Note: Descriptions are shown in the official language in which they were submitted.
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1
ORAL ITRACONAZOLE COMPOSITION WHICH IS NOT AFFECTED
BY INGESTED FOOD AND PROCESS FOR PREPARING SAME
FIELD OF THE INVENTION
The present invention relates to an oral composition of itraconazole
having improved itraconazole bioavailability which is not affected by ingested
food, and a process for the preparation thereof
BACKGROUND OF THE INVENTION
Itraconazole, a triazole compound, is known to have excellent
antifungal activity. However, the bioavailability of orally administered
itraconazole is very low because it has an exceedingly low solubility of less
than 1 ~,g/ml in water and it remains unionized in the gastric juice due to
its
pKa value of 3.7. Further, it is known that the degree of bioavailability of
orally administered itraconazole varies widely among individuals and depends
on other factors such as ingested foods.
PCT International Publication No. WO 85/02767 and U.S. Patent No.
4,764,604 teach a method for increasing the solubility of itraconazole by
employing a cyclodextrin inclusion compound of itraconazole. However, this
method has the problems that the incremental increase in the itraconazole
solubility is only marginal and various complicated preparative procedures are
required.
PCT International Publication No. WO 94/05263 discloses a coated
bead preparation, wherein a core made of pharmaceutically inert or neutral
sucrose, dextrine, starch and the like is coated with a mixture of
itraconazole
and a hydrophilic polymer and, then, the resulting bead is coated again with a
polymer, e.g., polyethylene glycol. Such a coated bead preparation is
30, commercially available from Janssen Pharmaceutica(Beerse, Belgium) under
the trade name of Sporanox~ capsule. However, the manufacturing process
of the above preparation is very complicated due to the fact the beads having
an average size of only 600 to 700 ~,m tend to undergo agglomeration during
the manufacturing process. In addition, the itraconazole bioavailability of
this
preparation varies widely depending on whether it ~is taken before or after
food
ingestion.
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2
PCT International Publication No. WO 97/44014 teaches a solid
dispersion of itraconazole in a water-soluble polymer, which is prepared by
subjecting a mixture of itraconazole and the water-soluble polymer to a
melt-extrusion process at a temperature ranging from 245 °C to 265
°C . This
solid dispersion is described to have an improved bioavailability of
itraconazole which is not influenced by ingested foods, and it is commercially
available from Janssen Pharmaceutica(Beerse, Belgium) under the trade name
of Sporanox~ tablet. However, the manufacturing process of the solid
dispersion is hampered by a number of difficulties in controlling various
process variables, and the in vivo bioavailability of itraconazole achievable
with the above dispersion is still low.
Sporanox~ liquid of pH 2, which is prepared by mixing a
hydroxypropyl- ~3 -cyclodextrin inclusion compound of itraconazole,
hydrochloric acid, propylene glycol, purified water, sodium hydroxide, sodium
saccharin and sorbitol, and is commercially available from Janssen
Pharmaceutica(Beerse, Belgium), exhibits a high bioavailability of
itraconazole
when administered before ingestion, but it has the problems that it must be
taken in great quantities due to its low itraconazole concentration of 10
mg/ml,
the active ingredient rapidly precipitates when it comes in contact with the
intestinal juice, and it is effective only against fungus infection of
esophagus.
Recently, PCT International Publication No. WO 98155148 discloses a
high viscosity composition comprising a drug which has a very low solubility
in water, cyclodextrin, water-soluble acid and a water-soluble organic
polymer.
However, this composition has a high viscosity, and accordingly, a large
amount of a dispersant is used to lower the viscosity during the capsule
making
process. In addition, the composition exhibits a very low dissolution rate of
less than 1 % under a neutral or alkaline condition of pH 6.8 or higher.
In this regard, the present inventors suggested a micro-emulsion
preconcentrate comprising an antiviral agent which has a very low solubility
in water, phosphoric acid, a co-surfactant, a surfactant and an oil in Korean
Application No. 2000-83717, and further suggested another micro-emulsion
composition modified based on said preconcentrate in Korean Application
No. 2001-36930. However, these compositions still exhibit unsatisfactory
itraconazole dissolution rates under a neutral or alkaline condition of pH 6.8
or higher, and thus their bioavailabilities of itraconazole more or less
depend
on ingested food.
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SUMMARY OF THE INVENTION
It is, therefore, a primary object of the present invention to provide an
oral composition of itraconazole having improved itraconazole bioavailability
which is little influenced by ingested food.
It is a further object of the present invention to provide a process for
preparing said oral composition.
In accordance with one aspect of the present invention, there is provided
a viscous and glassy composition for oral administration comprising
itraconazole, an acidifying agent, an amphiphilic additive, a surfactant and
an
oil.
In accordance with another aspect of the present invention, there is
provided a method of preparing said composition which comprises the steps of
(a) dissolving itraconazole uniformly in a mixture of the acidifying agent,
the
amphiphilic additive and a volatile solvent, (b) dissolving the surfactant and
the
oil in the resulting sohation, and (c) removing the volatile solvent
therefrom.
BRIEF DESCRIPTION OF THE DRAWINGS
The above and other objects and features of the present invention will
become apparent from the following description of the invention, when taken
in conjunction with the accompanying drawing, FIG. 1, which shows the
respective itraconazole bioavailabilities of the preparations prepared in
Example 1 and Comparative Example before and after food ingestion.
DETAILED DESCRIPTION OF THE INVENTION
The inventive composition comprising itraconazole as an active
ingredient may be prepared using the other following components:
(1) Acidifying agent
Representative examples of the acidifying agent which may be used in
the present invention to dissolve itraconazole include phosphoric acid, acetic
acid, hydrochloric acid, nitric acid, sulfuric acid, citric acid, fumaric
acid,
malefic acid, and an aqueous solution thereof, wherein 85% phosphoric acid or
a diluted solution thereof is preferred.
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(2) Amphiphilic additive
The amphiphilic additive which is used in the present invention serves
to dissolve itraconazole and adjust the viscosity of the composition to a
degree
suitable for filling into a capsule. Suitable amphiphilic additives that may
be
S used in the present invention include transcutol(diethyleneglycol monoethyl
ether, Gattefosse), dimethyl isosorbide(1,4:3,6-dianhydro-2,5-dimethyl-D-
glucitol), glycofurol(tetrahydrofurfuryl alcohol polyethylene glycol ether),
propylene glycol(1,2-dihydroxypropane), propylene carbonate(4-methyl-2-
oxo-1,3-dioxolane), solutol(macrogol 15 hydroxystearate, BASF) and a
mixture thereof, wherein transcutol is preferred.
(3) Volatile solvent
The volatile solvent employed during the manufacturing process, but
not present in the final product, assists the dissolution of itraconazole by
the
action of the acidifying agent. In the present invention, preferably used as
the
volatile solvent is a non-toxic organic solvent such as an alcohol, e.g.,
ethanol,
propanol and isopropanol, which can be easily volatilized at a temperature of
less than 100 °C .
(4) Surfactant
The surfactant used in the present invention assists the formulation of a
uniform emulsion of an oil and hydrophilic components, and keeps the
emulsion stable during storage. Representative examples of the surfactant
include:
~ polyoxyethylene glycolated natural or hydrogenated vegetable oils
such as polyoxyethylene glycolated natural or hydrogenated castor
oil(Cremophor~, BASF; HCO~, Nikkol),
~ polyoxyethylene-sorbitan-fatty acid esters wherein fatty acid is
mono- or tri-lauric, palmitic, stearic or oleic acid(Tween~, ICI), and
3~ polyoxyethylene fatty acid esters such as polyoxyethylene stearic
acid ester(Myrj, ICI).
(5) Oil
The oil component used in the present invention should be compatible
with the surfactant and capable of forming a stable microemulsion in an
aqueous medium. It may be one of the pharmaceutically acceptable oils such
as tocopherols and derivatives thereof including tocopheryl acetate,
tocopheryl
succinate, and polyethyleneglycol-1000-tocopheryl succinate(TPGS).
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WO 2005/023262 PCT/KR2004/002264
The inventive composition is prepared by (a) dissolving itraconazole in
a mixture of the acidifying agent, the amphiphilic additive and the volatile
solvent, (b) dissolving the surfactant and the oil in the resulting solution,
and
(c) removing the volatile solvent from the resulting mixed solution.
5 In step (c), the volatile solvent may be removed by the conventional
method, e.g., by heating under the ambient pressure or a vacuum, preferably at
a temperature ranging from 40 to 100 °C, more preferably at a
temperature
ranging from 40 to 80 °C .
In the above manufacturing process, itraconazole, the acidifying agent,
the amphiphilic additive, the volatile solvent, the surfactant and the oil are
used
in amounts corresponding to a weight ratio in the range of 1 : 0.5~15 : 0.5~20
0.5~20 : 0.5~l5 : 0.5~15, preferably 1 : 1~10 : 1~15 : 1~15 : 1~10 : 1~10.
The final composition of the present invention with the absence of
volatile solvent comprises itraconazole, the acidifying agent, the amphiphilic
additive, the surfactant and the oil in a weight ratio in the range of 1 :
0.5~15
0.5~20 : 0.5~15 : 0.5~15, preferably 1 : 1~10 : 1~15 : 1~10 : 1~10.
In addition, the inventive composition may comprise
pharnlaceutically acceptable additives for oral administration such as
anti-oxidants.
The pharmaceutical composition of the present invention may be
formulated to obtain various pharmaceutical preparations, e.g., a powder,
granule, tablet, coated preparation and liquid preparation, in accordance with
any of the conventional procedures. For instance, a hard capsule may be
prepared by adding a lubricant and other pharmaceutical additives to the
pharmaceutical composition, processing the mixture into a powder or granule
and filling the powder or granule into a hard gelatin capsule; a tablet, by
adding
a suitable additive to the pharmaceutical composition and tableting the
mixture;
a liquid preparation, by dissolving the pharmaceutical composition in water;
and a coated preparation, by coating a solution of the pharmaceutical
composition on a sugar bead such as Non-pareil~ (Edwaxd Mendell Co., UK).
The inventive itraconazole composition prepared is transparent and
glassy, i.e., it has no fluidity, and has a high viscosity of at least 10,000
cps at
25 °C . This is achievable by the combined action of the amphiphilic
additive
and the volatile solvent used in the inventive method. The high viscosity
glassy composition is much more compact as compared with a conventional
microemulsion composition.
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WO 2005/023262 PCT/KR2004/002264
6
The inventive composition has self microemulsifying capability to form
high stable and available microemulsion particles when orally administered in
the body fluid. Therefore, as the inventive composition can maintain a high
and stable level of itraconazole dissolution rate even under a neutral or
alkaline
condition of pH 6.8 or higher, the itraconazole bioavailability thereof is
little
influenced by ingested food; the itraconazole bioavailabilities of the
inventive
composition before and after ingestion are the same, the ratio of AUCbefore
ingestion and AUCafter ing~hon being close to 1 (AUC : area under the curve of
blood concentration), preferably 0.8 or higher.
The following Examples are intended to further illustrate the present
invention without limiting its scope.
Further, percentages given below for solid in solid mixture, liquid in
liquid, and solid in liquid are on a wt/wt, vol/vol and wt/vol basis,
respectively,
unless specifically indicated otherwise.
Example 1: Preparation of Hard Capsule -1 )
A hard capsule was prepared using the following ingredients:
Quantity(mglcapsule)
Itraconazole 50
Phosphoric acid 85% 208
Ethanol 300*
Transcutol 83
Polyoxyethylene-50-hydrogenated
castor oil(HCO~ 50) 70
Cremophor~ EL 220
dl- a -tocopherol 60
(*not present in the final composition)
Itraconazole was dissolved uniformly in a mixture of 85% phosphoric
acid, transcutol and ethanol, and other ingredients were added thereto and
dissolved. Then, the resulting mixture was concentrated while heating at
55 °C for 4 hrs to volatilize ethanol therefrom to obtain a viscous and
transparent composition having no fluidity. The composition was filled into a
hard capsule by the conventional method described in the General Preparation
Rule of Korea Pharmacopoeia.
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Example 2: Preparation of Soft Capsule
A soft capsule was prepared using the following ingredients:
Quantit~(m /g-capsule)
Itraconazole 50
Phosphoric acid 85% 200
Ethanol 300*
Transcutol 150
Polyoxyethylene-50-hydrogenated
castor oil(HCO~ 50) 80
Cremophor~ EL 200
dl- a -tocopherol 60
(*not present in the final composition)
The procedure of Example 1 was repeated using the above ingredients
to obtain a viscous and transparent composition having no fluidity. The
composition was filled into a soft capsule by the conventional method
described in the General Preparation Rule of Korea Pharmacopoeia.
Example 3: Preparation of Hard Capsule -2)
A hard capsule was prepared by the procedure of Example 1 using the
following ingredients:
Quantit y~m~psule)
Itraconazole 50
Phosphoric acid 85% 200
Ethanol 300*
Transcutol 83
Polyoxyethylene-50-hydrogenated
castor oil(HCO~ 50) 200
Cremophor~ EL 80
dl- a -tocopherol 60
(*not present in the final composition)
Example 4: Preparation of Hard Capsule -3)
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A hard capsule was prepared by the procedure of Example 1 using the
following ingredients:
Quantit Y(mg/capsule)
Itraconazole 50
Phosphoric acid 85% 200
Ethanol 300*
Transcutol 83
Polyoxyethylene-50-hydrogenated
castor oil(HCO~ 50) 200
Tween~ 20 80
dl- a -tocopherol 60
(*not present in the final composition)
Example 5: Preparation of Hard Capsule -4)
A hard capsule was prepared by the procedure of Example 1 using the
following ingredients:
Quantit~mg/capsule)
Itraconazole 50
Phosphoric acid 85% 200
Ethanol 300*
Transcutol 83
Polyoxyethylene-50-hydrogenated
castor oil(HCO~ 50) 150
Cremophor~ EL 150
dl- a -tocopherol 60
(*not present in the final composition)
Example 6: Preparation of Hard Capsule -5)
A hard capsule was prepared by the procedure of Example 1 using the
following ingredients:
~uantity~m~/capsule)
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WO 2005/023262 PCT/KR2004/002264
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Itraconazole 50
Phosphoric acid 85% 200
Ethanol 300*
Transcutol 83
Tween~ 20 200
Cremophor~ EL 80
dl- a -tocopherol 60
(*not present in the final composition)
Example 7: Preparation of Hard Capsule -6)
A hard capsule was prepared by the procedure of Example 1 using the
following ingredients:
Quantit Y(mg/capsule)
Itraconazole 50
Phosphoric acid 85% 200
Ethanol 300*
Transcutol 83
Tween~ 20 150
Cremophor~ EL 150
dl- a -tocopherol 60
(*not present in the final composition)
Example 8: Preparation of Hard Capsule -7)
A hard capsule was prepared by the procedure of Example 1 using the
following ingredients:
Quantity(m~psule)
Itraconazole 50
Phosphoric acid 85% 200
Ethanol 300*
Transcutol 83
Polyoxyethylene-50-hydrogenated
castor oil(HCO~ 50) 200
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WO 2005/023262 PCT/KR2004/002264
Cremophor~ EL 80
dl- a -tocopherol ° 120
(*not present in the final composition)
5 Example 9: Preparation of Hard Capsule -8)
A hard capsule was prepared by the procedure of Example 1 using the
following ingredients:
10 Quantit ~m/capsule)
Itraconazole 50
Phosphoric acid 85% 150
Ethanol 300*
Transcutol g3
Polyoxyethylene-50-hydrogenated
castor oil(HCO~ 50) 70
Cremophor~ EL 220
dl- a -tocopherol 60
(*not present in the final composition)
Example 10: Preparation of Hard Capsule -9)
A hard capsule was prepared by the procedure of Example 1 using the
following ingredients:
Quantit y(m~psule~
Itraconazole 50
Phosphoric acid 85% 208
Ethanol 300*
Dimethylisosorbide 83
Polyoxyethylene-50-hydrogenated
castor oil(HCO~ 50) ~ 70
Cremophor~ EL 220
dl- a -tocopherol 60
(*not present in the final composition)
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11
Exam 1p a 11: Preparation of Hard Capsule -10)
A hard capsule was prepared by the procedure of Example 1 using the
following ingredients:
Quantit y(m -g/capsule)
Itraconazole 50
Phosphoric acid 85% 208
Ethanol 300*
Glycofurol 83
Polyoxyethylene-50-hydrogenated
castor oil(HCO~ 50) 70
Cremophor~ EL 220
dl- a -tocopherol 60
(*not present in the final composition)
EXample 12: Preparation of Hard Capsule -11)
A hard capsule was prepared by the procedure of Example 1 using the
following ingredients:
Ouantit Y(m~psule)
Itraconazole 50
Hydrochloric acid 150
Ethanol 300*
Dimethylisosorbide 83
Polyoxyethylene-S 0-hydrogenated
castor oil(HCO~ 50) 70
Cremophor~ EL 220
dl- a -tocopherol 60
(*not present in the final composition)
Comparative Example: Preparation of Hard Capsule
A 'hard capsule was prepared by the procedure of Example 1, except
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12
that the amphiphilic additive, transcutol, was not employed, using the
following ingredients:
quantity ~mg/capsule)
S Itraconazole 50
Phosphoric acid 85% ~ 208
Ethanol 300*
Polyoxyethylene-50-hydrogenated
castor oil(HCO~ 50) 70
Cremophor~ EL 220
dl- a -tocopherol 60
(*not present in the final composition)
Test Example 1: Dissolution Test
The dissolution rates of itraconazole were determined for the inventive
preparation of Example 1; the preparation of Comparative Example;
Sporanox~ capsule;' Sporanox~ tablet; and Sporanox~ liquid (Janssen Korea),
in accordance with the dissolution test method II(paddle method) described in
the General Tests chapter of Korean Pharmacopoeia under the conditions listed
below:
Test apparatus: Erweka DT80(Erweka, Germany)
Test solutions: 900 ml of artificial gastric juice(pH 1.2)
900 ml of phosphate buffer(pH 6.8)
Temperature of test solutions: 37 ~ 0.5
Rotation speed: 100 ~ 4 rpm
Analytical method: liquid chromatography
- column: Cosmosil C18(150 mm x 4.6 mm;
Nacalai tesque, Japan)
- mobile phase: acetonitrile/phosphate buffer(pH 7.0) = 60:40
- flow rate: 1.2 ml/min.
- detector: UV 255 nrn
- inj ection volume: 10 ~,l
The amount of dissolved itraconazole is represented by the cumulative
amount of itraconazole eluted in 45 min. and the results are shown in Tables 1
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13
and 2.
Table 1
Dissolution rates in artificial gastric juice(pH 1.2)
Sample xamp Comparative Sporanox~ Sporanox~Sporanox~
a xamplc capsule tablet liquid
1
issolved
amount 98.5% 53.2% 93.1% 98.3%
(45min.) 99.7%
Table 2
Dissolution rates in phosphate buffer(pH 6.8)
Sample xamp Comparative Sporanox~ Sporanox~Sporanox~
1e xample capsule tablet '
1 squid
issolved
amount 96.3% 0.5% 0.5% 5.7%
(45min.) 97.2%
As can be seen in Tables 1 and 2, the preparation of Example 1 exhibits
higher amounts of itraconazole dissolved than those of Comparative Example
and the commercially available preparations at pH 1.2 or 6.8. In particular,
the result shows that, in pH 6.8, the itraconazole dissolution rate of the
preparation of Example 1 is remarkably enhanced as compared with the
commercially available preparations.
Test Example 2: In Vivo Absorption Test
In order to investigate the bioavailability of itraconazole contained in
the inventive preparations, in vivo absorption tests were carried out as
follows.
Twenty 14 to 15 week-old male Sprague-Dawly rats each weighing
about 300 g were fasted for over 48 hours while they were allowed free access
to water, and then divided into two groups of 10 each. Subsequently, for the
test after food ingestion, ordinary solid feed and water were continuously
supplied to the two groups of rats.
The two groups of rats were orally administered with the inventive
preparation of Example 1 and the preparation of Comparative Example,
respectively, at a dose of 20 mg itraconazole/kg body weight of the rat. Blood
samples were taken directly from the hearts of the rats before the
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14
administration and after 1, 2, 3, 4, 5, 7 and 24 hours from the
administration,
and the sera were separated therefrom.
Added to 500 ~,1 each of the serum samples were 50 ~,1 of an internal
standard solution(methanol solution containing 500 ~,g/ml of nitrate
econazole)
and 200 ~,1 of 1 M carbonate buffer(Ph 10.0). 7 ml of an extraction
solvent(n-heptane:isoamylalchol=9:1) was added thereto and the resulting
mixture was shaken at 80 rpm for 5 min. to obtain an extract. The extract was
centrifuged at 3,000 rpm for 10 min. and the solvent was evaporated at 50
°C
under a nitrogen atmosphere. To the resulting residue was added 200 ~.l of
0.05% triethylamine solution of 65% aqueous acetonitrile and the mixture was
subjected to HPLC under the following conditions. The observed results are
shown in Table 3 and FIG. 1:
- column: Inertsil ODS2(250 x 4.6 mm, 5 pxn; GL science, Japan)
- mobile phase: 65% aqueous acetonitrile solution
containing 0.05% triethylamine
- detector: W 258 nm
- flow rate: 1.2 ml/min.
- injection volume: 100 ~,1
Table 3
AUC*' Cmax*~ 'rmax*3 AUCbefore ingesrion
(ng~hr/m.~
(ng~~~) (~.) ~AUCafter ingesrion
before
i 5697.5753.6 545.680.2 3.51.2
ti
E n es
l on
x. 94.5%
after
i 6023.7732.5 583.575.6 3.61.1
ti
n es
on
before
C i 4532823.3 416.573.5 4.11.5
ti
omp. n es
on
76.1 /o
Ex. after
5956.61023.1 535.682.6 3.81.9
in esti
on
Area under the curve of blood concentration till 48 hours
*2 Maximum blood concentration
*3 Time at the maximum blood concentration
The results in Table 3 and FIG. 1 show that bioavailability of
itraconazole observed for the inventive preparation is far less influenced by
CA 02538019 2006-03-06 ~'('r~~ ~~~!!~~ ~ ~ ~ ~~
WO 2005/023262 PCT/KR2004/002264
ingested food as compared to that of Comparative Example.
While the invention has been described with respect to the above
specific embodiments, it should be recognized that various modifications and
5 changes may be made to the invention by those skilled in the art which also
fall
within the scope of the invention as defined by the appended claims.
