CA2142848C - Beads having a core coated with an antifungal and a polymer - Google Patents

Abstract

The present invention is concerned with beads comprising a 25-30 mesh core, a coating film of a hydrophilic polymer and an antifungal agent, and a seal coating layer; pharmaceutical dosage forms comprising said beads and a method of preparing said beads.

Description

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The present invention is concerned with a novel composition of antifungax agents which have low solubility in aqtyeous media, a process for preparing said composition and phaa-maceutical dosage forms for oral adrninistration comprising said novel composition.
The development of efficaceous pharmaceutical compositions of axole antifungals such as for example, itraconaxale and sapercona~ole, is haxnp~r~d considerably by the fact 1S that said antifungals are only nary sparingly soluble in water. The solubility and bioavailability of said compounds can be increased by complexation with cyclodextrins or deridadves thereof as described in''~'~ ~5/t72T6~' ~nd'l~~-4) 761, 6(?~.
'Y'et, tlaexe stilt exists an important demand for formu~arions of antifung~l agents with good bioavailability 'for orra~;l administration. .
Itraconaxole or ~)--4-C4~L4-C4-CC2-(2q4-dichlorophe~yl)-2-(1~,-1,2,4-txiaxol-1-ylnnethyl)-'1,~»diaxolata-4~yl] methoacy]phenyl]M 1-pipera~inyl] phenyl]-2,4~da hydro-2-( 1-methylpropyl)-3~,-1,2,4-txiazol-3-one, is a broadspectrum antifungal compound developed for ~ral, ~parenteral and topical ttse and is disclosed in U~-4,27,179. Its ~~uor~a analog; sap~rca~n~zole or (T~1-~,-4-[~-Ca-[~°CC2-(2>4°difluorophenyl)-2-(x~i-~'2~4_~a~hx-ylmethyl)-1,3-dioxolan-4«yl]methoxyJphenyl]-1-piperaa~nyl]-phenyl)-. . . _ 2,4-dihydrcr2-( 1-rnethoxypropyl)-~~-1,2,4-triaxol-~-one, has improved activity against Eispergilhas spp. and is disclose, in BUS-4,916,14.
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~0 '(unexpectedly, ]t has now been fund that the incarporattion of poorl~r soluble andfun~al hg~~ts in hydt~philic polymexss and applying this mixture hs a coat film over many small berg yields a connposition with good bioavail~bility which can conveniently be manufactur~i xnd vvhibh is suitably fir preparing pharmaceutical dosage forms for anal administration:
Tn partibular the present invention is concerned with beads which comprise (a) a central, rounded o~ spherical core, (b) a coating film of a hydrophilic polymer and an antifungal v~ ~~io~x~~ »cri~l~~~ox~x~ ~,..
_2_ agent and (c) a seal-coating polymer layer, characterized in that the care has a diameter of about 600 to about 7617 ~Zm (25-3f3 mesh).
Eeads obtainable from 25-~a 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 percen~ 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, ix the i0 cores are taa large, there is less surface area available for applying the drug coating layer, which results in thicker coating layers. "~"hfs raises p~ablems in the manufacturing process as an intensive drying step is needed to reduce residual solvent levels in the coating layer. ''~'he 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 fatal surface available far coating resulting in thinner coating layers. Cansetluently a far less intensive drying step can be used to decrease residual solvents levels. Cares which are too small, e.g. 30-35 mesh cores, however, have the disadvantage of showing considerable tendency to agglomerate during the coating process: 'pherefr~a~e, 25-~0 mesh cares represen t the 2~D optimum size where neither agglomeration nor an intensive drying step unduly constraint the manufacturing process.
Materials suitable for use as cores in the be~d5 according to the present invention are manifold, provided that said materials are pharmaceutically acceptable and have 2,5 appropriate dimensions (about 25-3a mesh) and firmness. Examples of such materials are polymers e.g. plastic resins; inorganic substances, ~.g. silica) glass, hydroxyapatite) salts (sodium ar 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 ,~ ~ i ; ! ~ ~ i 30 az~e saecharides'such as sugars, oligosacaharides~ polysaccharides arid their derivatives, f'ar ~xarraple) glucose, rhamnose, gaIactose, laGtose,~sucrose, mannital, sarbitol, dextrin, maltadextrin, cellulose, sodium carboxymethyl cellulose, starches (maize, rice, ~.. potato) wheat) tapioca) and the like saccharides..
35 A pairticularly pa~ferred material suitable far use as cores in the beads according to the present invention is represented by 2S-30mesh sugar spheres (NF XVTI, p 1989) which .. wo ~~iosz6~ ,~ 'c~ ~ ~ ~~cri~P~~ioz~z~
consist of 67.510 - 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 hydroxy-propyl methylcellulose (Methacelt~, Pharmacoatc9), methacrylate (Eudragit BC's), hydroxyprapylcellulose (~,IucelC~)) or a palyvrdane. Preferably hydraxypropyl methylcellulase with law viscosity, i.e, sheaf 5 mPa.s, is used, e.g.
hydraxypropyl methylcellulase 2910 5 mPa.s. Preferred antifungal agents for use as drugs in said dxug coating layer are lipophilic azale antifungals, in particular itraconazole and saperconaxale. 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 ar solution state as can be confirmed by differential scanning calorimetry.
A seal coating polymer layer is applied to the drug coated cares 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 hydraxyprapyl methylcellulose 2910 5 mPa.s; (c) 21 to 22 percent itr~aconazale or sapexcanaxole; and (d) 3 to A~ percent polyethylene ~lycal 20000.
In addition, thG 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 inga~edients, e.g:
antiinflammstory agents, antibacta~ials, disinfectants ar vitamins:
The beads according ~o the present invention can conveniently be formulated into various gharmhceudcal dosage farms. Suitable dosage (farms comprise an effective andfungal amount of beads as described hereinbefore. Preferably, the beads are filled in hard-gelatir~ capsules such that an ~maunt a~; for example, 50 or l00 mg of the active .. __ _.....
ingredient is available per dosage form: Eor example) hard-gelatin capsules of size 0 are suitable for foamulat~ng beads comprising 20 to 25 percent by weight itraconazole or sapercanazole) equivalent to about 100 mg active ingredient.
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The beads according to the present invention are conveniently prepared in the following manner, A dz ug coaring salutiar~ is prepared by dissolving into a suitable solve°,nt system appropriate amounts of'~n antifungal agent and a hydrophilic polymer. A
suitable solvent system comprises r mixture of methylenechloride and an alcohol) preferably ethanol which may be denatured, far example, with btxtanone. Said mixture should comprise at least 50% by weight of methylenechloride acting as a solvent for the drug substance. As hydroxypropyl methylcellulase does not dissolve corrtpletely in methylenechloride, at least lU°~/o alcohol has to be added. I~referabiy a relatively low retie of methylenechloride/alcohol is used in the coating solution, e.g. a raga 1~ methylenechloride / ethanol ranging from T5/25 (w/w) to SS/4S (w/w), in particular .
about dt7/40 (w/w). The amounts of solids, i.e. antifungal agent and hydrophilic polymer, in the drug coating solution may range from "7 to ldo/a (w/w) and preferably is about 8%.
1S The drug coating process of the ~5-~0 mesh cores is conveniently conducted in a fluidi~ed bed granutatar (e.g. Glatt type WSG-3f~) equipped with a Wurster bottom spray insert (e.g. an 18 inch '6~Vurster insert). tabviously the process parameters will depend on the equipment used. , ~U The spraying rate should be regulated carefully. 'raa low a spraying rate can cause same spray drying of the drug coating solution and result in a loss of product. 'roe high a spraying rate will cause averwetting 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 beds grow larger. , The atomising air pressctre with which the drug coating solution is applied also . influences the coating performance. I,aw atamizir~g air pressure results in the formation of larger droplets and an increased tendency toward agglomeration. ~3(igh atomizing air pressure could conceivably, carry the xisk,pf spray drying of the drug solution, but this ~0 was found not to be a problem, ~ansequently, atomizing air pressure may be set at ~..n~y maximum levels : .
. .. . . a ~ . .., . . . , 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.
~5 Too low an air volume will cause insufficient ~fluidi;~ation of the beads;
too high an air volume will interfere with the bead circulation due to counte~'curseni. air' screams developing in the apparatus. In the present process optimum coc~dxticins were obtained .:.. . ~w: , , ;. . . ,;.:v . .. . , .. ; . :. . . , ;,.. .. , .. . :; ~ : .~:
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W~I 94/0526 ~ g 1PG'I'/~P93/023~7 _5_ by opening the exhaust aix' valve to about 50% of its ~rraximum and gradually inc;reasir~g the opening thereof to about 60% of the maximum as the coating process proceeded.
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The coating process is advant~~eously conducted by employing an inlet-air temperature ranging from about 50°C to aboux 55°C. Higher temperatures may spend up the process but have the disadvantage that solvent evapci~tion is sa rapid that the canting liquid is not spread uniformly on the 'surface of the b~~ids 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 care and the antifungal agent, the batch volume, the solvent and the spraying rate.
1"arameter settings for optimum coating results are described in more detail in the example hereinafter. I~,unning the coating process under those conditions was found to yield very xeproducible 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. Coed zbsults may be obtained using a vacuum tumbler-drier operated at a temperature from about 60°C to about 90°C, preferably about 80°C, a reduced pressure ranging from about 150-400 mbar (15-40 kFa), preferably 200-300 mbar (20-30 lc'pa), for at feast 24 hours, preferably about 36 hears. The vacuum tumbler-drier is conveniently rotated at its minimum speed, e.g. 2 to 3 rpm. flfter drying; the drug coated cores may be sieved.
The seal coating polymer layer is applied to the drug coated cores in the fluidixed 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 ~nethylene chloride and an alcohol, preferably ethaqol which ntyay be,denatured with) for example) butan~ne. The ratio of methylene chlaride/alcohol used may be similar to the ratio used in the drug coating p~tess and this can range from about '~5/~',5 (w/w) to about 55/4'5 (w/w) and in particular is about 60/40 (w/w): 1"he amount of seal coating polymer in the seal coating spraying salutie~n 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 l~.st step is essentially similar to that used in the drug coating process. ,Appropriate conditions are described. in more detail in the v example hereinafter.

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A further drying step may be requixed after applying the seal coating polymer layer.
Excess solvent's 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.
s ~3oth 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 ground~i and provided with an appropriate solvent recovery system containing an efficient condensing system.
The drug coated and seal coated beads rnay be filled in hard-gelatin capsules using standard ~utoimatic capsule filling machines. Suitable earthing and de~ionisation equipment can advantageously prevent development of electrostatic charges.
1,5 Capsule filling speed may influence weight distribution and should be monitored. Good results are obtained when operating the equipment at about 75~'o to g5% of the maximum speed and in many cases when operating at full speed. , Using the process parameters described above, a convenient; reproducible 2Q manufacturing method for preparing beads comprising a ~5~30 mesh core, a drug coat Iayer of an antifungal agent and a hydrophilic polynner and a thin seal-Coating polymer Iayer can be obtained. Pharmacokinetic studies showed that the thus obtained beads have ~exc~llent dissolution and bioavailability properties.
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a~ ~I~'ole stvi udon An inox vessel was charged with methylene chloride (375 kg) and denanared ethanol (254 kg) through a filter (5 p.). Itracana~ole (21.7A~ kg) and hydroxypropyl . . ~ methylc~llt~Iose 291Q ~,mPa.s (3~2.6j1 leg), was added whip stirring.
Stirring was , continued until complete dissolution was obtained (A suitable saperconazole . .. ~~pmylng solution was obtained, using an identical praced~are).
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b) Caa'~ sF?Y~~ln utl n . . , , ,~,n mast vessel was charged with methylene chloride (21.13 kg) and polyethylene ~5 glycol ~,pp00 (ivtacrogol ~OOOQ) (3.913 kg) while starring. Denatured ethanol.
(14.4?9 kg) was added and the solution was stirred until homogeneous.

FC'~'J~1P93102~27 WC3 94!05263 _7_ c) D co~ tin~'Process A fluidized-bed granulator (Glatt, type WSG 30) equipped with a 18 inch Wurster (bottom spray) insert was loaded with 25-30 mesh (60d-7~3(? pm) sugax spheres (41,74 kg). The spheres were warmed with dry air of 5~°- 55°C.
Ttte fluidizing air volume was controlled by opening the exhaust air valve to approximately 50% of its maximum in the beginning) increasing up to 60°/a at the end of the spraying process.
The previously prepared itxacanazale spraying solution was then sprayed an the spheres waving in the apparatus. The solution was sprayed at an initial delivery rate of about ~ to 70(? g.min-1 at an atomizing air pressure of about 3.5 kg /cm2 (0.343 lvl,l~a). After delivery of about 30% of the spraying solution, the delivery rate was increased to 7(ln-8011 g/min.
When the s~i~ying process was completed, the cowed spheres were dried by further supplying dry air of 50°- 55°C far abort ld minutes. fihe coated spheres were then allowed to coal in the appaxatus by supplying dry air of ~(1-25°C for about 10 to 2t1 minutes. The apparatus was emptied and the coated spheres were collected.
d) In-be~wg~drvina Tn order to minimize residual solvent levels the coated spheres were then subjected to a drying step, The coated spheres were, introduced in a vacuum tumblex-drier and dried far at least ~4 hours, preferably about 36 hours, at a temperature of about 80°C
at a pressure of about IOU-3U0 mbax (Za-30 kl'a). The tumbler-drier was operated at its minimal rotation speed (2 to 3 rpm). 'The dried canted spheres were sieved with a sieve (Sweca S24C; sieve mesh width 1.14mtn).
2.5 e) ,~e~~~ coatiess The dried coated sphems were introduced again in the fluidized-bed granulatar equipped with the Wurster insert and warmed with dry air of 50 - 55°C.
The previously prepared seal-coating spraying solution was then sprayed on the coated spheres moving,in the apparatus., The,salutian was sprayed at an delivery rate of 1 about 400 to ~~00 g.min-1, at ~n atomizing air pressure of about ~.5 bar (0.~5 MP'a).
When the spraying process was completed, the beads were dried by further supplying dry air of 50 - 55 °C far 10 min. 'x'he coated spheres were then allowed to coal in the apparatus by supplying dry air of 20°-25°C for about 5 to 15 minutes.
The beads were removed from the apparatus and stored in suitable containers.

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~'~.~'~ f fling ~'he drug coated beads were filled into hard-gelatin capsules (size 0) using standard automatic capsule filling machines (e.g. Model Gl"fC-1500, :l~tiffliger,and I~arg.
Germany). Tn order tcs ~.;r~tain capsules with good weight distribution, capsule filling speed was induced to ab~ v.;t 75-85%a of °.,he maximum speed" : Mach capsule received , approximately 460 mg be:~;.ls, equivalent to about 100 m~ xtraconaxole.
't3sing the process parameters de;~cribed above, itraconaxole t00 mg hard-gelatin capsules were obtained which anet all the requirements, in particular the dissolution specifications. Saperconaxole 100 mg hard-gelatin capsules could be obtained by conducting the above-described procedures and using the saperconaxote spraying solution.

Claims (10)

Claims

1. A bead comprising a) a central, rounded ar 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 from about 600 to about 700 µm (25-30 mesh).

2. A bead according to claim 1 comprising 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.

3. A bead according to claim 2 wherein the care material is a 25-30 mesh sugar sphere, the hydrophilic polymer is hydroxypropyl methylcellulose and the antifungal agent is itracanaxole or saperconaxale.

4. A bead according to claim 3 wherein the weight to weight ratio of antifungal agent:
hydrophilic polymer is about 1:1 to about 1:2.

5. A bead according to Claim 2 wherein the seal-coating polymer is polyethylene glycol.

6. A bead according to claim 2 comprising approximately:
a) 26 to 38 percent sugar;
b) 32 to 33 percent hydroxypropyl methylcellulose 2910 5 mPa.s.
c) 21 to 22 percent itracanazole or saperconazole; and d) 3 to 4 percent polethylene glycol 2,0000.

7. A pharmaceutical dosage form comprising an effective antifungal amount of beads as claimed in any tine of claims 1 to 6.

8. A dosage form according to claim 7 wherein the dosage form is a hard-gelatin capsule comprising the antifungal agent itraconaxole or saperconazole in the form of beads as claimed in any one of claims 1 to 6.

9. A process far preparing heads as claimed in any one of claims 1 to 6 characterized by, a) coating 25-30 mesh cores by spraying with a solution of an antifungal agent and a hydrophilic polymer in an organic solvent consisting of methylene chloride and ethanol in a fluidixed-bed granulator equipped with a Wurster (bottom spray) insert;
b) drying the resulting coated cores in a vacuum tumbler-drier, and c) seal-coating the dried cores by spraying with a solution of a seal-coating polymer in an organic solvent consisting of methylene chloride and ethanol in a fluidixed- bed granulator equipped with a Wurster (bottom spray) insert.

10. Drug-coated beads obtainable by a process according to claim 9.