KR20110029249A - Pharmaceutical composition having the improved solubility of planlukast - Google Patents

Abstract

PURPOSE: A pharmaceutical composition is provided to improve pranlukast solubility and bioavailability. CONSTITUTION: A pharmaceutical composition for contains pranlukas(8(4(4-phenylbotoxy)benwoyl)amino-2-(5-tetrazolyl)-4-oxo-4h-1-benzopyrane) and two surfactants of polysorbate 20 and sorbitan monostearate 20. The pharmaceutical composition further contains lauroglycol FCC, triethyltrate, triethanol amine, benzyl alcohol as an additive. A solid dispersion is prepared using transparent liquid pharmaceutical composition with one or more saccharide alcohols. The solid dispersion is made in the form of powder, granule, and tablet.

Description

Pharmaceutical composition having the improved solubility of planlukast

The present invention relates to pharmaceutical compositions containing franlukast.

The present invention relates to franlukast (8- {4 (4-phenylbotoxy) benwoyl} amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran, which has low solubility in an aqueous medium. Franlukast) is a compound that has potent antagonism against luekotriene C4 (LTC4) and luekotriene D4 (LTD4) and is used as a treatment for bronchial asthma and allergic rhinitis. Although it is expected to be a treatment for sexual shock and various allergic inflammations, it is a drug that has a very wide range of application, and it is a poorly soluble drug that does not dissolve well in aqueous media. Because economic loss is large. Therefore, there is a need for development of a formulation having improved bioavailability. However, no formulation has been developed that has improved oral absorption by improving the elution of franlukast.

<Formula 1>

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 into 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 the lucast is lowered.

Formulations of the pharmaceutical composition of franlukast for solving the low bioavailability due to the adhesion cohesion and poorly water solubility of the franlukast to formulate, as described in International Patent Publication No. 96/41628 Franlukast granules, Method for improving the cohesiveness of the production process and the adhesion of franlukast and water-soluble pharmaceutical composition containing the benzopyran derivative as the main component, and franlukast powder aerosol with improved surface inhalation efficiency. Pharmaceutic al Research 1998, 15, 1748-1752), but these techniques are based on oils / surfactants / assistance surfactants that can greatly improve the elution of franlukast and increase oral absorption. Self-emulsify drug delivery system to increase the bioavailability by increasing the solubility of poorly soluble drugs ng drug delivery system (hereinafter referred to as SMEDDS) is significantly different from the present invention for the following reasons.

International Patent Publication No. 96/41628 discloses granules by dissolving saccharides, water-soluble polymers and / or surfactants in purified water, suspending franlukast, and spray drying to prepare granules. The surface properties were improved to facilitate only the formulation process. International Patent Publication No. 96/41628 suspends spray drying of franlukast powder in an aqueous solution in which additives are dissolved. Therefore, as determined by powder X-ray diffraction analysis, the crystallinity of franlukast remains unchanged. Elution is not greatly improved. The filler of a commercially available Onon capsule prepared using the technique of WO 96/41628 has a very low dissolution rate of less than 5% in an eluate of 37 ° C. and pH 6.8. (The commercially available Onon capsule described in Experimental Examples 5 and 6 of the present specification is a product according to the prior art.) International Patent Publication WO99 / 04790 Also, Francucas containing an aqueous solution of francaste containing a surfactant and a water-soluble polymer. It relates to liquid preparations such as wort suspension. These formulations may be administered orally as solutions or suspensions, but in the case of solutions, the concentration of franlukast is so low that hundreds of ml must be administered at one time to administer the upper dose, which is not suitable for oral preparations. Formulations with increased solubility by adjusting the pH of can be precipitated by gastric acid upon oral administration. In addition, in the case of the suspension, since the crystallinity of the franlukast is maintained, it is difficult to expect a significant improvement in the elutability of the franlukast or an increase in the oral absorption rate. In the case of formulating a mixture powder containing only additives to franlukast or by filling capsules, the packing material adheres to a manufacturing equipment and the like, which causes problems in continuous production of capsules or tablets. For this reason, there has been a great demand for a pharmaceutical composition that can alleviate the strong adhesion cohesion of franlukast, and as a pharmaceutical composition of franlukast that can solve the problem of adhesion cohesion to some extent, Korean Patent Registration No. 389606 Is disclosed in. Pharmaceutical compositions of such conventional franlukast include (A) franlukast; (B) at least one sugar such as lactose or mannitol; (C) 1 or more types of water-soluble polymers, such as hydroxypropyl cellulose, polyvinylpyrrolidone, or polyethylene glycol, or 1 type, such as (D) 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 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 at least one polymer of (A) amorphous francastast and (B) hydroxypropyl cellulose or hydroxypropyl methyl cellulose. It includes, the polymer of (B) is included in the ratio of 0.25-5 with respect to the weight 1 of the franlukast. 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 patients taking it. Furthermore, since the handling of organic solvents requires precautions and warming processes, The manufacturing process may be dangerous. Due to this problem 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 heating process This is constantly required.

Therefore, an object of the present invention is to prevent the coagulation of adhesion during the production of lanlukast and to improve the solubility in water and dissolution rate in the body without using an organic solvent that is harmful to the human body and is likely to remain after production. It is to provide a pharmaceutical composition containing lucast and a method for preparing the same.

It has been frequently pointed out that the poorly water-soluble drug has a low bioavailability due to the low dissolution rate in the digestive fluid upon oral administration. In order to improve these problems, there are methods such as crystallinity reduction, micropowder, solid dispersion, prodrug, self-microemulsifying drug delivery system (SMEDDS) and microemulsion.

 Among these, SMEDDS is a homogeneous mixture of liquid or solid state in which the water phase is removed from the components of the microemulsion, and when it meets water phases such as body fluid when taken, it refers to a drug delivery system that easily forms a microemulsion even by weak force such as gastrointestinal motility. . Unlike microemulsions, SMEDDS eliminates water (water) from its components, which can reduce volume, prevent drug changes due to hydrolysis, and eliminate the interaction between capsule layer and water. The capsule can be filled to prevent the change of the drug by oxidation and to facilitate the taking. SMEDDS is very stable against common emulsions because the self-microemulsifying base consisting of oil phase (oil), surfactant and cosurfactant forms a wide distribution interface between oil phase and water phase. Its solubility and bioavailability can be greatly increased, and it can provide the stability of the drug, the rapid expression of the drug, the uniformity of the content and the convenience of the expression of the drug and the convenience of handling. It is widely recognized as a useful means to increase the effective use of the limited drug.

  In this study, a self-emulsifying drug delivery system, which is a method of solubilizing a poorly soluble drug, Françast, is used to increase the solubility of poorly soluble drugs by using a dispersion system consisting of oil / surfactant and auxiliary surfactant. A self-emulsifying drug delivery system (SMEDDS) was prepared to evaluate solubility in each solvent to examine its potential as a new formulation.

In order to achieve the above object, the present invention has a solubility in water of 10 mg / ml or more in dissolving franlukast as a main component, and triethyl as a main component of franlukast and oil. Citrate, a pharmaceutical composition comprising polysorbate, sorbitan monostearate as surfactant, comprising polyethylene glycol, Lauroglycol FCC, triethanolamine and benzyl alcohol, using additives.

The pharmaceutical composition of the present invention using the surfactant and the additives as described above, the difficulty of the manufacturing process due to the adhesion of the main component and the water solubility at room temperature is significantly increased, and the dissolution rate from the small intestine upper part, which is an absorption part of the gastrointestinal tract, and the patient Oral administration can be expected to increase the efficacy by improving the bioavailability can be solved all the various technical problems of the conventional lancastast.

In the pharmaceutical composition of the present invention, as the surfactant, polysorbate, sorbitan monostearate, polyoxyl castor oil, sodium lauryl sulfate, and the like may be used individually or in combination thereof. It is preferable to use a combination of sorbate and sorbitan monostearate, and thus, the effect of increasing the solubility of franlukast in water and the effect of improving the dissolution rate in the body can be obtained. As a stabilizer, triethyl citrate and triethanolamine And benzyl alcohol may be mixed to ensure stability of the formulation.

In this case, the mass composition ratios of the polysorbate 20, triethyl citrate, triethanolamine, benzyl alcohol, and sorbitan monostearate are 60 to 80: 0 to 20: 0 to 10: 0 to 15: 5, respectively. The mass ratio of ˜25 can be used to make the solubility of franlukast to be more than 10mg / ml, and to ensure excellent stability without precipitation even in dissolution test at water and pH 6.8. It is preferred to include the composition. The mass ratio of each of these surfactants and additives is optimized in consideration of the adhesion cohesiveness of franlukast, the solubility in water and the dissolution rate in the body. Etc. can be reduced.

In the meantime, the researchers fixed the surfactant and co-surfactant at a constant ratio to dissolve the appropriate amount of franlukast, and then stabilized by adding 10, 20, 30, 40 and 70 w / w% of oil, respectively. In order to obtain a composition ratio of the prepared SMEDDS, numerous SMEDDS were prepared, and a small amount of distilled water was added dropwise to observe the change in turbidity to observe the area where the microemulsion was formed. Based on the anticipated SMEDDS, triethylsitate and benzyl alcohol as oils were mixed homogeneously with warm stirring under a zone where microemulsions were formed in a safe area to prepare stable SMEDDS. Evaluated. In addition, in order to increase the solubility of franc Lucas, various pharmaceutical additives were mixed to observe the dissolution patterns.

According to the method for preparing a pharmaceutical composition according to the present invention, polysorbate and sorbitan monostearate, etc., are used as surfactants to improve the solubility of franlukast, and triethyl citrate, triethanolamine, benzyl alcohol, and the like are added. Since the manufacturing process to ensure the stability of the solubilized franlukast formulation is made by a simple mixing process, it is considered to be a development of superior technology in the simplicity and ease of manufacturing process, and is generally harmful to the human body used for solubilizing poorly soluble formulation. In addition, since it does not use an organic solvent that may remain after manufacture, it is considered to be the best among the solubilization techniques of Franukast, because it is also secured to the human body.

In addition, it can be put into practical use. In terms of water and absorption, 6.8, which is the p H range, shows superior solubility and elution than commercially available products, maximizing the bioavailability of francaste and containing francastast in the invented formulation. Its solubility is 10mg / ml, preferably 20mg / ml or more, so that it can be developed into a dosage form that is sufficient for commercialization and can be developed in an appropriately large amount. It is considered to be the best formulation technology that completely solves the shortcomings.

In the method for preparing a pharmaceutical composition according to the present invention, the surfactant is a mixture of two materials, polysorbate, sorbitan monostearate, and then triethyl citrate, triethanolamine, and benzyl alcohol in this mixture. After adding and dissolving, the mass composition ratios of franukast, polysorbate 20, triethyl citrate, triethanolamine, benzyl alcohol and sorbitan monostearate were added to the melt to be 10 to 20: 60 to 80: 0 to 20. It is preferred to have a pharmaceutical composition comprising a mass ratio of: 0 to 10: 0 to 15: 5 to 25. 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 granules containing the solubilized franlukast, the powder can be prepared by mixing with the various pharmaceutical compositions prepared SMEDDS, Particular examples thereof include sugar alcohols such as lactose, mannitol, sorbitol, xylitol and the like.

In the manufacturing method of the present invention, in the step of forming the franlukast-containing powder, 0.5 to 20% by mass of the solubilized franlukast-containing FI is preferably used, so that children, the elderly, and swallowing ability are inferior. Powders, granules and tablets that can be taken without water for patients can be prepared.

As described above, according to the present invention, it is possible to fundamentally solve the adhesion cohesion which is a problem in the manufacturing process of franlukast and to greatly improve the solubility of the franlucast without organic solvent and additional physical process. It is possible to achieve a drastic reduction in production costs due to the simplification of the production process and the reduction of the amount of principal components, and to solve the problem that excessive drug dosage should be used by patients due to the poor water solubility of franlukast and to improve the bioavailability. It is a pharmaceutical composition that can be expected to achieve reduced drug dosage, reduced side effects and increased efficacy of a patient.

Hereinafter, examples and the like will be described in detail to help understand the present invention. However, embodiments according to the present invention can be modified in many different forms, the scope of the invention should not be construed as limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

EXAMPLES Preparation of Pharmaceutical Compositions Containing Franlukast

Experimental Example 1 Test of Application of Various Dissolving Aids for Dissolving Franlukast

As a result of measuring the solubility of franlukast using various oils and surfactants as shown in Table 1, polyoxyl castor oil, polysorbate 20, polysorbate 80, triethyl citrate, polyethylene glycol 400, lauro It was confirmed that the solubility in glycol F-C was relatively high. Therefore, the oil is triethyl citrate, the surfactant is polysorbate 20, polyoxyl castor oil and sorbitan monostearate, and the water-soluble solvent for improving solubility is polyethylene glycol 400, triethanolamine, lauro Glycol FC and benzyl alcohol were selected and used.

Experimental Example 2. A prescription example for SMEDDS having a franlukast solubility of 10 mg / ml.

Using the surfactant and additives obtained in Experimental Example 1, SMEDDS of franlukast was prepared as described in Table 2. The solubility of franlukast was measured, and the solubility of 10 mg / ml or more, or preferably 20 mg / ml. A prescription example representing the was selected.

Experimental Example 3. Dissolution Test

Using the automatic dissolution tester with 900 ml of pH 6.8 phosphate buffer solution, the dissolution rate for the pharmaceutical composition of Franlukast and the commercially available product (Onon) according to Formulation Examples 2 and 3 were tested. Table 3. shows the dissolution rate by using the prepared SMEDDS and the commercially available product (Onon) in the dissolution test for the pharmaceutical composition of Franlukast according to the formulations 2 and 3 in 900ml dissolution test solution of water, pH 6.8. Dissolution rate (%) was measured by taking the eluate 10, 30, 60, 90, 120 minutes after the start of dissolution.

1 is a graph showing the results of the dissolution rate test of the franlukast capsules prepared according to Formulation Examples D-2 and E-7. As described above, it was found that the pharmaceutical composition containing franlukast according to the present invention showed a dissolution rate superior to that of high commercial products.

The pharmaceutical composition of franlukast according to the present invention has a significant increase in solubility of franlukast, even though only water is used, not through an organic solvent and a heating process, which is suitable for the simplified and productive efficient mass production of the pharmaceutical composition. It has been found that it is possible to produce transparent franlukast SMEDDS, preferably at a high concentration of at least 20%.

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 is not limited thereto. Various modifications may be made without departing from the spirit of the invention as set forth in the claims.

Experimental Example 4. Stability Experiment

SMEDDS containing franlukast was prepared at 85 ° C. using Formulations 2 and 3, and stored at room temperature and 40 ° C. (75% RH) to evaluate stability by measuring the presence of precipitate and the amount of drug over time.

It was confirmed that exhibited stability of 90% or more without forming a precipitate for 10 days.

Experimental Example 5. Preparation of phase diagram

According to the composition of Formulation Examples 2 and 3, oil was added at 10, 20, 30, 40 and 70 w / w%, respectively, to prepare 24 SMEDDS. This formed area was observed. It was confirmed that the microemulsion is formed stably even in the compositions of Formulations 2 and 3, it can be expected that a high bioavailability is formed because the microemulsion is formed quickly in the living body.

Solubility of PL in various oil and surfactant at 30 ℃ Solvent Solubility (mg / ml) Cremophor EL 3.58 ± 0.04 Transcutol p 2.96 ± 0.02 Lauroglycol FCC 3.24 ± 0.06 Benzyl alchol 5.84 ± 0.08 Labrafil M 1944CS 0.93 ± 0.02 Labrasol 2.22 ± 1.64 Tween 20 7.76 ± 0.35 Tween 80 2.66 ± 0.38 PEG 400 2.12 ± 0.04 PEG 200 2.15 ± 0.01 Glyceryl triacetate 0.10 ± 0.00 Triethyl citrate 0.50 ± 0.01 Proplylene glycol 0.50 ± 0.02 Isopropyl myristate 0.11 ± 0.00 Triethanolamine 3.97 ± 0.20 Span 20 0.66 ± 0.01

Examples of various SMEDDS of manufactured franlukast. Prescription Example TEC ^{* 1} PSB20 ^{* 2} TEA ^{* 3} EL ^{* 4} FCC ^{* 5} BA ^{* 6} SMS20 ^{* 7} Franlukast
Solubility
(Mg / ml) One 10 55 10 10 5 10 - 14.68 ± 0.12 2 10 70 5 - - 5 10 21.75 ± 0.35 3 - 65 5 - - 10 20 20.62 ± 0.28

*One. TEC: Triethylcitrate

*2. PSB 20: Polysorbate 20

* 3. TEA: Triethanolamine

*4. EL: Cremophor E L

* 5. FCC: Lauroglycol FCC

* 6. B A: Benzyl alcohol

* 7. SMS20: Sorbitan monostearate20

Elution Rate of Franlukast in Water, pH 6.8 Elution Test Solution
pH 6.8 water time
(minute) Commercial item
(onon) Prescription Example 2 Prescription Example 3 Commercial item
(onon) Prescription Example 2 Prescription Example 3  10  0.52 99.63 75.73 1.77  100.63 69.78  30 0.82 101.14 82.76 2.08  102.78 71.42  60 0.95 101.81 102.36 3.62  103.69 94.10 120 1.12 104.681 102.26 4.13 104.24 101.07

Figure 1 is a graph showing the dissolution rate of the lanukast SMEDDS-containing hard capsules prepared according to the commercial product (a) and Formulation Examples 2 (b) and 3 (c).

2. Stability results at room temperature and 40 ° C. (RH 75%) storage conditions of Formulations 2 and 3.

Fig. 3. Phase equilibrium diagrams of Formulation Examples 2 (a) and 3 (b).

Claims (11)

A pharmaceutical composition containing franlukast as a main component and containing as a surfactant of polysorbate 20 and sorbitan monostearate 20 or polysorbate 20 and polysilyl castor oil. The pharmaceutical composition according to claim 1, wherein the water solubility of franlukast as a main component is 10 mg / ml or more at room temperature and crystals are not formed in the dissolution test in water. 2. The pharmaceutical composition according to claim 1, wherein the solubility in water is 10 mg / ml or more in dissolving franlukast as a main component, and as a main component, franlukast, polysorbate 20, and sorbitan mono A pharmaceutical composition comprising the use of triethyl citrate, triethanolamine, benzyl alcohol, while containing a surfactant of stearate 20. 2. The pharmaceutical composition of claim 1, wherein the solubility in water is 10 mg / ml or more in dissolving franlukast as a main component. Franlukast, polysorbate 20, and polyoxylcas as the main components of the pharmaceutical composition. A pharmaceutical composition comprising the use of an additive of lauroglycol FC, triethyl citrate, triethanolamine, benzyl alcohol, while containing a surfactant of teryu oil. The mass composition ratio of polysorbate 20, triethyl citrate, triethanolamine, benzyl alcohol, and sorbitan monostearate 20 is 60 to 80: 0 to 20: 0 to 10: 0 to 15: A pharmaceutical composition comprising a mass ratio of 5 to 25. The mass composition ratio of polysorbate 20, lauroglycol FC, triethyl citrate, triethanolamine, benzyl alcohol, and polyoxyl castor oil is 40 to 70: 0 to 15: 5 to 20: A pharmaceutical composition comprising a mass ratio of 5 to 20: 5 to 20: 5 to 20. 2. The pharmaceutical composition according to claim 1, wherein the water solubility of franlukast, which is a main component, is preferably 20 mg / ml or more at room temperature and crystals are not formed in the dissolution test in water. 8. The pharmaceutical composition according to claim 7, wherein the solubility in water has a solubility in water of 20 mg / ml or more in dissolving franlukast as a main component. A pharmaceutical composition comprising the use of an additive of triethyl citrate, triethanolamine, benzyl alcohol, while containing a surfactant of stearate 20. 8. The mass composition of polysorbate 20, triethyl citrate, triethanolamine, benzyl alcohol, and sorbitan monostearate 20 is 65 to 75: 0 to 15: 0 to 10: 2 to 15: A pharmaceutical composition comprising a mass ratio of 5 to 25. A method for producing a pharmaceutical composition, wherein the transparent liquid pharmaceutical composition is prepared by using at least one sugar alcohol using at least one type thereof. A pharmaceutical composition for preparing a solid dispersion prepared using claim 8 as a powder, granules, tablets.

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