MXPA00006188A - Orally administrable solid ribavirin dosage forms and process for making them - Google Patents

Abstract

An orally administrable solid dosage form containing a compacted ribavirin composition having an advantageously high tap density of at least 0.6 g/mL as well as surprisingly rapid disintegration and dissolution rates and wherein the ribavirin is substantially free of polymorphic forms of ribavirin and a process for making such solid dosage forms are disclosed.

Description

DOSAGE FORMS SOLIDAS OF RIBAVIRINA ORALMENTE ADMINISTRABLES AND PROCEDURE TO MAKE THE SAME BACKGROUND OF THE INVENTION This invention relates to an orally administrable solid dosage form comprising a compacted ribavirin composition and a process for making said solid dosage forms. The compacted ribavirin composition of this invention conveniently has a high whipped density as well as surprisingly fast disintegration and dissolution rates and contains a free flowing ribavirin of uniform physical characteristics that is substantially free of other polymorphic forms. Ribavirin is an antiviral agent that is currently administered in association with interferon alfa-2b to treat patients with chronic hepatitis C infections. Ribavirin 200 mg capsules are manufactured and marketed by ICN Pharmaceuticals in Canada under the trade designation Virazole ™ capsules . The ribavirin used to make the ribavirin composition in the Virazole capsules is a powder that does not flow freely with low and variable shaking densities in the range of 0.320 to 0.449 g / mL. A ribavirin composition with a batter density of at least 0.6 g / mL is required for the uniform filling of the 200 mg capsules. It would be convenient if the ribavirin composition had a uniformly high batter density of at least 0.6 g / mL to fill any capsule and to avoid excessive weight variation and excessive packing in the capsule shell during the filling operation, especially in the high-speed capsule filling equipment that operates at a filling speed of more than 20,000 capsules per hour. The dry compaction of the ribavirin formulation would be an attractive solution to this problem insofar as the heat produced during the compaction operation does not cause the formation of polymorphic forms of ribavirin, whose forms are unacceptable to obtain the health record. The Virazole capsules exhibited inconsistency to meet dissolution specifications that require that 80% of ribavirin dissolve in water in 30 minutes. The disintegration times of the Virazole composition were typically about 20 minutes. There is a need to obtain a ribavirin composition with a batter density of at least 0.6 g / mL and with improved dissolution rates and reduced disintegration times. There is also a need to compact the ribavirin composition to achieve such high beaten densities, while maintaining the ribavirin in the physical state substantially free of polymorphic forms.

BRIEF DESCRIPTION OF THE INVENTION The invention provides an orally administrable solid dosage form comprising a compacted rapidly dissolving ribavirin composition and a pharmaceutically acceptable disintegrant wherein said composition, after dry compaction has a batter density of at least 0.6 g / mL and where more 80% by weight of ribavirin dissolves in water in about 30 minutes. The invention also provides a rapidly dissolving compacted ribavirin composition comprising: a) an antivirally effective amount of ribavirin; b) an effective amount of at least one filling agent selected from the group consisting of anhydrous lactose, lactose monohydrate, sucrose, mannitol, microcrystalline cellulose, pregelatinized starches, calcium dihydrate dibasic dihydrate, calcium sulfate dihydrate and calcium sulfate trihydrate . c) an effective amount of a pharmaceutically acceptable disintegrant selected from the group consisting of croscarmellose sodium, sodium starch glycolate, corn starch, pregelatinized starches, sodium carboxymethylcellulose, potato starch, microcrystalline cellulose, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, aluminum magnesium silicate, Bentonite, alginic acid and alginates; and d) an effective amount of a lubricant selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, talc, propylene glycol, PEG 4000, PEG 5000, PEG 6000 and stearic acid; and wherein the batched density of the compacted composition is at least about 0.6 g / mL. In a preferred embodiment, the invention further provides an easily dissolvable compacted ribavirin composition comprising: Ingredient mq Ribavirin USP 150.0 to 250.0 Lactose monohydrate NF 30.0 to 50.0 Microcrystalline cellulose NF 37.5 to 62.5 Croscarmellose sodium NF 4.5 to 7.5 Magnesium stearate NF 2.25 to 5.0 and wherein the whipped density of the compacted composition is at least 0.6 g / mL. In a preferred embodiment, the invention provides a rapidly dissolving compacted ribavirin composition comprising: Ingredient mq Ribavirin USP 200.0 Lactose monohydrate NF 40.0 Microcrystalline cellulose NF 50.0 Croscarmellose sodium NF 6.0 Magnesium stearate NF 4.0 where the blended density of the compacted composition is at least 0.6 g / mL; and wherein ribavirin is substantially free of polymorphic forms of ribavirin. In another aspect, this invention provides a method for producing a rapidly dissolving compacted ribavirin composition comprising the steps of: a) mixing an antivirally effective amount of ribavirin, an effective amount of a pharmaceutically acceptable disintegrant, and an effective amount of at least one filling agent for a sufficient time to form a homogeneous mixture; b) compacting the homogeneous mixture from step a) to a compression force in the range of about 50 to about 75 kN for a sufficient time to produce an acceptable compact mass where ribavirin is substantially free of polymorphic forms; and c) mixing the acceptable compact mass of step b) with an effective amount of a lubricant for a sufficient time to produce a compactly dissolving ribavirin composition.

DETAILED DESCRIPTION OF THE INVENTION It has been surprisingly discovered that a uniform ribavirin composition can be consistently manufactured that consistently satisfies and exceeds dissolution specifications which requires that 80% of ribavirin dissolve in water in 30 minutes; about 90% of the ribavirin in the compacted ribavirin compositions of this invention dissolves consistently in water in 15 minutes and approximately 100% of the ribavirin in the compositions of this invention dissolves in 30 minutes. The disintegration time of the ribavirin compositions of this invention was reduced to less than 10 minutes compared to the composition of the Virazole capsule that disintegrated in 20 minutes (see Table 1). The ribavirin composition of this invention was combined and passed through a roller compactor at a compression force in the range of about 50 to 75 kiloNe tons (kN) for a sufficient time to produce an acceptable compact. "Acceptable compact", as used in the present invention means a compact which is in the form of a ribbon that is homogeneous, and almost completely free, ie more than 95% free, laminating and flaking, and substantially free of Polymorphic forms of ribavirin. A compression force in the range of 50 to about 75 kN consistently produced an acceptable compact. Typically suitable screw speeds and (in the compacted./ Fitzpatrick roller) roller speeds include (1) a screw speed of 40 revolutions per minute (RPM) with a roller speed of 10 RPM; (2) a screw speed of 30 RPM with a roller speed of 7 RPM; and (3) a screw speed of 22 RPM with a roller speed of 5 RPM. It was not possible to deduce a defined scale of the roller speeds and screw speeds of these results. However, it has been found that an acceptable compact is consistently obtained by maintaining the compression force on the scale of about 50 to about 75 kN. The compacted material is milled, combined with a lubricant and the whipped density obtained from the resulting ribavirin composition is at least 0.6 g / mL and preferably is significantly higher, for example, on the scale of about 0.75 to about 0.85 g / mL. The compacted ribavirin compositions of this invention surprisingly have substantially uniform physical and chemical characteristics and the ribavirin in the compacted ribavirin composition is substantially free of polymorphic forms of ribavirin, i.e., there are no signs of polymorphic change in the compacted ribavirin, as determined by differential scanning calorimetry. This result is particularly surprising in view of the large amount of heat generated during the compaction step that could normally produce polymorphic shapes. The rapidly dissolving ribavirin compositions of this invention are stable and have been subjected to three freeze-thaw cycles without any adverse impact on physical appearance, whipped density, dissolution and rate of disintegration. Typically, suitable disintegrants include pharmaceutically acceptable disintegrants that are chemically and physically compatible with ribavirin; preferably those disintegrants are selected from the group consisting of croscarmellose sodium, sodium starch glycolate, corn starch, pregelatinized starches, sodium carboxymethylcellulose, potato starch, microcrystalline cellulose, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, aluminum magnesium silicate, bentonite, alginic acid and alginates . The effective amount of a useful disintegrant in the ribavirin compositions of this invention is in the range of about 1.0 to about 3.0 weight percent, preferably 1.5 to about 2.05 weight percent, and more preferably about 2.0 percent by weight of the ribavirin compositions of this invention. Preferred disintegrants are croscarmellose sodium and polyvinylpyrrolidone or mixture thereof. The most preferred disintegrant is croscarmellose sodium. Typically suitable lubricants include any pharmaceutically acceptable solid or liquid lubricants which are used to increase the flow and prevent sticking of the ribavirin composition after compaction and which are chemically and physically compatible with ribavirin. Typically suitable lubricants include magnesium stearate, calcium stearate, zinc stearate, talc, propylene glycol, PEG 4000, PEG 5000, PEG 6000 and stearic acid. The effective amount of a lubricant useful in the ribavirin compositions of this invention is in the range of from about 0.75 to about 2.0 weight percent, preferably from about 1.0 to about 1.7 weight percent, and more preferably 1.3 percent. by weight of the ribavirin compositions of the invention. The preferred lubricant is magnesium stearate. Typically suitable fillers include any pharmaceutically acceptable filler that gives the ribavirin powder composition and that is physically and chemically compatible with ribavirin; preferably those fillers are selected from the group consisting of anhydrous lactose, lactose monohydrate, sucrose, mannitol, microcrystalline cellulose, pregelatinized starches, dibasic calcium phosphate dihydrate, calcium sulfate trihydrate and calcium sulfate dihydrate. Typically, two fillers are used in the ribavirin compositions of this invention. The effective amount of fillers useful in the ribavirin compositions of this invention is in the range of from about 20 to about 40 weight percent, preferably from about 25 to about 35 weight percent, and more preferably about 30 weight percent of the ribavirin compositions of this invention. One of the preferred fillers is lactose monohydrate which is typically present in the range of from about 10 to about 15 weight percent, more preferably from about 13 to about 14 weight percent of the ribavirin compositions of this invention. The other preferred filler is microcrystalline cellulose which is typically present in the range of from about 10 to about 20 weight percent, more preferably from about 12 to about 18 weight percent, and more preferably from about 16 to about 17 weight percent of the ribavirin compositions of this invention. The term "whipped density" as used herein means the measured mass of a powder obtained in a boundary volume measured in a cylinder after being "whipped", typically a mechanical device; typically whipped density is recorded as a mass in grams divided by volume in milliliters (mL). The whipped density is measured according to the procedure described in USP No. 23, NF 18, supplement 6 (1997), procedure < 616 > page 3768. The orally administrable ribavirin composition density of this invention is at least 0.6 g / mL, which is convenient when using a capsule containing 200 mg of ribavirin in the preferred composition of 300 mg of this invention. Typically, the batched densities of orally administrable ribavirin are on the scale of about 0.75 g / mL to about 0.85 g / mL. While the rapidly dissolving ribavirin compositions of this invention are described for ribavirin resistances of 200 mg in the form of capsules or tablets, other resistances for example 300 or 400 mg of ribavirin can be used wut departing from the scope of the present invention. invention.

Ribavirin (1600-1200 mg in single or divided daily doses, such as 600 mg four times a day, or 600 mg twice a day or 400 mg three times a day) is used in clinical trials in combination with subcutaneous injections of interferon alfa-2b (3 million international units, three times a week to treat patients with chronic hepatitis C. Thus, the term antivirally effective amount of ribavirin, as used in the present invention, means dose of ribavirin, for example 200 mg, 300 mg or 400 mg, as tablets or capsules, which provide 600-1200 mg / day, preferably 800-1200 mg / day or 1000-1200 mg / day of ribavirin used to treat patients with chronic hepatitis C in combination with interferon alfa-2b The ribavirin combinations of this invention can be filled into capsules or compressed into tablets.

Manufacturing procedure General manufacturing procedure (1) Load the ribavirin, one or more filling and disintegrating agents into a suitable double cone mixer. (2) Mix the charge of step (1) for a sufficient time to form a uniform mixture. (3) Optionally pass the combination of step (2) - if said mixture contained lumps - through a suitable milling equipment at medium speed to provide a lump-free mixture. (4) Pass the ground uniform mixture from step 2 or 3 through a suitable roller / compactor equipped with an oscillator for sieving, which is operated at a compression force of about 50 to about 70 kN, for a sufficient time for produce an acceptable compact; (5) combining the compacted sifted mixture from step (4) and loading said mixture to the mixer used in step (1). (6) Charge the lubricant to the combination of step (5) and combine the mixture for a sufficient time to produce a uniform mixture; (7) Fill the uniform mixture of step (6) into capsules. A large-scale batch of the capsule formulation was prepared using the formulations of Example 1 or 2.

Procedure 1.- Load ribavirin, microcrystalline cellulose, lactose monohydrate, and croscamellose sodium into a suitable double cone mixer of appropriate volume. 2. Combine the charge of step (1) for 10 to 15 minutes, preferably approximately 15 minutes. Download the mixture thus formed in plastic lined containers. a 3.- Optionally pass the combined mixture in step (2) through a suitable grinder at medium speed, impact hammers adapted forward with a sieve mesh No. 6. (This step is optional and can be eliminated if the combined mixture of step (2) is free of lumps). 4. Pass the combined mixture from step 2 or 3 through a suitable roller / compactor, such as a Bepex or Fitzpatrick compactor / roller equipped with oscillator for sieving. Operate the roller compactor at a compression force of about 50 to about 75 kN, for a sufficient time to produce an acceptable compact. (An acceptable compact is normally produced with a single pass of the milled combination of step (3) through the compactor.The compacted material is then fed directly into the oscillating mill with a sieve mesh No. 16). 5.- Combine the sifted, compacted mixture from step 4 and load the combination to the mixer used in step 1. Make the mixture for 10 minutes. Extract samples from the combination for test density and shake test. 6.- Charge the magnesium stearate to the combination in step 5 and combine for approximately 3 minutes or for a sufficient time to produce a uniform mixture. 7.- Fill with the uniform mixture, step 6, two-piece opaque white hard gelatin capsules No.1, using a suitable equipment for filling high-speed capsules, such as a Zanasi AZ40 or H &K 1500. 8. Polishing and dusting the filled capsules using a capsule polishing machine with a rotating brush, for example, Key Turbo-Kleen CP-300 equipped with an empty capsule remover.

Note a Analyze the combined mixture of step (2) for uniformity of the combination. Based on the analysis, it was determined that a mixing time of 10 to 15 minutes was sufficient to produce an acceptable uniformity of the combination. Ribavirin is mutagenic and teratogenic and appropriate precautions must be taken to ensure the safety of manufacturing personnel. The following examples illustrate, without limitation, the present invention: EXAMPLE 1 The manufacturing process described above may be used to combine, compact and grind the following compositions: Ingredient mq Ribavirin USP 150.0 to 250.0 Lactose monohydrate NF 30.0 to 50.0 Microcrystalline cellulose NF 37.5 to 62.5 Croscarmellose sodium NF 4.5 to 7.5 Magnesium stearate NF 2.25 to 5.0 The preceding compositions have a whipped density of at least 0.6 g / mL.

EXAMPLE 2 The procedure of Example 1 was followed to prepare the following composition: Ingredient ma Ribavirin USP 200.0 Lactose monohydrate NF1 40.0 Microcrystalline cellulose NF 50.0 Croscarmellose sodium NF 6.0 Magnesium stearate NF 4O Total 300 The whipped density was 0.77 g / mL. (1) Preferably, lactose monohydrate NF is spray dried. The composition was filled into capsules and the following dissolution results were recorded:% by weight of% by weight of Ribavirin Ribavirin dissolved Time (minutes) Average Scale 15 99 (93-103) 30 101 (98-103) 45 101 (98-104) 60 102 (99-104) 12 capsules of the formulation of Example 2 were tested, using a USP basket at 100 RPM in 900 mL of distilled water, operated according to the procedure described in USP No. 23, NF-18, procedure < 71 1 > . The formulation of Example 2 exhibited no signs of polymorphic changes in ribavirin, as determined by differential scanning calorimetry. USP No. 23, NF-18, supplement 6, procedure < 891 > , 1997. The disintegration time for the formulation of Example 2 was measured as described in Table 1; the capsules disintegrated in 7-9 minutes. The effect of the freeze-thaw cycle was determined for the formulation of Example 2 in capsules. The capsules were subjected to three freeze-thaw cycles. The first two freeze and thaw cycles lasted 24 hours. The last freeze-thaw cycle was 72 hours followed by 24 hours at room temperature, that is, at room temperature. Studies of physical observation, disintegration and dissolution were developed. There were no significant changes in physical appearance, disintegration time or dissolution rate, compared to the results of the initial tests. % by weight of Ribavirin% by weight of dissolved dissolved Ribavirin Time (minutes) Average for one capsule Scale 15 93 (84-100) 30 96 (89-100) 45 96 (86-101) 60 96 (86-101) Essentially, no changes were observed in the whipped density, dissolution rate or disintegration of the ribavirin composition of Example 2.

EXAMPLE 3 The following composition represents the composition of a typical 200 mg Virazole capsule (non-compacted): Ingredient mg Ribavirin USP 200.0 Lactose monohydrate NF, spray-dried 46.0 Microcrystalline cellulose NF 50.0 Magnesium stearate NF 0 Capsule filling weight 300.0 Capsule size No. 1 Capsule type Opaque white TABLE 1 Dissolution and comparative disintegration results for the rapidly dissolving Ribavirin composition of examples 2 and 3 A. Dissolution Weight% Ribavirin Dissolved Time Ribavirin compacted1 Virazole Composition2 91 84 30 98 96 45 99 60 99 B. Disintegration " Product Disintegration Time (minutes) Compacted ribavirin composition of example 2 of this invention 6-8 Virazole composition of example 3 -20 1. 12 capsules of Example 2 were tested, using a USP basket at 100 RPM in 900 mL of distilled water operated according to the procedure described in USP No. 23, NF-18, procedure <; 71 1 > , 1995. 2. The non-compacted Virazole composition of Example 3 was used. 3. 6 capsules were tested in a USP apparatus operated according to the procedure described in USP 23, NF 18, procedure < 701 > , 1995. Other modifications can be made to this invention without departing from the scope of the present invention. For example, the formulations of Examples 1 or 2 can be modified by substituting a portion of the croscarmellose sodium with polyvinylpyrrolidone and the composition thus formed can be compressed into tablets.

Claims (20)

NOVELTY OF THE INVENTION CLAIMS

1. An orally administrable solid dosage form comprising a rapidly dissolving ribavirin compacted composition comprising ribavirin and a pharmaceutically acceptable disintegrant, wherein said composition has a batter density of at least 0.6 g / mL and where more than about 80 % by weight of ribavirin dissolves in water, in about 30 minutes.

2. A rapidly dissolving compacted ribavirin composition comprising: a) an antivirally effective amount of ribavirin; b) an effective amount of at least one filling agent selected from the group consisting of anhydrous lactose, lactose monohydrate, sucrose, mannitol, microcrystalline cellulose, pregelatinized starches, calcium dihydrate dibasic dihydrate, calcium sulfate dihydrate and calcium sulfate trihydrate; c) an effective amount of a pharmaceutically acceptable disintegrant selected from the group consisting of croscarmellose sodium, sodium starch glycolate, corn starch, pregelatinized starches, sodium carboxymethylcellulose, potato starch, microcrystalline cellulose, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, magnesium aluminosilicate, Bentonite, alginic acid and alginates; and d) an effective amount of a lubricant selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, talc, propylene glycol, PEG 4000, PEG 5000, PEG 6000 and stearic acid; and wherein the batched density of the compacted composition is at least about 0.6 g / mL.

3. The orally administrable solid dosage form according to claim 1, further characterized in that the composition comprises approximately 200 to 400 mg of ribavirin.

4. A rapidly dissolving compacted ribavirin composition comprising Ingredient mg Ribavirin USP 150.0 to 250.0 Lactose monohydrate NF 30.0 to 50.0 Microcrystalline cellulose NF 37.5 to 62.5 Croscarmellose sodium NF 4.5 to 7.5 Magnesium stearate NF 2.25 to 5.0 and where the Whipped density of the compacted composition is at least 0.6 g / mL.

5. The orally administrable solid dosage form according to any of the preceding claims, further characterized in that the disintegrant is croscarmellose sodium or polyvinylpyrrolidone or mixture thereof.

6. The compacted ribavirin composition that dissolves rapidly according to any of the preceding claims, further characterized in that ribavlinine is substantially free of polymorphic forms of ribavirin.

7. The compacted rapidly dissolving ribavirin composition according to claim 4, further characterized in that more than 80% by weight of the ribavirin is dissolved in water in about 30 minutes.

8. The rapidly dissolving compacted ribavirin composition according to claim 4, further characterized in that the disintegration time of the composition is less than about 10 minutes.

9. The rapidly dissolving compacted ribavirin composition according to claim 4, further characterized in that the whipped density of the composition is in the range of about 0.75 g / mL to about 0.85 g / mL.

10. The compacted ribavirin composition which dissolves rapidly according to any of the preceding claims, in the form of a tablet or capsule.

11. A method for producing a rapidly dissolving compacted ribavirin composition comprising the steps of: a) mixing an antivirally effective amount of ribavirin, an effective amount of a pharmaceutically acceptable disintegrant and an effective amount of at least one agent of filling for a sufficient time to form a homogeneous mixture; b) compacting the homogeneous mixture from step a) to a compression force in the range of about 50 to about 75 kN for a sufficient time to produce an acceptable compact mass where ribavirin is substantially free of polymorphic forms; and c) mixing the acceptable compact mass of step b) with an effective amount of a lubricant for a sufficient time to produce a uniform composition of compacted ribavirin that dissolves easily.

12. The method according to claim 11, further characterized in that the fast-dissolving compacted ribavirin has a batter density of at least 0.60 g / mL and preferably the compacted rapidly dissolving ribavirin has a whipped density in the scale around from 0.75 g / mL to approximately 0.85 g / mL.

13. The method according to claim 1, further characterized in that more than 80% of the fast-dissolving compacted ribavirin composition dissolves in water in about 30 minutes, and preferably more than about 90% of the composition. Rapidly dissolving compacted ribavirin dissolves in water in about 15 minutes.

14. The method according to claim 1, further characterized in that at least one filling agent is selected from the group consisting of lactose anhydrous, lactose monohydrate, sucrose, mannitol, microcrystalline cellulose, pregelatinized starches, calcium phosphate dihydrate dibasic, calcium sulfate dihydrate and calcium sulfate trihydrate.

15. The method according to claim 11, further characterized in that the disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, corn starch, pregelatinized starches, sodium carboxymethylcellulose, potato starch, microcrystalline cellulose, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, magnesium aluminum silicate, bentonite, alginic acid and alginates.

16. The method according to claim 1, further characterized in that the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, talc, propylene glycol, PEG 4000, PEG 5000, PEG 6000 and stearic acid .

17. A rapidly dissolving compacted ribavirin composition comprising: Ingredient mg Ribavirin USP 200.0 Lactose monohydrate NF 40.0 Microcrystalline cellulose NF 50.0 Croscarmellose sodium NF 6.0 Magnesium stearate NF 4.0 where the whipped density of the compacted composition is at least 0.6 g / mL; and wherein ribavirin is substantially free of polymorphic forms of ribavirin; and wherein more than 80% by weight of the compacted composition dissolves in water in about 30 minutes.

18. The rapid dissolving compacted ribavirin composition according to claim 17, further characterized in that said composition is in the form of a capsule.

19. The rapid dissolving compacted ribavirin composition according to claim 17, further characterized in that more than 90% by weight of the compacted composition dissolves in water in about 15 minutes.

20. The rapid dissolving compacted ribavirin composition according to claim 17, further characterized in that the whipped density of the compacted composition is in the range of about 0.75 g / mL to about 0.85 g / mL.