Pharmaceutical compositions of rifaximin

Abstract

The present invention relates to stable pharmaceutical compositions comprising rifaximin and processes for their preparation.

Claims

1. A stable pharmaceutical composition of rifaximin comprising: (i) a mixture of Form α and Form β of rifaximin; and (ii) one or more pharmaceutically acceptable excipients, wherein the relative polymorphic distribution ratio of Form α to Form β is from 15:85 to 85:15, and wherein said ratio remains substantially unchanged in the pharmaceutical composition after exposure to a relative humidity of 75% and a temperature of 40° C. for at least three months.

2. The stable pharmaceutical composition according to claim 1, wherein the relative polymorphic distribution ratio of Form α to Form β is from 30:70 to 70:30.

3. The stable pharmaceutical composition according to claim 2, wherein the relative polymorphic distribution ratio of Form α to Form β is from 40:60 to 60:40.

4. The stable pharmaceutical composition according to claim 3, wherein the relative polymorphic distribution ratio of Form α to Form β is about 40:60.

5. The stable pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable excipients are selected from the group comprising diluents, disintegrants, binders, lubricants, glidants, or mixtures thereof.

6. The stable pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is selected from the group comprising tablets, capsules, pills, or granules.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) A first aspect of the present invention provides a stable pharmaceutical composition of rifaximin comprising: (i) a mixture of Form α and Form β of rifaximin; and (ii) one or more pharmaceutically acceptable excipients,
wherein the relative polymorphic distribution ratio of Form α to Form β is from about 15:85 to about 85:15, and wherein said ratio remains substantially unchanged in the pharmaceutical composition after exposure to a relative humidity of 75% and a temperature of 40° C. for at least three months.

(2) According to one embodiment of the above aspect, there is provided a stable pharmaceutical composition of rifaximin comprising: (i) a mixture of Form α and Form β of rifaximin; and (ii) one or more pharmaceutically acceptable excipients,
wherein the relative polymorphic distribution ratio of Form α to Form β is from about 30:70 to about 70:30, and wherein said ratio remains substantially unchanged in the pharmaceutical composition after exposure to a relative humidity of 75% and a temperature of 40° C. for at least three months.

(3) According to another embodiment of the above aspect, there is provided a stable pharmaceutical composition of rifaximin comprising: (i) a mixture of Form α and Form β of rifaximin; and (ii) one or more pharmaceutically acceptable excipients,
wherein the relative polymorphic distribution ratio of Form α to Form β is from about 40:60 to about 60:40, and wherein said ratio remains substantially unchanged in the pharmaceutical composition after exposure to a relative humidity of 75% and a temperature of 40° C. for at least three months.

(4) According to another embodiment of the above aspect, there is provided a stable pharmaceutical composition of rifaximin comprising: (i) a mixture of Form α and Form β of rifaximin; and (ii) one or more pharmaceutically acceptable excipients,
wherein the relative polymorphic distribution ratio of Form α to Form β is about 40:60, and wherein said ratio remains substantially unchanged in the pharmaceutical composition after exposure to a relative humidity of 75% and a temperature of 40° C. for at least three months.

(5) According to another embodiment of the above aspect, there is provided a stable pharmaceutical composition of rifaximin, wherein the pharmaceutically acceptable excipients are selected from the group comprising diluents, disintegrants, binders, lubricants, glidants, or mixtures thereof.

(6) A second aspect of the present invention provides a process for the preparation of a stable pharmaceutical composition of rifaximin, wherein the process comprises the steps of: (i) blending rifaximin with one or more of pharmaceutically acceptable excipients; and (ii) compressing the blend of step (i) into a tablet using appropriate tooling.

(7) A third aspect of the present invention provides a process for the preparation of a stable pharmaceutical composition of rifaximin, wherein the process comprises the steps of: (i) blending rifaximin with one or more of pharmaceutically acceptable excipients; (ii) dry granulating the blend of step (i) to obtain granules; and (iii) compressing the granules of step (ii) into a tablet using appropriate tooling.

(8) According to one embodiment of the above aspect, there is provided a process for the preparation of a stable pharmaceutical composition of rifaximin, wherein the process comprises the steps of: (i) blending rifaximin with one or more of pharmaceutically acceptable excipients; (ii) compacting the blend of step (i) in a suitable compactor to form the compacts; (iii) milling the compacts of step (ii) using a suitable mill to obtain granules; (iv) blending the granules of step (iii) with one or more pharmaceutically acceptable excipients; and (v) compressing the blend of step (iv) into a tablet using appropriate tooling.

(9) The term “stable”, as used herein, refers to a physical stability which means that the relative polymorphic distribution ratio of Form α to Form β in the pharmaceutical composition would remain substantially unchanged as determined by X-ray powder diffraction after exposure to a relative humidity of 75% and a temperature of 40° C., for a period of at least three months.

(10) The term “substantially”, as used herein, means the change in the relative polymorphic distribution ratio of Form α to Form β in the pharmaceutical composition is within ±10% of the initial value, preferably within ±5% of the initial value.

(11) The terms “Form α” and “Form β” of rifaximin, as used herein, refer to the two known polymorphic forms of rifaximin, identified and characterized in U.S. Pat. No. 7,045,620, the disclosure of which is incorporated herein by reference in its entirety.

(12) The term “relative polymorphic distribution ratio”, as used herein, refers to the amount of Form α and Form β relative to each other in the pharmaceutical composition. The relative polymorphic distribution ratio of the present invention is expected to remain substantially unchanged subsequent to the manufacturing process through the entire shelf-life of the pharmaceutical composition.

(13) The term “about”, as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.

(14) The term “pharmaceutical composition”, as used herein, includes tablets, capsules, pills, or granules. Preferably, the pharmaceutical composition of the present invention is a tablet.

(15) The term “pharmaceutically acceptable excipients”, as used herein, includes excipients that may be added intragranularly and/or extragranularly in the pharmaceutical compositions. The pharmaceutically acceptable excipients are selected from the group comprising diluents, disintegrants, binders, lubricants, glidants, or mixtures thereof.

(16) Suitable diluents are selected from the group comprising lactose, microcrystalline cellulose, starch, pregelatinized starch, calcium sulphate, calcium carbonate, powdered cellulose, mannitol, sorbitol, xylitol, lactitol, dicalcium phosphate, tricalcium phosphate, or mixtures thereof.

(17) Suitable disintegrants are selected from the group comprising croscarmellose sodium, sodium starch glycolate, microcrystalline cellulose, crospovidone, polyvinyl pyrrolidone, low-substituted hydroxypropyl cellulose, alginic acid, calcium salts and potassium salts of carboxymethyl cellulose, colloidal silicon dioxide, guar gum, magnesium aluminum silicate, methylcellulose, powdered cellulose, starch, sodium alginate, or mixtures thereof.

(18) Suitable binders are selected from the group comprising microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycols, polyvinyl acetate, polyvinyl alcohol, propylene glycol, starch and its derivatives such as corn starch, carboxymethyl cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or mixtures thereof.

(19) Suitable lubricants are selected from the group comprising magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, powdered stearic acid, magnesium oleate, calcium palmitate, potassium laureate, talc, glycerol monostearate, glycerol distearate, glycerol tristearate, glycerol tripalmitate, glycerol trimyristate, glycerol tribehenate, glycerol palmitate stearate, glycerol behenate, or mixtures thereof.

(20) Suitable glidants are selected from the group comprising colloidal silica, magnesium trisilicate, powdered cellulose, talc, tribasic calcium phosphate, or mixtures thereof.

(21) The manufacturing process of the pharmaceutical composition is critical as it could lead to a change in the relative polymorphic distribution ratio during the shelf-life of the pharmaceutical composition. The stable pharmaceutical compositions of the present invention are prepared by dry methods, such as direct compression and dry granulation. The dry granulation method may involve the use of a Chilsonator®, a suitable compactor, or the formation of slugs.

(22) The pharmaceutical composition of the present invention may be further coated with one or more functional or non-functional coating layers. Preferably, the pharmaceutical composition is coated with one or more non-functional coating layers. The coating layers may comprise one or more film-forming polymers and coating additives.

(23) Examples of film-forming polymers include cellulose and its derivatives such as ethyl cellulose, hydroxypropylmethyl cellulose, e.g., hypromellose 5 cP and hypromellose 15 cP, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes; and methacrylic acid polymers, e.g., Eudragit®, and the like. Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry®, may also be used.

(24) Coating additives may be selected from the group consisting of binders, plasticizers, chelating agents, coloring agents, lubricants, opacifiers, or mixtures thereof.

(25) Suitable plasticizers are selected from the group consisting of triethyl citrate, dibutyl sebacate, acetylated triacetin, tributyl citrate, glycerol tributyrate, monoglyceride, rapeseed oil, olive oil, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, glycerin sorbitol, diethyl oxalate, diethyl phthalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, or mixtures thereof.

(26) Suitable chelating agents are selected from the group consisting of ethylenediamine tetraacetic acid, or derivatives or salts thereof, e.g., disodium edetate; dihydroxyethyl glycine; glucamine; acids, e.g., citric acid, tartaric acid, gluconic acid, and phosphoric acid; or mixtures thereof.

(27) Coloring agents includes any FDA approved color for oral use such as iron oxide, titanium dioxide, zinc oxide, or mixtures thereof.

(28) Suitable opacifiers are selected from the group consisting of titanium dioxide, manganese dioxide, iron oxide, silicon dioxide, or mixtures thereof.

(29) Specific examples of solvents for coating include purified water, acetone, ethanol, isopropyl alcohol, methylene chloride, or combinations thereof.

(30) Coating may be performed by applying the coating composition as a solution/suspension/blend using any conventional coating technique known in the art, such as spray coating in a conventional coating pan or fluidized bed processor, dip coating, or compression coating.

(31) The invention may be further illustrated by the following examples, which are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

EXAMPLES

Example 1

(32) TABLE-US-00001 Quantity (mg/tablet) Ingredients Rifaximin 550.00 Microcrystalline cellulose 313.75 Sodium starch glycolate 41.25 Colloidal silicon dioxide 2.75 Glyceryl distearate 49.50 Talc 2.75 Magnesium stearate 5.00 Film Coating Opadry ® 25.00 Purified water q.s. Total Weight 990.00 mg
Procedure: 1. Rifaximin was sifted through a suitable sieve and blended with microcrystalline cellulose, sodium starch glycolate, and colloidal silicon dioxide in a suitable blender. 2. The blend of step 1 was blended with glyceryl diasterate. 3. The blend of step 2 was compacted in a suitable compactor to form a compact. 4. The compact of step 3 was comminuted using a suitable mill to obtain granules. 5. The granules of step 4 were sifted through a suitable sieve to obtain granules and fines which were repeatedly compacted, comminuted, and sieved until the desired granules to fines ratio was obtained. 6. The granules of step 5 were blended with microcrystalline cellulose, sodium starch glycolate, and colloidal silicon dioxide. 7. The blend of step 6 was lubricated with talc, glyceryl distearate, and magnesium stearate. 8. The lubricated blend of step 7 was compressed into a tablet. 9. Opadry® was dispersed in purified water. 10. The tablet of step 8 was coated in a conventional coating pan using the coating dispersion of step 9.

Example 2

(33) TABLE-US-00002 Quantity (mg/tablet) Ingredients Rifaximin 550.00 Microcrystalline cellulose 316.25 Sodium starch glycolate 41.25 Colloidal silicon dioxide 2.75 Glyceryl distearate 49.50 Talc 2.75 Magnesium stearate 5.00 Film Coating Hypromellose 5 cP 10.51 Hypromellose 15 cP 9.92 Titanium dioxide 5.95 Propylene glycol 1.98 Iron oxide red 0.60 Disodium edetate 0.08 Purified water q.s. Total Weight 996.54 mg
Procedure: 1. Rifaximin was sifted through a suitable sieve, and blended with microcrystalline cellulose, sodium starch glycolate, and colloidal silicon dioxide in a suitable blender. 2. The blend of step 1 was blended with glyceryl diasterate. 3. The blend of step 2 was compacted in a suitable compactor to form a compact. 4. The compact of step 3 was comminuted using a suitable mill to obtain granules. 5. The granules of step 4 were sifted through a suitable sieve to obtain granules and fines which were repeatedly compacted, comminuted, and sieved until the desired granules to fines ratio was obtained. 6. The granules of step 5 were blended with microcrystalline cellulose, sodium starch glycolate, and colloidal silicon dioxide. 7. The blend of step 6 was lubricated with talc, glyceryl distearate, and magnesium stearate. 8. The lubricated blend of step 7 was compressed into a tablet. 9. Disodium edetate and propylene glycol were dissolved in purified water. 10. Hypromellose 5 cP, hypromellose 15 cP, titanium dioxide, and iron oxide red were dispersed into the solution of step 9. 11. The tablet of step 8 was coated in a conventional coating pan using the coating dispersion of step 10.

Example 3

(34) TABLE-US-00003 Quantity (mg/tablet) Ingredients Rifaximin 550.00 Microcrystalline cellulose 313.75 Sodium starch glycolate 41.25 Colloidal silicon dioxide 2.75 Glyceryl distearate 49.50 Talc 2.75 Magnesium stearate 5.00 Film Coating Opadry ® 28.95 Purified water q.s. Total Weight 993.95 mg
Procedure: 1. Rifaximin was sifted through a suitable sieve and blended with microcrystalline cellulose, sodium starch glycolate, and colloidal silicon dioxide in a suitable blender. 2. The blend of step 1 was blended with glyceryl diasterate. 3. The blend of step 2 was compacted in a suitable compactor to form a compact. 4. The compact of step 3 was comminuted using a suitable mill to obtain granules. 5. The granules of step 4 were sifted through a suitable sieve to obtain granules and fines which were repeatedly compacted, comminuted, and sieved until the desired granules to fines ratio was obtained. 6. The granules of step 5 were blended with microcrystalline cellulose, sodium starch glycolate, and colloidal silicon dioxide. 7. The blend of step 6 was lubricated with talc, glyceryl distearate, and magnesium stearate. 8. The lubricated blend of step 7 was compressed into a tablet. 9. Opadry® was dispersed in purified water. 10. The tablet of step 8 was coated in a conventional coating pan using the coating dispersion of step 9.
Stability Data

(35) The tablets prepared according to Example 1, Example 2, and Example 3 were stored at a relative humidity of 75% and a temperature of 40° C. for a period of three months, and analyzed for relative polymorphic distribution ratio of Form α and Form β determined through X-ray powder diffraction method. The results of the analysis are represented in Table 1.

(36) TABLE-US-00004 TABLE 1 Results of the Stability Study of the Tablets Prepared According to Examples 1, 2, and 3 Stored at Relative Humidity of 75% and a Temperature of 40° C. Example 1 Example 2 Example 3 Condition Form α Form β Form α Form β Form α Form β Initial 38.47 61.53 74.37 25.63 59.65 40.35 One month 39.09 60.91 71.53 28.47 — — Three months 37.98 62.02 73.76 26.24 57.11 42.89

(37) From the above table, it is clear that the relative polymorphic distribution ratio of Form α and Form β remained substantially unchanged for a period of three months, which shows that the pharmaceutical compositions prepared according to Example 1, Example 2, and Example 3 remained stable for three months.