Patent Application: US-96231404-A

Abstract:
a method of treating and / or preventing mucositis which is an inflammation and ulceration of the mucous membranes , typically resulting from a toxic reaction to chemotherapy and / or radiotherapy by the application of water soluble immunomodulatory β - glucan .

Description:
the present invention relates to prevention or treatment of mucositis . more particularly , it relates to a method of preventing or treating oral mucositis . in a preferred embodiment , the oral mucositis is radiation and / or chemotherapy induced oral mucositis . the method of the invention comprises applying a preparation comprising water - soluble immunomodulatory β - glucan to the susceptible or affected mucosal surface . the preparation may be a rinse , mixture , gel , ointment , cream , or another suitable formulation . furthermore , water - soluble β - glucan may be the only active component in the preparation or the β - glucan may be combined with one or several other active components like e . g . antiseptics and / or antifungals , e . g . chlorhexidine , nystatin , clotrimazole ; sucralfate ; analgesics ; etc . the water - soluble immunomodulatory β - glucan used in the invention may be isolated from several organisms . glucans with known immunomodulatory activities are e . g . lentinan isolated from lentinus edodes having a β - 1 , 6 - linked single glucosyl unit for approximately every 3 main chain unit ( sasaki and takasuka 1976 ). similar glucans having β - 1 , 3 - linked main chain with single β - 1 - 6 - linked glucosyl units attached thereto are scleroglucan isolated from sclerotium sp . ( singh et al . 1974 ; farina et al . 2001 ) and shizophyllan isolated from schizophyllum commune ( akima et al . 1985 ). a soluble β - 1 , 3 - glucan can also be obtained from seaweed ( nelson and lewis 1974 ), and a water soluble β - 1 , 3 / 1 , 4 - glucan can be isolated from cereals ( estrada et al . 1997 ), or derived from lichens ( demleitner et al . 1992 ). bacterial β - 1 , 3 - glucan , curdlan , from alcaligenes faecalis can be made water soluble and immunomodulatory ( seljelid et al . 1984 ). preferably , the β - glucan originates from yeast , fungi , cereals , algae , or bacteria . more preferably , said glucan originates from yeast . even more preferably , said glucan originates from the yeast family saccharomyces . in a particularly preferred embodiment , the β - glucan originates from saccharomyces cerevisiae . the water - soluble immunomodulatory β - glucan may be of any structure , however , it is preferably a water - soluble non - derivatized β - 1 , 3 - glucan , with side - chains anchored to the backbone through a β - 1 , 6 - linkage . preferably , the backbone consists of β - 1 , 3 - linked d - glucopyranosyl units , while the side chains may comprise β - 1 , 3 - linked and / or β - 1 , 6 - linked d - glucopyranosyl units . the former type of side - chains are termed β - 1 , 3 side - chains , while the latter are termed β - 1 , 6 side - chains . preferably , said β - 1 , 6 side - chains consist of 0 to 4 units . more preferably , said side - chains consist exclusively of β - 1 , 3 - linked d - glucopyranosyl units . the above features are important both for the current β - glucan &# 39 ; s water solubility and immunomodulatory activity ( engstad 1994 ). as teached above , the glucan may contain certain amounts of β - 1 , 6 - linked glucosyl chains , but these are to a certain extent negative with respect to the β - glucans immunomodulatory abilities ( see engstad 1994 ), the content of which are incorporated herein by reference . these undesired β - 1 , 6 side - chains are found in other non - derivatized soluble yeast β - glucans described in the literature ( onderdonk et al . 1992 ) or patents ( jamas et al . 1994 ; kelly 2001 ). accordingly , an especially preferred glucan is a branched β - 1 , 3 - glucan with β - 1 , 3 side chains anchored through a β - 1 , 6 - linkage . the β - glucan concentration of the preparation may be in the range from 0 . 1 % to 25 % by weight , preferably 0 . 1 % to 10 % by weight , more preferably 0 . 5 % to 2 . 5 % by weight . the preparation may be administered either as a single daily treatment or repeated daily treatments before , and / or under , and / or after e . g . a cancer treatment regime or bone marrow transplantation . the preparation may be administered orally to contact the mucosal surfaces of the oral cavity , the pharynx and the intestinal tract to prevent and / or heal the formation of mucositis , e . g . in radio - or chemotherapy treated cancer patients . anal administration of the preparation is also possible . the method of the present invention may be applied to any animal , preferably a mammal , and more preferably a human being . another aspect of the current invention is a method for preparing a medicament comprising the β - glucan as described above . the process comprises first isolating intact yeast cell walls or any other source of β - glucan as described above . the intact cell walls , or alternative source , are treated with formic acid and optionally digested with a β -( 1 , 6 )- glucanase to form a gel with non - newtonian viscosity and thixotropic properties . this type of gel is ideal for mucosal application . a general method for isolation and manufacture of the current β - glucan is described in patent ep 0759089 the content of which are incorporated herein by reference . a further aspect of the current invention is a glucan for use in a therapeutic composition for treatment or prevention of mucositis , wherein said glucan is a water - soluble immunomodulatory β - 1 , 3 - glucan . the β - glucan is as described above . preferably , the water - soluble immunomodulatory β - 1 , 3 - glucan have a branched nature with β - 1 , 3 - linked side chains anchored through a β - 1 , 6 - linkage . more preferably , said side - chains consist exclusively of β - 1 , 3 - linked d - glucopyranosyl units . in a preferred embodiment the mucositis is oral mucositis . the mucositis may be caused by radiotherapy and / or chemotherapy . yet another aspect of the current invention is the use of immunomodulatory β - glucan for manufacturing a medicament for the treatment or prevention of mucositis in an animal in need thereof . the β - glucan is as described above . preferably , the water - soluble immunomodulatory β - 1 , 3 - glucan is branched with β - 1 , 3 - linked side chains anchored through a β - 1 , 6 - linkage . more preferably , said side - chains consist exclusively of β - 1 , 3 - linked d - glucopyranosyl units . in a preferred embodiment the mucositis is oral mucositis . the mucositis may be caused by radiotherapy and / or chemotherapy . the animal may be any animal , preferably a mammal , and most preferably a human being . all publications , patents and patent applications mentioned in this specification are indicative of the level of skill of those skilled in the art to which this invention pertains , and are herein incorporated by reference to the same extent as if each individual publication , patent or patent application was specifically and individually indicated to be incorporated by reference . the theory underlying the invention is not part of the claims and the inventor does not wish to be bound by any particular theory explaining the invention . in fact , it is fully anticipated that the theory underlying the present invention will evolve as science develop and mature . the following examples are meant to illustrate how to make and use the invention . they are not intended to limit the scope of the invention in any manner or to any degree . herein is described the use of soluble β - glucan ( sbg ) to prevent and or heal oral mucositis in conjunction to radiotherapy in a 30 year old male with head and neck cancer . sbg is a water soluble branched beta - 1 , 3 - linked yeast derived glucan with intact beta - 1 , 3 - linked side chains anchored through a beta - 1 , 6 - linkage to the main chain . a minority of side chains show repetitive beta - 1 , 6 - linkages . the intramolecular ratio of repetitive beta - 1 , 6 - linkages versus beta - 1 , 3 - linkages is approximately 1 : 50 , or less . the patient was diagnosed with cancer in the tongue in january 2002 and a surgical excision of the tumour was performed , whereafter local brachy therapy in the tongue was given . in november 2002 , 10 months after surgery , recurrence of the cancer was diagnosed in a lymph node in the neck , and the patient was readmitted to hospital for surgery in december 2002 and from january 2003 also radiotherapy to the neck region . radiotherapy ( a total of 60 gy ) was given 5 days per week for 6 consecutive weeks . concomitant to the radiotherapy the patient took approximately 80 - 100 mg sbg as a 20 mg / ml aqueous solution administered orally as a daily dose until 14 days after ending radiotherapy . the patient did not develop oral mucositis above grade i during or after the radiotherapy . an exploratory , randomized , parallel group study comparing the protective effect of soluble β - glucan or placebo in oral mucositis in head and neck cancer patients receiving radiation therapy is described . 40 patients undergoing radiation for histologically confirmed squamous cell carcinoma of the oral cavity or pharynx ( 1 . 8 - 2 . 0 gy / day , 5 days per week ; totally 59 . 4 - 70 gy ) is included in the study . a cohort also receives chemotherapy . soluble β - glucan ( sbg ) as an aqueous solution is given orally throughout the whole radiation period at a daily dosage of 500 - 1000 mg as a 15 mg / ml aqueous solution to 20 patients , whereas 20 patients are treated with methylcellulose as placebo . sbg is a water soluble branched beta - 1 , 3 - linked yeast derived glucan with intact beta - 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