WO2007064083A1

WO2007064083A1 - Spray-dried granules and processes for the preparation thereof

Info

Publication number: WO2007064083A1
Application number: PCT/KR2006/004400
Authority: WO
Inventors: Young-Joon Park; Sei-Yeon Park; Heui-Il Kang
Original assignee: Yuhan Corporation
Priority date: 2005-10-28
Filing date: 2006-10-27
Publication date: 2007-06-07
Also published as: KR20070045798A; KR100981750B1

Abstract

Provided are spray-dried granules consisting of micronized pranlukast; saccharides; and at least one selected from the group consisting of a water-soluble polymer and a surfactant, and a process for preparing the same. The spray-dried granules can improve the adhesiveness and solubility of pranlukast.

Description

SPRAY-DRIED GRANULES AND PROCESSES FOR THE

PREPARATION THEREOF

Technical Field

[1] The present invention relates to spray-dried granules containing micronized pranlukast and a process for preparing the same.

Background Art [2] Pranlukast (chemical name: 4-oxo-8-[4-(4-phenylbutoxy)benzoylamino] -

2-(tetrazol-5-yl)-4H-l-benzopyran hemihydrate), which has a potent antagonistic action against leukotriene C 4 and leukotriene D 4 , is used for the treatment of bronchial asthma and allergic rhinitis.

[3] However, pranlukast is a poorly water-soluble drug having very strong adhesiveness. Thus, when pranlukast is formulated into tablets or capsules, it adheres to a punch, a die, and the like, making continuous production difficult. Furthermore, since pranlukast has a low solubility in water of 2 D/ml or less and a very low bioavailability of 15% (Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10^th ed.), a therapeutic dosage of 200 mg or more is recommended.

[4] To improve the physical properties of pranlukast, U.S. Patent No. 5,876,760

(Korean Patent No. 389,606) discloses spray-dried granules prepared by spray-drying a suspension of pranlukast, saccharides, a water-soluble polymer and/or a surfactant in purified water. The surfactant is used to improve the wettability and dispersibility of pranlukast in the suspension, and pranlukast coated with the saccharides (e.g., lactose) can be present in a solid crystal form. Onon capsules (112.5 mg of pranlukast/capsule, two capsules per dose, Donga Pharmaceutical Co., Ltd.) are a commercially available form of the spray-dried granules disclosed in U.S. Patent No. 5,876,760.

[5] The spray-dried granules disclosed in U.S. Patent No. 5,876,760 effectively improves the adhesiveness of pranlukast but still shows low bioavailability due to very low dissolution rate. That is, the dissolution rate of Onon capsules in a buffered solution (pH 6.8, 37°C) for 6 hours is very low as less than 5%.

[6] Therefore, there is still need to develop a composition that contains pranlukast with improved solubility and adhesiveness and with increased dissolution rate and bioavailability. Disclosure of Invention Technical Problem

[7] While searching for solutions to the above problems, the present inventors found that when pranlukast particles were micronized and spay-dried with saccharides, and a water-soluble polymer and/or a surfactant to be made into granules, the adhesiveness of pranlukast was improved, and at the same time the dissolution of pranlukast was remarkably improved.

[8] Taking into consideration that U.S. Patent No. 5,876,760 does not disclose the physical properties (solubility and adhesiveness) of pranlukast being changed according to the particle size of pranlukast, these findings are very surprising. U.S. Patent No. 5,876,760 discloses that the particle size of the spray-dried granules may be 20 to 1,000 nm, but is silent about the particle size of pranlukast in the granules. Technical Solution

[9] According to an aspect of the present invention, there are provided spray-dried granules consisting of: micronized pranlukast; saccharides; and at least one selected from the group consisting of a water-soluble polymer and a surfactant.

[10] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising the spray-dried granules and a pharmaceutically acceptable carrier.

[11] According to still another aspect of the present invention, there is provided a process for preparing the spray-dried, which comprises: dissolving saccharides and at least one selected from the group consisting of a water-soluble polymer and a surfactant in water to produce an aqueous solution; adding pranlukast to the aqueous solution while stirring at 10,000 to 23,000 rpm to produce a suspension; and sp ray- drying the suspension.

Brief Description of the Drawings

[12] FlG. 1 illustrates the results of comparative dissolution tests for capsules made from spray-dried granules of the present invention and spray-dried granules made from non- micronized pranlukast; and

[13] FlG. 2 illustrates the results of dissolution tests according to the average particle size of pranlukast. Best Mode for Carrying Out the Invention

[14] In accordance with one embodiment, there are provided spray-dried granules consisting of micronized pranlukast; saccharides; and at least one selected from the group consisting of a water-soluble polymer and a surfactant.

[15] In the spray-dried granules according to the present invention, pranlukast particles are micronized (i.e., 30 D or less). Thus, the adhesiveness of pranlukast is reduced, and at the same time, the dissolution of pranlukast from formulations can be effectively increased. Generally, when a drug is micronized, the bioavailability of the drug is increased due to an increased solubility of the drug. However, it is common knowledge in pharmaceutics that, in the case of a drug with high adhesiveness, as a particle size decreases, the adhesiveness among drug particles increases and thus the dissolution of the drug decreases. Thus, very surprising is the finding that when pranlukast particles having very high adhesiveness are micronized and spray-dried with saccharide(s), a water-soluble polymer and/or a surfactant to be made into spray-dried granules, the adhesiveness of pranlukast can be effectively improved, and even more, the solubility and dissolution rate of pranlukast can be increased.

[16] The spray-dried granules according to the present invention consist of micronized pranlukast; saccharides; and at least one selected from the group consisting of a water- soluble polymer and a surfactant. In addition, the spray-dried granules of the present invention may consist of micronized pranlukast; saccharides; a water-soluble polymer; and a surfactant, in order to more effectively improve the dissolution of pranlukast.

[17] An average particle size of the micronized pranlukast in the spray-dried granules may be 0.4 - 30 D, preferably 0.8 - 20 D, and more preferably 7 - 15 D. The average particle size of pranlukast can be adjusted according to various pharmaceutical preparation processes. For example, the spray-dried granules of the present invention can be prepared by spray-drying a suspension obtained by adding pranlukast to an aqueous solution containing saccharides, a water-soluble polymer, and/or a surfactant while vigorously dispersing with, for example, a propeller-containing mixer, a ho- mogenizer, or an ultrasonic oscillator; or by vigorously dispersing a suspension containing pranlukast, saccharides, a water-soluble polymer, and/or a surfactant with, for example, a propeller-containing mixer, a homogenizer, or an ultrasonic oscillator, and spray-drying the dispersion. Of course, the spray-dried granules of the present invention can also be prepared using a method commonly used in the pharmaceutical industry, e.g., a microfluidizer or a high-pressure homogenizer, in addition to the above-illustrated methods. The micronized pranlukast may be contained in an amount of 40 to 60 wt%, preferably 45 to 55 wt%, based on the total weight of the spray-dried granules.

[18] The saccharides contained in the spray-dried granules of the present invention may be saccharides commonly used in the pharmaceutical industry. Examples of the saccharides include lactose, mannitol, sucrose, dextrin, dextran, trehalose, pullulan, maltose, and a mixture thereof.

[19] The water-soluble polymer may be a water-soluble polymer commonly used in the pharmaceutical industry. For example, the water-soluble polymer may be polyvinylpyrrolidone, (hydroxypropyl)methyl cellulose, (hydroxypropyl)cellulose, polyethylene glycol, polyvinyl alcohol, gelatin, xanthan gum, Arabic gum, alginic acid or its salt, polyacrylate copolymer (e.g., Eudragit E), etc. Among them, the water- soluble polymer may be selected from the group consisting of polyvinylpyrrolidone, (hydroxypropyl)methyl cellulose, (hydroxypropyl)cellulose, polyethylene glycol, polyvinyl alcohol, xanthan gum, and a mixture thereof.

[20] Examples of the surfactant include polyethylene glycol- 15-hydroxystearate (e.g.,

Solutol HS 15), polyoxyethylene glycolated natural or hydrogenated castor oils (e.g., Cremophor RH 40, Cremophor RH 60), polyoxyethylene-polyoxypropylene copolymers (e.g., Poloxamer 407, Poloxamer 118), sucrose fatty acid esters (e.g., Ryoto Sugar Ester S- 1570, S- 1670, P- 1570, P- 1670, L- 1695), synthetic vitamin E derivatives (e.g., vitamin E TPGS), sorbitan esters, polyoxyethylene sorbitan fatty acid esters (e.g., Polysorbate 80), polyoxyethylene alkylesters (e.g., Brij 52), polyoxyethylene stearates (e.g., myrj 52), fatty acid macrogol glycerides (e.g., Gelucire 44/14), polyglyceryl fatty acid esters (e.g., Plurol oleique), bile acids (e.g., Taurocholic acid), sodium lauryl sulfate, lecithin, glyceryl fatty acid esters (e.g., glyceryl monostearate), etc. Among them, the surfactant may be selected from the group consisting of polyethylene glycol- 15-hydroxystearate, polyoxyethylene glycolated natural or hydrogenated castor oils, polyoxyethylene-polyoxypropylene copolymers, synthetic vitamin E derivatives, sorbitan esters, polyoxyethylene sorbitan fatty acid esters, and polyoxyethylene alkylesters.

[21] The spray-dried granules of the present invention may consist of 40 to 80 parts by weight of saccharides, 5 to 15 parts by weight of a water-soluble polymer, and/or 10 to 60 parts by weight of a surfactant, based on 100 parts by weight of micronized pranlukast. Preferably, the spray-dried granules of the present invention consist of about 50 parts by weight of saccharides, about 10 parts by weight of a water-soluble polymer, and about 20 to 50 parts by weight of a surfactant, based on 100 parts by weight of micronized pranlukast.

[22] The present invention also provides a pharmaceutical composition comprising the above-described spray-dried granules and a pharmaceutically acceptable carrier.

[23] The pharmaceutically acceptable carrier includes a diluent, a disintegrating agent, a lubricant, etc. which are known and used in the art. Examples of the diluent that can be used herein include mannitol, maltitol, sucrose, lactose, silicon dioxide, dextrin, dextrate, microcrystalline cellulose, cellulose, glucose, polydextrose, starch, gelatinized starch, corn starch, croscarmellose sodium, crosspovidone, sodium starch glycolate, and a mixture thereof, examples of the disintegrating agent include sodium starch glycolate, croscarmellose sodium, and crosspovidone, and examples of the lubricant include sodium stearyl fumarate and magnesium stearate. The pharmaceutically acceptable carrier may be used in an amount of 30 to 70 wt% based on the total weight of the pharmaceutical composition. The pharmaceutically acceptable carrier can be appropriately selected according to final formulations.

[24] The pharmaceutical composition of the present invention may be selected from various dosage forms, including granules, tablets, capsules, or dry syrups. These dosage forms can be prepared according to a method commonly used in the pharmaceutical industry. For example, tablets can be prepared by mixing the above- described spray-dried granules with a diluent, a disintegrating agent, a lubricant, etc. and tabletting the mixture, and capsules can be prepared by filling capsules with the mixture. In addition, the dosage forms may also be subjected to film-coating or enteric- coating to improve stability, drug compliance, appearance, etc.

[25] The present invention also provides a process for preparing the pranlukast- containing spray-dried granules. That is, as described above, the spray-dried granules can be prepared by spray-drying a suspension obtained by adding pranlukast to an aqueous solution containing saccharides, a water-soluble polymer, and/or a surfactant while vigorously dispersing with, for example, a propeller-containing mixer, a ho- mogenizer, or an ultrasonic oscillator; or by vigorously dispersing a suspension containing pranlukast, saccharides, a water-soluble polymer, and/or a surfactant with, for example, a propeller-containing mixer, a homogenizer, or an ultrasonic oscillator, and spray-drying the dispersion. Preferably, the dispersing may be performed by stirring with a homogenizer at 10,000 to 23,000 rpm.

[26] Therefore, the present invention provides a process for preparing the spray-dried granules, which comprises dissolving saccharides and at least one selected from the group consisting of a water-soluble polymer and a surfactant in water to produce an aqueous solution; adding pranlukast to the aqueous solution while stirring at 10,000 to 23,000 rpm to produce a suspension; and spray-drying the suspension.

[27] The present invention also provides a process for preparing the spray-dried granules, which comprises dissolving saccharides and at least one selected from the group consisting of a water-soluble polymer and a surfactant in water and adding pranlukast to the resultant aqueous solution to produce a suspension; and stirring the suspension at 10,000 to 23,000 rpm for 5 to 30 minutes, preferably 10 to 20 minutes, followed by spray-drying.

[28] In the above-described processes, the spray-drying may be performed using a common granulator, e.g., a fluid-bed granulator, a cylindrical granulator, or a highspeed rotary granulator.

[29] As can be seen from the following examples and experimental examples, the spray- dried granules according to the present invention can have 100 to 400 times the solubility of pranlukast and at least 3 times the dissolution rate of pranlukast in commercially available formulations (Onon capsules).

[30] Hereinafter, the present invention will be described more specifically with reference to the following examples. The following examples are for illustrative purposes and are not intended to limit the scope of the invention. Mode for the Invention [31] Example 1: Preparation of spray-dried granules

[32] 10 g of (hydroxypropyl)methyl cellulose was dissolved in 500 ml of purified water and 50 g of lactose and 100 g of pranlukast were added thereto to produce a suspension. The suspension was homogenized with a homogenizer at about 15,000 to 18,000 rpm for 10 minutes. Then, the suspension was spray-dried using a Mini spray dryer (Buchi 190) under the conditions of an inlet temperature of 110-130 °C and an outlet temperature of 80-90 °C, to thereby produce spray-dried granules. The average particle size of pranlukast in the spray-dried granules was measured using an optical particle sizer - AccuSizer 780A (Particle Sizing Systems Inc., Santa Barbara, Calif., U.S. A.) according to dynamic light scattering technique. As a result, the average par tide size of pranlukast in the spray-dried granules was 32.78 D.

[33] [34] Example 2: Preparation of spray-dried granules [35] 1O g of poly vinylpyrrolidone and 20 g of Polysorbate 80 were dissolved in 350 ml of purified water and 50 g of lactose and 100 g of pranlukast were added thereto to produce a suspension. After the suspension was homogenized with a homogenizer at about 18,000 to 20,000 rpm for 20 minutes, spray-dried granules were prepared in the same manner as in Example 1. The average particle size of pranlukast in the spray- dried granules was 18.29 D.

[36] [37] Examples 3 - 6: Preparation of spray-dried granules [38] Spray-dried granules were prepared in the same manner as in Example 2, except that Solutol HS 15 (BASF), Cremophor RH 40 (BASF), Taurocholic acid (TCA, Sigma), and Poloxamer 407 (B ASF) were used instead of Polysorbate 80 in contents Ii sted in Table 1 below. The average particle sizes of pranlukast in the spray-dried granules were measured in the same manner as in Example 1. [39] Table 1

[40] PVP: polyvinylpyrrolidone

[41] (*): average particle size of pranlukast in granules

[42]

[43] Example 7: Preparation of spray-dried granules

[44] 10 g of polyvinylpyrrolidone, 20 g of Solutol HS 15 (BASF), and 30 g of

Poloxamer 407 (B ASF) were dissolved in 750 ml of purified water. 50 g of lactose and 100 g of pranlukast were added to the resultant solution while stirring with a magnetic stirrer, to produce a suspension.

[45] The suspension was spray-dried using a Mini spray dryer (Buchi 190) under the conditions of an inlet temperature of 110-130 °C and an outlet temperature of 80-90 °C, to thereby produce spray-dried granules. The average particle size of pranlukast in the spray-dried granules, which was measured in the same manner as in Example 1, was 98.12 D.

[46]

[47] Example 8: Preparation of spray-dried granules

[48] 10 g of polyvinylpyrrolidone, 20 g of Solutol HS 15 (BASF), and 30 g of

Poloxamer 407 (B ASF) were dissolved in 750 ml of purified water. 50 g of lactose and 100 g of pranlukast were added to the resultant solution while stirring with a magnetic stirrer, and homogenized with a homogenizer at 18,000 to 20,000 rpm for 5 minutes to produce a suspension.

[49] The suspension was spray-dried using a Mini spray dryer (Buchi 190) under the conditions of an inlet temperature of 110-130 °C and an outlet temperature of 80-90 °C, to thereby produce spray-dried granules. The average particle size of pranlukast in the spray-dried granules, which was measured in the same manner as in Example 1, was 52.92 D.

[50]

[51] Examples 9-11: Preparation of spray-dried granules

[52] Spray-dried granules were prepared in the same manner as in Example 8, except that the suspension was homogenized with a homogenizer at 18,000 to 20,000 rpm for 12 minutes (Example 9) and 20 minutes (Example 10).

[53] In addition, spray-dried granules were prepared in the same manner as in Example

8, except that the suspension was homogenized by 3 times passing through a mi- crofluidizer under a pressure of 20,000 to 23,000 psi without using a homogenizer.

[54] The average particle sizes of pranlukast in the spray-dried granules, which were measured in the same manner as in Example 1, were 27.82 D (Example 9), 14.25 D (Example 10), and 813 nm (Example 11).

[55]

[56] Example 12: Preparation of capsules using spray-dried granules [57] 8 g of the spray-dried granules prepared in Example 1, 6.8 g of microcrystalline cellulose, 0.5 g of primellose, 0.3 g of aerosil, and 0.4 g of magnesium stearate were mixed and filled in No. 1 capsules to produce capsules. The contents (mg) of the components in each capsule are presented in Table 2 below.

[58] Table 2

[59] [60] Examples 13-17: Preparation of capsules using spray-dried granules [61] Capsules were prepared in the same manner as in Example 12 using the spray-dried granules prepared in Examples 7-11.

[62] Table 3

[63] [64] Comparative Example 1: Preparation of spray-dried granules and capsules using the same

[65] 10 g of (hydroxypropyl)cellulose was dissolved in 500 ml of purified water and 50 g of lactose and 100 g of pranlukast were added thereto to produce a suspension. The suspension was stirred with a magnetic stirrer for 30 minutes, and then spray-dried in the same manner as in Example 1. The average particle size of pranlukast in the spray- dried granules, which was measured in the same manner as in Example 1, was 104.6 D.

[66] 8 g of the spray-dried granules prepared above, 6.8g of microcrystalline cellulose, 0.5g of primellose, 0.3 g of aerosil, and 0.4 g of magnesium stearate were mixed and filled in No. 1 capsules to produce capsules.

[67] [68] Experimental Example 1: Solubility test [69] The solubilities of the spray-dried granules prepared in Examples 1-11 and Comparative Example 1 were measured in purified water, a first solution (pH 1.2), and a second solution (pH 6.8). Each 1 g of pranlukast powder and the spray-dried granules prepared in Examples 1-11 and Comparative Example 1 was added to each 50 ml of purified water, the first solution, and the second solution, and vigorously stirred with a stirrer in a 25°C water bath for 6 hours. Samples were taken from the resultant solutions and filtered with a 0.45 D syringe filter. The concentration of pranlukast was measured using high performance liquid chromatography (HPLC), and the results are presented in Table 4 below. [70] Table 4

[71] X : below detection limit

[72]

[73] As shown in Table 4, the solubilities of the spray-dried granules of the present invention uniformly increased in all solvent conditions.

[74]

[75] Experimental Example 2: Comparative dissolution test

[76] The capsules prepared in Example 12 and Comparative Example 1 were subjected to comparative dissolution test. The comparative dissolution test was performed according to Method 2 (paddle method) specified in the Korean Pharmacopoeia.

[77] Each 900 ml of a 0.2% polysorbate 80-containing second solution (pH 6.8) was placed in a dissolution tester, and a dissolution rate with respect to time was measured while stirring at 100 rpm at a temperature of 37+0.5 °C. At predetermined time intervals, 3 ml of a dissolution medium was taken in a silicon-coated tube, filtered with a 0.45 D syringe filter, and analyzed with UV. The results are shown in FIG. 1.

[78] As shown in FIG. 1, in connection with the capsules made of the spray-dried granules containing therein pranlukast with an average particle size of 104.6 D, the maximum dissolution rate of pranlukast was 27 %. On the other hand, in connection with the capsules made of the spray-dried granules containing therein pranlukast with an average particle size of 32.78 D, the maximum dissolution rate of pranlukast was 62 %, which was 2 times the maximum dissolution rate of pranlukast from the capsules of Comparative Example 1.

[79]

[80] Experimental Example 3: Dissolution test

[81] The capsules prepared in Examples 13 - 17 were subjected to comparative dissolution test. The comparative dissolution test was performed according to Method 2 (paddle method) specified in the Korean Pharmacopoeia.

[82] Each 900 ml of a 0.2 % polysorbate 80-containing second solution (pH 6.8) was placed in a dissolution tester, and a dissolution rate with respect to time was measured while stirring at 100 rpm at a temperature of 37+0.5 °C. At predetermined time intervals, 3 ml of a dissolution medium was taken in a silicon-coated tube, filtered with a 0.45 D syringe filter, and analyzed with UV. The results are shown in FIG. 2.

[83] As shown in FIG. 2, as the average particle size of pranlukast in granules decreases, the average dissolution rate increases. In particular, when the average particle size of pranlukast is 30 D or less, the dissolution rate for 1 hour is greater than 75 %. According to the "dissolution standard guidelines for oral drug products" of the Korean Food & Drug Administration (KFDA), a dissolution test is terminated at the time when the dissolution rate of a drug reaches 80+5 %. Thus, the average particle size of pranlukast in granules is preferably 30 D or less. [84]

Industrial Applicability

[85] Spray-dried granules according to the present invention can improve the adhesiveness and solubility of pranlukast.

Claims

[I] Spray-dried granules consisting of: micronized pranlukast; saccharides; and at least one selected from the group consisting of a water-soluble polymer and a surfactant.

[2] The spray-dried granules of claim 1, which consisting of: micronized pranlukast; saccharides; the water-soluble polymer; and the surfactant.

[3] The spray-dried granules of claim 1, wherein the micronized pranlukast has an average particle size of 0.4 to 30 D.

[4] The spray-dried granules of claim 2, wherein the micronized pranlukast has an average particle size of 0.4 to 30 D.

[5] The spray-dried granules of any one of claims 1 through 4, wherein the saccharides are lactose, mannitol, sucrose, dextrin, dextran, trehalose, pullulan, maltose, or a mixture thereof.

[6] The spray-dried granules of any one of claims 1 through 4, wherein the water- soluble polymer is selected from the group consisting of polyvinylpyrrolidone, (hydroxypropyl)methyl cellulose, (hydroxypropyl)cellulose, polyethylene glycol, polyvinyl alcohol, xanthan gum, and a mixture thereof.

[7] The spray-dried granules of any one of claims 1 through 4, wherein the surfactant is selected from the group consisting of polyethylene glycol- 15-hydroxystearate, polyoxyethylene glycolated natural or hydrogenated castor oils, polyoxyethylene-polyoxypropylene copolymers, synthetic vitamin E derivatives, sorbitan esters, polyoxyethylene sorbitan fatty acid esters, and polyoxyethylene alkylesters.

[8] A pharmaceutical composition comprising the spray-dried granules of any one of claims 1 through 4 and a pharmaceutically acceptable carrier.

[9] The pharmaceutical composition of claim 8, which is in the form of granules, tablets, capsules, or dry syrups.

[10] A process for preparing the spray-dried granules of any one of claims 1 through

4, which comprises: dissolving saccharides and at least one selected from the group consisting of a water-soluble polymer and a surfactant in water to produce an aqueous solution; adding pranlukast to the aqueous solution while stirring at 10,000 to 23,000 rpm to produce a suspension; and spray-drying the suspension.

[II] A process for preparing the spray-dried granules of any one of claims 1 through 4, which comprises: dissolving saccharides and at least one selected from the group consisting of a water-soluble polymer and a surfactant in water and adding pranlukast to the resultant solution to produce a suspension; and stirring the suspension at 10,000 to 23,000 rpm for 5 to 30 minutes followed by spray-drying.