KR100715355B1 - Spray-Dried Granules Containing Franlukast and Methods for Making the Same - Google Patents

Abstract

The present invention relates to a spray-dried granule consisting of franlukast, a water-soluble polymer, and a surfactant, wherein the lanukast-containing spray- has a mean particle size of 0.5-20 μm of francastast in the granule. Dried granules and methods for their preparation are provided.

Spray-dried granules according to the present invention can improve the adhesion cohesiveness and solubility of franlukast without coating the franlukast with sugars such as lactose, and can increase the dissolution rate and bioavailability than conventional formulations. Dosage can be significantly reduced. In addition, the spray-dried granules of the present invention can be prepared without the use of organic solvents and are therefore suitable for mass production on an industrial scale.

Franlukast

Description

Spray-dried granules containing pranlukast and processes for the preparation according to the present invention

1A, 1B, 1C, 1D, and 1E are comparative dissolution test results of tablets prepared from the spray-dried granules of the present invention and commercially available formulations,

Figure 2 is a comparative dissolution test results of the capsules prepared from the spray-dried granules of the present invention and commercially available formulations,

Figure 3 shows the results of the body dynamics test in rats,

Figure 4 shows the results of the body dynamics test in humans.

FIELD OF THE INVENTION The present invention relates to spray-dried granules containing franlukast and a process for their preparation.

Chemical name 4-oxo-8- [4- (4-phenylbutoxy) benzoylamino] -2- (tetrazol-5-yl) -4H-1-benzopyran hemihydrate (4-oxo-8- [4 Furanlukast,-(4-phenylbutoxy) benzoylamino] -2- (tetrazol-5-yl) -4H-1-benzopyran hemihydrate, is a compound with potent antagonism against leukotriene C ₄ and leukotriene D ₄ , It is a drug being used as a treatment for bronchial asthma and allergic rhinitis. It is currently marketed as Onon Caps (Onon Cap., 112.5mg / capsule, 2 capsules once, Dong-A).

On the other hand, since lancastast is a water-soluble drug having very strong cohesiveness, when formulated into tablets or capsules, it is attached to punches or dies, making it difficult to manufacture, and it has a low bioavailability and is administered at a dose of 200 mg or more. Only has the disadvantage of showing the desired therapeutic effect.

In order to improve the physical properties of the above-mentioned franlukast, various studies have been conducted. For example, US Pat. No. 5,876,760 discloses spray-dried granules prepared by spray-drying a suspension obtained by suspending sugars, water-soluble polymers, and surfactants in purified water. The spray-dried granules improve the wettability and dispersibility of franlukast in the preparation of the suspension through surfactants and solidify the franlukast by coating the franlukast with sugars such as lactose. To exist in a state. Onon Cap. (Dong-A Pharmaceutical), currently on the market, is formulated with the spray-dried granules disclosed in U.S. Patent No. 5,876,760.

However, the spray-dried granules disclosed in US Pat. No. 5,876,760 have effectively improved the adhesion cohesiveness of franlukast, but have a problem that the bioavailability is still low because the dissolution rate is very low. That is, in the case of the Onon capsule, the dissolution rate for 6 hours in 37 ℃, pH 6.8 buffer is very low, less than 5%.

In addition, WO 01/89574 (Republic of Korea Patent Publication No. 2001-106006) discloses a solid dispersion comprising franlukast and hydroxypropylmethyl cellulose or hydroxypropyl cellulose. The solid dispersion increases the elution of franlukast by converting the crystalline form of franlukast to amorphous.

However, WO01 / 89574 discloses a process for dissolving franlukast and hydroxypropylmethyl cellulose or hydroxypropyl cellulose in an organic solvent (i.e., a mixed solvent of dichloromethane and methanol) to prepare a solid dispersion. Since this is essential, it may cause environmental pollution problems due to the use of the organic solvent, toxicity problems due to the residual of the organic solvent. Moreover, since the organic solvent must be used in excess in order to completely dissolve the franlukast, the drying (for example, spray-drying) process is complicated and takes a long time, so that it is difficult to actually commercialize.

In addition, as a lanukast containing composition, Int.J. Pharm. 172 (1998), 179-188 / 173 (1998), 243-251 and Pharmaceutical Research 11 (1998), 1748-1759 disclose powder aerosols containing franlukast, Japanese Patent Laid-Open No. 8-73353 Discloses liquid preparations such as eye drops, nasal drops or injections using polypinolidon or beta-cyclodextrin as dissolution aids. WO 99/004790 discloses surfactants, water-soluble cellulose derivatives, and water-soluble vinyls. Disclosed is a lanlukast-containing liquid composition comprising a polymer.

However, despite the prior art, as a composition that can improve the physical properties such as solubility and adhesion cohesiveness of franlukast, and effectively increase the dissolution rate and bioavailability, the composition of the composition that can solve the problems caused by the use of organic solvents Development is required in the art.

The present inventors have conducted various studies to solve the problems of the prior art, and when the modified (or coated) with a surfactant through a water-soluble polymer by miniaturizing the particle size of the franc Lucas contained as a main ingredient in spray-dried granules It has been found that there is no need to coat with sugars such as lactose and lactose, as well as to significantly improve the dissolution of franlukast.

This finding is very important given that U.S. Pat.No. 5,876,760 does not disclose at all that the physical properties (solubility and adhesion cohesion) of franlukast depend on the particle size of the franlukast contained in the spray-dried granules. It is amazing. (US Pat. No. 5,876,760 merely discloses that the preferred particle size of the spray-dried granules themselves (not granules of franlukast) is 20 to 1000 um.)

Moreover, the findings indicate that the spray-dried granules according to the prior art (US Pat. No. 5,876,760) use the surfactants to coat the franlukast with saccharides and to complete the coating. It is distinguished from improving dispersibility. In addition, when miniaturizing the particle size of franlukast contained in the spray-dried granules, it is possible to effectively improve the physical properties as well as improve the dissolution of the drug by using only a surfactant without using sugars. It is very amazing.

In addition, the spray-dried granules according to the present invention are different from the solid dispersion (WO99 / 004790), which changes the crystalline form of the drug in order to increase dissolution, and is an organic solvent which is essentially used for preparing the solid dispersion. The use of can be excluded.

Accordingly, it is an object of the present invention to provide franlukast-containing spray-dried granules.

It is also an object of the present invention to provide a method for producing the spray-dried granules.

According to one aspect of the present invention, there is provided a spray-dried granule composed of franlukast, a water-soluble polymer, and a surfactant, wherein the average particle size of franlukast in the granule is 0.5-20 μm, preferably Franlukast-containing spray-dried granules are provided that are 5-18 μm.

The franlukast-containing spray-dried granules according to the present invention are formulated with surfactants via water-soluble polymers while maintaining the particle size of the franlukast at a fine size (ie 20 μm or less). As granules prepared by (coating), it is possible to effectively reduce elution from the formulation while at the same time reducing the adhesion cohesiveness of franlukast itself. Thus, spray-dried granules can be prepared with improved adhesion cohesiveness and markedly increased solubility and dissolution rate without using any saccharides that must be used essentially in the prior art (US Pat. No. 5,876,760).

Furthermore, it is common pharmaceutical common knowledge that for drugs with high adhesion cohesion, the smaller the particle size, the higher the adhesion cohesion between particles and the lower the elution due to the strong aggregation. Nevertheless, when the surface of the drug is modified (coated) with a water-soluble polymer as a surfactant in a state in which the particle size of the drug (ie, franlukast) is refined, the solubility and solubility can be effectively improved. It is a surprising finding that the dissolution rate is also increased.

The franlukast-containing spray-dried granules of the present invention consist of franlukast, a water soluble polymer acting as a binder, and a surfactant modified on the molecular surface of the drug. The average particle size of franlukast in the granules is 0.5-20 μm, preferably 5-18 μm, more preferably 7-13 μm. The average particle size of the franlukast can be adjusted according to various pharmaceutical preparation procedures. For example, the franlukast can be dispersed while vigorously dispersing an aqueous solution of a water-soluble polymer and a surfactant (e.g., by dispersing it with propeller-containing mixers, homogenizers, ultrasonic vibrators, etc.). Spray-dried suspensions or vigorously disperse a suspension consisting of franlukast, a water-soluble polymer, and a surfactant (e.g., propeller-containing mixers, homogenizers, It may be prepared by dispersing in an ultrasonic vibrator or the like and then spray drying. Of course, in addition to the methods listed above, it can be prepared using a method commonly used in the pharmaceutical field, for example, a microfluidizer, a high pressure homogenizer and the like.

The water-soluble polymer used as the binder in the franlukast-containing spray-dried granules of the present invention may use a water-soluble polymer commonly used in the pharmaceutical field. For example, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyethylene glycol, polyvinyl alcohol, gelatin, xanthan gum, gum gum, alginic acid or its salts, polyacrylic acid copolymers (e.g., Eudragit E) and the like can be used. Among these, water-soluble polymers selected from the group consisting of polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cellulose, polyethylene glycol, polyvinyl alcohol, xanthan gum, and mixtures thereof can be preferably used.

Surfactants modified on the surface of the franlukast molecule in the spray-dried granules of the present invention may employ surfactants commonly used in the pharmaceutical art. For example, polyethylene glycol-15-hydroxystearate (e.g. Solutol ^® HS 15), polyoxyethylin glycolated natural or hydrogenated castor oil (e.g. Cremophor ^® RH 40, Cremo Pore ^® RH 60), polyoxyethylene-polyoxypropylene copolymers (e.g. poloxamer ^® 407, poloxamer ^® 118), sucrose fatty acid esters, synthetic vitamin E derivatives (e.g. vitamin E TPGS ^® ), Sorbitan esters and polyoxyethylene sorbitan fatty acid esters (eg polysorbate ^® 80), polyoxyethylene alkyl esters (eg Brij 52 ^® ), polyoxyethylene stearate (eg myrj 52 ^® ), Fatty acid macrogol glycerides (eg Gelucire 44/14 ^® ), polyglyceryl fatty acid esters (eg Plurol oleique ^® ), bile acids (eg taurocholic acid), sodium lauryl Sulfate, lecithin, text Sheryl fatty acid esters and the like can be used (e. G., Glyceryl monostearate). Among them, polyethylene glycol-15-hydroxystearate, polyoxyethylin glycolated natural or hydrogenated castor oil, polyoxyethylene-polyoxypropylene copolymer, synthetic vitamin E derivatives, sorbitan esters and polyoxyethylene sorbitan fatty acids Ester, or polyoxyethylene alkyl ester can be preferably used.

The franlukast-containing spray-dried granules of the present invention may be composed of 40 to 80% by weight of franlukast, 5 to 20% by weight of water-soluble polymer, and 10 to 50% by weight of surfactant, based on the total weight of the granules. have.

The present invention includes a pharmaceutical composition comprising said franlukast-containing spray-dried granules and a pharmaceutically acceptable carrier.

Pharmaceutically acceptable carriers include known and used excipients, disintegrants, glidants and the like. Excipients usable in the present invention include mannitol, maltitol, sucrose, lactose, silicon dioxide, dextrin, dexrate, microcrystalline cellulose, cellulose, glucose, polydextrose, starch, pregelatinized starch, corn starch, croscarmellose sodium, crospovidone, article Starch sodium lyconate and mixtures thereof; disintegrants include sodium starch glycolate, croscarmellose sodium, crospovidone, and the like; lubricants include sodium stearyl fumarate, magnesium stearate, and the like. do. The pharmaceutically acceptable carrier may be in the range of 30 to 70% by weight based on the total weight of the composition, which may be appropriately selected and used by those skilled in the art according to the finally obtained formulation.

The formulation of the pharmaceutical composition may be in various forms, but is preferably in the form of granules, tablets, capsules, or dry syrups. These formulations may be prepared according to methods commonly used in the pharmaceutical art. For example, tablets may be prepared by mixing the spray-dried granules with excipients, disintegrants, glidants, and the like, by compression, and also by encapsulating the mixture in capsules. In addition, film-coating or enteric-coating may be performed for the purpose of improving stability, convenience of taking, appearance and the like.

The present invention includes a process for producing the franlukast-containing spray-dried granules. That is, as described above, while vigorously dispersing an aqueous solution composed of a water-soluble polymer and a surfactant (for example, by dispersing with a propeller-containing mixers, homogenizers, ultrasonic vibrators, etc.) Spray-dried suspensions prepared by adding franlukast or vigorously disperse a suspension of franlukast, a water-soluble polymer, and a surfactant (e.g., propeller-containing mixers, homogenizers) It can be prepared by dispersing with a homogenizer, an ultrasonic vibrator, etc. and then spray drying. The dispersing may be preferably performed by stirring at 10,000 to 22,000 rpm with a homogenizer.

Thus, the present invention comprises the steps of dissolving a water-soluble polymer and surfactant in water to prepare an aqueous solution; Suspending the obtained aqueous solution by adding franlukast while stirring at 10,000-22,000 rpm; And spray-drying the obtained suspension, the method for producing the franlukast-containing spray-dried granules.

In addition, the present invention comprises the steps of dissolving a water-soluble polymer and a surfactant in water, the addition of franlukast suspending; And stirring the obtained suspension at 10,000-22,000 rpm for 5-30 minutes, preferably 10-20 minutes, followed by spray-drying the method for producing the franlukast-containing spray-dried granules. Include.

Spray-drying in the production method may be carried out in a conventional manner using a conventional granulator, for example, a fluidized bed granulator, a cylindrical granulator, a high speed granulator.

As can be seen in the following examples and test examples, the franlukast-containing spray-dried granules according to the present invention have twice the bioavailability of franlukast at oral administration compared to conventional commercial preparations (onon capsules), It can be increased up to 3 times, and even if a dose lower than the conventional commercial preparation containing franlukast (onon capsule: 2 capsules once, 225 mg as franlukast) is used (less than 100 mg as franlukast). Efficacy or more may be exhibited.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the scope of the present invention is not limited to these examples.

Example  1. Preparation of Spray-Dried Granules

20 g polyvinyl fun of money, 12 g solution toll ^® of ^{HS 15 (Solutol ® HS 15,} BASF , Inc.), and 28 g of Poloxamer ^® 407 (Poloxamer ^® 407, BASF Corporation) was dissolved in 500 ml of purified water I was. The resulting solution was suspended with a homogenizer while adding 100 g of franlukast while stirring at a rotational speed of about 18,000-20,000 rpm.

The resulting suspension was spray-dried using a Mini spray dryer (Buchi 190) (inlet temperature 120 to 130 ° C .; outlet temperature 80 to 90 ° C.) to prepare spray-dried granules. It was. Optical particle sizer-AccuSizer 780A (Particle sizing systems. Inc. Santa Barbara, Calif., USA) by means of dynamic light scattering Measured using. The average particle size of franlukast in the spray-dried granules is 9.79 μm.

Example  2-10. Preparation of Spray-Dried Granules

To the ingredients and contents of Table 1 below, spray-dried granules were prepared in the same manner as in Example 1. Purified water was used in an amount of 5 ml per gram of franlukast.

Example Francou Caste Polyvinyl pinolidon Solutol ^® HS 15 Cremophor ^® RH 40 Poloxamer ^® 407 Average Particle Size of Intra-Granuleart 2 100 g 20 g - 12 g 28 g 11.52 um 3 100 g 20 g 15 g - 35 g 10.84 um 4 100 g 20 g 21.6 g - 38.4 g 9.30 um 5 75 g 15 g 16.2 g - 28.8 g 9.35 um 6 75 g 15 g 11.25 g - 26.25 g 12.29 um 7 100 g 20 g - 10 g 50 g 7.94 um 8 100 g 20 g - 15 g 60 g 8.97 um 9 100 g 10 g - 20 g 50 g 7.16 um 10 100 g 10 g - - 70 g 15.92 um

Example  11. Preparation of Spray-Dried Granules

10 g of the polyvinyl fun of money, 15 g of Crescent mode pore ^{® RH 40 (Cremophor ® RH 40} , BASF , Inc.), and 37.5 g of Poloxamer ^® 407 (Poloxamer ^® 407, BASF Co.) in 500 ml of purified water Dissolved. 100 g of franlukast was added and suspended, stirring the obtained solution with the magnetic stirrer. The resulting suspension was homogenized for 10 minutes with a homogenizer at a rotational speed of 18,000-20,000 rpm. The suspension obtained was spray-dried (Fluid Bed Granulator, Glatt Co., Ltd.) (inlet temperature 110-130 ° C; spray pressure 1.0-2.0 bar) to prepare spray-dried granules, average The particle size was measured in the same manner as in Example 1. The average particle size of franlukast in the spray-dried granules is 11.30 μm.

Example  12-20. Preparation of Spray-Dried Granules

To the ingredients and contents of Table 2, spray-dried granules were prepared in the same manner as in Example 1. Purified water was used in an amount of 5 ml per gram of franlukast.

Example Franlukast Polyvinylpinolidon Hydroxypropyl Meltyl Cellulose Xanthan gum Solutol ^® HS 15 Taurocholine Acid Cremophor ^® RH 40 Poloxamer ^® 188 Vit. E TPGS ^® Polysorbate 80 Brij 52 ^® Particle size (*) 12 100 g 10 g - - - - 20 g 50 g - - - 12.57 um 13 100 g - 20 g - - - - 28 g - 15.49 um 14 100 g - 20 g - - - - - 18g 32 g - 11.75 um 15 100 g - - 20 g - 50 g - - - - - 14.13 um 16 100 g 20 g - - 12 g - - 28 g - - - 10.97 um 17 100 g 20 g - - - - 10 g 50 g - - - 8.63 um 18 100 g 20 g - - - - - 60 g - 15 g - 10.14 um 19 100 g - 20 g - - 12 g - - - - 28 g 17.29 um 20 100 g - - 10 g 28 g - - - - - 12 g 16.32 um

*: Average particle size of intragranular francastast

Example  21-26. Preparation of Spray-Dried Granules

To the ingredients and contents of Table 3, spray-dried granules were prepared in the same manner as in Example 11. Purified water was used in an amount of 10 ml per gram of franlukast.

Example Franlukast Polyvinylpinolidon Hydroxypropyl cellulose Hydroxypropylmethyl cellulose Solutol ^® HS 15 Vit. E TPGS ^® lecithin Particle size (*) 21 100 g 20 g - - 12 g - 28 g 14.43 um 22 100 g - 20 g - - 12 g 28 g 12.75 um 23 100 g - - 20 g 12 g - 35 g 15.63 um 24 100 g 20 g - - - 10 g 50 g 11.82 um 25 100 g 20 g - - - 15 g 60 g 10.07 um 26 100 g 10 g - - - 20 g 50 g 9.54 um

*: Average particle size of intragranular francastast

Example  27-29. Preparation of Spray-Dried Granules

Dissolved in 15 g of polyvinyl fun of money, 16.2 g of a solution toll ^{® HS 15 (Solutol ® HS 15} , BASF , Inc.), and 28.8 g of Poloxamer ^® 407 (Poloxamer ^® 407, BASF Co.) in 750 ml of purified water I was. 75 g of franlukast was added and suspended, stirring the obtained solution with the magnetic stirrer. The resulting suspension was homogenized with a homogenizer at a rotational speed of 18,000-20,000 rpm for 8 minutes and then spray-dried in the same manner as in Example 1 to prepare spray-dried granules (Example 27).

Spray-coarse granules were prepared by repeating the above procedure except homogenizing for 4 minutes at a rotational speed of 18,000-20,000 rpm with a homogenizer (Example 28). In addition, spray-coarse granules were prepared by repeating the above procedure except that the homogenizer was homogenized at a rotational speed of 18,000-20,000 rpm for 2 minutes (Example 29).

The average particle size of the franlukast in the spray-dried granules prepared in Examples 27 to 29 was measured in the same manner as in Example 1, and the results are shown in Table 4 below.

Example Francou Caste Polyvinyl pinolidon Solutol ^® HS 15 Poloxamer ^® 407 Average Particle Size of Intra-Granuleart 27 75 g 15 g 16.2 g 28.8 g 18.03 um 28 75 g 15 g 16.2 g 28.8 g 25.70 um 29 75 g 15 g 16.2 g 28.8 g 44.97 um

Example  30. Preparation of Tablets Using Spray-Dried Granules

150 g of the spray-dried granules prepared in Example 1, 42.19 g of corn starch, 98.44 g of lactose, 14.06 g of crospovidone, 4.69 g of aerosil, and 9.38 g of magnesium stearate were mixed and compressed. The obtained uncoated tablet was coated with 8 g of Opadry (OY-C-7000A White, Colorcon Co.) to prepare 800 tablets containing 100 mg of franlukast per tablet.

Example  31-35. Preparation of Tablets Using Spray-Dried Granules

Using the spray-dried granules prepared in Examples 2, 3, 7, 8, or 9, with the ingredients and contents of Table 5 below, a tablet containing 100 mg of franlukast sugar per tablet was prepared in the same manner as in Example 30. Prepared.

Ingredient (g) Example 31 32 33 34 35 Tablet core Spray-dried granules Example 2 160 - - - - Example 3 - 170 - - - Example 7 - - 180 - - Example 8 - - - 195 - Example 9 - - - - 180 Excipients / Disintegrants Microcrystalline Cellulose - - 94 102 94 Lactose 140 175 94 102 94 Corn starch 60 75 - - - Primelos 13 9 10 15 10 Crospovidone - 12 13 7 13 Aerosil 4 5 5 6 5 Lubricant Magnesium stearate 3 4 14 4 4 coating Opadry 10 14 12 12 12 Total weight 390 464 412 428 412

Example  36 and 37. Preparation of Tablets Using Spray-Dried Granules

Using the spray-dried granules prepared in Examples 4 and 5, with the ingredients and contents of Table 6 below, tablets containing 100 mg and 75 mg of franlukast per tablet were prepared in the same manner as in Example 30.

Ingredient (g) Example 36 37 Tablet core Spray-dried granules Example 4 180 - Example 5 - 135 Excipients / Disintegrants Microcrystalline Cellulose 114 85.5 Lactose 114 85.5 Primelos 10 9.5 Crospovidone 15 11.5 Aerosil 5 4 Lubricant Magnesium stearate 12 9 coating Opadry 14 10 Total weight 464 350

Example  38-44. Preparation of Tablets Using Spray-Dried Granules

Using the spray-dried granules or franlukast powder prepared in Examples 21 to 26, with the ingredients and contents shown in Table 7 below, a tablet containing 100 mg of franlukast sugar per tablet was prepared in the same manner as in Example 30. .

Ingredient (g) Example 38 39 40 41 42 43 44 Tablet core Spray-dried granules Example 21 160 - - - - - - Example 22 - 160 - - - - - Example 23 - - 170 - - - - Example 24 - - - 180 - - - Example 25 - - - - 195 - - Example 26 - - - - - 180 - Franlukast Powder - - - - - - 112.5 Excipient Microcrystalline Cellulose - - - 70 80 94 120 Lactose 140 140 175 70 80 94 120 Corn starch 60 60 75 - - - - Primelos 16 16 18 16 14 19 18.5 Aerosil 3 3 4 4 3 4 7 Lubricant Magnesium stearate 6 6 8 10 8 9 12 coating Opadry 10 10 13 10 10 12 10 Total weight 395 395 463 360 390 412 400

Example  45. Preparation of Capsules Using Spray-Dried Granules

128 g of the spray-dried granules prepared in Example 2, 59.2 g of microcrystalline cellulose, 59.2 g of lactose, 5.2 g of crospovidone, 1.6 g of aerosil, and 2.8 g of magnesium stearate were mixed, and then filled into capsule No. 1 capsule. Was prepared. The content (mg) of each component per capsule of the obtained capsule is shown in Table 8 below.

ingredient Content per Capsule (mg) Franlukast 100 Polyvinylpyrrolidone 20 Solutol ^® HS 15 12 Poloxamer ^® 407 28 Microcrystalline cellulose 74 Lactose 74 Crospovidone 6.5 Aerosil 2 Magnesium stearate 3.5 sum 320

Example  46-49. Preparation of Capsules Using Spray-Dried Granules

Capsules (Examples 46-49, respectively) were prepared in the same manner as in Example 45, except that the spray-dried granules prepared in Examples 5 and 27-29 were used.

Example  50. Preparation of Dry Syrup Using Spray-Dried Granules

126 g of the spray-dried granules prepared in Example 4, 1.4 g of xanthan gum, 0.7 g of titanium oxide, 3.5 g of strawberry flavor powder, 5.6 g of silicon dioxide and 105 g of maltodextrin were mixed, followed by further mixing 457.8 g per bag. To prepare a granular dry syrup containing 100 mg / g of lancastast. The content of each component per 1 g of the granules of the obtained dry syrup is shown in Table 9 below.

ingredient Mg / g of granules Franlukast 100 Polyvinylpyrrolidone 20 Solutol ^® HS 15 21.6 Poloxamer ^® 407 38.4 Maltodextrin 150 White sugar 654 Xanthan Gum 2 Titanium oxide One Strawberry flavor powder 5 Silicon dioxide 8 sum 1,000

Test Example  1. Solubility test

The solubility of the spray-dried granules prepared in Examples 7-9 was measured in purified water, a first liquid at pH 1.2, and a second liquid at pH 6.8. In 50 ml of purified water, a first solution of pH 1.2, and a second solution of pH 6.8, respectively, 1 g of franlukast powder, the spray-dried granules prepared in Examples 7 to 9, was added thereto each for 6 hours in a 25 ° C water bath. It was vigorously stirred with a stirrer. Samples were collected and filtered with a 0.45 um syringe filter, and then the concentration of franlukast was determined by HPLC, and the results are shown in Table 10 below.

Solubility (ug / ml) Purified water pH 1.2 pH6.8 Franlukast Powder 1.6 x 0.2 Example 7 672.87 111.83 835.23 Example 8 637.75 568.40 1206.89 Example 9 684.09 483.45 1274.53

X: less than detection limit

In Table 10, the spray-dried granules of the present invention can be seen that the solubility is evenly increased under all solvent conditions, in particular, the solubility in the first liquid of pH 1.2 is greatly improved.

Test Example  2. Liquidity Assessment

Compressibility of the granules (comparative granules) of franlukast powder, Onon capsule (Onon Cap., 112.5mg / capsules, Dong-A Pharmaceutical), spray-dried granules prepared in Examples 4, 5, 8 and 9 compressibility) to evaluate the fluidity of the powder and the results are shown in Table 11 below.

ρo ρt % Compressibility liquidity Franlukast Powder 0.17 0.30 43.33 Very, very bad Comparative granule 0.62 0.73 15.07 Very good Example 4 0.40 0.48 16.67 good Example 5 0.42 0.48 12.50 Very good Example 8 0.44 0.51 13.73 Very good Example 9 0.42 0.49 14.29 Very good

ρo: Bulk density

ρt: Tap density

% Compressibility = (ρo-ρt) / ρt * 100

In Table 11, it can be seen that the very strong adhesion cohesive franchast powder 40% or more of the fluidity is very poor powder. It can also be seen that the spray-dried granules of the present invention have very good fluidity.

Test Example  3. Disintegration Test

     The disintegration time of the tablets prepared in Examples 38 to 44 was measured according to the pharmacokinetic disintegration test method. After purified water was used as the test solution and the auxiliary plate was maintained at 37 ± 0.5 ℃, the time was measured until the residue of the sample was not in the glass tube, or there was a little soft or needle-like material. It is shown in Table 12 below.

Disintegration time (minutes) Example 38 12 to 14 Example 39 15 to 16 Example 40 13 to 15 Example 41 20 to 22 Example 42 20 ～ 23 Example 43 19 ～ 21 Example 44 More than 360 minutes

In the above Table 12, all tablets containing the spray-dried granules of the present invention were completely disintegrated within 30 minutes, but in the case of tablets containing franlukast with strong adhesion cohesiveness (Example 44), agglomerates were formed between powders. Disintegration was delayed.

Test Example  4. Dissolution rate  Measure

The dissolution rate of the tablets prepared in Examples 30 to 35 was measured. 900 ml of the second solution of pH 6.8 was added to the disintegration tester and maintained at 37 ± 0.5 ° C. for up to 45 minutes. Then, 10 ml of the sample was taken between the glass tube and the beaker in the diagonal direction of the glass tube including the sample. After the sample was filtered with a 0.45 um syringe filter, the first 5 ml of the filtrate was discarded and the next 2 ml of the filtrate were taken and analyzed by HPLC. The results are shown in Table 13 below. Onon capsule (Onon Cap., 112.5 mg / capsule, Dong-A Pharmaceutical) was used as a comparative agent.

Dissolution rate (%) Comparative Preparation 7.81 Example 30 35.71 Example 31 27.50 Example 32 32.83 Example 33 55.17 Example 34 98.37 Example 35 67.37

As shown in Table 13, it can be seen that the tablets prepared from the spray-dried granules of the present invention had a 4 to 12-fold increase in dissolution rate compared to the Onon capsule, which is a comparative formulation.

Test Example  5. Comparative Dissolution Test

The tablets prepared in Examples 36 and 37 and Onon capsules (Onon Cap., Franlukast 112.5mg / capsule, Dong-A Pharm.), Which were prepared in Examples 36 and 37, were subjected to comparative dissolution test in accordance with Method 2 (paddle method) of the Korean Pharmacopoeia Dissolution Test Method. Was performed.

In a dissolution tester, 900 ml of purified water, a first solution of pH 1.2, a pH 4.0 buffer, a second solution of pH 6.8, and a second solution of pH 6.8 containing 0.2% polysorbate 80 were added thereto and maintained at 37 ± 0.5 ° C. The dissolution rate was measured over time while stirring at a rotational speed of 100 rpm. At each time point, 3 ml of the eluate was collected in a tube coated with silicon, filtered through a 0.45 um syringe filter, and analyzed by UV. The results are shown in FIGS. 1A to 1E. 1A, 1B, 1C, 1D, and 1E are shown in a second solution at pH 6.8 containing purified water, a second solution at pH 6.8, a first solution at pH 1.2, a pH 4.0 buffer, and 0.2% polysorbate 80, respectively. The results of the dissolution test of. In the case of the Onon capsule, the dissolution rate in the first liquid at pH 1.2 and the second liquid at pH 4.0 was less than the limit of quantification.

As can be seen in FIGS. 1A-1E, tablets made from the spray-dried granules of the present invention under all conditions exhibited excellent dissolution patterns.

Test Example  6. Comparative Dissolution Test According to Particle Size of Suspension

Capsules and commercially available Onon capsules prepared by using the spray-dried granules prepared in Examples 5 and 27-29 (Onon Cap., Franlukast 112.5 mg / capsule, Dong-A Pharmaceutical Co., Ltd.) ) The comparative dissolution test was carried out according to the method (paddle method) of the Korean Pharmacopoeia Dissolution Test Method.

In the dissolution tester, the second solution of pH 6.8 containing 0.2% polysorbate 80 was put in 900 ml each, and the dissolution rate was measured over time while stirring at a rotational speed of 100 rpm while maintaining the temperature at 37 ± 0.5 ° C. At each time point, 3 ml of the eluate was taken in a tube coated with silicon, filtered with a 0.45 um syringe filter, and analyzed by UV. The results are shown in FIG. 2.

As shown in FIG. 2, in the case of capsules prepared from spray-dried granules having an average particle size of franlukast in the granules of 20 μm or less, the maximum dissolution rate is higher than 90%, while the average particle size of the franlukast is increased. Capsules prepared from spray-dried granules of 25.70 μm and 44.97 μm had maximum dissolution rates of 78.76% and 56.53%, respectively. In addition, the dissolution rate also increased for capsules prepared from spray-dried granules having an average particle size of franlukast in the granules of 20 μm or less, which resulted in a dissolution rate of about 80% or more at 15 minutes. According to "Guidelines for Setting Elution Standards for Oral Drugs" (Food and Drug Administration), the elution is terminated at more than 85%, making it difficult to determine the elution end point when the average particle size of franlukast is greater than 20 μm.

Test Example 7 Evaluation of Body Dynamics in Rats

The body kinetics in rats were evaluated using granules (comparative granules) contained in Onon capsules (Onon Cap., Franlukast 112.5 mg / capsule, Dong-A Pharmaceutical Co., Ltd.) manufactured according to the present invention.

Sprague-Dawley rats weighing 200-250 g were divided into three groups (n = 5), 11.25 mg / kg (group 1) of the tablet prepared in Example 37 on an empty stomach, 15 mg / kg (group 2) and comparative granules 33.75 mg / kg (group 3) were administered using an oral sonde. After administration, approximately 300 μl was collected through a polyethylene tube inserted into the carotid artery at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, and 8 hours and centrifuged at 10,000 rpm for 1 minute to obtain plasma. Isolated and 100 μl of plasma was taken and stored at −20 ° C. until quantification. Franlukast in plasma was quantified using LC / MS (FIG. 3).

The area under the plasma concentration-time curve (AUC) up to 8 hours post-dose was 442.71 ng.h / ml in group 1 and 628.36 ng.h / ml in group 2 (453.27 ng.h / ml). It is similar to or higher than 1.4 times. Therefore, it can be seen that the spray-dried granules according to the present invention exhibit high bioavailability and can exhibit the same level of drug efficacy even with about one-third dose of a commercial preparation.

Test Example 8 Evaluation of Body Dynamics in Humans

In-body kinetics in humans using tablets made from spray-dried granules prepared according to the present invention (Example 36) and commercially available Onon capsules (Onon Cap., Franlukast 112.5 mg / capsule, Dong-A Pharmaceutical) Was evaluated.

Eight healthy adults aged 30-40 years old were divided into two groups (n = 4), and the tablets (franlukast 100 mg) prepared in Example 36 on fasting (group 1) and the comparative formulation (2 capsules of Onon capsules above) , Franlukast 225 mg) (group 2) were cross-administered on an empty stomach with 200 ml of water. Immediately prior to dosing, 3.0 mL were drawn through the brachial vein at 1, 2, 3, 4, 4.5, 5, 5.5, 6, 7, 8, 10, and 24 hours post dose. The collected blood was placed in a heparinized vacuum tube, roller mixed for 5 minutes, transferred to an eppendorf tube, and centrifuged at 3,000 rpm for 5 minutes. Only plasma was taken and placed in sterile Eppendorf tubes and frozen at -70 ° C until analysis. Franlukast in plasma was quantified using LC / MS (FIG. 4).

The area under the plasma concentration-time curve (AUC) up to 24 hours after administration was 2386.8 ng · h / ml in the first group, whereas the comparative formulation was 1978.2 ng · h / ml, which was 20% higher. Therefore, the tablet prepared from the spray-dried granules according to the present invention shows a high bioavailability, it can be seen that even if administered 80 grams or less of lancus can exhibit the same level of efficacy as commercially available formulations.

Spray-dried granules according to the present invention can improve the adhesion cohesiveness and solubility of franlukast without coating the franlukast with sugars such as lactose, and can increase the dissolution rate and bioavailability than conventional formulations. Dosage can be significantly reduced. In addition, the spray-dried granules of the present invention can be prepared without the use of organic solvents and are therefore suitable for mass production on an industrial scale.

Claims (8)

Franlukast; Water-soluble polymers selected from the group consisting of polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cellulose, polyethylene glycol, polyvinyl alcohol, xanthan gum, and mixtures thereof; And spray-dried granules consisting of a surfactant, wherein the lanlukast-containing spray-dried granules have an average particle size of 0.5-20 μm of franlukast in the granules. 2. The franlukast-containing spray-dried granules according to claim 1, wherein the average particle size of the franlukast in the granules is 5-18 [mu] m. delete The method of claim 1 wherein the surfactant is polyethylene glycol-15-hydroxystearate, polyoxyethylin glycolated natural or hydrogenated castor oil, polyoxyethylene-polyoxypropylene copolymer, synthetic vitamin E derivatives, sorbitan esters And polyoxyethylene sorbitan fatty acid esters, or polyoxyethylene alkyl esters. A pharmaceutical composition comprising the franlukast-containing spray-dried granules according to any one of claims 1, 2 and 4 and a pharmaceutically acceptable carrier. 6. A pharmaceutical composition according to claim 5 in the form of granules, tablets, capsules or dry syrups. A water-soluble polymer and a surfactant selected from the group consisting of polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cellulose, polyethylene glycol, polyvinyl alcohol, xanthan gum, and mixtures thereof are dissolved in water to prepare an aqueous solution. step; Suspending the obtained aqueous solution by adding franlukast while stirring at 10,000-22,000 rpm; And spray-drying the obtained suspension, the method for producing a franlukast-containing spray-dried granule according to any one of claims 1, 2, and 4. Water-soluble polymers and surfactants selected from the group consisting of polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cellulose, polyethylene glycol, polyvinyl alcohol, xanthan gum, and mixtures thereof are dissolved in water, and francastast Adding to suspend; And a franlukast-containing according to any one of claims 1, 2 and 4 which comprises stirring and then spray-drying the obtained suspension at 10,000-22,000 rpm for 5-30 minutes. Process for the preparation of spray-dried granules.

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