US 20090028951A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0028951 A1 Czap (43) Pub. Date: Jan. 29, 2009 (54) COMPOSITIONS FOR ORAL Publication Classification ADMINISTRATION OF SUSTAINED RELEASE GLUTATHIONE, METHODS FOR (51) Int. Cl. THER PRODUCTION AND USES THEREOF A638/06 (2006.01) A6IR 9/14 (2006.01) Inventor: Al Czap, Dover, ID (US) A6IP 25/28 (2006.01) (76) A6IP 2L/00 (2006.01) Correspondence Address: A6IP 25/08 (2006.01) KNOBBE MARTENS OLSON & BEAR LLP A6IP35/00 (2006.01) 2040 MAINSTREET, FOURTEENTH FLOOR (52) U.S. Cl. ........................................... 424/489: 514/18 IRVINE, CA 92.614 (US) (57) ABSTRACT (21) Appl. No.: 11/995,680 A composition Suitable for oral administration for Sustained release of glutathione, the composition having from about (22) PCT Fled: Jul. 13, 2006 50% by weight to about 90% by weight glutathione; from about 0% by weight to about 10% by weight binder; from (86) PCT NO.: PCT/USO6/27126 about 10% by weight to about 50% by weight of at least one Sustained release agent; and a granule size of from about 850 S371 (c)(1), um to about 5000 um, is provided. Methods for preparing (2), (4) Date: May 15, 2008 Such compositions are also provided. Uses and methods of medical treatment by orally administering a composition for Related U.S. Application Data Sustained release of glutathione to a patient Suffering from or (60) Provisional application No. 60/698,478, filed on Jul. at risk of Suffering from a neurological disorder are also 13, 2005. provided. US 2009/0028951 A1 Jan. 29, 2009 COMPOSITIONS FOR ORAL ture, thereby forming a granulation, Such that the granulation ADMINISTRATION OF SUSTAINED comprises granules larger than about 850 Lum; d) removing RELEASE GLUTATHIONE, METHODS FOR granules less than 850 um from the granulation; e) blending at THER PRODUCTION AND USES THEREOF least one Sustained release agent with the granulation, thereby forming a blend: f) screening the blend with an 850 um mesh, BACKGROUND thereby forming a screened blend; and g) reblending the screened blend. The method may further comprise mixing a 0001. Glutathione is a tripeptide often referred to as GSH glidant or leucine with the composition. The method may (gamma-glutamyl-cysteinyl-glycine). Glutathione is known further comprise encapsulating the composition. The mixing to function directly and indirectly in many important biologi may occur for a duration of from about 2 minutes to about 6 cal mechanisms and is also known to be produced by the liver minutes or about 4 minutes. The adding may occur for a and distributed throughout a body via the bloodstream. Its duration of from about 4 minutes to about 9 minutes or about pharmacological use is well known, for example in perenteral 6.5 minutes. The blending may occur for a duration of from and oral pharmaceutical compositions for the treatment of about 2 minutes to about 6 minutes or about 4 minutes. The ethanol intoxication and for the prevention of the toxic effects reblending may occur for a duration of from about 2 minutes of chemotherapeutic agents. to about 6 minutes or about 4 minutes. 0002 Oral drug delivery of proteins and peptides has been described as a challenge because it can be difficult to avoid 0008. In another aspect, there is provided a composition breakdown of the peptide by the digestive system. In particu Suitable for oral administration for Sustained-release of glu lar, it can be difficult to deliver the protein or peptide past the tathione, the composition comprising: a) from about 50% by stomach where pepsins and other enzymes digest proteins. In weight to about 90% by weight glutathione; b) from about 1% many cases, the solution has been to protect the peptide with by weight to about 10% by weight binder; c) from about 10% gastroresistant materials to prevent or reduce digestion of the by weight to about 50% by weight of at least one sustained protein or peptide in the stomach. release agent; and d) a granule size of from about 850 um to 0003 Prescribing medicine to elderly patients may be par about 5000 um. The composition may provide sustained ticularly difficult for a number of reasons, including the num release of glutathione over a period of from about 2 hours to ber of drugs being prescribed and the changes in the normal about 12 hours or from about 4 hours to about 8 hours. The physiological conditions that occur with age. It is known that granule size may be from about 500 um to about 2000 um, elderly patients may have a poorer absorption of food and about 500 um to about 1000 um, about 500 um to about 850 um, about 750 um to about 850 um or about 850 Lum. The pharmaceuticals due to deterioration of the digestive tract, composition may further comprise a glidant. The glidant may including a decrease in the production of gastric hydrochloric be silicon dioxide. The composition may further comprise acid. The decrease in the production of gastric hydrochloric leucine. The glutathione may be presentat from about 60% by acid often leads to low gastric acidity. weight to about 80% by weight or at about 70% by weight. 0004 One of the signs of low gastric acidity is the pres The binder may be present at from about 1% by weight to ence of undigested food in the stool. Furthermore, it is known about 5% by weight or at about 2.8% by weight. The at least that orally administered medication may also appear in the one Sustained release agent is present at from about 20% by stool of people with low gastric acidity, often resulting in weight to about 40% by weight or at about 27.2% by weight. reduced efficacy of medication. The binder may be KollidonTM 30. The at least one sustained release agent may be MethocelTM KM100P CR and/or SUMMARY MethocelTM E4MCR. The MethocelTM KM100PCR may be 0005. This invention provides methods and compositions present at about 21.7% by weight and the MethocelTM E4M for oral administration of glutathione across a range of gastric CR may be present at about 5.5% by weight. The composition pHs, including formulations for Sustained-release of glu may be suitable for administration to a patient having a gastric tathione. In accordance with one aspect of the invention, pH of from about 1 to about 7, from about 2 to about 6, from compositions comprising glutathione Suitable for oral admin about 3 to about 5, about 1, about 1.5, about 2, about 2.5, istration to a patient Suffering from low gastric acidity may be about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, prepared by controlling the granule size of the composition. about 6 or about 6.5. A composition may comprise 70% by 0006. In one aspect, there is provided a method of medical weight glutathione, 2.8% by weight KollidonTM30, 21.7% by treatment comprising orally administering a composition for weight MethocelTM KM100P CR, 5.5% by weight Metho Sustained release of glutathione to a patient in need thereof. In celTM E4MCR. another aspect, there is provided a use of a composition Suit 0009. In another aspect, there is provided a method of able for oral administration for Sustained release of glu maintaining a serum glutathione concentration in a patient for tathione for treatment of a patient. in another aspect, there is a duration of from about 2 hours to about 12 hours comprising provided a use of a composition Suitable for oral administra administering a composition described herein. tion for Sustained release of glutathione for preparation of a 0010. In another aspect, there is provided a method of medicament for treatment of a patient. The patient in Such medical treatment comprising administering a composition cases may for example be suffering from Alzheimer's dis described herein to a patient suffering from at least one of the ease, Parkinson's disease or Autism. diseases selected from the group consisting of Addison's 0007. In another aspect, there is provided a method for disease, asthma, Autism, Celiac disease, dermatitis herpeti preparing a Sustained-release composition containing glu formis, diabetes mellitus, eczema, gallbladder disease, tathione, Suitable for oral administration, the method com Graves disease, chronic auto-immune disorders, hepatitis, prising: a) mixing glutathione and a binder, thereby forming chronic hives, lupus erythematosis, myasthenia gravis, a mixture; b) adding a granulating agent to the mixture, osteoporosis, pernicious anemia, psoriasis, rheumatoid thereby forming a wet mixture; c) granulating the wet mix arthritis, rosacea, Sorgren's syndrome, thyrotoxicosis, US 2009/0028951 A1 Jan. 29, 2009 hyperthyroidism, hypothyroidism, vitiligo, Alzheimer's dis 0018. In another embodiment, the compositions may com ease, Parkinson's disease, vascular disease, atherosclerosis prise at least one Sustained release agent. In another embodi and asthma. The patient may be suffering from a dementia, ment, the glutathione may be slowly released into the system Alzheimer's disease or Parkinson's disease. The patient may of a patient. The slow release of glutathione creates a phar be further suffering from low gastric acidity. macokinetic profile of glutathione within the plasma that 0011. In another aspect, there is provided a use of a com provides a Substantially constant Supply of glutathione. The position described hereinformaintaining a serum glutathione compositions may, therefore, slowly dissolve in vivo and concentration in a patient for a duration of from about 2 hours release a Substantially uniform amount of glutathione over a to about 12 hours. time period to be therapeutically effective for a patient. 0012. In another aspect, there is provided a use of a com 0019.