OH YONG HO (KR)
SHIN HO CHUL (KR)
JUNG JISUN (KR)
UM KEY AN (KR)
MIN DONG-SUN (KR)
KIM WOONG SIK (KR)
OH JOON GYO (KR)
OH YONG HO (KR)
SHIN HO CHUL (KR)
JUNG JISUN (KR)
UM KEY AN (KR)
MIN DONG-SUN (KR)
KIM WOONG SIK (KR)
| WO2006049433A1 | 2006-05-11 |
| US20030077322A1 | 2003-04-24 | |||
| US5876760A | 1999-03-02 | |||
| US6889899B2 | 2005-05-10 |
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. |
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-y l)-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 0 C 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 0 C, 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 0 C 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 0 C, 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 0 C, 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 0 C, 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 0 C) 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 0 C. 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.