Oral pharmaceutical composition based on compounds having antifungal activity, and how you can get

 

(57) Abstract:

The pharmaceutical composition is in the form of granules and includes as the active ingredient antifungal compound - Itraconazole or saperconazole. Granules are inert core size of 50 to 600 μm and the coating. The coating includes a single layer obtained by sputtering on the specified inert core solution, including Itraconazole or saperconazole, hydrophilic polymer and nonionic surfactant. The coating is carried out at a constant speed during the entire process. The said coating is subjected to a single stage drying at 45oC. the coating and drying are carried out in the same apparatus, which can be an advantage in cost, time of the process and improves the chemical and physical integrity of the granules. The pharmaceutical composition provides improved solubility of these antifungal compounds and their enhanced bioavailability. 2 s and 5 C.p. f-crystals.

The scope of the invention

The present invention relates to oral pharmaceutical compositions comprising a compound with antifungal activity, which solves the problems of low biodecomposition also relates to a method for obtaining this oral pharmaceutical composition, which has the advantage over conventional methods.

Background of the invention

The solubility problems associated with the chemical structure of azoles such as Itraconazole and saperconazole, compounds described in U.S. patents 4267179 and 4916134, trying to solve preparation of various pharmaceutical forms on the basis of different methods of administration.

It is known that the solubility of the compounds can be increased, if it is added to the hydrophilic polymer and apply the mixture to the inert core. This is a ready-made form of a composition which improves the bioavailability of the compounds.

In the patent EP 658103 (published in Spain as ES 2097536 T3) granules of Itraconazole and saperconazole prepared on the basis of this technology. The patent describes the preparation of a solution antifungal compounds and hydrophilic polymer hydroxypropylmethylcellulose (receiver array) in ethanol and methylene chloride, which is sprayed into the fluidized bed on the inert core having a size of 600 to 700 μm. After the sputtering process ends, the granules are dried in the same device for 10 min at 50-55oWith, and then they must be entered in a vacuum dryer for approximately 36 is passed for the formation of another layer with a solution of polyethylene glycol 20000 (PEG 20000). At the end of the process, the granules are dried in the unit for 10 min at 50-55oWith and then serves them dry air at 20-25oC for 5-15 minutes When the drying process is complete, the pellets are stored in appropriate containers.

In EP 658103 says that the second coating layer of PEG 20000, which is the insulating layer is applied to protect the grains from sticking together, and it is necessary that the inert cores have a size of between 600 and 700 microns in order to avoid problems of drying and aggregate grains. According to EP 658103, inert core, which has a larger size, have a lower specific surface area, therefore it is necessary that the layers of the coating was very thick and therefore difficult because of their drying, while, if the size of the inert core is too small, the result is a thin layer of coating, which is easily dried, but is subject to the phenomenon of agglomeration during the stage of coating.

Description of the invention

The present invention provides oral ready-made form of pharmaceutical compositions and method of production, which allows to solve problems of solubility, drying and bioavailability of pills or pellets antifungal compounds.

New form of composition, t is affected inert core, covered with a single layer of active ingredient, including antifungal compound. The coating on the inert core is performed by spraying the solution antifungal compounds.

Oral pharmaceutical composition of the present invention includes:

a) an inert core

b) soluble active layer, obtained from a solution, including:

active ingredient having antifungal activity;

- hydrophilic polymer;

- non-ionic surfactant.

Active ingredients that have antifungal activity covered by the scope of the present invention are Itraconazole, ()-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, and saperconazole, ()-CIS-4-[4-[4-[4-[2-(2,4-differenl)-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.

The inert cores are neutral spherical granules, which may contain one or more of the following ingredients: sorbitol, mannitol, sucrose, starch, microcrystalline cellulose.

In the present invention the solution is sprayed onto the inert cores, formed the active ingredient, having antifungal activity, dissolved in a mixture of organic solvents formed by ethanol and methylene chloride, which is dissolved hydrophilic polymer, and a surface-active substance.

The hydrophilic polymer may be a receiver array, hydroxypropylcellulose (LDCs), polyvinylpyrrolidone (PVP), methacrylates, etc., the Mass ratio of anti-fungal ingredient and the polymer (m/m) is in the range 1:1-1:3.

Non-ionic surface-active agent may be esters of propylene glycol, esters of glycerol, mono-, di-, tri-)acetylated, sorbitan, (mono-, di-, tri-)acetylated sucrose esters of fatty acids and polyoxyethylenesorbitan, polyoxyethylene alkalemia esters with fatty chain, copolymers of polyoxyethylene-polyoxy-propylene, etc., the Mass ratio of the antifungal agent and the surfactant is in the range of 1.5:1-29:1.

Another object of the present invention is a method for galenical finished drug forms of the invention.

The method described below, where special attention is paid to kolichestvo suitable size stainless steel. Add antifungal compound (2.8 to 5.0 wt.%), the hydrophilic polymer (a 3.5-6.3 wt.%) and surfactant (0.2 to 2.0 wt.%).

After this, the solution for coating sprayed into the fluidized bed at a neutral granules having a size of 50 to 600 μm, preferably 500-600 μm to obtain a single layer. Throughout the process, the spraying speed is constant, and the temperature is maintained at 45oC.

When the stage of coating the ends of the pellets is kept in the device for 15 min at 45oSince that is the last stage of drying.

This technology allows you to work with the inert nuclei size of 50 to 600 μm, which is smaller than the dimensions specified in EP 658103, and favors the coating process due to the increased surface area; surprisingly this size is not a problem of agglomeration and there is no need for additional sealing layer or an insulating coating of PEG 20000 as the inclusion of non-ionic surfactant to prevent agglomeration of the particles.

In the case of the present invention, the cost of the process is reduced by reducing the time and used equipment is the risk of failure to comply with Proper Manufacturing standards.

The present invention uses a fluidized bed, in which the coating process. There is no need to use another device for drying granules coated on the contrary, it is sufficient short stage of drying (15 minutes at 45o(C) carried out in the same device after completion of the coating of a single layer. Thus, not only reduces the process time compared to the patent EP 658103 because of pills or pellets, there is no need to place in a vacuum dryer; but at the same time is excluded stage of their exposure to extreme temperatures of the order of 80oWith over 36 PM

Temperature, which are the core during the process of spraying, 45oWith that lower the working temperature in the patent EP 658103, and it is also a positive factor for the regulation of the chemical stability of active and to avoid the disadvantages already discussed in EP 658103 related to the fact that high temperatures can accelerate the drying of the granules with the risk of the formation of inhomogeneous layers and having a high porosity.

Spraying speed during the deposition process recomended to start with a low speed, which gradually increases during the process; even mentions that excessive speed can cause excessive moisture of the granules, leading to agglomeration phenomena. In contrast, if the speed is low, can cause product loss due to drying of the spray. In EP 658103 spraying speed at the beginning of the coating, to obtain the first layer is about 600-700 g/min and increased to 800 g/min after you spent 30% solution for coating. This interval speed higher than used in the present invention. The speed of the coating in the present invention below and is maintained constant throughout the process.

In the present invention, the technology described in EP 658103, improved, since the process is carried out with inert cores smaller than the nuclei, is described in EP 658103 without causing agglomeration of the granules. On the other hand, spraying at a lower speed is achieved without any loss of product, and the final drying of the granules is carried out at lower temperatures and reducing the drying process almost to the time of boot.

The use of a single apparatus, the cat is estvo not only in cost, but also in time of the process, and this, in turn, entails less handling of the final granules and improve their chemical and physical integrity.

Example

In the stainless steel container mix 18,60 kg of methylene chloride and 10.00 kg of ethanol; then enter 0,98 kg Itraconazole, 1,32 kg hydroxypropylmethylcellulose and 0.39 kg poloxamer.

In a fluidized bed type 2 kg of inert cores consisting of sucrose (62,5 is 91.5%) and starch (37,5-8,5%), with the size of 500-600 μm, and cover them with a pre-prepared solution by nebulization rate of 30 g/min and the temperature of the product 45oC. After the stage of coating the ends of the loaded kernel is dried in the same device for 15 min at 45oC.

1. Oral pharmaceutical composition in the form of granules, comprising as active ingredient the compounds having antifungal activity, selected from the Itraconazole and saperconazole, inert core and a coating that includes the specified active ingredient, characterized in that the inert core has a size of 50 to 600 μm, and the said coating includes a single layer obtained by sputtering on the specified inert core of the second surface-active substance.

2. Oral pharmaceutical composition according to p. 1, characterized in that the inert core has a size of 500 to 600 microns.

3. Oral pharmaceutical composition according to p. 1, characterized in that the hydrophilic polymer is selected from the group containing hypromellose (receiver array), hydroxypropylcellulose (LDCs), polyvinylpyrrolidine (PVP) and methacrylates.

4. Oral pharmaceutical composition according to p. 1, characterized in that the nonionic surfactant chosen from esters of propylene glycol, esters of glycerol, mono-, di-, tri-)acetylated sorbitan, (mono-, di-, tri-) acetylated sucrose esters of fatty acids and polyoxyethylenesorbitan, polyoxyethylene alilovic esters with fatty chain and copolymers of polyoxyethylene-polyoxypropylene.

5. Oral pharmaceutical composition according to any one of the preceding paragraphs, wherein the amount of hydrophilic polymer, nonionic surfactant, the active ingredient and the inert core in the final granules, respectively, %: hydrophilic polymer - 25-60, preferably 27-55; non-ionic surfactant - 1-15, CLASS="ptx2">

6. Oral pharmaceutical composition according to any one of the preceding paragraphs, characterized in that the mass ratio of antifungal compounds and hydrophilic polymer is(1:1)-(1:3) and antifungal compounds and surfactants to 1.5:1-29:1.

7. The method of obtaining oral pharmaceutical composition according to any one of the preceding paragraphs, characterized in that carry out the following stages: a) a coating comprising a single layer on an inert core having a size of 50 to 600 μm, using spray solution consisting of antifungal agent, a hydrophilic polymer and non-ionic surfactant, at a constant speed coating throughout the entire process and (b) a single stage drying of the specified coating at 45oWith the same device.

 

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