WO2007024123A1

WO2007024123A1 - Pharmaceutical composition of pranlukast solid-dispersion with improved initial dissolution rate and the method of preparing the same

Info

Publication number: WO2007024123A1
Application number: PCT/KR2006/003368
Authority: WO
Inventors: Joon Gyo Oh; Yong Ho Oh; Ho Chul Shin; Jisun Jung; Key An Um; Dong-Sun Min; Woong Sik Kim
Original assignee: Sk Chemicals Co., Ltd.
Priority date: 2005-08-26
Filing date: 2006-08-25
Publication date: 2007-03-01
Also published as: CN101282716B; JP2009506027A; KR20070024047A; CN101282716A; JP5297194B2; AR055398A1; KR101233235B1

Abstract

The present invention relates to a pharmaceutical composition of pranlukast solid-dispersion with an improved initial dissolution rate and the preparation method thereof. More particularly, it relates to a pharmaceutical composition of pranlukast solid-dispersion prepared by mixing pranlukast solid-dispersion and anticoagulation agent with a certain range of HLB at a elevated temperature, which can be further granulated and capsulated, thus enabling to improve initial dissolution rate of pranlukast by solving the serious problem of pranlukast solid-dispersion to stick to capsule walls and, to improve bioavailability because it shows superior Cmax and AUC based on the same administration dose, as comared to the commercial pharmaceutical composition of pranlukast formulated by conventional method, along with the preparation method thereof.

Description

PHARMACEUTICAL COMPOSITION OF PRANLUKAST SOLID-DISPERSION

WITH IMPROVED INITIAL DISSOLUTION RATE AND THE METHOD OF

PREPARING THE SAME

TECHNICAL FIELD

The present invention relates to a pharmaceutical composition of pranlukast

solid-dispersion with an improved initial dissolution rate and the preparation

method thereof. More particularly, it relates to a pharmaceutical composition of

pranlukast solid-dispersion prepared by mixing pranlukast solid-dispersion and

anticoagulation agent with a certain range of HLB at a elevated temperature, which

can be further granulated and capsulated, thus enabling to improve initial

dissolution rate of pranlukast by solving the serioius problem of pranlukast

solid-dispersion to stick to capsule walls and, to improve bioavailability because it

shows superior Cmax and AUC based on the same administration dose, as

compared to the commercial pharmaceutical composition of pranlukast formulated

by conventional method, along with the preparation method thereof.

Pranlukast, i.e.

4-oxo-8-[4-(4-phenylbutoxy)benzoyl-amino]-2-(tetrazol-5-yl)-4H-l-benzopyran hemihydrate of formula 1 below, has a strong antagonistic activity against

leukotriene C4 (LTC4) and leukotriene D4 (LTD4), and thus has been used for

treating bronchial asthma and allergic rhinitis.

Formula 1

However, the pranlukast needs to be admistered in a large quantity because

it is nearly insoluble in water and low in bioavailability when orally admistered.

The resultant big economical loss has made it urgently necessary to develop novel

drug with such properties improved.

Thus, there have been various researches on pranlukast based on its

pharmaceutical usefulness. WO96/ 41628 or Korean patent no. 10-389606 discloses

granules containting pranlukast and the preparation method thereof. Accordig to

the aforementioned invention, the cohesiveness of pranlukast was improved by

dissolving saccharides, water-soluble polymer and surfactants in distilled water,

followed by spray-drying of suspension. However, the aforementioned invention only discloses a formulation

process for improving surface property, which still has problems that pranlukast

maintains crystallinity and dissolution property is not improved due to the process

of suspensionizing and spray-drying.

Japanese patent publication no. 8-73353 discloses formulations such as eye

drops, nasal drops or injections, which comprise pranlukast and

polyvinylpyrrolidone or β-cyclodextrin as a solubilizing agent. WO99/ 04790

discloses an aqueous pharmaceutical composition comprising benzopyran

derivatives as a main component and an aerosol for pranlukast powder with

improved inhalation efficiency [Pharmaceutical Research 1998, 15, 1748-1752], which

relates to liquid pharmaceutical composition such as an aqueous pranlukast solution

comprising surfactants and a pranlukast suspension comprising water-soluble

polymer.

BACKGROUND ART

However, the formulation disclosed in the Japanest patent publication no.

8-73353 and WO99/ 04790 has a problem of low concentration of pranlukast, i.e. a

unit dosage should be amount to several hundred milliliters. Further, the preparation with solubility improved by controlled pH may be precipitated by

gastric acid when administered orally, and also shows low dissolution rate and

bioavailability due to crystallinity of pranlukast as in Korean patent no. 10-389606.

Meanwhile, one way for improving oral bioavailability is to prepare

solid-dispersion. Solid-dispersion is a mixture where one or more active

ingredients are homogeneously dispersed onto solid-state polymer or inactive

vehicle, which is known to improve oral bioavailability by improving in vitro and in

vivo dissolution property

Coprecipitation, coevaporation, freeze drying, spray drying, and cogrinding

methods are known as methods for preprare the aforementioned solid-dispersion [/.

PHARM. ScL 1993, 82, 32-38].

Korean patent no. 10-0381834 discloses a pranlukast solid-dispersion for

improved dissolution property and oral bioavailability by means of dissolving

pranlukast in a mixture of dichloromethane and methanol.

Although the aforementioned invention is outstanding in that it provides a

pranlukast solid-dispersion for the first time and accomplish relatively high

dissolution rate, it still has serious problems of possibly remaining organic solvents

and environmental pollution due to the employment of spray-drying that needs to use organic solvent.

Further, thus prepared spray-dried products are impossible to capsulate

due to powder bulkiness, and they only may be used for tableting. This is a case

where the original product is approved as a capsule but tablet-form product has

been developed, which cause the approval procedure complicated or even

impossible. Even after approval, it may be difficult to be acknowledged to be

susbstitution item, thus making it hard to expect high profits.

Further, even the tablets prepared according to Korean patent no.

10-0381834 may have the following problems, as may be well aware to one skilled in

the art.

Hydroxypropyl cellulose, which is used for improving solubility of

pranlukast, is an ingredient generally used as matrix in preparing tablet for

controlled release. Excess amount of hydroxypropyl cellulose (1.5 times compared

to drugs) may cause delayed dissolution. Thus, it is inevitable to use a large

amount of disintegrants, which requires additional process such as anti-humiditive

coating or packing with resultant increase in manufacture cost.

To solve the aforementioned disadvantage, the present inventors previously

suggested a method for preparing amorphous pranlukast solid-dispersion by hot-melting pranlukast and one or more water-soluble polymer selected from

poly(vinylpyrrolidone-co-vinylacetate)_/ poly(vinylpyrrolidone) and polyvinyl

alcohol) in Korean patent application no 2004-89455. Pranlukast dissolution rate

and bioavailability was remarkably improved and the same pharmaceutical effect

may be accomplished by administration of smaller amount of the drugs as compared

to conventional spray-drying.

However, when a pharmaceutical composition prepared from the

aforementioned solid-dispersion is capsulated, water-soluble polymer sticks to

gelatine capsules in dissolution solution, thus delaying initial dissolution rate.

Thus, the aforementioned invention may have serious problems that it may take a

relatively long period of time to reach the effective concentration and maximum

plasma concentration may be low because elimination rate of the drug are higher

than the absorption rate. Further, the aforementioned problem of water-soluble

polymer sticking to gelatine is not solved even by using excess disintegrant, which

causes serious problems in commercialization of this solid-dispersion.

DISCLOSURE

TECHNICAL PROBLEM To solve the aforementioned problem, the present inventors performed an

extensive research and finally completed the present invention by finding that the

serious problem of pranlukast solid-dispersion sticking to capsule walls may be

solved by mixing anticoagulation agent with a certain range of HLB and pranlukast

solid-dispersion at an elevated temperature, which may also in turn improve initial

dissolution rate and in vivo bioavailability.

According to the present invention, therefore, when anticoagulation agent

such as poly(ethylene glycols) especially having HLB of 10-40 is used, initial

dissolution behavior and resultant in vivo bioavailability and Cmax may be

remarkably improved.

Accoridngly, the present invention aims to provide a pharmaceutical

composition of pranlukast solid-dispersion, which improves the serious problem of

pranlukast solid-dispersion sticking to capsule walls, along with the preparation

method thereof.

DESCRIPTION OF DRAWINGS

Figure 1 is a graph showing dissolution patterns of the capsules according

to Comparative Examples 1-4 and commercial Onon® capsule. Figure 2 is a graph showing dissolution patterns of the capsules according

to Examples 1-3.

Figure 3 is a graph showing dissolution patterns of the capsules according

to Example 1, Comparative Example 1 and Comparative Example 5 (commercial

Onon® capsule).

Figure 4 a graph showing the time-dependent plasma concentration of

pranlukast after administration of capsules according to Example 4 and

Comparative Example 1.

BEST MODE

The present invention is described more specifically by the following

Examples. Examples herein are meant only to illustrate the present invention, but

in no way to limit the claimed invention.

Examples 1-3: Preparation of pharmaceutical compositions of pranlukast

solid-dispersion by using anticoagulation agent

Pranlukast solid-dispersion was prepared by hot-melting pranlukast in

solid state with copovidone, which is a kind of water-soluble polymer, and thus prepared pranlukast solid-dispersion was verified to be amorphous by using XRD

(X-Ray Diffraction).

6 g of the pranlukast solid-dispersion and 0.06 g of anticoagulation agent

specified in Table 1 was mixed in double-jacketed beaker at 60 ⁰C for 30 minutes to

preprare granules. The granules were cooled at room temperature and sieved

through a 20-mesh sieve, thus providing a granular pharmaceutical composition of

pranlukast solid-dispersion.

The pharmaceutical composition of pranlukast solid-dispersion was well

mixed with lubricant and filled into capsules by using a manual capsule filling

machine.

TABLE 1

Comparative Examples 1-3: Preparation of pharmaceutical compositions of

pranlukast solid-dispersion by using super disintegrants

A pharmaceutical composition of pranlukast solid-dispersion was prepared

by using the same pranlukast solid-dispersions as in Examples 1-3 and mixing three

kinds of widely-used super disintegrant shown in Table 2. The pharmaceutical

composition was mixed with lubricant and filled into capsules as described in

Examples 1-3.

Comparative Example 4: Preparation of a pharmaceutical composition of

pranlukast solid-dispersion without using disintegrant

The same pranlukast solid-dispersions as in Examples 1-3 was mixed with

lubricant and filled into capsules as described in Examples 1-3, but without using

anticoagulation agent and disintegrants.

TABLE 2

Comparative Example 5: Commercial pranlukast products

Commercial Onon® capsules from Dong-A Pharmaceutical (225 mg of

pranlukast per one capsule) were compared to a pharmaceutical composition of

pranlukast solid-dispersion according to the present invention.

Examples 4-15: Preparation of pharmaceutical compositions of pranlukast

solid-dispersion by using various quantities of anticoagulation agent

A granular pharmaceutical composition of pranlukast solid-dispersion was

prepared by mixing 1 g of the same pranlukast solid-dispersion as in Examples 1-3

with anticoagulation agents in the ratio specified in Table 3 at 60 ⁰C, followed by the

same procedure as described in Examples 1-3.

TABLE 3

Experimental Example 1: Measuring dissolution rates with time

The capsules prepared in Examples 1-15 and Comparative Examples 1-4 as

well as the commercial Onon® capsules in Comparative Example 5 were subject to

dissolution test at a temperature of 37.5 ⁰C and pH 6.8 dissolution medium under

stirring with a speed of 50 rpm for 60 minutes. Time-dependent dissolution was

analyzed with HPLC, and dissolution rates were calculated with the following

Mathematical formula 1, as provided in Table 4.

Mathematical Formula 1

_, . . ,. , . .. .. Pranlukaststandardweight(mg)x Peak area of test solutionx 2x900 _{1 ΛΛ}

Pranlukastdissoluticn rate (%) = — — — x 100

Peak area of standardsolutionx C

wherein C represents the weight(mg) of pranlukast per a capsule. TABLE 4

Experimental Example 2: Observation of disintegration behavior depending on

pH conditions

Disintegration behavior was observed for the capsules prepared in Example

4 and Comparative Example 1 for 60 minutes at pH below by using dissolution tester (Paddle method, 50rpm), and the results were provided in Table 5.

TABLE 5 pH 1.2 Distilled water pH 4.0

Example 4 Within 5 minutes Within 5 minutes Within 5 minutes

Comp. Ex . 1 Within 15 minutes Within 15 minutes Within 15 minutes

The capsules of Example 4 showed more than three times fater disintegration

at pH 1.2 and 4.0 and in distilled water compared to those of Comparative Example

1.

Experimental Example 4: Measuring in vivo bioavailability

The capsules (pranlukast 100 mg) prepared in Example 4 and Comparative

Example 1 were orally administered to six healthy adults. The plasma

concentration of drug was analyzed with LC-Mass, and in vivo bioavailability was

determined as shown in Table 6.

TABLE 6

As shown in Table 6, the administration of capsules of Example 4, where the dissolution rate after the lapse of 15 minutes was improved up to 70% or higher,

increased Cmax and AUC by 1.5 times and shortened Tmax, as compared to the

capsules of Comparative example 1, where dissolution rate after the lapse of 30

minutes were 20% or less.

MODE FOR INVENTION

According to one aspect of the present invention, there is provided a

pharmaceutical composition of pranlukast solid-dispersion comprising 100 weight

parts of pranlukast solid-dispersion and 0.1-10 weight parts of anticoagulation

agent, which is in solid or semi-solid state at room temperature and has 10-40 of

HLB.

According to another aspect of the present invention, there is provided a

method of preparing a pharmaceutical composition of pranlukast solid-dispersion

comprising (a) preparing a mixture of pranlukast solid-dispersion and

anticoagulation agent by admixing the pranlukast solid-dispersion and the

anticoagulation agent, which is in solid or semi-solid state in room temperature and

has 10-40 of HLB, while controlling the temperature within 40-90 ⁰C, and (b) cooling

and granulation of the mixture. Hereunder is provided a detailed description of various embodiments of the

present invention.

According to the present invention, pranlukast solid-dispersion is mixed

with anticoagulation agent with a certain range of HLB at an elevated temperature,

followed by granulation and capsulation, thus enabling to prevent pharmaceutical

composition of pranlukast solid-dispersion sticking to capsule walls and to improve

initial dissolution rate of pranlukast. Further, a pharmaceutical composition of the

present invention shows increased in-vivo Cmax and AUC values and improves

in-vivo bioavailability based on the same dosage as compared to conventional

preparation of pranlukast.

A pharmaceutical composition of pranlukast solid-dispersion according to

the present invention comprises pranlukast solid-dispersion and anticoagulation

agent having a certain range of HLB.

The pranlukast solid-dispersion has amorphous structure with improved

solubility, which is prepared from crystalline prnlukast using water-soluble polymer

according to spray-drying or hot-melting methods, preferably hot-melting method.

The anticoagulation agent has 10-40 of HLB (hydrophobic lipophilic

balance). Anticoagulation agent with HLB below 10 is less hydrophilic and would not improve coagulation problem. Further, the anticoagulation agent is preferred

to be solid or semi-solid state at room temperature considering processability and

the effect on capsules.

Examples of the anticoagulation agent include without limitation

poly(ethylene glycols), fatty acid ester derivatives of ρoly(ethylene glycol),

polysorbates, poloxamers, fatty acid esters of sucrose, sodium lauryl sulfate and

their mixture. In generally, poly(ethylene glycol) 1500, poly(ethylene glycol) 1540,

poly(ethylene glycol) 2000, poly(ethylene glycol) 3000, poly(ethylene glycol) 3350

and poly (ethylene glycol) 4000, etc. may be used as the poly (ethylene glycols).

Preferably poly(ethylene glycol) 1500 or Gelucire^® (Gattefosse company), which

comprises fatty acid ester of poly(ethylene glycol) 1500 as main component, may

serve as the poly (ethylene glycols), may serve as the poly (ethylene glycols). Either

polysorbate 61 or polysorbate 65, which is in solid state at room temperature, may be

used as the polysorbates. Poloxamer 188, poloxamer 237, poloxamer 338 or

poloxamer 407 may be used as the poloxamers. Saturated or unsaturated fatty

acids with 14-20 carbons may be used for the fatty acid esters of the sucrose.

Espcially, sucrose stearic acid, sucrose oleic acid, sucrose palmitic acid, sucrose

miristic acid and sucrose lauric acid may be used for the aforementioned purpose. One or more of the aforementioned species may be used as his

anticoagulation agent in an amount of 0.1-10 wt parts relative to 100 wt parts of

pranlukast solid-dispersion. The amount below 0.1 wt parts may cause

non-homogeneousness and unpreferable variation in quality of products. When

the amount is above 10 wt parts, in contrast, the release time of drugs may be too

long and the excess of surfactant may cause side effects in the gastro-intestinal cells.

The pharmaceutical composition of pranlukast solid-dispersion according to

the present invention may further comprise pharmaceutically acceptable additives

such as diluent, disintegrant, binder and lubricant.

The present invention of pharmaceutical composition of pranlukast

solid-dispersion, which has the aforementioned properties, are prepared by mixing

pranlukast solid-dispersion and anticoagulation agent at an elevated temperature,

followed by cooling, granulation and capsulation.

The pranlukast solid-dispersion is prepared by using water-soluble polymer

and spray-drying or preferably hot-melting crystalline pranlukast into amorphous

pranlukast having improved solubility.

When mixing pranlukast solid-dispersion and anticoagulation agent, the

temperature is controlled within 40-90 ⁰C, which is important to make sure that the solid-state or semi-solid-state anticoagulation agent is sufficiently wet or coated to

pranlukast solid-dispersion. The temperature below 40 °C may not accomplish

desired effect of preventing coagulation due to insufficient contact between

anticoagulation agent and pranlukast solid-dispersion. In contrast, when the

temperature is above 90 ⁰C, pranlukast solid-dispersion and anticoagulation agent

may be instable due to the elevated temperature. Further, considering additional

temperature elevation is required in formulation, conventional hot water (around

90 ⁰C) ma not sufficient and special heater should be used instead, thus increasing

production cost and in turn deteriorating productivity.

The cooling temperature is preferred to be 20-30 ⁰C. After sufficient

mixing and cooling, the mixture is granulated into particles of 20-200 mesh,

preferably 60-200 mesh. If it is below 200 mesh, the disintegration is delayed

because of relatively low penetration of water into the composition. In contrast, the

particle size of above 60 mesh, comparatively long time may be required until drug

is dissolved into the solution even after disintegration.

The granulated pharmaceutical composition of pranlukast solid-dispersion

does not stick to capsule walls even after capsulation. The resultant increase in

initial dissolution rate of drugs may be accomplished without using disintegrant unlike in the conventional method, which also improves in vivo bioavailability rate

and in vivo bioavailability with smaller amount of administration.

INDUSTRIAL APPLICABILITY

As set forth above, the present invention solved the problem that pranlukast

solid-dispersion sticks to capsules, thus resulting in lower initial dissolution rate and

decrease in Cmax, which may happen when using pranlukast solid-dispersion along

with conventional disintegrant.

Further, the present invention provides a pharmaceutical composition of

pranlukast solid-dispersion with increased initial dissolution rate, even at a

half-dose of commercial products, enabling to improve in vivo bioavailability rate

and in vivo bioavailability. Thus, the pharmaceutical composition of pranlukast

solid-dispersion according to the present invention shows even superior

antagonistic activity against leukotrien with smaller amount of administration.

Claims

1. A pharmaceutical composition of pranlukast solid-dispersion comprising 100

weight parts of pranlukast solid-dispersion and 0.1-10 weight parts of

anticoagulation agent, which is in solid or semi-solid state at room temperature

and has 10-40 of HLB.

2. The pharmaceutical composition of pranlukast solid-dispersion of claim 1,

wherein the pranlukast solid-dispersion has amorphous structure and is prepared

by spray-drying or hot-melting crystalline pranlukast with water-soluble polymer.

3. The pharmaceutical composition of pranlukast solid-dispersion of claim 2,

wherein the pranlukast solid-dispersion has amorphous structure and is prepared

by hot-melting crystalline pranlukast with water-soluble polymer.

4. The pharmaceutical composition of pranlukast solid-dispersion of claim 1,

wherein the anticoagulation agent is selected from the group consisting of

poly(ethylene glycols), fatty acid ester derivatives of poly(ethylene glycol), polysorbates, poloxamers, fatty acid esters of sucrose, sodium lauryl sulfate and

their mixture.

5. The pharmaceutical composition of pranlukast solid-dispersion of claim 3,

wherein the anticoagulation agent is selected from the group consisting of

poly(ethylene glycol), fatty acid ester derivatives of poly(ethylene glycol), lauryl

macrogol glyceride, sodium lauryl sulfate and their mixture.

6. A method of preparing a pharmaceutical composition of pranlukast

solid-dispersion comprising:

(a) preparing a mixture of pranlukast solid-dispersion and anticoagulation agent

by admixing the pranlukast solid-dispersion and the anticoagulation agent,

which is in solid or semi-solid state at room temperature and has 10-40 of

HLB, while controlling the temperature within 40-90 °C, and

(b) cooling and granulation of the mixture.