FIELD OF THE INVENTION

The present invention relates to a solid oral pharmaceutical composition comprising rifampicin, piperine as a bioenhancer for rifampicin and isoniazid is in delayed release form.

The present invention further relates to process for preparing a solid oral pharmaceutical composition comprising rifampicin, piperine as a bioenhancer for rifampicin and isoniazid is in delayed release form. 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.

The management of tuberculosis treatment is difficult due to development of drug resistance by the microbes. Fixed dose combination (FDC) tablets provide a simple approach to delivering the drugs at their correct dosage when the drugs are formulated in a single tablet.

Some marketed pharmaceutical composition of rifampicin and / or isoniazid involves the use of variety of excipients in the composition which are as under:

a) Rimactan ^® Capsules (Rifampicin 150 mg) from Sandoz contains Lactose monohy- drate, Soya-bean lecithin, Gelatin, Dimeticone, Shellac, Calcium stearate, Titanium dioxide, Iron oxide

b) Rifadin ^® Capsules (Rifampicin 150 mg / 300 mg) from Ab Ferrosan contains Indigo carmine, Titanium dioxide, Starch, Magnesium stearate, Gelatin and Cochineal Red A

c) Rifampin Capsule (Rifampicin 150 mg) from Actavis Totowa contains Lactose mono- hydrate, Magnesium stearate, Methylparaben, Propylparaben, Silicon dioxide, Sodium lauryl sulfate, Corn starch, Talc, and Titanium dioxide.

d) Rifampin Capsule (Rifampicin 150 mg / 300 mg) from Lannett Company contains Pregelatinized starch, Colloidal silicon dioxide, Talc, Magnesium stearate, and Tita- nium dioxide.

e) Rifampin Capsule (Rifampicin 150 mg) from VersaPharm Incorporated contains Lactose monohydrate, Magnesium stearate, Sodium lauryl sulfate, Talc, and Titanium dioxide. f) Rimactazid ^® Tablets (Rifampicin 450 mg + Isoniazid 300 mg or Rifampicin 150 mg + Isoniazid 75 mg ) from Ciba contains Calcium stearate, Sodium lauryl sulphate, Maize starch, Sodium carboxymethylcellulose, Talc, Hydroxypropyl methylcellulose, Povidone, Titanium dioxide, Cellulose, Polyethylene glycol, Sugar (Sucrose), Red iron oxide, Yellow iron oxide

g) Tibinide ^® Tablets (Isoniazid 300 mg) Recipharm Stockholm AB contains microcrystal- line cellulose, Stearic acid, Talc and Colloidal silicondioxide

WHO recommended fixed dose combination of rifampicin and isoniazid for daily therapy includes rifampicin and isoniazid in a ratio of 2 1 or 3 2 The amount of rifampicin is 60 mg and 150 mg In all such pharmaceutical composition rifampicin content is equal to or higher than isoniazid content

Examples of fixed dose combination of rifampicin and Isoniazid recommended by WHO includes

1 Rifampicin 150 mg

Isoniazid 75 mg

2 Rifampicin 60 mg

Isoniazid 30 mg

3 Rifampicin 450 mg

Isoniazid 300 mg

US Patent No 5,439,891 (US '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 A pharmaceutical composition of US '891 involve the use of piperine in the range of 0 4 to 0 9% by weight of antituberculosis drugs or antileprosy drugs

Us patent No 7,195,769 (US 769) discloses about the pharmaceutical composition of Anti-tubercular drugs and process for their preparation It discloses examples of rifampicin and isoniazid wherein amount of rifampicin and isoniazid are in a therapeutic dose as per WHO guidelines The amount of Rifampicin is higher than Isoniazid in these formulations The amount of incorporated drugs does not suggest significant bioenhancement of rifampicin

Surprisingly, it was observed when Isoniazid is added to the pharmaceutical compositions comprising rifampicin and piperine the enhanced bioavailability of Rifampicin by piperine was lost The present invention provides pharmaceutical compositions comprising rifampicin, isoniazid and piperine wherein the enhanced bioavailability of rifampicin by piperine is maintained in presence of isoniazid

SUMMARY OF THE INVENTION:

The object of present invention is to provide a solid oral pharmaceutical composition comprising rifampicin, piperine as a bioenhancer for rifampicin, and isoniazid, wherein enhanced bioavailability of rifampicin by piperine is maintained

Another object of the present invention is to provide a solid oral pharmaceutical composition comprising rifampicin, piperine and isoniazid in delayed release form to maintain bioenhancement of rifampicin by piperine

Yet another object of the present invention is to provide process for preparing a solid oral pharmaceutical composition comprising rifampicin, piperine and isoniazid in delayed re- lease form to maintain bioenhancement of rifampicin by piperine

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to provide a solid oral pharmaceutical composition comprising rifampicin, piperine as a bioenhancer for rifampicin and isoniazid wherein en- hanced bioavailability of rifampicin is maintained

It is known that addition of piperine to rifampicin enhances bioavailability of rifampicin by 40 to 60%

However, when isoniazid was administered separately with the pharmaceutical composition containing rifampicin and piperine, the bioavailability of rifampicin was found to be significantly reduced as compared to administration of the pharmaceutical composition containing rifampicin and piperine

It is also observed that isoniazid when incorporated into pharmaceutical composition containing rifampicin and piperine, the bio-effect of piperine on bioavailability of rifampicin is lost This is observed as long as all these ingredients are in immediate release form

Thus, there is a need to provide a pharmaceutical composition wherein improved bioavailability of Piperine is maintained in presence of Isoniazid

Surprisingly, it is observed that when isoniazid is provided as a delayed release form, the enhanced bioavailability of Rifampicin by Piperine is maintained

As per present invention, the pharmaceutical composition for daily therapy of nfam- picin, isoniazid and Piperine are such that required amount of rifampicin is lower than isoniazid due to enhanced bioavailability of rifampicin by piperine This is in contrast to available formulation wherein amount of rifampicin is more than isoniazid

The ratio of rifampicin to isoniazid as per current invention for daily therapy ranges from 0 3 to 0 9 In the present invention process of preparing pharmaceutical composition comprising rifampicin, piperine as a bioenhancer for rifampicin and isoniazid in delayed release form comprises following steps

A) Preparing rifampicin and piperine blend

B) Preparing isoniazid delayed release form

C) processing step - A with step - B to give pharmaceutical composition of rifampicin, piperine and Isoniazid

The Rifampicin and Piperine are selected from powder form, granulation or tablet They need to be preferably in immediate release form

The Isoniazid delayed release form is prepared by coating Isoniazid with polymer to delay its release Enteric coating is one of the methods for delayed release

The delayed release polymer used as per present invention are selected from natural and semi-synthetic and synthetic polymerns such as cellulose and cellulose derivatives like methyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, cel- lulose acetate phthalate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate trimellitate, cellulose carboxymethyl ethers and their salts, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate and other delayed release polymers like polymethacrylates

The preferred range of piperine quantity is 5mg to 20 mg by weight

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), car- boxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vege- table 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 Nonionic surfactant are, selected from polyoxyethylamme 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 de- πvatives thereof, and the like anionic surfactant, there can be used known ones, for example, 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 disintegrates are selected from alginic acid, carboxymethyl cellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, sodium starch glycolate, crospovi- done, polacrilin potassium, powdered cellulose, pregelatmized starch, sodium alginate and starch 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 or 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-dιchloroethane, carbon tetrachloride and the like The esters are of any solvent from this class sucjh as for example one or more of ethyl acetate, n - propyl acetate, isopropyl acetate, n - butyl acetate and the like The ethers are of any solvent from this class sucjh as for example one or more of dimethyl ether, diethyl ether, methyl tertiary-butyl ether, ethyl methyl ether, di isopropyl ether, tetrahydrofuran, dioxane and the like

The invention is further illustrated with following non-limiting examples

Example I: The following example demonstrates the loss of bioenhancinq property of piperine with respect to rifampicin in presence of isoniazid:

Formulation A: It was prepared by mixing rifampicin (200 mg) and other pharmaceutically acceptable excipients The formulation was filed in hard gelatin capsule Formulation B: It was prepared by mixing rifampicin (200mg), piperine (10 mg) and other pharmaceutically acceptable excipients The formulation was filed in hard gelatin capsule

Formulation C: It was prepared by mixing rifampicin, piperine, and other pharmaceutically acceptable excipients The rifampicin (200 mg), piperine (10 mg) and other pharmaceutically acceptable excipients were filed in hard gelatin capsule The isoniazid capsule containing 300 mg isoniazid with immediate release was administered separately

Formulation D: It was prepared by mixing rifampicin, isoniazid, piperine and other pharma- ceutically acceptable excipients The rifampicin (200 mg), isoniazid (300 mg), piperine (10 mg) and other pharmaceutically acceptable excipients were filed in hard gelatin capsule

These formulations were subjected to pharmacokinetic studies in human volunteers for evaluating bioavailability of rifampicin The data of the same for rifampicin is summarized as follows

The formulation B had a significant enhancement of bioavailability of rifampicin as compared to formulation A It was also observed that the formulation B shows pharmacokinetic results equivalent to formulation of rifampicin containing 450 mg of rifampicin as a conventional dosage form without piperine

However, when isoniazid was added to the formulation B (ι e formulation C and formulation D), the enhancement of bioavailability of rifampicin by piperine was reduced and found to be similar with formulation A

Example II: The following example illustrates pharmaceutical composition as per pre- sent invention:

Formulation E:

1 Rifampicin 270 mg

2 Isoniazid delayed release tablet 300 mg

3 Piperine tablet 20 mg

Formulation F:

1 Rifampicin 200 mg

2 Isoniazid delayed release granules 300 mg

3 Piperine granules 10 mg

Formulation G:

1 Rifampicin 200 mg

2 Isoniazid delayed release pellets 300 mg

3 Piperine granules 15 mg

Formulation H:

1 Rifampicin 270 mg

2 Isoniazid delayed release pellets 300 mg 3 Piperine granules 10 mg

Formulation I:

1 Rifampicin 70 mg

2 Isoniazid delayed release granules 75 mg

3 Piperine granules 10 mg

Formulation J:

1 Rifampicin 200 mg

2 Isoniazid delayed release tablets 300 mg

3 Piperine granules 20 mg

The results of above formulations demonstrate that bioavailability of rifampicin maintained in presence of isoniazid, when isoniazid is administered in delayed release form and rifampicin and piperine are administered in immediate release form

Example III: The following examples demonstrate enhanced bioavailability of

Rifampicin by piperine in presence of isoniazid: Formulation K: It was prepared by mixing rifampicin, piperine, isoniazid and other pharmaceutically acceptable excipients, wherein piperine is in tablet form and isoniazid is in delayed release tablet form

The rifampicin blend from stage-A, single tablet of piperine from stage-B and two delayed release tablet 150 mg each from stage-C were filled in hard gelatin capsule

Formulation L: It was prepared by mixing rifampicin, piperine, isoniazid and other pharma- ceutically acceptable excipients, wherein piperine is in granule form and isoniazid is in delayed release tablet form

Process description:

A. Isoniazid delayed release Tablet:

I. Core Tablet

I . Isoniazid was sifted through 40# s s screen and was mixed, granulated. Dried and lubricated with suitable pharmaceutically acceptable excipients followed by compressed into tablets.

II. Seal Coating

1. The tablets were barrier coated with lnstacoat Moist shield using Non-aqueous

coating.

III. Coating-I

1. The tablets were coated with lnstacoat ^® EN-HPMC-P using Non-aqueous coating.

B. Piperine Granules:

1. Piperine was sifted through 30# s.s screen and was mixed with suitable pharmaceutically acceptable excipients to give piperine granules.

C. Rifampicin Blend:

1. Rifampicin, Starch and Magnesium stearate were sifted through 60 # s.s screen and mixed well.

The two delayed release_tab!ets of Isoniazid 150 mg each from stage-A, granules of piperine from stage-B and blend of rifampicin from stage-C were filled in hard gelatin capsule.

The formulation K and formulation L were subjected to pharmacokinetic studies in human volunteers for evaluating bioavailability of Rifampicin. The data of the same for rifampicin is summarized as follows:

The pharmacokinetic parameters C _max (μg/ml), AUC ₍₀ . ₍₎ (hr X μg/ml) and AUC ₍₀ .« ₎ (hr X μg/ml) of formulation K and formulation L shows enhanced bioavailability of rifampicin as compared to formulation C and formulation D of example I The values were bioequivalent to formulation B of example I

The above results demonstrate that bioavailability of rifampicin maintained in presence of isoniazid, when isoniazid is administered in delayed release form and rifampicin and piperine are administered in immediate release form