Probiotic composition based on the enterococcus strain and used as a treatment means and method for the production thereof



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95. WO2004044186 - 27.05.2004
PROBIOTIC ADDITIVE AND THE PRODUCTION METHOD THEREOF

URL EPO = http://v3.espacenet.com/textdoc?F=3&CY=ep&LG=en&IDX=WO2004044186


Inventor(s): KULAKOV GENNADY VASILIEVICH (--); IVASCHENKO ALEXANDR AFANASIEVI (--); SAVCHUK ALEXANDR VASILIEVICH (--); MIKHAILOV VIKTOR VASILIEVICH (--); KOLOSKOV ALEXANDR VALENTINOVIC (--)
Applicant(s): ZAKRYTOE AKTSIONERNOE OBSCHEST (RU)
IP Class 4 Digits: A61K; A23K; C12N; F26B; C12R
IP Class: C12N1/20; A23K1/165; A61K35/66; F26B5/16; C12R1/07
E Class: A23K1/00C2B; A23K1/00B3; A23K1/18L2; A23K1/18S; F26B5/16
Application Number: WO2003RU00443 (20031020)
Priority Number: RU20020129938 (20021111)
Family: WO2004044186
Cited Document(s): RU2182009; RU2184774; RU2008589; RU2043587; SU1730138; US5374425
Abstract:

THE INVENTION RELATES TO BIOENGINEERING AND AGRICULTURE AND CAN BE USED FOR PRODUCING COMPOUND FEED CONTAINING PROBIOTICS FOR FARM ANIMALS, POULTRY AND FISH BREEDING STOCK. THE INVENTIVE PROBIOTIC ADDITIVE IS PRODUCED BY MIXING A BACTERIAL BIOMASS OF BASILLUS SUBTILIS B-2250 AND/ OR BASILLUS LICHENIFORMIS B-2252 WITH AUXILIARY SUBSTANCES SUCH AS A SORBENT-CARRIER AND HIGH-ABSORBENCY FILLER. THE SORBENT CARRIER IS EMBODIED IN THE FORM OF A HYDROPHILIC AEROSILS AND AM HYDROPHOBIC AEROSILS, THE HIGH-ABSORBENCY FILLER IS EMBODIED IN THE FORM OF KB-4P-2 AND KU-2-8 TCHS CATIONIC RESINS AT A GIVEN COMPONENT RATIO IN TERMS OF DRY SUBSTANCE. THE DRY MICROCAPSULATED PROBIOTIC ADDITIVE IS PRODUCED BY MEANS OF A CAPILLARY-SORPTION DRYING OF A COMPONENT MIXTURE AS FAR AS A MOISTURE CONTENT IN A FINISHED PRODUCT RANGES FROM 8 TO 25 %. SAID INVENTION MAKES IT POSSIBLE TO PRODUCE THE MICROCAPSULATED PROBIOTIC ADDITIVE WHICH CONTAINS PROBIOTIC, IS EASY FOR USE AND CONSUMPTION AND PRESERVES STABILISED PROPERTIES AT ALL PRODUCTION STAGES. SAID PROBIOTIC ADDITIVE SUBTILIS DRY MICROCAPSULATED IMPROVES FOOD CONVERSION AND GENERAL STATE OF ANIMALS, INCREASES GAIN IN WEIGHT AND PREVENTS ANIMAL MORTALITY.



96. WO2004069156 - 19.08.2004
INACTIVATED PROBIOTIC BACTERIA AND METHODS OF USE THEREOF

URL EPO = http://v3.espacenet.com/textdoc?F=3&CY=ep&LG=en&IDX=WO2004069156


Inventor(s): RAZ EYAL (US); RACHMILEWITZ DANIEL (IL)
Applicant(s): UNIV CALIFORNIA (US); RAZ EYAL (US); RACHMILEWITZ DANIEL (IL)
IP Class 4 Digits: A61K
IP Class: A61K
Application Number: WO2003US41547 (20031218)
Priority Number: US20030443922P (20030130)
Family: WO2004069156
Cited Document(s): US3842831; US5964096; US5891617; US6140123; US5689961


Abstract:

THE PRESENT INVENTION PROVIDES FORMULATIONS COMPRISING INACTIVATED PROBIOTIC BACTERIA, AND TREATMENT METHODS USING THE FORMULATIONS.Description:

INACTIVATED PROBIOTIC BACTERIA AND METHODS OF USE THEREOF

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH [0001] The U. S. government may have certain rights in this invention, pursuant to grant nos.


AI40682 and DK-35108 awarded by the National Institutes of Health.
FIELD OF THE INVENTION [0002] The present invention is in the field of probiotics.
BACKGROUND OF THE INVENTION [0003] Probiotics are live microorganisms that alter the enteric microflora and have a beneficial effect on health. Probiotic formulations have been used as dietary supplements for many years. Resident probiotic bacterial strains live and reproduce in each person's digestive tract. Transient probiotic bacterial strains typically are introduced into the body through ingested food or by means of dietary supplements. Formulations of probiotic bacteria have been used to treat various gastrointestinal disorders, such as gastric ulcers, inflammatory bowel disease, acidic gut syndrome, gastritis, food allergies, and lactose intolerance. The use of probiotic bacteria to attenuate allergic disorders is also practiced.
[0004] There is a need in the art for formulations of probiotic bacteria that are storage stable and that can survive elevated temperatures. The present invention addresses this need by providing formulations comprising inactivated probiotic bacteria, which formulations are useful in a variety of treatment methods.
Literature [0005] U. S. Patent Nos. 6,461, 607,6, 426,099, 6,468, 525,6, 329,002, 6,203, 797,6, 060,050,

6,264, 952, 6, 100, 388, 5,922, 375,5, 824,538 ; Pereyra et al. (1991) Eur. Cytokine Netw. 2: 299- 303 ; WO 01/62207 ; Schultz et al. (2002) Inflammatory Bowel Diseases 8: 71-80; Steidler (2001) Microbes and Infection 3: 1157-1166; Isolauri et al. (2002) Gut 50 (Suppl. III) : iii54- iii59 ; Salminen et al. (2002) Clin. Infect. Dis. 35: 1155-1160; Shanahan (2001) Gut 48: 609;

Kaur et al. (2002) Sur. J : Pharm. Sci. 15: 1-9; Marteau et al. (2001) Am. J. Clin. Nutr.
73 (suppl. ) : 430S-436S ; Teitelbaum and Walker (2002) Ann. Rev. Nutr. 22: 107-138 ;

Rachmilewitz et al. (2002) Gastroenterology 122: 1428-1441; Kaila et al. (1992). Pediatr Res

32: 141-144; Saavedra et al. (1994) Lancet 344: 1046-1049; Corthier (1997) In : Probiotics 2.
Applications and Practical Aspects (Fuller R, ed. ). Chapman & Hal, London pp. 40-64;

Gorbach et al. (1987) Lancet 2: 1519; Goldin and Gorbach"Probiotics for humans. "In :


Probiotics. The Scientific Basis (Fuller, ed) Chapman & Hall ; London: 1992; 355-376; Biller et al. (1995) JPediatr Gastroenterol Nutr 21 : 224-226; Colombel et al. (1987) Lancet 1: 43;

Corthier et al. (1985) Appl Environ Microbiol 49: 250-252; Banerjee and Lamont (2000) Curr Op Infect Dis 13: 215-219; D'Souza et al. (2002) Brit Med J324 : 1361; Gionchetti et al. (2000) J Gastroenterol Hepatol 15: 489-493; Venturi et al. (1999) Ailment Pharmacol Ther 13: 1103-

1108; Gionchetti et al. (2000) Gastroenterology 119: 305-309; Kruis et al. (1997) Aliment

Pharmacol Ther 11: 835-8; Bazzocohi et al. (1998) Gastroenterol Intern 11: 111; Kim et al.


(2003) Aliment Pharmacology & Therapeutics 17: 895; De Simone et al. (1995) Microecol

Ther 25: 32-36; Delia et al. (2002) Am J : Gastroenterol 97 : 2150; Canducci et al. (2000) AlimentPharmocol Ther 14: 1625; Li et al. (2003) Hepatology 37: 343; Macfarlane and Manzel (1998) JImmunol 160 : 1122-1131 ; Majamaa and Isolauri (1997) JAllergy Clin Imnzunol

99: 179; Isolauri et al. (2000) Clin Exp Allergy 30 : 1604; Kalliomaki et al. (2001) Lancet

357: 1076; Helin et al. (2002) Allergy 37: 243; Wheeler et al. (1997) Ann Allergy Asthma

Immunol 79 : 229; Matricardi et al. (2003) Allergy 58: 461 ; Sudo et al. (1997) JImmunol

157: 1739-1745.


SUMMARY OF THE INVENTION [0006] The present invention provides formulations comprising inactivated probiotic bacteria, and treatment methods using the formulations.
FEATURES OF THE INVENTION [0007] The present invention features an enteral formulation that includes at least about 5% by weight inactivated probiotic bacteria; and a pharmaceutically acceptable excipient. The bacteria are inactivated by a process other than extreme heat inactivation or bacteriophage infection. In some embodiments, the formulation is a liquid or gel formulation and includes an agent selected from a flavoring agent and a coloring agent. In other embodiments, the formulation is a solid formulation includes a solid-based dry material. In some embodiments in which the formulation is a solid formulation, the solid-based dry material is selected from a starch, gelatin, sucrose, dextrose, trehalose, and malto-dextrin. A subject formulation may be in the form of a capsule, tablet, a liquid, a gel, or a food product.
[0008] In some embodiments, the pharmaceutically acceptable excipient is a food-grade carrier. In some embodiments in which the pharmaceutically acceptable excipient is a food- grade carrier, the food-grade carrier is one or more of a carrier selected from an edible oil (e. g., olive oil), an emulsifier, a soluble fiber, a flavoring agent, a coloring agent, an edible fiber, and a sweetener.

[0009] In some embodiments, the inactivated bacteria are present in the formulation at a concentration of from about 1 x 105 bacteria per dosage unit to about 1 x 1014 bacteria per dosage unit, e. g. , per gram, per ml, per tablet, per packet, per capsule, per lozenge, or per serving size.


[0010] The present invention features a food product comprising subject inactivated bacteria.
In some embodiments, the inactivated bacteria are present in the food product at a concentration of from about 1 x 105 bacteria per dosage unit to about 1 x 1014 bacteria per dosage unit, e. g. , per gram, per ml, per tablet, per packet, per capsule, per lozenge, or per serving size. In some embodiments, the food product is a milk-based food product, e. g. , milk, cheese, yogurt, butter, ice cream, frozen yogurt, whipped toppings, cream, custard, pudding, nutritional drinks, infant formula, and milk chocolate. In other embodiments, the food product is a soy-based food product. In other embodiments, the food product is a starch-based food product. In other embodiments, the food product is a grain-based food product.
[0011] In some embodiments, the formulation further includes a non-steroidal anti- inflammatory agent. In other embodiments, the formulation further includes an antibiotic. In some embodiments, the formulation further includes an immunosuppressive agent. In other embodiments, the formulation further includes at least a second therapeutic agent for the treatment of a gastrointestinal disorder. In other embodiments, the formulation further includes at least a second therapeutic agent for the treatment of an allergic disorder.
[0012] The invention further features a method for treating gastrointestinal inflammation in a subject. The method generally involves administering to a subject suffering from gastrointestinal inflammation an effective amount of a subject formulation. In some embodiments, the formulation is administered orally. In other embodiments, the formulation is administered rectally. In some embodiments, the gastrointestinal inflammation is chronic gastrointestinal inflammation. In some embodiments, the chronic gastrointestinal inflammation is caused by inflammatory bowel disease. In some embodiments, the inflammatory bowel disease is ulcerative colitis. In other embodiments, the inflammatory bowel disease is Crohn disease. In many embodiments, from about 1 x 105 bacteria per gram to about 1 x 1014 bacteria per unit dosage form are administered. In some embodiments, the method further involves administering an additional therapeutic agent for treating gastrointestinal inflammation. In other embodiments, the formulation further includes at least a second therapeutic agent for the treatment of diarrhea.
[0013] The present invention further features a method for treating an allergic disorder. The method generally involves administering to a subject suffering from an allergic disorder an

effective amount of a subject formulation. In some embodiments, the formulation is administered orally. In many embodiments, from about 1 x 105 bacteria per gram to about 1 x 1014 bacteria per unit dosage form are administered. In some embodiments, the method further involves administering an additional therapeutic agent for treating the allergic disorder. In some embodiments, the allergic disorder is allergic asthma. In some embodiments, the allergic disorder is an allergic reaction to a plant allergen, a food allergen, an animal allergen, or a drug allergen. In some embodiments, the allergic disorder is selected from atopic dermatitis, a food allergy, allergic asthma, allergic gastroenteritis, and allergic rhinitis.


[0014] The present invention further features a method of treating a diarrheal disease in an individual in need thereof. The method generally involves administering to an individual suffering from a diarrheal disease an effective amount of a subject formulation. In some embodiments, the formulation is administered orally. In many embodiments, from about 1 x 105 bacteria per gram to about 1 x 1014 bacteria per unit dosage form are administered.
Diarrheal diseases that are amenable to treatment with a subject formulation include diarrhea that results from a bacterial infection, a viral infection, or a mixed bacterial and viral infection ; radiation-induced diarrhea; and antibiotic-induced diarrhea.
[0015] The present invention further features a method of treating a microbial infection in an individual. The method generally involves administering to an individual suffering from infection with a pathogenic microorganism an effective amount of a subject formulation. In some embodiments, the formulation is administered orally. In many embodiments, from about 1 x 105 bacteria per gram to about 1 x 1014 bacteria per unit dosage form are administered. In some embodiments, the pathogenic microorganism is one that gives rise to an opprtunistic infection, e. g. , in an immunodeficient individual. In other embodiments, the microorganism is one that gives rise to or is associated with gastric ulcers, e. g., Helicobacter pylori.
[0016] The present invention further features a method for treating a non-alcoholic fatty liver disease in an individual. The method generally involves administering to a subject suffering from non-alcoholic fatty liver disease an effective amount of a subject formulation. In some embodiments, the formulation is administered orally. In many embodiments, from about 1 x 105 bacteria per gram to about 1 x 1014 bacteria per unit dosage form are administered. In some embodiments, the non-alcoholic liver disease is steatosis. hi other embodiments, the non-alcoholic liver disease is non-alcoholic steatohepatitis. Non-alcoholic fatty liver disease frequently results in fibrosis or cirrhosis. The subject methods for treating non-alcoholic fatty liver disease reduce the risk that an individual suffering from non-alcoholic fatty liver disease

will develop fibrosis or cirrhosis of the liver. Thus, the invention further features a method for reducing the risk that an individual will develop hepatic fibrosis or cirrhosis.


BRIEF DESCRIPTION OF THE DRAWINGS [0017] Figures lA-C depict immunostimulatory activities of probiotic DNA.
[0018] Figures 2A-C depict detection of bacterial DNA at systemic sites.
DEFINITIONS [0019] As used herein, the term"inactivated probiotic bacteria"refers to probiotic bacteria that are inactivated in a manner such that the bacteria retain a beneficial effect in treating a disorder in an individual, e. g. , a gastrointestinal inflammatory disorder and/or an allergic disorder and/or a microbial infection. Viable probiotic bacteria are typically found in the gastrointestinal tract as part of the normal flora in healthy individuals. Probiotic bacteria for use in a subject formulation are generally non-pathogenic and non-toxigenic when viable, e. g., bacteria suitable for use herein are non-pathogenic and non-toxic even before inactivation.
Inactivated probiotic bacteria of the instant invention typically do not elicit an immune response to an antigen of the probiotic bacteria, and typically do not elicit an immune response that provides protection against the probiotic bacteria. Inactivated probiotic bacteria of the instant invention generally comprise nucleic acid that is capable of stimulating a Thl-type immune response in an individual.
[0020] As used herein, the terms"treatment", "treating", and the like, refer to obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse affect attributable to the disease. "Treatment,"as used herein, covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) reducing the incidence and/or risk of relapse (remission,"flare-up") of the disease during a symptom-free period; (b) relieving or reducing a symptom of the disease ; (c) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (d) inhibiting the disease, i. e. , arresting its development (e. g. , reducing the rate of disease progression); (e) reducing the frequency of episodes of the disease; and (f) relieving the disease, i. e. , causing regression of the disease.
[0021] The terms"individual, ""host,""subject,"and"patient,"used interchangeably herein, refer to a mammal, particularly a human.

[0022] "Gastrointestinal inflammation"as used herein refers to inflammation of a mucosal layer or all of the layers of the gastrointestinal tract, and encompasses acute and chronic inflammatory conditions. Acute inflammation is generally characterized by a short time of onset and infiltration or influx of neutrophils. Chronic inflammation is generally characterized by a relatively longer period of onset and infiltration or influx of mononuclear cells. Chronic inflammation can also typically characterized by periods of spontaneous remission and spontaneous occurrence. "Mucosal layer of the gastrointestinal tract"is meant to include mucosa of the bowel (including the small intestine and large intestine), rectum, stomach (gastric) lining, oral cavity, and the like. Certain gastrointestinal disorders affect all layers of the gastrointestinal tract. For example, Crohn disease is known to involve all layers of the gastrointestinal tract, including the mucosal layer, the muscle layer, and the serosal layer.


[0023]"Chronic gastrointestinal inflammation"refers to inflammation of the mucosa of the gastrointestinal tract that is characterized by a relatively longer period of onset, is long-lasting (e. g. , from several days, weeks, months, or years and up to the life of the subject), and is associated with infiltration or influx of mononuclear cells and can be further associated with periods of spontaneous remission and spontaneous occurrence. Thus, subjects with chronic gastrointestinal inflammation may be expected to require a long period of supervision, observation, or care. "Chronic gastrointestinal inflammatory conditions" (also referred to as "chronic gastrointestinal inflammatory diseases") having such chronic inflammation include, but are not necessarily limited to, inflammatory bowel disease (IBD), colitis induced by environmental insults (e. g., gastrointestinal inflammation (e. g., colitis) caused by or associated with (e. g. , as a side effect) a therapeutic regimen, such as administration of non-steroidal anti- inflammatory drugs (NSAIDS), chemotherapy, radiation therapy, and the like), colitis in conditions such as chronic granulomatous disease (Schappi et al. Arch Dis Child. 2001

Feb ; 84 (2): 147-151), celiac disease, celiac sprue (a heritable disease in which the intestinal lining is inflamed in response to the ingestion of a protein known as gluten), food allergies, gastritis, infectious gastritis or enterocolitis (e. g., Helicobacter pylori-infected chronic active gastritis) and other forms of gastrointestinal inflammation caused by an infectious agent, and other like conditions.


[0024] As used herein,"inflammatory bowel disease"or"IBD"refers to any of a variety of diseases characterized by inflammation of all or part of the intestines. Examples of inflammatory bowel disease include, but are not limited to, Crohn disease and ulcerative colitis. Reference to IBD in this specification is often referred to in the specification as exemplary of gastrointestinal inflammatory conditions, and is not meant to be limiting.

[0025] The term"allergic disorder"generally refers to a disease state or syndrome whereby the body produces an immune response to environmental antigens comprising immunoglobulin E (IgE) antibodies which evoke allergic symptoms such as itching, sneezing, coughing, respiratory congestion, rhinorrhea, skin eruptions and the like, as well as severe reactions, such as asthma attacks and systemic anaphylaxis. Examples of allergic diseases and disorders which can be treated by the methods of this invention include, but are not limited to, drug hypersensitivity, allergic rhinitis, bronchial asthma, ragweed pollen hayfever, anaphylactic syndrome, urticaria, angioedema, atopic dermatitis, erythema nodosum, erythema multiforme,

Stevens Johnson Syndrome, cutaneous necrotizing venulitis, bullous skin diseases, allergy to food substances and insect venom-induced allergic reactions, as well as any other allergic disease or disorder.
[0026] The terms"CD4+-deficient"and"CD4+-low"are used interchangeably herein, and, as used herein, refer to a state of an individual in whom the number of CD4+ T lymphocytes is reduced compared to an individual with a healthy, intact immune system. CD4+ deficiency includes a state in which the number of functional CD4+T lymphocytes is less than about 600 CD4+T cells/mm3 blood ; a state in which the number of functional CD4+T cells is reduced compared to a healthy, normal state for a given individual ; and a state in which functional CD4+ T cells are completely absent.
[0027] As used herein, a"CD4+-deficient individual"is one who has a reduced number of functional CD4+-T cells, regardless of the reason, when compared to an individual having a normal, intact immune system. In general, the number of functional CD4+-T cells that is within a normal range is known for various mammalian species. In human blood, e. g. , the number of functional CD4+-T cells which is considered to be in a normal range is from about

600 to about 1500 CD4+-T cells/mm3 blood. An individual having a number of CD4+-T cells below the normal range, e. g. , below about 600/mm3, may be considered"CD4+-deficient."

Thus, a CD4+-deficient individual may have a low CD4+ T cell count, or even no detectable CD4+ T cells. A CD4+-deficient individual includes an individual who has a lower than normal number of functional CD4+-T cells due to a primary or an acquired immunodeficiency.
[0028] A"functional CD4+-T cell"is a term well understood in the art and refers to a CD4+-T cell which is capable of providing T cell help, directly or indirectly, to effect one or more of the following responses: CTL activation; antibody production; macrophage activation ; mast cell growth; and eosinophil growth and differentiation.

[0029] As used herein, the terms"immunodeficient,""immunosuppressed,"and "immunocompromised, "used interchangeably herein, refer to a state of a CD4+-deficient individual.


[0030] As used herein, "pharmaceutically acceptable carrier"includes any material which, when combined with an active ingredient of a composition, allows the ingredient to retain biological activity and without causing disruptive reactions with the subject's immune system.
Examples include, but are not limited to, any of the standard pharmaceutical carriers such as a phosphate buffered saline solution, water, emulsions such as oil/water emulsion, and various types of wetting agents. Preferred diluents for aerosol or parenteral administration are phosphate buffered saline or normal (0. 9%) saline. Compositions comprising such carriers are formulated by well known conventional methods (see, for example, Remington's

Pharmaceutical Sciences, Chapter 43, 14th Ed. or latest edition, Mack Publishing Co. , Easton

PA 18042, USA ; A. Gennaro (2000)"Remington : The Science and Practice of Pharmacy",

20th edition, Lippincott, Williams, & Wilkins ; Pharmaceutical Dosage Forms and Drug

Delivery Systems (1999) H. C. Ansel et al. , eds 7th ed. , Lippincott, Williams, & Wilkins ; and

Handbook of Pharmaceutical Excipients (2000) A. H. Kibbe et al. , eds., 3rd ed. Amer.


Pharmaceutical Assoc.
[0031] Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
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