RIFAXIMIN COMPLEXES

Abstract

There is provided a complex comprising rifaximin and a complexing agent, wherein the complexing agent is a polyvinyl pyrrolidone (PVP) or a cyclodextrin. There is also provided a process for preparing the complex, a pharmaceutical composition including the complex and therapeutic uses of the complex.

Claims

1-24. (canceled)

25. A method of treating bowel disorders, the method comprising: administering to a patient a therapeutically effective amount of a complex comprising rifaximin and a complexing agent, wherein the complex is in an amorphous form and exhibits enhanced solubility compared to a physical mixture of rifaximin and the complexing agent.

26. The method of claim 25, wherein the complex is a component of a tablet, a pellet, or a capsule.

27. The method of claim 25, wherein the bowel disorder is travelers' diarrhea.

28. The method of claim 25, wherein the bowel disorder is a bowel disease.

29. The method of claim 25, wherein the bowel disorder is irritable bowel syndrome, Crohn's disease, chronic pancreatitis, pancreatic insufficiency and/or colitis.

30. The method of claim 25, wherein the bowel disorder is microbe associated diarrhea.

31. The method according to claim 25, wherein the ratio of rifaximin to complexing agent ranges from 20:1 to 1:20 w/w.

32. The method according to claim 25, wherein the ratio of rifaximin to complexing agent ranges from 10:1 w/w to 1:2 w/w.

33. The method according to claim 25, wherein the rifaximin complex is administered with one or more pharmaceutically acceptable excipients.

34. A method of treating bowel disorders, the method comprising: administering to a patient a therapeutically effective amount of a complex comprising rifaximin and a complexing agent, wherein the complex is in an amorphous form and exhibits enhanced solubility compared to a physical mixture of rifaximin and the complexing agent, the complex is a component of a tablet, and the rifaximin complex is administered with one or more pharmaceutically acceptable excipients.

35. A method of treating bowel disorders, the method comprising: administering to a patient a therapeutically effective amount of a complex comprising rifaximin and a complexing agent, wherein the complex is in an amorphous form and exhibits enhanced solubility compared to a physical mixture of rifaximin and the complexing agent, the complex is a component of a tablet or a capsule, the bowel disorder is a bowel disease, and the rifaximin complex is administered with one or more pharmaceutically acceptable excipients.

36. A method of treating bowel disorders, the method comprising: administering to a patient a therapeutically effective amount of a complex comprising rifaximin and a complexing agent, wherein the complex is in an amorphous form and exhibits enhanced solubility compared to a physical mixture of rifaximin and the complexing agent, the complex is a component of a tablet or a capsule, the bowel disorder is microbe associated diarrhea, and the rifaximin complex is administered with one or more pharmaceutically acceptable excipients.

Description

BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS

[0053] FIG. 1—intrinsic dissolution profile of (1:2 w/w rifaximin:PVP) PVP complex of rifaximin of the present invention compared with that of a physical mixture of β-rifaximin and PVP (1:2 w/w rifaximin:PVP) by an HPLC-UV method.

[0054] FIG. 2—intrinsic dissolution profile of (1:1 w/w rifaximin:PVP) PVP complex of rifaximin of the present invention compared with that of a physical mixture of β-rifaximin and PVP (1:1 w/w rifaximin:PVP) by an HPLC-UV method

[0055] FIG. 3—intrinsic dissolution profile of (4:1 w/w rifaximin:PVP) PVP complex of rifaximin of the present invention compared with that of a physical mixture of β-rifaximin and PVP (4:1 w/w rifaximin:PVP) by an HPLC-UV method.

[0056] FIG. 4—intrinsic dissolution profile of (10:1 w/w rifaximin:PVP) PVP complex of rifaximin of the present invention compared with that of a physical mixture of β-rifaximin and PVP (10:1 w/w rifaximin:PVP) by an HPLC-UV method.

[0057] FIG. 5—intrinsic dissolution profile of (1:2 w/w rifaximin:β-CD) β-cyclodextrin complex of rifaximin of the present invention compared with that of a physical mixture of β-rifaximin and CD (1:2 w/w rifaximin:β-CD) by an HPLC-UV method.

[0058] FIG. 6 indicates intrinsic dissolution profile of (1:1 w/w rifaximin:β-CD) β-cyclodextrin complex of rifaximin of the present invention compared with that of a physical mixture of β-rifaximin and CD (1:1 w/w rifaximin:β-CD) by an HPLC-UV method

[0059] FIG. 7 indicates intrinsic dissolution profile of (4:1 w/w rifaximin:β-CD) β-cyclodextrin complex of rifaximin of the present invention compared with that of a physical mixture of β-rifaximin and CD (4:1 w/w rifaximin:β-CD) by an HPLC-UV method.

[0060] FIG. 8 indicates intrinsic dissolution profile of (10:1 w/w rifaximin:β-CD) β-cyclodextrin complex of rifaximin of the present invention compared with that of a physical mixture of β-rifaximin and CD (10:1 w/w rifaximin:β-CD) by an HPLC-UV method.

[0061] FIG. 9 indicates an X-ray powder diffractogram (XRD) of a β-cyclodextrin complex of rifaximin at 1:1 w/w concentration.

[0062] FIG. 10 indicates an X-ray powder diffractogram (XRD) of (10:1 w/w rifaximin:PVP) a PVP complex of rifaximin.

DETAILED DESCRIPTION OF THE INVENTION

[0063] The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

[0064] The present invention provides a form of rifaximin with enhanced solubility and stability. This form of rifaximin comprises a complex of rifaximin with a complexing agent. The complexing agents used in the present invention include more particularly a polyvinyl pyrrolidone or a cyclodextrin.

[0065] There is also provided by the present invention a process for preparing the rifaximin-complexing agent complex of the present invention, the process comprising:

[0066] a) dissolving the rifaximin in a suitable solvent;

[0067] b) adding the complexing agent to the rifaximin solution either as such or in the form of solution to form a mixture;

[0068] c) isolating the complex, for example by concentrating the reaction mass obtained in step b) and further drying to obtain the complex.

[0069] The rifaximin used in the process of the present invention may be obtained by any one of the methods disclosed in the prior art. For example, the rifaximin used in the process of the present invention may be in the polymorphic form α, β, γ, δ or ε. In a preferred embodiment of the present invention, the rifaximin used is in the β-form. The β-form of rifaximin is the least soluble known form of rifaximin.

[0070] The solvent used may be selected from ethers, alcohols, esters, aldehydes, halogenated solvents, hydrocarbons and combinations thereof.

[0071] In the process of the present invention, the complexing agent used may be selected from polyvinyl pyrrolidone (PVP) or cyclodextrin (CD).

[0072] Polyvinyl pyrrolidone (PVP, also known as “povidone”) is commercially available as a white powder of a given molecular weight. Generally, the molecular weights of PVP polymers are given by their K-values, e.g., K-15 to K-90. The K-value indicates the average molecular weight ranging from 20,000 to 1,000,000. A preferred PVP is K-30, typically having a molecular weight of about 40,000. An unusual property of PVP is its solubility in water as well as in various organic solvents.

[0073] In the process of the present invention, the PVP may be selected from the group consisting of PVP K-12, K-15, K-17, K-25, K-30, K-60, K-80, K-90 and K-120. Preferably, K-25, K-30, K-90, and most preferably K-30.

[0074] In the process of the present invention, the cyclodextrin used to form the complex may be in any form of cyclodextrin, including α-cyclodextrin having 6 glucose units, β-cyclodextrin having 7 glucose units, or γ-cyclodextrin having 8 glucose units. The cyclodextrin may also be in anhydrous or hydrated form. The preferred cyclodextrin is β-cyclodextrin.

[0075] The complexing agent may be added as such or as a solution in a suitable solvent. The amount of rifaximin that can be encapsulated is directly related to the molecular weight of the rifaximin.

[0076] In some embodiments, one mole of complexing agent encapsulates one mole of rifaximin. Preferably, the amounts of rifaximin and complexing agent used in the formulation are typically sufficient to provide the desired therapeutic effect. On a weight basis, the ratio between rifaximin and complexing agent in the given composition (termed “w/w”), ranges from 20:1 to 1:20, preferably from 10:1 to 1:2. Typically, the ratio of rifaximin to complexing agent ranges from 4:1 to 1:2. The ratio may be 1:1.

[0077] The solvent may be removed rapidly and completely by vacuum drying or vacuum evaporation. In an embodiment, the solvent may be removed by spray drying to yield the rifaximin complex. In another embodiment, the rifaximin complex may be obtained freeze drying. In yet another embodiment, the rifaximin complex may be isolated by microwave treatment techniques.

[0078] According to a third aspect of the present invention, there is provided a rifaximin complex which enhances at least one of the following:—

[0079] a) stabilization of rifaximin against degradation (e.g. hydrolysis, oxidation, etc)

[0080] b) enhancement of water solubility of rifaximin [0081] c) better dissolution [0082] d) free flowing and non-hygroscopic rifaximin [0083] e) modified solubility, delivery or performance

[0084] f) safe handling of rifaximin

[0085] The rifaximin complex of the present invention is not a simple physical mixture of the ingredients. This rifaximin complex is superior to the conventional free base of rifaximin, for example in terms of storage stability.

[0086] Further, it was observed that the use of a complexing agent as an excipient in the formulation enhances solubility to some extent but the formation of a complex with rifaximin enhances solubility much more than mixing it physically as an excipient. Further, the aqueous solubility of the rifaximin complex with cyclodextrin or PVP is found to be greater than the aqueous solubility of rifaximin. The enhanced solubility of the complex can further increase dissolution rate as shown in FIGS. 1 to 8 and thus makes these complexes more bio-available in the body. This increase in bioavailability and stability of the complex further allows for smaller doses to achieve the desired therapeutic effect compared to a larger dose of rifaximin alone. Further, these complexes avoid interconversion of crystalline forms of rifaximin. In addition, these complexes can be used to reduce or prevent gastrointestinal and ocular irritation, to reduce or eliminate unpleasant smells or tastes, as well as to prevent drug-drug or drug-additive interactions.

[0087] According to another aspect of the present invention, there is provided a rifaximin complex characterized by having an intrinsic dissolution profile as shown in any one of FIGS. 1 to 8.

[0088] To measure the intrinsic dissolution of a rifaximin complex, for example a rifaximin-PVP complex or a rifaximin-CD complex, rifaximin samples were measured to compare the influence of the different parameter settings. At appropriate time intervals, an automated sample collector removes aliquots from the dissolution medium for analysis. The time interval for sampling can vary, for example, from 2 to 30 minutes, depending on the properties of the drug and dissolution medium used. Suitable dissolution equipment for these operations includes LAB INDIA DISSO 2000.

[0089] The complexes may be used in a variety of applications. In an embodiment, the composition of the present invention is in the form of a tablet, a capsule or a liquid oral. The composition may further optionally include additional components to enhance or achieve the desired therapeutic effect of rifaximin. Examples of such components include, but are not limited to surfactants, excipients, disintegrating agents, binders, lubricants, dispersing agents, thickening agents.

[0090] The present invention will now be further illustrated by the following examples, which do not limit the scope of the invention in any way.

Example 1—Preparation of Rifaximin-PVP Complex (1:2 w/w Ratio)

[0091] Preparation 1

[0092] 2 g of rifaximin was dissolved in 30 ml of ethanol at 25-30° C. 4 g of PVP K-30 was dissolved in 40 ml ethanol. The solution of PVP K-30 was added to the rifaximin solution and stirred. The reaction mass was concentrated under vacuum at 35° C. till dryness and then dried completely at 30-35° C. for 24 hours to get 5.4 g rifaximin-PVP complex.

[0093] Preparation 2

[0094] 5 g of rifaximin was dissolved in 75 ml of ethanol at 25-30° C. The reaction mass was heated to 35° C. and 10 g of PVP K-30 was added to the rifaximin solution and stirred. The reaction mass was concentrated under vacuum at 35° C. till dryness and then dried completely at 30-35° C. for 24 hours to get 13 g rifaximin-PVP complex.

Example 2—Preparation of Rifaximin-PVP Complex (1:1 w/w Ratio)

[0095] Preparation 1

[0096] 2 g of rifaximin was dissolved in 30 ml of ethanol at 25-30° C. 2 g of PVP K-30 was dissolved in 20 ml of ethanol. The solution of PVP K-30 was added to the rifaximin solution and stirred. The reaction mass was concentrated under vacuum at 35° C. till dryness and then dried completely at 30-35° C. for 24 hours to get 3.1 g rifaximin-PVP complex.

[0097] Preparation 2

[0098] 5 g of rifaximin was dissolved in 75 ml of ethanol at 25-30° C. The reaction mass was heated to 35° C. and 5 g of PVP K-30 was added to the rifaximin solution and stirred. The reaction mass was concentrated under vacuum at 35° C. till dryness and then dried completely at 30-35° C. for 24 hours to get 8.8 g rifaximin-PVP complex.

Example 3—Preparation of Rifaximin-PVP Complex (4:1 w/w Ratio)

[0099] Preparation 1

[0100] 10 g of rifaximin was dissolved in 150 ml of ethanol at 30-35° C. A solution of PVP K-30 was prepared by dissolving 2.5 g of PVP K-30 in 25 ml of ethanol. This solution was added to the rifaximin solution at 30-35° C. The reaction mass was stirred, concentrated to dryness under vacuum at 30-35° C. and then dried completely at 70° C. for 24-30 hours to get 12.5 g rifaximin-PVP complex.

[0101] Preparation 2

[0102] 5 g of rifaximin was dissolved in 75 ml of ethanol at 25-30° C. The reaction mass was heated to 35° C. and 1.25 g of PVP K-30 was added to the rifaximin solution and stirred. The reaction mass was concentrated under vacuum at 35° C. till dryness and then dried completely at 30-35° C. for 24 hours to get 5.5 g rifaximin-PVP complex.

Example 4—Preparation of Rifaximin-PVP Complex (10:1 w/w Ratio)

[0103] Preparation 1

[0104] 10 g of rifaximin was dissolved in 150 ml of ethanol at 30-35° C. A solution of PVP K-30 was prepared by dissolving 1 g of PVP K-30 in 15 ml of ethanol. The solution was added to the rifaximin solution. The reaction mass was stirred at 30-35° C., concentrated to dryness under vacuum at 30-35° C. and then dried completely at 30-35° C. for 24-30 hours to get 10.3 g rifaximin-PVP complex.

[0105] Preparation 2

[0106] 5 g of rifaximin was dissolved in 75 ml of ethanol at 25-30° C. The reaction mass was heated to 35° C. and 0.5 g of PVP K-30 was added to the rifaximin solution and stirred. The reaction mass was concentrated under vacuum at 35° C. till dryness and then dried completely at 30-35° C. for 24 hours to get 5.0 g rifaximin-PVP complex.

Example 5—Preparation of the Rifaximin-β-Cyclodextrin Complex (1:2 w/w Ratio)

[0107] Preparation 1

[0108] 2 g of rifaximin was dissolved in 30 ml of ethanol at 25-30° C. To this solution 4 g of β-cyclodextrin was added and stirred. The reaction mass was concentrated under vacuum at 35° C., stripped with 20 ml of ethanol. This residue was concentrated to dryness and dried under vacuum at 30-35° C. for 20-24 hours to get 5.1 g rifaximin-0 cyclodextrin complex.

[0109] Preparation 2

[0110] 4 g of rifaximin was dissolved in 60 ml of ethanol at 25-30° C. The reaction mass was heated to 35° C. and 8 g of β-cyclodextrin was added to the rifaximin solution and stirred.

[0111] The reaction mass was concentrated under vacuum at 35° C. till dryness and then dried completely at 30-35° C. for 24 hours to get 10.7 g rifaximin-β cyclodextrin complex.

Example 6—Preparation of Rifaximin β-Cyclodextrin Complex (1:1 w/w Ratio)

[0112] 2 g of rifaximin was dissolved in 30 ml of ethanol at 25-30° C. To this solution 2 g of β-cyclodextrin was added and stirred. The reaction mass was concentrated under vacuum at 35° C. and then dried completely at 30-35° C. for 20-24 hours to get 2.8 g rifaximin-β cyclodextrin complex.

Example 7—Preparation of the Rifaximin-β-Cyclodextrin Complex (4:1 w/w Ratio)

[0113] 7 g of rifaximin was dissolved in 100 ml of ethanol at 30-35° C. To this solution 1.75 g of β-cyclodextrin was added and stirred. The reaction mass was stirred, concentrated to dryness under vacuum at 30-35° C. and then dried completely at 30-35° C. for 24-30 hours to get 8.1 g rifaximin-β cyclodextrin complex.

Example 8—Preparation of the Rifaximin-O-Cyclodextrin Complex (10:1 w/w Ratio)

[0114] 7 g of rifaximin was dissolved in 100 ml of ethanol at 30-35° C. To this solution 0.7 g of β-cyclodextrin was added and stirred. The reaction mass was stirred, concentrated to dryness under vacuum at 30-35° C. and then dried completely at 30-35° C. for 24-30 hours to get 6.75 g rifaximin-β cyclodextrin complex.

[0115] Comparative Intrinsic Dissolution Study

Example 9—Preparation of Tablet

[0116] General Process for Preparing Tableting Mixture Comprising Rifaximin Complex:—

[0117] A tableting mixture (100 mg) comprising solely rifaximin complex prepared according to any of the examples 1 to 8 (i.e. with no excipients) was prepared and compressed to a pellet using a manual hand press operating at a compression pressure of 2.5 tones for 5 minutes.

[0118] General Process for Preparing Tableting Mixture Comprising a Physical Mixture of Rifaximin and Complexing Agent:—

[0119] Similarly a tableting mixture (100 mg) comprising a solely physical mixture of rifaximin and complexing agent in the proportionate ratio (i.e. with no excipients) was prepared by mixing the rifaximin and complexing agent in the desired ratio in a mortar and pestle for 5 minutes and compressing to a pellet using a manual hand press operating at a compression pressure of 2.5 tones for 5 minutes.

Example 10—Preparation of 1:2 Physical Mixture Comprising Rifaximin and PVPK (where PVPK is PVP K-30)

[0120] 100 mg of input API of rifaximin and 200 mg of PVPK were mixed uniformly and used for pellet preparation. (Inj volume: 30 μl)

[0121] In-vitro dissolution studies were performed on the 100 mg pellet in a LAB INDIA DISSO 2000.

[0122] The pellet was fixed in a PFTE holder, such that only the pellet surface came into contact with the dissolution medium. The PFTE loaded holder was placed in the dissolution vessel containing 900 ml of 0.1M of sodium dihydrogen phosphate having pH 7.4 at 37±0.5° C. 30 Two pellets were measured for each run of the design of the experiments. Stirring was performed with a paddle rotating at 100 rpm. The dissolution was followed up to 1440 min and the concentration of active ingredient, rifaximin, dissolved in the test medium was determined by removing samples of 10 ml at the specified time.

[0123] The concentration of rifaximin complex was quantified by HPLC UV method at a maximum wavelength of 300 nm under the conditions as specified below: [0124] Mobile Phase Buffer:Acetonitrile: 45:55 [0125] Buffer 0.025M Sodium dihydrogen phosphate. The pH adjusted to 3.0 with orthophosphoric acid [0126] Column Zorbax SB-phenyl, 4.6 mm, 5 μm [0127] Column Temp 25° C. [0128] Flow 1.0 ml/min [0129] Injection Volume 30 μL [0130] Diluent Buffer:Acetonitrile: 1:1 [0131] Standard Preparation 25 mg standard dissolved to 25 ml with diluent. 5 ml of this solution diluted to 50 ml with dissolution medium.

[0132] The percentage of rifaximin released from the PVPK complex (1:2 w/w) as well as from the physical mixture (1:2 w/w) were plotted against time as shown in FIG. 1. The intrinsic dissolution rate was derived from the slope of this curve. Table 1 shows the results in tabular form.

TABLE-US-00001 TABLE 1 TIME IN (1:2) PVP (1:2) PVPK MINS COMPLEX PHYSICAL MIXTURE 15 0.65 0.12 30 0.97 0.11 45 1.92 0.14 60 2.62 0.19 120 6.42 0.42 180 9.78 1.34 240 11.51 3.10 360 15.98 10.09 480 20.08 15.48 600 26.79 18.02 720 30.40 21.20 840 31.25 21.10 960 32.40 22.78 1080 31.40 23.65 1200 30.86 22.66

Example 11—Preparation of 1:1 Physical Mixture Comprising Rifaximin and PVPK

[0133] 100 mg of input API of rifaximin and 100 mg PVPK respectively were mixed uniformly and used for pellet preparation. (Inj volume: 20 μl)

[0134] The percentage of rifaximin released from the PVP complex (1:1 w/w) as well as from the physical mixture (1:1 w/w) were plotted against time as shown in FIG. 2. The intrinsic dissolution rate was derived from the slope of this curve. Table 2 shows the results in tabular form.

TABLE-US-00002 TABLE 2 TIME IN (1:1) PVP (1:1) PVP MINS COMPLEX PHYSICAL MIXTURE 15 0.86 0.19 30 1.71 0.16 45 2.54 0.19 60 3.39 0.20 120 7.15 0.37 180 10.39 0.94 240 13.21 2.22 360 18.45 5.69 480 23.42 8.33 600 28.48 10.72 720 33.64 12.67 840 38.94 14.23 960 42.13 15.28 1080 42.46 16.17 1200 42.26 16.99

Example 12—Preparation of 4:1 Physical Mixture Comprising Rifaximin and PVPK

[0135] 100 mg of input API of rifaximin and 25 mg PVPK were mixed uniformly and used for pellet preparation. (Inj volume: 15 μl) The percentage of rifaximin released from the PVP complex (4:1 w/w) as well as from the physical mixture (4:1 w/w) were plotted against time as shown in FIG. 3. The intrinsic dissolution rate was derived from the slope of this curve. Table 3 shows the results in tabular form.

TABLE-US-00003 TABLE 3 TIME IN (4:1) PVPK (4:1) PVPK MINS COMPLEX PHYSICAL MIXTURE 15 1.37 0.17 30 2.68 0.27 45 5.65 0.48 60 7.09 0.77 120 13.22 1.29 180 18.01 2.06 240 20.34 3.09 360 29.76 7.99 480 37.20 15.86 600 41.53 22.53 720 49.81 27.01 840 54.99 29.87 960 60.41 32.22 1080 66.82 35.53 1200 71.08 33.83

Example 13—Preparation of 10:1 Physical Mixture Comprising Rifaximin and PVPK

[0136] 100 mg of input API of rifaximin and 10 mg PVPK were mixed uniformly and used for pellet preparation. (Inj volume: 10 μl)

[0137] The percentage of rifaximin released from the PVP complex (10:1 w/w) as well as from the physical mixture (10:1 w/w) were plotted against time as shown in FIG. 4. The intrinsic dissolution rate was derived from the slope of this curve. Table 4 shows the results in tabular form.

TABLE-US-00004 TABLE 4 TIME IN (10:1) PVPK (10:1) PVPK MINS COMPLEX PHYSICAL MIXTURE 15 1.01 0.41 30 1.81 0.38 45 2.63 0.44 60 3.41 0.54 120 6.50 0.94 180 9.65 1.34 240 12.76 1.83 360 18.78 3.86 480 24.96 7.32 600 30.90 10.83 720 36.68 13.82 840 42.74 16.43 960 48.70 18.73 1080 53.95 21.13 1200 59.02 23.50 1320 63.10 25.54 1440 65.72 27.08

Example 14

[0138] Example 10 was repeated using Beta cyclodextrin instead of PVPK and the percentage of rifaximin released from the CD complex (1:2 w/w) as well as from the physical mixture (1:2 w/w) were plotted against time as shown in FIG. 5. The intrinsic dissolution rate was derived from the slope of this curve. Table 5 shows the results in tabular form.

TABLE-US-00005 TABLE 5 (1:2) BETA (1:2) BETA TIME IN CYCLODEXTRIN CYCLODEXTRIN MINS COMPLEX PHYSICAL MIXTURE 15 0.48 0.17 30 0.82 0.25 45 1.35 0.35 60 2.05 0.48 120 4.83 0.80 180 7.67 1.33 240 9.87 1.81 360 15.23 2.82 480 20.21 4.14 600 23.58 4.84 720 25.33 6.43 840 24.97 6.97 960 25.67 7.19 1080 26.37 8.80 1200 26.37 8.50

Example 15

[0139] Example 11 was repeated using Beta cyclodextrin instead of PVPK and the percentage of rifaximin released from the CD complex (1:1 w/w) as well as from the physical mixture (1:1 w/w) were plotted against time as shown in FIG. 6. The intrinsic dissolution rate was derived from the slope of this curve. Table 6 shows the results in tabular form.

TABLE-US-00006 TABLE 6 (1:1) BETA (1:1) BETA TIME IN CYCLODEXTRIN CYCLODEXTRIN MINS COMPLEX PHYSICAL MIXTURE 15 0.85 0.17 30 1.46 0.29 45 2.29 0.40 60 3.04 0.53 120 6.02 0.95 180 9.07 1.39 240 12.08 1.89 360 17.88 2.86 480 23.66 4.97 600 29.22 4.93 720 34.43 5.88 840 37.54 6.69 960 38.32 7.27 1080 38.49 7.82 1200 38.66 8.32

Example 16

[0140] Example 12 was repeated using Beta cyclodextrin instead of PVPK and the percentage of rifaximin released from the CD complex (4:1 w/w) as well as from the physical mixture (4:1 w/w) were plotted against time as shown in FIG. 7. The intrinsic dissolution rate was derived from the slope of this curve. Table 7 shows the results in tabular form.

TABLE-US-00007 TABLE 7 (4:1) BETA TIME IN (4:1)BETA CYCLODEXTRIN MINS CYCLODEXTRIN PHYSICAL MIXTURE 15 1.09 0.52 30 2.85 0.64 45 3.54 0.81 60 6.29 1.01 120 10.61 1.91 180 15.88 2.33 240 18.66 3.09 360 26.97 3.64 480 34.74 4.28 600 42.07 4.36 720 47.29 8.14 840 54.05 8.92 960 60.82 11.09 1080 66.13 10.90 1200 68.04 11.39

Example 17

[0141] Example 13 was repeated using Beta cyclodextrin instead of PVPK and the percentage of rifaximin released from the CD complex (10:1 w/w) as well as from the physical mixture (10:1 w/w) were plotted against time as shown in FIG. 8. The intrinsic dissolution rate was derived from the slope of this curve. Table 8 shows the results in tabular form.

TABLE-US-00008 TABLE 8 (10:1) BETA TIME IN (10:1) BETA CYCLODEXTRIN MINS CYCLODEXTRIN PHYSICAL MIXTURE 15 0.96 0.28 30 1.78 0.38 45 2.58 0.49 60 3.36 0.56 120 6.65 1.00 180 9.84 1.37 240 12.87 1.78 360 19.00 2.58 480 25.52 3.41 600 31.48 4.22 720 37.35 4.92 840 43.19 5.65 960 46.88 6.34 1080 48.74 7.01 1200 49.97 7.67 1320 49.81 8.28 1440 50.01 8.86

[0142] The results were reported on an average of 2 results each.

[0143] When compared with a physical mixture of rifaximin with a complexing agent, the rifaximin complex exhibited a superior rate of dissolution as shown in Tables 9 and 10 below.

[0144] The percentage of actual release of rifaximin is calculated from the characteristics data obtained in the FIGS. 1 to 8. The formula for calculating the percentage of actual release of rifaximin from the complex is given below:

[00001]$\%\mathrm{of}\mathrm{actual}\mathrm{release}\mathrm{of}\mathrm{rifaximin}=\frac{\%\mathrm{release}\mathrm{of}\mathrm{rifaximin}\mathrm{from}\mathrm{the}\mathrm{complex}}{\mathrm{wt}\%\mathrm{of}\mathrm{rifaximin}\mathrm{in}\mathrm{the}\mathrm{complex}}\times 100$

TABLE-US-00009 TABLE 9 The Actual release of Rifaximin from Rifaximin- PVP complex compared with physical mixture:- Content of complexing % Rifaximin released % Rifaximin released agent (w/w) from PVP complex from Physical mixture 1:2 92.67 68.05 1:1 84.52 33.98 4:1 88.85 42.29 10:1  73.00 30.09

[0145] The above data shows that the PVP complex has more advantage over a physical mixture. This advantage is maximum at lower concentration of PVP i.e. when ratio is 10:1 (73:30), whereas at high concentration i.e. when ratio is 1:2 or 33.3% the advantage is about 1.36 times (92.67:68.05)

TABLE-US-00010 TABLE 10 The Actual release of Rifaximin from Rifaximin-CD complex compared with physical mixture:- Content of complexing % Rifaximin released % Rifaximin released agent (w/w) from CD complex from Physical mixture 1:2 79.18 25.52 1:1 77.32 16.64 4:1 85.00 14.23 10:1  55.55 9.84

[0146] The above data shows that, the CD complex has more advantage over a physical mixture. This advantage is maximum at a lower concentration of CD i.e. when the ratio is 10:1 (55.55:9.84), whereas at high concentration i.e. when ratio is 1:2 or 33.3% the advantage is about 3.1 times (79.18:25.52)

[0147] These results further proved that rifaximin complex had been formed after this technique.

[0148] It will be appreciated that the invention may be modified within the scope of the appended claims.