The present invention relates to an inclusion complex of Rifampicin and cyclodextrin (CD) that can be used as an anti-tubercular drug. The present invention also relates to a process for synthesizing inclusion complexes of the anti-tubercular drug, Rifampicin, with β-CD (β-cyclodextrin) and HP-β-CD (2-hydroxy propyl cyclodextrin) and characterization of these inclusion complexes.

BACKGROUND OF INVENTION

The present invention relates to an inclusion complex comprising Rifampicin and cyclodextrin useful as drug in tuberculosis. The present invention also relates to synthesis of Rifampicin-cyclodextrin inclusion complexes, which find use in tuberculosis therapy as drug delivery systems.

Rifampicin is an international nonproprietary name. Other names used are Rifamycin AMP, Rifampin and Rifaldazine. Rifampicin is designated by IUPAC rules as 2,7-(epoxy pentadeca[1,11,13]trienimino)naphtho[2,1-b]furan1,11(2H)-dione5,6,9,17,19,21-hexa-
hydroxy-23-methoxy-2,4,12,16,18,20,22-hepta methyl-8-[N-(4-methyl-1-
piperazinyl)formimidoyl]-21-acetate. Rifampicin is a commonly used anti-mycobacterial drug for the treatment of tuberculosis.

Cyclodextrins (CDs) are cyclic oligosaccharides possessing hydrophobic cavities. CDs can be used in combination with various drugs either for complexation or as auxiliaries such as diluents, solubilizers or tablet ingredients (Comprehensive Supramolecular Chemistry, Vol 3, Szejtli J, Osa T, Pergamon, UK, 1996). The advantage of using CDs mainly comes from their inclusion complex formation. The complexation can protect the molecule and can eventually have considerable pharmaceutical potential.

There are various advantages for drug delivery using inclusion complex formation. Incompatible drugs can be mixed when one of them is complexed with CDs. The release rate of drugs can be controlled. The solubility of water insoluble drugs can be improved. The instability of drugs in water and the acidic environment of the stomach conditions can be improved, since the rate of hydrolysis, photo-decomposition, auto-catalytic reactions etc., are considerably reduced. Furthermore, percutaneous or rectal absorption can be improved by the enhanced release of drugs from ointments or suppository bases. Thus, CD inclusion complexes of drugs have several advantages.

The inclusion complex formation can be characterized by powder X-ray diffraction patterns and IR spectroscopy (Comprehensive Supramolecular Chemistry, Vol 3, Szejtli J, Osa T, Pergamon, UK, 1996).

A recent publication has reported the impaired bioavailability of Rifampicin in the presence of Isoniazid, an antimycobacterial drug also used in treatment of tuberculosis, in fixed dose combinations (FDCs) due to the decomposition of Rifampicin in the stomach (Chronicle Pharmabiz, p. 28, Dec. 20, 2001). The acidic environment of the stomach causes Rifampicin to be hydrolyzed to an insoluble, less absorbable form. Thus, there is a need for a formulation that protects Rifampicin from degradation in the acidic environment of the stomach.

The present invention contemplates a Rifampicin and β-cyclodextrin containing inclusion complex that may be used in the treatment of tuberculosis. This formulation is also potentially advantageous since stability and release can be controlled. Combinations of Rifampicin and cyclodextrin formulations reported so far are only dispersions of Rifampicin and cyclodextrin (East. Pharm., p. 133, vol. 41(492), 1998), that have not been isolated and characterized inclusion complexes containing Rifampicin and cyclodextrin.

Accordingly, studies were undertaken to make the inclusion complexes of Rifampicin with β-cyclodextrin (β-CD) and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD).

SUMMARY OF THE INVENTION

The present invention relates to an inclusion complex of Rifampicin with cyclodextrin (CD) that can be used as an anti-tubercular drug. The present invention also relates to a process for synthesizing inclusion complexes of the anti-tubercular drug, Rifampicin, with β-CD (β-cyclodextrin) and HP-β-CD (2-hydroxy propyl cyclodextrin) and characterization of these inclusion complexes. In addition, a further aspect of the invention is to provide a general process for preparing inclusion complexes of cyclodextrin with large size molecules.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an inclusion complex of Rifampicin with cyclodextrin as an anti-tubercular drug.

One embodiment of the invention provides an inclusion complex, wherein the cyclodextrin used is selected from β-cyclodextrin and 2-hydroxy propyl cyclodextrin.

The inclusion complex enhances the bioavailability and solubility of the drug Rifampicin.

The inclusion complex and the drug exist in an encapsulated form can lead to controlled release of the drug.

Fixed dose combination (FDC) formulations facilitate treatment of tuberculosis since the correct number of drugs in the correct dosages are combined in a single tablet. The inclusion complex of the present invention provides a new approach to anti-tuberculosis therapy containing fixed dose combination.

The inclusion complex is characterized by X-ray diffraction and infrared studies as shown in the Examples section.

The encapsulation of the drug under solid conditions is achieved to enhance bioavailability and solubility.

β-cyclodextrin (β-CD) is a cyclic oligosaccharide consisting of seven glucose units, with 2-Hydroxypropyl-α-cyclodextrin (HP-β-CD) being a β-cyclodextrin molecule substituted with a hydroxypropyl group at the 2-position of the glucose. HP-β-CD has also been used as a drug carrier due to its low toxicity, high tolerance and excellent solubilizing and stabilizing abilities. HP-β-CD has generally been found to be safe and no adverse effects were observed in human studies. (Comprehensive Supramolecular Chemistry, Vol 3, Szejtli J, Osa T, Pergamon, UK, 1996).

The cyclodextrins (FIG. 1) are cyclic oligosaccharides possessing hydrophobic cavities and mimic enzymes in their capability to bind substrates selectively and catalyze chemical reactions. β-Cyclodextrin consists of seven glucose units linked by α-1,4 glycosidic bonds into a macrocycle with a hydrophobic cavity. HP-β-CD is a substituted β-CD at 2-position with a 2-hydroxy propyl group. Each cyclodextrin has its own ability to form inclusion complexes with specific guests into the hydrophobic cyclodextrin cavity. The most important pharmaceutical application of cyclodextrins is to enhance the solubility and bioavailability of drug molecules.

In another embodiment, the present invention provides a process for preparation of inclusion complexes of Rifampicin with β-cyclodextrin, the process comprising adding Rifampicin to cyclodextrin and grinding in an agate mortar to form an uniform powdery material of Rifampicin-dextrin inclusion complex.

The process for the preparation of inclusion complexes of Rifampicin with β-cyclodextrin (β-CD) or 2-Hydroxypropyl β-cyclodextrin (HP-β-CD) which comprises a phenomenon of converting a free drug into an encapsulated form under solid state conditions. The formation of cyclodextrin complexes with Rifampicin may be with β-CD or HP-β-CD.

The Examples show a process for the synthesis of inclusion complexes of the anti-tubercular drug, Rifampicin with β-cyclodextrin (β-CD) or 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), which has been achieved for the first time.

The inclusion complexes of the anti-tubercular drug Rifampicin with cyclodextrins were prepared by adding Rifampicin in equimolar ratio to the respective cyclodextrins and intimately grinding the mixture using mortar and pestle for varying reaction times ranging from five to eight hours.

Accordingly, the present invention deals with the synthesis of inclusion complexes of the anti-tubercular drug, Rifampicin with β-CD or HP-β-CD. The synthesis of each compound perse is known in the art.

The compounds of the present invention contemplate a formulation for Rifampicin which is more stable and has considerable pharmaceutical potential. Incorporation of Rifampicin into an inclusion complex also allows for greater control over the drug release rate in the subject. There is also a possibility of improving the stability of Rifampicin in fixed dose combinations (FDCs). This invention may provide a new approach to anti-tuberculosis therapy containing FDCs.
 

Claim 1 of 14 Claims

1. An inclusion complex of Rifampicin and cyclodextrin with an X-ray diffraction profile where there are peaks at about 18.6, 25.5 and 46.4.
 

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