FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising rifampicin and piperine with enhancement in bioavailability of rifampicin by piperine. The present invention further relates to process for preparing pharmaceutical composition comprising rifampicin and piperine.

BACKGROUND OF THE INVENTION

Tuberculosis (abbreviated as TB for tubercle bacillus or Tuberculosis) is a common and often deadly infectious disease caused by mycobacteria. Tuberculosis usually attacks the lungs (as pulmonary TB) but can also affect the central nervous system, the lymphatic system, the circulatory system, the genitourinary system, the gastrointestinal system, bones, joints, and even the skin. Other mycobacteria such as Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti, and Mycobacterium microti also cause tuberculosis, but these species are less common in humans.

US Patent No. 5,439,891 discloses about the process for preparation of pharmaceutical composition for the treatment of tuberculosis and leprosy, said composition comprising piperine in combination with known antituberculosis drugs. It does not disclose excipients or quality of active ingredients. When such pharmaceutical compositions are made having rifampicin, these formulations showed different pharmacokinetic properties.

Thus, there is a need to develop a pharmaceutical composition comprising rifampicin and piperine with enhancement in the bioavailability of rifampicin by piperine with use of appropriate excipients and quality of active ingredients.

According to present invention, it is found that bioenhancernent property of piperine with rifampicin containing formulation depends on type of rifampicin, selection of excipients and manufacturing process.

SUMMARY OF THE INVENTION:

The object of the present invention is to provide a pharmaceutical composition of rifampicin and piperine with enhanced bioavailability.

Another object of the present invention is to provide a pharmaceutical composition comprising rifampicin and piperine with enhancement in bioavailability of rifampicin by piperine.

Another object of the present invention is to provide excipients for manufacturing of pharmaceutical composition comprising rifampicin and piperine with enhancement in bioavailability of rifampicin by piperine. Another object of the present invention is to provide process for manufacturing of pharmaceutical composition comprising rifampicin and piperine with enhancement in bioavailability of rifampicin by piperine.

It has surprisingly found that use of compacted form of rifampicin resulted in reduction of bioavailability of rifampicin, wherein powdered form of rifampicin resulted in enhanced bioavailability of rifampicin.

It was further found that the mere admixture of piperine and powder rifampicin was not show the enhancement in bioavailability of rifampicin. It was surprisingly found that bioenhancing property of piperine depends on physical property of rifampicin, selection of excipients and manufacturing process.

It was observed that blending of rifampicin powder, starch and magnesium stearate with piperine tablets / powder / granules showed higher bioavailability of rifampicin.

The piperine portion of the formulation was prepared by wet granulation / compaction / direct blending. The rifampicin portion of the formulation was prepared by direct blending process using starch and magnesium stearate.

The formulation of the present invention is used to prepare capsules or tablets.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to a pharmaceutical composition comprising rifampicin and piperine with enhancement in bioavailability of rifampicin by piperine.

The composition of some of the marketed samples of rifampicin is provided as below: a) Rimactan ^® Capsules from Sandoz contains Lactose monohydrate, Soya-bean lecithin, Gelatin, Dimeticone, Shellac, Calcium stearate, Titanium dioxide, Iron oxide b) Rifadin ^® Capsules from Ab Ferrosan contains Indigo carmine, Titanium dioxide, Starch, Magnesium stearate, Gelatin and Cochineal Red A

c) Rifampin Capsule from Actavis Totowa contains Lactose monohydrate, Magnesium stearate, Methylparaben, Propylparaben, Silicon dioxide, Sodium lauryl sulfate, Corn starch, Talc, and Titanium dioxide.

d) Rifampin Capsule from Lannett Company contains Pregelatinized starch, Colloidal silicon dioxide, Talc, Magnesium stearate, and Titanium dioxide.

e) Rifampin Capsule from VersaPharm Incorporated contains Lactose monohydrate, Magnesium stearate, Sodium lauryl sulfate, Talc, and Titanium dioxide.

The present invention relates to a pharmaceutical composition comprising rifampicin and piperine with enhancement in bioavailability of rifampicin by piperine wherein the said composition has desired stability, bioavailability and which is easy to swallow.

Generally it is believed that increased bulk density improves bioavailability. However, surprisingly it was observed that bioavailability is better with a powder form of rifampicin compared to compacted form of rifampicin with identical bulk density or high bulk density. As per the present invention, the enhanced bioavalability of rifampicin by piperine is observed with powder form of rifampicin with bulk density > 0.4 gm/cc and particle size d ₉₀ < 250 μ.

In the present invention process of preparing pharmaceutical composition of rifampicin and piperine comprising steps:

A) Preparing rifampicin blend comprises steps:

A1 ) Preparing a mixture by mixing rifampicin powder and starch A2) lubricating the mixture of step - A1 with magnesium stearate to give rifampicin Blend.

B) Preparing piperine tablet comprises steps:

B1) Preparing a base granule.

This is achieved by granulating a mixture of lactose, starch and Sodium lauryl sulphate by starch paste followed by drying and shifting

B2) preparing a mixture of piperine and base granules of step - B1)

B3) mixing the step - B2) with Sodium lauryl sulphate, croscarmellose sodium and colloidal solicondioxide followed by lubricating with magnesium stearate B4) slugging the mixture of step - B3 followed by shifting

B5) lubricating the mixture of step - B4) with colloidal solicondioxide and

magnesium stearate

B6) compressing mixture of step - B5) into tablets.

C) Processing step - A with step - B to give a pharmaceutical composition of rifampicin

The rifampicin blend (rifampicin portion) of the formulation was prepared by preparing a mixture of rifampicin powder + starch followed by lubricating with magnesium stearate.

The base granules prepared by granulating a mixture of lactose, starch and Sodium lauryl sulphate by starch paste followed by drying and shifting.

The piperine tablets (piperine portion) of the formulation was prepared by mixing the mixture of base granules + piperine with the mixture of Sodium lauryl sulphate, croscarmellose sodium and colloidal solicondioxide, followed by lubricating with magnesium stearate. The prepared mixture was slugged and shifted through 30 # s.s screen, followed by lubricating with colloidal solicondioxide and magnesium stearate and further compressed to give piperine tablets.

The rifampicin blend (rifampicin portion) of the formulation and the piperine tablets (piperine portion) of the formulation were processed further to give a pharmaceutical composition comprising rifampicin and piperine.

The pharmaceutically acceptable excipients includes diluent, binder, disintegrant, lubricant, glidant, stabilizer, surfactant, organic solvent, water, film forming polymer, opacifier, plasticizer, modified release polymer and the like. The diluents are selected from microcrystalline cellulose, directly compressible grade microcrystalline cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, maltodextrin, mannitol and the like, preferably starch.

The binders are selected from acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), Hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate and starch.

The surfactant like polysorbate, anionic surfactant and nonionic surfactant improves the effect of piperine on bioavailability of rifampicin. Examples of the above-mentioned nonionic surfactant are, for instance, polyoxyethylamine oxides, alkylamine oxides, polyoxyethylene alkyl ethers, polyoxyethylene alkyl phenyl ethers, polyoxyethylene fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, glycerine esters, polyoxyethylene alkylamine, the derivatives thereof, and the like. Anionic surfactants are selected from higher fatty acid and its salt, alkyl sulfate, alkyl sulfonate, alkyl aryl sulfonate, alkyl phosphoric acid ester and the like, preferably Sodium lauryl sulphate. The stabilizer like citric acid is also useful in present invention.

The lubricants are selected from Magnesium stearate, Sodium stearyl fumarate, Stearic acid, Talc, Colloidal silicon dioxide and the like, preferably Magnesium stearate.

The disintegrants are selected from alginic acid, croscarmellose sodium, sodium starch glycolate, crospovidone, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate and starch, preferably croscarmellose sodium. The disintegrant is in the range of 0.1% to 10% of total weight of dosage form. Surprisingly, it was found that use of croscarmellose sodium in piperine granules / tablets resulted in better bioavailability of rifampicin.

.The solvents are selected from purified water, alcohols, ketones, esters, ethers, halogenated solvents, hydrocarbons, nitriles, or mixtures thereof. Lower alkanols are useful and any alcohol such as for example one or more of the primary, secondary or tertiary alcohols having from one to about six carbon atoms. The lower alkanol is selected from one or more of methanol, ethanol, denatured spirits, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol and the like. The ketones are of any solvent from this class such as for example one or more of acetone, propanone, 2-butanone and the like. The halogenated solvent is of any solvent from this class such as for example one or more of chloroform, dichloromethane, 1 , 2-dichloroethane, carbon tetrachloride and the like.

The invention is further illustrated with following non-limiting examples: Example I: The following are the examples of pharmaceutical composition to demonstrate the effect of quality of rifampicin on rifampicin bioavailability

Formulation A was prepared by mixing powder form of rifampicin and other

pharmaceutically acceptable excipients. No piperine was added in the formulation A.

Formulation B was prepared by mixing compacted form of rifampicin, piperine and other pharmaceutically acceptable excipients.

Formulation C was prepared by mixing powder form of rifampicin, piperine and other pharmaceutically acceptable excipients.

# Powder form of Rifampicin with bulk density of 0.76 gm/cc and particle size dg_ is 150

^* Compacted form of Rifampicin with bulk density of 0.82 gm/cc and particle size doo is 150

Process description:

For Formulation A:

1. Rifampicin was sifted through 16 # s.s screen.

2. A blend of Citric acid, Lactose, Starch, Sodium starch glycolate, Magnesium stearate, Sodium lauryl sulphate and Colloidal silicon dioxide were sifted through 40 # s.s screen.

3. Rifampicin and blend from step 2 were mixed thoroughly.

4. The blend from step 3 was filled in hard gelatin capsule shell.

For formulation B and Formulation C:

1. Rifampicin was sifted through 16 # s.s screen. 2. Piperine and a blend of Citric acid, Lactose, Starch, Sodium starch glycolate, Magnesium stearate, Sodium lauryl sulphate and Colloidal silicon dioxide were sifted through 40 # s.s screen.

3. Rifampicin and blend from step 2 were mixed thoroughly.

4. The blend from step 3 was filled in hard gelatin capsule shell.

These formulations were subjected to in-vivo studies in human volunteers. The observation based on the study is summarized as follows:

a. The pharmacokinetic parameters C _max (μg/ml), AUC ₍₀ - _t ) (hr X μg/ml) and AUC(O--) (hr X μg/ml) of formulation A was lowest and with formulation C was highest.

b. The parameters were higher with formulation B compared to formulation A but were surprisingly significantly lower than formulation C.

The above results demonstrate that piperine enhances the bioavailability of rifampicin. The powder grade of rifampicin provides better bioavailability than compacted grade rifampicin inspite of lower bulk density and same particle size.

Example II: The following examples shows the effect of excipients on

bioenhancement of rifampicin

Formulation A and formulation B were prepared by mixing powder form of rifampicin, piperine and other pharmaceutically acceptable excipients.

Process description:

A. Rifampicin Blend for Formulation A 1. Rifampicin was sifted through 16 # s.s screen.

2. Citric acid, Lactose, Starch, Sodium starch glycolate, Magnesium stearate, Sodium lauryl sulphate and Colloidal silicon dioxide were sifted through 40 # s.s screen.

3. Rifampicin and blend from step 2 was mixed thoroughly.

A'. Rifampicin Blend for Formulation B

1. Rifampicin and starch were sifted through 16 # s.s screen and 40 # s.s screen respectively and mixed

2. Magnesium stearate was sifted through 40 # s.s screen

3. lubricated the mixture of step -1 with step - 2.

B. Piperine Tablet

For Formulation A and Formulation B, the rifampicin blend and piperine tablet were filled in hard gelatin capsule.

These Formulation A and Formulation B were subjected to pharmacokinetic studies in human volunteers for evaluating bioavailability of Rifampicin.

The pharmacokinetic parameters like C _max AUC ₍₀ -t) and AUC ( ₀ -») were found to be higher with Formulation B compared to formulation A by 42%, 24% and 15.31% respectively. Thus, the preferred composition shows enhanced bioavailability of rifampicin.

Example III: The following example shows the effect of dissolution profile of piperine tablet on rifampicin bioavalability:

Rifampicin blend and piperine tablets with various dissolution profiles were prepared. When it was added to rifampicin blend, the bioavalability of rifampicin was found to be higher with a piperine tablet having higher dissolution.

The tablets of piperine were made with dissolution profile more than 90% in 10 minutes to 70% in 90 minutes.

The rifampicin bioavalability was lower with piperine tablet having dissolution profile 70% in 90 minutes and was higher with piperine tablets having dissolution profile more than 90% in 10 minutes.

For Formulation A and Formulation B ₁ the rifampicin blend and piperine tablet were filled in hard gelatin capsule. The dissolution profile of piperine for formulation B was 20% more than formulation A in 10 minutes.

These Formulation A and Formulation B were subjected to pharmacokinetic studies in human volunteers for evaluating bioavailability of Rifampicin.

The pharmacokinetic parameters like C _max , AUC ₍₀ - _t ) and AUC _(0- » ₎ were found to be higher with Formulation B compared to formulation A. Example IV: The following examples shows the effect of form of piperine in a formulation on bioenhancement of rifampicin

Formulation A: Rifampicin Blend + Piperine (10 mg)

Formulation B: Rifampicin Blend + Piperine Tablet

Process description:

A. Rifampicin Blend

B. Piperine Tablet for Formulation B

1. Piperine was sifted through 60 # s.s screen.

a. Base granules:

1. Lactose, Starch and Sodium lauryl sulphate were sifted through 40 # s.s screen.

2. Above blend was granulated with starch paste prepared in purified water.

3. The wet mass was dried in tray dryer. 4. Dried granules were sifted through 30 # s.s screen.

b. Pre Lubrication:

1. The base granules and piperine were mixed geometrically.

2. Sodium lauryl sulphate, Croscarmellose sodium, Colloidal silicondioxide and Magnesium stearate were sifted through 40 # s.s screen.

3. The blend from step 1 and step 2 were mixed thoroughly.

Slugging:

1. The above blend was slugged and was sifted through 30 # s.s screen.

c. Final Lubrication.

1. Colloidal silicon dioxide and Magnesium stearate were sifted through 40 # s.s screen.

The slugged granules and lubricants were mixed and compressed into tablets.

For Formulation A, the rifampicin blend and powdered piperine were added in hard gelatin capsule. For Formulation B, the rifampicin blend and piperine tablet were filled in hard gelatin capsule.

These Formulation A and Formulation B were subjected to pharmacokinetic studies in human volunteers for evaluating bioavailability of Rifampicin.

The pharmaceokinetics parameters like C _ma χ, AUC ₍₀ -t) and AUC _(0- ~) were found to be higher with Formulation B compared to formulation A

The above results demonstrate that bioenhancement of rifampicin by piperine depends on form of rifampicin and piperine as well as pharmaceutical excipients used.