WO2005046567B1

WO2005046567B1 - Synergistic formulation of antioxidants and antimycobacterial agents: a method of making the same

Info

Publication number: WO2005046567B1
Application number: PCT/IN2004/000278
Authority: WO
Inventors: Meena Shelgaonkar; Shriniwas Shelgaonkar
Original assignee: Meena Shelgaonkar; Shriniwas Shelgaonkar
Priority date: 2003-09-10
Filing date: 2004-09-08
Publication date: 2005-10-27
Also published as: WO2005046567A3; WO2005046567A2

Abstract

The present invention pertains to a six compound pharmaceutical formulation and its process of making comprising of antituberculosis agents like Rifampicin, Isoniazid, Pyrazinamide, and Ethambutal with addition of antioxidants such as d-alpha tocopherol or tocopheryl acetate and pharmaceutically accepted salts thereof and ascorbic acid in required therapeutic quantities for use in treatment of tuberculosis in mammals. This six drug formulation shows synergistic mycobactericidal activity coming along with reduction in oxidative stress, leading to reduction in lung cell damages. The present invention further demonstrates mycobactericidal activity of antioxidants such as d-alpha tocopherol and tocopheryl acetate.

Claims

AMENDED CLAIMS [received by the International Bureau on 05 August 2005 (05.08.05), original claims 1 to 16 replaced by amended claims 1 to 16 (4 pages)]

1. A single dosage composition of drugs comprising: a. Antituberculosis agents in therapeutically effective dosage in a drug regime which is selected from one or more of first line antituberculosis agents and second line antituberculosis agents; where i. first line antituberculosis agents consist of a two drug combination regime containing Rifampicin or Rifabutin or Rifapentine and Isoniazid; a three drug combination regime as Rifampicin or Rifabutin or Rifapentine, isoniazid and Ethambutol; a four drug combination regime as Rifampicin or Rifabutin or Rifapentine, Isoniazid, Ethambutol, and Pyrazinamide ; ii. second line antituberculosis agents consist of one or more of second line drugs including ethioπamide, cycloserine, p-aminosalicylic acid, , macrolides eg azithromycin, clarithromycin, quinolones e.g. ciprofloxacin, Levofloxacin, Moxifloxacin, Fleroxacin and sparfloxacin b. One or more of drug or drugs with antioxidant and antimicrobial property in therapeutically effective dosage. c. One or more of antioxidant or antioxidants in dosage therapeuticaiiy effective to lower blood lipid peroxidation levels in the human body d. Optionally containing pharmaceutically acceptable excipients including binders, sweeteners, flavoring agents, fillers, adsorbents, diluents, coating agents, disintegrating agents, preservatives, lubricants, time delay agents, dispersing and or suspending agents, emulsifying agents, and effervescent agents.

2. Composition of claim no. 1 wherein the range of use of the said antituberculosis agents individually are - Rifampicin used within a range of 60mg to 600mg , Rifabutin used within a range of 150 mg to 600 mg, Rifapentine used within the range of 300 to 900mg, Isoniazid used within a range of 60 mg to 1500mg, Ethambutol, used within a range of 60mg to 25Q0mg , Pyrazinamide, used within a range of "IQOmg to 2000mg , Ethionamide used within a range of 100mg to 1000mg, cycloseriπe used within a range of 250mg to 750 mg, p-aminosalicyiic acid used within a range of ( 8g to 12g), macrolide eg azithromycin used within a range of 250 to 1500mg, clarithromycin, used within a range of 250mg to 1500mg, quinolones eg ciprofloxacin, used within a range of 500 to 2000mg, ofloxacin, used within a range of 100 to 1200mg, fleroxacin used within a range of 150 rng to 1000mg, sparfloxin used within a range of 150mg to 1000mg . 11

3. Composition of claim no.1 wherein the said antioxidant or antioxidants with antimicrobial properties of sub claim b. of claim 1 is Vitamin E, comprising homologues of all natural as well as synthetic tocol and tocotrienol and their derivatives including esters characterized by derivatives of 6-chromanol ring with phytoi side chain qualitatively exhibiting biological activity of natural alpha tocopherol.

4. Composition of claim no. 3 wherein Vitamin E is d alpha tocopherol or tocopheryl acetate used within the range of 200 IU to 2000 IU, more particularly at 400 IU to 800 IU per dose.

5. Composition of claim no. 1 wherein the said antioxidant or antioxidants of sub claim c of claim 1 are selected from one or more of: a. Vitamin E, comprising homologues of all natural as well as synthetic tocol and tocotrienol and their derivatives including esters characterized by derivatives of 6- chromanol ring with phytoi side chain qualitatively exhibiting biological activity of natural alpha tocopherol used within a range of 200 IU to 2000 IU, more particularly within a range of 400 IU to 800 IU per dose ; b. ascorbic acid or sodium ascorbate used within the range of 50 mg to 1000mg , more particularly within a range of 150 to 500 mg per dose.

6. Composition of claim 1 containing the said pharmaceutically acceptable excipients, which include sweetening agents, fillers, binders, diluents, coating agents, disintegrating agents, preservatives, lubricants, time delay agents, dispersing and or suspending agents, emulsifying agents, effervescent agents and adsorbents added, when all the added excipients are put together, within pharmaceutically permissible range of 0.5 to 1 % of total weight of a single dose,

7. A single dose composition of claim 1 comprising: a. Anti tuberculosis agents in following quantities - Rifampicin powder 300 to 450 mg Isoniazid powder 300 to 600 mg iii. Pyrizinamide powder 1200 to 1500 iv. Ethambutal powder 600 to 800 mg b. Tocopheryl acetate 400 mg to 800 mg or d-alpha tocopherol 400 IU to 800 IU c. Ascorbic acid 125 to 500 mg d. Pharmaceutically acceptable excipients including sweetening agent saccharin added as per taste; flavoring agents as per choice including lemon, orange, anise, 12

liquorice, raspberry; permissible fillers, adsorbents, diluents, coating agents, disintegrating agents, preservatives, lubricants, time delay agents, dispersing or suspending agents, emulsifying agents, and effervescent agents in sufficient quantity, all excipients put together added in the range of 0.5 to 1 % of total weight of a single dose. Composition of claim no. 1 given in an effervescent form to be taken orally after dispersing in a suitable liquid. Composition of claim 8 wherein the said "suitable liquids is one or more of water, milk, fruit juice, a beverage. Composition of claim 1 modified to one or more of other dosage forms including liquid composition, capable of oral administration. A method of use of Vitamin E, comprising homologues of all natural as well as synthetic tocol and tocotrienol and their derivatives including esters characterized by derivatives of 6-chromanol ring with phytoi side chain qualitatively exhibiting biological activity of natural alpha tocopherol including tocopherols or tocotrienols or tocopheryl acetate at dosages therapeutically effective for antimicrobial effect A Pharmaceutical Composition containing Vitamin E, comprising homologues of all natural as well as synthetic tocol and tocotrienol and their derivatives including esters characterized by derivatives of 6-chromanol ring with phytoi side chain qualitatively exhibiting biological activity of natural alpha tocopherol containing tocopherols or tocotrienols or tocopheryl acetate in therapeutic amounts effective as antimicrobial agents in general and as anti-mycobactericidal agents in particular. A Pharmaceutical Composition of claim 12 containing one or more of a. tocopherol esters including one or more of tocopherol acetate, tocopheryl succinate or tocopheryl nicotinate used collectively in the range of 200 to 2000 mg, more particularly in the range of 400 to 800mg b. tocopherols or tocotrienols used collectively in the range of 200 IU to 2000 IU, more particularly in the raπge of 400 IU to 800 IU. A process of preparing Composition of claim no. 1 , claim no. 7, claim 12 and claim no. 13 wherein: 13

a. Ingredients of the composition are taken as powder, or granules weighed and mixed, using mixer machines used normally in pharmaceutical manufacturing, to a homogeneous free flowing form. b. Weighing the powder or granules in unit dosages suitable to provide the desired quantity of the individual ingredients in a single unit dose c. Sealing the single dose in one or more forms of containers including sachets, bottles, which are preferably airtight and light impervious. A method of treating tuberculosis by using compositions of claim 1 or claim 7. A method of treating miαobial diseases using compositions of claim 1 , claim 7, claim 12 or claim 13.