Title of Invention	NOVEL ORAL COMPOSITIONS
Abstract	The present invention describes novel oral dose comprising composition of antioxidant, preferably Factor Alpha tx and vitamin C with other anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrazinamide and Ethambutol to treat patient with tuberculosis, more particularly pulmonary tuberculosis. More particularly present invention describes oral dosage, synergistic composition in combination or as a combipack of individual anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrazinamide and Ethambutol with Factor Alpha tx and vitamin C useful in the treatment of pulmonary tuberculosis.

Title of Invention

NOVEL ORAL COMPOSITIONS

Abstract

The present invention describes novel oral dose comprising composition of antioxidant, preferably Factor Alpha tx and vitamin C with other anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrazinamide and Ethambutol to treat patient with tuberculosis, more particularly pulmonary tuberculosis. More particularly present invention describes oral dosage, synergistic composition in combination or as a combipack of individual anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrazinamide and Ethambutol with Factor Alpha tx and vitamin C useful in the treatment of pulmonary tuberculosis.

Full Text	FORM 2 THE PATENTS ACT 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10, Rule 13] “NOVEL ORAL COMPOSITIONS” (a) SAPTE VINAY RAMAKANT (b) 3/1, Shree Datta Buvan, Off. Gokhale Road (N), Dadar, Mumbai - 400 028, Maharashtra, India. (c) Indian National. The following specification describes the nature of this invention and the manner in which it is to be performed. Technical Field of the invention: The present invention relates to novel oral dose comprising composition of antioxidant, preferably Factor Alpha tx and vitamin C with other anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrazinamide and Ethambutol to treat patient with tuberculosis, more particularly pulmonary tuberculosis. More particularly present invention relates to oral dosage, synergistic composition in combination or as a combipack of individual anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrazinamide and Ethambutol with Factor Alpha tx and vitamin C useful in the treatment of pulmonary tuberculosis. Background of invention: Mycobacterium tuberculosis bacilli (MTB) are the most common causative organism for pulmonary tuberculosis (PTB). Studies before the advent of modern anti-tubercular drugs showed that l/3rd of the patients died within a year after diagnosis and !4 of survivors within five years. Of the survivors after 5 years 60% had undergone spontaneous remission whereas remaining 40% still continued to excrete tubercle bacilli. Even after the advent and use of antitubercular drugs current scenario as per World Health Organization, the global epidemic of tuberculosis is growing and becoming more dangerous. Currently, there are 2 billion people worldwide (one third of the world's population) infected with the TB bacillus (having latent TB infection, or LTBI). Five to ten percent of the people who are infected with TB (but who are not infected with HIV) become sick or infectious at some time during their life. The epidemics of HIV/AIDS and multi-drug resistant tuberculosis (MDR-TB) have also impacted on the spread of TB. Tuberculosis is the single most common opportunistic infection for people with HIV. Thus, TB is a major cause of death in people who are HIV positive. It accounts for about 11 % of AIDS deaths worldwide. If TB control measures are not further strengthened and present trends continue, it is estimated that between the year 2000 and the year 2020: approximately 1 billion people will be newly infected with the TB bacillus; 150 million people will get sick with active TB disease; and 36 million people will die from TB 2 disease. The causative organism MTB is a facultative intracellular parasite that has evolved successful strategies to invade and persist inside macrophages which are first line defense cells in lungs. MTB have number of peculiarities. These organisms are sluggishly motile, slow to multiply, neither produce exotoxin nor endotoxin which can cause toxic effects in diseased person. They have peculiarly different cell wall structure when compared with other common microorganisms capable of producing diseases in human populations. The cell wall structure has given these organisms; a peculiar resistance to acids washes in staining procedures and are often called as Acid Fast Bacilli (AFB). Recent developments in knowledge of structure and chemistry of mycobacterium have demonstrated three structural components: plasma membrane, cell wall and capsule. The innermost structure is plasma membrane which appears to be typical bacterial membrane, playing little part in the pathological process. The cell wall is peculiar in having an unusual layer of lipid (mycolate esters) which forms a permeability barrier to polar substances. In structure it forms a covalently linked 'Cell wall skeleton' with associated numerous non-covalently linked substances. The outermost compartment of cell consists of a mixture of polysaccharide, protein and lipid which is called as 'capsule'. The constituents of this envelope are non-covalently bound to the cell wall and structurally it behaves like a capsule. The envelope is a dynamic structure. In growing mycobacterium molecules are moving within and through the envelope and contribute to a very stable wall skeleton which is continuously reconstructed. This peculiar 'Capsule' determines which constituents of the organism are allowed to be 'seen' by the host cell, which constituents of the host can reach the inside of mycobacterium and how readily anti-mycobacterial drugs can reach the interior of organism. This envelope protects the intracellular organism from being killed by the host bactericidal mechanisms in initial stages of infection. The remarkable resistance of mycobacterium tuberculosis to damage is well known and is attributable to remarkable impermeability of the 'capsule' which defends it from host destructive mechanisms like 3 host enzymes, reactive oxygen species (Free radicals) by modulating host immune response and by processing host derived materials for use by mycobacterium. The sheer size of the population worldwide infected by MTB points to the intimate pathogen macrophage interaction, which is so successfully governed in favor of MTB due to cell wall's chemical and biological constituents. In the early phase of infection recognition of foreign material signal by host is followed by movement of alveolar non activated macrophages. The bacilli are actively phagocytosed by the alveolar macrophages where all efforts are directed towards destruction of the bacilli with the help of proteolytic enzymes, cytokines and free radicals. Free radicals act as micro missiles having affinity for many cell membrane constituents and intracellular constituents. Free radical attack on cell membrane constituents results in cell membrane damage which ultimately leads to cell death. Cell wall of many common organisms causing diseases in human shows susceptibility to destruction by free radicals. Virulent strains of mycobacterium tuberculosis shows peculiar resistance to damage by free radicals. Non-virulent strains of MTB are susceptible to destruction by free radicals. On the other hand cell membrane of human cells is susceptible to damage by free radicals. Usually this phase ends in intracellular multiplication of MTB which eventually destroy the macrophages. This early stage of nonspecific host response is followed by stimulation of host immune system leading to a more specific cell mediated immune response involving T lymphocytes which are stimulated by antigens processed and presented by the alveolar macrophages. This response has two components. One is tissue damaging response and other one is macrophage activating response. The tissue damaging response is due to delayed type of hypersensitivity (DTH) reaction to bacillary .antigens which destroys non-activated macro phages containing multiplying bacilli. The macrophage activating response is a cell mediated phenomenon causing activation of macrophages that are capable of killing and digesting tubercle bacilli. Balance between these two responses determines the form of tuberculosis that will 4 develop subsequently. Relatively weaker macrophage activating response causes extensive tissue destruction. The lesions tend to enlarge further and surrounding tissue is progressively damaged. The central caseous material liquefies; bronchial wall as well as blood vessels are invaded and destroyed, leading to cavity formation. The liquefied caseous material containing large number of tubercle bacilli is drained through bronchi. Within the cavity, tubercle bacilli multiply well and spread into environment through expectorated sputum. Activated macrophages kill or inhibit the growth of tubercle bacilli probably by more than one way. There are several evidences to show that H2O2 & reactive oxygen intermediates (Superoxide anions, hydroxyl ion, singlet oxygen etc), are produced by macrophage during its metabolism are detrimental to the organism. Gatey et al have isolated a lymphokine which is capable of increasing the intracellular concentration of hydrogen peroxide. Free radicals or reactive oxygen species are extraordinarily active species of molecules which act as unguided missiles which can react with cell membrane of microorganisms as well as human cells leading to cell membrane damage by peroxidation of polyunsaturated fatty acids and which can eventually lead to cell mutation and / or cell death. All currently available antitubercular drugs are either bactericidal or bacteriostatic. None of these agents have been shown to possess antioxidant or immuno-stimulant effect. Alpha tocopherol herein after referred to as Factor Alpha tx is known to be an agent of use in symptomatic vitamin E deficiency. High doses of Factor Alpha tx have been shown to improve parameters of immune function, protective against cardiovascular disease, possibly by inhibiting LDL oxidation and brochopulmonary displasia and retrolental fibroplasias in premature babies. Factor Alpha tx acts as chain-breaking antioxidant and is an efficient pyroxyl radical scavenger, which protects LDLs and polyunsaturated fatty acids in cell membranes from oxidation. Factor Alpha tx also inhibits prostaglandin synthesis and activities of protein kinase C and phospholipase A2. 5 Vitamin C is known to be an agent of use in scurvy, idiopathic methhaemoglobinaemia, in high doses to prevent viral respiratory infection and in cancer patients. Vitamin C maintains Factor Alpha tx in reduced state and thereby increases Factor Alpha tx 's antioxidant effect. Factor Alpha tx & Vitamin C combination is complimentary in nature. Aims and objectives of antitubercular therapy in pulmonary tuberculosis patients, with currently available antitubercular drugs during the intensive phase of therapy are twofold. 1) To convert sputum smear positive cases who can spread the disease by airborne droplets, in minimum possible period into sputum smear negative cases so that further spread of MTB is prevented to non-infected individuals in the society, and 2) To kill causative organisms so as to eliminate them from the infected individual and to make him / her disease free. Currently available method of treatment of pulmonary tuberculosis does not address to damages caused by increasingly generated free radicals to host cells and alteration in a favorable way of suppressed / altered immune system response observed in tuberculosis patients. Object of invention: The object of current investigation is to develop a suitable dosage form composition in combination or as a combipack of individual anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrazinamide and Ethambutol with Factor Alpha tx and vitamin C for treatment with a comprehensive approach towards various patho-physiological changes occurring during tubercular affection of lungs so that an increased bactericidal activity against tubercle bacilli is achieved with routinely used antitubercular drugs alongwith lessened damage to host tissue cells 6 Summary of the Invention: The present invention discloses novel oral dosage form in the form of synergistic composition or a combipacks for improvement in the field of treatment of pulmonary tuberculosis in which first action or actions of an agent or agents, produce a combination of effects which synergistically enhance the reduction in the count of tubercle bacilli in the sputum along with the reduction in cell injury to already suppressed cells of host immune system, lungs and surrounding tissue cells due to generated free radicals in the course of disease as well as routine therapy, with a comprehensive approach of addressing all known derangements which occur in the disease and therapy process of an animal. More particularly the said combipack comprises a) amy one anti-tubercular drug such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx; b) combination of any of the two anti-tubercular drugs such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx; c) combination of any of the three anti-tubercular drugs such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx; d) combination of four anti-tubercular drugs namely Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx in a therapeutically effective dosage quantities in a daily dosage form. Oral powder / granule synergistic compositions comprising upto 4 anti-TB drugs namely Rifampicin, Isoniazid, Ethambutol and Pyrazinamide (SCC-4), in combination with Factor Alpha tx, in palatable powder form, which can be consumed by mixing the powder in a glass of water or juice with meal is disclosed. This invention further discloses oral / powder / granule compositions of any two, any three and any four anti-TB drugs in combination with Factor Alpha tx in a therapeutically effective dosage quantities in a daily dosage form. Detailed description of the invention: The present invention comprises suitable dosage form synergistic composition in 7 combination or as a combipack of individual anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrazinamide and Ethambutol with Factor Alpha tx for the treatment of patients diagnosed as having pulmonary tuberculosis. This invention comprises of the administering of an effective amount of an antioxidant concomitantly with antitubercular drugs to patients diagnosed as having pulmonary tuberculosis. Even more particularly, the method of the present investigation comprises of administering an effective amount of Factor Alpha tx concomitantly with other antitubercular drugs to patients with such disease. To date, there has been no information as to Factor Alpha tx's use in the treatment of tuberculosis either alone or along with other antitubercular agent. The present inventors herein disclose that this drug is effective in the treatment of tuberculosis when used concomitantly with other antitubercular drugs. The antioxidants and concomitantly used antitubercular drugs of the present investigation may be administered orally. Factor Alpha tx and antitubercular drugs used concomitantly are available commercially. For example the following are commercially available forms. The combipack of the present invention comprising either of the following 1) at least one anti-tubercular drug such as Rifampicin, Isoniazid, Pyrazinamide and Ethambutol with Alpha Factor tx; 2) Any two anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrazinamide and Ethambutol with Alpha Factor tx; 3) Any three anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrazinamide and Ethambutol with Alpha Fafctor tx and 4) All four anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrazinamide and Ethambutol with Alpha Factor tx. All the drugs used were administered orally. Therapeutically effective daily doses of Factor Alpha tx and antitubercular drugs were administered. The exact mechanism by which concomitant Factor Alpha tx use exert beneficial effect in pulmonary tuberculosis patients is unknown. However the inventors postulate that Factor 8 Alpha tx used to quench free radicals liberated, and thereby causes reduction in cell membrane damage of macrophages and other cells involved in cell mediated immunity. This improved immune cell functions results in increased bactericidal activity by host defense cells. In addition to this the damage to lung tissue at the site of the lesion by released free radicals is also reduced due to quenching by antioxidants used concomitantly. The present invention relates to oral dosage form in the form of synergistic composition or a combipacks for improvement in the field of treatment of pulmonary tuberculosis in which first action or actions of an agent or agents, produce a combination of effects which synergistically enhance the reduction in the count of tubercle bacilli in the sputum along with the reduction in cell injury to already suppressed cells of host immune system, lungs and surrounding tissue cells due to generated free radicals in the course of disease as well as routine therapy, with a comprehensive approach of addressing all known derangements and which occur in the disease and therapy process an animal. More particularly the said combipack comprises a) any one anti-tubercular drug such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx; b) combination of any of the two anti-tubercular drugs such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx; c) combination of any of the three anti-tubercular drugs such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx; d) combination of four anti-tubercular drugs namely Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx in a therapeutically effective dosage quantities in a daily dosage form. The present invention discloses Oral powder / granule synergistic compositions comprising upto 4 anti-TB drugs namely Rifampicin, Isoniazid, Ethambutol and Pyrazinamide, in combination with Factor Alpha tx, in palatable powder form, which can be consumed by mixing the powder in a glass of water or juice with meal. Further oral / powder / granule synergistic compositions comprises a) any one anti-tubercular drug such as Rifampicin, Isoniazid, Pyrizinamide, Ethambutal and Factor Alpha tx; b) combination 9 of any of the two anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrizinamide, Ethambutal and Factor Alpha tx; c) combination of any of the three anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrizinamide, Ethambutal and Factor Alpha tx; d) combination of four anti-tubercular drugs namely Rifampicin, Isoniazid, Pyrizinamide, Ethambutal and Factor Alpha tx in a therapeutically effective dosage quantities in a daily dosage form. The strength of anti-tubercular drugs in the present combipack and synergestic compositions is Rifampicin in the range 60 to 600mg; Isoniazid in the range 75 to 700mg; Ethambutol Hydrochloride in the range 100 to 1000mg; and Pyrazinamide is in the range 150 to 1500 mg. The Factor Alpha tx is in the range 200 to 1000 mg. The present invention improves upon one or more shortcomings or disadvantages in the currently available treatment for pulmonary tuberculosis through the use of antioxidants. In the preferred embodiments, the invention contemplates the use of antioxidants, and particularly Factor Alpha tx and vitamin C concomitantly with other antitubercular drugs to treat patients with tuberculosis. In certain embodiments, the present invention concerns a method for treating tuberculosis by the application of a therapeutically effective dose of antioxidants, and preferably Factor Alpha tx and vitamin C to human subjects with the disease. As used herein, the term" Treating a disease by application of therapeutically effective dose of antioxidants concomitantly with antitubercular drugs" is used to signify that the antioxidants and the antitubercular drugs supplied to the patients in amounts and for a period of time, that are effective to provide improvement in one or all of the clinically measurable parameters of the disease. Several other infective, non-infective diseases showing raised levels oxidative stress are proposed to be treated with concomitant use of antioxidants of the present investigation such as infectious hepatitis, rheumatic disease, diseases with autoimmune disorders, haematological disorders and neoplasms. 10 To determine whether there has been an improvement in one or more of clinically measured parameters of the disease, one would determine the value of such a parameter in a given patient both before and during treatment. Various clinical signs and symptoms are known to be suitable by those of skill in the art to be suitable as markers of disease severity. For example, sputum smear AFB , radiological findings and lipid peroxidation levels. A peculiar advantage of the present invention is that it involves application and use of agents in use clinically as nutrients. By utilizing substances that are already been approved for clinical use for some or other disorder, the present inventors have provided safe agents for use in new modified and improved treatment strategies against above diseases and disorders. Accordingly, Antioxidants are considered to be of concomitant use with other suitable therapeutic agent in above diseases. The inventors propose that the Factor Alpha tx may be administered to the patients in any pharmaceutically acceptable vehicle and by any route heretofore acceptable for these agents and other concomitant medicament. The preferred route of administration is oral, although one may, if desired, choose to administer the drugs parenteraly, sublingually, a sustain release preparation, or by inhalation. The combipack of the present invention is illustrated with the following examples. Example 1 The composition of the present invention is in the form of combipack for the treatment of pulmonary tuberculosis contains Capsule Rifampicin / tablet Isoniazid / Tablet Pyrizinamide / Tablet Ethambutal and Factor Alpha tx in a daily dosage form. 11 Example 2 The composition of the present invention is in the form of combipack for pulmonary tuberculosis contains combination of any of the two anti-tubercular drugs such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx as a daily dosage form. Example 3 The composition of the present invention is in the form of combipack for pulmonary tuberculosis contains combination of any of the three anti-tubercular drugs such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx as a daily dosage form. Example 4 The composition of the present invention is in the form of combipack for pulmonary tuberculosis contains four anti-tubercular drugs namely Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx as a daily dosage form. Example 5 Synergistic composition comprising four Anti-tubercular drugs along with Factor Alpha tx in the SACHET INGREDIENTS WEIGHT (mg/Sachet) % WAV Rifampicin 450.00 11.16 Isoniazid 225 5.59 Ethambutol 825 20.47 12 Pyrazinamide 1200 29.78 Factor Alpha tx 1000 24.81 Betacyclodextrin 135 3.34 Flavour Orange 75 1.87 Aspartem 120 2.98 EXAMPLE 6: Synergistic composition comprising three Anti-tubercular drugs along with Factor Alpha tx in the SACHET INGREDIENTS WEIGHT(mg/Sachet) %W/W Rifampicin 450.00 19.19 Isoniazid 225 9.59 Ethambutol 825 35.18 Factor Alpha tx 600 25.59 Betacyclodextrin 75 3.21 Flavour Orange 50 2.13 Aspartem 120 5.11 EXAMPLE 7 : Synergistic composition comprising two Anti-tubercular drugs along with Factor Alpha tx in the SACHET 13 INGREDIENTS WEIGHT(mg/Sachet) %W/W Rifampicin 450.00 43.69 Isoniazid 225 21.84 Factor Alpha tx 200 19.42 Betacyclodextrin 35 3.40 Flavour Orange 40 3.88 Aspartem 80 7.77 The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in the light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention. EXAMPLE I Trial of antioxidants concomitantly with antitubercular drugs in patients of pulmonary tuberculosis 1. Methods Fifty four patient of pulmonary tuberculosis were included in this study. Thirty patients were treated with four antitubercular drugs only, 24 patients were treated with four antitubercular drugs and antioxidant drugs concomitantly. Four antitubercular drugs were given by oral route to all 54 patients in doses and frequency as shown below for a period of 60 days. 14 The regime is called as 2EHRZ and is as follows orally, daily. Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal Out of this 24 patients received in addition to above four antitubercular drugs, Factor Alpha tx for 60 days daily orally Chest radiology, sputum smears for AFB and lipid peroxidation values were conducted both before and during the study. The patients were assessed at zero, two, four and eight weeks. Various clinical parameters were measured along with chest radiology, sputum smear for AFB and lipid peroxidation values. The outcome of clinical improvement was accessed by following parameters 1) Sputum AFB test In both the groups three sputum samples for each patient were collected & were analyzed for the presence of AFB after 15 days, 30 days & at the end of 2 months by Ziehl-Neelson (hot) stain method. The reports were documented as positive for presence of bacilli & negative for absence of bacilli. 2) Radiological assessment was conducted before & at the end of two months. The observation were reported as favorable response (Static, Improved, and clear) or unfavorable response as deterioration 3) Levels of LPO in terms of MDA-TBA complex nmol / g of Hb All the patients were routinely checked up for symptomatic relief after every 15 days during the intensive phase. Body weight & Hb % was measured before and at the end of the studies. Eligible patients were selected from the TB outpatient department population. To be 15 eligible for enrollment in the study, each patient must first meet the following Inclusion Criteria. Inclusion Criteria 1. Patient must have clinically definite pulmonary tuberculosis diagnosed for the first time. 2. Patient should be between 21 and 55 years of age inclusive. 3. Patients should have demonstrable pulmonary lesion on chest radiography. 4. Patient's sputum should be positive for AFB. Exclusion Criteria 1. Patients having age less than 21 years & more than 55 years. 2. Pregnant females & lactating mothers. 3. Patients with sputum AFB negative & or extra pulmonary tuberculosis. 4. Patients already taking treatment for PTB or previously diagnosed for PTB. 5. Patients of PTB with concomitant diseases like Diabetes, asthma, cancer or HIV. At the screening visit after the patient has been informed about all aspects of the study and a detailed history of the patient has been obtained, the patients will have a chest x-ray, sputum smear for AFB and 5 ml blood was taken from anticubital vein which was analyzed for hemoglobin % and lipid peroxidation values. The patient will also have general examination and respiratory system examination and cardiovascular system examination. The eligible patients were enrolled into the study and will be treated with four antitubercular drugs in daily oral doses mentioned above. This group of patients will be randomly divided into two groups. Control group received Rifampicin, Isoniazid, Ethambutol and Pyrazinamide in daily oral doses mentioned above on Out Patient Department (OPD) basis for 60 days. The study group received Vitamin E and Vitamin C oral daily single dose concomitantly with four 16 antitubercular drugs on OPD basis. Chest x-ray, Sputum smear for AFB, and Lipid peroxidation levels were done on day zero, fifteen, thirty and sixty days on OPD basis. The results of the study indicated that treated group showed better sputum negativity (50% in 30 days) as compared to control group (14 % in 30 days), X-ray findings showed better improvement in treated group as compared to control probably indicating lessened lung damage. Levels of oxidative stress measured in terms of lipid peroxidation were reduced in treated group and on the contrary showed a persistent rise in control group. Better and early control of spread of tuberculosis along with lessened lung tissue damage appears to be the main benefit primarily for TB patients and for human society at large. The concurrent administration of the Factor Alpha tx with routine antitubercular agents has shown synergistic effects in augmenting sputum negativity by increasing the bactericidal action of antitubercular agents on one hand while due to correction of oxidant / antioxidant imbalance there is better radiological improvement and lessened lung damages The combination method of Factor Alpha tx and antitubercular agents appears to be effective in correcting the drawbacks of current treatment of MTB. The results of the study of antibacterial activity of the Factor Alpha tx carried in LJ Medium it is effective against the sensitive strains of Micobacterium Tbubeculosis bacilli (MTB) as well as the Rifampicin resistant, Isoniazid Resistant and Multi drug Resistant strains. The results of studies conducted in broth and tested by culture growth after 24 hrs shows that the Factor Alpha tx has antibacterial activity against Pseudonamas, Staphylocooi and E.coli. 17 Detailed Description of Drawing : Figure 1 illustrates the combipack comprises any one of the anti-tubercular drug such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal with Factor Alpha tx as a daily dosage form. Nol. indicates any of the anti-tubercular drug such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and no. 2 denotes Factor Alpha tx. Figure 2 illustrates the combipack comprises any of the two anti-tubercular drug such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal along with Factor Alpha tx as a daily dosage form. No 3 indicates combination of any two anti-tubercular drugs such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambuta and no.4 denotes Factor Alpha tx. Figure 3 illustrates the combipack comprises any of the three anti-tubercular drug such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal along with Factor Alpha tx as a daily dosage form. No. 5 indicates combination of any three anti-tubercular drugs such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and No. 6 denotes Factor Alpha tx. i Figure 4 illustrates the combipack comprises four anti-tubercular drug such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal with Factor Alpha tx as a daily dosage form. No. 7 indicates combination of four anti-tubercular drug namely Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and no. 8 denotes Factor Alpha tx. While the present invention is described above in connection with preferred illustrative embodiments, these embodiments are not intended to be exhaustive or limiting of the invention. Rather, the invention is intended to cover all alternatives, modifications and equivalents included within its scope, as defined by the appended claims. 18 I claim, 1. Oral dosage form in the form of synergistic compositions or a combipacks for improvement in the field of treatment of pulmonary tuberculosis in which first action or actions of an agent or agents, produce a combination of effects which synergistically enhance the reduction in the count of tubercle bacilli in the sputum along with the reduction in cell injury to already suppressed cells of host immune system, lungs and surrounding tissue cells due to generated free radicals in the course of disease as well as routine therapy, with a comprehensive approach of addressing all known derangements which occur in the disease and therapy process of an animal wherein the said combipack comprises a) any one anti-tubercular drug such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx; b) combination of any of the two anti-tubercular drugs such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx; c) combination of any of the three anti-tubercular drugs such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx; d) four anti-tubercular drugs namely Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx in a therapeutically effective dosage quantities in a. daily dosage form wherein the said synergistic compositions in powder or granule form comprises a) any one anti-tubercular drug such as Rifampicin, Isoniazid, pyrizinamide, Ethambutal and Factor Alpha tx; b) combination of any of the two anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrizinamide, Ethambutal and Factor Alpha tx; c) combination of any of the three anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrizinamide, Ethambutal and Factor Alpha tx; 19 d) four anti-tubercular drugs namely Rifampicin, Isoniazid, Pyrizinamide, Ethambutal and Factor Alpha tx in a therapeutically effective dosage quantities in a daily dosage form 2. A combipack as claimed in claim 1 wherein a method of presentation of the combipack of any one of the antitubercular drug such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx is as in Figure 1. 3. A combipack as claimed in claim 1 wherein a method of presentation of the combipack of combination of any two of the anti-tubercular drugs Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx is as in Figure 2. 4. A combipack as claimed in claim 1 wherein a method of presentation of the combipack of combination of any three of the anti-tubercular drugs Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx is as in Figure 3. 5. A combipack as claimed in claim 1 wherein a method of presentation of the combipack of combination of four anti-tubercular drugs Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx is as in Figure 4. 6. A combipack as claimed in claims 1 to 5 wherein the strength of the said anti-tubercular drug, Rifampicin or rifampicin capsule is in the range of 60 to 600 mg. 7. A combipack as claimed in claims 1 to 5 wherein the strength of the said anti-tubercular drug, Isoniazid or isoniazid tablet is in the range of 75 to 700 mg. 20 8. A combipack as claimed in claims 1 to 5 wherein the strength of the said anti-tubercular drug, Pyrizinamide or Pyrizinamide Tablet is in the range of 150 to 1500 mg. 9. A combipack as claimed in claims 1 to 5 wherein the strength of the said ant-tubercular drug, Ethambutal or Ethambutal Tablet is 100 to 1000 mg. 10. A combipack as claimed in claims 1 to 5 wherein the strength of the said Factor Alpha tx is in the range of 200 to 1000 mg. 11. A novel method for improvement in the field if treatment of pulmonary tuberculosis in which first action or actions of an agent or agents, produce a combination of effects which synergistically enhance the reduction in the count or tubercle bacilli in the sputum along with the reduction in cell injury to already suppressed cells of host immune system, lungs and surrounding tissue cells due to generated free redicals in the course of disease as well as routine therapy, with a comprehensive approach of addressing all know derangements which occur in the disease and therapy process an animal comprising: administration to the said animal an amount of Factor Alpha tx concomitantly with other antitubercular drugs in sufficient quantity and for sufficient duration to clinically cure pulmonary tuberculosis in the said animal. 12. The method according to claim 11 wherein said Factor Alpha tx used concomitantly with other antitubercular drugs enhanced the clinical outcome of antitubercular treatment by way of synergism. 13. The method according to claim 11 wherein the said animal is a human. 14. The process for the manufacture of the product according to claim 1 to 11. 15 The product as claimed in claims 1 to 11 wherein the antibacterial activity of Factor 21 Alpha tx against the Micobacterium Tuderculi including all the strains of the same including all the strains of the same including all the strains of the same including Rifampicin resistant, Isoniazid Resistant and multi drug resitant strains 16. The product as claimed in claims 1 to 11 wherein the antibacterial activity of Factor Alpha tx against the bacterium Pseudomonas, Staphylocooi, E-coli etc. 17. Oral dosage form in the form of synergistic composition or a combipacks for improvement in the field of treatment of pulmonary tuberculosis in which first action or actions of an agent or agents, produce a combination of effects which synergistically enhance the reduction in the count of tubercle bacilli in the sputum along with the reduction in cell injury to already suppressed cells of host immune system, lungs and surrounding tissue cells due to generated free radicals in the course of disease as well as routine therapy, with a comprehensive approach of addressing all known derangements and which occur in the disease and therapy process an animal as substantially described herein with reference to the following examples 1 to 7 and example I. Dated this the 7th day of May 2004 22 Abstract: The present invention describes novel oral dose comprising composition of antioxidant, preferably Factor Alpha tx and vitamin C with other anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrazinamide and Ethambutol to treat patient with tuberculosis, more particularly pulmonary tuberculosis. More particularly present invention describes oral dosage, synergistic composition in combination or as a combipack of individual anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrazinamide and Ethambutol with Factor Alpha tx and vitamin C useful in the treatment of pulmonary tuberculosis.

Full Text

FORM 2
THE PATENTS ACT 1970
(39 of 1970)
COMPLETE SPECIFICATION
[See section 10, Rule 13]
“NOVEL ORAL COMPOSITIONS”
(a) SAPTE VINAY RAMAKANT
(b) 3/1, Shree Datta Buvan, Off. Gokhale Road (N), Dadar, Mumbai - 400 028, Maharashtra, India.
(c) Indian National.
The following specification describes the nature of this invention and the manner in which it is to be performed.

Technical Field of the invention:
The present invention relates to novel oral dose comprising composition of antioxidant, preferably Factor Alpha tx and vitamin C with other anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrazinamide and Ethambutol to treat patient with tuberculosis, more particularly pulmonary tuberculosis. More particularly present invention relates to oral dosage, synergistic composition in combination or as a combipack of individual anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrazinamide and Ethambutol with Factor Alpha tx and vitamin C useful in the treatment of pulmonary tuberculosis.
Background of invention:
Mycobacterium tuberculosis bacilli (MTB) are the most common causative organism for pulmonary tuberculosis (PTB). Studies before the advent of modern anti-tubercular drugs showed that l/3rd of the patients died within a year after diagnosis and !4 of survivors within five years. Of the survivors after 5 years 60% had undergone spontaneous remission whereas remaining 40% still continued to excrete tubercle bacilli. Even after the advent and use of antitubercular drugs current scenario as per World Health Organization, the global epidemic of tuberculosis is growing and becoming more dangerous. Currently, there are 2 billion people worldwide (one third of the world's population) infected with the TB bacillus (having latent TB infection, or LTBI). Five to ten percent of the people who are infected with TB (but who are not infected with HIV) become sick or infectious at some time during their life. The epidemics of HIV/AIDS and multi-drug resistant tuberculosis (MDR-TB) have also impacted on the spread of TB. Tuberculosis is the single most common opportunistic infection for people with HIV. Thus, TB is a major cause of death in people who are HIV positive. It accounts for about 11 % of AIDS deaths worldwide. If TB control measures are not further strengthened and present trends continue, it is estimated that between the year 2000 and the year 2020: approximately 1 billion people will be newly infected with the TB bacillus; 150 million people will get sick with active TB disease; and 36 million people will die from TB
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disease.
The causative organism MTB is a facultative intracellular parasite that has evolved successful strategies to invade and persist inside macrophages which are first line defense cells in lungs. MTB have number of peculiarities. These organisms are sluggishly motile, slow to multiply, neither produce exotoxin nor endotoxin which can cause toxic effects in diseased person. They have peculiarly different cell wall structure when compared with other common microorganisms capable of producing diseases in human populations. The cell wall structure has given these organisms; a peculiar resistance to acids washes in staining procedures and are often called as Acid Fast Bacilli (AFB).
Recent developments in knowledge of structure and chemistry of mycobacterium have demonstrated three structural components: plasma membrane, cell wall and capsule. The innermost structure is plasma membrane which appears to be typical bacterial membrane, playing little part in the pathological process. The cell wall is peculiar in having an unusual layer of lipid (mycolate esters) which forms a permeability barrier to polar substances. In structure it forms a covalently linked 'Cell wall skeleton' with associated numerous non-covalently linked substances. The outermost compartment of cell consists of a mixture of polysaccharide, protein and lipid which is called as 'capsule'. The constituents of this envelope are non-covalently bound to the cell wall and structurally it behaves like a capsule. The envelope is a dynamic structure. In growing mycobacterium molecules are moving within and through the envelope and contribute to a very stable wall skeleton which is continuously reconstructed.
This peculiar 'Capsule' determines which constituents of the organism are allowed to be 'seen' by the host cell, which constituents of the host can reach the inside of mycobacterium and how readily anti-mycobacterial drugs can reach the interior of organism. This envelope protects the intracellular organism from being killed by the host bactericidal mechanisms in initial stages of infection. The remarkable resistance of mycobacterium tuberculosis to damage is well known and is attributable to remarkable impermeability of the 'capsule' which defends it from host destructive mechanisms like
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host enzymes, reactive oxygen species (Free radicals) by modulating host immune response and by processing host derived materials for use by mycobacterium. The sheer size of the population worldwide infected by MTB points to the intimate pathogen macrophage interaction, which is so successfully governed in favor of MTB due to cell wall's chemical and biological constituents.
In the early phase of infection recognition of foreign material signal by host is followed by movement of alveolar non activated macrophages. The bacilli are actively phagocytosed by the alveolar macrophages where all efforts are directed towards destruction of the bacilli with the help of proteolytic enzymes, cytokines and free radicals. Free radicals act as micro missiles having affinity for many cell membrane constituents and intracellular constituents. Free radical attack on cell membrane constituents results in cell membrane damage which ultimately leads to cell death. Cell wall of many common organisms causing diseases in human shows susceptibility to destruction by free radicals. Virulent strains of mycobacterium tuberculosis shows peculiar resistance to damage by free radicals. Non-virulent strains of MTB are susceptible to destruction by free radicals. On the other hand cell membrane of human cells is susceptible to damage by free radicals. Usually this phase ends in intracellular multiplication of MTB which eventually destroy the macrophages.
This early stage of nonspecific host response is followed by stimulation of host immune system leading to a more specific cell mediated immune response involving T lymphocytes which are stimulated by antigens processed and presented by the alveolar macrophages. This response has two components. One is tissue damaging response and other one is macrophage activating response. The tissue damaging response is due to delayed type of hypersensitivity (DTH) reaction to bacillary .antigens which destroys non-activated macro phages containing multiplying bacilli. The macrophage activating response is a cell mediated phenomenon causing activation of macrophages that are capable of killing and digesting tubercle bacilli.
Balance between these two responses determines the form of tuberculosis that will
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develop subsequently. Relatively weaker macrophage activating response causes extensive tissue destruction. The lesions tend to enlarge further and surrounding tissue is progressively damaged. The central caseous material liquefies; bronchial wall as well as blood vessels are invaded and destroyed, leading to cavity formation. The liquefied caseous material containing large number of tubercle bacilli is drained through bronchi. Within the cavity, tubercle bacilli multiply well and spread into environment through expectorated sputum.
Activated macrophages kill or inhibit the growth of tubercle bacilli probably by more than one way. There are several evidences to show that H2O2 & reactive oxygen intermediates (Superoxide anions, hydroxyl ion, singlet oxygen etc), are produced by macrophage during its metabolism are detrimental to the organism. Gatey et al have isolated a lymphokine which is capable of increasing the intracellular concentration of hydrogen peroxide. Free radicals or reactive oxygen species are extraordinarily active species of molecules which act as unguided missiles which can react with cell membrane of microorganisms as well as human cells leading to cell membrane damage by peroxidation of polyunsaturated fatty acids and which can eventually lead to cell mutation and / or cell death.
All currently available antitubercular drugs are either bactericidal or bacteriostatic. None of these agents have been shown to possess antioxidant or immuno-stimulant effect.
Alpha tocopherol herein after referred to as Factor Alpha tx is known to be an agent of use in symptomatic vitamin E deficiency. High doses of Factor Alpha tx have been shown to improve parameters of immune function, protective against cardiovascular disease, possibly by inhibiting LDL oxidation and brochopulmonary displasia and retrolental fibroplasias in premature babies. Factor Alpha tx acts as chain-breaking antioxidant and is an efficient pyroxyl radical scavenger, which protects LDLs and polyunsaturated fatty acids in cell membranes from oxidation. Factor Alpha tx also inhibits prostaglandin synthesis and activities of protein kinase C and phospholipase A2.
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Vitamin C is known to be an agent of use in scurvy, idiopathic methhaemoglobinaemia, in high doses to prevent viral respiratory infection and in cancer patients. Vitamin C maintains Factor Alpha tx in reduced state and thereby increases Factor Alpha tx 's antioxidant effect.
Factor Alpha tx & Vitamin C combination is complimentary in nature.
Aims and objectives of antitubercular therapy in pulmonary tuberculosis patients, with currently available antitubercular drugs during the intensive phase of therapy are twofold.
1) To convert sputum smear positive cases who can spread the disease by airborne droplets, in minimum possible period into sputum smear negative cases so that further spread of MTB is prevented to non-infected individuals in the society, and
2) To kill causative organisms so as to eliminate them from the infected individual
and to make him / her disease free.
Currently available method of treatment of pulmonary tuberculosis does not address to damages caused by increasingly generated free radicals to host cells and alteration in a favorable way of suppressed / altered immune system response observed in tuberculosis patients.
Object of invention:
The object of current investigation is to develop a suitable dosage form composition in combination or as a combipack of individual anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrazinamide and Ethambutol with Factor Alpha tx and vitamin C for treatment with a comprehensive approach towards various patho-physiological changes occurring during tubercular affection of lungs so that an increased bactericidal activity against tubercle bacilli is achieved with routinely used antitubercular drugs alongwith lessened damage to host tissue cells
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Summary of the Invention:
The present invention discloses novel oral dosage form in the form of synergistic composition or a combipacks for improvement in the field of treatment of pulmonary tuberculosis in which first action or actions of an agent or agents, produce a combination of effects which synergistically enhance the reduction in the count of tubercle bacilli in the sputum along with the reduction in cell injury to already suppressed cells of host immune system, lungs and surrounding tissue cells due to generated free radicals in the course of disease as well as routine therapy, with a comprehensive approach of addressing all known derangements which occur in the disease and therapy process of an animal. More particularly the said combipack comprises a) amy one anti-tubercular drug such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx; b) combination of any of the two anti-tubercular drugs such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx; c) combination of any of the three anti-tubercular drugs such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx; d) combination of four anti-tubercular drugs namely Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx in a therapeutically effective dosage quantities in a daily dosage form.
Oral powder / granule synergistic compositions comprising upto 4 anti-TB drugs namely Rifampicin, Isoniazid, Ethambutol and Pyrazinamide (SCC-4), in combination with Factor Alpha tx, in palatable powder form, which can be consumed by mixing the powder in a glass of water or juice with meal is disclosed. This invention further discloses oral / powder / granule compositions of any two, any three and any four anti-TB drugs in combination with Factor Alpha tx in a therapeutically effective dosage quantities in a daily dosage form.
Detailed description of the invention:
The present invention comprises suitable dosage form synergistic composition in
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combination or as a combipack of individual anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrazinamide and Ethambutol with Factor Alpha tx for the treatment of patients diagnosed as having pulmonary tuberculosis. This invention comprises of the administering of an effective amount of an antioxidant concomitantly with antitubercular drugs to patients diagnosed as having pulmonary tuberculosis. Even more particularly, the method of the present investigation comprises of administering an effective amount of Factor Alpha tx concomitantly with other antitubercular drugs to patients with such disease.
To date, there has been no information as to Factor Alpha tx's use in the treatment of tuberculosis either alone or along with other antitubercular agent. The present inventors herein disclose that this drug is effective in the treatment of tuberculosis when used concomitantly with other antitubercular drugs. The antioxidants and concomitantly used antitubercular drugs of the present investigation may be administered orally.
Factor Alpha tx and antitubercular drugs used concomitantly are available commercially. For example the following are commercially available forms.
The combipack of the present invention comprising either of the following 1) at least one anti-tubercular drug such as Rifampicin, Isoniazid, Pyrazinamide and Ethambutol with Alpha Factor tx; 2) Any two anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrazinamide and Ethambutol with Alpha Factor tx; 3) Any three anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrazinamide and Ethambutol with Alpha Fafctor tx and 4) All four anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrazinamide and Ethambutol with Alpha Factor tx.
All the drugs used were administered orally. Therapeutically effective daily doses of Factor Alpha tx and antitubercular drugs were administered.
The exact mechanism by which concomitant Factor Alpha tx use exert beneficial effect in pulmonary tuberculosis patients is unknown. However the inventors postulate that Factor
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Alpha tx used to quench free radicals liberated, and thereby causes reduction in cell membrane damage of macrophages and other cells involved in cell mediated immunity. This improved immune cell functions results in increased bactericidal activity by host defense cells. In addition to this the damage to lung tissue at the site of the lesion by released free radicals is also reduced due to quenching by antioxidants used concomitantly.
The present invention relates to oral dosage form in the form of synergistic composition or a combipacks for improvement in the field of treatment of pulmonary tuberculosis in which first action or actions of an agent or agents, produce a combination of effects which synergistically enhance the reduction in the count of tubercle bacilli in the sputum along with the reduction in cell injury to already suppressed cells of host immune system, lungs and surrounding tissue cells due to generated free radicals in the course of disease as well as routine therapy, with a comprehensive approach of addressing all known derangements and which occur in the disease and therapy process an animal. More particularly the said combipack comprises a) any one anti-tubercular drug such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx; b) combination of any of the two anti-tubercular drugs such as Capsule
Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha
tx; c) combination of any of the three anti-tubercular drugs such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx; d) combination of four anti-tubercular drugs namely Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx in a therapeutically effective dosage quantities in a daily dosage form.
The present invention discloses Oral powder / granule synergistic compositions comprising upto 4 anti-TB drugs namely Rifampicin, Isoniazid, Ethambutol and Pyrazinamide, in combination with Factor Alpha tx, in palatable powder form, which can be consumed by mixing the powder in a glass of water or juice with meal. Further oral / powder / granule synergistic compositions comprises a) any one anti-tubercular drug such as Rifampicin, Isoniazid, Pyrizinamide, Ethambutal and Factor Alpha tx; b) combination
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of any of the two anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrizinamide, Ethambutal and Factor Alpha tx; c) combination of any of the three anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrizinamide, Ethambutal and Factor Alpha tx; d) combination of four anti-tubercular drugs namely Rifampicin, Isoniazid, Pyrizinamide, Ethambutal and Factor Alpha tx in a therapeutically effective dosage quantities in a daily dosage form.
The strength of anti-tubercular drugs in the present combipack and synergestic compositions is Rifampicin in the range 60 to 600mg; Isoniazid in the range 75 to 700mg; Ethambutol Hydrochloride in the range 100 to 1000mg; and Pyrazinamide is in the range 150 to 1500 mg. The Factor Alpha tx is in the range 200 to 1000 mg.
The present invention improves upon one or more shortcomings or disadvantages in the currently available treatment for pulmonary tuberculosis through the use of antioxidants. In the preferred embodiments, the invention contemplates the use of antioxidants, and particularly Factor Alpha tx and vitamin C concomitantly with other antitubercular drugs to treat patients with tuberculosis.
In certain embodiments, the present invention concerns a method for treating tuberculosis by the application of a therapeutically effective dose of antioxidants, and preferably Factor Alpha tx and vitamin C to human subjects with the disease. As used herein, the term" Treating a disease by application of therapeutically effective dose of antioxidants concomitantly with antitubercular drugs" is used to signify that the antioxidants and the antitubercular drugs supplied to the patients in amounts and for a period of time, that are effective to provide improvement in one or all of the clinically measurable parameters of the disease.
Several other infective, non-infective diseases showing raised levels oxidative stress are proposed to be treated with concomitant use of antioxidants of the present investigation such as infectious hepatitis, rheumatic disease, diseases with autoimmune disorders, haematological disorders and neoplasms.
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To determine whether there has been an improvement in one or more of clinically measured parameters of the disease, one would determine the value of such a parameter in a given patient both before and during treatment. Various clinical signs and symptoms are known to be suitable by those of skill in the art to be suitable as markers of disease severity. For example, sputum smear AFB , radiological findings and lipid peroxidation levels.
A peculiar advantage of the present invention is that it involves application and use of agents in use clinically as nutrients. By utilizing substances that are already been approved for clinical use for some or other disorder, the present inventors have provided safe agents for use in new modified and improved treatment strategies against above diseases and disorders. Accordingly, Antioxidants are considered to be of concomitant use with other suitable therapeutic agent in above diseases.
The inventors propose that the Factor Alpha tx may be administered to the patients in any pharmaceutically acceptable vehicle and by any route heretofore acceptable for these agents and other concomitant medicament. The preferred route of administration is oral, although one may, if desired, choose to administer the drugs parenteraly, sublingually, a sustain release preparation, or by inhalation.
The combipack of the present invention is illustrated with the following examples.
Example 1
The composition of the present invention is in the form of combipack for the treatment of pulmonary tuberculosis contains Capsule Rifampicin / tablet Isoniazid / Tablet Pyrizinamide / Tablet Ethambutal and Factor Alpha tx in a daily dosage form.
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Example 2
The composition of the present invention is in the form of combipack for pulmonary tuberculosis contains combination of any of the two anti-tubercular drugs such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx as a daily dosage form.
Example 3
The composition of the present invention is in the form of combipack for pulmonary tuberculosis contains combination of any of the three anti-tubercular drugs such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx as a daily dosage form.
Example 4
The composition of the present invention is in the form of combipack for pulmonary tuberculosis contains four anti-tubercular drugs namely Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx as a daily dosage form.
Example 5
Synergistic composition comprising four Anti-tubercular drugs along with Factor Alpha tx in the SACHET

INGREDIENTS WEIGHT (mg/Sachet) % WAV
Rifampicin 450.00 11.16
Isoniazid 225 5.59
Ethambutol 825 20.47
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Pyrazinamide 1200 29.78
Factor Alpha tx 1000 24.81
Betacyclodextrin 135 3.34
Flavour Orange 75 1.87
Aspartem 120 2.98
EXAMPLE 6:
Synergistic composition comprising three Anti-tubercular drugs along with Factor Alpha tx in the SACHET

INGREDIENTS WEIGHT(mg/Sachet) %W/W
Rifampicin 450.00 19.19
Isoniazid 225 9.59
Ethambutol 825 35.18
Factor Alpha tx 600 25.59
Betacyclodextrin 75 3.21
Flavour Orange 50 2.13
Aspartem 120 5.11
EXAMPLE 7 :
Synergistic composition comprising two Anti-tubercular drugs along with Factor Alpha tx in the SACHET
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INGREDIENTS WEIGHT(mg/Sachet) %W/W
Rifampicin 450.00 43.69
Isoniazid 225 21.84
Factor Alpha tx 200 19.42
Betacyclodextrin 35 3.40
Flavour Orange 40 3.88
Aspartem 80 7.77
The following examples are included to demonstrate preferred embodiments of the
invention. It should be appreciated by those of skill in the art that the techniques
disclosed in the examples which follow represent techniques discovered by the inventor
to function well in the practice of the invention, and thus can be considered to constitute

preferred modes for its practice. However, those of skill in the art should, in the light of
the present disclosure, appreciate that many changes can be made in the specific
embodiments which are disclosed and still obtain a like or similar result without
departing from the spirit and scope of the invention.

EXAMPLE I Trial of antioxidants concomitantly with antitubercular drugs in patients of
pulmonary tuberculosis
1. Methods
Fifty four patient of pulmonary tuberculosis were included in this study. Thirty patients were treated with four antitubercular drugs only, 24 patients were treated with four antitubercular drugs and antioxidant drugs concomitantly.
Four antitubercular drugs were given by oral route to all 54 patients in doses and frequency as shown below for a period of 60 days.
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The regime is called as 2EHRZ and is as follows orally, daily.
Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal
Out of this 24 patients received in addition to above four antitubercular drugs, Factor Alpha tx for 60 days daily orally
Chest radiology, sputum smears for AFB and lipid peroxidation values were conducted both before and during the study. The patients were assessed at zero, two, four and eight weeks. Various clinical parameters were measured along with chest radiology, sputum smear for AFB and lipid peroxidation values.
The outcome of clinical improvement was accessed by following parameters
1) Sputum AFB test
In both the groups three sputum samples for each patient were collected & were analyzed for the presence of AFB after 15 days, 30 days & at the end of 2 months by Ziehl-Neelson (hot) stain method. The reports were documented as positive for presence of bacilli & negative for absence of bacilli.
2) Radiological assessment was conducted before & at the end of two months. The
observation were reported as favorable response (Static, Improved, and clear) or
unfavorable response as deterioration
3) Levels of LPO in terms of MDA-TBA complex nmol / g of Hb
All the patients were routinely checked up for symptomatic relief after every 15 days during the intensive phase. Body weight & Hb % was measured before and at the end of the studies.
Eligible patients were selected from the TB outpatient department population. To be
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eligible for enrollment in the study, each patient must first meet the following Inclusion Criteria.
Inclusion Criteria
1. Patient must have clinically definite pulmonary tuberculosis diagnosed for the
first time.
2. Patient should be between 21 and 55 years of age inclusive.
3. Patients should have demonstrable pulmonary lesion on chest radiography.
4. Patient's sputum should be positive for AFB.
Exclusion Criteria
1. Patients having age less than 21 years & more than 55 years.
2. Pregnant females & lactating mothers.
3. Patients with sputum AFB negative & or extra pulmonary tuberculosis.
4. Patients already taking treatment for PTB or previously diagnosed for PTB.
5. Patients of PTB with concomitant diseases like Diabetes, asthma, cancer or HIV.
At the screening visit after the patient has been informed about all aspects of the study and a detailed history of the patient has been obtained, the patients will have a chest x-ray, sputum smear for AFB and 5 ml blood was taken from anticubital vein which was analyzed for hemoglobin % and lipid peroxidation values. The patient will also have general examination and respiratory system examination and cardiovascular system examination.
The eligible patients were enrolled into the study and will be treated with four antitubercular drugs in daily oral doses mentioned above. This group of patients will be randomly divided into two groups.
Control group received Rifampicin, Isoniazid, Ethambutol and Pyrazinamide in daily oral doses mentioned above on Out Patient Department (OPD) basis for 60 days. The study group received Vitamin E and Vitamin C oral daily single dose concomitantly with four
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antitubercular drugs on OPD basis. Chest x-ray, Sputum smear for AFB, and Lipid peroxidation levels were done on day zero, fifteen, thirty and sixty days on OPD basis.
The results of the study indicated that treated group showed better sputum negativity (50% in 30 days) as compared to control group (14 % in 30 days), X-ray findings showed better improvement in treated group as compared to control probably indicating lessened lung damage. Levels of oxidative stress measured in terms of lipid peroxidation were reduced in treated group and on the contrary showed a persistent rise in control group. Better and early control of spread of tuberculosis along with lessened lung tissue damage appears to be the main benefit primarily for TB patients and for human society at large.
The concurrent administration of the Factor Alpha tx with routine antitubercular agents has shown synergistic effects in augmenting sputum negativity by increasing the bactericidal action of antitubercular agents on one hand while due to correction of oxidant / antioxidant imbalance there is better radiological improvement and lessened lung damages
The combination method of Factor Alpha tx and antitubercular agents appears to be effective in correcting the drawbacks of current treatment of MTB.
The results of the study of antibacterial activity of the Factor Alpha tx carried in LJ Medium it is effective against the sensitive strains of Micobacterium Tbubeculosis bacilli (MTB) as well as the Rifampicin resistant, Isoniazid Resistant and Multi drug Resistant strains.
The results of studies conducted in broth and tested by culture growth after 24 hrs shows that the Factor Alpha tx has antibacterial activity against Pseudonamas, Staphylocooi and E.coli.
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Detailed Description of Drawing :
Figure 1 illustrates the combipack comprises any one of the anti-tubercular drug such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal with Factor Alpha tx as a daily dosage form. Nol. indicates any of the anti-tubercular drug such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and no. 2 denotes Factor Alpha tx.
Figure 2 illustrates the combipack comprises any of the two anti-tubercular drug such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal along with Factor Alpha tx as a daily dosage form. No 3 indicates combination of any two anti-tubercular drugs such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambuta and no.4 denotes Factor Alpha tx.
Figure 3 illustrates the combipack comprises any of the three anti-tubercular drug such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal along with Factor Alpha tx as a daily dosage form. No. 5 indicates combination of any three anti-tubercular drugs such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and No. 6 denotes Factor Alpha tx.
i
Figure 4 illustrates the combipack comprises four anti-tubercular drug such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal with Factor Alpha tx as a daily dosage form. No. 7 indicates combination of four anti-tubercular drug namely Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and no. 8 denotes Factor Alpha tx.
While the present invention is described above in connection with preferred illustrative embodiments, these embodiments are not intended to be exhaustive or limiting of the invention. Rather, the invention is intended to cover all alternatives, modifications and equivalents included within its scope, as defined by the appended claims.
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I claim,
1. Oral dosage form in the form of synergistic compositions or a combipacks for improvement in the field of treatment of pulmonary tuberculosis in which first action or actions of an agent or agents, produce a combination of effects which synergistically enhance the reduction in the count of tubercle bacilli in the sputum along with the reduction in cell injury to already suppressed cells of host immune system, lungs and surrounding tissue cells due to generated free radicals in the course of disease as well as routine therapy, with a comprehensive approach of addressing all known derangements which occur in the disease and therapy process of an animal wherein the said combipack comprises
a) any one anti-tubercular drug such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx;
b) combination of any of the two anti-tubercular drugs such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx;
c) combination of any of the three anti-tubercular drugs such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx;
d) four anti-tubercular drugs namely Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx
in a therapeutically effective dosage quantities in a. daily dosage form wherein the said synergistic compositions in powder or granule form comprises
a) any one anti-tubercular drug such as Rifampicin, Isoniazid, pyrizinamide, Ethambutal and Factor Alpha tx;
b) combination of any of the two anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrizinamide, Ethambutal and Factor Alpha tx;
c) combination of any of the three anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrizinamide, Ethambutal and Factor Alpha tx;
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d) four anti-tubercular drugs namely Rifampicin, Isoniazid, Pyrizinamide,
Ethambutal and Factor Alpha tx
in a therapeutically effective dosage quantities in a daily dosage form
2. A combipack as claimed in claim 1 wherein a method of presentation of the combipack of any one of the antitubercular drug such as Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx is as in Figure 1.
3. A combipack as claimed in claim 1 wherein a method of presentation of the combipack of combination of any two of the anti-tubercular drugs Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx is as in Figure 2.
4. A combipack as claimed in claim 1 wherein a method of presentation of the combipack of combination of any three of the anti-tubercular drugs Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx is as in Figure 3.
5. A combipack as claimed in claim 1 wherein a method of presentation of the combipack
of combination of four anti-tubercular drugs Capsule Rifampicin, Tablet Isoniazid, Tablet Pyrizinamide, Tablet Ethambutal and Factor Alpha tx is as in Figure 4.
6. A combipack as claimed in claims 1 to 5 wherein the strength of the said anti-tubercular drug, Rifampicin or rifampicin capsule is in the range of 60 to 600 mg.
7. A combipack as claimed in claims 1 to 5 wherein the strength of the said anti-tubercular drug, Isoniazid or isoniazid tablet is in the range of 75 to 700 mg.
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8. A combipack as claimed in claims 1 to 5 wherein the strength of the said anti-tubercular drug, Pyrizinamide or Pyrizinamide Tablet is in the range of 150 to 1500 mg.
9. A combipack as claimed in claims 1 to 5 wherein the strength of the said ant-tubercular drug, Ethambutal or Ethambutal Tablet is 100 to 1000 mg.

10. A combipack as claimed in claims 1 to 5 wherein the strength of the said Factor Alpha tx is in the range of 200 to 1000 mg.
11. A novel method for improvement in the field if treatment of pulmonary tuberculosis in which first action or actions of an agent or agents, produce a combination of effects which synergistically enhance the reduction in the count or tubercle bacilli in the sputum along with the reduction in cell injury to already suppressed cells of host immune system, lungs and surrounding tissue cells due to generated free redicals in the course of disease as well as routine therapy, with a comprehensive approach of addressing all know derangements which occur in the disease and therapy process an animal comprising:
administration to the said animal an amount of Factor Alpha tx concomitantly with other antitubercular drugs in sufficient quantity and for sufficient duration to clinically cure pulmonary tuberculosis in the said animal.
12. The method according to claim 11 wherein said Factor Alpha tx used concomitantly
with other antitubercular drugs enhanced the clinical outcome of antitubercular
treatment by way of synergism.
13. The method according to claim 11 wherein the said animal is a human.
14. The process for the manufacture of the product according to claim 1 to 11.
15 The product as claimed in claims 1 to 11 wherein the antibacterial activity of Factor
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Alpha tx against the Micobacterium Tuderculi including all the strains of the same including all the strains of the same including all the strains of the same including Rifampicin resistant, Isoniazid Resistant and multi drug resitant strains
16. The product as claimed in claims 1 to 11 wherein the antibacterial activity of Factor Alpha tx against the bacterium Pseudomonas, Staphylocooi, E-coli etc.
17. Oral dosage form in the form of synergistic composition or a combipacks for improvement in the field of treatment of pulmonary tuberculosis in which first action or actions of an agent or agents, produce a combination of effects which synergistically enhance the reduction in the count of tubercle bacilli in the sputum along with the reduction in cell injury to already suppressed cells of host immune system, lungs and surrounding tissue cells due to generated free radicals in the course of disease as well as routine therapy, with a comprehensive approach of addressing all known derangements and which occur in the disease and therapy process an animal as substantially described herein with reference to the following examples 1 to 7 and example I.
Dated this the 7th day of May 2004

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Abstract:
The present invention describes novel oral dose comprising composition of antioxidant, preferably Factor Alpha tx and vitamin C with other anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrazinamide and Ethambutol to treat patient with tuberculosis, more particularly pulmonary tuberculosis. More particularly present invention describes oral dosage, synergistic composition in combination or as a combipack of individual anti-tubercular drugs such as Rifampicin, Isoniazid, Pyrazinamide and Ethambutol with Factor Alpha tx and vitamin C useful in the treatment of pulmonary tuberculosis.

NOVEL ORAL COMPOSITIONS

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