Oral antifungal composition

A pharmaceutical composition comprising: PA1 i) substantially inert beads; wherein said beads are coated with PA1 ii) an antifungal agent which is (-)-(2R-cis)-4-4-4-4--5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-tr iazol-1-ylmethyl)furan-3-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-2,4-dihyd ro-2-(S)-1-ethyl-2(S)-hydroxypropyl!-3H-1,2,4-triazol-3-one; PA1 iii) a binder to enables the antifungal compound to adhere to said beads. The composition enables the antifungal compound, which has very low water solubility, to have enhanced bioavailability in mammals, such as humans.

This application claims benefit of USC Provisional appln. Ser. No. 
60/020,666, filed Jun. 28, 1996. 
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 Jun. 1995, 
teaches a novel class of tetrahydrofuran/triazole antifungal compounds. 
One particular compound, 
(2R-cis)-4-4-4-4--5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazo 
l-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: 
##STR1## 
iii) a binder to enables the antifungal compound to adhere to said beads. 
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 D.C., 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&gt;aqueous suspension&gt;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 Jun. 1995 discloses antifungal compounds of the 
formula: 
##STR2## 
wherein R.sup.1 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 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-(1H-1,2,4-t 
riazol-1-ylmethyl)furan-3-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-2,-4-dih 
ydro-2-(S)-1-ethyl-2(S)-hydroxypropyl!-3H-1,2,4-triazol-3-one ("the 
antifungal compound"); Formula: C.sub.37 H.sub.42 F.sub.2 N.sub.8 O.sub.4 
; Molecular weight: 700.8; m.p. 164.degree.-165.degree. C., 
a!.sub.D.sup.25 -29.degree. C..+-.3.degree. (c=1.0, CHCl.sub.3), whose 
structure is depicted below: 
##STR3## 
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, Pa. 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, 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 
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, N.J. A source of microcrystalline cellulose beads 
is known as Celphere, tradename of the FMC Corporation, Philadelphia, Pa. 
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 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, Pa. 
Opadry powders may contain hydroxypropylmethylcellulose, 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--refers to a surfactant which lacks a net ionic charge 
and do not dissociate to an appreciable extent in aqueous media. The 
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 (--OCH.sub.2 CH.sub.2 --) 
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: 
##STR4## 
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.RTM.F68 surfactant, trademark of 
the BASF Corporation, Mount Olive, N.J., USA. Pluronic.RTM.F68 surfactant 
is also known as Poloxamer 188. This surfactant has an average molecular 
weight of 8400, is a solid at 20.degree. C., has a viscosity (Brookfield) 
of 1000 cps at 77.degree. 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; 
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, Lauromacrogols (a series of 
lauryl ethers of macrogols 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 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'l-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. 
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. 
C.sub.max 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. 
______________________________________ 
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. 
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 
Ingredient 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. 
Testing 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 C.sub.max 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. 
______________________________________ 
Powder 
Coated Coated Control Mixture in 
Beads in Beads in Suspension- 
Capsules- 
Indicator of 
Capsules- 
Capsules- 
Comparative 
Comparative 
Bioavailabillity: 
Example 1 
Example 2 
Example 3 
Example 4 
______________________________________ 
C.sub.max (ug/ml) 
1.43 1.37 1.21 0.95 
AUC.sub.(0-72 hr) 
50.21 50.17 47.98 29.72 
ug/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% 
______________________________________