Title of Invention

"NATURAL POLYMER MICROSPHERES AND A PROCESS FOR THE PREPARATION THEREOF"

Abstract

This invention relates to a process for the preparation of alginate microspheres having a plurality of drugs such as a combination of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) encapsulated therein comprising: (i) preparing an aqueous solution of said drugs in distilled water (DW) or normal saline (NS) or phosphate buffer saline (PBS) in a ratio of 1:0.1-100 followed by addition of an organic solvent, such as methanol to enhance the solubility of hydrophobic drugs, if used; (ii) mixing an aqueous solution of sodium alginate with the solution of said drugs; (iii) introducing the mixture onto calcium chloride aqueous solution containing a stabilizer to produce microspheres; (iv) allowing the microspheres to mature, recovering the microspheres by, fitration, washing and subsequent drying.

Full Text

FIELD OF INVENTION This invention relates to natural polymer microspheres having a plurality of drugs encapsulated therein, which can be administered orally, and to a process for the preparation thereof. In particular this invention relates to alginate microspheres having a plurality of drugs encapsulated therein. By way of example, and without intending to imply any limitation, the encapsulated drugs may be antitubercular drugs (AID). BACKGROUND OF INVENTION The need to administer multiple ATD daily for 6-9 months is responsible for patient non-compliance as well as drug related hepatotoxicity, which result in therapeutic failure. Another consequence of incomplete/irregular treatment is the emergence of drug resistance. Controlled release drug delivery systems employing biodegradable polymers have been extensively studied. Of the several procedures available such as double-emulsion solvent evaporation, microemulsion, gelification of anionic polyacchariedes etc., none is perfect in terms of particle size, drug encapsulation efficiency and drug release kinetics. Further, multidrug encapsulation in single formulation is not yet reported. OBJECTS OF INVENTION An object of this invention is to propose alginate microspheres having a plurality of drugs encapsulated therein and to a process for the preparation thereof. Another object of this invention is to propose alginate microspheres having a plurality of drugs encapsulated therein and to a process for the preparation thereof and wherein the drugs are ATD drugs, namely a combination of rifampicin (RTF), isoniazid (INH) and pyrazinamide (PZA) encapsulated and obviates the disadvantages associated with the known art. Still another object of this invention is to propose alginate microspheres having a plurality of drugs encapsulated therein and to a process for the preparation thereof, said drugs being a combination of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) which provides a prolonged and sustained release of said drugs. Yet another object of this invention is to propose alginate microspheres having a plurality of drugs encapsulated therein and to a process for the preparation thereof, said plurality of drugs being, such as, a combination of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) and capable of being modulated to entrap maximum drug. A further object of this invention is to propose alginate microspheres having a plurality of drugs encapsulated therein and to a process for the preparation thereof, said drugs being such as a combination of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) and capable of distributing the drug(s) evenly to different organs where tubercle bacteria reside. A still further object of this invention is to propose alginate microspheres having a plurality of drugs encapsulated therein and to a process for the preparation thereof, said drugs being such as a combination of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) encapsulated which is ready for oral use without requiring any further treatment. Yet a further object of this invention is to propose alginate microspheres having a plurality of drugs encapsulated therein and to a process for the preparation thereof, said drugs being such as a combination of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) encapsulated which does not exhibit hepatotoxicity. BRIEF DESCRIPTION OF THE INVENTION According to this invention there is provided a process for the preparation of alginate microspheres having a plurality of drugs such as a combination of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) encapsulated therein comprising: i) preparing an aqueous solution of said drugs in distilled water (DW) or normal saline (NS) or phosphate buffer saline (PBS) in a ratio of 1:0.1-100 followed by addition of an organic solvent, such as methanol to enhance the solubility of hydrophobic drugs, if used; ii) mixing an aqueous solution of sodium alginate with the solution of said drugs; iii) introducing the mixture onto calcium chloride aqueous solution containing a stabilizer to produce microspheres; iv) allowing the microspheres to mature, recovering the microspheres by, fitration, washing and subsequent drying. Further, according to this invention there is provided alginate microspheres having a plurality of drugs encapsulated therein. In accordance with this invention, an aqueous solution of drug is prepared in DW/NW/PBS in the ratio of 1:0 1-100 weight by volume (w/v). Methanol may be added (if one of the drugs is hydrophobic) in a ratio of 0.2:1-10 volume by volume (v/v). A 1.5-3.5% w/v aqueous solution of sodium alginate is also prepared and mixed with the drug solution to ensure that drug and polymer ratio is kept preferably at 1:1 w/w. The mixture can comprise an excess amount of the drug solution or sodium alginate solution, but which would only constitute a waste. The mixture is added drop wise at the rate of 60-100 drops/min into calcium chloride solution (0.1-0.5M) so that 'mixture', calcium chloride ratio is 1:15-25 v/v. The calcium chloride solution also contain the stabilizer chitosan, maintaining alginate: chitosan preferably, but not limited thereto, at a ratio of 1:1 w/w. The microspheres formed are left as such in a calcium chloride solution for 8-12 hr and subsequently filtered, washed with DW and dried in a desiccator. A process for the preparation of alginate microspheres having ATD encapsulated in explained by the following example: 10 mg INH, lOmg PZA and lOmg RIF were dissolved in 1 mL DW containing 0.2mL methanol. This was mixed with 1.2mL of 2.5% w/w sodium alginate solution. The mixture was added drop wise @ 60 drops/mm into 0.1M calcium chloride solution (50mL, containing 30 mg chitosan), the microspheres left as such for 8 hr, recovered by filtration, washed thrice with DW and dried in a desiccator. Oral administration of the microspheres was found to produce sustained plasma drug levels for 5 days and tissues (lung, liver & spleen) for 7 days, thereby suggesting a weekly therapeutic regimen. The microspheres were administered orally to infected guinea pigs and the results are given in Table 1. TABLE 1- Colony forming units (CPUs) of M. tuberculosis in lungs of guinea pigs after drug treatment. (Table Removed) Determination of drug content in alginate microspheres The drug encapsulation efficiency was as under: RIF - 80-85% INH - 68-72% PZA - 68-72% The alginate microspheres did not produce any hepatotoxicity as assessed by plasma bilirubin, alanine transaminase and alkaline phosphatase. WE CLAIM 1. A process for the preparation of alginate microspheres having a plurality of drugs such as a combination of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) encapsulated therein comprising: i) preparing an aqueous solution of said drugs in distilled water (DW) or normal saline (NS) or phosphate buffer saline (PBS) in a ratio of 1:0.1-100 followed by addition of an organic solvent, such as methanol to enhance the solubility of hydrophobic drugs, if used; ii) mixing an aqueous solution of sodium alginate with the solution of said drugs; iii) introducing the mixture onto calcium chloride aqueous solution containing a stabilizer to produce microspheres; iv) allowing the microspheres to mature, recovering the microspheres by, fitration, washing and subsequent drying. 2. A process as claimed in claim 1 wherein methanol is added to DW/NS/PBS in a ratio of 0.2:1-10 v/v. 3. A process as claimed in claim 1 wherein aqueous solution of sodium alginate is 1.5- 3.5% w/v and mixed with the drug solution preferably at a ratio of 1: Iw/w. 4. A process as claimed in claim 1 wherein the mixture is added drop wise at the rate of 60-100 drops per minute onto 0.1-0.5M calcium chloride solution so that the ratio of mixture to calcium chloride is 1:15-25 v/v. 5. A process as claimed in claim 1 wherein the calcium chloride aqueous solution contains a stabilizer such as chitosan so that the ratio of alginate: chitosan is preferably 1:1 w/w. 6. A process as claimed in claim 1 wherein the micropheres formed are left for 8-12 hrs for maturity. 7. A process for the preparation of alginate micropheres having a plurality of drugs encapsulated therein substantailly as herein described and illustrated in the example.

Documents:

1033-del-2003-abstract.pdf

1033-del-2003-claims.pdf

1033-del-2003-complete specification (granted).pdf

1033-DEL-2003-Correspondence Others-(30-06-2011).pdf

1033-DEL-2003-Correspondence-Others-(31-03-2009).pdf

1033-del-2003-correspondence-others.pdf

1033-del-2003-correspondence-po.pdf

1033-del-2003-description (complete).pdf

1033-del-2003-form-1.pdf

1033-DEL-2003-Form-15-(30-06-2011).pdf

1033-DEL-2003-Form-15-(31-03-2009).pdf

1033-del-2003-form-19.pdf

1033-del-2003-form-2.pdf

1033-DEL-2003-Form-26-(31-03-2009).pdf

1033-del-2003-form-3.pdf

1033-del-2003-pa.pdf