MXPA99004411A - Pellets having a core coated with an antifungal and a polymer - Google Patents

Abstract

The present invention is concerned with pellets comprising a 250 - 355&mgr;m (45-60 mesh) sugar sphere, a coating film of a water-soluble polymer and an antifungal agent, and a seal coating layer;pharmaceutical dosage forms comprising said pellets and a method of preparing said pellets.

Description

PELLETS THAT HAVE A NUCLEUS COVERED WITH AN ANTIMIC AND A POLYMER DESCRIPTIVE MEMORY The present invention relates to novel small itraconazole pellets, a method for preparing said pellets, and oral dosage forms comprising a therapeutically effective amount of said pellets wherein a single dose can be administered once a day to a suffering patient. of a fungal infection. The development of effective pharmaceutical compositions of azole antimicotics, such as itraconazole, is considerably hampered by the fact that said antifungals are only water soluble very sparingly. The solubility and bioavailability of said compounds can be increased by the complex formation with cyclodextrins or derivatives thereof as described in WO-85/02767 and EUA-4,764,604. In WO-94/05263, published on March 17, 1994, spheres having a sugar core of 25-30 mesh (600-710 μm) coated with an antifungal, very particularly itraconazole (or saperconazole), are described, and a polymer, very particularly, hydroxypropylmethylcellulose. Finished with a seal layer coating, said cores are called spheres. The spheres are filled in capsules suitable for oral administration. Traconazole is easily released from the surface of the coated spheres, which leads to the improved bioavailability of itraconazole (or saperconazole) in the recognized oral dosage forms of itraconazole. The preparation of coated spheres as described in WO-94/05263 requires special techniques and special equipment in a plant built for a particular purpose. In fact, the spheres described in the prior art are prepared in a very complex form that requires a large number of handling steps. First, a drug coating solution is prepared by dissolving in a suitable solvent system appropriate amounts of the antifungal agent and a hydrophilic polymer, preferably hydroxypropylmethylcellulose (HPMC), A suitable solvent system comprises a mixture of methylene chloride and a alcohol. Said mixture should comprise at least 50% by weight of methylene chloride which act as a solvent for the drug substance. Since hydroxypropylmethylcellulose does not completely dissolve in methylene chloride, at least 10% must be added. Subsequently, the 25-30 mesh sugar cores are coated with drug in a fluidized bed granulator equipped with a lower spray insert. Not only should the spray speed be regulated carefully, but also the temperature control in the fluidized bed granulator is crucial. However, said process requires a great control to obtain a reproducible product of good quality. Furthermore, said technique, suitably, but still partially, solves the problem of residual organic solvents such as methylene chloride and methanol or ethanol, being present in the coating. To remove any solvent that may remain in the drug coated intermediate product, an additional drying step is required. Subsequently, a sealing coating is applied. WO-94/05263 further mentions that the size of the cores is of considerable importance. On the one hand, if the cores are very large, there is less surface area available to apply the drug coating layer, which results in thicker coating layers. The above gives rise to problems in the manufacturing process since an intensive drying step is required to reduce the residual solvent levels in the coating layer. Intense drying conditions can adversely affect drug dissolution of the pellets and therefore must be controlled extremely well during the manufacturing process. On the other hand, small cores have a larger total area available for the coating to result in thinner coating layers. As a result, a much less intensive drying step can be used to reduce residual solvent levels. The nuclei that were very small, ie cores of 500-600 μm (30-35 mesh mesh) however, had the disadvantage of showing a considerable tendency to agglomerate during the coating process. Therefore, it was concluded that the cores of 600-710 μm (25-30 mesh) represented the optimal size where neither the agglomeration nor the intensive drying step unduly affected the manufacturing process. Spheres of approximately 460 mg, equivalent to approximately 100 mg of itraconazole, were filled into a hard gelatin capsule (size 0) two of said capsules were administered once a day to a patient suffering from a fungal infection. The total weight of the medicine ingested daily was 2 x (460 + 97) = 1010 mg. The capsules are commercially available in several countries under the trade name Sporanox ™. To achieve the desired antifungal effect, unfortunately it is essential that two capsules be taken after each meal. It would be highly desirable to have a pharmaceutical dosage form, the unit of which would contain the required daily dose of the active ingredient, instead of the two units. Itraconazole or (+) - cis-4- [4- [4- [4 - [[2- (2,4-dichlorophenyl) -2- (1 H-1, 2,4-triazole-1-yl- methyl) -1, 3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- (1-methylpropyl) -3H-1, 2,4-triazole-3 -one, is a broad spectrum antifungal compound developed for oral, parenteral and topical use and is described in document EUA-4,267,179. Its difluor analogue, saperconazole or (+) - cis-4- [4- [4- [4 - [[2- (2,4-difluorophenyl) -2- (1 H-1, 2,4-triazole- 1-ylmethyl) -1, 3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- (1-methoxypropyl) -3H-1, 2,4 -triazol-3-one, has an improved activity against Aspergilllus spp. and is described in document US-4,916,134. Itraconazole and saperconazole consist of a mixture of four diastereoisomers, whose preparation and utility are described in WO 93/1901: the diastereoisomers of itraconazole and saperconazole are called [2R- [2cc, 4a4 (R *)] +, [2R- [2a, 4a, 4 (S *)] j \ [2S- [2a, 4a, 4 (S *)]] and [2S- [2a, 4a.4) R *)]]. "itraconazole", as used hereinafter, will be broadly construed and comprises the free base form and also pharmaceutically acceptable salts of itraconazole, or one of its stereoisomers, or a mixture of two or three of its stereoisomers. The preferred itraconazole compound is the (±) - (cis) form of the free base form. The acid addition forms can be obtained by reacting the base form with a suitable acid. Suitable acids comprise, for example, inorganic acids such as hydrohalic acids, i.e., hydrochloric or hydrobromic acid; sulfuric acid, nitrate acid - phosphoric acid and the like; or organic acids such as, for example, acetic, propanoic hydroxyacetic, 2-hydroxy-propanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z) -butanedioic, (E) -butanedioic, 2-hydroxybutanedioic, 2-hydroxybutanedioic acid , 2,3-dihydroxy-butanedioic acid, 2-hydroxy-1,2,3-propanedicarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzene sulfonic acid, 4-methylbenzenesulfonic acid, cyclohexane sulphonic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid and similar acids. It should be noted that therapeutically effective plasma levels of itraconazole can be easily maintained for at least 24 hours since its half-life is high enough. The condition is that itraconazole must reach the plasma. The absorption of dissolved itraconazole from the stomach is not a problem. In this way, a sustained release dosage form of itraconazole is not required, an immediate release form will suffice. In other words, the main problem with the administration of traconazole in the therapeutically effective amounts relates initially to the assurance that a sufficient amount of itraconazole remains in the solution long enough to allow it to circulate, and not to become a which is not readily bioavailable, in particular crystalline itraconazole (which is formed for example when itraconazole is precipitated in an aqueous medium). Unexpectedly, it has been found that pellets considerably smaller than those described in WO-94/05263 and with good bioavailability can conveniently be manufactured after all. In these new pellets, the core volume is considerably less than that of the spheres in the prior art and the total volume of a 200 mg dose of itraconazole can be filled in one, instead of two capsules. In addition, the total weight of the daily ingested medication is less than 1010 mg. The present invention provides pharmaceutical compositions of traconazole (or saperconazole) and a water soluble polymer that can be administered to a patient suffering from a fungal infection, wherein a single dosage form can be administered once a day. The dosage forms comprise a therapeutically effective amount of new pellets as described in detail below.

In particular, the present invention relates to pellets comprising: (a) a central, rounded or spherical core, (b) a coating film of a water-soluble polymer and an antifungal agent and (c) a polymer cap of seal coating, characterized in that the core has a diameter of from about 250 to about 600 μm (30-60 mesh), preferably from about 250 to about 500 μm (35-60 mesh), most preferably from about 250 to about 450 μm (40-60 mesh), and optimally from about 250 to about 350 μm (45-60 mesh). Pellets, spheres or cores of the dimensions mentioned herein may be obtained by sieving through nominal standard test sieves as described in CRC Handbook, 64 ed., Page F-114. The nominal standard sieves are characterized by the mesh / orifice width (μm), of DIN 4188 (mm), standard values of ASTM E 11-70 (No), Tyler® (mesh) or BS 410 (mesh). Through said description and the claims, the particle sizes are designated as reference to the mesh / orifice width in μm and to the corresponding screen Not in the standard ASTM E11-70. The materials suitable for use as cores in the pellets according to the present invention are multiple, since said materials are pharmaceutically acceptable and have adequate dimensions and firmness (approximately 45-60 mesh). Examples of said materials and polymers, such as, for example, plastic resins; inorganic substances, ie, silica, glass, hydroxyapatite, salts (sodium or potassium chloride, calcium or magnesium carbonate) and the like; organic substances, for example, activated carbon, acids (citric, fumaric, tartaric, ascorbic and similar 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, sorbitan, dextrin, maltodextrin, cellulose, microcrystalline cellulose, sodium carboxymethylcellulose, starches (corn, rice, potatoes, wheat, tapioca) and similar saccharides. A particularly preferred material suitable for use as cores in the pellets according to the present invention is represented by the 45-60 mesh sugar spheres (USP 22 / NF XVII, p.1989) which consist of 62.5% - 91.5 % (w / w) of sucrose, the residue being starch and possibly also the dextrins, and which are pharmaceutically inert or neutral. Accordingly, said cores are also known in the art as neutral pellets. The pellets that are obtained from the 45-60 mesh sugar cores comprise approximately, by weight based on the total weight of the pellet: (a) 10 to 25% core material; (b) 39 to 60% water soluble polymer; (c) 26 to 40% antifungal agent; and (d) 4 to 7% seal coating polymer.

The water-soluble polymer in the pellets according to the present invention is a polymer having an apparent viscosity of 1 to 100 mPa.s when dissolved in a 2% aqueous solution at 25 ° C of solution. For example, the water-soluble polymer can be selected from the group consisting of: alkylcelluloses such as methylcellulose, hydroxy alkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose, hydroxyalkylalkylcelluloses such as hydroxyethylmethylcellulose and hydroxypropylmethylcellulose, carboxyalkylcelluloses such as carboxymethylcellulose, alkali metal salts of carboxyalkylcelluloses such as sodium carboxymethylcellulose, carboxyalkylquiniculoses such as carboxymethylethylcellulose, carboxyalkylcellulose esters, starches, pectins such as sodium carboxymethylammopectin, chitin derivatives such as chitosan, polysaccharides such as alginic acid, alkali metal and ammonium salts thereof, carrageenans, galactomannans, tragacanth, agar-agar, gum arabic, guar gums and xanthan gums, polyacrylic acids and the salts thereof, polymethacrylic acids and the salts thereof, copolymers of methacrylate, polyvinyl alcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate, polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide.

Polymers not listed that are pharmaceutically acceptable, if they have suitable physicochemical properties as defined above, are equally suitable for preparing particles according to the present invention. The drug coating layer preferably comprises a water soluble polymer such as hydroxypropylmethylcellulose (Methocel®, Pharmacoat®, methacrylate (Eudragit®), hydroxypropylcellulose (Klucel®), or a polyvidone.) Preferred water-soluble polymers are hydroxypropylmethylcelluloses. or HPMC, said HPMC contain sufficient hydroxopropyl and methoxy groups to make them soluble in water HPMC having a degree of methoxy substitution of about 0.8 to about 2.5 and a molar substitution of hydroxypropyl of about 0.05 to about 3.0 are generally soluble in water The degree of methoxy substitution refers to the average number of methyl ether groups present per anhydrous glucose unit of the cellulose molecule.The molar substitution of hydroxypropyl refers to the average number of moles of propylene oxide that have reacted with each anhydroglucose unit of the cellulose molecule. Hydroxypropylmethylcellulose is the name adopted in the United States for hypromellose (see Martindale, The Extra Pharmacopoeia, 29th edition, page 1435). Preferably, hydroxypropylmethylcellulose with low viscosity is used, ie about 5 mPa.s, ie hydroxypropylmethylcellulose 2910 of 5 mPa.s. in the four digit numbers "2910", the first two digits represent the approximate percentage of methoxy groups and the third and fourth digits represent the approximate percentage of hydroxypropyl group composition. 5 mPa.s is a value indicative of the apparent viscosity of 2% aqueous solution at 20 ° C. Suitable HPMCs include those having a viscosity of from about 1 to about 100 mPa.s, in particular from about 3 to about 15 mPa.s, preferably about 5 mPa.s. The most preferred type of HPMC having a viscosity of 5 mPa.s, is commercially available HPMC 29105. Preferred antifungal agents for use as drugs in said drug coating layer are lipophilic azole antifungals, in particular itraconazole. Optimal dissolution results are obtained when the substance of the drug is present in a solid dispersion or solution state, as can be confirmed by differential scanning calorimetry.

The drug / polymer weight / weight ratio is in the range of 1: 1 to 1: 12, preferably 1: 1 to 1: 5. In the case of (itraconazole): (HPMC 2910 5 mPa.s), said ratio may vary from about 1: 1 to about 1: 2, and optionally is about 1: 1.5 (or 2: 3). The weight / weight ratio of ditraconazole to other water-soluble polymers can be determined by a person skilled in the art by direct experimentation. The lower limit is determined by practical considerations. In fact, given the therapeutically effective amount of itraconazole (from about 50 mg to about 300 mg, preferably about 200 mg per day), the lower limit of the ratio is determined by the maximum amount of mixture that can be processed in a form of dose of practical size. When the relative amount of water soluble polymer is very high, the absolute amount of the mixture necessary to reach the therapeutic level will be too high to be processed in a capsule or tablet. The capsules, for example, have a maximum volume of about 0.95 mi (size 00) and the pellets can be counted for a maximum of about 70% (w / v) thereof, corresponding to the weight of approximately 0.665 g. Accordingly, the lower limit of the amount of itraconazole in hydroxypropylmethylcellulose will be about 1: 12 (50 mg of itraconazole + 600 mg of water-soluble polymer). On the other hand, if the ratio is very high, this means that the amount of itraconazole is relatively high compared to the amount of the water soluble polymer, then there is a risk that itraconazole does not dissolve enough in the water soluble polymer, and This form will not obtain the required bioavailability. The upper limit of 1: 1 is determined by the fact that it is observed that the above ratio of itraconazole has not completely dissolved in the HPMC. It will be appreciated that the upper limit of 1: 1 can be underestimated for the particular water-soluble polymers. Although the foregoing can be easily established except for the experimentation time in question, solid dispersions wherein the drug: polymer ratio is greater than 1: 1 will also be within the scope of the present invention. The drug coating layer of the pellets, as described below, may further comprise one or more pharmaceutically acceptable excipients such as, for example, plasticizers, flavors, colorants, preservatives and the like. These excipients must be inert; in other words, they should not show any degradation or decomposition under the manufacturing conditions. In the current itraconazole: formulations of HPMC 2910 5 mPa.s, the amount of plasticizer is preferably small, in the order of 0% to 15% (w / w), preferably less than 5% (w / w), very preferably 0% (w / w). With other water-soluble polymers, the plasticizers can be cooled in different amounts, often higher. Suitable plasticizers are pharmaceutically acceptable and include low molecular weight polyalcohols such as ethylene glycol, propylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol; polyethylene glycols such as diethylene glycol, triethylene glycol, tetraethylene glycol; other polyethylene glycols having a molecular weight less than 1000 g / moles; polypropylene glycols that have a molecular weight lower than 200 g / moles; glycol ethers such as monopropylene glycol monoisopropyl ether; propylene glycol monoethyl ether; diethylene glycol monoethyl ether; ester-type plasticizers such as sorbitan lactate, ethyl lactate, butyl lactate, ethyl glycolate, allyl glycolate; and amines such as monoethanolamine, diethanolamine, triethanolamine, monoisopropanolamine; triethylenetetramine, 2-amino-2-methyl-1,3-propanediol and the like. Of the above, low molecular weight polyethylene glycols, ethylene glycol, low molecular weight propylene glycols and especially propylene glycol are preferred. A coat of seal coating polymer is applied to the drug coated cores to prevent adhesion of the pellets, which would have an undesired effect of a concomitant reduction in the rate of dissolution of the bioavailability. Preferably, a thin layer of polyethylene glycol (PEG), in particular polyethylene glycol 20000 (Macrogol 20000) is used as a layer of seal coating polymer. Preferred pellets comprise approximately: a) 16.5 to 19% sugar core; b) 43 to 48% hydroxypropylmethylcellulose 2910 5 mPa.s; c) 29 to 33% of itraconazole; and d) 5 to 6% polyethylene glycol 20,000. In addition, the pellets, according to the present invention, can contain various additives such as thickening agents, lubricants, surfactants, preservatives, complexing and chelating agents, electrolytes or other active ingredients. , that is, anti-inflammatory, antibacterial, disinfectant or vitamin agents. The pellets, according to the present invention, can conveniently be formulated in various pharmaceutical dosage forms. The pharmaceutical dosage forms comprise an effective anti-fungal amount of pellets as described above. Preferably, the pellets are filled into hard gelatin capsules such as an amount of, for example, 100 or 200 mg of the available active ingredient per dosage form. For example, hard gelatin capsules of size 00 are suitable for formulating pellets comprising 29 to 33% by weight of itraconazole or saperconazole, equivalent to approximately 200 mg of active ingredient. The pellets according to the present invention are conveniently prepared in the following manner. A drug coating solution is prepared by dissolving it in a suitable solvent system in appropriate amounts of an antifungal agent and a water soluble polymer. A suitable solvent system comprises a mixture of methylene chloride and an alcohol, preferably ethanol, which can be denatured, for example, with butanone. Said mixture should comprise at least 50% by weight of the methylene chloride which acts as a solvent for the drug substance. Since hydroxypropylmethylcellulose does not dissolve completely in methylene chloride, at least 10% alcohol must be added. Preferably, a relatively low methylene chloride / alcohol ratio is used in the coating solution, ie, a methylene chloride / ethanol ratio ranging from 75/25 (w / w) to 55/45 (w / w). p), in particular approximately 60/40 (w / w). The amounts of solids, ie, antifungal agent and water soluble polymer, in the drug coating solution can vary from 7 to 10% (w / w) and are preferably about 8.7%. The drug coating process (on an industrial scale) is conveniently conducted in a fluidized bed granulator (ie, Glatt type WSG-30 or GPCG-30) equipped with a lower Wurster spray insert (ie, a Wurster insert of 45.7 cm). The development of the laboratory-scale procedure can be carried out in a Glatt WSG-1 with a lower Wurster insert of 15.25 cm. Obviously, the parameters of the procedure depend on the equipment used. The spray speed must be regulated carefully. A very low spray speed can cause some spray drying of the drug coating solution and result in a loss of product. A very high sprinkling speed will cause over wetting with subsequent agglomeration. Being the agglomeration the most serious problem, the lower spray speeds can be used initially, to increase according to the progress of the coating process and the growth of the pellets.

The atomization air pressure with which the drug coating solution is applied also influences the development of the coating. The atomizing air pressure results in the formation of larger droplets and an increased tendency towards agglomeration. The high atomization air pressure can conceivably entail the risk of spray drying the drug solution, but no problem is found therein. As a result, the atomization air pressure can be set at almost maximum levels. The volume of fluid air can be monitored by operation of the exhaust air valve of the apparatus and should be set in such a way as to obtain optimum circulation of the pellet. A very low volume of air will cause insufficient fluidization of the pellets; a very high volume of air will interfere with the circulation of the pellet, due to the countercurrent air currents that develop in the apparatus. In the present process optimum conditions were obtained by opening the exhaust air valve to approximately 50% of its maximum capacity and gradually increasing the opening thereof to approximately 60% of the maximum capacity as the coating process progressed. The coating process is advantageously conducted by using an inlet air temperature ranging from about 50 ° C to about 55 ° C. Higher temperatures may accelerate the process, but have the disadvantage that the evaporation of the solvent is too rapid so that the coating liquid does not spread uniformly on the surface of the pellets resulting in the formation of a drug coating layer. with high porosity.

As the volume of the coated pellets increases, the dissolution of the drug can be significantly reduced to unacceptable levels.

Obviously, the optimum temperature of the procedure will also depend on the equipment used, the nature of the nucleus and the antifungal agent, the batch volume, the solvent and the spray speed. The parameter settings for the optimal coating results are described in more detail in the following example. It was found that the application of the coating process under said conditions yielded very reproducible results. To reduce the levels of residual solvent in the drug coating layer, the drug coated cores can conveniently be dried in any suitable drying apparatus. Good results can be obtained by using a vacuum stirrer operated at a temperature of about 60 ° C to about 90 ° C, preferably about 80 ° 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 approximately 36 hours. The vacuum stirrer is conveniently rotated at its minimum speed, ie 2 to 3 rpm. After drying, the drug coated cores can be screened.

The seal coating polymer cap is applied to the drug coated cores in the fluidized bed granulator with the lower spray insert of Wurster. The seal coating solution can be prepared by dissolving a suitable amount of a seal coating polymer in a suitable solvent system. Said system is, for example, a mixture of methylene chloride and an alcohol, preferably ethanol that can be denatured, for example, with butanone. The methylene chloride / alcohol ratio used may be similar to the ratio used in the drug coating process and thus may vary from about 75/25 (w / w) to about 55/45 (w / w) and in particular it is approximately 60/40 (w / w). The amount of the seal coating polymer in the seal coating spray solution can vary from 7 to 12% (w / w) and is preferably approximately 10%,. The seal coating spray solution is advantageously stirred during the seal coating process. The setting of the parameter to conduct this last step is essentially similar to that used in the drug coating process. The appropriate conditions are described in more detail in the example below. Another drying step may be required after applying the coating coating polymer layer. Excess solvents can be easily removed by operating the apparatus at the parameter settings used for approximately 5 to 15 minutes after the spray is complete.

The drug coating process and the seal coating process of preference are carried out under an inert atmosphere, for example nitrogen. The coating equipment should preferably be shredded and supplied with a suitable solvent recovery system that contains an efficient condensation system. The coated drug and the seal-coated pellets can be filled into hard gelatin capsules using standard automatic capsule filling machines. Adequate earthing and deionization equipment can advantageously prevent the development of electrostatic charges. The filling speed of the capsule can influence the weight distribution and should be monitored. Good results are obtained when operating the equipment from approximately 75% to 85% of the maximum speed and in many cases when operating at full speed. Also contemplated are pharmaceutical dosage forms for oral administration such as tablets. These can be produced by conventional tabletting techniques with conventional ingredients or excipients and with conventional tabletting machines. In addition, they can be produced at low cost. The shape of the tablets can be round, oval or oblong. To facilitate the passage of large dosage forms by a patient, it is convenient to provide the tablets with a suitable form. The tablets that can be eaten comfortably, because they are preferably elongated rather than round. Biconvex tablets flattened at the ends are especially preferred. As described later in more detail, a film coating on the tablet also contributes to the ease with which it can be ingested. Tablets that give an immediate release of antifungal agent in oral ingestion and have a good bioavailability are designed in such a way that the tablets disintegrate rapidly in the stomach (immediate release) and the particles that are released in this way are kept apart between yes, so that they are not impacted, they give high local concentrations of antifungal agent and the opportunity for the drug to precipitate (bioavailability). The desired effect can be obtained by distributing said particles homogeneously in a mixture of a disintegrator and a diluent. Suitable disintegrators are those that have a high coefficient of expansion. Examples thereof are hydrophilic, insoluble or poorly water soluble interlaced polymers, such as crospovidone (crosslinked polyvinylpyrrolidone) and croscarmellose (crosslinked sodium carboxymethylcellulose). The amount of disintegrator in the immediate release tablets according to the present invention can conveniently range from about 3 to about 15% (w / w) and preferably is from about 7 to 9%, in particular about 8.5% (p. / p). Said amount tends to be higher than usual in the tablets to ensure that the particles are spread over a large volume of stomach contents upon ingestion. Because disintegrators, due to their nature, yield sustained release formulations when used in volume, it is convenient to dilute them with an inert substance called diluent or filler. A variety of materials can be used as diluents or fillers. Examples of these may be spray-dried or anhydrous lactose, sucrose, dextrose, mannitol, sorbitan, starch, cellulose, ie microcrystalline cellulose Avicel ™), calcium phosphate dibasic dihydrate or anhydrous, and others known in the art, and mixtures thereof thereof. The preferred one is a commercial spray-dried mixture of lactose monohydrate (75%) with microcrystalline cellulose (25%) which is commercially available as Microcelac ™. The amount of diluent or filler in the tablets can conventionally range from about 20% to about 40% (w / w) and preferably ranges from about 25% to about 32% (w / w). The tablet may include a variety of one or more conventional excipients such as binders, pH regulating agents, lubricants, sliders, thickening agents, sweetening agents, flavors and colors. Some excipients may serve multiple purposes. Lubricants and sliders can be used in the manufacture of certain dosage forms, and will usually be used to produce the tablets. Examples of lubricants and sliders are hydrogenated vegetable oils, ie, hydrogenated cottonseed oil, magnesium stearate, stearic acid, sodium lauryl sulfate, magnesium lauryl sulfate, colloidal silica, talc, mixtures thereof, and others known in the art. technique. The interesting lubricants and sliders are magnesium stearate, and mixtures of magnesium stearate with colloidal silica. A preferred lubricant is type I (micronized) of hydrogenated vegetable, most preferably hydrogenated, deodorized cottonseed oil (commercially available from Karlshamns as Akofine NF ™ (formerly called Sterotex ™)). Lubricants and sliders generally comprise 0.2 to 7.0% of the total weight of the tablet. Other excipients such as coloring agents and pigments may also be added to the tablets of the present invention. Coloring agents and pigments include titanium dioxide and colorants suitable for food. A coloring agent is an optional ingredient in the tablet of the present invention, but when the coloring agent is used it may be present in an amount of up to 3.5% based on the total weight of the tablet. The flavors are optional in the composition and may be selected from synthetic flavors and aromatic flavor oils or natural oils, extracts from the leaves of plants, flowers, fruits and other combinations thereof. The above may include cinnamon oil, qaulteria oil, peppermint oil, bay oil, anise oil, eucalyptus, thyme oil. Also useful are the flavors of vanilla, citrous oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, etc. The amount of flavor will depend on the number of factors including the desired organoleptic effect. Generally the flavor will be present in an amount from about 0% to about 3% (w / w). As is known in the art, tablet blends can be either dry granulated or wet granulated prior to tabletting. The tabletting process itself is in another standard form and is easily practiced by forming a tablet with the desired mixture or mixture of ingredient in the proper manner using a conventional tablet pressure. The tablets of the present invention can also be coated with layers to improve the taste, to provide ease in ingestion and an elegant appearance. Many polymeric film coating materials are known in the art. A preferred film coating material is hydroxypropylmethylcellulose HPMC, especially HPMC 2910 5 mPa.s. Other suitable film-forming polymers can also be used herein, including the copolymers of hydroxypropylcellulose and acrylate-methacrylate. In addition to the film-forming polymer, the film coating may further comprise a plasticizer (i.e., propylene glycol) and optionally a pigment (i.e., titanium dioxide). The film coating suspension may also contain talc as an anti-adhesive agent. In the immediate release tablets according to the invention, the film coating is small and in terms of weight counts for less than about 3. 5% (w / w) of the total weight of the tablet. Preferred dosage forms are those in which the weight of the particles varies from 40% to 60% of the total weight of the total dosage form, that of the diluent varies from 20 to 40%, and that of the disintegrant varies from 3 to 10. %, the residue being counted by one or more of the excipients described above. As an example of the oral dosage form comprising 200 mg of traconazole, the following formula can be given: sugar spheres 250-355 μm (45-60 mesh / 265) itraconazole (200 mg) HPMC 2910 5 mPa.s . (200 mg) microcrystalline cellulose (529 mg) micronized hydrogenated type I vegetable oil (6 mg). Using the process parameters described above, a convenient, reproducible manufacturing method for preparing the pellets can be obtained comprising a 45-60 mesh core, a drug coating layer and an antifungal agent and a water soluble polymer and a layer of polymer coating stamps. Pharmacokinetic studies showed that pellets obtained in this way have excellent dissolution and bioavailability properties.

Preferred dosage forms according to the present invention are those of which at least 85% of the available traconazole are dissolved in 60 minutes when a dose form equivalent to 200 mg of itraconazole is tested, as established in the USP test. < 711 > in a USP-2 dissolution apparatus under at least as stringent conditions as the following: 900 ml of artificial gastric juice (1.8 g NaCl, 6. 3 my HCI concentrate and 9 g of polysorbate 20 diluted with distilled water to 900 mi), 37 ° C with paddles that rotate at 100 rpm. It can be said that capsules that meet the above definition have Q > 85% (60 '). Preferably, the capsules according to the present invention will dissolve faster and will have Q > 85% (30 '). The present invention also relates to an improved method for measuring the dissolution rates of pellet formulations characterized by the fact that the dissolution medium comprises about 1% (w / v) of a weight nonionic surfactant low molecular weight such as polysorbate 20. The advantage of such modified dissolution media in the dissolution media known in the art is that unexpectedly a greater correlation is obtained between kinetic drug parameters calculated from the in vivo experiments in the dissolution data in vitro In one study, several batches of pellet formulations were compared, being formulations of known and new pellets, as well as a number of formulations of pellets copied without authorization.

When the rate of dissolution in the artificial gastric juice (1.8 g NaCl, 6.3 ml of concentrated HCl diluted with distilled water to 900 ml) of these formulations was compared with the measured AUC ratios (area under curve - bioavailability index) and Cmax ratios (maximum plasma level), the correlation coefficients were 0.900 (AUC) and 0. 8913 (Cmax) respectively; in the new method said correlation coefficients were 0.957 g (AUC) and 0.9559 (Cma?) respectively. In addition, the present invention relates to pellets, as described above, for the use and preparation of a pharmaceutical dosage form for oral administration to a patient suffering from a fungal infection, wherein a single dose form is You can administer this patient once a day. The present invention also relates to the use of pellets according to the above described, for the preparation of a pharmaceutical dosage form for oral administration to a patient suffering from a fungal infection, wherein a single dosage form can be administered once a day to said patient.

EXAMPLE The following coating processes are carried out in a small apparatus having limited capacity. The procedure is therefore interrupted approximately in half to divide the material into two equal portions that are processed separately from that point. It is evident that in a large apparatus suitable for manufacturing on an industrial scale, the process does not need to be interrupted and the coating processes can be carried out in one step. a) Itraconazole spray solution 1 A stainless steel vessel (15L) was charged with methylene chloride (6.383 kg) diethanol (4.255 kg) by means of a filter (5μ). Itraconazole (370 g) and hydroxypropylmethylcellulose 2910 5 mPa.s (555 g) were added during stirring. Stirring was continued until complete dissolution was obtained. b) Itraconazole sprays 2 and 3 A stainless steel vessel (10 I) was charged with methylene chloride (5,434 kg) and ethanol (3,623 kg) by means of a filter (5 μ). Traconazole (315 g) and hydroxypropylmethylcellulose 2910 5 mPa.s (472.5g) were added during stirring. Agitation of traconazole spray solution 2 was continued until complete dissolution was obtained. The procedure was repeated for solution 3 of itraconazole spray. c) Seal coating spray solutions 1 and 2 A stainless steel vessel (5 I) was charged with methylene chloride (472.5 g) and ethanol (315 g) during stirring. Polyethylene glycol 20000 (Macrogol 20000) (87.5 g) was added and solution 1 was stirred until it became homogeneous. Solution 2 was prepared in an identical form. d) Drug coating procedure A fluidized bed granulator (Glatt, type WSG 1) equipped with a Wuster insert (bottom spray) was loaded with 250-355 μm (45-60 mesh) of sugar steel (575 g) . The spheres were heated with dry air at approximately 50 ° C. The volume of fluidizing air was controlled by the opening of the exhaust air valve at approximately 45% of its maximum capacity. Iraconazole spray solution 1 was then sprayed on the spheres that move in the apparatus. The solution was sprayed at a delivery rate of approximately 15 g.min -1 at an atomization air pressure of approximately 1.9-2.0 bar (0.19-0.2 MPa). When the spray procedure was completed, the coated spheres were dried by another dry air supply of 60 ° C for about 2 minutes. The coated spheres could then be cooled in the apparatus by the supply of dry air of 20-25 ° C for about 10 to 20 minutes. The apparatus was emptied, the partially coated drug spheres were harvested and divided into two equal parts of approximately 730 g each. The apparatus was loaded with part 1 of the partially coated drug spheres. The spheres were heated with dry air of approximately 50 ° C. The volume of fluidizing air was controlled by the opening of the exhaust air valve to approximately 45% of its maximum capacity. The spray solution 2 of itracolazole was then sprayed on the spheres that move in the apparatus. The solution was sprayed at a delivery rate of approximately 15 g.min -1 at an atomization air pressure of approximately 1.9-2.0 bar (0.19-0.2 MPa). When the spray procedure was completed, the coated spheres were dried by another dry air supply of 60 ° C for about 2 minutes. The coated spheres could then be cooled in the apparatus by the supply of dry air of 20-25 ° C for about 10 to 20 minutes. The apparatus was emptied, all the drug-coated spheres were collected and stored in a stainless steel cylinder. Part 2 of the partially drug-coated spheres was converted in the same manner with the itraconazole spray solution 3 for the completely drug-coated spheres. e) Internal drying To bring the residual solvent levels to a minimum, the coated spheres were subjected to a drying step. The coated spheres were dried for 24 hours, at a temperature of about 80 ° C at a pressure of about 200-300 mbar (20-30 kPa). The dried coated spheres were sieved with a sieve (Sweco SW U; sieve mesh width 0.75 mm) to remove agglomerates (approximately 300 g), yielding approximately 2,594 kg of pellet which was divided again into two equal parts. f) Seal coating process Part 1 of the dried coated spheres was again introduced into the fluidized bed granulator equipped with the Wurster insert and heated with dry air of about 50 ° C. The seal coating spray solution 1 was then sprayed on the coated spheres moving in the apparatus. The solution was sprayed at a delivery rate of approximately 15 g.min -1, at an atomization air pressure of approximately 1.6 bar (0.16 Mpa). When the spray procedure was completed, the pellets were dried by another 60 ° C dry air supply for 4 minutes. The coated spheres could then be cooled in the apparatus by providing 20-25 ° C dry air for about 5 to 15 minutes. The pellets were removed from the apparatus and stored in suitable containers. Part 2 of the dried coated spheres was coated with the spray coating solution 2 in an identical manner. g) Capsule filling The drug-coated pellets were filled into hard gelatin capsules (size 00) using standard automatic capsule filling machines (ie, Model GFK-1500, Hoffliger and Karg, Germany). To obtain capsules with good weight distribution, the filling speed of the capsule was reduced to approximately 75-85% of the maximum speed. Each capsule receives approximately 650 mg of pellets, equivalent to approximately 200 mg of itraconazole. Using the parameters of the procedure described above, 200 mg of itraconazole were obtained from hard gelatine capsules, which met all the requirements, in particular the dissolution specifications. h) Dissolution properties The studies of in vitro solutions were carried out in the 200 mg capsule formulation. The medium was 900 ml of artificial gastric juice (1.8 g NaCl, 6.3 mL of HCl and 9 g of polysorbate 20 diluted with distilled water at 900 mL) at 37 ° C in apparatus 2 (USP 23, <711> Dissolution , pp, 1791-1793) (propeller, 100 rpm). The following results were obtained: i) Tablet formulation Following the procedure described above, a batch of pellets having a weight / weight ratio of (itraconazole): (HPMC 2910 5 mPa.s) = 1: 1 was prepared. 665 mg of pellets (comprising 265 mg of sugar spheres 250-355 μm, 200 mg of itraconazole and 200 mg of polymer) were mixed with 529 mg of microcrystalline cellulose and 6 mg of hydrogenated vegetable oil type I (micronized) and They were compressed in an Exenterpress Courtois 27 device. A die of 20 mm x 9.5 mm, oval, surface area = 167.26 mm2 was used at a compression pressure of 2700 kg / cm2 yielding a tablet having a nominal weight of 1200 mg and having a hardness of 10.2 DaN. The tablet prepared in this way disintegrated in less than 2 minutes.

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. - A pellet comprising: a) a central, rounded or spherical core; b) a coating film of a water-soluble polymer and an antifungal agent, and c) a seal coating polymer layer, characterized in that the core has a diameter of about 250 to about 600 μm (30-60 mesh).

2. A pellet ading to claim 1, comprising by weight based on the total weight of the pellet: a) 10 to 25% core material; b) 39 to 60% of water-soluble polymers; c) 26 to 40% antifungal agent; d) 4 to 7% of seal coating polymer.

3. A pellet ading to claim 2, further characterized in that the core material is a sugar sphere of 250-355 μm (45-60 mesh), the water-soluble polymer is hydroxypropylmethylcellulose and the antifungal agent is itraconazole.

4. A pellet ading to claim 3, further characterized in that the weight-to-weight ratio of the antifungal agent: water-soluble polymer is from about 1: 1 to about 1: 2.

5. - A pellet ading to claim 2, further characterized in that the seal coating polymer is polyethylene glycol.

6. A pellet ading to claim 3, comprising approximately: a) 16.5 to 19 percent sugar core; b) 43 to 48 percent hydroxypropylmethylcellulose; 2910 5 mPa.s .; c) 29 to 33 percent of itraconazole or saperconazole; and d) 5 to 6 percent polyethylene glycol 20,000.

7. A pharmaceutical dosage form comprising an effective anti-fungal amount of pellets ading to any of claims 1 to 6.

8. A dosage form ading to the claim 7, further characterized in that the dosage form is a hard gelatin capsule.

9. A process for preparing pellets ading to any of claims 1 to 6, further characterized in that a) the coating of the sugar spheres of 250-355 μm (45-60 mesh) by spraying therewith a solution of an antifungal agent and a water soluble polymer in an organic solvent consists of methylene chloride and ethanol in a fluidized bed granulator equipped with a Wurster insert (bottom spray); b) drying the resulting coated cores; and c) sealing the dried cores by spraying therewith a solution of a seal coating polymer in an organic solvent consisting of methylene chloride and ethanol in a fluidized bed granulator equipped with a Wurster insert (bottom spray) ).

10. The drug coated pellets that are obtained by a method ading to claim 9.