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WO2000023085A1 - Traitement de la mammite avec un glucan particulaire - Google Patents

Traitement de la mammite avec un glucan particulaire Download PDF

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Publication number
WO2000023085A1
WO2000023085A1 PCT/AU1999/000910 AU9900910W WO0023085A1 WO 2000023085 A1 WO2000023085 A1 WO 2000023085A1 AU 9900910 W AU9900910 W AU 9900910W WO 0023085 A1 WO0023085 A1 WO 0023085A1
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WO
WIPO (PCT)
Prior art keywords
mastitis
glucan
treatment
composition
daltons
Prior art date
Application number
PCT/AU1999/000910
Other languages
English (en)
Inventor
Graham Edmund Kelly
Alan James Husband
Original Assignee
Novogen Research Pty. Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novogen Research Pty. Ltd. filed Critical Novogen Research Pty. Ltd.
Priority to AU11407/00A priority Critical patent/AU1140700A/en
Publication of WO2000023085A1 publication Critical patent/WO2000023085A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters

Definitions

  • the present invention relates to processes for the treatment of mastitis and compositions for effecting the same in the treatment of mastitis. 5
  • Mastitis is a disease condition which effects the preponderance of lactating mammals. Mastitis presents serious economic consequences in commercial milk producing 10 operations, such as those involving cows, sheep and goats, which may collectively be regarded as the "dairy industry".
  • Bovine mastitis (subclinical and clinical) is a disease complex that results from the interaction of the cow, the environment (including the milking machine), and
  • S. aureus mastitis infection is characterised by the presence of viable bacteria in the milk and elevated numbers of somatic cells in the mammary gland and milk (Anderson, 1982; Craven and Williams, 1981; Daley et al. 1991; Fox and McDonald, 1988). In an infected 30 gland, these host cells are >95% polymorphonuclear leukocytes (PMN).
  • PMN polymorphonuclear leukocytes
  • the development of chronic S. aureus mastitis depends on the interaction between invading bacteria and these cells of the defence system (Derbyshire and Berman, 1968; Paape and Wergin, 1977). Although the defence mechanisms of mammary gland can be effective in eliminating the infection from mammary gland as much as 3 to 4 logs of bacteria.
  • a process for the treatment of mastitis which comprises administering to an affected mammary site of a lactating mammal a composition including paniculate glucan in association with a physiologically acceptable carrier and optionally an excipient.
  • composition for the treatment of mastitis which includes particulate glucan in association with a physiologically acceptable carrier and optionally an excipient.
  • composition may be presented in a manner specifically indicated for the treatment of mastitis such as by labelling of a container which contains the composition.
  • a method for the prevention of mastitis in a dairy animal which comprises administering to a teat of the animal a composition as herein described.
  • the invention relates to a composition which includes paniculate glucan, an antibiotic, and a physiologically acceptable carrier and/or excipient.
  • the antibiotic is preferably present at a low dose.
  • Glucan is a generic term referring to an oligo- or polysaccharide composed predominantly or wholly of the monosaccharide D-glucose. Glucans are widely distributed in nature with many thousands of forms possible as a result of the highly variable manner in which the individual glucose units can be joined (glucosidic linkages) as well as the overall steric shape of the parent molecule.
  • Glucan is a well described molecule and is found primarily in the cell wall of most fungi such as yeasts, moulds and bacteria.
  • Paniculate glucan which may be used in this invention includes glucan having a molecular weight from about 500,00 to about 3,000,000 daltons or more, preferably about 1,000,000 to about 3,000,000 daltons.
  • Paniculate glucan generally has a particle size from about 0.1 ⁇ m to about 20 ⁇ m, preferably about 5 ⁇ m to about 10 ⁇ m and may be referred to as microparticulate glucan.
  • the glucan is isolated from the yeast Saccharomyces cerevisiae which has been shown by many groups to be acceptable in terms of efficacy and safety as an immune stimulant in animals and humans.
  • Glucan prepared from Saccharomyces cerevisiae is referred to hereafter as (“Sc”)-glucan.
  • Saccharomyces cerevisiae is referred to hereafter as (“Sc")-glucan.
  • Sp Saccharomyces cerevisiae
  • Predominantly or wholly -1,3 glucans from other fungi, bacteria or plants may also be used.
  • microparticulate glucan Various processes have been described for the production of microparticulate glucan. See for example Hassid et al (1941), Manners (1973), DiLuzio (1979) and US Patents Nos. 4,810,694 and 2,992,540, which are incorporated herein by reference.
  • the extraction of microparticulate glucan from whole yeast cells depends on the fact that the bulk of the cell wall glucan is insoluble in water, strong alkali, acid and organic solvents whereas all other cell wall components are suspended in one or more of these solutions.
  • the essential principles of microparticulate glucan extraction of Sc-glucan are (i) lysis of the yeast cell to allow the intact cell walls to be separated from the less dense cytoplasmic contents, and (ii) subsequent or concomitant dissolution of unwanted wall components such as other carbohydrates (glycogen, mannan, glucosamine), lipids and proteins using various combinations of water, alkali, acid and organic solvents. It is preferred in such processes that the three-dimensional matrix structure of the cell wall remains unaltered and intact as a cell wall skeleton (also known as a "cell sac"), comprised predominantly of -(l,3)(l,6)-glucan.
  • the cell wall skeletons characteristically are spherical, hollow structures of approximately 4 to 20 ⁇ m diameter and with a molecular weight of between approximately 1,000,000 to 3,000,000 daltons and they are insoluble in water.
  • the cells then are exposed to acid (pH 1 to 5) with heat to effect dissolution of certain residual non-glucan components and to effect some hydrolysis of the -1,6 side-branches.
  • acid pH 1 to 5
  • the rigour of this step varies considerably between the known processes of relatively mild acid treatment where the conformational changes are minimal and many of the side-branches are retained, through too extensive acid treatment where little or no side-branches remain.
  • solvents particularly ether or petroleum ether
  • microparticulate glucan is formed is not significant to this invention.
  • the inventors have found that glucan having a molecular weight of about 500,000 to 3,000,000 daltons or more, which is insoluble in water, and which forms a microparticulate suspension in water is useful in the invention.
  • Large glucan particles which may be produced by extraction processes can be easily ground to a relatively fine particle size.
  • the microparticulate glucan is combined with a physiologically acceptable carrier and optionally an excipient in a form suitable for administration to an effected mammary area.
  • caniers include: water physiologically saline, isotonic solutions containing dextrose, glycerol or other agents conferring isotonicity, lower alcohols, vegetable oils, polyethylene glycol, glycerol triacetate and other fatty acid glycerides.
  • the glucan is present suspended or admixed in the corners.
  • Examples of other caniers which may be used include cream forming agents, gel forming agents and the like.
  • Excipients include buffers, stabilisers, emulsion forming agents, colouring compounds, salts, amino acids, antibiotics and other anti-bacterial compounds chelating agents and the like. More than one excipient and canier may be used.
  • antibiotics interact synergistically with the paniculate glucan in the treatment and prevention of mastitis.
  • lower amounts of antibiotics than are currently used can be employed, for example preferably 50% or less of the standard antibiotic dose cunently employed in the art for the treatment of mastitis. This is advantageous from a perspective of cost, and from a perspective of reduced levels of exposure to antibiotics.
  • Antibiotics which may be used include tetracyclines, penicillin-streptomycin combination, penicillin G-neomycin combination, penicillin-nitrofurazone combination, penicillin-tylosin combination, novobiocin, sodium cloxacillin, ampicillin, furaltadone, erythromycin, spiramycin, cephalosporins (e.g. cefoperazone), and combinations of said one or more antibiotics (see Radostits, D.C., et al, Veterinary Medicine, 8th Edition, 1994, Bailliere Tindall).
  • One or more antibiotics may be used at a "low dose", that is at a dose of 50% or less than that currently in use for the treatment of mastitis, such as from 5 to 50% , 5 to 40%, 5 to 30% or 5 to 20% of the conventional daily dose.
  • a standard daily dose of a tetracycline is 400 mg per day per treatment.
  • a low dose may be from 20 to 200 mg.
  • composition which includes paniculate glucan, an antibiotic, and a physiologically acceptable carrier and/or excipient.
  • the antibiotic is preferably present at a low dose.
  • compositions may be used in dry cow therapy, that is, during the non-milking period.
  • the composition of the invention either obviates the need for antibiotics, or uses low doses of antibiotics in conjunction with glucan.
  • Such composition may be routinely used during the "dry" period, for example as a once-treatment preventative, or as a therapeutic for mastitis treatment.
  • compositions according to the invention are prepared by simple admixture of microparticulate glucan particles with carriers and/or excipients.
  • composition of this invention may be in various forms, such as a solution with particles suspended therein, a cream, a gel or ointment or like forms for infusion into an infected mammary gland or topical application to a mastitis affected mammary area.
  • microparticulate glucan solutions, creams, gels or the like may be infused into an infected mammary gland by way of a syringe, a needle or other tubular projection for introducing the composition into the mammary gland and being of a sufficient diameter to allow glucan particles to pass into the mammary gland.
  • Creams, gels, foams, ointments and the like may be topically applied to a mastitis infected mammary area. Topical application has been found to be effective.
  • a one off treatment such as a one off or single infusion of a microparticulate glucan suspension
  • a microparticulate glucan containing suspension may be infused or injected into a mastitis affected teat, and a cream containing particulate glucan and optionally an antibiotic may be topically applied to the effected area. Rapid treatment ensues within about one to five days.
  • Prior art treatment regimens include by way of contrast a three day or weekly treatment such as once per day.
  • This invention may be used in the treatment of any lactating mammal such as cows, sheep, goats, buffalo, horses, dogs, cats, and human females.
  • Mastitis may be prevented by treatment during the non-milking period. Therefore according to an aspect of this invention there is provided a method for the prevention of mastitis in a dairy animal which comprises administering to a mammary area, such as a teat and/or udder or breast area of an animal, a composition as described herein.
  • a mammary area such as a teat and/or udder or breast area of an animal
  • Microparticulate glucan is prepared as follows:
  • a 400 g sample of commercial Saccharomyces cerevisiae in dry form is added to four litres of 4% w/v sodium hydroxide and heated to 100°C for one hour with vigorous stirring.
  • the suspension is allowed to cool to between 45°C and 50°C before the lysed yeast cells are separated from the alkaline hydrolysate by centrifugation at 800 g for ten minutes.
  • the lysed yeast cells are resuspended in a fresh batch of three litres of 3% w/v sodium hydroxide and boiled for 15 minutes.
  • the lysed yeast cells are resuspended in a fresh batch of two litres of 3% w/v sodium hydroxide and boiled for 15 minutes followed by standing at 70 °C for 16 hours. Following separation by centrifugation, the lysed yeast cells are resuspended in water and boiled for 10 minutes. The latter step is repeated once. Following centrifugation, the lysed yeast cells are resuspended in a fresh aliquot of 2 L water, the pH adjusted to 4.5 by the addition of phosphoric acid and the suspension then boiled for thirty minutes.
  • Microparticulate Sc-glucan is prepared as follows:
  • a 400 g sample of commercial Saccharomyces cerevisiae in dry form is added to four litres of 4% w/v sodium hydroxide and heated to 100°C for one hour with vigorous stirring.
  • the suspension is allowed to cool to between 45 °C and 50°C before the lysed yeast cells are separated from the alkaline hydrolysate by centrifugation at 800 g for ten minutes.
  • the lysed yeast cells are resuspended in a fresh batch of three litres of 3% w/v sodium hydroxide and boiled for 15 minutes. Following separation by centrifugation, the lysed yeast cells are resuspended in a fresh batch of two litres of 3% w/v sodium hydroxide and boiled for 15 minutes followed by standing at 70 °C for 16 hours.
  • the lysed yeast cells are resuspended in water and boiled for 10 minutes. The latter step is repeated once. Following centrifugation, the lysed yeast cells are resuspended in a fresh aliquot of 2 L water, the pH adjusted to 4.5 by the addition of hydrochloric acid and the suspension then boiled for ten minutes. Five hundred mL of chloroform then is added and the suspension subjected to vigorous agitation for ten minutes, following which the suspension is allowed to settle for 10 minutes in a separating funnel. The lower chloroform phase plus a greyish intermediate phase are discarded, leaving an aqueous phase which is collected and exposed as before to a fresh batch of 500 ml of chloroform. The final aqueous phase is collected and boiled for 10 minutes to remove any residual chloroform and then dried using a spray-drier.
  • glucan 200mg of glucan (5mg/ml) and 40 ml of pyrogen free saline (0.9%) were infused into the mammary gland in infected and healthy cows to determine the effect of glucan therapy on the course of chronic Staphylococcal infection in the mammary gland.
  • Milk samples were collected from the cows before, and 2,5 and 10 days after glucan treatment. Blood was also taken to examine the changes in total and differential cells in the blood. Body temperature was monitored during the course of the study.
  • compositions containing 5 mg/ml paniculate glucan in 0.9% saline are prepared, which additionally contained antibiotics.
  • One such composition contains 100 mg of tetracyline per dose.
  • Such compositions were particularly effective in the treatment or prevention of mastitis.
  • Topical compositions containing 10 mg/ml paniculate glucan in a cream base are prepared.
  • One such composition contains 150 mg antibiotic (streptomycin-penicillin combination).
  • antibiotic streptomycin-penicillin combination
  • Such compositions were effective in the treatment and prevention of mastitis.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur un procédé de traitement et de prévention de la mammite, ce procédé consistant à administrer sur un site mammaire une composition comprenant un glucan particulaire en association avec un excipient physiologiquement acceptable. L'invention porte également sur des compositions destinées au traitement de la mammite.
PCT/AU1999/000910 1998-10-19 1999-10-19 Traitement de la mammite avec un glucan particulaire WO2000023085A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU11407/00A AU1140700A (en) 1998-10-19 1999-10-19 Mastitis treatment with particulate glucan

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPP6591A AUPP659198A0 (en) 1998-10-19 1998-10-19 Mastitis treatment
AUPP6591 1998-10-19

Publications (1)

Publication Number Publication Date
WO2000023085A1 true WO2000023085A1 (fr) 2000-04-27

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Application Number Title Priority Date Filing Date
PCT/AU1999/000910 WO2000023085A1 (fr) 1998-10-19 1999-10-19 Traitement de la mammite avec un glucan particulaire

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AU (1) AUPP659198A0 (fr)
WO (1) WO2000023085A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU599045B2 (en) * 1985-08-19 1990-07-12 The Administrators Of The Tulane Eductional Fund Soluble phosphorylated glucan
AU6441190A (en) * 1989-09-08 1991-04-08 Alpha-Beta Technology, Inc. Method for producing soluble glucans
WO1998048627A1 (fr) * 1997-04-29 1998-11-05 Medicarb Ab Produit pour trempage des trayons

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU599045B2 (en) * 1985-08-19 1990-07-12 The Administrators Of The Tulane Eductional Fund Soluble phosphorylated glucan
AU6441190A (en) * 1989-09-08 1991-04-08 Alpha-Beta Technology, Inc. Method for producing soluble glucans
WO1998048627A1 (fr) * 1997-04-29 1998-11-05 Medicarb Ab Produit pour trempage des trayons

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
P. REINHOLD ET AL.: "Zur behandlung akuter mastitiden des rindes 1. Mitteilung: Therapeutischer einsatz von glukose-losungen", ARCHIV FHUR EXPERIMENTELLE VETERINHARMEDIZIN,, vol. 40, no. 4, July 1986 (1986-07-01), (LEIPZIG, GERMANY), pages 627 - 638 *
R. MULLER AND M. BERCHTOLD.: "Glukose-losung zur verbesserung der behandlungsergebnisse bei akuten mastitiden des rindes", SCHWEIZER ARCHIV FHUR TIERHEILKUNDE,, vol. 123, no. 3, March 1981 (1981-03-01), (ZURICH, GERMANY), pages 121 - 127 *
VETERINARY MICROBIOLOGY, Volume 16, issued 1988 by Elsevier Science Publishers B.V. (Amsterdam, The Netherlands), B. BUDDLE et al., "Protective effects of glucan against experimentally induced Staphylococcal mastitis in ewes", pages 67-76. *

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Publication number Publication date
AUPP659198A0 (en) 1998-11-12

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