Title of Invention

PROCESS FOR PREPARING MEDICAMENTS EFFECTIVE AGAINST VIRAL INFECTIONS AND AS CELLULAR IMMUNITY STIMULANT.

Abstract

The present invention relates to a process for preparing medicaments effective against viral infections and also as cellular immunity stimulant. The process resides in preparing aqueous alcoholic solutions of five different constituents (i) cyclophosphamide, (ii) cyclosporin, (iii) azathioprine, (iv) methotrexate and (v) prednisolone such that the final concentration ranges between 10-12 and 10-18M. Additional components like sulfasalazine and AS2O3 may also be included in the composition. Isopropanol may be used as additional diluent-cum-excipient, and benzalkonium chloride may be added to the final composition as a stabilizer in an amount varying between 5 and 25 ppm.

Full Text

The present invention relates to a process for preparing medicaments effective against viral infections and as cellular immunity stimulant. More particularly this invention pertains to a process for preparing medicaments using a number of drugs in their molecular form at concentration levels varying from picogram (10-12) to altogram (10-18) when used in combination have been found to procedure surprisingly effective action against different types of viral infections and also capable of enhancing cellular immunity level. Way back in 1918, Toyama and Kolmer observed that feeding low concentrations of arsenic enhances antibody production, while antibody suppression occurs following high-level exposure. There is also evidence in laboratory animals that nickel exposure results in altered resistance to viras and bacteria (Adkins et. al. 1978). As regards 'drugs' recent studies have indicated that certain toxic drugs may cause alterations in the immunity level of persons under treatment. In support of biphasic action of molecular phases of toxic drugs, the case of "Tamoxiphen" may be cited. Using a cell line of human breast cancer cells (MCF7), Horwitz et. al. (1978) found that the action of "Tamoxiphen" was biphasic in that at low extracellular levels (10-7 M) the drug showed agonistic properties in stimulating growth and inducing progesterone receptors. Higher doses (10-6M) were antagonistic. Interference with oestradiol may take the form of blocking the binding of oestradiol to cytosolic receptors, and of reducing the number of receptors available for the natural hormone (Coulson, Tayler & Francis). It is noteworthy that inventions of antibiotics and chemotherapeutic agent (e.g. anti-malarial and unti-neoplasic, etc.) are great achievements during World War II and thereafter, but their effectiveness are gradually on the wane due to increased resistance to drugs and toxicity of these compounds. As a consequence thereof, more broad-spectrum antibiotics are needed today to treat even a common infection which could be cured by simply administering penicillin a decade earlier. However, no study was initiated to observe the efficiency of a mixture of toxic drugs in combatting a rather long list of diseases in their extreme dilutions e.g. (10-12 M - 10-18 M), and the present invention has produced unforeseen, surprising result by using a mixture of toxic drugs which act synergistically in raising the cellular immunity level in treated humans/animals, apart from being effective against a number of viral infections. The principal object of this invention is to provide a process for preparing medicaments which can effectively combat a number of viral infections and can also enhance cellular immunity levels. A further object of this invention is to provide a process for preparing medicaments acting as immunostimulant where some of the constituent components are known to be immunodepressants. A still further object of this invention is to provide a process for preparing medicaments wherein the ingredients are present in amounts varying between 10-12 and 10-18 M. Another object of this invention is to provide a process for producing storage stable medicaments having anti-viral activity and also capable of raising cellular immunity level. The foregoing objects are achieved by the present invention according to which there is provided a process for preparing medicaments effective against viral infections and as cellular immunity stimulant which comprises making aqueous alcoholic solutions of the following compounds :- (i) "cyclophosphamide" - Bis (2-chloroethyl) phosphamide cyclic propanolamide ester monohydrate, mol. wt. 279.1; (ii) "cyclosporin" - A member of a group of non-polar cyclic oligopeptides, having molecular weight of about 1203; (iii) "azathioprine" - 6 - [(1 -Methyl - 4- nitro -1H- imidazol - 5-yl) thio]-1H -purine, mol.wt. 277.3; (iv) "methotrexate" - 4 - Amino - 10 - methyl-folic acid, mol. wt. 454.4, and (v) "prednisolone" - (II 0) - 11, 17, 21 - Trihydroxypregna - 1,4 - diene - 3, 20 - dione, mol. wt. 360.5, diluting the individual solutions/suspensions with aqueous alcohol until the solution has a concentration varying between 10-12 and 10-18M, and thereafter mixing the individual solutions in equal volumes to obtain a homogenous solution showing biphasic action against viral infections and also enhancing cellular immunity level. For the sake of brevity and convenience, brand names or trivial names as appearing above in respect of the individual constituents have been used in this specification text. In order to dissolve and dilute the constituent components/compounds of the above medicaments, it has been observed that 70% ethanol (v/v) can be optimally used. Dilution of the aforesaid components is carried out in the following mmanner: (i) "cyclophosphamide" - IC contain 1.93 mgm; 0.0965 mg diluted with 99 drops of alcohol, (ii) "cyclosporin" - IC contain 6.666 mgm; 0.3333 mg diluted with 99 drops of alcohol, (iii) "azathioprine" - 50 mgm mixed with 4950 mg. of sugar of milk and then dissolved in aqueous ethanol (trituration 1:99); (iv) "methotrexate" - IC contain 1.666 mgm; .0833 mg diluted with 99 drops of alcohol, (v) "prednisolone" - IC contain 2.666 mgm; 0.1333 mg diluted with 99 drops of ethanol, and thereafter the individual solutions are mixed in equal volumes. For enhancing shelf life and also for preventing deterioration of activity on prolonged storage, use has been made of benzalkonium chloride which is added to the final solution. The amount of this stabilizer varies between 5 and 25 ppm. One may also use isopropanol as an additional diluent, if needed or desired. Apart from the foregoing compounds, or nurse compounds selected from the following have been found to enhance the effectiveness of the subject composition in a synergistic manner. The amounts added vary between 10-12 to 10-18 M, as is the case with other ingredient drugs :- (i) "sulfasalazine" - 5-[p-( 2 - pyridylsultamoyl) phenylazo]-salicylic acid, and (ii) "arsenious oxide" - AS2O3. Some of the aforesaid constituents are known to be immunosuppresant. But surprisingly when used in combination within concentration ranges of 10-12 - 10-18M, they not only show capability to effectively combat viral infections, they even act as immunostimulants. Antiviral drugs are available in modern, present day medicines. Most of them are toxic and prolonged administration often produce adverse side effects. On the contrary the medicaments of the present invention are harmless, safe to administer even for prolonged period of time and extremely cost - effective. An extremely toxic abused-drug like AS2O3 has been found to cause immune-alteration at alto-gram level in admixture with other ingredients. The medicaments on clinical trial have shown encouraging results as would be evidenced by the observed data given in a tabular form in the following Example which is given by way of illustration and not by way of limitation. Furthermore, the medicaments produced by the process of the present invention have been found to be effective, inter alia, against the following : (i) Infection - Viral diseases : measles, mumps, chicken pox, viral fever, viral hepatitis (B and non B), herpes; (ii) Disfunctional uterine haemorrhage; (iii) Dysmenorrhea (iv) Diabetes mellitus (non - insulin dependent); (v) Epilepsy; (vi) Attention deficit hyperactive syndrome; (vii) Mental retardation; (viii) Autism; (ix) Parkinsonism; (x) Allergies (Type I, II, III, IV, Gell comb); (xi) Diarrhoea of all forms and (xii) Various forms of pain including pain from carcinoma. It may also be noted that the data included in the Example appearing hereinbefore, the medicaments prepared by the process of the present invention are effective as cellular immunity stimulant which is manifested by the enhancement of CD4-CD8 levels in the human system, even though some of the constituent components are known to be immunodepressants. Level and extent of stimulation are considerably enhanced by the mutual interaction of the components, thereby establishing synergistic action in the aforesaid medicaments. While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without deviating from the spirit and scope of this invention. Thus the disclosure contained herein includes within its ambit the obvious equivalents and substitutes as well. Having described the invention in detail with particular reference to the illustrative "Example" given above, it will now be more specifically defined by means of claims appended hereafter. We Claim : 1. A process for preparing medicaments effective against viral infections and as cellular immunity stimulant, which comprises making aqueous alcoholic solutions of the following compounds :- (i) "cyclophosphamide" - Bis (2-chloroethyl) phosphamide cyclic propanolamide ester monohydrate, mol. Wt. 279.1; (ii) "cyclosporin" - A member of a group of non-polar cyclic oligopeptides, having molecular weight of about 1203; (iii) "azathioprine" - 6 - [(1-Methyl - 4 nitro - 1H - imidazol - 5-yl) this] - 1H-purine, mol. Wt. 277.3; (iv) "methotrexate" - 4 - Amino - 10 - methyl - folic acid, mol. Wt. 454.4, and (v) "prednisolone" - (11 β) - 11, 17, 21 - Trihydroxypregna - 1,4 - diene - 3, 20 - dione, mol. Wt. 360.5, diluting the individual solutions / suspensions with aqueous alcohol until the solution has a concentration varying between 10-12 and 10-18 M, and thereafter mixing he individual solutions in equal volumes to obtain a homogeneous solution showing biphasic action against viral infections and also enhancing cellular immunity level. 2. A process as claimed in Claim 1, wherein the alcohol used for dissolution and dilution is 70% v/v ethanol. 3. A process as claimed in Claims 1 and 2, wherein dilution of the individual component is carried out in the following manner :- (i) "cyclophosphamide" - 0.0965 mg diluted with 99 drops of alcohol; (ii) "cyclosporin" - 0.3333 mg diluted with 99 drops of alcohol; (iii) "azathioprine" - 50 mgm mixed with 4950 mg. of sugar of milk and then dissolved in aqueous ethanol (trituration 1:99); (iv) "methotrexate" - 0.0833 mg diluted with 99 drops of alcohol (v) "prednisolone" - 0.1333 mg diluted with 99 drops of ethanol, followed by mixing the solutions in equal volumes to arrive at the desired product. A process as claimed in Claims 1 to 3, wherein there is added benzalkonium chloride to the final solution in an amount varying between 5 and 25 ppm. A process as claimed in Claims 1 to 4, wherein isopropanol is used as an additional diluent and / or excipient. A process as claimed in Claims 1 to 5, wherein at least one of the following compounds is added as constituent components of the said medicament in similar proportion as indicated in Claims 1 and 3 : (a) "sulfasalazine" - 5 - [ p - ( 2 - pyridylsulfamoyl) phelylazo J - salicyclic acid and (b) "arsenious oxide" AS2O3 A process for preparing medicaments effective against viral infections and as cellular immunity stimulant, substantially as herein before described with particular reference to the Example given above. The present invention relates to a process for preparing medicaments effective against viral infections and also as cellular immunity stimulant. The process resides in preparing aqueous alcoholic solutions of five different constituents (i) cyclophosphamide, (ii) cyclosporin, (iii) azathioprine, (iv) methotrexate and (v) prednisolone such that the final concentration ranges between 10-12 and 10-18M. Additional components like sulfasalazine and AS2O3 may also be included in the composition. Isopropanol may be used as additional diluent-cum-excipient, and benzalkonium chloride may be added to the final composition as a stabilizer in an amount varying between 5 and 25 ppm.

Documents:

424-KOL-2003-CORRESPONDENCE-1.1.pdf

424-KOL-2003-CORRESPONDENCE.pdf

424-KOL-2003-FORM 27-1.1.pdf

424-KOL-2003-FORM 27.pdf

424-kol-2003-granted-abstract.pdf

424-kol-2003-granted-claims.pdf

424-kol-2003-granted-correspondence.pdf

424-kol-2003-granted-description (complete).pdf

424-kol-2003-granted-examination report.pdf

424-kol-2003-granted-form 1.pdf

424-kol-2003-granted-form 18.pdf

424-kol-2003-granted-form 2.pdf

424-kol-2003-granted-form 3.pdf

424-kol-2003-granted-form 5.pdf

424-kol-2003-granted-pa.pdf

424-kol-2003-granted-reply to examination report.pdf

424-kol-2003-granted-specification.pdf