KR100591786B1 - Pharmaceutical composition containing pranlukast and preparation process thereof - Google Patents

Abstract

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a pharmaceutical composition containing franlukast and a method for producing the same, and in particular, to improve the solubility and dissolution rate of franlukast, a poorly soluble substance in water, and to improve the cohesiveness of franlukast. It relates to a pharmaceutical composition containing franlukast which can be produced.

The pharmaceutical composition containing franlukast according to the present invention is one selected from the group consisting of (a) franlukast and (b) oleoyl macrogol-6 glyceride, diethylene glycol monoethyl ether and sodium lauryl sulfate The above surfactant is included.

Franlukast, Cohesion Adhesion, Dissolution Rate, Solubility, Sodium Lauryl Sulfate, Oleoyl Macrogol-6 Glyceride, Diethylene Glycol Monoethyl Ether

Description

Pharmaceutical composition containing franlukast and preparation method thereof {PHARMACEUTICAL COMPOSITION CONTAINING PRANLUKAST AND PREPARATION PROCESS THEREOF}

1 is a flow chart briefly showing a method for preparing a pharmaceutical composition containing franlukast according to an embodiment of the present invention,

Figure 2 is a graph showing the dissolution rate test results of the pharmaceutical composition containing franlukast according to Preparation Examples 1 and 2.

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a pharmaceutical composition containing franlukast and a method for producing the same, and in particular, to improve the solubility and dissolution rate of franlukast, a poorly soluble substance in water, and to improve the cohesiveness of franlukast. It relates to a pharmaceutical composition containing franlukast which can be produced.

Franlukast having the structure of Formula 1, ie, N- [4-oxo-2- (1H-tetrazol-5-yl) -4H-1-benzopyran-8-yl] -4- (4-phenylbutoxy) benzamide (hereinafter abbreviated as "franlukast") has potent antagonistic action against leukotriene C4 (LTC4) and leukotriene D4 (LTD 4). As the compound to be used, it is used as a therapeutic agent for various allergic diseases such as allergic bronchus or lung disease, allergic shock and allergic inflammation.

[Formula 1]

However, since the franlukast is present in the form of fine powder with strong adhesion cohesion, there is a problem in that each fine powder is aggregated and aggregated in the process of formulating it in the form of tablet or capsule. In other words, when the lanukast is in contact with water during the formulation, the pullukast powder is agglomerated and aggregated like mud, so when the capsule is filled in the capsule, the contact area of the lanukast becomes smaller in the body. There is a problem that the body dissolution rate and bioavailability of lucast is lowered.

In addition, due to the strong adhesion cohesiveness of the franlukast, when formulated by tableting or capsule-filling the mixture powder containing only the additive to the franlukast, the powder is adhered to a capsule or mortar or turntable to form a capsule or It also interferes with the continuous production of tablets.

For this reason, the pharmaceutical composition which can alleviate the strong adhesion cohesion of franlukast has been largely required, and as a pharmaceutical composition of franlukast which can solve the problem of such adhesion cohesion to some extent, it was registered in Korea patent. There is one disclosed in 389606.

Pharmaceutical compositions of such conventional franlukast include (A) franlukast; (B) at least one sugar such as lactose or mannitol; (C) 1 or more water-soluble polymers, such as hydroxypropyl cellulose, polyvinylpyrrolidone, or polyethylene glycol, or (D) 1 type, such as polysorbate, polyoxyethylene hardened castor oil, sorbitan monostearate, or alkyl sulfate The above surfactant is included.

That is, in this prior art, by spray-drying the pharmaceutical composition made as described above in the form of a suspension and preparing it as a granulated body, the strong adhesion cohesiveness of franlukast can be improved to some extent.

However, in addition to the problems caused by adhesion cohesion, franlukast is very poorly soluble in water, and thus, when the drug containing the drug is actually applied, the concentration of franlukast in the drug is very low. There is a problem that the drug is to be administered to the patient, and also, since the dissolution rate and the bioavailability of the active substance is also very low, there is a problem that the amount of the drug to be administered is much higher.

Nevertheless, the pharmaceutical composition of franlukast described in Korean Patent Registration No. 389606 above can only solve some of the problems due to the strong adhesion cohesiveness of franlukast, and it is difficult for the poor solubility and low body dissolution rate of franlukast. The problem cannot be solved at all.

For this reason, there has been a continuous demand for the development of a pharmaceutical composition that can solve the problems caused by poor solubility and low body dissolution rate of franlukast. Accordingly, Korean Patent Registration No. 381834 describes the dissolution rate of franlukast in the body. The composition of the pharmaceutical composition improved to the extent has been disclosed.

The pharmaceutical composition according to the prior art comprises (A) amorphous franlukast and (B) at least one polymer of hydroxypropylcellulose or hydroxypropylmethylcellulose, wherein the polymer of (B) is It is included in the ratio of 0.25-5 with respect to the weight 1.

That is, according to this prior art, by mixing a predetermined polymer in an amorphous franlukast in a predetermined weight ratio to prepare a pharmaceutical composition, the dissolution rate of franlukast in the body can be increased to some extent, thereby, The bioavailability can be improved to some extent to address the problem that drugs containing franlukast must be administered to patients in too large an amount.

However, even with this prior art, there is a problem in that the poor solubility of franlukast in water is not improved at all, so that the drug containing franlukast still needs to be administered in a large amount. In addition, in the above prior art, in order to improve the poor solubility of franlukast even a little, it is added to the organic mixed solvent such as dichloromethane-methanol and warming it, according to this method harmful to the human body Organic solvents may remain in the pharmaceutical composition of franlukast and may cause harm to the patient taking it. Moreover, the preparation of franlukast is required because it requires precautions in handling the organic solvent and requires a warming process. The process may be dangerous.

Due to these problems of the prior art, the pharmaceutical composition of franlukast which can improve the adhesion cohesiveness of franlukast while simultaneously improving the poor solubility and low body dissolution rate of franlukast without going through the organic solvent and the heating process This is constantly required.

Accordingly, it is an object of the present invention to provide a pharmaceutical composition and a method of preparing the same, which can improve the adhesion cohesiveness of franlukast, and also improve the solubility in water and the dissolution rate in the body.

In order to achieve this object, the present invention provides one or more surfactants selected from the group consisting of (a) franlukast and (b) oleoyl macrogol-6 glycerides, diethylene glycol monoethyl ether and sodium lauryl sulfate It provides a pharmaceutical composition comprising.

In the pharmaceutical composition of the present invention, all of the surfactants such as oleoyl macrogol-6 glyceride, diethylene glycol monoethyl ether and sodium lauryl sulfate are included in the pharmaceutical composition of the franlukast, even at room temperature The solubility of franlukast in water (or a mixed solvent of water and ethanol) can be greatly improved. Therefore, it is possible to avoid the presence of franlukast eggs without going through the heating process and organic solvents such as dichloromethane-methanol, which are harmful to the human body. It is possible to solve all the problems of the prior art according to the availability.

Furthermore, since the addition of the surfactants makes franlukast a solubility in water solubility, it is a weakly acidic liquor similar to water when administering such a pharmaceutical composition of the present invention to a patient. Solubilization in 37 ℃, pH 6.8) is also solubilized in the body dissolution rate and thus the bioavailability of the franlukast can be greatly improved.

In addition, since the surfactant included in the pharmaceutical composition of the present invention, in particular, diethylene glycol monoethyl ether, acts to solubilize franlukast to water and to improve adhesion cohesiveness of franlukast. Including the pharmaceutical composition of the present invention can improve the adhesion cohesiveness of franlukast, and also greatly improve the solubility and dissolution rate of the active substance in water to solve all the problems of the prior art.

In the pharmaceutical composition of the present invention, the surfactant may include all three substances of the oleoyl macrogol-6 glyceride, diethylene glycol monoethyl ether and sodium lauryl sulfate, and accordingly, The greatest effect can be achieved in the adhesion cohesiveness improvement effect, the solubility improvement effect in water, and the dissolution rate in the body.

In this case, the lanlukast: oleoyl macrogol-6 glyceride: diethylene glycol monoethyl ether: sodium lauryl sulfate is 1: 0.15: 0.05: 0.02 to 1: 0.20: 0.10: 0.05 in the weight ratio of the present invention It is preferably included in the pharmaceutical composition. The weight ratio of each of these surfactants is optimized in consideration of the adhesion cohesiveness of franlukast, the solubility in water and the dissolution rate in the body.If the weight ratio is out of this range, any one or more of gastric adhesion cohesion, solubility in water, or dissolution rate in the body Can be degraded.

On the other hand, the present invention also comprises the steps of dissolving at least one surfactant selected from the group consisting of oleoyl macrogol-6 glycerides, diethylene glycol monoethyl ether and sodium lauryl sulfate in water or a mixed solvent of water and ethanol; Spraying the solution in which the surfactant is dissolved into franlukast to form solubilized franlukast-containing granules; And drying the solubilized franlukast-containing granules to form franlukast-containing dry granules.

That is, according to the method for preparing the pharmaceutical composition according to the present invention, a surfactant such as oleoyl macrogol-6 glyceride, diethylene glycol monoethyl ether or sodium lauryl sulfate is sprayed on the franlukast to form such an active substance. After solubilizing in water (or a mixed solvent of water and ethanol), the final franlukast pharmaceutical composition is prepared. It can solve the problem that the drug containing lucast should be administered to the patient in an excessively large amount. Therefore, in the present invention, there is no problem of danger in the residue and heating process of the organic solvent harmful to the human body.

In addition, as described above, the surface cohesiveness of franlukast can be improved and the dissolution rate of the body can be improved by surfactants such as oleoyl macrogol-6 glyceride, diethylene glycol monoethyl ether or sodium lauryl sulfate. In addition to maximizing the bioavailability of franlukast, it is possible to completely solve the problem, such as the drug containing franlukast should be administered in an excessively large amount.

In the method for preparing a pharmaceutical composition according to the present invention, the surfactant may be water (or water and ethanol) of all three substances such as oleoyl macrogol-6 glyceride, diethylene glycol monoethyl ether and sodium lauryl sulfate In a mixed solvent), and in this case, the mixing ratio of each of the surfactants is preferably in a weight ratio of 1: 0.15: 0.05: 0.02 to 1: 0.20: 0.10: 0.05 based on the weight of the franlukast. Do. The specific reason for this is as described above, and further description will be omitted.

In addition, in the method for producing a pharmaceutical composition according to the present invention, in the step of forming the solubilized franlukast-containing granules, the mixed solution of the surfactant and water (or a mixed solvent of water and ethanol) is Francucas It may be sprayed on a mixture of lute, excipient and disintegrant. As such excipients and disintegrants, conventional materials used in various pharmaceutical compositions can be used, and representative examples thereof include lactose or sodium starch glycolate.

In the manufacturing method of the present invention, in the step of forming the franlukast-containing dry granules, the solubilized franlukast-containing granules are 30 to 60 ° C. until the moisture content is 0.5 to 2.0 wt%. Drying at temperature is preferred, most preferably drying at a temperature of 50 ° C. In the prior art, an organic mixed solvent such as dichloromethane-methanol is used to increase the solubility of franlukast, and therefore, it is necessary to proceed a high temperature drying process for a long time so as not to leave organic solvents harmful to the human body. The handling of the pharmaceutical composition of the present invention requires handling, but since the lanukast is sufficiently solubilized in water (or a mixed solvent of water and ethanol), the solubility becomes high, and thus no need for the use of harmful organic solvents. By proceeding the drying process as described above, may be prepared a pharmaceutical composition of franlukast.

In addition, the method for producing a pharmaceutical composition of the present invention, comprising the steps of sizing the lanukast containing dry granules and mixing with a lubricant; And forming the resultant mixed with the lubricant in the form of a tablet or capsule. In this way, the pharmaceutical composition containing franlukast prepared according to the invention can be finally formulated in tablet or capsule form.

In the preparation method of such a pharmaceutical composition, the glidants may be used all conventionally used lubricants, preferably magnesium stearate or stearic acid. In addition, in sizing the franlukast-containing dry granules, it may be formed into particles having a size of about 30 Mesh.

In addition, the step of formulating in the form of tablets or capsules, according to the conventional method, the resultant mixed with the lubricant is molded into a tablet with a rotary tableting machine, or mixed with the lubricant to a predetermined weight using a capsule filling machine It can proceed by filling the result.

Hereinafter, with reference to the accompanying Figure 1, it will be described in more detail the manufacturing method of the pharmaceutical composition according to an embodiment of the present invention.

1 is a flow chart briefly showing a method for preparing a pharmaceutical composition containing franlukast according to an embodiment of the present invention.

Referring to FIG. 1, a first step for preparing a pharmaceutical composition containing franlukast is a step of dissolving each surfactant for solubilizing franlukast by adding water (or a mixed solvent of water and ethanol) to dissolve it. Surfactants of oleoyl macrogol-6 glyceride, diethylene glycol monoethyl ether, and sodium lauryl sulfate were added to water (or water in a weight ratio of 0.15: 0.05: 0.02 to 0.20: 0.10: 0.05 based on the weight of franlukast. And ethanol mixed solvent). At this time, polyvinyl alcohol, polyvinylpyrrolidone, or the like may optionally be added to the solvent and dissolved therein as a binder.

In the second step, franlukast and conventional excipients such as lactose or sodium starch glycolate and disintegrant are placed in a fluid bed granulator and mixed.

Next, the third step is the preparation of the solubilized franlukast-containing granules, in which the mixture of the surfactant and the solvent formed in the first step is sprayed onto the mixture of the franlukast formed in the second step, solubilizing franucas. The step of preparing a vitreous-containing granules.

Then, the drying step is carried out as a fourth step, wherein the solubilized franlukast-containing granules formed in the third step are 30 to 60 ° C, more preferably, until the water content is 0.5 to 2.0% by weight. By drying at 50 ° C., franlukast-containing dry granules are formed. In addition, the franlukast-containing dry granules are formed into particles having a size of about 30 Mesh through a sizing machine.

The fifth step is a final mixing step of the lubricant, in which the dry powder established in the fourth step is placed in a suitable mixer, and the lubricant is added and mixed. As such a lubricant, a conventional lubricant such as magnesium stearate or stearic acid is used.

Finally, in the sixth step, the granules prepared in the fifth step are molded into tablets or filled into capsules. In the case of tablet molding, molding is carried out using a general rotary tablet press, and the preferred tablet weight is about 250 mg, and the preferred hardness of the tablet after molding is about 5 to 7 kp with an Erveka hardness tester. Also, in the case of filling the capsule, the granule of the fifth step is filled into the capsule using a conventional capsule filling machine, and the preferred target content weight is 250 mg.

Tablets molded in this manner may be coated using a coating agent approved by the Pharmacopoeia, and a colorant approved for granules may be used prior to molding into tablets and capsules.

Hereinafter, the present invention will be described in more detail with reference to preferred embodiments of the present invention. However, this is presented as an example and thereby does not determine the scope of the present invention.

Preparation Example 1 Preparation of Pharmaceutical Composition Containing Franlukast

       Composition weight ratio (mg)

Polyvinylpyrrolidone 5

          Sodium Lauryl Sulfate 1-10

          Oleoyl Macrogol-6 Glyceride 5-30

          Diethylene glycol monoethyl ether 5 to 50

Lactose 10-60

          Sodium starch glycolate 5-20

          Franlukast 112.5

          Water or water-alcohol mixed solvent suitable amount

          Magnesium Stearate 3-10

Having a composition as described above, a pharmaceutical composition containing franlukast was prepared in the order described below.

First, the polyvinylpyrrolidone, sodium lauryl sulfate, oleoyl macrogol-6 glyceride and diethylene glycol monoethyl ether are weighed according to the weight ratio, and then dissolved in water or water-alcohol mixed solvent in the tank. I was. This mixed solution was then sprayed onto a mixture of lactose, sodium starch glycolate and franlukast mixed in the above weight ratio to form solubilized franlukast containing granules.

The solubilized franlukast-containing granules were then dried in a fluid bed dryer at a temperature of 50 ° C. for about 40 minutes to form franlukast-containing dry granules. Thereafter, the lancastast-containing dry granules were formed into particles using a 30-mesh sizing machine, and the granulated granules were put into a mixer and mixed with magnesium stearate.

Finally, the capsules of franlukast were finally prepared by filling the capsules with a target content weight of 250 mg by using a capsule filling method of powder filling the granules mixed with the magnesium stearate. In addition, tablets of franlukast were finally prepared by molding granules mixed with the magnesium stearate into tablets using a rotary tablet press. At this time, the target weight of the tablet was 250 mg, and the hardness of the tablet after molding was about 5 with an Erveka hardness tester.

Preparation Example 2 Preparation of Pharmaceutical Composition Containing Franlukast

        Composition weight ratio (mg)

  Polyvinylpyrrolidone 5

  Oleoyl Macrogol-6 Glyceride 5-30

  Diethylene glycol monoethyl ether 5 to 50

  Lactose 10-60

  Sodium starch glycolate 5-20

  Franlukast 112.5

  Water or water-alcohol mixed solvent suitable amount

  Magnesium Stearate 3-10

Having the composition as described above, tablets and capsules of franlukast were prepared in the same manner as described in Preparation Example 1.

Experimental Example 1: Dissolution rate test of the pharmaceutical composition containing franlukast according to Preparation Examples 1 and 2

Preparation of eluate: Fran according to Preparation Examples 1 and 2, using 900 ml of diluted pH 6.8 phosphate buffer (1-> 4) solution (1-> 500) of polysorbate 80 The dissolution rate for the pharmaceutical composition of Lucast was tested. The dissolution rate was measured by taking the eluate 45 minutes after the start of dissolution.

Figure 2 is a graph showing the results of the dissolution rate test of the franlukast capsules prepared in Preparation Examples 1, 2. As can be seen in Figure 2, the pharmaceutical composition of Preparation Example 1 containing all three surfactants of oleoyl macrogol-6 glyceride, diethylene glycol monoethyl ether, and sodium lauryl sulfate was about 45 minutes later. The dissolution rate of franlukast was nearly 80%, and the pharmaceutical composition of Preparation Example 2 using only two surfactants, oleoyl macrogol-6 glyceride and diethylene glycol monoethyl ether, also reached about 60%. High dissolution rate of franlukast was shown. As such, it has been demonstrated that the pharmaceutical composition containing franlukast according to the present invention exhibits high dissolution rate in the body.

In addition, the present inventors tested and measured in the process of preparing the pharmaceutical composition of franlukast through Preparation Examples 1 and 2, the pharmaceutical composition of franlukast according to the present invention has almost no adhesion cohesiveness in the preparation process. Not observed, and also using only water (or a mixed solvent of water and ethanol) without going through an organic solvent and warming process, the solubility of franlukast increases significantly, which is 1%, which is suitable for the efficient mass production of pharmaceutical compositions. It has been found that the above-mentioned high concentrations can dissolve franlukast in a solvent.

As described above, the pharmaceutical composition containing franlukast and the preparation method thereof according to the present invention have been described in detail with reference to Preparation Examples, Experimental Examples, and the accompanying drawings, but the scope of the present invention includes the Preparation Examples, Experimental Examples, and the like. Without being limited to the drawings, various modifications may be made within the scope of the technical idea of the present invention described in the claims below.

As described above, according to the present invention, since the solubility of franlukast can be greatly improved without going through an organic solvent and a heating process that is harmful to the human body, the drug of franlukast is excessively used due to the poor solubility of franlukast. Problems to be solved, problems due to residual organic solvents harmful to the human body, and risks in the organic solvent and the heating process can all be solved.

In addition, according to the present invention, not only the dissolution rate of franlukast can be greatly improved, but also the adhesion cohesiveness of franlukast can be improved, thus making it possible to efficiently manufacture the pharmaceutical composition containing franlukast. At the same time, the bioavailability of franlukast can be greatly improved.

Claims (8)

A pharmaceutical composition comprising (a) franlukast and (b) three surfactants: oleoyl macrogol-6 glyceride, diethylene glycol monoethyl ether, and sodium lauryl sulfate. delete The method of claim 1, wherein the franlukast: oleoyl macrogol-6 glyceride: diethylene glycol monoethyl ether: sodium lauryl sulfate is contained in a weight ratio of 1: 0.15: 0.05: 0.02 to 1: 0.20: 0.10: 0.05 Pharmaceutical compositions. Dissolving three surfactants, oleoyl macrogol-6 glyceride, diethylene glycol monoethyl ether and sodium lauryl sulfate, in water or a mixed solvent of water and ethanol to dissolve; Spraying the solution in which the surfactant is dissolved into franlukast to form solubilized franlukast-containing granules; And Drying the solubilized franlukast-containing granules to form franlukast-containing dry granules. delete The method of claim 4, wherein the mixing ratio of the oleoyl macrogol-6 glyceride, diethylene glycol monoethyl ether and sodium lauryl sulfate is 1: 0.15: 0.05: 0.02 to 1: 0.20: 0.10 A method for producing a pharmaceutical composition in a weight ratio of 0.05. 5. The method of claim 4, further comprising the steps of: establishing said franlukast-containing dry granules and mixing with glidants; And Forming the resultant mixture with the lubricant in the form of a tablet or capsule further comprising the preparation of a pharmaceutical composition. The method of claim 7, wherein the lubricant is magnesium stearate or stearic acid.

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