Note: Descriptions are shown in the official language in which they were submitted.
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ORAL COMPOSITION COIvIP'RTSTNG A TRIAZOLE ANTfFUNGAL COMPOUND
= 5
BACKGROUND OF THE INVENTION
= The present invention relates to compositions having enhanced or improved
bioavailability for a novel triazole antifungal compound.
International Patent Publication Number WO 95/17407 published 29 June
1995, teaches a novel class of tetrahydrofuran/triazole antifungal compounds.
One particular compound, (2R-cis)-4-[4-[4-[4-[[-5-(2,4-diffuorophenyl)-
tetrahydro-5-(1 H-1,2,4-triazol-1-ylmethyl)furan-3-yl]methoxy]phenyl]-1-
piperazinyl]phenyl]2-4-dihydro-2-[(S)-1-ethyl-2(S)-hydroxypropyl)-3H-1,2,4-
Triazol-3-One ("the antifungal compound"), was found to have potent antifungal
activity in suspensions against opportunistic fungi such as Aspergillis,
Candida,
Cryptococcus and other opportunistic fungi. However, solid compositions, such
as powders or granules, were found to have reduced anti-fungal activity and/or
bioavailability, presumably due to this compound's extremely low water
solubility. It would be desirable to provide this antifungal compound in a
pharmaceutical composition whose antifungal and/or bioavailabilty would be
enhanced or improved.
SUMMARY OF THE INVENTION
The present invention is directed to a pharmaceutical composition
comprising:
i) a plurality of beads; wherein said beads are coated with
ii) an antifungal agent of the formula:
O H3C
/
H O/ \ NN aN N S S CH3
N
HO
F R O
= I ~ NiN
\-N
and
iii) a binder to enables the antifungal compound to adhere to said beads.
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The pharmaceutical composition may also contain other excipients such
as iv) surfactants, v) plasticizers, vi) defoaming agents and coloring agents.
The
pharmaceutical composition can also be formulated into any other suitable
delivery system or dosage form, such as capsules, tablets, or beads for
reconstitution.
It has also been surprisingly and unexpectedly found that the coating of
beads with the antifungal compound using a suitable binder, can enhance or be
equivalent to the bioavailability of the antifungal compound compared to
suspensions. These results are truly surprising and unexpected, since known
references, such as Peter G. Welling, Pharmacokinetics, Processes and
Mathematics, American Chemical Society, Washington DC, ACS Monograph
185, 1986, page 57, teaches that solutions and suspensions generally give rise
to more satisfactory bioavailability than capsules or tablets. J.G. Nairn,
Remington's Pharmaceutical Sciences, 18th Edition, 1990, Mack Publishing
Co., Chapter 83, page 1519 also teaches that since drugs are absorbed in their
dissolved state, frequently it is found that the absorption rate of oral
dosage
forms decreases in the following order: aqueous solution>aqueous
suspension>capsule or tablet.
The present invention has the advantage of being able to provide the
antifungal compound in a pharmaceutical composition that can conveniently be
formulated into solid or "dry" delivery systems or dosage forms such as
capsules, tablets or loose beads having effective antifungal activity and/or
bioavailabilty.
DETAILED DESCRIPTION OF THE EMBODIMENTS
WO 95/17407 published 29 June 1995 discloses antifungal compounds of the
formula:
0
/-\
H O NN &N N- R'
N
F R p
N N
F
'=N
wherein Rl is a straight or branch chain (C3 to C8) alkyl group substituted by
one or two hydroxy moieties; esters and ethers thereof or a pharmaceutically
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acceptable salt thereof. An especially preferred compound of the above group
taught in Examples 24 and 32 of WO 95/17407 is the antifungal compound, (-)-
(2R-cis)-4-[4-[4-[4-[[-5-(2,4-difluorophenyl)-tetrahydro-5-(1 H-1,2,4-triazol-
l-
yimethyl)furan-3-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,-4-dihydro-2-j(S)-
1-
ethyl-2(S)-hydroxypropyl]-3H-1,2,4-triazol-3-one ("the antifungal compound");
Formula: C37H42F2N804; Molecular weight: 700.8; m.p. 164-165 C, [a]p25
-29 C 3 (c = 1.0, CHCI3), whose structure is depicted below:
O H3C
/!1
H O~ NN N N S S
N CH3
HO
F R p
N/ N
F
N
Micron-sized particles of the antifungal compound can be obtained either
by the final step during the manufacture of the antifungal compound or by the
use of conventional micronizing techniques after the conventional
crystallization
procedure(s).
Where micronizing techniques are employed, the antifungal compound
may be micronized to the desired particle size range by conventional
techniques, for example, using a ball mill, ultrasonic means, or preferably
using
fluid energy attrition mills such as the trost fluid energy mill from
Plastomer
Products, Newton, Pennsylvania 18940. When using a fluid energy attrition
mill, the desired particle size can be obtained by varying the feed rate of
the
antifungal into the mill.
About 99% of the of the micronized antifungal particle are less than or
equal to 100 microns in length, of which 95% are less than or equal to 90
microns. Preferably, about 99% of the micronized particles are less than or
equal to 50 microns, of which 95% are less than or equal to 40 microns. More
preferably, 99% of the micronized particles are less than or equal to 20
microns,
. 25 of which 95% are less than or equal to 10 microns.
The antifungal compound is employed in the composition- in amounts
effective to control the organism or fungi of interest. Such amounts can range
from about 2% to about 50% by weight of the composition, more preferably from
6% to about 40%, most preferably from about 5 to about 33% by weight. The
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amount of composition in the particular dosage form, e.g. capsule, tablet,
etc.,
can range from about 10 to about 300 mg antifungal compound per dosage
form, preferably from about 50 to about 200 mg.
Compositions of the present invention can be prepared by dissolving or
suspending the antifungal compound in an a suitable solvent system containing
a binder, and optionally with one or more ingredients such as a surfactant,
plasticizer, defoaming agent and/or coloring agent and coating the solution or
suspension on the inert beads.
The pharmaceutical composition of the present invention can be
formulated into any suitable dosage form, such as capsules, tablets or loose
beads for constitution. For example, the above composition can be compressed
into tablet form using a suitable cushioning agent, such as microcrystalline
cellulose, and optionally, a disintegrant, lubricant, glident, and the like.
The following terms are used to describe the present pharmaceutical
compositions, ingredients which can be employed in its formulation and
methods for assessing its bioactivity or bioavailability.
The beads or seeds are discrete particles, preferably spherical particles
or spheres, which serve as the solid substrate upon which the antifungal
compound is coated, and make up the major portion of the composition or
dosage form. Beads can be made of sugars such as lactose, sucrose, mannitol
and sorbitol; other beads can be derived from starches derived from wheat,
corn
rice and potato; and celluloses such as microcrystalline cellulose. A source
of
sugar beads (non-pareil seeds) is known as Nu-pareil PG, tradename of
Crompton and Knowles Ingredient Technology Corporation, of Mahawah, New
Jersey. A source of microcrystalline cellulose beads is known as Celphere,
tradename of the FMC Corporation, Philadelphia, Pennsylvania. Beads of
differing mesh sizes can be employed, such as 18/20 mesh, 25/30 mesh and
40/50 mesh. Such mesh sizes refer to particle or bead sizes whose diameters
can ranges from about 1.0 millimeters (mm) to about 0.297 mm. Preferably the
bead sizes or diameters are within a relative narrow range such as, for
example, between about 1.0-0.84 mm (18/20 mesh), or between about 0.71-
0.59 mm (25/30 mesh), or between about 0.42-0.297 mm (40/50 mesh). The
beads should be "inert" meaning that the beads themselves have little or no
antifungal effectiveness. The amount of beads in the composition can range
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from about 50 to about 90% by weight of the total composition, preferably from
about 60 to about 80%, more preferably from about 65 to about 75% by weight.
Binders - refers to substances that bind or "glue" the antifungal
compound and other ingredients onto the beads, enabling the beads to be
coated. Suitable binders include sugars such as sucrose; starches derived
from wheat, corn rice and potato; natural gums such as acacia, gelatin and
tragacanth; derivatives of seaweed such as alginic acid, sodium alginate and
ammonium calcium alginate; cellulosic materials such as methylcellulose,
hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose
and sodium carboxymethylcellulose; polyvinylpyrrolidone (Povidones); protein
hydrolysates; methacrylic acid and salts thereof; and inorganic compounds
such as magnesium aluminum silicate. A commercially available formulation
useful as a binder is known as Opadry powders, tradename of the Coloron
Corporation, West Point, Pennsylvania. Opadry powders may contain
hydroxypropyimethylcellulose, along with a plasticizer such as polyethylene
glycol and a surfactant such as polysorbate-80. The amount of binder in the
composition can range from about 1 to about 10% by weight of the composition,
preferably from about 2 to about 8% by weight, more preferably from about 3 to
about 6%.
Disintegrants - refers to materials added to the composition to help it
break apart (disintegrate) and release the medicaments. Suitable disintegrants
include starches; "cold water soluble" modified starches such as sodium
carboxymethyl starch; natural and synthetic gums such as locust bean, karaya,
guar, tragacanth and agar; cellulose derivatives such as methylcellulose and
sodium carboxymethylcellulose; microcrystalline celluloses and cross-linked
microcrystalline celluloses such as sodium croscarmellose; alginates such as
alginic acid and sodium alginate; clays such as bentonites; and effervescent
mixtures. The amount of disintegrant in the composition can range from about 2
to about 15% by weight of the composition, more preferably from about 4 to
about 10% by weight.
Surfactant - refers to a compound that can reduce the interfacial tension
between two immiscible phases and this is due to the molecule containing two
localized regions, one being hydrophilic in nature and the other-hydrophobic.
Non-ionic surfactant - refet=s to a surfactant which lacks a net ionic charge
and do not dissociate to an appreciable extent in aqueous media. The
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properties of non-ionic surfactants are largely dependent upon the proportions
of the hydrophilic and hydrophobic groups in the molecule. Hydrophilic groups
include the oxyethylene group (-OCH2CH2-) and the hydroxy group. By varying
the number of these groups in a hydrophobic molecule, such as a fatty acid,
substances are obtained which range from strongly hydrophobic and water
insoluble compounds, such as glyceryl monostearate, to strongly hydrophilic
and water-soluble compounds, such as the macrogols. Between these two
extremes types include those in which the proportions of the hydrophilic and
hydrophobic groups are more evenly balanced, such as the macrogol esters
and ethers and sorbitan derivatives. Suitable non-ionic surfactants may be
found in Martindale, The Extra Pharmacopoeia, 28th Edition, 1982, The
Pharmaceutical Press, London, Great Britain, pp. 370 to 379. Such non-ionic
surfactants include block copolymers of ethylene oxide and propylene oxide,
glycol and glyceryl esters of fatty acids and their derivatives,
polyoxyethylene
esters of fatty acids (macrogol esters), polyoxyethylene ethers of fatty acids
and
their derivatives (macrogol ethers), polyvinyl alcohols, and sorbitan esters.
Preferably, the non-ionic surfactant is a block copolymer of ethylene oxide
and
propylene oxide.
Suitable block copolymers of ethylene oxide and propylene oxide
generically called "Poloxamers" and include those represented by the following
chemical structure:
CH3
HO(CH2CH2O)a(CH2CHO)b(CH2CH2O),H
wherein a is an integer ranging from about 10 to about 110, preferably from
about 12 to 101; more preferably from about 12 to 80; and
b is an integer ranging from about 20 to about 60, more preferably from
about 20 to about 56; also from about 20 to 27. Most preferably, a is 80 and b
is
27, otherwise known as Pluronic F68 surfactant, trademark of the BASF
Corporation, Mount Olive, New Jersey, USA. Pluronic F68 surfactant is also
known as Poloxamer 188. This surfactant has an average molecular weight of
8400, is a solid at 20 C, has a viscosity (Brookfield) of 1000 cps at 77 C.
Other
suitable block copolymers of ethylene oxide and propylene oxide include
Pluronic F87, also known as Poloxamer 237 wherein a is 64 and b is 37; and
Pluronic F127, also known as Poloxamer 407 wherein a is 101 and b is 56.
Suitable glycol and glyceryl esters of fatty acids and their derivatives
include glyceryl monooleate and similar water soluble derivatives;
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Suitable polyoxyethylene esters of fatty acids (macrogol esters) include
polyoxyethylene castor oil and hydrogenated castor oil derivatives;
Suitable polyoxyethylene ethers of fatty.acids and their derivatives
(macrogol ethers) include Cetomacrogel 1000, Lauromacrogois (a series of
lauryl ethers of macrogois of differing chain lengths) e.g. Laureth 4, Laureth
9
and Lauromacrogol 400.
Suitable Sorbitan esters (esters of one or more of the hydroxyl groups in
the sorbitans, with a fatty acid, such as stearic, palmitic, oleic or lauric
acid)
include, e.g. Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65,
Polysorbate 80, Polysorbate 85, Sorbitan Monolaurate, Sorbitan Mono-oleate,
Sorbitan Monopalmitate, Sorbitan Monostearate, Sorbitan Sesquioleate,
Sorbitan Trioleate and Sorbitan Tristearate.
The amount of surfactant in the composition can range from about 0.5 to
about 25% by weight of the total composition, more preferably from about 5 to
about 15% by weight.
Anionic surfactant - refers to a surfactant which has a net negative ionic
charge and dissociates to an appreciable extent in aqueous media. Optionally,
the present composition may also contain an anionic surfactant, e.g. sodium
lauryl sulfate, the amount of which can range from about 1 to about 10% by
weight of the total composition, more preferably from about 3 to about 8% by
weight.
Plasticizers-refers to substances which make the binder flexible.
Suitable plasticizers include propylene glycol, glycerin, diethylphthalate,
dibutyl
sebacate, triethyl citrate, hydrogenated glycerides, polyethylene glycols,
polyethylene oxides, triacetin and the like. The amount of plasticizer in the
composition can be in the range of about 1-2 to about 5% by weight.
Defoaming agents, also known as antifoaming agents, are substances
used to reduce foaming due to mechanical agitation or to gases, nitrogenous
materials or other substances which may interfere during processing. Examples
include metallic salts such as sodium chloride; C6 to C12 alcohols such as
octanol; sulfonated oils; silicone ethers such as simethicone; organic
phosphates and the like. The amount of defoaming agent in the composition can
range from about 0.05 to 5%, preferably from about 0.1 to 2%.
Glidents - materials that prevent caking and improve the flow
characteristics of granulations, so that flow is smooth and unifom. Suitable
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glidents include silicon dioxide and talc. The amount of glident in the
composition can range from about 0.1 % to about 5% by weight of the total
composition, preferably from about 0.5 to about 2% by weight.
Lubricant - refers to a substance added to the dosage form to enable the
tablet, granules, etc. after it has been compressed, to release from the mold
or
die by reducing friction or wear. Suitable lubricants include metallic
stearates
such as magnesium, calcium or potassium stearate; stearic acid; high melting
point waxes; and water soluble lubricants such as sodium chloride, sodium
benzoate, sodium acetate, sodium oleate, polyethylene glycols and d'i-leucine.
Lubricants are usually added at the very last step before compression, since
they must be present on the surfaces of the granules and in between them and
the parts of the tablet press. The amount of lubricant in the composition can
range from about 0.2 to about 5% by weight of the composition, preferably from
about 0.5 to about 2%.
Coloring agents - excipients that provide coloration to the composition or
the dosage form. Such excipients can include food grade dyes and food grade
dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide. The
amount of the coloring agent can vary from about 0.1 to about 5% by weight of
the composition, preferably from about 0.1 to about 1%.
Dosage form - composition containing the antifungal compound
formulated into a delivery system, i.e., tablet, capsule, oral gel, powder for
constitution or suspension in association with inactive ingredients.
Capsule - refers to a special container or enclosure made of methyl
cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or
containing compositions comprising the active antifungal compound. Hard
shell capsules are typically made of blends of relatively high gel strength
bone
and pork skin gelatins. The capsule itself may contain small amounts of dyes,
opaquing agents, plasticizers and preservatives.
Tablet- refers to a compressed or molded solid dosage form containing
the active ingredient (antifungal compound) with suitable diluents. The tablet
can be prepared by compression of mixtures or granulations obtained by wet
granulation, dry granulation, compaction or compression of mixtures containing
coated active beads.
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Beads for constitution refers to the loose, coated beads which can be
suspended in water, juices or sauces such as applesauce.
Bioavailability - refers to the rate and extent to which the active drug
ingredient or theraputic moiety is absorbed into the systemic circulation from
an
administered dosage form as compared to a standard or control.
Cmax values refers to the maximum concentration of the antifungal
compound measured (i.e. "peak") in the plasma serum.
AUC (0-72 hr) values refer to the area under the plasma/serum
concentration-time curve for the antifungal over a designated time.
Conventional methods for preparing tablets are known. Such methods
include dry methods such as direct compression and compression of
granulation produced by compaction, or wet methods or other special
procedures.
The following examples describe compositions of the present invention
containing the antifungal compound, but they are not to be interpreted as
limiting the scope of the claims.
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Example 1. Coated Beads in Capsules ~
Ingredient g/batch % wt basis
Antifungal compound, 135 20.3
micronized
Opadry YS-1-7006 30 4.5
Simethicone 1.42 0.2
Water purified, USP 700 mL -
(evaporates)
Non-Pareil Seeds (25/30 mesh) 500 75
666.42 100%
Example 2. Coated Beads in Capsules
Ingredient mg/batch % wt basis
Antifungal compound, 75 11.0
micronized
Opadry YS-1-7006 30 4.4
Pluronic F68 surfactant 75 11.0
Simethicone 0.7 0.1
Water purified, USP 500 mL -
(evaporates)
Non-Pareil Seeds (25/30 mesh) 500 73.5
680.7 100%
Preparation of Coated Beads in Capsules in Examples 1. 2 and 5
Dissolve the Opadry YS-1-7006, Pluronic F68 or sodium lauryl sulfate in water.
Add simethicone while stirring. Add the antifungal compound while stirring
slowly until a homogeneous suspension is formed. Screen the suspension
through a 25 mesh hand screen. Spray the suspension onto the non-pareil
seeds using a fluid bed coater. Dry the coated beads overnight and assay the
coated beads to determine the amount of antifungal compound. Fill the coated
beads into suitable size capsules to the requisite fill weight.
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Preparation of Aqueous Suspension in Comparative Example 3
Prepare a suspension containing 59.8 mg Pluronic F68 in four mL of distilled
water. Add 200 mg of antifungal compound to the above solution and mix to
give a homogeneous suspension.
Preparation of Powder Mixture in Capsules in Comparative Example 4
In, req dient mg/capsule % wt basis
Antifungal compound, 100.0 28.6
micronized
Sodium lauryl sulfate surfactant 22.5 6.4
Microcrystalline cellulose 178.0 50.9
Sodium starch glycolate 45.0 12.8
Magnesium stearate 4_5 1_3
350 100
Mix the antifungal compound, sodium lauryl sulfate (a surfactant),
microcrystalline cellulose, and sodium starch glycolate in a blender for 10
minutes. Add magnesium stearate and mix for 5 minutes to form a
homogeneous powder. Fill the powder into suitable size capsules to the
requisite fill weight.
Testina for Bioavailability
Dogs are administered a 200 mg dose of the antifungal compound using two
capsules or in suspension. Samples of serum are collected at selected times
and analyzed by an HPLC/UV detection procedure using a high pressure liquid
chromatograph equipped with an ultra-violet detector. In the table below, the
Cmax and AUC (0-72 hr) values are indicators of the antifungal compound's
bioavailability. The larger the AUC value, the greater the total amount of
antifungal compound that accumulated in the plasma serum over the 72 hour
period.
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Indicator of Coated Beads Coated Beads Control Powder in Capsules- in Capsules-
Suspension- Mixture in
Bioavailabillitv Capsules-
Example 1 Example 2 Comparative Comparative
Example 3 Example 4
Cmax u ml 1.43 1.37 1.21 0.95
AUC(o-72 hr) 50.21 50.17 47.98 29.72
= u/hr/ml
The results above show that capsules of Examples 1 and 2 exhibit enhanced
bioavailability over that of the aqueous suspension of Comparative Example 3
and
especially over the powdered mixture in capsules of Comparative Example 4.
Example 5. Coated Beads in Capsules
Ingredient /g batch % wt basis
Antifungal compound, 75.0 11.80
micronized
Opadry YS-1-7006 30.0 4.72
Sodium lauryl sulfate 30.0 4.72
Simethicone 1.0 0.16
Water purified, USP 500 mL -
(evaporates)
Non-Pareil Seeds (25/30 mesh) 500.0 78.60
636.0 100%
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