Title of Invention | A PROCESS FOR PREPARATION OF INCULSION COMPLEXES OF RIFAMPICIN WITH CYCLODEXTRIN |
---|---|
Abstract | A process for preparation of inclusion complexes of Rifampicin with cyclodextrin The present invention relates to a process for preparation of inclusion complexes of Rifampicin with cyclodextrin which is useful for treatment of tuberculosis. The invention also provides an inclusion complex of Rifampicin with cyclodextrin. The complex comprises equimolar ratio of Rifampicin and cyclodextrin and prepared by adding Rifampicin to cyclodextrin in equimolar ratio, grinding in mortar and pestle for a period of 5 to 8 hours to form a uniform powdery material of Rifampicin-dextrin inclusion complex. |
Full Text | The present invention relates to a process for preparation of an inclusion complex of rifampicin and cyclodextrin useful as an anti-tubular drug. The present invention also relates to synthesis of Rifampicin- cyclodextrin inclusion complexes, which find use in tuberculosis therapy as drug delivery systems. Background Art Rifampicin is the international nonproprietary name and 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 Jfuran 1, 11 ( 2H )- dione 5,6, 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. Cyclodextrins (CDs) are cyclic oligosaccharides possessing hydrophobic cavities. CDs can be used in drugs either for complexation or as auxiliaries such as diluents, solubilisers 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. Various advantageous effects of inclusion complex formation are as follows. i) Incompatible drugs can be mixed when one of them is complexed with CDs. ii) The release rate of drugs can be controlled. iii) The solubility of water insoluble drugs can be improved. iv) The instability of drugs in water / acidic stomach conditions can be improved as the rate of hydrolysis, photo decomposition, auto catalytic reactions etc. are considerably reduced. iv) 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 identified by powder X-ray diffraction patterns and IR spectroscopy (Comprehensive Supramolecular Chemistry, Vol 3, Szejtli J, Osa T, Pergamon, UK, 1996). Detailed of the Invention The present invention provides an inclusion complex of Rifampicin with cyclodextrin for treatment of tuberculosis comprising equimolar ratio of Rifampicin and cyclodextrin. In an embodiment of the invention provides an inclusion of complex, wherein the cyclodextrin used is selected from P-cyclodextrin and 2-hydroxy propyl cyclodextrin. Still another embodiment, the inclusion complex is characterized by X-ray diffraction and Infrared studies and the inclusion of complex has following physical and chemical characteristics. Still another embodiment, the inclusion complex enhances the bioavailability and solubility of the drug Rifampicin. Still another embodiment, the inclusion complex and the drug exist in an encapsulated form leading to controlled release of the drug. Yet another embodiment, the inclusion complex has an improved stability of Rifampicin in fixed dose combination. Yet, another embodiment, the inclusion complex of the present invention, gives a new approach to anti-tuberculosis therapy containing fixed dose combination. Statement of invention Accordingly, present invention provides a process for preparation of inclusion complexes of Rifampicin with cyclodextrin, the said process comprising characterized in that adding Rifampicin to cyclodextrin in equimolar ratio, grinding by using mortar and pestle for a period of 5 to 8 hours to form a uniform powdery material of Rifampicin-dextrin inclusion complex. Another embodiment, the encapsulation of the drug under solid condition is achieved which enhances bioavailability and solubility. In another embodiment of the invention, provides a process for the preparation of inclusion complexes of Rifampicin with P-cyclodextrin (P-CD) or 2-Hydroxypropyl P-cyclodextrin (HP-p-CD) which comprises a phenomenon of converting a free drug into an encapsulated form under solid state conditions. Still another embodiment, the cyclodextrins forms inclusion complexes with Rifampicin an anti TB drug, are P-CD or HP-P-CD. Still another embodiment, the formation of cyclodextrin complexes with Rifampicin and these may be p-CD or HP-P-CD. In an embodiment of the invention provides an inclusion complex of Rifampicin with cyclodextrin as an anti-tubercular drug. The recent finding {Chronicle Pharmabiz, p.28, Dec.20, 2001) of impaired bioavailability of Rifampicin in the presence of Isoniazid in fixed dose combinations (FDCs) due to decomposition of Rifampicin in the stomach before it is absorbed into the body has prompted us to make inclusion complexes of Rifampicin with ß-cyclodextrin and ( 2-hydroxypropyl)- ß-cyclodextrin and characterize them . They have the potential to be used as new drug delivery systems for stability and slow release. However, the combinations reported so far are only dispersions of Rifampicin and cyclodextrin (East. Pharm., p. 133, vol. 41(492), 1998), but the inclusion complexes have not yet been isolated and characterized. Accordingly, studies were undertaken to make the inclusion complexes of Rifampicin with ß-cyclodextrin (ß-CD) and 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD). Objects of the invention The main object of the invention is to establish a inclusion complex comprising Rifampicin and cyclodextrins for the treatment of tuberculosis. Another object of the present invention, is to establish a process for the formation of Rifampicin with ß-CD or HP-ß-CD for possible use as drug delivery system. Another object of the present invention is to establish a process for the formation of inclusion complexes of cyclodextrins with large size molecules. Brief description of the accompanying drawings In the drawings accompanying this specification, Fig 1 represents the structures of ß-cyclodextrin and (2-Hydroxypropyl) - ß-cyclodextrin. Fig 2 represents Rifampicin. Summary of the invention Accordingly, the present invention provides an inclusion complex of Rifampicin with cyclodextrin for treatment of tuberculosis comprising equimolar ratio of Rifampicin and cyclodextrin. In addition, the present invention provides a process for the synthesis of inclusion complexes of the anti-tubercular drug "Rifampicin" with ß-CD or HP-ß-CD and characterization of these inclusion complexes. Detailed of the Invention The present invention provides an inclusion complex of Rifampicin with cyclodextrin for treatment of tuberculosis comprising equimolar ratio of Rifampicin and cyclodextrin. In an embodiment of the invention provides an inclusion of complex, wherein the cyclodextrin used is selected from β-cyclodextrin and 2-hydroxy propyl cyclodextrin. Still another embodiment, the inclusion complex is characterized by X-ray diffraction and Infrared studies and the inclusion of complex has following physical and chemical characteristics. Still another embodiment, the inclusion complex enhances the bioavailability and solubility of the drug Rifampicin. Still another embodiment, the inclusion complex and the drug exist in an encapsulated form leading to controlled release of the drug. Yet another embodiment, the inclusion complex has an improved stability of Rifampicin in fixed dose combination. Yet, another embodiment, the inclusion complex of the present invention, gives a new approach to anti-tuberculosis therapy containing fixed dose combination. Statement of invention Accordingly, present invention provides a process for preparation of inclusion complexes of Rifampicin with cyclodextrin, the said process comprising characterized in that adding Rifampicin to cyclodextrin in equimolar ratio, grinding by using mortar and pestle for a period of 5 to 8 hours to form a uniform powdery material of Rifampicin-dextrin inclusion complex. Another embodiment, the encapsulation of the drug under solid condition is achieved which enhances bioavailability and solubility. In another embodiment of the invention, provides a 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. Still another embodiment, the cyclodextrins forms inclusion complexes with Rifampicin an anti TB drug, are β-CD or HP-β-CD. Still another embodiment, the formation of cyclodextrin complexes with Rifampicin and these may be β-CD or HP-β-CD. In an embodiment of the invention provides an inclusion complex of Rifampicin with cyclodextrin as an anti-tubercular drug. In another embodiment of the present invention, the substrate forming inclusion complex with cyclodextrins is the anti-tubercular drug " Rifampicin". In another embodiment of the present invention, the cyclodextrins which form inclusion complexes with "Rifampicin" are P-cyclodextrin which is a cyclic oligosaccharide consisting of seven glucose units and 2-Hydroxypropyl-pcyclodextrin (HP-p-CD) which is a p-cyclodextrin substituted with hydroxypropyl group at 2-position. HP-P-CD has also been used as a drug carrier due to its low toxicity, high tolerance and excellent solubilizing and stabilizing abilities. HP-P-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). As a result of above, an intensive study conducted by the inventors with the aim of achieving the afore mentioned objectives, a process for the synthesis of inclusion complexes of the anti-tubercular drug, Rifampicin with P-cyclodextrin (p- CD) or 2-hydroxypropyl-p-cyclodextrin (HP-p-CD) has been achieved for the first time. Accordingly, the present invention deals with the synthesis of inclusion complexes of the anti-tubercular drug , Rifampicin with P-CD or HP-P-CD. The synthesis of each compound has been described in detail. The process involves the inclusion complex formation of Rifampicin with cyclodextrins. The cyclodextrins (Fig-1) are cyclic oligosaccharides possessing hydrophobic cavities and mimic enzymes in their capability to bind substrates selectively and catalyze chemical reactions. p-Cyclodextrin consists of seven glucose units linked by a-1,4 glycosidic bonds into a macrocycle with a hydrophobic cavity. HP-P-CD is a substituted P-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. 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. The following examples are given by way of illustration and therefore should not construe the limit of the scope of the present invention. EXAMPLE 1 Rifampicin -0- cyclodextrin inclusion complex: The cyclodextrin inclusion complex was prepared by the grinding method under solid state conditions. p-Cyclodextrin (13.79 g) was taken in an agate mortar and Rifampicin (lOg) was added while mixing intimately. The ingredients were continuously ground ranging from 5-8 hrs to form a uniform powdery material. The inclusion complex of "Rifampicin" with p-cyclodextrin thus formed has been characterized by the powder X-ray diffraction patterns and IR spectral data. The inclusion complex has been identified by comparing its X-ray and IR spectral data with Rifampicin and p-CD. Powder X-ray Studies: Instrument: Powder X-ray Diffractometer, Siemens / D-5000 The powder X-ray diffractograms were measured in 20 angles. The most significant measurements are as follows: p-CD: 4.3, 6.2, 8.9, 10.4, 12.6, 18.6, 22.6, 27.0, 35.2 Rifampicin: 7.8, 9.5, 10.9, 12.6, 15.8, 16.9, 19.6, 21.3, 26.0 Rifampicin~p-cyclodextrin complex (Rif- 0- CD): 4.3, 8.7, 10.6, 12.6, 15.7, 18.8, 25. 5, 35.2, 46.4 In the inclusion complex, some significant peaks are either shifted, disappeared or some new peaks have appeared. The peaks at 18.8 and 22.6 in P-CD have disappeared in the complex. The peaks at 4.3,12.6 and 27.0 in p- CD have been reduced in intensity in the complex. The new peaks that appeared in the complex are at 18.6,25.5 and 46.4 Similar comparison of data with Rifampicin is as follows. The following peaks of Rifampicin that disappeared in the complex are 9.5, 10.9, 19.6 and 26.0. The significant peaks of Rifampicin at 12.6, 15.8, 16.9 and 21.3 are reduced in intensity. Infrared spectral studies: Instrument: Perkin Elmer Spectrum RX /Ft IR system 500-3500 cm"1 The IR spectra of the drug Rifampicin complex with P-CD and also the individual drug Rifampicin have been recorded as KBr pellets. The inclusion complex formation has also been proved by IR spectroscopy. Bands due to the included part of the guest molecule have shifted or their intensities altered. The acetoxyl C=O vibration at 1728.2 cm"1 and carbonyl C=O absorption at 1730.4 cm"1 of Rifampicin have been shifted to lower frequency and appear as single peak at!722.2 cm"1 where as the amide NH-C=O shows only a minor shift from 1651.2 cm"1 to 1647.8cm"1. However, only a small shift was observed for C=C vibration from 1566.4 cm"1 in the drug to 1565.1cm"1 in the complex .This clearly indicates the formation of inclusion complex of Rifampicin with p-CD. EXAMPLE 2 Rifampicin -2-Hydroxypropyl -P- cyclodextrin inclusion complex: To Rifampicin (10 g) in an agate mortar, 2- hydroxypropyl -p-cyclodextrin (16.77 g) was added and ground well for periods ranging from 5 to 8 hrs to form an uniform powdery material. The inclusion complex of the drug thus formed was isolated and characterized. Powder X-ray studies: Rifampicin with 2- hydroxypropyl -P-cyclodextrin (HP-P-CD) complex has been confirmed by comparing its data of X-ray diffraction pattern with the parent drug and HP-P-CD. The important peaks are shown hereunder. 2-HP-p-CD: 4.8, 11.6, 17.4, 19.1, 23.1, 29.1, 33.0, 35.0, 39.9 Rifampicin-2-hydroxy propyl-p-cyclodextrin inclusion complex (Rif- 2HP- p-CD ): 1.4, 5.9, 12.8, 14.2, 16.3, 18.2, 21.4, 25.8, 30.6 and 31.8 Comparison of the data of the complex with Rifampicin and HP-P-CD are as follows. The following peaks of Rifampicin at 7.8, 9.5 and 10.9 have disappeared in the complex. The peak at 21.3 was reduced in intensity as compared to Rifampicin. As compared to HP-P-CD, new peaks have appeared at 14.2,25.8 and disappearance of the peaks at 4.8 and 11.6 was observed. The peak at 23.1 was reduced in intensity. Thus the difference in the X-ray diffraction patterns of the inclusion complexes of the drug Rifampicin with p-CD and HP-P-CD and that of the individual components by the appearance of new peaks, disappearance of some peaks and also reduction in intensity of some more peaks as described above clearly indicates the formation of inclusion complex of Rifampicin with P-CD and HP-p-CD. Infrared spectral studies: Infrared spectral studies have also been carried out to confirm the formation of inclusion complex. The IR spectrum of RIF-HP-P-CD complex shows the merging of the acetoxyl C=O at 1728.2 cm"1 and carbonyl C=O absorption at 1730.4 cm"1 of Rifampicin to give a single peak at a lower frequency 1719.8 cm"1 , whereas the amide NH-C=O absorption of Rifampicin at 1651.2cm"1 shifts to a lower frequency at 1648.4 cm"1 . A significant shift in C=C absorption band from 1566.4 cm"1 to 1562.8 cm'1 has also been observed. This data clearly indicates the formation of inclusion complex of Rifampicin with HP-p-CD. The main advantages of the present invention are: 1) The inclusion complex of Rifampicin with P-CD and HP-P-CD protects the drug and this can have considerable pharmaceutical potential. 2) It may be possible to control the release rate of the anti-tubercular drug, Rifampicin. 3) There is also a possibility of improving the stability of Rifampicin in fixed dose combinations ( FDCs) 4) This invention may give new approach to anti-tuberculosis therapy containing FDCs. We claim: 1. A process for preparation of inclusion complexes of Rifampicin with cyclodextrin , the said process comprising characterized in that adding Rifampicin to cyclodextrin in equimolar ratio, grinding by using mortar and pestle for a period of 5 to 8 hours to form a uniform powdery material of Rifampicin-dextrin inclusion complex. 2. A process as claimed in claim 1, wherein cyclodextrin used is selected from p- cyclodextrin and 2-hydroxy propyl cyclodextrin. 3. An inclusion complex comprising Rifampicin and cyclodextrin as obtained by a process as claimed in claim 1 useful for tuberculosis. 4. A process for preparation of inclusion complexes of Rifampicin with cyclodextrin substantially as herein described with reference to examples accompanying this specification. |
---|
2929-DELNP-2004-Abstract-(13-03-2009).pdf
2929-DELNP-2004-Abstract-(27-03-2009).pdf
2929-DELNP-2004-Abstract-(28-01-2009).pdf
2929-DELNP-2004-Claims-(13-03-2009).pdf
2929-DELNP-2004-Claims-(27-03-2009).pdf
2929-DELNP-2004-Claims-(28-01-2009).pdf
2929-delnp-2004-complete specification (granted).pdf
2929-DELNP-2004-Correspondence-Others-(10-02-2009).pdf
2929-DELNP-2004-Correspondence-Others-(13-03-2009).pdf
2929-DELNP-2004-Correspondence-Others-(27-03-2009).pdf
2929-DELNP-2004-Correspondence-Others-(28-01-2009).pdf
2929-delnp-2004-correspondence-others.pdf
2929-delnp-2004-description (complete)-(13-03-2009).pdf
2929-DELNP-2004-Description (Complete)-(28-01-2009).pdf
2929-delnp-2004-description (complete).pdf
2929-DELNP-2004-Form-1-(13-03-2009).pdf
2929-DELNP-2004-Form-1-(27-03-2009).pdf
2929-DELNP-2004-Form-1-(28-01-2009).pdf
2929-DELNP-2004-Form-2-(13-03-2009).pdf
2929-DELNP-2004-Form-2-(27-03-2009).pdf
2929-DELNP-2004-Form-2-(28-01-2009).pdf
2929-DELNP-2004-Form-3-(28-01-2009).pdf
2929-DELNP-2004-Petition-137-(10-02-2009).pdf
Patent Number | 233634 | ||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Indian Patent Application Number | 2929/DELNP/2004 | ||||||||||||||||||
PG Journal Number | 17/2009 | ||||||||||||||||||
Publication Date | 24-Apr-2009 | ||||||||||||||||||
Grant Date | 31-Mar-2009 | ||||||||||||||||||
Date of Filing | 29-Sep-2004 | ||||||||||||||||||
Name of Patentee | COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH | ||||||||||||||||||
Applicant Address | RAFI MARG, NEW DELHI-110 001,INDIA | ||||||||||||||||||
Inventors:
|
|||||||||||||||||||
PCT International Classification Number | A61K 31/496 | ||||||||||||||||||
PCT International Application Number | N/A | ||||||||||||||||||
PCT International Filing date | |||||||||||||||||||
PCT Conventions:
|