WO2007064084A1

WO2007064084A1 - Granules containing pranlukast and processes for the preparation thereof

Info

Publication number: WO2007064084A1
Application number: PCT/KR2006/004402
Authority: WO
Inventors: Young-Joon Park; Sei-Yeon Park
Original assignee: Yuhan Corp
Current assignee: Yuhan Corp
Priority date: 2005-10-28
Filing date: 2006-10-27
Publication date: 2007-06-07
Anticipated expiration: 2008-04-28
Also published as: KR100981751B1; KR20070045799A

Abstract

Provided are pranlukast-containing granules, comprising: a granular core; and a drug coating layer which comprises pranlukast, a water-soluble polymer, and a surfactant, and is formed on the granular core, and a process for preparing the same. The granules, in which the surface of pranlukast is modified (or coated) with a surfactant, can improve the adhesiveness and solubility of pranlukast and increase the dissolution rate and bioavailability of pranlukast, and thus, can be administered at a remarkably decreased dose relative to conventional formulations. Furthermore, the granules can be prepared in the absence of an organic solvent, thereby enabling large-scale mass production without a toxicity problem of residual solvent.

Description

GRANULES CONTAINING PRANLUKAST AND PROCESSES FOR THE PREPARATION THEREOF

Technical Field

[1] The present invention relates to granules containing 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. Pranlukast is currently commercially available in the form of capsules (Onon capsules, 112.5 mg of pranlukast/capsule, two capsules per dose, Donga Pharmaceutical Co., Ltd.).

[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, due to low bioavailability, a therapeutic dosage of 200 mg or more is recommended.

[4] In view of these problems, various studies have been conducted to improve disadvantages of pranlukast. For example, U.S. Patent No. 5,876,760 discloses spray- dried granules prepared by spray-drying a suspension of saccharide(s), a water-soluble polymer, and 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 saccharide(s) (e.g., lactose) can be present in a solid crystal form. Onon capsules (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 improve the adhesiveness of pranlukast. However, since solubility and/or agglomerate- forming property of pranlukast is not improved, agglomerates are formed at dissolution thereof, and thus bioavailability is still low 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] PCT Publication No. WO01/89574(corresponding to Korean Patent Laid-Open

Publication No. 2001-106006) discloses a solid dispersion comprising pranlukast and (hydroxypropyl)methyl cellulose or (hydroxypropyl)cellulose. Pranlukast exists in amorphous form in the solid dispersion to increase the dissolution rate of pranlukast.

[7] In the PCT publication document, however, the preparation of the solid dispersion involves dissolving pranlukast and (hydroxypropyl)methyl cellulose or (hydroxypropyl)cellulose in an organic solvent (i.e., a mixed solvent of dichloromethane and methanol), and thus, problems such as the probability of environmental contamination and the potential toxicity of residual organic solvent may be caused. Furthermore, since a large amount of the organic solvent is required to completely dissolve pranlukast, drying (e.g., spray-drying) is complicated and requires a long time, which renders commercialization difficult.

[8] In addition, examples of pranlukast-containing compositions are reported in Int. J.

Pharm. 172(1998), 179-188 / 173(1998), 243-251 and Pharmaceutical Research 11(1998), 1748-1759, which discloses a pranlukast-containing powder aerosol; Japanese Patent Laid-Open Publication No. Hei. 8-73353, which discloses a liquid preparation, such as an ophthalmic solution, nasal drops, or an injectable solution, containing polypyrrolidone or beta-cyclodextrin as a solubilization aid; and PCT Publication No. WO99/004790, which discloses a pranlukast-containing liquid composition containing a surfactant, a water-soluble cellulose derivative, and a water- soluble vinyl polymer.

[9] However, there is still need to develop a composition that contains pranlukast with improved solubility and adhesiveness and with increased dissolution rate and bioavailability, and can solve the problems that may be caused by the use of an organic solvent.

Disclosure of Invention Technical Problem

[10] While searching for solutions to the above problems, the present inventors found that when granular cores are coated with a suspension of pranlukast, a water-soluble polymer, and a surfactant to form granules, the adhesiveness of pranlukast can be effectively improved and the dissolution rate of pranlukast is increased. Technical Solution

[11] According to an aspect of the present invention, there are provided pranlukast- containing granules, comprising: a granular core; and a drug coating layer which comprises pranlukast, a water-soluble polymer, and a surfactant, and is formed on the granular core.

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

[13] According to still another aspect of the present invention, there is provided a process for preparing the pranlukast-containing granules, which comprises: dissolving pranlukast, a water-soluble polymer and a surfactant in water to produce a suspension; and spray-coating the suspension on a granular core. Brief Description of the Drawings

[14] FlG. 1 illustrates the results of comparative dissolution tests for tablets made from granules of the present invention and a commercially available formulation. Best Mode for Carrying Out the Invention

[15] In accordance with one embodiment, there are provided pranlukst-containing granules, comprising a granular core; and a drug coating layer which comprises pranlukast, a water-soluble polymer, and a surfactant, and is formed on the granular core.

[16] In the pranlukast-containing granules according to the present invention, pranlukast is surface-modified (or coated) with a surfactant via a water-soluble polymer. Thus, the adhesiveness of pranlukast is reduced, and at the same time, the dissolution of pranlukast from formulations can be effectively increased. Therefore, the pranlukast- containing granules according to the present invention differ from the spray-dried granules disclosed in U.S. Patent No. 5,876,760 in which pranlukast is coated with a saccharide, and the wettability and dispersibility of pranlukast are improved using a surfactant to complete the coating of pranlukast with the saccharide. In addition, the pranlukast-containing granules according to the present invention are different from the solid dispersion of WO99/004790 containing amorphous pranlukast to increase the dissolution rate of pranlukast. An organic solvent essential for the preparation of the solid dispersion is not used in the preparation of the pranlukast-containing granules of the present invention.

[17] The pranlukast-containing granules of the present invention include a granular core.

[18] The granular core includes inert materials for granular cores which are commonly used in the art when preparing granules. Examples of the inert materials include mannitol, maltitol, sucrose, lactose, silicon dioxide, dextrin, dextrate, microcrystalline cellulose, cellulose, glucose, polydextrose, starch, gelatinized starch, corn starch, and a mixture thereof. In addition, commercially available sugar spheres such as Non-pareil, Nu-Core, and Nu-Pareil, sugar spheres mixed with corn starch etc., and micro- crystalline cellulose spheres such as Cellus can be used. The granular core may be used in an amount of approximately 35 to 70 wt%, preferably approximately 40 to 60 wt%, based on the total weight of the granules.

[19] The pranlukast-containing granules of the present invention include a drug coating layer which comprises pranlukast, a water-soluble polymer as a binder, and a surfactant coated on a surface of pranlukast, and is formed on the granular core.

[20] 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, polyvinyl alcohol, and a mixture thereof.

[21] The surfactant may be a surfactant commonly used in the pharmaceutical industry.

For example, the surfactant may be selected from polyethylene glycol- 15-hydroxystearate (e.g., Solutol HS 15), polyoxyethylene glycolated natural or hy- drogenated 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, and 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, sucrose fatty acid esters, polyoxyethylene-polyoxypropylene copolymers, synthetic vitamin E derivatives, and sorbitan esters.

[22] The drug coating layer may comprise 50 to 70 wt% of pranlukast, 3-20 wt% of a water-soluble polymer, and 10-40 wt% of a surfactant, based on the total weight of the drug coating layer.

[23] The present invention also provides a pharmaceutical composition comprising the above-described pranlukast-containing granules and a pharmaceutically acceptable carrier.

[24] 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 amounts of the pharmaceutically acceptable carrier can be appropriately selected according to final formulations. [25] 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.

[26] The present invention also provides a process for preparing the pranlukast- containing granules, which comprises: dissolving pranlukast, a water-soluble polymer, and a surfactant in water to produce a suspension; and spray-coating the suspension on a granular core.

[27] In the above-described processes, the spray-coating of the suspension on the granular core may be performed using a common granulator, e.g., a fluid-bed granulator, a cylindrical granulator, or a high-speed rotary granulator, with the fluid- bed granulator being preferred.

[28] As can be seen from the following examples and experimental examples, when the pranlukast-containing granules according to the present invention are orally administered, the bioavailability of pranlukast can be at least two times higher than that of commercially available formulations (Onon capsules). Even when the pranlukast- containing granules are administered in a smaller dose (100 mg or less pranlukast) than commercially available pranlukast-containing formulations (Onon capsules: two capsules once, 225 mg of pranlukast), they show a drug effect equal to or greater than the commercially available pranlukast-containing formulations.

[29] 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

[30] Example 1: Preparation of granules

[31] 75 g of polyvinylpyrrolidone, 37.5 g of Cremophor RH 40 (BASF), and 187.5 g of

Poloxamer 407 (BASF) were dissolved in 1,313 ml of purified water at 80°C. 375 g of pranlukast was then added to the resultant solution while stirring with a magnetic stirrer to produce a suspension.

[32] The suspension was spray-dried on a mixture of 262.5 g of lactose and 262.5 g of microcrystalline cellulose using a fluid bed granulator (Glatt) at 80 °C to produce granules (1,152 g). The conditions of the fluid bed granulator were as follows:

[33] Inlet temperature: 65-80 °C; [34] Product temperature: 35-45 °C; and [35] Spray pressure: 1.0-2.0 bar. [36] [37] Example 2: Preparation of granules [38] 70 g of polyvinylpyrrolidone, 70 g of Solutol HS 15 (BASF), and 105 g of Poloxamer 407 (BASF) were dissolved in 1,400 ml of purified water. 350 g of pranlukast was then added to the resultant solution while stirring with a magnetic stirrer to produce a suspension.

[39] The suspension was spray-dried on a mixture of 490 g of lactose and 210 g of corn starch using a fluid bed granulator (Glatt) to produce granules (1,217.3 g). The conditions of the fluid bed granulator were as follows:

[40] Inlet temperature: 80-90 °C; [41] Product temperature: 35-45 °C; and [42] Spray pressure: 1.0-2.0 bar. [43] [44] Example 3: Preparation of granules [45] Granules (1,125 g) were prepared in the same manner as in Example 2, except that a mixture of 525 g of microcrystalline cellulose and 28 g of crosspovidone was used, instead of the mixture of lactose and corn starch, as a granular core.

[46] [47] Examples 4-11: Preparation of granules [48] Granules were prepared in the same manner as in Example 1 according to the components and contents listed in Table 1 below. Purified water was used in an amount of 10 ml per 1 g of pranlukast.

[49] Table 1

[50] PVP: polyvinylpyrrolidone [51] HPMC: (hydroxypropyl)methyl cellulose

[52] TA: Taurocholic acid [53] [54] Example 12: Preparation of tablets using granules [55] 1.120 g of the granules prepared in Example 1, 56 g of sodium starch glycolate, 14 g of colloidal silicon dioxide, and 35 g of magnesium stearate were mixed and made into tablets. The tablets were coated with 36.4 g of Opadry (OY-C-7000A White, Colorcon), to thereby produce tablets each containing 100 mg of pranlukast.

[56] [57] Examples 13-15: Preparation of tablets using spray-dried granules [58] Tablets (each containing 100 mg of pranlukast) were prepared in the same manner as in Example 12 using the granules prepared in Examples 2 and 3 according to the components and contents listed in Table 2 below (Examples 13 and 14).

[59] Tablets (each containing 100 mg of pranlukast) were prepared in the same manner as in Example 12 using pranlukast powder instead of the granules (Example 15). [60] Table 2

[61] [62] Experimental Example 1: Flowability test

[63] The compressibilities of pranlukast powder, granules (reference granules) of Onon capsules (112.5 mg of pranlukast/capsule, Donga Pharmaceutical Co., Ltd.), and the granules prepared in Examples 12-15 were evaluated to determine flowabilities. The results are presented in Table 3 below.

[64] Table 3

[65] po: Bulk density [66] pt: Tap density [67] compressibility (%) = (po - pt)/pt* 100 [68] [69] As shown in Table 3, the pranlukast powder with very strong adhesiveness exhibited 40% or more compressibility. Thus, it can be seen that pranlulast powder has very poor flowability. On the other hand, the granules of the present invention exhibited excellent flowability. [70] [71] Experimental Example 2: Comparative dissolution test

[72] In a 0.2% polysorbate 80-containing second solution (pH 6.8), the tablets prepared in Examples 12-15, and commercially available formulations, Onon capsules (112.5 mg of pranlukast/capsule, Donga Pharmaceutical Co., Ltd.), were subjected to comparative dissolution test. The comparative dissolution test was performed according to Method 2 (paddle method) specified in the Korean Pharmacopoeia.

[73] 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. With respect to Onon capsules, the dissolution rates of pranlukast was approximately 30% at 120 minutes. On the other hand, the dissolution rates of pranlukast from the tablets made from the granules of the present invention were approximately 90% or more, and thus at least 3 times higher than those of the reference formulations, Onon capsules.

[74]

[75] Experimental Example 3: Disintegration test

[76] The disintegration times of the tablets prepared in Examples 12-15 were measured according to the disintegration test specified in the Korean Pharmacopoeia. Purified water used as a test medium was moved up and down using an auxiliary plate at 37+0.5°C. The time period until no sample residue was observed or some soft or muddy materials were observed in a glass tube was measured, and the results are presented in Table 4 below.

[77] Table 4

[78]

[79] As shown in Table 4, all the tablets containing the granules of the present invention were disintegrated within 30 minutes. On the other hand, in the tablets containing the pranlukast powder with strong adhesiveness (Example 15), powder agglomerates were created, thereby leading to delayed disintegration.

[80] [81] Experimental Example 4: Pharmacokinetic evaluation in rats [82] Pharmacokinetic evaluation in rats was performed using the granules prepared according to the present invention, and granules (reference granules) contained in commercially available formulations, Onon capsules (112.5 mg of pranlukast/capsule, Donga Pharmaceutical Co., Ltd.).

[83] Sprague-Dawley rats (body weight: 200-25Og) were grouped into two (n=6). 15 mg/kg of the granules prepared in Example 1 (first group) and 33.75 mg/kg of the reference granules (second group) were orally administered into the rats on an empty stomach using an oral sonde. At 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, and 8 hours after the oral administration, about 300 D of blood samples were collected through polyethylene tubes cannulated in the carotid arteries and centrifuged at 10,000 rpm for one minute to separate the plasma. 100 D of the plasma was taken and stored at -20 °C until quantification. Pranlukast in the plasma was quantified using LC/MS, and pharmacokinetic parameters were calculated (Table 5).

[84] Table 5

[85] [86] These results reveal that the granules of the present invention exhibit high bioavailability, and thus, even at about 1/2 dose of the commercially available formulations, they have the same drug effect as the commercially available formulations.

[87]

Industrial Applicability [88] Granules according to the present invention, in which the surface of pranlukast is modified (or coated) with a surfactant, can improve the adhesiveness and solubility of pranlukast and increase the dissolution rate and bioavailability of pranlukast, and thus can be administered at a remarkably decreased dose relative to conventional formulations. Furthermore, the granules of the present invention can be prepared in the absence of an organic solvent, thereby enabling large-scale mass production without a toxicity problem of residual solvent.

Claims

[1] Pranlukast-containing granules, comprising: a granular core; and a drug coating layer which comprises pranlukast, a water-soluble polymer, and a surfactant, and is formed on the granular core.

[2] The pranlukast-containing granules of claim 1, wherein the granular core is mannitol, maltitol, sucrose, lactose, silicon dioxide, dextrin, dextrate, micro- crystalline cellulose, cellulose, glucose, polydextrose, starch, gelatinized starch, corn starch, or a mixture thereof.

[3] The pranlukast-containing granules of claim 1, wherein the water-soluble polymer is selected from the group consisting of polyvinylpyrrolidone, (hydroxypropyl)methyl cellulose, (hydroxypropyl)cellulose, polyvinyl alcohol, and a mixture thereof.

[4] The pranlukast-containing granules of claim 1, wherein the surfactant is selected from the group consisting of polyethylene glycol- 15-hydroxystearate, poly- oxyethylene glycolated natural or hydrogenated castor oils, sucrose fatty acid esters, polyoxyethylene-polyoxypropylene copolymers, synthetic vitamin E derivatives, and sorbitan esters.

[5] A pharmaceutical composition comprising the pranlukast-containing granules of any one of claims 1 through 4 and a pharmaceutically acceptable carrier.

[6] The pharmaceutical composition of claim 5, which is in the form of granules, tablets, capsules, or dry syrups.

[7] A process for preparing the pranlukast-containing granules of any one of claims

1 through 4, which comprises: dissolving pranlukast, a water-soluble polymer and a surfactant in water to produce a suspension; and spray-coating the suspension on a granular core.

[8] The process of claim 7, wherein the coating is performed using a fluid bed granulator.