KR102209104B1 - A method for producing an oral crumbling film comprising meloxicam and a oral crumbling film produced thereby - Google Patents

Abstract

The present invention relates to a method for producing an oral disintegrating film comprising meloxicam and an oral disintegrating film comprising meloxicam prepared thereby, and more particularly, to a film to facilitate oral administration of meloxicam A method for manufacturing an oral disintegrating film containing meloxicam, characterized in that the solubility is improved by dispersing meloxicam in a polymer after solubilizing meloxicam with NaOH in order to improve the therapeutic effect, and meloxicam prepared thereby It is an invention related to an oral disintegrating film containing roxicam.

Description

A method for manufacturing an oral disintegrating film containing meloxicam and an oral disintegrating film containing meloxicam produced thereby {A METHOD FOR PRODUCING AN ORAL CRUMBLING FILM COMPRISING MELOXICAM AND A ORAL CRUMBLING FILM PRODUCED THEREBY}

The present invention relates to a method for producing an oral disintegrating film comprising meloxicam and an oral disintegrating film comprising meloxicam produced thereby, and more particularly, to facilitate oral administration of meloxicam A method of manufacturing an oral disintegrating film containing meloxicam, characterized in that the solubility is improved by dispersing meloxicam in a polymer after solubilizing meloxicam with NaOH in order to improve the therapeutic effect, and It is an invention related to an oral disintegrating film containing meloxicam.

Formulations administered orally include various oral dissolution formulations such as tablets, chewable tablets, sublingual tablets, capsules, and liquids. Among them, general tablets and capsules have disadvantages of difficulty in taking drugs for patients who have difficulty in taking drugs, and liquid preparations have disadvantages that stability is poor and the dosage is not accurate. Accordingly, there is a need for a new formulation that can be easily taken orally.

Accordingly, formulations with new drug delivery systems are emerging through various studies. Oral disintegrating tablet (ODT), which was developed in the form of oral disintegration, is one of these results. However, it was pointed out that the oral disintegrating tablet also does not disintegrate all the drugs in a constant fast time, and the problem is that it is often necessary to take water again.

In order to solve this problem, a lot of research has recently been conducted on oral disintegrating film formulations. Oral disintegrating film formulations provide several advantages different from conventional solid, liquid and oral disintegrating tablets. Since the oral disintegrating film formulation can be taken without water, it is very useful not only for the elderly who have difficulty in taking tablets or capsules, but also children, the disabled, patients in bed, and busy modern people. It is evaluated to be a more advanced form than any existing formulation. In particular, when the drug is absorbed into the oral mucosa, the first pass of the liver can be avoided, and thus the oral disintegrating film has the advantage that it can be applied to drugs that receive a lot of liver metabolism among drugs absorbed from the digestive tract. Accordingly, many attempts have been made to manufacture oral disintegrating film formulations of various technologies for the physical properties of the film and patient compliance.

Meloxicam is an enolic acid-based nonsteroidal anti-inflammatory drug (hereinafter referred to as'NSAIDS') represented by the following structural formula, and its formula is 4-hydroxy-2-methyl-N-( 5-methyl-2-thiazyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.

[constitutional formula]

Meloxicam has a molecular weight of 351.4 and, like other NSAIDs, inhibits the synthesis of prostaglandin by inhibiting the activity of cyclooxygenase (COX), thereby exhibiting an anti-inflammatory effect, compared to cyclooxygenase-1 (COX-1). It more selectively inhibits sigenase-2 (COX-2).

However, meloxicam is a poorly water-soluble drug that reaches the highest blood concentration after 7-11 hours when administered orally, so there is a problem that it takes a long time to show efficacy after administration, and thus it is difficult to dissolve in the body. In the case of poorly water-soluble drugs, various solubilization methods are being studied to improve their solubility.

Solubilization refers to a phenomenon in which the solubility of a substance that is not well soluble in water increases due to the presence of a substance such as a surfactant. Typical solubilization methods include a method of increasing the surface area by reducing the size of a particle, a method of using a co-solvent, There is a method of making a soluble salt of an acid or base by attaching a counter ion to a poorly soluble substance, and a method of binding a polymer compound or a ligand. In addition, a method of increasing the solubility of a poorly soluble substance by forming micelles using a surfactant has been recently studied a lot.

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Korean Patent Publication No. 10-2015-0058563

It is an object of the present invention to provide a method for manufacturing an oral disintegrating film comprising meloxicam, which improves the solubility and convenience of administration in order to improve the therapeutic effect of a pharmaceutical composition containing meloxicam.

Another object of the present invention is to provide an oral disintegrating film manufactured by the manufacturing method of the present invention.

In order to solve the above problems, the present invention

(A) preparing a drug solution of dispersing meloxicam in a water-miscible solvent and then solubilizing it with 50% NaOH solution;

(B) preparing a polymer solution in which the polymer is dissolved in ethanol and then an excipient is added and mixed; And

(C) After mixing the drug solution and the polymer solution, adding a plasticizer to prepare a film shape; provides a method for manufacturing an oral disintegrating film comprising meloxicam.

In the method for manufacturing an oral disintegrating film containing meloxicam according to the present invention, the disintegrating egg solid preparation (film, granule, tablet, enteric tablet, capsule, etc.) disappears after a certain time in a test solution similar to gastric juice or a general test of the Korean Pharmacopoeia It refers to the phenomenon of dispersing below the particle state specified in the disintegration test of the method. In general, a disintegrant to promote disintegration in the digestive tract in the body may be added to the solid preparation.

In the method for producing an oral disintegrating film comprising meloxicam according to the present invention, meloxicam, which is one of the nonsteroidal anti-inflammatory agents, is poorly soluble and generally does not dissolve at low pH, but dissolves at high pH. In the present invention, it is characterized in that such meloxicam is solubilized by adding 50% by weight NaOH solution to increase solubility and to prepare an oral disintegrating film.

In the method for producing an oral disintegrating film comprising meloxicam according to the present invention, the water-miscible solvent may be a polar solvent selected from water, alcohol, acetone, and combinations thereof. The alcohol is preferably at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol or t-butanol, of which ethanol is more preferable.

In the method for producing an oral disintegrating film comprising meloxicam according to the present invention, (B) in the polymer solution production step of dissolving the polymer in ethanol and then adding an excipient to mix, the excipient is maltose, fructose, It is characterized by including sugar alcohol, which is one or more water-soluble carbohydrates selected from sucrose, lactose, glucose, galactose, trehalose, xylitol, sorbitol, erythritol, maltitol, mannitol, isomalt, and combinations thereof.

In the method for producing an oral disintegrating film comprising meloxicam according to the present invention, the excipient is characterized in that it is included in a ratio of 70 to 120 parts by weight based on 100 parts by weight of ethanol. In addition, the excipient is characterized in that it is included in a ratio of 35 to 46 parts by weight, specifically, 34 to 37 parts by weight, based on 100 parts by weight of the total polymer solution. In addition, the excipient is characterized in that it is included in a ratio of 90 to 140 parts by weight, specifically, 90 to 95 parts by weight, based on 1 part by weight of meloxicam. Further, the excipient is characterized in that it is included in a ratio of 30 to 42 parts by weight, specifically, 30 to 33 parts by weight, based on 100 parts by weight of the total oral disintegrating film.

In the method for producing an oral disintegrating film containing meloxicam according to the present invention, (B) in the polymer solution manufacturing step of dissolving the polymer in ethanol and then adding an excipient to mix, the polymer is pullulan, hydroxypropyl Methylcellulose, polyvinylpyrrolidone, gelatin, pectin, low viscosity pectin, low viscosity hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, carboxymethylcellulose, polyvinyl alcohol, polyacrylic acid, methylmethacrylate Selected from the group consisting of copolymers, carboxyvinyl polymer, polyethylene glycol, alginic acid, low viscosity alginic acid, sodium alginate, carrageenan, modified starch, casein, gluten, acacia gum, gum arabic, xanthan gum, guar gum, gellan gum, and locust bean gum It is characterized by being.

In the method for producing an oral disintegrating film containing meloxicam according to the present invention, in the step of preparing a polymer solution in which the (B) polymer is dissolved in ethanol and then mixed by adding an excipient, the polymer is 1 weight by weight of meloxicam. It is characterized in that it is contained in a ratio of 30 to 140 parts by weight based on parts.

In the method for producing an oral disintegrating film comprising meloxicam according to the present invention, in the step of (C) mixing the drug solution and the polymer solution and then adding a plasticizer to prepare an oral disintegrating film, the film The plasticizer used to impart flexibility and elasticity to the formulation includes at least one material selected from the group consisting of polyethylene glycol (PEG) and glycerin, and 100% by weight of an oral disintegrating film formulation comprising the meloxicam It characterized in that it contains 0.1 to 30% by weight with respect to.

The present invention also provides an oral disintegrating film comprising meloxicam prepared by the production method of the present invention. The oral disintegrating film containing meloxicam prepared according to the present invention may be preferably used for animals.

The medicinal product containing meloxicam prepared according to the present invention can be easily taken when administered orally to an animal by preparing meloxicam in an oral disintegrating film formulation.

In addition, the present invention has the effect of remarkably improving the solubility by solubilizing meloxicam with NaOH and dispersing it in a polymer.

1 shows the results of testing the dissolution rate of a film prepared according to an example of the present invention for 15 minutes in a pH 1.2 buffer solution.
2 shows the results of testing the dissolution rate of a film prepared according to an example of the present invention for 15 minutes in a pH 4.0 buffer solution.
3 shows the results of testing the dissolution rate of a film prepared according to an example of the present invention for 15 minutes in a pH 7.4 buffer solution.

Hereinafter, examples are presented to aid in understanding the present invention. However, the following examples are provided for easier understanding of the present invention, and the present invention is not limited to the following examples.

<Example 1> Preparation of oral disintegrating film

First, 200 mg of meloxicam was dispersed in 1,100 mg of ethanol, and 50 wt% NaOH prepared by mixing 200 mg of NaOH in 200 mg of purified water was mixed with ethanol in which the meloxicam was dispersed to prepare a solution to solubilize meloxicam. I did.

Thereafter, 6510 mg of Polyvinylpyrrolidone K30 (Kolidon 30) was dissolved in 8,600 mg of ethanol at 60° C., and then 8000 mg of D-mannitol was added to prepare a dispersed polymer solution.

The meloxicam solubilization solution and the polymer solution were mixed, and 5,000 mg of polyethylene glycol (PEG 400) was added as a plasticizer for the flexibility of the film to prepare an oral disintegrating film.

<Example 2>

When preparing the polymer solution, an oral disintegrating film was prepared in the same manner as in Example 1, except that 12,280 mg of D-mannitol was dissolved in 17,200 mg of ethanol.

<Example 3>

When preparing the polymer solution, an oral disintegrating film was prepared in the same manner as in Example 1, except that 18,420 mg of D-mannitol was dissolved in 26,300 mg of ethanol.

<Example 4>

When preparing the polymer solution, an oral disintegrating film was prepared in the same manner as in Example 1 except that D-mannitol 27,440 mg was dissolved in ethanol 26,300 mg.

<Experimental Example 1> Peelability evaluation

For Examples 1 to 4, a peeling test was performed on 10 healthy adult males, and the test results were shown in Table 1 by evaluating according to the following evaluation criteria. At this time, the test subjects were blinded in all tests.

Example 1 Example 2 Example 3 Example 4 Subject #1 4 4 2 0 Subject #2 4 4 2 0 Subject #3 4 3 One 0 Subject #4 4 4 2 0 Subject #5 4 4 One 0 Subject #6 4 3 2 0 Subject #7 4 4 2 0 Subject #8 4 4 One 0 Subject #9 4 4 One 0 Subject #10 4 3 One 0 Average 4 3.7 1.5 0

0 points-Can be easily peeled off.

1 point-Can be peeled off.

2 points-Can peel, but difficult to peel.

3 points-Peeling was possible, but the film was broken.

4 points-Cannot peel at all.

As a result of the above test, in the case of the oral disintegrating film prepared in Examples 1 and 2, it was difficult to manufacture the oral disintegrating film formulation because it did not peel.

On the other hand, it can be seen that the oral disintegrating film prepared in Examples 3 and 4 has excellent peelability and is suitable as an oral disintegrating film formulation.

Experimental Example 2> Sensory evaluation

Functionality was evaluated according to the following evaluation criteria under the same experimental conditions as the peelability evaluation, and the results are shown in Table 2.

Example 1 Example 2 Example 3 Example 4 Subject #1 4 2 2 One Subject #2 4 3 One One Subject #3 4 3 One One Subject #4 4 3 2 One Subject #5 4 2 2 One Subject #6 4 2 2 One Subject #7 4 3 2 One Subject #8 4 3 One One Subject #9 4 3 2 One Subject #10 4 2 2 One Average 4 2.6 1.7 One

0 points-No stickiness is felt at all.

1 point-There is almost no stickiness.

2 points-It is sticky enough to not mind.

3 points-There is some stickiness, but it does not come out on my hands.

4 points-Stickiness is severe and comes out on hands.

As a result of the above test, in the case of the oral disintegrating film prepared in Examples 1 and 2, the stickiness was severe, and it was difficult to prepare the oral disintegrating film formulation.

On the other hand, in the case of the oral disintegrating film prepared in Examples 3 and 4, there was little stickiness, and it was found that the oral disintegrating film formulation is most suitable for storage.

<Experimental Example 3> Drug dissolution rate comparison

First, in order to prepare a test solution, 6 samples of meloxicam 4.6mg, 4.2mg, 3.5mg, and 2.9mg respectively were taken for Examples 1 to 4, respectively, and were used as samples. Considering the conditions in the oral cavity, the eluate was subjected to a dissolution test at 37°C and 75 rpm in accordance with the second method of dissolution test method with each of 6 samples using 200 mL of pH7.5 buffer. After 15 minutes elapsed, 3 mL of the eluate was taken and filtered through a membrane filter having a pore of 0.45 µm to obtain a sample solution. Next, in order to prepare a standard solution, 4.0 mg of Meloxicam standard product was accurately taken and placed in a 100 mL volumetric flask. 50 mL of methanol was added, and the mixture was completely dissolved by ultrasonic shaking for 20 minutes, then cooled to room temperature, and methanol was added to make 100 mL. Thus, 40, 20, 10, 5, 2.5, 1.25 µg/mL standard solutions were prepared by diluting with an appropriate amount of mobile phase.

The dissolution rates were compared under the following conditions using High Performance Liquid Chromatography (HPLC), and are shown in Table 3.

Comparative Example 1 Example 3 Example 4 Dissolution rate (%) for 15 minutes in pH 1.2 buffer 12.1 69.8 72.6 Dissolution rate (%) for 15 minutes in pH 4.0 buffer 12.4 56.8 45.2 Dissolution rate (%) for 15 minutes in pH 7.4 buffer 64.5 81.55 48.5

-Mobile phase: A 1:1 (v/v) mixture of methanol and purified water was added with phosphoric acid to a pH of 2.6. (Buffer solution composition 3.6 g/L Sodium-1-decane sulfonate in water)

-Column: C18 (Aegispak 5μm C18-L or similar column) 150 x 4.60mm

-Retention time: 8 minutes

-Column temperature: 45 °C

-Detector: UV 230nm

-Flow rate: 2.0mL/min

-Injection volume: 20μL

As a comparative example, as a drug for pets used in the past, 0.2 mg of meloxicam per kg of body weight is initially administered orally, but 0.1 mg of meloxicam per kg of body weight at 24 hour intervals until symptoms are treated. Was orally administered..

The results of the dissolution experiment are shown in FIGS. 1 and 2. In FIGS. 1 and 2, the films prepared in Examples 3 and 4 exhibited higher dissolution rates than Comparative Example 1 in pH 1.2 and pH4.0 buffer solutions. Particularly, as shown in FIG. 3, Example 3 exhibited the highest dissolution rate in the pH 7.4 buffer solution, which is an oral condition.

In view of these experimental results, it can be seen that the dissolution rate is significantly higher in the oral disintegrating film prepared in the example of the present invention than the chewable tablet, which is a form of the conventional meloxicam drug.

Claims (4)

(A) dispersing meloxicam in ethanol, and then preparing a solubilized drug solution to solubilize with a NaOH solution;
(B) preparing a polymer solution in which polyvinylpyrrolidone is dissolved in ethanol and then mannitol is added and mixed; And
(C) After mixing the drug solution and the polymer solution, as a method for producing an oral disintegrating film comprising meloxicam comprising the step of preparing an oral disintegrating film by adding polyethylene glycol,
The mannitol is a method for producing an oral disintegrating film comprising meloxicam, which is included in an amount of 92.1 parts by weight based on 1 part by weight of meloxicam.
The method of claim 1,
In the step of preparing a polymer solution in which the (B) polyvinylpyrrolidone is dissolved in ethanol and then mannitol is added and mixed
The mannitol is characterized in that it is contained in a ratio of 70 to 120 parts by weight based on 100 parts by weight of ethanol,
Oral disintegrating film manufacturing method comprising meloxicam.
delete Oral disintegrating film comprising meloxicam produced by the manufacturing method of claim 1 or 2.

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