Patent Application: US-27784506-A

Abstract:
the invention is a method of treatment of the symptoms related to inflammation that accompanies the release of tumor necrosis factor - alpha in diseases such as viral infection such as those affecting the respiratory tract by providing systemic glutathione by oral administration of glutathione in a liposome encapsulation or by the intravenous administration of reduced glutathione . the administration of a therapeutically effective amount of oral liposomal glutathione results in improvement of symptoms of disease induced by the release of tnf - α in infectious disease states such as respiratory and other viruses . the product is novel in that it is stable across the temperature ranges encountered in shipping and does not need to be refrigerated for storage . compounds enhancing the effect of the liposomal glutathione as well as intravenous glutathione are contemplated such as selenium .

Description:
% w / w deionized 74 . 4 water glycerin 15 . 00 lecithin 1 . 50 potassium 0 . 10 sorbate ( optional spoilage retardant ) glutathione 8 . 25 ( reduced ) a lipid mixture having components lecithin , and glycerin were commingled in a large volume flask and set aside for compounding . in a separate beaker , a water mixture having water , glycerin , glutathione were mixed and heated to 50 . degree . c . the water mixture was added to the lipid mixture while vigorously mixing with a high speed , high shear homogenizing mixer at 750 - 1500 rpm for 30 minutes . the homogenizer was stopped and the solution was placed on a magnetic stirring plate , covered with parafilm and mixed with a magnetic stir bar until cooled to room temperature . normally , a spoilage retardant such as potassium sorbate or bht would be added . the solution would be placed in appropriate dispenser for ingestion as a liquid or administration as a spray . analysis of the preparation under an optical light microscope with polarized light at 400 × magnification confirmed presence of both multilamellar lipid vesicles ( mlv ) and unilamellar lipid vesicles . notably , there is no requirement of cooling , or production at a certain temperature . the preferred embodiment includes the variations of the amount of glutathione to create less concentrated amounts of glutathione . the methods of manufacture described in keller et al , u . s . pat . no . 5 , 891 , 465 , apr . 6 , 1999 , are incorporated into this description . components are commingled and liposomes are made using the injection method ( lasic , d ., liposomes , elsevier , 88 - 90 , 1993 ). when liposome mixture cooled down 0 . 7 ml was drawn into a 1 ml insulin syringe and injected into the open - end of a soft gelatin capsule then sealed with tweezers . the resulting one gram capsule contains 898 iu of vitamin e . large scale manufacturing methods for filling gel caps , such as the rotary die process , are the preferred method for commercial applications . the preferred dosing schedule of the invention for the treatment of influenza symptoms is 600 mg ( land ½ teaspoon ) of the invention to be taken at the first onset of symptoms . a dose of 400 mg ( 1 teaspoon ) to 600 mg is to be repeated each hour until symptoms are relieved . once symptom relief is achieved , the dose is repeated immediately upon the return of symptoms . the anticipated amount to be taken is 1 to 2 ounces in 24 hours . see case examples . if symptoms recur in the following 24 hours the regimen may be repeated as stated . 1 teaspoon of the invention of oral liposomal glutathione reduced contains approximately 440 mg gsh . a preferred mode sets a suggested dose based on body weight . recommended amounts are for use in the treatment of influenza symptoms . for best results it is suggested that the invention be used at the early onset of flu symptoms of as a preventative after exposure the flu . as stated , the initial dose should be according to body weight . for adults the dose is 1 and ½ teaspoon initially and repeat every 1 to 2 hours over 24 hour period . the amount and frequency of doses may be decreased as the individual begins to improve . the period of treatment is usually 24 hours . ingestion of the liposomal preparation of reduced glutathione results in a rapid reduction in influenza symptoms as related in the examples cited . the mechanism may be related to one or more of the methods described . the rapid addition of reduced glutathione to the system by the invention has a number of avenues to facilitate restoration of normal general cell and immune cell function that results in the reduction of symptoms related to virus infection in general and including influenza . macrophage have a predilection to ingest particulate materials ( 6 ) such as liposomes , so the delivery of glutathione directly to these cells , responsible for directing immune responses , is particularly effective . the invention has been demonstrated to have benefit in diseases associated with intracellular glutathione deficiency such as parkinson &# 39 ; s disease , and cystic fibrosis . these benefits have been claimed by this inventor in provisional application ser . no . 60 / 522 , 785 on nov . 7 , 2004 entitled “ liposomal formulation for oral administration of glutathione ( reduced )” which is adopted and incorporated herein by reference , and in a presently pending application by f . t . guilford , the inventor herein , u . s . utility application ser . no . 10 / 289 , 934 filed nov . 7 , 2002 entitled systemic administration of nac as an adjunct in the treatment of bioterror exposures such as anthrax , smallpox or radiation and for vaccination prophylaxis , and use in combination with dhea ” which is adopted and incorporated herein by reference . the clinically effective use of glutathione in its pure form directly without any additive encapsulation or transformation ( in the “ neat ” form ) has been previously limited to the intravenous administration of the biochemical in the reduced state . demopoulus et al , u . s . pat . no . 6 , 204 , 248 , mar . 20 , 2001 , describes the use of the glutathione in combination with crystalline ascorbic acid enclosed in a gel cap for oral administration to alter redox state of cells and improve disease processes . however , no suggestion is made of glutathione encapsulated in a liposome for the treatment of influenza , nor is any suggestion made as to the actual efficacy of glutathione delivery to the cell system set out . a recent patent , smith , u . s . pat . no . 6 , 764 , 693 , jul . 20 , 2004 , claims the use of liposomes containing a combination of glutathione with at least one other antioxidant material to increase intracellular and extra cellular antioxidants . the smith patent claims a mechanism of action of the liposome that involves the peroxidation and lysis of the liposome with resulting release of liposome content of the mixture of glutathione and other nutrients into the plasma . by contrast , the preferred method of composition of the liposome claimed in this invention is for a liposome that functions by fusion or engulfing of the liposome into the cellular immune cell and transfer of the glutathione content into cells . evidence for this method of action is provided in the clinical examples of improvement in the red blood cell level of glutathione paralleling clinical improvement in individuals with cystic fibrosis , f . t . guilford provisional application ser . no . 60 / 522 , 785 on nov . 7 , 2004 entitled “ liposomal formulation for oral administration of glutathione ( reduced )” which is referred to in the discussion earlier . the preferred composition for oral use of the invention is for a liposome encapsulating only reduced glutathione , without other components . liposomes have been documented to fuse to cells such as red blood cells and deliver their content into the cells ( 7 ). another preferred mode is delivery of the liposomal glutathione is by placing the liposome containing glutathione into a gel cap . this allows a capsule delivery of unit dose . capsule delivery facilitates storage , delivery and ingestion of the invention for many situations . the liposome preparations claimed in this invention allow the manufacture of a stable product , which can be used for the administration of glutathione in a form that is convenient . the liposome - glutathione preparation described is also stable from oxidation . the preferred embodiment of the invention has been demonstrated to maintain glutathione in the reduced state , both after manufacture and at 14 months of storage at room temperature . the preferred mode of the invention describes the lipid encapsulation of the glutathione ( reduced ) into the lipid vesicle of liposomes and administered orally for the transmucosal absorption into the nose , mouth , throat or gastrointestinal tract providing the ability to conveniently supply therapeutically effective amounts of glutathione ( reduced ). the invention may also be administered topically for dermal and transdermal administration , intravenously or in an encapsulation such as a gel cap . another form of the invention is the intravenous infusion of glutathione in solution for treatment in adult respiratory distress syndrome ( ards ) even if not in liposomal form . while harbin et al , u . s . pat . no . 6 , 835 , 811 , dec . 28 , 2004 , have reported a method of preparing glutathione in an intravenous solution , treatment for ards was not proposed . this invention provides for a considerably more stable liposomal formulation of glutathione than the less stable method in harbin &# 39 ; 811 . the proposed uses in harbin &# 39 ; 811 for the less stabilized non - liposomal glutathione are uses of this invention of the stable formulation or solution of reduced glutathione in liposomes which can be used herein for oral administration and direct intravenous infusion . the solution used for intravenous administration is prepared with glutathione concentrations of 200 mg per cc . the material is stored in vials of 10 cc for a total of 2000 mg per vial . the infusion may consist of 600 mg to 2000 mg given by rapid push infusion through an intravenous line . the infusion may be repeated on an hourly or as needed basis lessen the flu symptoms . providing the intravenous glutathione in a concentration that provides physiologic osmolarity is important . osmolarity is a measure of the osmotic pressure exerted by a solution across a perfect semi - permeable membrane . osmolarity is dependent on the number of particles in solution , but independent of the nature of the particles . the following table provides concentrations of glutathione in sterile water to create normal or hypertonic osmolarity . the average osmolarity of human serum is 290 mosm . solutions in the range of 240 to 340 mosm are considered isotonic . solutions that are hypotonic relative to cells have fewer dissolved solids or solutes than the interior of surrounding cells and results in fluid being pulled into cells . thus , hypotonic fluids cause cells to swell and are considered dangerous to cells . strategies for formulating concentrations of the fluids for intravenous infusion that create isotonic or hypertonic solutions are more desirable than using hypotonic solutions . examples utilizing “ non - liposomal ” “ plain vanilla glutathione are as follows . the principles illustrated for resulting relative osmolarity are correlative to results using the composition of this invention . for glutathione 2000 mg vol in ml milliosmoles / ml total milliosmoles rlg 200 mg / ml 8 . 00 1 . 89 15 . 12 sterile water 12 . 00 0 . 00 0 . 00 total 20 . 00 15 . 12 osmolarity : 856 no toxicity of glutathione has been reported . amounts such as 1500 mg / m2 ( cancer ( 8 ) and 2500 mg daily for 5 days ( 9 ) have been reported to be well tolerated and reduce the effects of chemotherapy . case 1 . gg , a 59 year old woman in excellent general health developed symptoms of chills , low grade fever and ache all over consistent with the onset of influenza . the symptoms began at approximately 7 pm in the evening . the individual began the ingestion of liposomal glutathione with an initial dose of 600 mg ( 1 and ½ teaspoons ). after one hour the symptoms were lessened , but still present and an additional 600 mg . of liposomal glutathione was ingested . this pattern continued for the next 4 hours with a total of 6 doses of land ½ teaspoons ( 600 mg ) resulting in a total of 3600 mg . the individual noted significant reduction in clinical symptoms allowing a restful nights sleep . in the morning gg noted some mild achiness and fatigue , but a significantly lessened set of symptoms . liposomal glutathione was continued at a dose of 1 teaspoon ( 400 mg ) every 2 hours for 3 additional doses . the individual noted at that time that the influenza symptoms were no longer present . the total amount ingested was approximately 2 ounces or 5000 mg . in the 18 hour period until the resolution of the symptoms . chris t is a 37 year old man who presents with fatigue , weakness , diaphoresis , pallor and a sense of exhaustion . the symptoms had been present and progressing over a 14 day period of time , following an episode described as a “ bad flu ”. at the time of evaluation at 10 am he was considering returning to bed as even light lifting tasks and standing as part of his sales job was exhausting . 600 mg of oral liposomal glutathione was administered and the individual observed . he noted that approximately 45 minutes after ingesting the invention his symptoms began to lessen . his color returned to normal , the diaphoresis ceased and he felt a significant return of energy and strength . the improvement lasted almost an hour when his symptoms began to return . chris t . repeated the 600 mg dose and 20 to 30 minutes later again felt resolution of his symptoms . he repeated this schedule every 1 to 2 hours through the day . by 8 pm he had ingested 1 and ½ ounces ( approximately 3750 mg ) of the invention and his symptoms had resolved completely . using the invention through the day , he was able to complete his sales job , which on that day included standing all day , some light lifting of his product and interacting with customers continually through the day . the next morning in this example 2 , chris t ., reported that his flu symptoms had abated . however , his sales companion , s ? was now reporting the onset of similar flu symptoms . example 3 , s ., a 39 year old woman , developed the onset of symptoms including head and body ache , fatigue , low grade fever , mild pallor , and mild diaphoresis approximately 2 hours prior to evaluation . 600 mg of the invention was ingested orally . approximately 40 minutes later she reported significant improvement in her symptoms . she reports that she continued the regimen of repeating ingestion of 400 to 600 mg of the invention every 1 to 2 hours . she ingested approximately 3750 mg that day and continued the protocol with doses of 400 mg every two to three hours the next day . the flu symptoms did not progress , and while she felt mild symptoms for another day or two , the symptoms of influenza never progressed beyond the symptoms she experienced at the onset . the embodiments represented herein are only a few of the many embodiments and modifications that a practitioner reasonably skilled in the art could make or use . the invention is not limited to these embodiments . alternative embodiments and modifications which would still be encompassed by the invention may be made by those skilled in the art , particularly in light of the foregoing teachings . therefore , the following claims are intended to cover any alternative embodiments , modifications or equivalents which may be included within the spirit and scope of the invention as claimed . 1 . seo s h , webster r g . tumor necrosis factor 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