Beads having a core coated with an antifungal and a polymer

The present invention is concerned with beads comprising a 25-30 mesh core, a coating of a hydrophilic polymer and an antifungal agent, and a seal outer coating layer; pharmaceutical dosage forms comprising said beads and a method of preparing said beads. Preferred antifungal agents are lipophilic azole antifungals, such as itraconazole and saperconazole.

CROSS-REFERENCE TO RELATED APPLICATIONS 
This application is based upon PCT Application Serial No. PCT/EP 93/02327, 
filed Aug. 27, 1993, which claims priority from European patent 
application Serial No. 92.202.664.6, filed on Sep. 3, 1992. 
The present invention is concerned with a novel composition of antifungal 
agents which have low solubility in aqueous media, a process for preparing 
said composition and pharmaceutical dosage forms for oral administration 
comprising said novel composition. 
The development of efficaceous pharmaceutical compositions of azole 
antifungals such as for example, itraconazole and saperconazole, is 
hampered considerably by the fact that said antifungals are only very 
sparingly soluble in water. The solubility and bioavailability of said 
compounds can be increased by complexation with cyclodextrins or 
derivatives thereof as described in WO 85/02767 and U.S. Pat. No. 
4,764,604. Yet, there still exists an important demand for formulations of 
antifungal agents with good bioavailability for oral administration. 
Itraconazole or 
(.+-.)-cis-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmet 
hyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2- 
(1-methylpropyl)-3H-1,2,4-triazol-3-one, is a broadspectrum antifungal 
compound developed for oral, parenteral and topical use and is disclosed 
in U.S. Pat. No. 4,267,179. Its difluoro analog, saperconazole or 
(.+-.)-cis-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2(1H-1,2,4-triazol-1-ylmeth 
yl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]-phenyl]-2,4-dihydro-2- 
(1-methoxypropyl)-3H-1,2,4-triazol-3-one, has improved activity against 
Aspergillus spp. and is disclosed in U.S. Pat. No. 4,916,134. 
Unexpectedly, it has now been found that the incorporation of poorly 
soluble antifungal agents in hydrophilic polymers and applying this 
mixture as a coat film over many small beads, yields a composition with 
good bioavailability which can conveniently be manufactured and which is 
suitable for preparing pharmaceutical dosage forms for oral 
administration. 
In particular the present invention is concerned with beads which comprise 
(a) a central, rounded or spherical core, (b) a coating film of a 
hydrophilic polymer and an antifungal agent and (c) a seal-coating polymer 
layer, characterized in that the core has a diameter of about 600 to about 
700 .mu.m (25-30 mesh). 
Beads obtainable from 25-30 mesh cores comprise approximately, by weight 
based on the total weight of the bead: (a) 20 to 60 percent core material; 
(b) 25 to 50 percent hydrophilic polymer; (c) 10 to 25 percent antifungal 
agent; and (d) 2 to 5 percent seal coating polymer. 
The particular size of the cores is of considerable importance. On the one 
hand, if the cogs are too large, there is less surface area available for 
applying the drug coating layer, which results in thicker coating layers. 
This raises problems in the manufacturing process as an intensive drying 
step is needed to reduce residual solvent levels in the coating layer. The 
intense drying conditions may adversely effect drug dissolution from the 
beads and should therefore be controlled extremely well during the 
manufacturing process. On the other hand, small cores have a larger total 
surface available for coating resulting in thinner coating layers. 
Consequently a far less intensive drying step can be used to decrease 
residual solvents levels. Cogs which are too small, e.g. 30-35 mesh cores, 
however, have the disadvantage of showing considerable tendency to 
agglomerate during the coating process. Therefore, 25-30 mesh cons 
represent the optimum size where neither agglomeration nor an intensive 
drying step unduly constraint the manufacturing process. 
Materials suitable for use as cores in the beads according to the present 
invention are manifold, provided that said materials are pharmaceutically 
acceptable and have appropriate dimensions (about 25-30 mesh) and 
firmness. Examples of such materials are polymers e.g. plastic resins; 
inorganic substances, e.g. silica, glass, hydroxyapatite, salts (sodium or 
potassium chloride, calcium or magnesium carbonate) and the like; organic 
substances, e.g. activated carbon, acids (citric, fumaric, tartaric, 
ascorbic and the like acids), and saccharides and derivatives thereof. 
Particularly suitable materials are saccharides such as sugars, 
oligosaccharides, polysaccharides and their derivatives, for example, 
glucose, rhamnose, galactose, lactose, sucrose, mannitol, sorbitol, 
dextrin, maltodextrin, cellulose, sodium carboxymethyl cellulose, starches 
(maize, rice, potato, wheat, tapioca) and the like saccharides. 
A particularly preferred material suitable for use as cons in the beads 
according to the present invention is represented by 25-30 mesh sugar 
spheres (NF XVII, p 1989) which consist of 67.5%-91.5% (w/w) sucrose, the 
remainder being starch and possibly also dextrines, and which are 
pharmaceutically inert or neutral. 
The drug coating layer preferably comprises a hydrophilic polymer such as 
hydroxypropyl methylcellulose (Methocel.RTM., Pharmacoat.RTM.), 
methacrylate (Eudragit E.RTM.), hydroxypropylcellulose (Klucel.RTM.), or a 
polyvidone. Preferably hydroxypropyl methylcellulose with low viscosity, 
i.e. about 5 mPa.s, is used, e.g. hydroxypropyl methylcellulose 2910 5 
mPa.s. Preferred antifungal agents for use as drugs in said drug coating 
layer are lipophilic azole antifungals, in particular intaconazole and 
saperconazole. Optimum dissolution results are obtained when using a drug: 
polymer ratio (w/w) of about 1:1 to about 1:2, preferably about 1:1.5. In 
the drug coating layer, the drug substance is present in a solid 
dispersion or solution state as can be confirmed by differential scanning 
calorimetry. 
A seal coating polymer layer is applied to the drug coated cores to prevent 
sticking of the beads which would have the undesirable effect of a 
concomitant decrease of the dissolution rate and of the bioavailability. 
Preferably a thin layer of polyethylene glycol (PEG), in particular 
polyethylene glycol 20000 is used as a seal coating polymer layer. 
The preferred beads comprise approximately: (a) 26 to 38 percent sugar; (b) 
32 to 33 percent hydroxypropyl methylcellulose 2910 5 mPa.s; (c) 21 to 22 
percent itraconazole or saperconazole; and (d) 3 to 4 percent polyethylene 
glycol 20000. 
In addition, the beads according to the present invention may further 
contain various additives such as thickening agents, lubricants, 
surfactants, preservatives, complexing and chelating agents, electrolytes 
or other active ingredients, e.g. antiinflammatory agents, antibacterials, 
disinfectants or vitamins. 
The beads according to the present invention can conveniently be formulated 
into various pharmaceutical dosage forms. Suitable dosage forms comprise 
an effective antifungal amount of beads as described hereinbefore. 
Preferably, the beads are filled in hard-gelatin capsules such that an 
amount of, for example, 50 or 100 mg of the active ingredient is available 
per dosage form. For example, hard-gelatin capsules of size 0 are suitable 
for formulating beads comprising 20 to 25 percent by weight itraconazole 
or saperconazole, equivalent to about 100 mg active ingredient. 
The beads according to the present invention are conveniently prepared in 
the following manner. A drug coating solution is prepared by dissolving 
into a suitable solvent system appropriate amounts of an antifungal agent 
and a hydrophilic polymer. A suitable solvent system comprises a mixture 
of methylenechloride and an alcohol, preferably ethanol which may be 
denatured, for example, with butanone. Said mixture should comprise at 
least 50% by weight of methylenechloride acting as a solvent for the drug 
substance. As hydroxypropyl methylcellulose does not dissolve completely 
in methylenechloride, at least 10% alcohol has to be added. Preferably a 
relatively low ratio of methylenechloride/alcohol is used in the coating 
solution, e.g. a ratio methylenechloride/ethanol ranging from 75/25 (w/w) 
to 55/45 (w/w), in particular about 60/40 (w/w). The amounts of solids, 
i.e. antifungal agent and hydrophilic polymer, in the drug coating 
solution may range from 7 to 10% (w/w) and preferably is about 8%. 
The drug coating process of the 25-30 mesh cores is conveniently conducted 
in a fluidized bed granulator (e.g. Glatt type WSG-30) equipped with a 
Wurster bottom spray insert (e.g. an 18 inch Wurster insert). Obviously 
the process parameters will depend on the equipment used. 
The spraying rate should be regulated carefully. Too low a spraying rate 
can cause some spray drying of the drug coating solution and result in a 
loss of product. Too high a spraying rate will cause overwetting with 
subsequent agglomeration. Agglomeration being the most serious problem, 
lower spraying rates may be used initially, to be increased as the coating 
process proceeds and the beads grow larger. 
The atomizing air pressure with which the drug coating solution is applied 
also influences the coating performance. Low atomizing air pressure 
results in the formation of larger droplets and an increased tendency 
toward agglomeration. High atomizing air pressure could conceivably carry 
the risk of spray drying of the drug solution, but this was found not to 
be a problem. Consequently, atomizing air pressure may be set at nearly 
maximum levels. 
Fluidizing air volume can be monitored by operating the exhaust air-valve 
of the apparatus and should be set in such a manner that optimum bead 
circulation is obtained. Too low an air volume will cause insufficient 
fluidization of the beads; too high an air volume will interfere with the 
bead circulation due to countercurrent air streams developing in the 
apparatus. In the present process optimum conditions were obtained by 
opening the exhaust air valve to about 50% of its maximum and gradually 
increasing the opening thereof to about 60% of the maximum as the coating 
process proceeded. 
The coating process is advantageously conducted by employing an inlet-air 
temperature ranging from about 50.degree. C. to about 55.degree. C. Higher 
temperatures may speed up the process but have the disadvantage that 
solvent evaporation is so rapid that the coating liquid is not spread 
uniformly on the surface of the beads resulting in the formation of a drug 
coating layer with high porosity. As the bulk volume of the coated beads 
increases, drug dissolution may decrease significantly to unacceptable 
levels. Obviously, the optimum process temperature will further depend on 
the equipment used, the nature of the core and the antifungal agent, the 
batch volume, the solvent and the spraying rate. 
Parameter settings for optimum coating results are described in more detail 
in the example hereinafter. Running the coating process under those 
conditions was found to yield very reproducible results. 
In order to decrease residual solvent levels in the drug coating layer, the 
drug coated cores can conveniently be dried in any suitable drying 
apparatus. Good results may be obtained using a vacuum tumbler-drier 
operated at a temperature from about 60.degree. C. to about 90.degree. C., 
preferably about 80.degree. C., a reduced pressure ranging from about 
150-400 mbar (15-40 kPa), preferably 200-300 mbar (20-30 kPa), for at 
least 24 hours, preferably about 36 hours. The vacuum tumbler-drier is 
conveniently rotated at its minimum speed, e.g. 2 to 3 rpm. After drying, 
the drug coated cores may be sieved. 
The seal coating polymer layer is applied to the drug coated cores in the 
fluidized bed granulator with Wurster bottom spray insert. The seal 
coating solution can be prepared by dissolving an appropriate amount of a 
seal coating polymer into a suitable solvent system. Such a system, is, 
e.g. a mixture of methylene chloride and an alcohol, preferably ethanol 
which may be denatured with, for example, butanone. The ratio of methylene 
chloride/alcohol used may be similar to the ratio used in the drug coating 
process and thus can range from about 75/25 (w/w) to about 55/45 (w/w) and 
in particular is about 60/40 (w/w). The amount of seal coating polymer in 
the seal coating spraying solution may range from 7 to 12% (w/w) and 
preferably is about 10%. The seal coating spraying solution is 
advantageously stirred during the seal coating process. The parameter 
setting for conducting this last step is essentially similar to that used 
in the drug coating process. Appropriate conditions are described in more 
detail in the example hereinafter. 
A further drying step may be required after applying the seal coating 
polymer layer. Excess solvents could easily be removed while operating the 
apparatus at the parameter settings used for about 5 to 15 minutes after 
the spraying had been completed. 
Both the drug coating process and the seal coating process are preferably 
conducted under an inert atmosphere of e.g. nitrogen. The coating 
equipment should preferably be grounded and provided with an appropriate 
solvent recovery system containing an efficient condensing system. 
The drug coated and seal coated beads may be filled in hard-gelatin 
capsules using standard automatic capsule filling machines. Suitable 
earthing and de-ionisation equipment can advantageously prevent 
development of electrostatic charges. 
Capsule filling speed may influence weight distribution and should be 
monitored. Good results are obtained when operating the equipment at about 
75% to 85% of the maximum speed and in many cases when operating at full 
speed.

Using the process parameters described above, a convenient, reproducible 
manufacturing method for preparing beads comprising a 25-30 mesh core, a 
drug coat layer of an antifungal agent and a hydrophilic polymer and a 
thin seal-coating polymer layer can be obtained. Pharmacokinetic studies 
showed that the thus obtained beads have excellent dissolution and 
bioavailability properties. 
EXAMPLE 
a) Itraconazole Spraying Solution 
An inox vessel was charged with methylene chloride (375 kg) and denatured 
ethanol (250 kg) through a filter (5.mu.). Itraconazole (21.74 kg) and 
hydroxypropyl methylcellulose 2910 5 mPa.s (32.61 kg) was added while 
stirring. Stirring was continued until complete dissolution was obtained 
(A suitable saperconazole spraying solution was obtained using an 
identical procedure). 
b) Seal-Coating Spraying Solution 
An inox vessel was charged with methylene chloride (21.13 kg) and 
polyethylene glycol 20000 (Macrogol 20000) (3.913 kg) while stirring. 
Denatured ethanol (14.09 kg) was added and the solution was stirred until 
homogeneous. 
c) Drug Coating Process 
A fluidized-bed granulator (Glatt, type WSG 30) equipped with a 18 inch 
Wurster (bottom spray) insert was loaded with 25-30 mesh (600-700 .mu.m) 
sugar spheres (41.74 kg). The spheres were warmed with dry air of 
50.degree.-55.degree. C. The fluidizing air volume was controlled by 
opening the exhaust air valve to approximately 50% of its maximum in the 
beginning, increasing up to 60% at the end of the spraying process. The 
previously prepared itraconazole spraying solution was then sprayed on the 
spheres moving in the apparatus. The solution was sprayed at an initial 
delivery rate of about 600 to 700 g.min.sup.-1 at an atomizing air 
pressure of about 3.5 kg/cm.sup.2 (0.343 MPa). After delivery of about 30% 
of the spraying solution, the delivery rate was increased to 700-800 
g/min. 
When the spraying process was completed, the coated spheres were dried by 
further supplying dry air of 50.degree.-55.degree. C. for about 10 
minutes. The coated spheres were then allowed to cool in the apparatus by 
supplying dry air of 20.degree.-25.degree. C. for about 10 to 20 minutes. 
The apparatus was emptied and the coated spheres were collected. 
d) In-Between Drying 
In order to minimize residual solvent levels the coated spheres were then 
subjected to a drying step. The coated spheres were introduced in a vacuum 
tumbler-drier and dried for at least 24 hours, preferably about 36 hours, 
at a temperature of about 80.degree. C. at a pressure of about 200-300 
mbar (20-30 kPa). The tumbler-drier was operated at its minimal rotation 
speed (2 to 3 rpm). The dried coated spheres were sieved with a sieve 
(Sweco S24C; sieve mesh width 1.14 mm). 
e) Seal-Coating Process 
The dried coated spheres were introduced again in the fluidized-bed 
granulator equipped with the Wurster insert and warmed with dry air of 
50.degree.-55.degree. C. The previously prepared seal-coating spraying 
solution was then sprayed on the coated spheres moving in the apparatus. 
The solution was sprayed at an delivery rate of about 400 to 500 
g.min.sup.-1, at an atomizing air pressure of about 2.5 bar (0.25 MPa). 
When the spraying process was completed, the beads were dried by further 
supplying dry air of 50.degree.-55.degree. C. for 10 min. The coated 
spheres were then allowed to cool in the apparatus by supplying dry air of 
20.degree.-25.degree. C. for about 5 to 15 minutes. The beads were removed 
from the apparatus and stored in suitable containers. 
f) Capsule Filling 
The drug coated beads were filled into hard-gelatin capsules (size 0) using 
standard automatic capsule filling machines (e.g. Model GFK-1500, 
H6offliger and Karg. Germany). In order to obtain capsules with good 
weight distribution, capsule filling speed was reduced to about 75-85% of 
the maximum speed. Each capsule received approximately 460 mg beads, 
equivalent to about 100 mg itraconazole. Using the process parameters 
described above, itraconazole 100 mg hard-gelatin capsules were obtained 
which met all the requirements, in particular the dissolution 
specifications. Saperconazole 100 mg hard-gelatin capsules could be 
obtained by conducting the above-described procedures and using the 
saperconazole spraying solution.