WO2010062996A2

WO2010062996A2 - Ribavirin composition

Info

Publication number: WO2010062996A2
Application number: PCT/US2009/065992
Authority: WO
Inventors: Ashok Katdare; Kavita Vermani
Original assignee: Adamas Pharmaceuticals, Inc.
Priority date: 2008-11-28
Filing date: 2009-11-25
Publication date: 2010-06-03
Also published as: WO2010062996A3

Abstract

A pharmaceutically-acceptable ribavirin composition is provided that requires few processing steps and excipients and provides high drug loading in oral dosage forms.

Description

Ribavirin Composition

[001] Background of the Invention

[002] The field of the invention is a method of making a ribavirin composition suitable for oral administration.

[003] Ribavirin has been approved in the United States for the treatment of hepatitis C virus and respiratory syncytial virus. The active pharmaceutical ingredient (API) is a white crystalline powder that is freely soluble in water. When used to make dosage forms for oral administration, such as tablets or capsules, ribavirin is typically processed with excipients to improve flowability and density properties. Examples of such processes include compaction (e.g. see US Pat. No. 6,335,032 to Schering et al.) and wet granulation (e.g. see US Pat. No. 6,720,000, to Kerrish et al, and US Pat Appl No. 2005/0123612 to Sobel et al.). These methods involve multiple processing steps and require the use of several types of excipients.

[004] It is an object of the present invention to provide a simplified method of making a pharmaceutically-acceptable ribavirin composition that requires fewer processing steps and excipients than prior methods, and, consequently, is less expensive to manufacture. Another object of the invention is to provide a ribavirin composition having a high drug loading.

[005] Summary of the Invention

[006] One aspect of the invention is a method of making a ribavirin composition, the method comprising: (a) combining ribavirin with a binder to produce ribavirin granules; and (b) drying the ribavirin granules. In specific embodiments, the binder is selected from hydroxypropylmethyl cellulose and hydroxyethyl cellulose. The dried ribavirin granules may consist essentially of the ribavirin and the binder. Preferably, the dried granules comprise less than 1.5 wt.% binder.

[007] The method may further comprise passing the dried granules through a sieve or blending the ribavirin granules with excipients. Preferably, the excipients comprise less than 40 wt.% or 30 wt.% of the composition.

[008] The granules may be filled into capsules or compressed into tablets. [009] Another aspect of the invention is a ribavirin composition comprising granules consisting essentially of ribavirin and a soluble binder. In various embodiments, the granules are less than 1.2 mm or 0.8 mm. The composition may comprise one or more extragranular ingredients. An extragranular ingredient may include an additional active pharmaceutical ingredient, such as an additional antiviral agent. Typically, the extragranular ingredients comprise less than 40 wt.% or 30 wt.% of the composition. The composition may be filled into a capsule or compressed into tablets.

[010] Detailed Description of Specific Embodiments of the Invention

[011] One aspect of the invention is a method of making a ribavirin composition by combining ribavirin with a binder to make granules. As used herein, the term ribavirin refers to l-(β-D-Ribofuranosyl)-lH-l,2,4-triazole-3-carboxamide and salts and derivatives thereof (e.g. the 3-carboxamidine derivative, viramidine). The binder can be prepared as a solution that is combined with the ribavirin by spraying or pouring over the ribavirin and mixed to form a wet mass. The wet mass is then dried using conventional drying equipment such as a fluidized bed drier, tray drier etc. Alternatively, ribavirin is granulated with a binder solution in a fluidized bed drier where the binder solution is sprayed on ribavirin and the wet mass is dried simultaneously. The binder solution is preferably prepared with a fully-soluble binder. Suitable water- and/or alcohol-soluble binders include hydroxypropylmethyl cellulose, hydroxyethyl cellulose, povidone, gums such as acacia, tragacanth, xanthan gum, gelatin, ethyl cellulose and polymethacrylates. Sufficient amounts of water and/or alcohol are added to the binder to make a sprayable or pourable solution. Alternatively, the binder can be partially soluble or swellable such as starch (starch paste). Typically the amount of water and/or alcohol in the binder solution or paste will be about 10-40 wt.% or 15-35 wt.% of the total wet mass. The binder solution or paste is preferably sprayed or poured directly onto ribavirin while mixing, without additional excipients, to result in granules that consist essentially of the ribavirin and the binder.

[012] The granules are then dried. Optionally, large granules or clumps of granules can be removed by passing the granules through a sieve to obtain a granule size of less than 2.0 mm, and preferably less than 1.5 mm, 1.2 mm, 1.0 mm, 0.8 mm, or 0.6 mm. [013] After the drying and optional sieving steps, the ribavirin granules may be filled directly into capsules or compressed into tablets. Alternatively, the granules are blended with extragranular ingredients that improve the ability of the composition to be filled into capsules or compressed into tablets, or contribute to or impart other desired properties such as dissolution properties, stability, taste, etc. Exemplary ingredients include soluble fillers (e.g. lactose, mannitol), insoluble fillers (e.g. calcium phosphate or dicalcium phosphate, microcrystalline cellulose typically in amounts of about 10-20% by weight of the total composition), polymers (e.g. hydroxypropyl cellulose, hydroxypropylmethyl cellulose, povidone, ethyl cellulose, Eudragit™, etc ), lubricants (e.g. talc, magnesium Stearate, sodium stearyl fumarate etc.), glidants (e.g. colloidal silicon dioxide), etc. Typically, the extragranular ingredients comprise less than 40 wt.%, and preferably less than 35 wt.%, 30 wt.%, or 25 wt.% of the total mass of the composition. In some embodiments, an extragranular ingredient may be one or more additional active pharmaceutical agent, such as an additional antiviral agent.

[014] Another aspect of the invention is a ribavirin composition comprising granules consisting essentially of ribavirin and a binder. The granules preferably comprise less than 2.0 wt.%, 1.5 wt.%, or 1.0 wt.% binder. In specific embodiments, the amount of binder in the granule is about 0.2 to about 2.0 wt.%, and preferably about 0.5 to about 1.0 wt.% . Preferably, substantially all the granules have a size less than 2.0 mm, 1.5 mm, 1.0 mm, 0.8 mm, or 0.6 mm.

[015] The composition may additionally comprise one or more extragranular ingredients. Preferably, the extragranular ingredients comprise less than 40 wt.% of the composition, and more preferably, less than 35 wt.% , 30 wt.%, or 25 wt.% of the composition. In preferred embodiments, the drug composition comprises at least 70 wt.%, 75 wt.% or 80 wt.% ribavirin.

[016] In a specific embodiment, the composition has an in vitro dissolution profile for ribavirin of less than 80% in thirty minutes and more than 90% in sixty minutes as measured using a USP type 2 (paddle) apparatus at 50 rpm at a temperature of 37 ± 5° C with 500 ml water as the dissolution medium.

[017] The composition may be filled into capsules or sachets or compressed into tablets for oral administration. In one embodiment, an amount of the composition comprising at least 200 mg ribavirin is filled into a size 2 or 3 capsule. The capsules or sachets may be opened and the contents sprinkled onto food such as applesauce or pudding for administration to patients who have difficulty swallowing pills. The composition may be used for treatment of viral infections.

[018] Example 1

[019] Ribavirin was granulated using an aqueous binder solution (prepared by dissolving hydroxypropylmethyl cellulose in water) in a high shear mixer and the resulting granules were dried in a fluidized bed drier. Extragranular excipients as shown in Table 1 below were added to the dried granules and the resulting blend was lubricated and filled in empty hard gelatin capsule shells.

[020] Table 1

[021] Example 2

[022] Ribavirin was granulated using an aqueous binder solution (prepared by dissolving hydroxyethyl cellulose in water) in a high shear mixer and the resulting granules were dried in a fluidized bed drier. Extragranular excipients as shown in Table 2 below were added to the dried granules and the resulting blend was lubricated and filled in empty hard gelatin capsule shells. [023] Table 2

[024] Example 3

[025] Ribavirin was granulated using an aqueous binder solution (prepared by dissolving hydroxyethyl cellulose in water) in a high shear mixer and the resulting granules were dried in a fluidized bed drier. Extragranular excipients as shown below were added to the dried granules and the resulting blend was lubricated and filled into empty hard gelatin capsule shells.

[026] Table 3

[027] Example 4

[028] Ribavirin was granulated using an aqueous binder solution (prepared by dissolving hydroxyethyl cellulose in water) in a high shear mixture. The wet mass (water content of 32.35%) was dried in a fluidized bed drier. The granules were sifted through mesh # 30 and had a bulk density - 0.56 g/ml, tapped density - 0.71 gm/ml and angle of repose - 37. The granules were blended with extragranular excipients as shown in table below and then lubricated. The lubricated blend had a bulk density - 0.61 g/ml, tapped density - 0.75 gm/ml and angle of repose - 34.50. The lubricated blend was filled into empty hard gelatin capsule shells of size 2.

[029] Table 4

Dissolution of capsules of Example 4 is given below: [030] Table 5

[031] Example s

[032] Ribavirin was granulated using an aqueous binder solution (prepared by dissolving hydroxyethyl cellulose in water) in a high shear mixture. The wet mass (water content of 25.5%) was dried in a fluidized bed drier. The granules were sifted through #30 mesh and had a bulk density - 0.40 g/ml, tapped density - 0.60 gm/ml. The granules were blended with extragranular excipients as shown in table below, lubricated and filled into empty hard gelatin capsule shells of size 2.

[033] Table 6

Dissolution of capsules of Example 5 is given below: [034] Table 7

[035] Example 6

[036] Ribavirin was granulated using an aqueous binder solution (prepared by dissolving hydroxyethyl cellulose in water) in a high shear mixture. The wet mass (water content of 25.5%) was dried in a fluidized bed drier. The granules were sifted through #30 mesh and had a bulk density - 0.40 g/ml, tapped density - 0.60 gm/ml. The granules were blended with extragranular excipients as shown in table below, lubricated and filled into empty hard gelatin capsule shells of size 2.

[037] Table 8

Dissolution of capsules of Example 6 is given below: [038] Table 9

[039] Example 7

[040] Ribavirin was granulated using water as a granulating solvent in a high shear mixture. The wet mass was dried in a tray dryer. The granules were sifted through #30 mesh and had a bulk density - 0.50 g/ml. The granules were blended with extragranular excipients as shown in table below, lubricated and filled into empty hard gelatin capsule shells of size 2.

[041] Table 10

Dissolution of capsules of Example 7 is given below: [042] Table 11

[043] Example 8

[044] Ribavirin was granulated using water as a granulating solvent in a high shear mixture. The wet mass was dried in a tray dryer. The granules were sifted through #30 mesh and had a bulk density - 0.50 g/ml. The granules were blended with extragranular excipients as shown in table below, lubricated and filled into empty hard gelatin capsule shells of size 2. [045] Table 12

Dissolution of capsules of Example 8 is given below: [046] Table 13

[047] Example 9

[048] Ribavirin was granulated using an aqueous binder solution (prepared by dissolving hydroxyethyl cellulose in water) in a high shear mixer and the resulting granules were dried in a fluidized bed drier. Extragranular excipients as shown in Table 14 below were added to the dried granules and the resulting blend was lubricated and filled in empty hard gelatin capsule shells. [049] Table 14

Dissolution of capsules of Example 9 is given below: [050] Table 15

Claims

WHAT IS CLAIMED IS:

1. A method of making a ribavirin composition, said method comprising:

(a) combining ribavirin with a binder to produce ribavirin granules; and

(b) drying the ribavirin granules.

2. The method of claim 1 , wherein the binder is selected from hydroxypropylmethyl cellulose and hydroxyethyl cellulose.

3. The method of claim 1 or claim 2, wherein during the combining step the binder is in a solution that is poured or sprayed onto the ribavirin.

4. The method of any one of claims 1-3, wherein the dried ribavirin granules consist essentially of the ribavirin and the binder.

5. The method of claim 4, wherein the dried granules comprise less than 1.5 wt.% binder.

6. The method of any one of claims 1 -5 further comprising:

(c) passing the dried granules through a sieve to remove from the composition granules larger than 1.0 mm.

7. The method of any one of claims 1-6 further comprising:

(d) blending the ribavirin granules with excipients, wherein the excipients comprise less than 40 wt.% of the composition.

8. The method of claim 7, wherein the excipients comprise less than 30 wt.% of the composition.

9. The method of claim 6, wherein granules larger than 0.8 mm are removed from the composition.

10. The method of any one of claims 1-9 further comprising:

(e) filling the dried ribavirin granules into a capsule.

11. The method of claim 10, wherein at least 200 mg ribavirin is filled into the capsule and the capsule size is 2 or smaller.

12. A pharmaceutical composition comprising granules consisting essentially of ribavirin and a soluble binder.

13. The composition of claim 12 wherein the binder is selected from the group consisting of hydroxy ethyl cellulose and hydroxypropylmethyl cellulose.

14. The composition of claim 12 or 13 wherein the amount of binder in the granules is about 0.2 to about 2.0 wt.%.

15. The composition of claim 12, wherein substantially all the granules are less than 1.2 mm.

16. The composition of claim 12, wherein substantially all the granules are less than 0.8 mm.

17. The composition of any one of claims 12-16 comprising one or more extragranular ingredients.

18. The composition of claim 17, wherein the extragranular ingredients comprise less than 40 wt.% of the composition.

19. The composition of claim 17, wherein the extragranular ingredients comprise less than 30 wt.% of the composition.

20. The composition of any one of claims 12-19 that is filled into a capsule.

21. The composition of claim 20, wherein the capsule is size 2 or less and at least 200 mg ribavirin is filled into the capsule.

22. The composition of any one of claims 12-19 that is compressed into a tablet.

23. The composition of any one of claims 17-19, wherein one of the extragranular ingredients is an additional active pharmaceutical ingredient.