Background of the Invention Ribavirin, its chemical name being 1-beta-D-ribofuranosyl-1, 2,4-triazole-3-carboxamide, is a substance having antiviral effects. It is a nucleoside analogue of formula I demonstrating, both in vitro and in vivo, an activity against certain DNA and RNA viruses. The dosage forms of the antiviral agent-ribavirin-used simultaneously with a2b interferon or a2b peg- interferon are used particularly for combined treatment of chronic hepatitis C.

Various ribavirin dosage forms, having the form of topic preparations (gel, cream), parenteral preparations (liquid injections), oral solid and liquid dosage forms, and dosage forms intended for inhaling, have been described in literature. Ribavirin filled into capsules or tablets represents the dosage form particularly suitable for oral application. Virazole capsules and Rebetol capsules manufactured by the companies ICN and Schering-Plough, respectively, are particularly used in the current clinical practice.

Ribavirin-the medicinal substance, both unprocessed and processed by milling and/or sieving to obtain the particle size suitable for pharmaceutical use-has a low tap density and a bad bulk density; this makes the preparation of the dosage form, particularly mixing of the active substance with suitable pharmaceutically acceptable excipients, and also particularly reproducible and sufficiently quick release of the active substance from the dosage form after being administered to the patient, rather complicated. Due to unsuitable physical characteristics of ribavirin, the capsule filled with Virazole""preparation contains a badly flowing powder having a low and fluctuating tap density ranging between 0.320 and 0.449 g. cm~3. Such fluctuation frequently results in a significant variability of capsule weights during filling, particularly when high-duty encapsulation machines are used. In addition, Virazole capsules have other deficiencies, namely, an unsuitable disintegration time of the said dosage form and an unsuitable release rate of the active substance during the dissolution test. The deficiencies mentioned above are partially solved in Rebetole preparation, the capsules of which, containing a high portion of the active component in the composition, are prepared using the dry granulation method according to WO 9932128. The substance of the solution of the problem consists in homogenization of an effective ribavirin quantity with an effective quantity of a pharmaceutically acceptable releasing agent and with at least one pharmaceutically acceptable filler. The homogeneous mixture is compacted using a compression force ranging between 50 and 75 kN for the time sufficient for manufacturing of appropriate compacts (aggregates). These compacts are then crushed by milling or sieving and then mixed with a slipping substance and filled into capsules. This method enables obtaining ribavirin composition having high contents of the active substance, having a high tap density at least 0.6 g. cm~3 and a good dissolution profile. The disadvantage of the said problem solution using dry granulation is a rather complex manufacturing demanding a special processing equipment. Further factors limiting the dry granulation method seem to be the must to ensure a high plastic deformability of the powder mixture and also a heat stress of the mixture mentioned when higher compacting pressures necessary for formation of sufficiently rigid agglomerates are used. A granulate prepared using further milling of compacted agglomerates usually consists of fragments having uneven forms and sharp edges which affect adversely the liquidity of the composition. In addition, the granulate usually contains also a portion of superfine particles, the quantity of which depends on the agglomerate rigidity that affects significantly its bulk characteristics. The granulates manufactured using the dry granulation method also have a decreased porosity due to their compacting. The above mentioned facts result in a longer release time of the active substance from the composition like this. The cohesive properties advantageous for further possible processing into tablets are gradually lost during the processing of the granulate using the dry granulation method when compacting is also performed. The tablets have in this case a reduced cohesion (i. e. low radial strength) and a high abrasion.

These problems are essentially solved by the pharmaceutical composition and the method of manufacturing thereof according to the invention.

Summary of the Invention The invention relates to a pharmaceutical composition containing ribavirin as active substance in the mixture with at least one pharmaceutically acceptable excipient characterized in that it is a freely flowing granulate prepared using the wet granulation of a mixture, wetted with water, of ribavirin and at least one pharmaceutically acceptable filler selected from the group including cellulose and its derivatives and carbonates, phosphates, sulfates and silicates of metals, and optionally at least one pharmaceutically acceptable excipient.

The mixture wetted with water and intended for the wet granulation contains advantageously ribavirin at the amount equal to at least 65 % by weight, and at least one pharmaceutically acceptable filler insoluble in water, at the amount equal to not more than 25 % by weight, related always to the dry-weight basis of the mixture mentioned.

The composition contains advantageously microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate or hydrated forms thereof as the pharmaceutically acceptable fillers insoluble in water. In order to ease granulate formation, its disintegration and ribavirin dissolution from the composition according to the invention, the mixture advantageously contains at least one pharmaceutically acceptable binder and/or releasing agent. Polysaccharides and/or modified polysaccharides can be, for example, used as the releasing agent.

The pharmaceutical composition according to the invention forms the granulate which is filled into capsules, particularly gelatine capsules, or into sacks. The granulate obtained can be also compacted into tablets. The pharmaceutical composition according to the invention forms the granulate having a predominantly regular and rounded shape and having the good liquidity. In order to enhance the liquidity of the granulate mentioned, a pharmaceutically acceptable slipping agent, for example, magnesium stearate, is advantageously added. In order to ensure a good disintegration of the possibly formed agglomerates, a pharmaceutically acceptable external release agent, for example, polysaccharide and/or modified polysaccharide, is added.

The invention relates also to the method of manufacturing of the pharmaceutical composition according to the invention characterized in that the mixture of ribavirin wetted with water, at least one pharmaceutically acceptable filler insoluble in water selected from the group including cellulose and its derivatives and carbonates, phosphates, sulfates and silicates of metals, and at least one pharmaceutically acceptable excipient is granulated under wet conditions to obtain the granulate, then optionally at least one pharmaceutically acceptable external releasing agent and/or at least one pharmaceutically acceptable slipping agent are added to the granulate obtained, and the granulate, or optionally the mixture, obtained are optionally filled into capsules or sacks or compacted into tablets. The manufacturing method described is simple and has no special demands for the processing equipment. The granulate obtained has a high portion of the active substance-ribavirin-and a predominantly rounded shape and its particle size ensures the good liquidity of the composition. The composition according to the invention has also a very good disintegration and a good release of the active substance during the dissolution tests.

The wet granulation method consists in that the liquid phase is added to the dry mixture while being simultaneously agitated in a suitable equipment. The wet granulate prepared using the process mentioned is optionally extruded, dried and then processed into the finished form. The mixture processed using the wet granulation has a significantly better aggregation and thus particularly drugs with high portions of the active substance in the composition obtain during the wet granulation the necessary bulk characteristics that represent one of the necessary conditions for their further processing into the final dosage forms because the formation of fragments of undefined shapes with sharp edges and a portion of superfine particles affecting adversely their uniform filling into capsules or matrixes of a tablet-making machine is thus eliminated. The granulates prepared using the wet granulation retain also their natural porosity, enhancing their plastic deformability, enabling also their good compacting into tablets.

In order to reach the parameters demanded in the wet granulation, pharmaceutically acceptable fillers insoluble in water selected from the group including cellulose and its derivatives and carbonates, phosphates, sulfates and silicates of metals should be used in preparation of ribarivin dosage form in the wet granulation that in combination with a hydrophilic active substance ensures advantageously the instant release of the active substance at the amount equal to not more than 25 % by weight, related to the dry-weight basis of the mixture intended for the granulation. In the dissolution tests according to USP, at least 80 % by weight of the active substance were released within 30 minutes because the fillers mentioned above are not dissolved during the wet granulation and therefore no interactions with hydrophilic active substance occurs. By such unique combination of the hydrophilic active substance and the insoluble filler, a porous granulate, the porosity of which enables a quick penetration of the dissolution medium into the dosage form and thus the activation of the release agent, is formed during the process of the preparation. This results in a surprisingly quick granule disintegration, and thus in an enlargement of the active agent surface and thus in its quicker dissolution in the dissolution medium or in gastric juices. It was additionally found out that when hydrophilic fillers, as lactose, are used, the event mentioned above does not occur and disintegration, or dissolution, of the composition is significantly slower.

The fillers insoluble in water also prevent an excessive wetting of the granulate and thus enable maintaining the standard production even during possible changes of the physical parameters of the active substance.

Examples The examples given below explain in more details the composition and the method of manufacturing of the pharmaceutical composition containing ribavirin as active substance according to the invention, without limiting its scope. Reaching the surprisingly advantageous characteristics of the dosage forms, when the fillers insoluble in water are used in the composition (Examples 1 and 2) in opposition to Example 3 in which lactose was used as the filler soluble in water, is particularly demonstrated.

The weights specified in examples are given in parts by weight.

Example 1 1. Ribavirin, medicinal substance 200. 00 2. Microcrystalline cellulose (Avicel) 59.00 3. Modified starch (Starch 1500) 30.00 4. Sieved cellulose carboxymethyl sodium salt (Ac-Di-Sol) 8.00 5. Magnesium stearate 3. 00 Sieve Ribavirin (1), Avicel (2) and Starch 1500 (3) through a sieve fitted with 0. 8 x 0.8 mm mesh in size, mix the mixture in a high-speed masticator for 1 minute; Add 100 parts by weight of water and mix in the high-speed masticator for 2 minutes; Press the wet mass through the sieve fitted with 2 x 2 mm mesh in size ; Dry the granulate in a fluidization drier at the temperature of 50 °C until the humidity of 1 - 3 % by weight is reached; homogenize the dry granulate using the sieve fitted with 1 x 1 mm mesh in size; Add Ac-Di-Sol (4) and magnesium stearate (5), and mix in the high-speed masticator for 1 minute; Fill the granulate into hard gelatine capsules or compact it into tablets having 10 mm in diameter and the radial strength of 70-120 N.

The granulate amount in the individual dosage form is 300 mg.

Characteristics of Granulate Bulk density (g.cm-3) 0.526 Tap density (g.cm-3) 0.610 Bulking value (g.s-1) 5.9 Example 2 1. Ribavirin, medicinal substance 200.00 2. Calcium hydrogen phosphate, anhydrous (DI-CAFOS) 55.00 3. Modified starch (Starch 1500) 30.00 4. Sieved cellulose carboxymethyl sodium salt (Ac-Di-Sol) 12.00 5. Magnesium stearate 3. 00 Sieve Ribavirin (1), DI-CAFOS (2) a Starch 1500 (3) through a sieve fitted with 0. 8 x 0. 8 mm mesh in size ; Mix the mixture in a high-speed masticator for 1 minute; Add 80 parts by weight of water and mix in the high-speed masticator for 2 minutes; # Press the wet mass through the sieve fitted with 2 x 2 mm mesh in size; Dry the granulate in a fluidization drier at the temperature of 50 °C until the humidity of 1 - 3 % by weight is reached; # Homogenize the dry granulate using the sieve fitted with 1 x 1 mm mesh in size; 'Add Ac-Di-Sol (4) and magnesium stearate (5) and mix in the high-speed masticator for 1 minute; # Fill the granulate into hard gelatine capsules or compact it into tablets having 10 mm in diameter and the radial strength of 70-120 N.

The granulate amount in the individual dosage form, a tablet or a capsule is 300 mg.

Characteristics of Granulate Bulk density @ (g.cm-3) cm'-') 0.590 Tap density (g. cm-3) 0.725 Bulking value (g. s ) 5. 9 Example 3 1. Ribavirin, medicinal substance 200.00 2. Lactose, monohydrate (Pharmatose 200 M) 59.00 3. Modified starch (Starch 1500) 30.00 4. Sieved cellulose carboxymethyl sodium salt (Ac-Di-Sol) 8.00 5. Magnesium stearate 3.00 Sieve Ribavirin (1), lactose (2) and Starch (3) through a sieve fitted with 0.8 x 0.8 mm mesh in size ; Mix the mixture in a high-speed masticator for 1 minute; Add 100 parts by weight of water and mix in the high-speed masticator for 2 minutes; 'Press the wet mass through the sieve fitted with 2 x 2 mm mesh in size; Dry the granulate in a fluidization drier at the temperature of 50 °C until the humidity of 1 - 3 % by weight is reached; 'Homogenize the dry granulate using the sieve fitted with 1x1 mm mesh in size; 'Add Ac-Di-Sol (4) and magnesium stearate (5) and mix in the high-speed masticator for 1 minute; Fill the granulate into hard gelatine capsules or compact it into tablets having 10 mm in diameter and the radial strength of 70-120 N.

The granulate amount in the individual dosage form, a tablet or a capsule is 300 mg.

Characteristics of Granulate Bulk density (g. crri) 0. 586 Tap density (g. cm-3 0. 674 Bulking value (g. s-1) 5.2 The advantageous release of the active substance-ribavirin-from capsules or tablets prepared according to the invention is documented in Tables 1 a 2 and Figures 1 a 2 below.

Table 1: The time course of the active substance-ribavirin-release from hard gelatine capsules prepared according to Examples 1 to 3 in comparison with the preparation Rebetol# (manufactured by Schering-Plough) Conditions of the dissolution test: According to USP, the basket method Medium: Water, 900 ml Speed: 100 rpm Medium temperature: 37 °C Amount of the active substance released is given in % by weight Time (minutes) Rebetol Example 1 Example 2 Example 3 2 5.7 9.5 2.4 2.8 4 39. 6 61. 4 34. 9 9. 6 6 59.9 82.9 61.5 17.6 8 78. 7 91. 6 80. 2 29. 9 10 91.6 93.8 86.8 43 12 97.6 94.6 89.5 51.9 14 98. 8 94.9 91.1 57.6 16 99. 2 95. 2 91. 8 61. 8 18 99. 3 95. 4 92. 3 65 20 99. 5 95. 6 92. 7 67. 8 25 99. 7 95. 7 93. 1 73. 3 30 99.8 95.8 93.5 77.3 35 99.8 96 93.7 80.3 40 99. 8 96 94 82. 8 45 99. 9 96. 1 94. 2 84. 8 50 99. 9 96. 1 94. 3 86. 4 55 99. 9 96. 2 94. 5 87. 8 This dissolution profile is represented graphically in Fig. 1.

Table 2: The time course of the active substance-ribavirin-release from tablets prepared according to Examples 1 to 3 Conditions of the dissolution test: According to USP, the basket method Medium: Water, 900 ml Speed: 100 rpm Medium temperature: 37 °C Amount of the active substance released is given in % by weight Time (minutes) Example 1 Example 2 Example 3 2 17.0 24.1 10. 5 4 30.4 46.9 18.1 6 42.8 68.3 25.5 8 57. 1 84. 4 31. 3 10 69. 0 95. 6 36. 8 12 81.5 99.3 41.7 14 89. 9 99. 3 46. 5 16 95. 6 99. 3 50. 9 18 97. 6 99. 3 55. 3 20 98.3 99.3 59.5 25 98. 4 99. 3 69. 1 30 98.4 99.3 77.5 35 98.4 99.3 85.2 40 98. 4 99. 3 91. 5 45 98. 4 99. 3 96. 5 50 98.4 99.3 99.2 55 98. 4 99. 3 100. 4 60 98.4 99.3 100.9 This dissolution profile is represented graphically in Fig. 2.