Pellet, its preparation and pharmaceutical composition

 

(57) Abstract:

The invention can be used in medicine to combat fungal diseases. Offered granules containing composition have a high bioavailability and solubility, which will increase the effectiveness of the treatment. The pellet contains the Central core, rounded or spherical with a diameter of 25-30 mesh that cover the film of the hydrophilic polymer and an antifungal agent, and a layer of polymeric sealing coating. The preferred composition of the granules, wt.%: 20-60 - material core, 25-50 - hydrophilic polymer, 10-25 - antifungal agent and 2-5 - polymer, forming a sealing coating. The pharmaceutical composition contains an effective antifungal action the number of granules. The composition may be in the form of capsules made of gelatin containing itraconazol or saperconazole in the form of granules. A method of producing granules includes 3 stages: 1. The coated cores 25-30 mesh by spraying a solution of an antifungal agent and a hydrophilic polymer in an organic solvent, which contains methylene chloride and ethanol, the pellet fluidized bed equipped with insert Wurster (bottom spray). 2. Drying the obtained cover the Oia of the polymer solution, forming a coating of an organic solvent. This solution contains methylene chloride and ethanol. The application is carried out in the granulator, fluidized bed equipped with insert Wurster (bottom spray). 3 S. and 6 C.p. f-crystals.

This invention relates to a new composition of antifungal drugs with low solubility in aqueous media, the method of production of specified composition and pharmaceutical dosage forms for oral administration that contain the specified new comp.

The development of effective pharmaceutical compositions azole antifungal drugs such as Itraconazole and saperconazole significantly hampered by the fact that these antifungal drugs are very poorly soluble in water. The solubility and bioavailability of these compounds can be increased by formation of complexes with cyclodextrins or their derivatives, as described in WO 85/02767 and US -4.764.604. However, there is still an important need in the compositions of antifungal drugs with good bioavailability for oral administration.

Itraconazole, or ()-CIS-4-[4-[4-[4-[[2-(2,4-dichlorophenyl-) 4-triazole-3-one, is an antifungal compound with a wide spectrum developed for oral, parenteral and topical use, and described in US-4.267.179. His diversional,saperconazole,or()-CIS-4-[4-[4-[4-[[2-(2,4-differenl-) -2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-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 described in US-4.916.134.

Unexpectedly it was found that the introduction of membrane not easily soluble antifungal drugs in hydrophilic polymers and applying the mixture to form the coating film on the many small granules leads to compositions with good bioavailability, which is convenient to manufacture and which is suitable for the production of pharmaceutical dosage forms for oral administration.

In particular, the present invention relates to granules comprising (a) a Central core of rounded or spherical shape, (b) covering the film of the hydrophilic polymer and an antifungal drug, and (C) a sealing layer of polymer coating, and wherein the core has a diameter from about 600 to about 700 microns (25 - 30 mesh).

Granules, which can be obtained from cores reprofiling polymer, (C) 10 - 25% antifungal drug and (g), 2 - 5% of the polymer constituting the sealing cover.

Essential the specific size of the nuclei. On the one hand, if the kernel is too large, for applying medicinal covering layer is smaller surface area, which leads to a thicker cover layer. This fact causes problems in the production process, as to reduce the content of residual solvent in the covering layer requires intensive stage of drying. Conditions of intense dehydration can adversely affect the dissolution of the drug from pellets and should therefore extremely well controlled during the manufacturing process. On the other hand, small nuclei have a larger total surface available for coating, resulting in more than a thin cover layers. As a consequence, to reduce the residual content of solvent you can use much less intense stage of drying. However, too small nuclei, i.e. with the size of 30 - 35 mesh, have the disadvantage that they have a strong tendency to agglomeration during the coating process. Therefore, the optimum size of the cores 25 - 30 mesh, which ProTV as the cores of the granules of the present invention are suitable for many materials, provided that they are pharmaceutically acceptable and have the proper size (about 25 - 30 mesh) and hardness. Examples of such materials are polymers, such as plastic resin, inorganic substances such as silica, glass, hydroxyapatite, salt (sodium chloride or potassium or calcium carbonate or magnesium), etc., organic substances, such as activated carbon, acids (citric, fumaric, tartaric, ascorbic, etc), as well as sugars and their derivatives. Particularly suitable materials are sugars, such as sugar, oligosaccharides, polysaccharides and their derivatives, such as glucose, rhamnose, galactose, lactose, sucrose, mannitol, sorbitol, dextrin, maltodextrin, cellulose, sodium carboxymethyl cellulose, starches (maize, rice, potato, wheat, tapioca) and similar sugars.

Especially preferred material suitable for use as the core of the granules according to the present invention are sugar beads size 25 - 30 mesh (NE XVII, p 1989), which consist 67.5 - 91,5% (V/V) of sucrose, and the rest is starch and possibly dextrins and which are pharmaceutically inert or neutral.

Covering drug , Pharmacoat), methacrylate (EudragitE), hydroxypropylcellulose (KIuceIor polyvidone. Preferably use a low viscosity hypromellose, i.e. about 5 mPas, such as hypromellose 2910 5 mPas. Preferred antifungal agents for use as drugs in covering the drug layer are lipophilic azole antifungal agents, in particular Itraconazole and saperconazole. Optimum results by solution obtained when using the ratio (in/in) drug: polymer of from about 1:1 to about 1:2, preferably about 1:1,5. In covering the drug-layer pharmaceutical substance is present in a solid dispergirovannom or dissolved, it is possible to confirm differential scanning calorimetry.

The layer of polymeric sealing coating is applied on the coated drug cores to prevent adhesion of granules, which may have an undesirable effect concomitant decrease the dissolution rate and bioavailability. Preferably as a layer of polymeric sealing coating to use a thin layer of polyethylene glycol (PEG), in particular is hydroxypropylmethylcellulose 2910 5 mPas, (in) 21 - 22% of Itraconazole or saperconazole and (g) 3 - 4% polyethylene glycol 20000.

In addition, the granules of the present invention may optionally contain various additives, such as thickeners, lubricants, surfactants, preservatives, complexing and chelating agents, electrolytes or other active ingredients, for example anti-inflammatory agents, antibacterial agents, disinfectants or vitamins.

Granules of the present invention can be conveniently translated into various pharmaceutical dosage forms. Suitable dosage forms contain effective anti-fungal action number of the above granules. Preferably the granules are filled capsules of hard gelatin so that one dosage form was available, for example, 50 or 100 mg of active ingredient. For example, capsules of hard gelatin size 0 usable granules, containing by weight 20 - 25% of Itraconazole or saperconazole, equivalent to about 100 mg of the active ingredient.

Granules of the present invention conveniently be obtained as follows. Prepare a solution for coating medication by Rast is varicela. A suitable solvent system comprises a mixture of methylene chloride and alcohol, preferably ethanol, which can be are denatured, for example, butanone. The specified mix shall contain not less than 50% by weight of methylene chloride, which acts as a solvent for the drug. As hydroxypropylcellulose is not soluble in methylene chloride completely, you need to add at least 10% alcohol. Preferably in solution for coating is to use a relatively low ratio of methylene chloride/alcohol, for example, in the range from 75/25 (V/V) to 55/45 (V/V), in particular about 60/40 (V/V). The amount of solid substances, that is, antifungal agents and hydrophilic polymer in the solution for applying a drug coating can be in the range from 7 to 10% (V/V) and preferably be about 8%.

Convenient to carry out the process of applying a drug coating on the kernel size 25 - 30 mesh in the granulator, fluidized bed (e.g., type of Glatt WSG-30) equipped with an insert for the bottom spray (for example, 18-inch insert Wurster). It is obvious that the process parameters will depend on the equipment used.

Skinney spray drying of the solution to cover the drug and lead to loss of product. Too high speed spraying will cause excessive wetting and subsequent agglomeration. Since agglomeration is the most serious problem, you can first use the lower spray rates that increase as flow coating process and increase the size of the granules.

Pressure spraying air through which the solution is applied to cover the drug also affects the conducting coating. Low pressure spraying air leads to the formation of larger droplets and increased tendency to agglomerate. High pressure spraying air would, as it seems to cause a risk of spray drying of a solution of the drug, however, it was found that this is not a problem. Therefore, the spraying air pressure can be set to almost maximum levels.

Volume pseudoviruses air can be controlled via an air valve device and should be installed in such a way as to achieve optimal circulation of the granules. Too little air will result in insufficient fluidization of the granules, too much air will interfere with the circulation of the granules obtained by following the output opening of the air valve to approximately 50% of its maximum bandwidth and a gradual increase in his hole up to about 60% of the maximum as the flow of the coating process.

Advantageous to carry out the coating process using the temperature of the incoming air in the range of from about 50oC to about 55oC. higher temperatures can speed up the process, but not it is advantageous that the solvent evaporates so quickly that the liquid coating is not distributed evenly on the surface of the granules, which leads to the formation of drug coating layer with a high degree of porosity. As the apparent volume of the coating of the granules is increased, the dissolution of drugs can be significantly reduced to unacceptable levels. It is clear that the optimal process temperature will also depend on the equipment used, the nature of the kernel and antifungal drug loaded volume of the solvent and spray rates.

Settings for best results, the coating described in more detail in the subsequent example. It was found that carrying out the coating process under these conditions leads to a well-reproducible results.

In order to reduce the residual solvent content in medicinal covering layer coated drug cores can conveniently be dried in any PR drying apparatus, working at a temperature of from about 60oC to about 90oC, preferably about 80oC, under reduced pressure in the range from about 150 to 400 mbar (15 - 40 kPa), preferably at 200 to 300 mbar (20 - 30 kPa) for at least 24 hours, preferably about 36 hours. Vacuum drum drying machine is convenient to rotate at a minimum speed, for example 2 to 3 rpm After drying, the core is coated with medicine, you can sift through.

The layer of polymeric sealing coating is applied on the coated drug cores in the granulator, fluidized bed with insert Wurster for bottom spray. The solution for the deposition of the sealing layer can be prepared by dissolving the appropriate amount of polymer for sealing coating in a suitable solvent system. Such a system, for example, is a mixture of methylene chloride and alcohol, preferably ethanol, which can be are denatured, for example, butanone. Used the ratio of methylene chloride/alcohol can be the same as the ratio used in the process of applying a drug coating, and thus lie in the range from about 75/25 (V/V) to about 55/45 (V/V), and in particular about 60/40 (V/V). The number of polymer DV/V) and preferably is about 10%. The solution for spraying the sealing coating is preferably stirred during application of the sealing cover. The setting for this last stage is basically the same as during the process of applying a drug coating. Appropriate conditions are described in more detail in the following example.

After applying a layer of polymeric sealing coating may require an additional stage of drying. Excess solvent can be easily removed during operation of the apparatus when used settings for about 5 - 15 minutes after spraying.

As the process of applying a drug coating, and the process of applying the sealing coating is preferably carried out in an inert atmosphere, e.g. nitrogen. Preferably, the equipment for coating was grounded and equipped with a proper system of regeneration of the solvent containing an effective system of condensation.

Covered medications and covered with a sealing layer of granules can be made into capsules of hard gelatin using standard automatic machine for filling capsules. To prevent electrostatic the fill Rate of the capsules can affect the weight distribution and its need to control. Good results are obtained when the machine is running with a speed of approximately 75 - 85% of maximum, and in many cases when working with full speed.

When using the above parameters of the process can be made easy, reproducible production method for producing granules containing the kernel size 25 - 30 mesh, medicinal covering layer of the antifungal drug and a hydrophilic polymer, and a thin layer of sealing polymeric coating. Pharmacokinetic studies have shown that the thus obtained granules have excellent properties on dissolution and bioavailability.

Example.

a) the Solution for dispersion of Itraconazole

In a vessel made of stainless material through the filter (5 μm) made methylene chloride (375 kg) and denatured ethanol (250 kg). Under stirring was added Itraconazole (21,74 kg) and hydroxypropylcellulose 2910 5 mPas (32,61 kg). Stirring is continued until complete dissolution (using identical methodology was obtained suitable solution for spraying saperconazole).

b) the Solution for spray sealing coating

Under stirring objavili denatured ethanol (14,09 kg) and the solution was stirred to achieve a homogeneous state.

in the Process of applying a drug coating

Granulator fluidized bed (Gltt, type WSG 30) equipped with 18-inch insert Wurster (bottom spray) were loaded beads size 25 - 30 mesh (600 - 700 µm) (41,74 kg). The beads were heated dry air to a temperature of 50 - 55oC. Scope pseudoviruses air was regulated by opening the output valve in approximately 50% of the maximum at the beginning and increased to 60% at the end of the spraying. After that, the balls moving in the apparatus, sprayed previously prepared solution for spraying Itraconazole. The solution was sprayed with an initial flow rate of about 600 - 700 g/min when the spraying air pressure of about 3.5 kg/cm2(0,343 MPa). After spending about 30% solution for spraying flow rate was increased to 700 - 800 g/min

When the spraying was completed, the coated beads were dried for about 15 minutes additional supply of dry air to a temperature of 50 - 55oC. the coated beads were left to cool in the apparatus by feeding dry air with a temperature of 20 - 25oC for about 10 - 20 minutes. The device is drained and collected covered balls.

g) intermediate millet is AI drying. Coated beads were made in a vacuum drum drier and dried for at least 24 hours, preferably about 36 hours, at a temperature of approximately 80oC under a pressure of about 200 - 300 mbar (20 - 30 kPa). Drum dryer worked with a minimum rotation speed (2 to 3 rpm). Dried coated beads were sieved through a sieve (Sweco S24C: cell width of 1.14 mm sieve).

d) the Process of applying the sealing coating

The dried coated beads were again introduced in the granulator, fluidized bed equipped with insert Wurster, and heated dry air to a temperature of 50 - 55oC. Then, the coated balls moving in the apparatus, sprayed previously prepared solution for spray sealing coating. The solution was sprayed with a flow rate of 400 to 500 g/min when the spraying air pressure of about 2.5 bar (0.25 MPa). When the spraying was completed, the granules were dried an additional supply of dry air to a temperature of 50 - 55oC for 10 minutes. After that covered balls were left to cool in the apparatus when the supply of dry air with a temperature of 20 - 25oC for 5 - 15 minutes. The granules were removed from the apparatus and placed in appropriate containers.

e) Szowaniem standard automatic machine for filling capsules (e.g., model GFK-1500, Hoff Iiger and Karg, Germany). To obtain capsules with good weight distribution of the rate of filling of the capsules was reduced to approximately 75 - 85% of maximum speed. Each capsule was introduced approximately 460 mg of granules, equivalent to about 100 mg of Itraconazole. When using the above process parameters were obtained capsules of hard gelatin containing 100 mg of Itraconazole, which meets all the requirements, in particular technical requirements for dissolution. Carrying out the above procedure and using the solution for spraying saperconazole, you can get capsules of hard gelatin containing 100 mg of saperconazole.

1. The pellet, containing a Central, rounded or spherical core, with a diameter of 25 - 30 mesh covering film of a hydrophilic polymer and an antifungal agent and a polymer sealing cover.

2. The pellet under item 1, containing, in wt.%: 20 - 60 - core material, 25 - 50 - hydrophilic polymer, 10 to 25 - antifungal agent and 2 - 5 - polymer constituting the sealing cover.

3. The pellet under item 2, in which the core material is a sugar ball with a size of 25 - 30 mesh, the hydrophilic polymer is hydroxyprop is where the ratio of the antifungal agent : hydrophilic polymer is from 1 : 1 to 1 : 2 (wt/wt).

5. The pellet under item 2, in which the polymer forming the coating is polyethylene glycol.

6. The pellet under item 2, which contains, wt%: 41 - 42 sugar ball, 32 - 33 - hydroxypropylmethylcellulose with a dynamic viscosity 2910 5 MPa, 21 - 22 - Itraconazole or saperconazole and 3 - 4-polyethylene glycol 20000.

7. Pharmaceutical composition comprising effective antifungal action the number of granules according to any one of paragraphs.1 - 6.

8. The composition according to p. 7, which is a capsule of hard gelatin, which contains the antifungal agent Itraconazole or saperconazole, in the form of granules according to any one of paragraphs.1 - 6.

9. A method of producing granules described in any of paragraphs.1 to 6, comprising the coating of cores size 25 - 30 mesh by spraying a solution of an antifungal agent and a hydrophilic polymer in an organic solvent, which contains methylene chloride and ethanol, the pellet fluidized bed equipped with insert Buster (bottom spray); drying the obtained coated cores in a vacuum dryer drum; applying to the dried kernel of the sealing coating by spraying the polymer solution, forming a sealing coating, organicheskaja insertion of Vastera (bottom spray).

 

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