moisture in the air, and then the bottle was kept for 2 hours under fluorescent lamps for home / industrial lighting, LED lamps, sodium lamps, and anti-fading fluorescent lamps. After storing upside down and analyzed the flexible material. Each case was tested by adjusting the brightness of each lamp or adjusting the distance of the lamp such that the conditions were about 1000 lux and about 200 lux in each lamp. The total degree of the resulting flexible material is shown in Tables 6 and 7 below.

brightness About 1000 lux Example Ordinary fluorescent light LED light Sodium Fading prevention
Fluorescent lamp Incandescent light bulb 1 hours 1.8 0.4 0.4 0.5 0.7 2 hours 3.1 0.5 0.5 0.8 1.3

brightness About 200 lux Example Ordinary fluorescent light LED light Sodium Fading prevention
Fluorescent lamp Incandescent light bulb 1 hours 0.6 0.3 0.3 0.3 0.3 2 hours 0.9 0.3 0.3 0.4 0.6

As shown in Tables 6 and 7, under the fluorescent lamps, about 0.63% of a flexible substance was generated when exposed to 200 lux for 1 hour. However, under LED light or anti-fade fluorescent light, up to 0.51% of flexible material was generated in 1 hour even under 1000 lux light source.

In the case of a drug that generates a flexible material by light, the exposure time should be shortened to suppress the generation of the flexible material as much as possible. In addition, it is advantageous that the illuminance is high in order for the worker to visually check the product for abnormalities. In the case of LED lamps, sodium lamps, or anti-fade fluorescent lamps, the amount of flexible material does not increase by 15 minutes at 1000 lux and does not increase significantly by 30 minutes. However, after 15 minutes of exposure, ordinary fluorescent lamps start to increase the amount of flexible substances. After 30 minutes of exposure, the amount of flexible substances increases by more than 50% by weight.

&Lt; Example 7 >

A film formulation comprising montelukast sodium was prepared according to the formula below. All materials were dissolved in solvent (water) and then mixed uniformly. This was dried in an oven at 80 ° C., but a film was prepared such that LOD (loss on drying, 120 ° C., 10 minutes) was 4 to 5 wt%. The film produced was cut to the appropriate size to be about 103.88 mg. There was about 10.4 mg of montelukast sodium. The thickness of the produced film was about 50 ~ 150um.

Ingredients Input (g) Montelukast Sodium 4.45 Hydroxyl propyl cellulose 30 glycerin 10 water 50

<Experimental Example 6>

The film prepared in Example 1 and the Singulare ^TM 10mg tablet (Comparative Example 1, Manufacturer: Merck Sharp & Dohme Limited, UK) were stored under the same conditions, and then the total amount of calcified material of montelukast was compared. Specifically, the oral film sample and singular tablets made in Example 1 were packaged in an aluminum pouch and stored in a chamber maintaining a temperature of 50 degrees Celsius and 75% relative humidity. The result of comparing the moisture content of the sample stored after 6 months storage is shown in the following table.

Example 7 Comparative Example 1 6 months 1.52% 1.59%

As shown in the experimental results of Table 9 and various previous experimental results, in the case of montelukast oral film preparations using starch, modified starch, hydroxypropyl cellulose or mixtures thereof as polymers, hygroscopic and flexible materials are produced compared to other polymers. Excellent stability in terms of back.

Claims (8)

Montelukast or a pharmaceutically acceptable salt thereof; A polymer that is a film former; And Oral dispersible film (Oral Dispersible Film) comprising a plasticizer,
Montelukast oral disintegrating film, characterized in that the drying loss of the film is 1-8% by weight. The montelukast oral disintegrating film according to claim 1, wherein the polymer is at least one selected from the group consisting of starch, modified starch and hydroxypropyl cellulose. The montelukast oral disintegrating film of claim 1, wherein the plasticizer is at least one selected from the group consisting of glycerin, propylene glycol, polyethylene glycol, and triacetin. (S1) preparing a liquid composition in which montelukast or a pharmaceutically acceptable salt thereof, a polymer that is a film forming agent, and a lye device are dissolved or dispersed,
(S2) applying the liquid composition for film molding and
(S3) drying the applied and formed film until the drying loss is 1-8% by weight
Method for producing a montelukast oral disintegrating film, characterized in that it comprises. 5. The method of claim 4, wherein the preparation is performed under an LED lamp, sodium lamp or UV-blocking fluorescent lamp. 6. The method of claim 4, wherein the polymer is at least one selected from the group consisting of starch, modified starch, and hydroxypropyl cellulose. The method of claim 4, wherein the plasticizer is at least one selected from the group consisting of glycerin, propylene glycol, polyethylene glycol, and triacetin. The method of claim 7, wherein the plasticizer is glycerin.