FORM-2 THE PATENTS ACT, 1970
(39 of 1970) ,
&
THE PATENTS RULES, 2003
PROVISIONAL
Specification
(See section 10 and rule 13)
NOVEL MEDICINAL FORMULATION FOR INDUCING AN IMMUNE RESPONSE IN PATIENTS WITH CHRONIC AND
RECURRING INFECTIONS
DR, RAJESH SHAH
an Indian National
of Life Force Center, 415, Krushal Commercial Complex, 4 floor,
Above Shopper's Stop, M. G. Road, Ghatkopar (E), Mumbai 400 089,
Maharashtra, India
THE FOLLOWING SPECIFICATION DESCRIBES THE INVENTION.

Field of invention
The present invention relates to a novel medicinal formulation for inducing an immune response in patients with chronic and recurring infections.
In particular, this invention relates to a novel medicinal formulation for prevention and treatment of various symptoms and conditions associated with pre-tuberculosis, active tuberculosis and post tuberculosis states of infection and other chronic infections.
Definitions:
As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
Antigenicity means the ability of a substance to trigger an immune response in a particular organism.
LTBI means Latent TB infection.
Potency means capacity of the formulation to produce strong immunological response and / or defense.
Background and Prior Art:
Tuberculosis (commonly abbreviated as TB) is an infection caused by the bacterium Mycobacterium tuberculosis, which most commonly affects the lungs (pulmonary TB) but can also affect the central nervous system
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(meningitis), lymphatic system, circulatory system (Miliary tuberculosis), genitourinary system, gastrointestinal system, eyes, bones and joints.
Most of those infected (90%) have asymptomatic latent TB infection (LTBI). There is a 10% lifetime chance that LTBI will progress to TB disease which, if left untreated, could kill more than 50% of its victims. TB is one of the top four infectious killing diseases in the world.
Although tuberculosis can generally be controlled using chemotherapy such treatment is not sufficient to prevent the spread of the disease. Furthermore, Potential hepatotoxicity of some of the first-line antitubercular agents remains a problem, especially during the initial period of treatment. There is always a risk of discontinuation by the patient because of side effects . For example, drugs like isoniazid, rifampin or pyrazinamide are sometimes discontinued by patients because of severe side effects like hepatotoxicity , exanthema and arthralgia.
Infected individuals may be asymptomatic, but contagious, for some time. In addition, compliance with the treatment regimen is critical. Some patients do not complete the course of treatment, which can lead to ineffective treatment and the development of drug resistant mycobacteria.
Several efforts have been made for the preparation of a vaccine for tuberculosis.
UK patent 2236480 describes tuberculosis vaccine. The UK patent describes vaccine to provide protection against tuberculosis.
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An immunotherapeutic agent administered through parenteral route, consisting essentially of killed cells of Mycobacterium Vaccae, useful for treatment of Mycobacterial disease like tuberculosis or leprosy as an adjuvant to chemotherapy, is disclosed in US patent 4724144.
Vaccine containing specific immunogenic portion of Mycobacterium Vaccae for nonspecific immune-response amplifier is described in US Patent 6001361.
WO03075825 describe the method of treatment of tuberculosis involving administration of a formulation prepared using Mycobacterium w, while manufacture of a pharmaceutical composition containing cells of Mycobacterium w along with a carrier in a single formulation is disclosed in WO03075824.
Furthermore, WO05042013, WO03089462, US Patent application 20030236393, WO0198460, WO0175096, WO0039301, US Patent 20010012888, US 6613881, US Patent 20030147911, EP 1398379 describe the use of various proteins, peptides, non peptides derived from different strains of Mycobacterium for improving the immune response in patients with tuberculosis.
Currently, vaccination with live bacteria is the most efficient method for inducing protective immunity. The most common mycobacterium employed for this purpose is Bacillus Calmette-Guerin (BCG), an avirulent strain of Mycobacterium bovis.
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However, the safety and efficacy of BCG is a source of controversy. The protective efficacy of vaccine against TB, bacille Calmette-Guerin (BCG) varies considerably from region to region- from around 80% protection to none. The protective effect of BCG, where observed, is mainly in neonates and children against non-infectious forms of primary disease, such as meningitis, but there is little or no protection against infectious, post-primary, pulmonary TB in adolescents and adults.
Other strains of mycobacterium like Mycobacterium vaccae, Mycobatectrium w have been used for immunotherapy for tuberculosis, and leprosy. However, there is little information on the efficacy of these preparations.
Furthermore, administration of a vaccine in people with weaker immune systems, such as the elderly, those on steroid therapy and those under significant stress can pose serious risk.
For centuries, homeopathic practitioners have suggested that serially agitated dilutions of infectious agents (called "nosodes") are effective in the prevention of infectious disease.
A 'nosode' is a homeopathic remedy prepared from a pathological specimen. The starting material for preparation of a nosode can be blood, pus, any other body secretion or excretion, or even a diseased fragment of tissue, such as a growth. Rabies nosode, for example, starts with the saliva of a rabid dog and is then "potentized".
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The prepration of nosodes derives from homotoxicology, a type of homeopathic therapy created by Hans-Heinrich Reckeweg in Germany in the first part of 18th century.
Homeopathic medicine, since its inception under Hahneman at the beginning of the 19th century, follows the principle of "infinitesimals." From this notion, the dosages of nosodes are in very minute and diluted forms. Thus, nosodes are not nearly as harmful as the untreated pathological product.
A 'nosode' is similar to an "oral vaccine" in the sense that its purpose is to "immunize" the body against a specific as well as related disease conditions. The major difference between a nosode and a vaccine is, of course, the extremely small quantity of antigenic material in a nosode.
In the case of nosodes from bacteria, viruses or diseased tissues, the preparation introduces the molecular imprints of possible antigens and other constituents of the pathological agent to the immune system. The working of the nosode is based on the fact that the immune system is induced to develop a defence mechanism which is effective against variety of antigens with this kind of molecular imprint, without being exposed to the virulence of the living agent.
Nosodes are also used as inter-current remedies in the treatment of chronic disease. This is the most common use of nosodes in Homeopathic practice.
Presently available nosodes like Tuberculinum Bovinum, and Bac. A Tuberculosis Nosode ( Bacillinum), a maceration made from a tubercular
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sputum contain antigens from limited strains of Mycobacterium and therefore they suffer from the drawback of providing limited immune protection .
Presently available nosodes like Tuberculinum Bovinum and BaciUinum are sourced from macerated lung tissues of the patient suspected to be suffering from Tuberculosis and from the sputum of such suspected patient. The preparations used presently are sourced from over 50 years old samples and, then prepared from the said sources.
The limitations with the present preparations are:
1. No one is sure of the exact source as bacteriological evaluation was not in practice in early 1940s.
2. No one has made any new preparations since then.
3. The preparations made from the infected lung tissues would obviously have many other organisms (mixed infections) as well as the diseased tissue itself.
4. The strain of Mycobacterium organism was never available, as it was never investigated in the light of current understanding.
The old preparations as well as the presently available preparations , thus, present many uncertainties, unscientific nature of the source, non-reproducibility, and limited antigenicity and hence a major drawback of providing limited immune protection.
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Therefore, there is a need for a formulation that can induce protective immunity against a broad spectrum of antigens related to tuberculosis and other chronic infections associated with tuberculosis as well as allergic infections of the respiratory system, in a re-producible manner and which has better safety profile than vaccines.
Summary
It is an object of this invention to provide a novel, broad spectrum immunity enhancing, reliable medicinal formulation prepared from the culture of the specific organisms, so as to prevent and cure various conditions, usually prevalent among patients with active or inactive tuberculosis infection and other chronic affections.
Another object of the present invention is to provide a novel medicinal formulation with a mixture of antigens from killed cells of Mycobacterium of different strains namely, Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium microti, Mycobacterium African and Mycobacterium laprae.
Yet another object of this invention is to provide a safe medicinal formulation containing serially agitated dilutions of mixture of antigens from aforementioned strains of Mycobacterium.
Yet another object of this invention is to provide a therapeutic measure for the treatment of various disease states, which may be present by one or more of the following indications:
1. Recurring fever
2. Recurring cough and cold
3. Loss of appetite
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4. Malnourished state of health
5. Loss of weight due to any chronic infection (or due to any unknown reason) or an inability to gain weight
6. Recurring respiratory allergies and secondary infections in asthmatics, etc.
7. Shortening the span of recovery phase in case of any subacute infection such as Pneumonia, Septic tonsillitis, Liver abscess, tuberculosis of any organ, etc.
Yet another object of this invention is to provide a method for preparation of a novel formulation, potentiated by means of a mathematico-mechanical process for maximal therapeutic benefits.
Yet another object of this invention is to provide a novel medicinal formulation which is reproducible and which contains precisely defined antigenic material.
Yet another object of this invention is to provide a novel medicinal formulation offering better patient compliance and thereby minimizing the risk of multidrug-resistant type of infections.
Description: Mycobacterium complex:
Mycobacterium complex includes a wide range of Mycobacterium group of bacilli, inclusive of typical and atypical variants.
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Mycobacterium is a genus of Actinobacteria, given its own family, the Mycobacteriaceae. All mycobacteria are aerobic and acid fast.
Cell walls of Mycobacteria are hydrophobic, waxy and rich in mycolic acids/mycolates and they are thicker than in many other bacteria,.
The genus Mycobacterium includes many pathogens known to cause serious diseases in mammals, including tuberculosis and leprosy they are also capable of affecting most organs in the human body such as lungs, skin, bones, brain, intestines, liver, eyes, kidney, etc. Some of the most common variants are:
1. Mycobacterium tuberculosis (culture) (strain A)
2. Mycobacterium bovis (culture) (strain B)
3. Mycobacterium microti (culture) (strain C)
4. Mycobacterium African (culture) (strain D
5. Mycobacterium Lapre (from cultivation on the mouse footpad) (strain E)
Cultures of the organisms numbered 1 to 4 in the above list are procured separately from a reputed Pathological Laboratory who regularly deal with bacterial cultures. Various strains of organisms (1 to 4) when detected in the sputum or other diseased tissues were cultured for specific strains.
Colonies of the specific organisms form the culture media are carefully isolated with probe and put in normal saline for further processing. About 10 ml of each of the saline containing the specified organism from cultures are mixed separately in 20 ml normal saline. These are called as Primary culture. Thus 4 Primary cultures for Mycobacterium strains A, B, C, and D are prepared and are labeled as Ape, BPc, Cpc, DPc.
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In case of Mycobacterium Laprae, Mycobacterium leprae organism grown on armadillo, separated and centrifuged, with residues of some tissues (100% wash not possible), containing millions of live organisms (over 10"8 (bacteria) per ml is used for making a Primary culture. This was sources from a leading Leprosy research institute of India, located in Mumbai.
About 2 ml of the Mycobacterium leprae culture is taken in a sterile test tube and mixed with 2 ml of ethyl alcohol (90 to 100%) to kill the organisms to obtain EPC. The killed Mycobacterium leprae organisms are known to retain antigenicity.
Thus, 5 Primary cultures for 5 strains of Mycobacterium labeled as APC, BPC, Cpc, Dpc and EpC., are prepared . About (2ml) of Primary culture(2ml) is mixed with a vehicle selected from a group of vehicles consisting of normal saline, distilled water and ethyl alcohol(90 to 100 %). Preferably, ethyl alcohol (90 to 100 %) is used as a vehicle.
The proportion of mixing of primary culture with the vehicle can range from 1:99 to 50:50. Preferably 2ml of the primary culture is mixed with 90 ml of the vehicle.
Serial Dilution And Potentiation :
Potentiation is a mathematico-mechanical process for rendering inert or poisonous antigen containing pathological residues, to a state of physical solubility, physiological assimilability so as to enhance their therapeutic activity and harmlessness, for use as a healing remedy.
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The primary object of potentiation is to reduce all substances designed for therapeutic use to "a state of approximately perfect solution or complete ionization, which is fully accomplished only by infinite dilution." (Arrhenius.)
Each resulting diluted culture is typically stroked by holding the bottle in a closed fist and striking the fist on a hard surface repeatedly at a regular frequency or by exercising similar powerful stroke using a mechanical device which can strike a bottle on a hard surface. Such strokes are given 10 times. This preparation is labeled as Strain lc potency. Thus 5 different preparations of lc are obtained and labeled as A-lc, B-lc, C-lc, D-lc and E-lc.
In accordance with the preferred embodiment of this invention, the bottle containing the preparation for stroking is a securely stoppered glass bottle and a mechanical device is adopted to exert a force of at least 6 dynes rhythmically at a frequency of 10 strokes in two minutes.
This procedure of serial dilution followed by stroking is repeated 4 times with each lc potency preparations to obtain respective 5c preparations for each strain. These are thus labeled as A-5c, B-5c, C-5c, D-5c and E-5c.
Preparation of Mycobacterium Complex:
At this point, about 2ml liquid from A-5c along with 2ml liquid taken from at least one 5c preparation selected from a group of 5c preparations consisting of B-5c, C-5c, D-5c and E-5c is taken in a separate bottle and about 70 drops of vehicle are added to obtain different Mycobaterium Complex preparations such as Mycobacterium Complex AB 5c, Mycobacterium Complex AC 5c, Mycobacterium Complex AD 5c, Mycobacterium Complex AE , 5c, Mycobacterium Complex ABC 5c, Mycobacterium Complex ABD 5c,
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Mycobacterium Complex ABE 5c, Mycobacterium Complex ACD 5c, Mycobacterium Complex ACE 5c, Mycobacterium Complex ADE 5c, Mycobacterium Complex ABCD 5c, Mycobacterium Complex ABCE 5c, Mycobacterium Complex ABDE 5c and Mycobacterium Complex ACDE 5c.
A vehicle is selected from a group of vehicles consisting of normal saline, distilled water and ethyl alcohol. Preferably ethyl alcohol (90 to 100%) is used as a vehicle.
Above mentioned Mycobacterium complex 5c preparations thus obtained are then further subjected to serial dilutions and potentiation to obtain preparations with higher potencies like M.C.-6c, M.C.-7c, M.C. -8c...M.C-50c... M.C. -1000c. M.C. -50000c and above.
While considerable emphasis has been placed herein on the specific steps of the preferred process, it will be appreciated that many steps can be made and that many changes can be made in the preferred steps without departing from the principles of the invention. These and other changes in the preferred steps of the invention will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation.
Advantage and Application of the new preparation Mycobacterium complex 6c to 50000c (and above):
These preparations are prepared from the specific bacterial strains but they lack the bacterial toxicity.
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Preliminary clinical investigations have shown that the formulations prepared according to the above process help to retain the capacity to induce immune response in the body, which helps in prevention and treatment of various conditions, such as recurring upper and lower respiratory infections and allergies, recurring viral infections, Anorexia (loss of appetite), weight loss or not gaining weight.
Furthermore, they positively alter the course of any form of tuberculosis and are useful for preventing, controlling or treating all sorts of opportunistic infections commonly found in cases of Tuberculosis as well as other chronic infections such as AIDS.
Dated this 6th day of July, 2006

Mohan Dewan ofR.K. Dewan&Co Applicant's Patent Attorney
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