KR20070045798A - Spray-dried granules and processes for the preparation thereof - Google Patents

Abstract

The present invention relates to micronized franlukast; Saccharides; And spray-dried granules composed of at least one selected from the group consisting of water-soluble polymers and surfactants, and methods for producing the same.

The spray-dried granules according to the invention can simultaneously improve the adhesion cohesiveness and solubility of franlukast.

Franlukast

Description

Spray-dried granules and processes for the preparation etc

1 is a comparative dissolution test results of the capsules made of the spray-dried granules of the present invention and the spray-dried granules made of franlukast not refined,

Figure 2 is a dissolution test results according to the average particle size of franlukast.

FIELD OF THE INVENTION The present invention relates to spray-dried granules containing micronized 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.

However, franlukast is a very poorly cohesive water-soluble drug, and when formulated into tablets or capsules, it is attached to punches, dies, etc., making it difficult to prepare, and solubility in water is 2 ug / It is lower than ml and the bioavailability of the drug is also very low (15%) (Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed.).

In order to improve the physical properties of such franlukast, U.S. Patent No. 5,876,760 (Korean Patent Registration No. 389,606) sprays a suspension obtained by suspending franlukast, sugars, and water-soluble polymers and / or surfactants in purified water. -Spray-dried granules prepared by drying are disclosed. 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. (Onon Cap., Franlukast 112.5mg / capsule, 2 capsules once, Dong-A Pharmaceutical) which is currently commercially available is formulated with the spray-dried granules disclosed in US Pat. 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 a buffer of 37 ℃, pH 6.8 is very low, less than 5%.

Therefore, there is a need in the art for the development of a composition capable of improving physical properties such as solubility and adhesion cohesiveness of franlukast and effectively increasing the dissolution rate and bioavailability.

The present inventors have conducted various studies to solve the problems of the prior art, and as a result, the granules obtained by miniaturizing the particle size of franlukast by spray-drying with sugars and water-soluble polymers and / or surfactants improve adhesion cohesion. At the same time, it has been found that the elution of franlukast can be significantly improved.

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.)

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

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 invention, micronized franlukast; Saccharides; And spray-dried granules comprising at least one selected from the group consisting of water-soluble polymers and surfactants.

Spray-dried granules according to the present invention can effectively increase elution from the formulation while at the same time reducing the cohesiveness of the franlukast itself by using micronized (preferably about 30 μm or less) franlukast. In general, micronization of the drug increases the solubility of the drug in vivo and increases the bioavailability. However, in the case of a drug with a high adhesion cohesive force, as the particle size decreases, the adhesion cohesion between particles increases and the elution decreases due to strong aggregation. It is a common pharmaceutical common sense. Nevertheless, when the granules of franlukast having very high adhesion cohesion are refined to be prepared as spray-dried granules together with sugars and water-soluble polymers and / or surfactants, they can effectively improve adhesion cohesion as well as solubility. And it is surprising that the dissolution rate is also increased.

Spray-dried granules of the invention include micronized franlukast; sugars; And one species selected from the group consisting of water-soluble polymers and surfactants. In addition, the spray-dried granules of the present invention include micronized franlukast; sugars; Water-soluble polymers; And surfactants are preferred since they can further increase the elution of franlukast.

The average particle size of the micronized franlukast contained in the spray-dried granules of the present invention is preferably 0.4-30 µm, more preferably 0.8-20 µm, particularly preferably 7-15 µm. The average particle size of the franlukast can be adjusted according to various pharmaceutical preparation procedures. For example, while vigorously dispersing an aqueous solution of sugars, water-soluble polymers and / or surfactants (e.g., with 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. 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 micronized franlukast may be contained in an amount of 40 to 60% by weight, preferably 45 to 55% by weight, based on the total weight of the spray-dried granules.

The sugars contained in the spray-dried granules of the present invention may use sugars commonly used in the pharmaceutical field. For example, lactose, mannitol, white sugar, dextrin, dextran, trehalose, pullulan, maltose, mixtures thereof and the like can be used.

The water-soluble polymer may be used 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.

Such surfactants include, for example, polyethylene glycol-15-hydroxystearate (e.g. Solutol ^® HS 15), polyoxyethylin glycolated natural or hydrogenated castor oil (e.g. Cremophor ^® RH 40, Cremophor ^® RH 60), polyoxyethylene-polyoxypropylene copolymers (e.g. poloxamer ^® 407, poloxamer ^® 118), sucrose fatty acid esters (e.g. Lotto Sugar Easter ^® (Ryoto Sugar Ester ^® ) S-1570, S-1670, P-1570, P-1670, L-1695), synthetic vitamin E derivatives (e.g. vitamin E TPGS ^® ), sorbitan esters and polyoxyethylene sorbitan fatty acids 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 (e.g. Taurocholic acid), sodium lauryl sulfate, lecithin, glyceryl fatty acid esters (e.g. glyceryl monostearate) and the like. 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 spray-dried granules of the present invention may be composed of 40 to 80 parts by weight of saccharides, and 5 to 15 parts by weight of a water-soluble polymer and / or 10 to 60 parts by weight of surfactant, based on 100 parts by weight of the micronized franlukast. . Preferably, the spray-dried granules of the present invention consist of about 50 parts by weight of sugars, about 10 parts by weight of water-soluble polymers, and about 20-50 parts by weight of surfactant, based on 100 parts by weight of micronized franlukast.

The present invention includes a pharmaceutical composition comprising the 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, water-soluble polymers and / or surfactants; And spray-drying the suspension prepared by adding franlukast while vigorously dispersing an aqueous solution of saccharides (for example, by dispersing with a propeller-containing mixers, a homogenizer, an ultrasonic vibrator, etc.). Or vigorously disperse the suspension of franlukast, sugars, water soluble polymers and / or surfactants (e.g., with propeller-containing mixers, homogenizers, ultrasonic vibrators, etc.). Disperse and then spray drying. The dispersing may be preferably performed by stirring at 10,000 to 23,000 rpm with a homogenizer.

Therefore, the present invention comprises the steps of dissolving at least one selected from the group consisting of water-soluble polymers and surfactants and sugars (saccharides) in water to prepare an aqueous solution; Suspending the resulting aqueous solution by adding franlukast while stirring at 10,000-23,000 rpm; And spray-drying the obtained suspension.

In addition, the present invention comprises the steps of dissolving at least one selected from the group consisting of water-soluble polymers and surfactants and sugars (saccharides) in water, by adding franlukast; And stirring the resulting suspension at 10,000-23,000 rpm for 5-30 minutes, preferably 10-20 minutes, followed by spray-drying.

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 spray-dried granules according to the present invention can increase the solubility of franlukast by more than 100 times, up to 400 times, and the dissolution rate is also available in conventional commercial formulations (Onon capsules). 3 times more than).

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

10 g of hydroxypropylmethyl cellulose was dissolved in 500 ml of purified water, and 50 g of lactose and 100 g of francaste were added to prepare a suspension. The resulting suspension was homogenized with a homogenizer for 10 minutes at a rotational speed of about 15,000-18,000 rpm. The resulting suspension was spray-dried using a Mini spray dryer (Buchi 190) (inlet temperature 110-130 ° C .; outlet temperature 80-90 ° 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 32.78 μm.

Example  2. Preparation of Spray-Dried Granules

A suspension was prepared by dissolving 10 g of polyvinylpinolidon and 20 g of Polysorbate ^® 80 in 350 ml of purified water and adding 50 g of lactose and 100 g of francast. The suspension obtained was homogenized for 20 minutes at a rotational speed of about 18,000-20,000 rpm with a homogenizer, and then spray-dried granules were prepared in the same manner as in Example 1. The average particle size of franlukast in the spray-dried granules is 18.29 μm.

Example  3-6. Preparation of Spray-Dried Granules

Polysorbate 80 instead of the solution toll ^{® HS 15 (Solutol ® HS 15} , BASF , Inc.), Crescent mode pore ^{® RH 40 (Cremophor ® RH 40} , BASF , Inc.), choline acid (Taurocholic acid, TCA, Sigma Co.) to tau, And poloxamer ^® 407 (Poloxamer ^® 407, BASF Co., Ltd.), in the same manner as in Example 2, by using the content of Table 1 below, spray dried granules were prepared in the same manner as in Example 1 The average particle size of franlukast was measured.

Example Francou Caste Polyvinyl pinolidon Lactose Solutol ^® HS 15 Cremophor ^® RH 40 TCA Poloxamer ^® 407 Average Particle Size of Intra-Granuleart 3 100 g 10 g 50 g 20 g - - 35 g 13.23 um 4 100 g 10 g 50 g - 20 g - 38.4 g 9.49 um 5 100 g 10 g 50 g - - 20 g 28.8 g 11.73 um 6 100 g 10 g 50 g - - - 26.25 g 16.87 um

Example  7. Preparation of Spray-Dried Granules

Dissolved in 10 g of polyvinyl fun of money, 20 g of a solution toll ^{® HS 15 (Solutol ® HS 15} , BASF , Inc.), and 30 g of Poloxamer ^® 407 (Poloxamer ^® 407, BASF Co.) in 750 ml of purified water I was. 50 g of lactose and 100 g of lancastast were added and suspended, stirring the obtained solution with the magnetic stirrer.

The resulting suspension was spray-dried using a Mini spray dryer (Buchi 190) (inlet temperature 110-130 ° C .; outlet temperature 80-90 ° C.) to prepare spray-dried granules. It was. The average particle size of franlukast in the spray-dried granules measured in the same manner as in Example 1 is 98.12 μm.

Example  8. Preparation of Spray-Dried Granules

Dissolved in 10 g of polyvinyl fun of money, 20 g of a solution toll ^{® HS 15 (Solutol ® HS 15} , BASF , Inc.), and 30 g of Poloxamer ^® 407 (Poloxamer ^® 407, BASF Co.) in 750 ml of purified water I was. While the resulting solution was stirred with a magnetic stirrer, 50 g of lactose and 100 g of franlukast were added and suspended, and homogenized with a homogenizer at a rotational speed of 18,000-20,000 rpm for 5 minutes.

The resulting suspension was spray-dried using a Mini spray dryer (Buchi 190) (inlet temperature 110-130 ° C .; outlet temperature 80-90 ° C.) to prepare spray-dried granules. It was. The average particle size of franlukast in the spray-dried granules measured in the same manner as in Example 1 is 52.92 μm.

Example  9-11. Preparation of Spray-Dried Granules

Spray-dried granules were prepared in the same manner as in Example 8, except that the homogenizer was homogenized for 12 minutes (Example 9) and 20 minutes (Example 10) at a rotational speed of 18,000-20,000 rpm. Prepared.

In addition, the spray-dried granules were prepared in the same manner as in Example 8 except that the homogenizer was passed through a microfluidizer three times at a pressure of 20,000-23,000 psi instead of homogenizer. Prepared (Example 11).

The average particle size of franlukast in the spray-dried granules measured in the same manner as in Example 1 is 27.82 μm (Example 9), 14.25 μm (Example 10), and 813 nm (Example 11), respectively.

Example  12. Preparation of Capsules Using Spray-Dried Granules

8 g of the spray-dried granules prepared in Example 1, 6.8 g of microcrystalline cellulose, 0.5 g of primelose, 0.3 g of aerosil, and 0.4 g of magnesium stearate were mixed, and then filled into No. 1 capsule to prepare a capsule. It was. The content (mg) of each component per capsule of the obtained capsule is shown in Table 2 below.

ingredient Content per Capsule (mg) Franlukast 100 Hydroxypropyl cellulose 10 Lactose 50 Microcrystalline cellulose 136 Primelos 10 Aerosil 5 Magnesium stearate 8 sum 320

Example  13-17. Preparation of Capsules Using Spray-Dried Granules

Using the spray-dried granules prepared in Examples 7 to 11, capsules were prepared in the same manner as in Example 12.

Content per Capsule (mg) Example 13 14 15 16 17 Spray-dried granules Example 7 210 - - - - Example 8 - 210 - - - Example 9 - - 210 - - Example 10 - - - 210 - Example 11 - - - - 210 additive Microcrystalline cellulose 93 93 93 93 93 Primelos 10 10 10 10 10 Aerosil 3 3 3 3 3 Magnesium stearate 4 4 4 4 4 Gross weight 320 320 320 320 320

Comparative example  1. Preparation of Spray-Dried Granules and Capsules Using the Same

10 g of hydroxypropyl cellulose was dissolved in 500 ml of purified water and 50 g of lactose and 100 g of francaste were added to prepare a suspension. The resulting suspension was stirred for 30 minutes with a magnetic stirrer, spray-dried in the same manner as in Example 1, and the average particle size was measured. The average particle size of franlukast in the spray-dried granules is 104.6 μm.

8 g of the spray-dried granules prepared above, 6.8 g of microcrystalline cellulose, 0.5 g of primelose, 0.3 g of aerosil, and 0.4 g of magnesium stearate were mixed, and then filled into No. 1 capsule to prepare a capsule.

Test Example  1. Solubility test

The solubility of the spray-dried granules prepared in Examples 1 to 11 and Comparative Example 1 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 liquid of pH 1.2, and a second liquid of pH 6.8, 1 g of each of the franlukast powder, the spray-dried granules prepared in Examples 1 to 11 and Comparative Example 1, was added, respectively, and a 25 ° C water bath. Vigorously stirred with a stirrer for 6 hours. The sample was collected and filtered through a 0.45 um syringe filter, and then the concentration of franlukast was quantified by HPLC, and the results are shown in Table 4 below.

Solubility (ug / ml) Purified water pH 1.2 pH6.8 Franlukast Powder 1.6 x 0.2 Example 1 154.45 34.53 234.53 Example 2 421.94 153.19 633.92 Example 3 631.00 513.29 978.96 Example 4 617.57 468.40 906.89 Example 5 684.09 583.45 974.53 Example 6 341.91 224.93 556.81 Example 7 93.96 24.93 158.98 Example 8 241.91 90.18 356.81 Example 9 470.49 118.22 721.66 Example 10 575.20 252.02 937.42 Example 11 692.55 452.02 1138.44 Comparative Example 1 31.96 9.18 58.98

X: less than detection limit

In Table 4, it can be seen that the spray-dried granules of the present invention have increased solubility evenly under all solvent conditions.

Test Example  2. Comparative Dissolution Test

The capsules prepared in Example 12 and Comparative Example 1 were subjected to a comparative dissolution test in accordance with the second method (paddle method) of the pharmacopeia 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 at 37 ± 0.5 ° C. 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 FIG. 1.

As can be seen in FIG. 1, for capsules prepared from spray-dried granules having an average particle size of franlukast in the granules of 104.6 μm, the maximum dissolution rate is 27%, whereas the average particle size of the franlukast is Capsules prepared from 32.78 μm spray-dried granules have a maximum dissolution rate of 62% and more than double the dissolution rate.

Test Example  3. Dissolution Test

The dissolution test was performed in accordance with the Korean Pharmaceutical Dissolution Test Method 2 (paddle method) of the capsules prepared in Examples 13 to 17.

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 collected in a tube coated with silicon, filtered through a 0.45 um syringe filter, and analyzed by UV. The results are shown in FIG. 2.

As can be seen in Figure 2, as the average particle size of the franlukast in the granules decreases, the average dissolution rate increases, in particular, when the average particle size of the franlukast is 30 um or less, the dissolution rate for 1 hour is 75% Exceeds. According to "Guidelines for Setting Elution Standards for Oral Drugs" (Food and Drug Administration), dissolution criteria can be set for oral medicines when the dissolution rate is 80 ± 5%. The particle size is preferably 30 um or less.

The spray-dried granules according to the invention can simultaneously improve the adhesion cohesiveness and solubility of franlukast.

Claims (11)

Micronized franlukast; Saccharides; And at least one spray-dried granule selected from the group consisting of water-soluble polymers and surfactants. The method of claim 1, further comprising: micronized franlukast; sugars; Water-soluble polymers; And spray-dried granules consisting of a surfactant. 2. Spray-dried granules according to claim 1, characterized in that the average particle size of the micronized lanlukast is 0.4-30 [mu] m. 3. Spray-dried granules according to claim 2, characterized in that the average particle size of the micronized lanlukast is 0.4-30 [mu] m. The spray-dried according to any one of claims 1 to 4, wherein the saccharide is lactose, mannitol, white sugar, dextrin, dextran, trehalose, pullulan, maltose, or a mixture thereof. Granules. The method of claim 1, wherein the water-soluble polymer is polyvinyl pyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cellulose, polyethylene glycol, polyvinyl alcohol, xanthan gum, and mixtures thereof. Franlukast-containing spray-dried granules, characterized in that it is selected from the group consisting of: The method according to any one of claims 1 to 4, wherein the surfactant is polyethylene glycol-15-hydroxystearate, polyoxyethylin glycolated natural or hydrogenated castor oil, polyoxyethylene-polyoxypropylene copolymer, Spray-dried granules, characterized in that they are synthetic vitamin E derivatives, sorbitan esters and polyoxyethylene sorbitan fatty acid esters, or polyoxyethylene alkyl esters. A pharmaceutical composition comprising the spray-dried granules according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier. A pharmaceutical composition according to claim 8 in the form of a granule, tablet, capsule, or dry syrup. Preparing an aqueous solution by dissolving at least one selected from the group consisting of water-soluble polymers and surfactants and saccharides in water; Suspending the resulting aqueous solution by adding franlukast while stirring at 10,000-23,000 rpm; And spray-drying the obtained suspension, the method for producing the spray-dried granules according to any one of claims 1 to 4. Dissolving at least one and saccharides selected from the group consisting of water-soluble polymers and surfactants in water and suspending by adding franlukast; And spray-drying the obtained suspension at 10,000-23,000 rpm for 5-30 minutes, and then spray-drying the method according to any one of claims 1 to 4.

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