Granules having a core coated with an antifungal drug and polymer

 

(57) Abstract:

The invention relates to the pharmaceutical industry. Granules include diabetes kernel size 710-1180 μm (16-25 mesh), a film coating of a water-soluble polymer and an antifungal drug and an outer protective layer, where the residual concentration of dichloromethane below 600 ppm. The pharmaceutical dosage form includes the granules. Carry out the coating of sugar cores by spraying them solution antifungal drug and a water-soluble polymer in an organic solvent consisting of methylene chloride and ethanol, the pellet fluidized bed, drying the obtained cores coated in vacuum by irradiation of these nuclei microwave or radio frequency radiation, spray dried kernel of the solution of an outer protective polymer in an organic solvent consisting of methylene chloride and ethanol, the pellet fluidized bed. The invention improves the purity of the product. 3 S. and 7 C.p. f-crystals.

The present invention relates to new Itraconazole pellets, the method of obtaining the above granules and dosage forms for oral administration, comprising a therapeutically effective the drugs on the basis of asola, such as Itraconazole, largely hampered by the fact that these antifungal drugs have only slight solubility in water. The solubility and bioavailability of these compounds can be increased by complexation with cyclodextrins or their derivatives, as described in WO 85/02767 and U.S. patent 4764604.

In WO 94/05263, published on March 17, 1994, disclosed granules having diabetes kernel size 25-30 mesh (600-710 μm) coated with anti-fungal agent-based azole, more specifically, Itraconazole (or saperconazole), and polymer, more specifically, hypromellose. Covered with an outer protective layer of sugar cores belong to the granules. Approximately 460 mg of granules, equivalent to 100 mg of Itraconazole, placed in a hard gelatin capsule (size 0), suitable for oral administration. In many countries capsules are commercially available under the brand name SporanoxTM. Antifungal agent-based azole easily liberated on the surface of the coated granules, resulting in better bioavailability compared with previously known medicinal forms of antifungal drugs on the basis of azole for oral administration.

In WO 94/05263 explained that the size of nuclei is essential. On the one hand, if the kernel is too large, there is less surface area for applying a film layer of the drug, resulting in a thicker film layers. This leads to problems in the production process, as a necessary stage of intensive drying to reduce the residual solvent in the coating layer. Conditions of intensive drying can affect the dissolution of the drug from the granules and, therefore, they should be strictly controlled during the manufacturing process. On the other hand, small cores have a large total surface available for coating, which leads to more thin film coatings. Therefore, you can use the stage is much less intensive drying to reduce residual solvents. Nuclei, which were too small the Yu to agglomeration during the coating process. Therefore, it was concluded that the kernel size 600-710 μm (25-30 mesh) was the optimum size, where neither agglomeration nor intensive stage of drying was not difficult way.

It would be very desirable to have access to pharmaceutical dosage forms, comprising a coated core, where the core is relatively large, 710-1180 μm (25-16 mesh), in particular 710-1000 μm (25-18 mesh) and especially 710-850 μm (25-20 mesh), and where the residual content of solvent in said coated cores is within the limits established by the International conference on harmonization (ICH) [ICH Topic Q3C Impurities: residual solvents (CPMP/ICH, 283/95), with effect from March 1998]. There both, dichloromethane and methanol, are solvents class 2 whose presence in pharmaceutical products should be limited; their respective permitted daily exposure (PDE) is 6 and 30 mg/day; their respective limits concentrations in pharmaceutical dosage forms are equal to 600 ppm and 3,000 ppm.

As mentioned previously, to achieve these values, residual solvents in granules with a relatively large nucleus and a relatively thick film layer of the drug/ polymer is the MS of the residual solvent. The diffusion rate of the solvent is proportional to its concentration gradient, it follows that the reduction of pressure will help to reduce the residual solvent content.

However, at the same time, low pressure reduces the efficiency of heat transfer to the coated granules when using conventional methods of heating and, thus, slows down the evaporation of residual solvent. The present invention discloses a method of efficiently transferring the heat to the coated film by coating cores at low pressure, allowing thereby to obtain a coated film by coating cores that meet the above guidelines, published ICH. The first method allows to obtain relatively large granules, consistent with the latest international limits of residual solvents in pharmaceutical products.

Itraconazole, or ()-CIS-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazole-1-yl-methyl)-1,3-dioxolane-4-yl] methoxy] phenyl]-1-piperazinil]phenyl] -2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazole-3-one, is an antifungal drug with a broad spectrum of activities designed for oral, parenteral and topical use and is disclosed in U.S. patent dioxolan-4-yl] methoxy] phenyl] -1-piperazinil] phenyl] -2,4-dihydro-2-(1-methoxypropyl)-3H-1,2,4-triazole-3-one, possesses improved activity against Aspergillus spp, and disclosed in U.S. patent 4916134. As Itraconazole and saperconazole consist of a mixture of four diastereoisomers, receipt and use of which is disclosed in WO 93/19061; diastereoisomer Itraconazole and saperconazole denoted [2R-[2, 4, 4(R*)]], [2R-[2, 4, 4(S*)]], [2S-[2, 4, 4(S*)] ] and [2S-[2, 4, 4(R*)] ] . The term "Itraconazole", as used below, should be interpreted broadly, and it includes a free base and pharmaceutically acceptable additive salts of Itraconazole or one of its stereoisomers, or a mixture of two or three stereoisomers. The preferred connection of Itraconazole is ()-(CIS)-the form of the free base. Acid additive salts can be obtained by reaction of the free base with the appropriate acid. Appropriate acids comprise, for example, inorganic acid, such as halogen acids, such as hydrochloric and Hydrobromic acid; sulfuric acid; nitric acid; phosphoric acid and the like, or organic acids such as acetic, propionic, hydroxyestra, 2-hydroxypropionate, 2-oxopropionate, tanginoa acid, proportionaly acid, batandjieva acid, (Z)-butandione is droxi-1,2,3-propanetricarboxylate, methansulfonate, econsultancy, benzolsulfonat, 4-methylbenzenesulfonate, cyclohexanesulfamic, 2-hydroxybenzoic and 4-amino-2-hydroxybenzoic and the like acids.

It may be noted that therapeutically effective levels of Itraconazole in plasma can easily be maintained for at least 24 hours, because its half-life is quite large. The condition is that Itraconazole should reach blood plasma. The absorption of dissolved Itraconazole from the stomach itself is not a problem. Thus, there is no need in the pharmaceutical form of Itraconazole with extended-release form of immediate-release performs its task. In other words, the main problem with the introduction of Itraconazole in therapeutically effective amounts primarily concerned with ensuring that a sufficient number of Itraconazole were left in solution for a sufficiently long period of time to allow it to enter the bloodstream and does not degenerate into a form that is not readily bioavailable, in particular in crystalline Itraconazole (which is formed when Itraconazole is deposited in the aquatic environment).

Suddenly now it is located within, these ICH, primarily to produce, in spite of this. These new pellets residual content of solvent is reduced when irradiated pellets in vacuum microwave or radio frequency radiation. Possible improved efficiency of the drying method using radiation can explain the excellent heat transfer; whereas conventional heating is based on the energy transfer in the collision of particles, radiation directly transmits the energy required for evaporation of the solvent, the particles with a film coating.

The present invention also discloses pharmaceutical compositions of Itraconazole and water-soluble polymer that can be entered to a patient suffering from a fungal disease. Dosage forms include an effective amount of new granules, as described below.

In particular, the present invention relates to granules, which include (a) a Central, rounded or spherical core having a diameter of about 710-1180 μm (25-16 mesh), in particular 710-1000 μm (25-18 mesh) and especially 710-850 μm (25-20 mesh), (b) a film coating of a water-soluble polymer and an antifungal drug, and C) an outer protective polymer stanovlennia International conference on harmonization (ICH) [ICT Topic Q3C Impurities: residual solvents (CPMP/ICH/ 283/95), valid from March 1998], i.e., the concentration of dichloromethane in these granules is less than 600 ppm, preferably less than 300 ppm and most preferably less than 250 ppm.

Alcohol co-solvent required for film coating of the drug in the core is preferably ethanol, the solvent 3 class, to a greater extent than with methanol, the solvent class 2, despite the fact that ethanol has a higher boiling point and higher latent heat of evaporation and, thus, they require more power than methanol.

Kernel these sizes can be obtained by sifting through the nominal standard test sieves, as described in the CRC Handbook, 64thed., page F-114. Nominal standard sieves are characterized by the standard performance mesh/hole width (μm), DIN 4188 (mm), ASTM E 11-70 (No), TylerR(mesh) or BS 410 (mesh). In this description and in the claims, the particle size is indicated when accessing the index mesh/hole width in microns and the corresponding number of sieves in the standard system ASTM E-11-70.

Substances suitable for use as cores in the granules of the present invention, are mnogoobrazny (approximately 16-25 mesh, preferably about 20-25 mesh) and neogreene. Examples of such compounds are polymers, such as plastics; inorganic substances such as silica, glass, hydroxyapatite, salt (sodium chloride or potassium or calcium carbonate or magnesium) and the like; organic substances such as activated carbon, acids (citric, fumaric, tartaric, ascorbic, and the like acids and sugars and their derivatives. The most suitable substances are sugars, such as sugar, oligosaccharides, polysaccharides and their derivatives, such as glucose, rhamnose, galactose, lactose, sucrose, mannitol, sorbitol, dextrin, maltodextrin, cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, starches (corn, rice, potato, wheat, tapioca) and similar sugars.

Especially preferred material suitable for use as cores in the granules of the present invention are sugar kernel size 20-25 mesh (USP 22/NF XVII, R. 1989), which consist of 62,5 is 91.5% (weight to weight) of sucrose, the remainder is starch and possibly also dextrins and which are pharmaceutically inert or neutral. Therefore, these nuclei the Yaya-based sugar balls the size 20-25 mesh, include approximately by weight, based on the total weight of granules (a) from 35 to 60% of the substance core; b) from 23 to 37% of water-soluble polymer; (C) from 15 to 25% antifungal drug and d) from 2 to 4% covering the coating polymer.

A water-soluble polymer granules according to the present invention is a polymer that has an apparent viscosity of 1 to 100 mPas, being dissolved in 2% aqueous solution at 20oC. for Example, water-soluble polymer can be selected from the group including

- alkylaryl, such as methylcellulose;

- hydroxyethylcellulose, such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxyethylcellulose;

- hydroxyethylmethylcellulose, such as hydroxyethylmethylcellulose and hypromellose;

- karboksimetsiltsellyulozy, such as carboxymethylcellulose;

- alkali metal salts of carboxymethylcellulose, such as sodium carboxymethyl cellulose;

- carboxylmethylcellulose, such as karboksimetiltselljuloza;

- esters of carboxymethylcellulose;

- starches;

- pectins, such as the sodium salt of carboxymethylaminomethyl;

- chitin derivatives, such as hee is Lantmannen, tragakant, agar-agar, Arabic gum, guar gum and xanthan gum;

- polyacrylic acids and their salts;

- polymethacrylic acid and their salts, copolymers of methacrylate;

- polyvinyl alcohol;

- polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate;

- polyalkylene, such as polyethylene oxide and polypropyleneoxide, and copolymers of ethylene oxide and propylene oxide.

Not listed polymers, which are pharmaceutically acceptable and have the relevant physico-chemical properties, as defined earlier, equally useful for obtaining a coated drug cores of the present invention.

The covering layer of the preparation preferably includes a water-soluble polymer, such as hypromellose (Methocel, Pharmacoat), methacrylate (Eudragit E), hydroxypropylcellulose (Klucelor polyvidone. Preferred water-soluble polymers are hydroxypropylmethylcellulose or a receiver array. These receiver array contain enough hydroxypropionic and metaxylene groups to make them water-soluble. A receiver array having a degree of substitution methoxyl approximately 3,0, usually are water-soluble. The degree of substitution metaxylene groups refers to the average number of methyl ester groups per anhydroglucose unit in the cellulose molecule. Molar substitution hydroxypropionate groups refers to the average number of moles of propylene oxide, which react with each anhydroglucose unit in the cellulose molecule. The hypromellose is admitted to the U.S. name for hypromellose (see Martindale, The Extra Pharmacopoeia, 29thedition, page 1435). Preferably used hypromellose, low viscosity, i.e., about 5 mPas, e.g. hypromellose 2910, 5 mPas. In a four-digit number "2910" the first two digits indicate the approximate percentage metaxylene groups, and the third and fourth digits - estimated percentage hydroxypropyl groups. 5 mPas is a value indicating the apparent viscosity of 2% aqueous solution at 20oC.

Suitable receiver array include those having a viscosity from about 1 to 100 mPas, in particular from about 3 to about 15 mPas, preferably about 5 mPas. The most preferred type of receiver array having a viscosity of 5 mPas, is a commercially available receiver array 2910 5 mPas.

The ratio (weight to weight) of the drug : polymer ranges from 1: 1 to 1:5, preferably from 1:1 to 1:3. If (Itraconazole) : (receiver array 2910 5 mPas) this ratio can vary from about 1: 1 to about 1:2 and optimally is approximately 1:1.5 (or 2:3). The ratio of weight-to-weight of Itraconazole to other water-soluble polymers can be determined by a specialist in this area by direct experimentation. The lower limit is determined by practical considerations. In fact, asking a 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 number of mixtures, which can be downloaded in a single dosage form, suitable for the practice size. When the relative amount of water-soluble polymer is too high, the absolute amount of the mixture required to achieve therapeutic levels, will be if the m 35% of which are core, the remaining 65% (300 mg) are the maximum number of antifungal drug and polymer. Therefore, the lower limit of the ratio of the number of Itraconazole and hydroxypropylmethylcellulose will be approximately 1:5 (50 mg Itraconazole +250 mg of water-soluble polymer).

On the other hand, if the ratio is too high, this means that the number of Itraconazole is relatively high compared to the amount of water-soluble polymer, then there is a risk that Itraconazole will not be sufficiently dissolved in the water-soluble polymer, and, thus, will not receive the required bioavailability. The upper limit of 1: 1 is determined by the observation that when the above ratio is not the whole Itraconazole dissolved in a receiver array. It is clear that the upper limit of 1:1 may be underestimated for certain water-soluble polymers. Because it is easy to install, but for experimentation takes time, solid dispersion ratio of drug and polymer greater than 1:1 are also included in the scope of the present invention.

Film coating of pellets, as described above, may optionally include one or more pharmaceutically acceptable napoletane. These fillers should be inert, in other words, they should not show any degradation or decomposition in a production environment.

In the most common compositions of Itraconazole (receiver array 2910 5 mPas) the amount of the plasticizer is preferably small, about 0 to 15% (weight to weight), preferably less than 5% (weight to weight), most preferably 0% (weight to weight). Although other water-soluble polymers, plasticizers can be used in other, often higher quantities. Suitable plasticizers are pharmaceutically acceptable and include low molecular weight polyalcohol, such as ethylene glycol, propylene glycol, 1,2-butyleneglycol, 2,3-butyleneglycol, styrallyl; glycols, such as diethylene glycol, triethylene glycol, tetraethylene glycol, other glycols having a molecular weight of below 1000 g/mol; polypropyleneglycol having a molecular weight less than 200 g/mol; glycol ethers, such as monopropellants monoisopropyl ether, propylene glycol monotropy ether, diethylene monotropy ester; plasticizers of the type of esters, such as sorbitrate, ethyl ester of lactic acid, butyl er monoethanolamine, diethanolamine, triethanolamine, monoisopropanolamine, Triethylenetetramine, 2-amino-2-methyl-1,3-propandiol, and the like. Of these low molecular weight glycols, ethylene glycol, low molecular weight polypropylenglycol, especially propylene glycol, are preferred.

An outer protective polymer layer is applied to the coated core to prevent clumping of the pellets, which will have undesirable effects, manifested in the accompanying decrease in the dissolution rate and bioavailability. Preferably used as an outer protective polymer layer is a thin layer of polyethylene glycol (PEG), in particular polyethylene glycol 20000 (Macrogol 20000).

Preferred granules consist of approximately from 40% to 43% sugar cores; (b) from 30 to 35% of hydroxypropylmethylcellulose 2910 5 mPas; (C) from 20 to 25% of Itraconazole and (d) from 2 to 4% polyethylene glycol 20000.

In addition, the granules of the present invention may optionally include various additives, such as thickeners, lubricants, surfactants, preservatives, complexing, hepatoblastoma compounds, electrolytes and other active ingredients, such as prothiofos the uly of the present invention can preferably be included in various pharmaceutical dosage forms. Suitable dosage forms include an effective amount of antifungal granules, as described previously. Preferably the granules are placed in hard gelatin capsules so that the quantity of 100 mg of the active ingredient, is in the dosage form. For example, hard gelatin capsules of size 0 are suitable for inclusion granules containing from 20 to 25% by weight of Itraconazole or saperconazole, equivalent to about 100 mg of the active ingredient.

Granules of the present invention is convenient to prepare the following way. Solution of the drug film coating is prepared by dissolving in a suitable system of solvents appropriate quantity of antifungal drug and a water-soluble polymer. A suitable solvent system comprises a mixture of methylene chloride and alcohol, preferably ethanol, which can be denatured, for example butanone. This mix should include at least 50% by weight of methylene chloride, which acts as a solvent for the drug. Because the hypromellose is not completely soluble in methylene chloride, it is necessary to add at least 10% alcohol. Preferably, the film coating solution is of canola in the range from 75/25 (mass to mass) to 55/45 (weight to weight) in particular about 60/40 (weight to weight). The amount of solid substances, i.e antifungal drug and a water-soluble polymer in the solution covering the drug is in the range from 7 to 10% (weight to weight) and preferably equal to about 8.7%.

The method of film coating (industrial scale) is conveniently carried out in the granulator, fluidized bed (e.g., Glatt type WSG-30 or GPCG-30) equipped with a Wurster insert for spraying in the bottom (for example, 18-inch Wurster insert). The development of the method in the laboratory can be Glatt type WSG-1 with 6-inch Wurster insert. It is clear that the process parameters are dependent on the equipment used.

Should carefully monitor the spraying speed. Too low speed spray may cause spray drying of the solution covering the drug and lead to loss of product. Too high speed spraying will cause waterlogging and subsequent agglomeration. Agglomeration is the most serious problem, so initially you can use low spray rates, and as the process of coating and increase the pellets should be increased.

Pressure who is. Low air pressure when spraying leads to the formation of larger droplets and greater tendency to agglomerate. High pressure air spraying may have the risk of leakage of spray drying of a solution of the drug, but it was not found the problem. Therefore, the air pressure when spraying can be set at levels close to the maximum.

The volume of air for fluidization can be controlled by adjusting the exhaust, air valve apparatus, and should be installed so that was obtained optimal circulation of the granules. Too low volume of air will be insufficient to cause fluidization of the granules; too much air will interfere with the circulation of the granules due to the jet of air, the developing apparatus. In the present method, the optimum conditions were obtained at the outlet opening of the air valve approximately 50% of the maximum, and as the process of gradual increase its opening up about 60% of the maximum.

The method of covering mainly performed by using the temperature of the intake air in the range of about 50 to 55oC. higher temperature covering the liquid is distributed evenly over the surface of the granules, leading to the formation of a coating layer of a drug with a high porosity. As mass increases the amount of coated granules, can be significantly reduced to unacceptable levels, the dissolution of the drug. It is clear that the optimal process temperature will additionally depend on the equipment used, the nature of the kernel and antifungal drug, lot sizes, solvent and spray rates.

Set parameters for optimum coverage in more detail in the examples below. It was found that when carrying out the method of coating under these conditions result in a very reproducible results.

In order to reduce the residual content of solvent in the film coating of the kernel, can preferably be dried in a microwave vacuum apparatus, for example as described in U.S. patent 4882851 Fitzpatrick Co. of Elmhurst, 111., USA. Good results can be obtained using a vacuum in the range of about from 150 to 400 mbar (15-40 kPa), preferably 200-300 mbar (20-30 kPa). Microwave (or RF) power can be applied continuously, but preferably in a pulsed mode, as described in U.S. patent 5440104. After drying cores coated can p the fluidized bed with Wurster insert for spraying in the bottom. Protective covering solution can be prepared by dissolving an appropriate quantity of the protective coating of the polymer in an appropriate solvent system. Such a system is, for example, a mixture of methylene chloride and alcohol, preferably ethanol, which can be denatured, for example butanone. Used the ratio of methylene chloride/alcohol may be similar to the ratio used in the method of coating the drug, and thus, may be in the range from about 75/25 (weight to weight) to about 55/45 (weight to weight) and, in particular, is approximately 60/40 (weight to weight). The number of outer protective polymer in the protective covering solution for spraying can vary from 7 to 12 (weight to weight) and preferably is about 10%. Protective covering solution for spraying mixed mainly during the method of applying a protective coating. Set parameters for this last stage is essentially the same as those used in the method of coating the drug. Appropriate conditions are described in more detail in the examples below.

As a way to cover the drug and how protective coating of prepact to ground and to ensure appropriate system for recovery of solvents, including an effective system cooling.

Coated and covered with a covering layer of the granules may be placed in hard gelatin capsules using conventional automatic machine for filling capsules. Suitable equipment for earthing and deionization can mainly prevent the development of electrostatic charges.

The rate of filling of the capsules may affect the distribution of mass and should be controlled. Good results are obtained when the equipment is operated for approximately 75-85% of maximum speed, and in many cases when working at full speed.

Also provides pharmaceutical dosage forms for oral administration such as tablets, including kernel-coated (preferably without covering membrane). They can be prepared by conventional methods with conventional tabletting ingredients or fillers and conventional machines for tableting. In addition, they can be produced at low cost. The tablets can be round, oval or elongated. In order to relieve the patient swallowing large dosage forms, mainly to give the tablets shootin elongated, than rounded. Especially preferred lenticular, flattened tablet. As discussed in more detail below, a thin film on the tablet additionally facilitate its ingestion.

Tablets that provide instant release of antifungal drug when administered orally and which have good bioavailability, is designed so that the tablets rapidly disintegrate in the stomach (immediate release) and that kernel with a film coating, which are released at the same time, separated from each other so that they do not stick together. Thus, the local concentration of antifungal drug remain low, and there is little chance that the drug will precipitate (bioavailability). The desired effect can be obtained with a homogeneous distribution of these coated cores in a mixture of loosening agent and diluent.

Suitable loosening agents are those that have a large ratio spread. Examples are hydrophilic, insoluble or slightly soluble in water cross-linked polymer such as crosspovidone (crosslinked polyvinylpyrrolidone) and crosscarmellose (sodium salt of cross-linked carboxymethyl which may preferably be vary from approximately 3 to, about 15% (weight to weight), and preferably is approximately 7 to 9%, in particular about 8.5% (weight to weight). This number more pills than usual, to ensure that the coated cores are distributed in a large volume of gastric contents in the event of ingestion. Due to the fact that loosening agents, by their nature, give compositions with prolonged release when used in large quantities, it is advantageous to dilute them with an inert substance called diluent or excipient.

Various substances can be used as diluents or fillers. Examples are spray dried or anhydrous lactose, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (e.g. microcrystalline cellulose AvicelTM), the dihydrate or anhydrous dibasic calcifolic, and others known in this area and their mixtures. Preferred is a commercially available spray dried mixture of lactose monohydrate (75%) with microcrystalline cellulose (25%), which is commercially available under the trademark MicrocelacTM. The amount of diluent or filler in tablets may consequently vary from about 20 to about 40>The tablet may include a variety of one or more other conventional excipients such as binders, buffering agents, lubricants, slip agents, thickeners, sweeteners, flavoring agents and coloring compounds. Some fillers can serve many purposes.

Lubricating and sliding substances can be used in the production of some dosage forms, and they usually will be used in the manufacture of tablets. Examples of lubricating and sliding substances are hydrogenated vegetable oils, for example hydrogenated oil of cotton seed, magnesium stearate, stearic acid, sodium lauryl sulfate, lauryl sulfate, magnesium, colloidal silica, talc, mixtures thereof and others known in this area. Of particular interest lubricating and sliding substances are magnesium stearate and mixtures of magnesium stearate with colloidal silica. The preferred lubricant is hydrogenated oil type I (micronized), most preferably hydrogenated deodorized oil of cotton seeds (commercially available from Karlshamns as Akofine NFTM(formerly known as SterotexTM). With the m according to the present invention it is possible to add other fillers, such as coloring compounds and pigments. Coloring compounds and pigments include titanium dioxide and dyes suitable for food products. Coloring the connection is an optional ingredient in the tablet of the present invention, but when used, the dye compound may be present in amounts up to 3.5% based on the total weight of the tablet.

Flavorings are optional in the composition and can be selected from synthetic aromatic oils and flavor fragrances or natural oils, extracts from plant leaves, flowers, fruits and so forth and combinations thereof. They can include cinnamon oil, Wintergreen oil, oil of peppermint, Bay oil, anise oil, eucalyptus, thyme oil. Also as flavouring substances are suitable vanilla, oil of citrus, including lemon, orange, grape, lime and grapefruit, and fruit essences, including Apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth. The amount of flavoring substance may depend on a number of factors, including the desired organoleptic effect. Usually flavouring substance will be present in the amount of primewell dry or wet granulation prior to pelletizing. The way tabletting itself is somehow standard and may be easily obtained by forming the tablets of the desired composition or a mixture of ingredients in the proper form, using conventional press for tableting.

Tablets of the present invention can be coated film to improve the taste, for easy swallowing and graceful appearance. In this area there are many known suitable polymer material for film coating. The preferred substance for film shell is hypromellose receiver array, especially a receiver array 2910 5 mPas. It is also possible to use other suitable polymers forming the film, including hydroxypropylcellulose and copolymers of acrylate-methacrylate. In addition to the polymer forming the film, the film membrane may optionally include a plasticizer (e.g., propylene glycol) and optional pigment (e.g. titanium dioxide). Suspension film membrane may also include talc as anticlimaxes funds. Tablets with immediate-release film according to the invention, the shell is small and when the expression in the mass is less than Primera, in which the weight of the coated cores is in the range from 40 to 60% of the total mass of all dosage forms, such diluent ranges from 20 to 40% and such for loosening agent ranges from 3 to 10%, the rest have one or more of the excipients described above.

As an example, pharmaceutical forms for oral administration, contains 100 mg of Itraconazole, may be represented by the following structure:

sugar cores 710-850 μm (20-25 mesh/192 mg),

Itraconazole (100 mg),

A receiver array 2910 5 mPas (150 mg),

microcrystalline cellulose (452 mg),

hydrogenated vegetable oil type I micronized 6mg.

Using the method described above, it is possible to get reproducible production method of producing granules comprising a core size of 20-25 mesh, a film coating consisting of an antifungal drug and a water-soluble polymer, and a thin outer protective polymer layer. Pharmacokinetic studies show that the thus obtained granules have excellent properties in respect of dissolution and bioavailability.

Preferred dosage forms according to this 60 min, when the dosage form equivalent to 100 mg of Itraconazole, tested as described in USP test <711> in the apparatus for dissolving a USP-2 in terms of, at least, exactly corresponding to the following: 900 ml of artificial gastric juice (1.8 g NaCl, 6.3 ml of concentrated Hcl and 9 g of Polysorbate 20, diluted with distilled water to 900 ml, 37oWhen the rotation speed of the stirrer at 100 rpm Can say that the capsules that meet the previous definition, have a Q>85% (60'). Preferably the capsules of the present invention will dissolve faster and have a Q>85% (30').

Example.

a) a Solution of Itraconazole spray 1

In a vessel of stainless steel (10 l) was loaded methylene chloride (4,722 kg) and ethanol (3,147 kg) through the filter (5 MK). Under stirring added Itraconazole (300 g) and hypromellose 2910 5 mPas (450 g). A stirring solution of Itraconazole for spraying was continued until complete dissolution.

b) a Protective covering solution for spray

In a vessel of stainless steel (5 l) was loaded methylene chloride (291,6 g) and ethanol (194,4 g) with stirring. Added polyethylene glycol 20000 (Macrogol 20000) (54 g) and the solution was stirred until it became homogeneous.

c) Spycam Wurster (bottom spray), downloaded diabetes kernel size 710-850 μm (20-25 mesh) (575 g). Kernel heated dry air with a temperature of about 50oC. the Volume of air for fluidization controlled by the outlet opening of the air valve approximately 45% of its maximum. The solution of Itraconazole to spray and then sprayed on the engine, moving the device. The solution was sprayed with a feed rate of about 15 communes-1when the air pressure when spraying around 1.9-2.0 bar (0,19-0.2 MPa). When the spraying was completed, the coated cores were dried at additional supply of dry air with a temperature of 60oC for 2 minutes Cores coated then allowed to cool in the apparatus when the supply of dry air with a temperature of 20-25oC for about 10 to 20 minutes the Device is unloaded and core coated collected and kept in the cylinder of stainless steel.

d) Microwave drying

In order to reduce the residual content of solvent, the coated cores were then transferred into a vacuum processor (Gral 25), equipped with a microwave generator (demand include Collette) and irradiated for 1 h at 25 kPa and 1 to 1.2 kW. The granules were mixed every three minutes to obtain a homogeneous drying.

e) the Way Nanase is equipped with a Wurster insert, and heated dry air with a temperature of about 50oC. Protective covering solution for dispersion is then sprayed on the coated cores moving in the apparatus. The solution was sprayed with a feed rate of about 15 communes-1when the air pressure when spraying approximately 1.6 bar (0.16 MPa). When the spraying was completed, the granules were dried at additional supply of dry air with a temperature of 60oC for 4 minutes Covered cores then allowed to cool in the apparatus when the supply of dry air with a temperature of 20-25oC for about 5 to 15 minutes, the Pellets were unloaded from the device and stored in suitable containers.

f) Filling capsules

Covered with a protective polymer layer pellets filled in hard gelatin capsules (size 0), using standard automatic machine for filling capsules (e.g., Model GFK-1500, Hfflinger and Karg, Germany). In order to obtain capsules with a good distribution of weight, speed of filling capsules reduced to approximately 75-85% of maximum speed. Each capsule downloaded approximately 460 mg cores, equivalent to about 100 mg of Itraconazole. Using the settings described above have been hard gelatin capsules with 100 mg of itracona the P> (g) the dissolution Properties

In vitro conducted experiments on dissolution with capsules containing 100 mg of Itraconazole. The medium consisted of 900 ml of artificial gastric juice (1.8 g NaCl, 6.3 ml of concentrated Hcl and 9 g of Polysorbate 20, diluted with distilled water 900 ml) at 37oIn apparatus 2 (USP 23, <711>, Dissolution, p. 1791-1793 (stirrer, 100 rpm).

h) Preparation of tablets

Following the procedure described previously prepared batch of granules having a ratio of weight to mass (Itraconazole): (receiver array 2910, 5 mPas)=1:1,5. 460 mg of the granules (including 192 mg sugar balls the size 710-850 μm; 100 mg of Itraconazole and 150 mg of polymer) was mixed with 452 mg microcrystalline cellulose and 6 mg hydrogenated vegetable oil type 1 (micronized) and compressed on Exenterpress Courtois 27, receiving the tablet having a nominal weight of 900 mg.

i) Comparison with pellets, dried using conventional heating

Party granules, prepared as described in paragraph (C), tested on the residual content of dichloromethane before drying and after drying at 60oC for 8, 24, 32 and 48 h in a vacuum drum dryer (25 kPa).

The condition is that the Concentration of dichloromethane (ppm)
<C, 48 h 1310

Samples of pellets, dried following the procedure of paragraph (d), given the following data.

The condition is that the Concentration of dichloromethane (ppm)

Before drying - 2550

1 h - <250l

1. Pellet comprising (a) a Central, rounded or spherical core having a diameter of from about 710 to 1180 microns (16-25 mesh.), b) a film coating of a water-soluble polymer and an antifungal drug, and C) an outer protective polymer layer, characterized in that the residual concentration of dichloromethane in the above-mentioned granule less than 600 hours/million

2. The pellet under item 1, comprising by weight, relative to the total mass of granules: (a) from 35 to 60% of the substance of the nucleus, b) from 23 to 37% of water-soluble polymer, C) from 15 to 25% of the antifungal drug, and (d) from 2 to 4% of an outer protective polymer.

3. The pellet under item 2, where the core material is a sugar core size 710-850 μm (20-25 mesh.), a water-soluble polymer is hypromellose and anti-fungal agent is Itraconazole.

4. The pellet under item 3, where the ratio by weight of antifungal drug: water-soluble polymer is from 1:1 to 1:2.

5. The pellet under item 2, where an outer protective polymer of userobjectclass, viscosity of 5 mPas, (C) from 20 to 25% of Itraconazole or saperconazole, and (d) from 2 to 4% of polyethylene glycol with an average molecular weight of 20000.

7. Pharmaceutical dosage form comprising granules with an effective amount of an antifungal drug according to any one of paragraphs.1-6.

8. Dosage form under item 7, where the dosage form is a hard gelatin capsule.

9. A method of producing granules on one of the PP.1-6, characterized in that a) the sugar coating of the cores is carried out by spraying on them of a solution of anti-drug and a water-soluble polymer in an organic solvent consisting of methylene chloride and ethanol in the granulator fluidized bed, provided with a liner for bottom spray, b) obtained cores coated is dried in a vacuum by radiation of these nuclei microwave or radio frequency radiation, and (C) is sprayed on the dried coated core solution of an outer protective polymer in an organic solvent consisting of methylene chloride and ethanol, the pellet fluidized bed, provided with a liner for bottom spray.

10. The pellet under item 1, obtained by the method according to p. 9.

 

Same patents:

The invention relates to N-[alkoxyl(ethylenoxy)carbonylmethyl]ammonium chlorides of the formula (I) having fungistatic and bactericidal activity, and method of production thereof

The invention relates to medicine and concerns based tools terbinafine, which has antifungal activity

The invention relates to medicine, namely to homeopathic, treatment and prevention tools for internal and external use, has tonic, anti-inflammatory, wound healing, detoxifying, anti-microbial, antianginal, anti-atherosclerotic, antioxidant, antihypoxic, neuroprotective, sedative, cardioprotective, anti-arrhythmic, angioprotective, stress-protective, immunotropic, antifungal, nephroprotective, hepatoprotective, gastroprotective, thermoprotector, lipoic, megaproducer, radioprotective, and retinoprotective anticoordination action
The invention relates to the field of pharmacy and relates to antifungal agents and method of its production

The invention relates to a pharmaceutical composition comprising: 1) an antifungal agent, which is (-)-(2R-CIS-)-4-[4-[4-[4-[[5-(2,4-differenl)tetrahydro-5-(1H-1,2,4-triazole-1-ylmethyl)furan-3-yl] methoxy] phenyl] -1-piperazinil] phenyl] -2,4-dihydro-2-[(S)-hydroxypropyl]-3H-1,2,4-triazole-3-one, 2) at least one nonionic surfactant and (3) diluent
The invention relates to medicine, in particular chemical-pharmaceutical industry, such as medications, used to treat fungal diseases, namely candidiasis of the gastrointestinal tract, intestinal kandidonoshitelstvo, candidiasis internal organs, chronic granulomatous and disseminated forms of candidiasis, koktsidioidoze, cryptococcosis, blastomycosis, in addition, successfully used in the treatment of pnevmatikatos, Candida nasopharynx and other fungal diseases

The invention relates to tablets comprising a Central, rounded or spherical core diameter of 250-355 µm (45-60 mesh), the coating film of the water soluble polymer and Itraconazole, and a layer of protective polymer coatings for pharmaceutical dosage form, as well as to a method for the specified bean

The invention relates to medicine, namely to create drugs with complex medical and preventive action, and for the composition for the prevention of atherosclerosis, cardiovascular disease and maintenance therapy of viral diseases

The invention relates to medicine, namely to create drugs with complex medical and preventive action, and for the composition for the prevention of atherosclerosis, cardiovascular disease and maintenance therapy of viral diseases

The invention relates to the pharmaceutical industry and relates to a mixture of primary fatty acids derived from sugar-cane wax

The invention relates to the field of medicine and for the solution of cyclosporine
The invention relates to chemical-pharmaceutical industry, namely to medicinal drug for the treatment of degenerative dystrophic diseases of joints - osteoarthritis, made in the form of a capsule containing chondroitin sulfate, stearic acid or calcium stearate and lactose

The invention relates to the field of pharmaceutical industry and relates to improved pharmaceutical compositions for oral administration containing substituted pyridinesulfonamide and a carrier comprising a polymer with vinylpyrrolidone links or a copolymer of vinylpyrrolidone and vinyl acetate, located mainly in the form of a capsule, coated, containing a mixture of substituted pyridinesulfonamide and polymer

The invention relates to the field of medicine and for the preparation of Amazed with bacteriostatic and bactericidal action

The invention relates to tablets comprising a Central, rounded or spherical core diameter of 250-355 µm (45-60 mesh), the coating film of the water soluble polymer and Itraconazole, and a layer of protective polymer coatings for pharmaceutical dosage form, as well as to a method for the specified bean
Up!