WO2019177332A1 - Method for producing orally disintegrating film comprising meloxicam and orally disintegrating film comprising meloxicam produced thereby - Google Patents

Abstract

The present invention relates to a method for producing an orally disintegrating film comprising meloxicam and an orally disintegrating film comprising meloxicam produced thereby and, more specifically, to a method for producing an orally disintegrating film comprising meloxicam and an orally disintegrating film comprising meloxicam produced thereby, the method in which meloxicam is made into a film formulation to facilitate oral administration thereof, wherein meloxicam is solubilized with NaOH and then dispersed in polymer to improve the solubility thereof, thereby improving the therapeutic effects.

Description

Method for producing oral disintegrating film containing melocampal and oral disintegrating film comprising melocampal prepared thereby

The present invention relates to a method for producing oral disintegrating film comprising meloxycamps and an orally disintegrating film comprising meloxycam prepared by the present invention, and more particularly, to facilitate oral administration of meloxycam. Oral disintegrating film manufacturing method comprising a hydroxycampham, characterized in that to improve the solubility by dissolving in the polymer to prepare a film formulation, solubilizing hydroxycam with NaOH to improve the therapeutic effect The invention relates to an oral disintegrating film containing meloxycam.

Orally administered formulations include various oral dissolving agents such as tablets, chewable tablets, sublingual tablets, capsules, and liquids. Among these, general tablets and capsules have disadvantages such as difficulty in taking the drug for patients who have difficulty in taking the drug. Accordingly, there is a need for a new formulation that can be easily taken orally.

Accordingly, various formulations have recently emerged with new drug delivery systems. Oral disintegrating tablet (ODT), which developed a solid in the form of oral disintegration, is one such result. However, it was pointed out that oral disintegrating tablets also generally do not disintegrate all drugs at a constant and fast time, and often have to take water again.

In order to solve this problem, oral disintegrating film formulations have been studied a lot recently. Oral disintegrating film formulations offer several other advantages over conventional solids, solutions and oral disintegrating tablets. Because oral disintegrating film preparations can be taken without water, it is very useful for children, the disabled, patients lying in bed, and busy modern people, as well as disintegrating drugs, as well as elderly people who have difficulty taking tablets or capsules. It is evaluated to be an advanced form than any existing formulation. In particular, when the drug is absorbed into the oral mucosa can be avoided the first pass, the oral disintegrating film has an advantage that can be applied to drugs that are subjected to a lot of liver metabolism among drugs absorbed from the digestive tract. Therefore, many attempts have been made to prepare oral dispersible film formulations of various techniques for the physical properties of the film and the patient's dose compliance.

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

[constitutional formula]

Meloxycham has a molecular weight of 351.4 and, like other NSAIDs, inhibits the synthesis of cyclooxygenase (COX) to inhibit prostaglandin synthesis and thus exhibits anti-inflammatory activity. Cyclooxyl than cyclooxygenase-1 (COX-1) More selectively inhibits cigenase-2 (COX-2).

However, meloxycamp is a poorly water-soluble drug that reaches the highest blood concentration after 7-11 hours of oral administration, and thus, it takes a long time to show its efficacy after administration, and thus it is difficult to dissolve in the body. In the case of poorly water-soluble drugs, various solubilization methods have been studied to improve their solubility.

Solubilization refers to a phenomenon in which the solubility of a substance that is insoluble in water increases due to the presence of a substance such as a surfactant. Representative solubilization methods include a method of increasing the surface area by reducing the size of particles, using a cosolvent, And a method of making a soluble salt of an acid or a base by attaching a counterion to a poorly soluble substance, or a method of binding a high molecular compound or a ligand. In addition, a method of increasing the solubility of poorly soluble substances by forming micelles using surfactants has been studied in recent years.

An object of the present invention is to provide a method for producing oral disintegrating film containing melocampal to increase the solubility and improve the ease of taking in order to improve the therapeutic effect of the pharmaceutical composition containing melocampum.

The present invention also aims to provide an oral disintegrating film produced by the production method of the present invention.

The present invention to solve the above problems is

(A) dissolving meloxycam in a water miscible solvent, and then solubilizing the drug solution with 50% NaOH solution;

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

(C) after mixing the drug solution and the polymer solution, and adding a plasticizer to produce a film form; provides a method for producing oral disintegrating film comprising a hydroxycam including.

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

In the method for producing oral disintegrating film comprising meloxycam according to the present invention, meloxycamp, 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, solubilization of the Meloxycham by adding 50% by weight of NaOH solution to increase the solubility and is characterized in that the oral disintegration film is prepared.

In the method for producing oral disintegrating film comprising melocampum 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 preferred.

In the method for producing oral disintegrating film comprising melocampal according to the present invention, (B) in the polymer solution manufacturing step of dissolving the polymer in ethanol and then adding and mixing the excipient, the excipient is maltose, fructose, Sucrose, lactose, glucose, galactose, trehalose, xylitol, sorbitol, erythritol, maltitol, mannitol, isomalt and sugar alcohols which are one or more water-soluble carbohydrates selected from the combination.

In the method for producing oral disintegrating film comprising meloxycam according to the present invention, the excipient is characterized in that it is included in a ratio of 70 to 120 parts by weight with respect to 100 parts by weight of ethanol.

In the method for producing oral disintegrating film comprising melocampal according to the present invention, (B) in the polymer solution manufacturing step of dissolving the polymer in ethanol and then adding and mixing the excipient, the polymer is pullulan, hydroxypropyl Methyl cellulose, polyvinylpyrrolidone, gelatin, pectin, low viscosity pectin, low viscosity hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, polyacrylic acid, methyl methacrylate Selected from the group consisting of copolymers, carboxyvinyl polymers, polyethylene glycols, alginic acid, low viscosity alginic acid, sodium alginate, carrageenan, modified starch, casein, gluten, acacia gum, gum arabic, xanthan gum, guar gum, gellan gum, locust bean gum It is characterized by.

In the method for producing oral disintegrating film containing melocampum according to the present invention, in the polymer solution manufacturing step of dissolving the (B) polymer in ethanol and then adding and mixing an excipient, the polymer is 1 weight of meloxycam It is characterized in that it is included in the ratio of 30 to 140 parts by weight relative to the part.

In the method for manufacturing oral disintegrating film comprising melocampal according to the present invention, after mixing the drug solution and the polymer solution (C), in the step of preparing the oral disintegrating film by adding a plasticizer, the film Plasticizers used to impart flexibility and elasticity to the formulations include at least one material selected from the group consisting of polyethylene glycol (PEG) and glycerin, and 100 wt% It is characterized in that it comprises 0.1 to 30% by weight relative to.

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

Medicines containing meloxycamp prepared by the present invention can be prepared by oral disintegration film formulation of Meloxycamp in oral administration to animals.

In addition, the present invention has the effect of remarkably improving the solubility by solubilizing melooxycam in NaOH and dispersed in the polymer.

Figure 1 shows the results of testing the dissolution rate of the film prepared according to an embodiment of the present invention for 15 minutes in a pH 1.2 buffer.

Figure 2 shows the results of testing the dissolution rate of the film prepared according to one embodiment of the present invention for 15 minutes in a pH 4.0 buffer.

Figure 3 shows the results of testing the dissolution rate of the film prepared by one embodiment of the present invention for 15 minutes in pH 7.4 buffer.

Hereinafter, examples are provided to help understand the present invention. However, the following examples are provided only to more easily understand 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 Meloxycham was dispersed in 1,100 mg of ethanol, and 50% by weight of NaOH prepared by mixing 200 mg of NaOH with 200 mg of purified water was mixed with the ethanol in which Meloxycum was dispersed to solubilize Meloxycham. The solution was prepared.

Thereafter, 6,510 mg of polyvinylpyrrolidone K30 (Kolidon 30) was dissolved in 8,600 mg of ethanol at 60 ° C., and then 8,000 mg of D-mannitol was added to prepare a polymer solution.

The meloxycam 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>

In preparing the polymer solution, 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>

In preparing the polymer solution, 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>

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

Experimental Example 1 Evaluation of Peelability

Peelability test was performed on 10 healthy adult males of Examples 1 to 4, and the test results are shown in Table 1 according to the following evaluation criteria. At this time, the subjects were blinded to all the 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 point-It can peel easily.

1 point-can be peeled off.

2 points-Can peel off, but hard to peel off.

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

4 points-can not be peeled off at all;

As a result of the test, in the case of oral disintegrating films prepared in Examples 1 and 2 was not peeled, there was a difficulty in preparing the oral disintegrating film formulation.

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

Experimental Example 2> Sensory Evaluation

In the same experimental conditions as the peelability evaluation, the functionalities were evaluated according to the following evaluation criteria, 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-almost no stickiness.

2 points-It is sticky enough to not care.

3 points-Although it is sticky to some extent, it does not get on a hand.

4 points-It is sticky and comes out on a hand.

As a result of the test, the orally disintegrating film prepared in Examples 1 and 2 was very sticky, it was difficult to prepare the oral disintegrating film formulation.

On the other hand, the orally disintegrating film prepared in Examples 3 and 4 has almost no stickiness, it was found that the most suitable as the oral disintegrating film formulation is easy to store.

Experimental Example 3 Drug Dissolution Rate Comparison

First, in order to prepare a sample solution, each of the amounts corresponding to Meloxycham 4.6 mg, 4.2 mg, 3.5 mg, and 2.9 mg was taken in Examples 1 to 4, respectively, to prepare a sample. In consideration of the conditions in the oral cavity, the eluate was six samples each using 200 mL of pH 7.5 buffer, and the dissolution test was carried out at 37 rpm 75 ° C in accordance with the second dissolution test method. After 15 minutes, 3 mL of the eluate was taken out and filtered through a membrane filter having 0.45 μm pores to obtain a sample solution. Next, 4.0 mg of Meloxycam standard was accurately taken to prepare a standard solution and placed in a 100 mL volumetric flask. Methanol 50 mL was added, sonicated for 20 minutes, completely dissolved, cooled to room temperature, and methanol was added to make 100 mL. This was diluted with an appropriate amount of mobile phase to prepare a standard solution of 40, 20, 10, 5, 2.5, 1.25 μg / mL.

It was shown in Table 3 by comparing the dissolution rate under the following conditions using High Performance Liquid Chromatography (HPLC).

Comparative Example 1 Example 3 Example 4 15 min elution rate in pH 1.2 buffer 12.1 69.8 72.6 15 min elution rate in pH 4.0 buffer 12.4 56.8 45.2 15 min elution rate in pH 7.4 buffer 64.5 81.55 4 8.5

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

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

-Retention time: 8 minutes

Column temperature: 45 ° C

Detector: UV 230 nm

Flow rate: 2.0 mL / min

Injection volume: 20 μL

As a comparative example of the conventionally used pet melocamham drug, 0.2 mg of hydroxycampham per kg body weight is orally administered first, but thereafter, 0.1 mg of melocamham per kg body weight every 24 hours until symptoms are treated. Was administered orally.

The dissolution test results are shown in FIGS. 1 and 2. The films prepared in Examples 3 and 4 in FIGS. 1 and 2 showed higher dissolution rates than Comparative Example 1 in pH 1.2 and pH 4.0 buffers. In particular, Example 3 showed the highest dissolution rate in the pH 7.4 buffer in the oral condition as shown in FIG.

In view of these experimental results, it can be seen that the dissolution rate is significantly higher in the orally disintegrating film prepared in the embodiment of the present invention than the chewable tablet, which is a form of the conventionally available Meloxycam drug.

Claims (7)

(A) solubilizing drug solution prepared by dissolving melooxycamp in a water miscible solvent, solubilizing with NaOH solution; (B) preparing a polymer solution in which the polymer is dissolved in ethanol and then mixed with an excipient; and (C) mixing the drug solution and the polymer solution, and then adding a plasticizer to prepare an oral disintegrating film; Oral disintegrating film production method comprising a hydroxycam containing a. The method of claim 1, In the drug solution manufacturing step of dissolving the (A) meloxycam in a water miscible solvent, solubilizing with NAOH solution Wherein said water miscible solvent is a polar solvent selected from water, alcohol, acetone and combinations thereof Method for producing oral disintegrating film comprising Meloxycam. The method of claim 1, In the polymer solution manufacturing step of dissolving the polymer (B) in ethanol and then added and mixed with excipients  The excipient is one or more water-soluble carbohydrates selected from maltose, fructose, sucrose, lactose, glucose, galactose, trehalose, xylitol, sorbitol, erythritol, maltitol, mannitol, isomalt and combinations thereof Being Method for producing oral disintegrating film comprising Meloxycam. The method of claim 1, In the polymer solution manufacturing step of dissolving the polymer (B) in ethanol and then added and mixed with excipients 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 Method for producing oral disintegrating film comprising Meloxycam. The method of claim 1, In the polymer solution manufacturing step of dissolving the polymer (B) in ethanol and then added and mixed with excipients The polymer is pullulan, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, gelatin, pectin, low viscosity pectin, low viscosity hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, polyvinyl Alcohol, polyacrylic acid, methyl methacrylate copolymer, 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 Sword, locust bean gum is selected from the group consisting of Method for producing oral disintegrating film comprising Meloxycam. The method of claim 1, In the polymer solution manufacturing step of dissolving the polymer (B) in ethanol and then added and mixed with excipients The polymer is characterized in that it is included in the ratio of 30 to 140 parts by weight with respect to 1 part by weight of melocampum Method for producing oral disintegrating film comprising Meloxycam. An oral disintegrating film comprising melooxycamp prepared by the method of any one of claims 1 to 6.

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